Color Atlas of Pharmacology

Color Atlas ofPharmacology3rd edition, revised and expandedHeinz Lüllmann, M.D.Former Professor and ChairmanDepartment of PharmacologyUniversity of KielGermanyKlaus Mohr, M.D.ProfessorDepartment of Pharmacologyand ToxicologyUniversity of BonnGermanyLutz Hein, M.D.ProfessorDepartment of PharmacologyUniversity of FreiburgGermanyDetlef Bieger, M.D.Professor EmeritusDivision of Medical SciencesFaculty of MedicineMemorial University ofNewfoundlandSt. John’s, NewfoundlandCanadaWith 170 color plates by Jürgen WirthThiemeStuttgart · New York

IVLibrary of Congress Cataloging-in-Publication DataTaschenatlas der Pharmakologie. Englisch.Color atlas of pharmacology/Heinz Luellmann ...[et al.]; 172 color plates by Juergen Wirth.—3rd ed., rev. and expandedp. ; cm.Rev. and expanded translation of: Taschenatlasder Pharmakologie. 5th ed. c2004.Includes bibliographical references and index.ISBN 3-13-781703-X (GTV: alk. paper)—ISBN 1-58890-332-X (alk. paper)1.Pharmacology—Atlases.2.Pharmacology—Handbooks, manuals, etc. [DNLM: 1. Pharmacology—Atlases.2. Pharmacology—Handbooks.3. Drug Therapy—Atlases. 4. Drug Therapy—Handbooks. 5. Pharmaceutical Preparations—Atlases. 6. Pharmaceutical Preparations—Handbooks.QV 17 T197c 2005a] I. Lüllmann, Heinz.II. Title.RM301.12.T3813 2005615’.1—dc22Translator: Detlef Bieger, M.D.2005012554Illustrator: Jürgen Wirth, Professor of VisualCommunication, University of Applied Sciences,Darmstadt, GermanyImportant note: Medicine is an ever-changingscience undergoing continual development. Researchand clinical experience are continuallyexpanding our knowledge, in particular ourknowledge of proper treatment and drug therapy.Insofarasthisbookmentionsanydosageorapplication, readers may rest assured that theauthors, editors, and publishers have madeevery effort to ensure that such references arein accordance with the state of knowledge atthetimeofproductionofthebook.Nevertheless, this does not involve, imply, orexpress any guarantee or responsibility on thepart of the publishers in respect to any dosageinstructions and forms of applications stated inthe book. Every user is requested to examinecarefully the manufacturers’ leaflets accompanyingeachdrugandtocheck,ifnecessaryin consultation with a physician or specialist,whether the dosage schedules mentionedtherein or the contraindications stated by themanufacturers differ from the statements madein the present book. Such examination is particularlyimportant with drugs that are eitherrarely used or have been newly released on themarket. Every dosage schedule or every form ofapplication used is entirely at the user’s own riskand responsibility. The authors and publishersrequest every user to report to the publishersany discrepancies or inaccuracies noticed.© 2005 Georg Thieme Verlag,Rüdigerstrasse 14, 70469 Stuttgart, Germanyhttp://www.thieme.deThieme New York, 333 Seventh Avenue,New York, NY 10001 USAhttp://www.thieme.comCover design: Cyclus, StuttgartTypesetting by primustype Hurler GmbH,NotzingenPrinted in Germany by Appl, WemdingISBN 3-13-781703-X (GTV)ISBN 1-58890-332-X (TNY)Some of the product names, patents, and registereddesigns referred to in this book are in factregistered trademarks or proprietary nameseven though specific reference to this fact isnot always made in the text. Therefore, theappearance of a name without designation asproprietary is not to be construed as a representationby the publisher that it is in the publicdomain.This book, including all parts thereof, is legallyprotected by copyright. Any use, exploitation, orcommercialization outside the narrow limits setby copyright legislation, without the publisher’sconsent, is illegal and liable to prosecution. Thisapplies in particular to photostat reproduction,copying, mimeographing, preparation of microfilms,and electronic data processing and storage.

VPreface to the 3rd editionIn many countries, medicine is at presentfacing urgent political and economic callsfor reform. These socioeconomic pressuresnotwithstanding, pharmacotherapy has alwaysbeen an integral part of the health caresystem and will remain so in the future.Well-founded knowledge of the preventiveand therapeutic value of drugs is a sine quanon for the successful treatment of patientsentrusting themselves to a physician orpharmacist.As the new edition was nearing completion,several high-profile drugs experienced withdrawalfrom the market, substantive changein labeling, or class action litigation againsttheir manufacturers. Amid growing concernover effectiveness of drug safety regulations,“pharmacovigilance” has become a newpriority. It is hoped that this compendiummay aid in promoting the critical awarenessand rational attitude required to meet thatdemand.Because of the plethora of proprietary medicinesand the continuous influx of newpharmaceuticals, the drug market is dif cultto survey and hard to understand. This istrue not only for the student in search of alogical system for dealing with the wealth ofavailable drugs, but also for the practicingclinician in immediate need of independentinformation.We are grateful for comments and suggestionsfrom colleagues, and from students,both doctoral and undergraduate. Thanksare due to Professor R. Lüllmann-Rauch forhistological and cell-biological advice. Weare indebted to Ms. M. Mauch and Ms. K.Jürgens, Thieme Verlag, for their care andassistance and to Ms. Gabriele Kuhn for harmoniouseditorial guidance.Clearly, a pocket atlas can provide only abasic framework. Comprehensive knowledgehas to be gained from major textbooks.As is evident from the drug lists included intheAppendix,some600drugsarecoveredin the present Atlas. This number should besuf cient for everyday medical practice andcould be interpreted as a Model List. Theadvances in pharmacotherapy made in recentyears have required us to incorporatenew plates and text passages, and to expungeobsolete approaches. Several platesneeded to be brought in line with newknowledge.Heinz Lüllmann, KielKlaus Mohr, BonnLutz Hein, FreiburgDetlef Bieger, St. John’s, CanadaJürgen Wirth, DarmstadtDisclosure: TheauthorsoftheColor Atlas ofPharmacology have no financial interests orother relationships that would influence thecontent of this book.

VIContentsContentsGeneral Pharmacology 1History of Pharmacology. ....... 2TheIdea ................ 2TheImpetus.............. 2EarlyBeginnings............ 3Foundation............... 3Consolidation—General Recognition . 3StatusQuo............... 3Drug Sources .............. 4DrugandActivePrinciple........ 4The Aims of Isolating ActivePrinciples................. 4European Plants as Sources ofEffective Medicines . . . . . . ..... 6Drug Development ........... 8Congeneric Drugs and NameDiversity ................. 10Drug Administration .......... 12OralDosageForms............ 12Drug Administration by Inhalation . . . 14DermatologicalAgents......... 16SkinProtection(A)............ 16Dermatological Agents as Vehicles (B). 16From Application to Distribution intheBody ................. 18Cellular Sites of Action ......... 20Potential Targets of Drug Action . . . . 20Distribution in the Body ........ 22ExternalBarriersoftheBody...... 22Blood–TissueBarriers.......... 24MembranePermeation......... 26Possible Modes of Drug Distribution . . 28BindingtoPlasmaProteins....... 30Drug Elimination ............ 32The Liver as an Excretory Organ . . . . 32BiotransformationofDrugs....... 34Drug Metabolism by CytochromeP450.................... 38The Kidney as an Excretory Organ . . . 40PresystemicElimination......... 42Pharmacokinetics ............ 44Drug Concentration in the Body asa Function of Time—First Order(Exponential) Rate Processes . . . . . . 44Time Course of Drug ConcentrationinPlasma................. 46Time Course of Drug Plasma Levelsduring Repeated Dosing (A) . . . . . . . 48Time Course of Drug Plasma LevelsduringIrregularIntake(B)........ 48Accumulation: Dose, Dose Interval,and Plasma Level Fluctuation (A) . . . . 50Change in Elimination CharacteristicsduringDrugTherapy(B)......... 50Quantification of Drug Action ..... 52Dose–Response Relationship . . . . . . 52Concentration–Effect Relationship (A) . 54Concentration–Effect Curves (B) . . . . 54Drug–Receptor Interaction. ...... 56Concentration–Binding Curves . . . . . 56TypesofBindingForces......... 58CovalentBonding........... 58NoncovalentBonding......... 58Agonists—Antagonists.......... 60Models of the Molecular Mechanismof Agonist/Antagonist Action (A) . . . . 60OtherFormsofAntagonism....... 60Enantioselectivity of Drug Action . . . . 62ReceptorTypes.............. 64Mode of Operation of G-ProteincoupledReceptors............66Time Course of Plasma ConcentrationandEffect................. 68Adverse Drug Effects .......... 70Undesirable Drug Effects, SideEffects................... 70

ContentsVIICausesofAdverseEffects........ 70DrugAllergy............... 72CutaneousReactions .......... 74Drug Toxicity in Pregnancy andLactation................. 76Genetic Variation of Drug Effects ... 78Pharmacogenetics............ 78Drug-independent Effects ....... 80Placebo(A)................ 80Systems Pharmacology 83Drugs Acting on the SympatheticNervous System ............. 84SympatheticNervousSystem...... 84Structure of the SympatheticNervousSystem............. 86AdrenergicSynapse........... 86Adrenoceptor Subtypes andCatecholamineActions......... 88SmoothMuscleEffects......... 88Cardiostimulation............ 88MetabolicEffects............. 88Structure–Activity RelationshipsofSympathomimetics.......... 90IndirectSympathomimetics....... 92α-Sympathomimetics,α-Sympatholytics ............ 94β-Sympatholytics (β-Blockers)..... 96Types of β-Blockers........... 98Antiadrenergics ............. 100Drugs Acting on the ParasympatheticNervous System ............. 102Parasympathetic Nervous System . . . 102CholinergicSynapse........... 104Parasympathomimetics......... 106Parasympatholytics ........... 108Nicotine. ................. 112ActionsofNicotine ........... 112Localization of Nicotinic AChReceptors................. 112Effects of Nicotine on Body Function . 112AidsforSmokingCessation....... 112Consequences of Tobacco Smoking . . 114Biogenic Amines. ............ 116Dopamine................. 116Histamine Effects and TheirPharmacologicalProperties....... 118Serotonin................. 120Vasodilators ............... 122Vasodilators—Overview ......... 122OrganicNitrates ............. 124Calcium Antagonists . . . ........ 126I. Dihydropyridine Derivatives . . . . . . 126II. Verapamil and Other CatamphiphilicCa 2+ Antagonists............. 126Inhibitors of the Renin–Angiotensin–Aldosterone System ........... 128ACEInhibitors............... 128DrugsActingonSmoothMuscle ... 130Drugs Used to Influence SmoothMuscleOrgans.............. 130Cardiac Drugs .............. 132CardiacGlycosides............ 134AntiarrhythmicDrugs.......... 136I. Drugs for Selective Control ofSinoatrialandAVNodes........ 136II. Nonspecific Drug Actions onImpulse Generation and Propagation 136Electrophysiological Actions ofAntiarrhythmics of the Na + -ChannelBlockingType............... 138Antianemics ............... 140Drugs for the Treatment of Anemias . . 140Erythropoiesis(A)........... 140Vitamin B 12 (B) ............ 140FolicAcid(B).............. 140IronCompounds............. 142Antithrombotics ............. 144Prophylaxis and Therapy of Thromboses 144Vitamin K Antagonists and Vitamin K . 146Possibilities for Interference (B). . . . . 146Heparin(A)................ 148

VIIIContentsHirudinandDerivatives(B)....... 148Fibrinolytics................ 150Intra-arterial ThrombusFormation(A) .............. 152Formation, Activation, andAggregationofPlatelets(B)....... 152Inhibitors of PlateletAggregation(A)............. 154PresystemicEffectofASA........ 154Plasma Volume Expanders ....... 156Drugs Used in Hyperlipoproteinemias 158Lipid-loweringAgents.......... 158Diuretics ................. 162Diuretics—AnOverview......... 162NaCl Reabsorption in the Kidney (A). . 164Aquaporins(AQP)............ 164OsmoticDiuretics(B).......... 164Diuretics of the Sulfonamide Type . . . 166Potassium-sparing Diuretics andVasopressin................ 168Potassium-sparing Diuretics (A) . . . . 168Vasopressin and Derivatives (B) . . . . 168Drugs for the Treatment of PepticUlcers ................... 170Drugs for Gastric and DuodenalUlcers................... 170I. Lowering of Acid Concentration . . 170II.ProtectiveDrugs.......... 172III. Eradication of Helicobacterpylori(C)................ 172Laxatives ................. 1741.BulkLaxatives............ 1742.IrritantLaxatives.......... 1762a. Small-Bowel Irritant Purgative . . 1782b. Large-Bowel Irritant Purgatives . 1783.Lubricantlaxatives......... 178Antidiarrheals .............. 180AntidiarrhealAgents........... 180Drugs Acting on the Motor System . 182Drugs Affecting Motor Function . . . . 182MuscleRelaxants............. 184Nondepolarizing Muscle Relaxants . . . 184Depolarizing Muscle Relaxants . . . . . 186AntiparkinsonianDrugs......... 188Antiepileptics............... 190Drugs for the Suppression of Pain .. 194Pain Mechanisms and Pathways . . . . 194Antipyretic Analgesics ......... 196Eicosanoids................ 196Antipyretic Analgesics vs. NSAIDs. . . . 198Nonsteroidal Anti-inflammatoryDrugs(NSAIDs).............. 198Nonsteroidal Anti-inflammatoryDrugs ................... 200Cyclooxygenase (COX) Inhibitors . . . . 200Local Anesthetics ............ 202Opioids .................. 208Opioid Analgesics—Morphine Type . . . 208General Anesthetics ........... 214General Anesthesia and GeneralAnestheticDrugs............. 214InhalationalAnesthetics......... 216InjectableAnesthetics.......... 218Psychopharmacologicals ........ 220Sedatives,Hypnotics........... 220Benzodiazepines............. 222BenzodiazepineAntagonist...... 222Pharmacokinetics of Benzodiazepines . 224Therapy of Depressive Illness . . . . . . 226Mania................... 230TherapyofSchizophrenia........ 232Neuroleptics.............. 232Psychotomimetics (Psychedelics,Hallucinogens).............. 236Hormones. ................ 238Hypothalamic and HypophysealHormones................. 238ThyroidHormoneTherapy........ 240Hyperthyroidism and AntithyroidDrugs ................... 242GlucocorticoidTherapy ......... 244I.ReplacementTherapy......... 244

ContentsIXII. Pharmacodynamic Therapy withGlucocorticoids(A) ........... 244Androgens, Anabolic Steroids,Antiandrogens.............. 248InhibitoryPrinciples.......... 248Follicular Growth and Ovulation,Estrogen and Progestin Production . . 250OralContraceptives........... 252Antiestrogen and AntiprogestinActivePrinciples............. 254AromataseInhibitors .......... 256InsulinFormulations........... 258Variations in Dosage Form . . . . . . 258Variation in Amino Acid Sequence. . 258Treatment of Insulin-dependentDiabetes Mellitus. ............ 260UndesirableEffects.......... 260Treatment of Maturity-Onset(Type II) Diabetes Mellitus. . . ..... 262OralAntidiabetics............ 264Drugs for Maintaining CalciumHomeostasis............... 266Antibacterial Drugs ........... 268Drugs for Treating BacterialInfections................. 268Inhibitors of Cell Wall Synthesis . . . . 270Inhibitors of TetrahydrofolateSynthesis................. 274InhibitorsofDNAFunction....... 276InhibitorsofProteinSynthesis..... 278Drugs for Treating MycobacterialInfections................. 282Antituberculardrugs(1) ....... 282Antileproticdrugs(2)......... 282Antifungal Drugs ............ 284Drugs Used in the Treatment ofFungalInfections............. 284Antiviral Drugs .............. 286Chemotherapy of Viral Infections. . . . 286Drugs for the Treatment of AIDS . . . . 290I. Inhibitors of ReverseTranscriptase—Nucleoside Agents . . 290NonnucleosideInhibitors....... 290II.HIVproteaseInhibitors....... 290III.FusionInhibitors.......... 290Antiparasitic Drugs ........... 292Drugs for Treating Endoparasiticand Ectoparasitic Infestations . . . . . . 292Antimalarials ............... 294OtherTropicalDiseases......... 296Anticancer Drugs ............ 298Chemotherapy of MalignantTumors .................. 298Targeting of Antineoplastic DrugAction(A)................. 302Mechanisms of Resistance toCytostatics(B) .............. 302Immune Modulators .......... 304Inhibition of Immune Responses . . . . 304Antidotes ................. 308Antidotes and Treatment ofPoisonings................. 308Therapy of Selected Diseases 313Hypertension............... 314AnginaPectoris ............. 316AntianginalDrugs............ 318Acute Coronary Syndrome—MyocardialInfarction .......... 320CongestiveHeartFailure ........ 322Hypotension............... 324Gout.................... 326Obesity—Sequelae andTherapeuticApproaches......... 328Osteoporosis ............... 330RheumatoidArthritis........... 332Migraine.................. 334CommonCold .............. 336Atopy and Antiallergic Therapy . . . . . 338BronchialAsthma............. 340Emesis................... 342AlcoholAbuse............... 344LocalTreatmentofGlaucoma...... 346

XContentsFurther Reading 349Drug Indexes 351Trade Name – DrugName....... 352 DrugName– TradeName........ 369Subject Index 381

AbbreviationsXIAbbreviations6-APAAAABPACACEAChAChEADHAHAPATPAVPBMIBPBPCAHcAMPCGcGMPCHHCHOCHTCMLCNSCOMTCRHDAGDHFDHTDNADPTADRCECLEDRFEEGEFVEMT6-aminopenicillanic acidamino acidarterial blood pressureadrenal cortexangiotensin-convertingenzymeacetylcholineacetylcholinesteraseantidiuretic hormone(= vasopressin, AVP)adenohypophysealaction potentialadensosine triphosphatevasopressin (= antidiuretichormone, ADH)Body-Mass-Indexblood pressureboiling pointcarbonic anhydrasecyclic adenosinemonophosphatecardiac glycosidecyclic guaniidine monophosphatecorticotropin-releasinghormoneChinese hamster ovaryspecific choline-transporterchronic myeloic leukemiacentral nervous systemcatecholamine O-methyltransferasecorticotropin-releasinghormonediacylglyceroldihydrofolic acid, dihydrofolatedihydrotestosteronedeoxyribonucleic aciddiethylenetriaminopentaaceticaciddose–response curvesenterochromaf n-likeendothelium-derived relaxantfactorelectroencephalogramextracellular fluid volumeextraneuronal monoaminetransporterER endoplasmic reticulumFSH follicle stimulating hormoneGABA γ-aminobutyric acidGDP guanosine diphosphateGnRH gonadotropin-releasinghormone = gonadorelin:GRH growth hormone-releasinghormone = somatorelinGRIH growth hormone release-inhibitinghormone= somatostatinGTP guanosine triphosphateHCG human chorionic gonadotropinHIT II heparin-induced thrombocytopeniatype IIHMG human menopausalgonadotropini.m. intramuscular(ly)i.v. intravenous(ly)IFN interferonIFN-α interferon alphaIFN-β interferon betaIFN-γ interferon gammaIGF-1 insulin-like growth factor 1IL interleukinsIOP intraocular pressureIP 3 inositol trisphosphateISA intrinsic sympathomimeticactivityISDN isosorbide dinitrateISMN 5-isosorbide mononitrateLH luteinizing hormoneM moles/liter, mol/lMAC minimal alveolar concentrationMAO monoamine oxidasemesna sodium 2-mercaptoethanesulfonateMHC major histocompatibilitycomplexMI myocardial infarctionmM millimoles/liter, mmol/lmmHg millimeters of mercurymRNA messenger RNAmTOR mammalian target ofrapamycinMW molecular weightNAChR nicotinic receptor

XIIAbbreviationsNAT norepinephrine transporterNE norepinephrineNFAT nuclearfactorofactivatedT cellsNH neurohypophysealNMDS N-methyl-d-asparateNSTEMI non-STEMI (non-STelevation MI)NTG nitroglycerinNYHA New York Heart AssociationPABA p-aminobenzoic acidPAMBA p-aminomethylbenzoic acidPDE phosphodiesterasePF3 platelet factor 3PL phospholipidPLC phospholipase CPPARα peroxisome proliferatoractivatedreceptor alphaPPARγ peroxisome proliferatoractivatedreceptor gammaPRIH prolactin release inhibitinghormone = dopamineREM rapid eye movementrER rough endoplasmic reticulumRNA ribonucleic acidrt-PA recombinant tissue plasminogenactivatorRyR ryanodine receptorss.c. subcutaneous(ly)sER smooth endoplasmic reticulumSERM selective estrogen receptormodulatorsSJSTENSRSSRISTEMITHFTIVATMPTTNFαt-PATRHVAChTVMATSteven–Johnson syndrometoxic epidermal necrolysissarcoplasmic reticulumselective serotonin reuptakeinhibitorsST elevation MItetrahydrofolic acid,tetrahydrofolatetotal intravenous anaesthesiathiopurine methyltransferasenecrosis factor αtissue plasminogen activatorthyrotropin-releasing hormone= protirelinvesicular ACh transportervesicular monoamine transporterPharmacokinetic parametersBB maxc 0Cl totc maxc tFkK Dt ½V app

General PharmacologyHistory of Pharmacology 2Drug Sources 4Drug Development 8Drug Administration 12Cellular Sites of Action 20Distribution in the Body 22Drug Elimination 32Pharmacokinetics 44Quantification of Drug Action 52Drug–Receptor Interaction 56Adverse Drug Effects 70Genetic Variation of Drug Effects 78Drug-independent Effects 80

2 History of Pharmacology History of PharmacologySince time immemorial, medicaments havebeen used for treating disease in humansand animals. The herbal preparations ofantiquity describe the therapeutic powersof certain plants and minerals. Belief in thecurative powers of plants and certain substancesrested exclusively upon traditionalknowledge, that is, empirical informationnot subjected to critical examination.The ImpetusThe IdeaClaudius Galen (AD 129–200) first attemptedto consider the theoretical backgroundof pharmacology. Both theory andpractical experience were to contributeequally to the rational use of medicinesthroughinterpretationoftheobservedandthe experienced results:The empiricists say that all is found byexperience. We, however, maintain that it isfound in part by experience, in part by theory.Neither experience nor theory alone is apt todiscover all.Theophrastus von Hohenheim(1493–1541), called Paracelsus, began toquestion doctrines handed down from antiquity,demanding knowledge of the activeingredient(s) in prescribed remedies, whilerejecting the irrational concoctions and mixturesof medieval medicine. He prescribedchemically defined substances with suchsuccess that professional enemies had himprosecuted as a poisoner. Against such accusations,he defended himself with the thesisthat has become an axiom of pharmacology:If you want to explain any poison properly,what then is not a poison? All things are poison,nothing is without poison; the dose alonecauses a thing not to be poison.

History of Pharmacology 3Early BeginningsConsolidation—General RecognitionJohann Jakob Wepfer (1620–1695) was thefirst to verify by animal experimentation assertionsabout pharmacological or toxicologicalactions.Iponderedatlength.FinallyIresolvedtoclarify the matter by experiments.FoundationRudolf Buchheim (1820–1879) founded thefirst institute of pharmacology at the Universityof Dorpat (Tartu, Estonia) in 1847, usheringin pharmacology as an independent scientificdiscipline. In addition to a descriptionof effects, he strove to explain the chemicalproperties of drugs.The science of medicines is a theoretical, i. e.,explanatory, one. It is to provide us with knowledgeby which our judgment about the utility ofmedicines can be validated at the bedside.Oswald Schmiedeberg (1838–1921), togetherwith his many disciples (12 of whom wereappointed to chairs of pharmacology),helped establish the high reputation of pharmacology.Fundamental concepts such asstructure–activity relationships, drug receptors,and selective toxicity emerged from thework of, respectively, T. Frazer (1840–1920)in Scotland, J. Langley (1852–1925) in England,and P. Ehrlich (1854–1915) in Germany.Alexander J. Clarke (1885–1941) in Englandfirst formalized receptor theory in the early1920s by applying the Law of Mass Actionto drug–receptor interactions. Together withthe internist Bernhard Naunyn (1839–1925),Schmiedeberg founded the first journal ofpharmacology, which has been publishedsince without interruption. The “Father ofAmerican Pharmacology,” John J. Abel(1857–1938) was among the first Americansto train in Schmiedeberg’s laboratory andwas founder of the Journal of Pharmacologyand Experimental Therapeutics (publishedfrom 1909 until the present).Status QuoAfter 1920, pharmacological laboratoriessprang up in the pharmaceutical industryoutside established university institutes.After 1960, departments of clinical pharmacologywere set up at many universities andin industry.

4 Drug Sources Drug and Active PrincipleUntil the end of the 19th century, medicineswere natural organic or inorganic products,mostly dried, but also fresh, plants or plantparts. These might contain substances possessinghealing (therapeutic) properties, orsubstances exerting a toxic effect.In order to secure a supply of medicallyuseful products not merely at the time ofharvest but year round, plants were preservedby drying or soaking them in vegetableoils or alcohol. Drying the plant, vegetable,or animal product yielded a drug (fromFrench “drogue” = dried herb). Colloquially,this term nowadays often refers to chemicalsubstances with high potential for physicaldependence and abuse. Used scientifically,this term implies nothing about the qualityofaction,ifany.Initsoriginal,widersense,drug could refer equally well to the driedleaves of peppermint, dried lime blossoms,dried flowers and leaves of the female cannabisplant (hashish, marijuana), or the driedmilky exudate obtained by slashing the unripeseed capsules of Papaver somniferum(raw opium).Soaking plants or plant parts in alcohol(ethanol) creates a tincture. Inthisprocess,pharmacologically active constituents of theplant are extracted by the alcohol. Tincturesdo not contain the complete spectrum ofsubstances that exist in the plant or crudedrug, but only those that are soluble in alcohol.In the case of opium tincture, these ingredientsare alkaloids (i. e., basic substancesof plant origin) including morphine, codeine,narcotine = noscapine, papaverine, narceine,and others.Using a natural product or extract to treata disease thus usually entails the administrationof a number of substances possiblypossessing very different activities. Moreover,the dose of an individual constituentcontained within a given amount of the naturalproduct is subject to large variations,depending upon the product’s geographicalorigin (biotope), time of harvesting, or conditionsand length of storage. For the samereasons, the relative proportions of individualconstituents may vary considerably.Starting with the extraction of morphinefrom opium in 1804 by F.W. Sertürner(1783–1841), the active principles of manyother natural products were subsequentlyisolated in chemically pure form by pharmaceuticallaboratories. The Aims of Isolating ActivePrinciples1. Identification of the active ingredient(s).2. Analysis of the biological effects (pharmacodynamics)of individual ingredients andof their fate in the body (pharmacokinetics).3. Ensuring a precise and constant dosage inthe therapeutic use of chemically pureconstituents.4. The possibility of chemical synthesis,which would afford independence fromlimited natural supplies and create conditionsfor the analysis of structure–activityrelationships.Finally, derivatives of the original constituentmay be synthesized in an effort to optimizepharmacological properties. Thus, derivativesof the original constituent with improvedtherapeutic usefulness may be developed.Modification of the chemical structure ofnatural substances has frequently led topharmaceuticals with enhanced potency.An illustrative example is fentanyl, whichacts like morphine but requires a dose only0.1–0.05 times that of the parent substance.Derivatives of fentanyl such as carfentanyl(employed in veterinary anesthesia of largeanimals) are actually 5000 times more potentthan morphine.

Drug and Active Principle 5A. From poppy to morphineRaw opiumPreparationofopium tinctureOpium tincture (laudanum)MorphineCodeineNarcotinePapaverineetc.

6 Drug Sources European Plants as Sources ofEffective MedicinesSince prehistoric times, humans have attemptedto alleviate ailments or injurieswith the aid of plant parts or herbal preparations.Ancient civilizations have recordedvarious prescriptions of this kind. In theherbal formularies of medieval times numerousplantswerepromotedasremedies.Inmodern medicine, where each drug is requiredto satisfy objective criteria of ef cacy,few of the hundreds of reputedly curativeplant species have survived as drugs withdocumented effectiveness. Presented beloware some examples from local old-world florasthat were already used in prescientifictimes and that contain substances that tothis day are employed as important drugs.A. A group of local plants used since themiddle ages to treat “dropsy” comprisesfoxglove (digitalis sp.), lily of the valley(Convallaria majalis), christmas rose (Helleborusniger), and spindletree (Evonymuseuropaeus). At the end of the 18th centurythe Scottish physician William Witheringintroduced digitalis leaves as a tea intothe treatment of “cardiac dropsy” (edemaof congestive heart failure) and describedthe result. The active principles in theseplants are steroids with one or more sugarmolecules attached at C3 (see p.135). Provenclinically most useful among all availablecardiac glycosides, digoxin continuesto be obtained from the plants Digitalispurpurea or D. lanata because its chemicalsynthesisistoodif cultandexpensive.B. The deadly nightshade of middle Europe(Atropa belladonna, a solanaceous herb) 1contains the alkaloids atropine, inallitsparts, and scopolamine, in smalleramounts. The effects of this drug werealready known in antiquity; e. g., pupillarydilation resulting from the cosmetic use ofextracts as eye drops to enhance femaleattractiveness. In the 19th century, thealkaloids were isolated, their structureselucidated, and their specific mechanismof action recognized. Atropine is the prototypeof a competitive antagonist at theacetylcholine receptor of the muscarinictype (cf. p.108).C. The common white and basket willow(Salix alba, S. viminalis) contain salicylicacid derivatives in their bark. Preparationsof willow bark were used from antiquity;in the 19th century, salicylic acid wasisolated as the active principle of this folkremedy. This simple acid still enjoys useas an external agent (keratolytic action)but is no longer taken orally for the treatmentof pain, fever, and inflammatory reactions.Acetylation of salicylic acid (introducedaround1900)toyieldacetylsalicylicacid (ASA, Aspirin®) improved oraltolerability.D. The autumn crocus (Colchicum autumnale)belongs to the lily family and flowerson meadows in late summer to fall; leavesand fruit capsules appear in the followingspring. All parts of the plant contain thealkaloid colchicine. This substance inhibitsthe polymerization of tubulin to microtubules,which are responsible for intracellularmovement processes. Thus, underthe influence of colchicine, macrophagesand neutrophils lose their capacity for intracellulartransport of cell organelles.This action underlies the beneficial effectduring an acute attack of gout (cf. p. 326)Furthermore, colchicine prevents mitosis,causing an arrest in metaphase (spindlepoison)._1 This name reflects the poisonous property ofthe plant: Atropos was the one of the three Fates(moirai) who cut the thread of life.

European Plants as Sources of Medicines 7A. European plants as sources of drugsDigitalis purpureaAtropa belladonnaOHOCH 3OCNOH 3 COHH 3O C CHCH 2 OHDigoxin(Digitoxose) 3AtropineOSalix albaColchicum autumnaleH 3 COOCOOHOHH 3 COH 3 CONHOCCH 3Salicylic acidColchicineOCH 3

8 Drug Development Drug DevelopmentThe drug development process starts withthe synthesis of novel chemical compounds.Substances with complex structures may beobtained from various sources, e. g., plants(cardiac glycosides), animal tissues (heparin),microbial cultures (penicillin G) or culturesof human cells (urokinase), or bymeans of gene technology (human insulin).As more insight is gained into structure–activityrelationships, the search for newagents becomes more clearly focused.Preclinical testing yields information onthe biological effects of new substances. Initialscreening may employ biochemical-pharmacologicalinvestigations (e. g., receptorbinding assays, p. 56) or experiments on cellcultures, isolated cells, and isolated organs.Since these models invariably fall short ofreplicating complex biological processes inthe intact organism, any potential drug mustbe tested in the whole animal. Only animalexperiments can reveal whether the desiredeffects will actually occur at dosages thatproducelittleornotoxicity.Toxicological investigationsserve to evaluate the potentialfor: (1) toxicity associated with acute orchronic administration; (2) genetic damage(genotoxicity, mutagenicity); (3) productionof tumors (oncogenicity or carcinogenicity);and (4) causation of birth defects (teratogenicity).In animals, compounds under investigationalso have to be studied with respectto their absorption, distribution, metabolism,and elimination (pharmacokinetics).Even at the level of preclinical testing, onlya very small fraction of new compounds willprove potentially fit for use in humans.Pharmaceutical technology provides themethods for drug formulation.Clinical testing starts with Phase I studieson healthy subjects and seeks to determinewhether effects observed in animal experimentsalso occur in humans. Dose–responserelationships are determined. In Phase II,potential drugs are first tested on selectedpatients for therapeutic ef cacy in those diseasestates for which they are intended. If abeneficial action is evident, and the incidenceof adverse effects is acceptably small,Phase III is entered, involving a larger groupof patients in whom the new drug will becompared with conventional treatments interms of therapeutic outcome. As a form ofhuman experimentation, these clinical trialsare subject to review and approval by institutionalethics committees according to internationalcodes of conduct (Declarations ofHelsinki, Tokyo, and Venice). During clinicaltesting, many drugs are revealed to be unusable.Ultimately, only one new drug typicallyremains from some 10 000 newly synthesizedsubstances.The decision to approve a new drug ismade by a national regulatory body (Foodand Drug Administration in the UnitedStates.;theHealthProtectionBranchDrugsDirectorate in Canada; the EU Commission inconjunction with the European Agency forthe Evaluation of Medicinal Products, London,United Kingdom) to which manufacturersare required to submit their applications.Applicants must document by meansof appropriate test data (from preclinical andclinical trials) that the criteria of ef cacy andsafety have been met and that product forms(tablet, capsule, etc.) satisfy general standardsof quality control.Followingapproval,thenewdrugmaybemarketed under a trade name (pp.10, 352)and thus become available for prescriptionby physicians and dispensing by pharmacists.As the drug gains more widespreaduse, regulatory surveillance continues inthe form of postlicensing studies (Phase IVof clinical trials). Only on the basis of longtermexperience will the risk–benefit ratiobe properly assessed and, thus, the therapeuticvalue of the new drug be determined.If the new drug offers hardly any advantageover existing ones, the cost–benefit relationshipneeds to be kept in mind.

Drug Development 9A. From drug synthesis to approvalClinicaltrialPhase 4Approval§§§§General useLong-term benefit-risk evaluation§1Substance§Clinical trialPhase 1 Phase 2 Phase 3Healthy subjects:effects on body functions,dose definition,pharmacokineticsEEGBloodpressureSelected patients:effects on disease;safety, efficacy, dose,pharmacokineticsPatient groups:Comparison withstandard therapyECGBloodsample10SubstancesCells(bio)chemicalsynthesisAnimalsIsolated organsPreclinicaltesting:Effects on bodyfunctions, mechanismof action, toxicity10000SubstancesTissuehomogenate

10 Drug Development Congeneric Drugs and NameDiversityThe preceding pages outline the route leadingto approval of a new drug. The pharmaceuticalreceives an International NonproprietaryName (INN)andabrandortradename chosen by the innovative pharmaceuticalcompany. Patent protection enables thepatent holder to market the new substancefor a specified period of time. As soon as thepatent protection expires, the drug concernedcan be put on the market as a genericunder a nonproprietary name or as a successorpreparationunderotherbrandnames.Since patent protection is generally alreadysought during the development phase, protectedsale of the drug may occur only for afew years.The value of a new drug depends onwhether one deals with a novel active principleor merely an analogue (or congeneric)preparation with a slightly changed chemicalstructure. It is of course much more arduousto develop a substance that possessesa novel mechanism of action and therebyexpands therapeutic possibilities. Examplesof such fundamental innovations from recentyears include the ACE inhibitors(p.128), the lipid-lowering agents of the statintype (p.158), the proton pump inhibitors(p.170), the gonadorelin superagonists(p. 238), and the gyrase inhibitors (p. 276).Much more frequently, “new drugs” areanalogue substances that imitate the chemicalstructure of a successful pharmaceutical.These compounds contain the requisite featuresin their molecule but differ from theparent molecule by structural alterationsthat are biologically irrelevant. Such analoguesubstances, or “me-too” preparations,do not add anything new regarding themechanism of action. A model example forthe overabundance of analogue substancesare the β-blockers: about 20 individual substanceswith the same pharmacophoricgroups differ only in the substituents at thephenoxy residue. This entails small differencesin pharmacokinetic behavior and relativeaf nity for β-receptor subtypes (examplesshown in A). A small fraction of these substanceswould suf ce for therapeutic use.The WHO Model formulary names only oneβ-blocker from the existing profusion,marked in A by an asterisk. The correspondingphenomenon is evident among variousother drug groups (e. g., benzodiazepines,nonsteroidal anti-inflammatory agents, andcephalosporins). Most analogue substancescan be neglected.After patent protection expires, competingdrug companies will at once market successful(i. e., profitable) pharmaceuticals assecond-submission successor (or “followon”)preparations. Since no research expensesare involved at this point, successordrugs can be offered at a cheaper price, eitheras generics (INN + company name) orunder new fancy names. Thus some commondrugs circulate under 10 to 20 differenttrade names. An extreme example is presentedin B for the analgesic ibuprofen.The excess of analogue preparations andthe unnecessary diversity of trade names foroneandthesamedrugmakethepharmaceuticalmarkets of some countries (e. g.,Germany) rather perplexing. A critical listingof essential drugs is a prerequisite for optimalpharmacotherapy and would be of greatvalue for medical practice.

Congeneric Drugs and Name Diversity 11A. β-Blockers of similar basic structureSubstitutedphenoxy Isopropanol IsopropylamineOresidueCH 3MetoprololH 2CO CH 2 CH CH 2 NH CHCH2O CH3OHCH 3RCH 3ONH C CH 3OCHAtenolol *3 H 2 CIsobutylamine O C NH2PenbutololC H 3OO CH 2 CH CH 2OxprenololOBupranololClOBetaxololOOCCH3AcebutololHNOPindololCH 2 CH 2 O CH 2 HCCH 2CH 2NH C CH2CH2CH3OH 3 COOBisoprololCH 2 O CH 2 CH 2 OCH 3CHCH 3ONadololONHOCCOCH3NC2H5C2H5CeliprololOCOOCH 3CH 3NHCH 3MetipranolCarazololOHOO TalinololOHC CH3OOHNNNH C NS NCarteololOHNOOOOCH 2 CHAlprenololPropanololHNCH 2 CH3OTimololMepindololB. Successor preparations for a pharmaceuticalIbuprofen = 2-(4-isobutylphenyl)propionic acidH 3 CCH 3CH CH 2CH 3CH COOH1. Generic ibuprofen from eight manufacturers2. Ibuprofen under different brand names; introduced as Brufen® (no longer available)Aktren®, Contraneural®, Dismenol®, Dolgit®, Dolodoc®, Dolopuren®, Dolormin®, Dolosanol®, Esprenit®,Eudorlin®, Gynofug®, Gynoneuralgin®, Ibu®, Ibu-acis®, Ibu-Attritin®, Ibubeta®, Ibudolor®, Ibu-Eu-Rho®,Ibuflam®, Ibuhemo-pharm®, Ibuhexal®, Ibu-KD®, Ibumerck®, Ibuphlogont®, Ibupro®, Iburatiopharm®,Ibu-TAD®, Ibutop®, Ilvico®, Imbun®, Jenaprofen®, Kontragripp®, Mensoton®, Migränin®, Novogent®,Nurofen®, Optalidon®, Opturem®, Parsal®, Pharmaprofen®, Ratiodolor®, Schmerz-Dolgit®, Spalt-Liqua®,Tabalon®, Tempil®, Tispol®, Togal®, Trauma-Dolgit®, Urem®

12 Drug Administration Oral Dosage FormsThe coated tablet contains a drug within acore that is covered by a shell, e. g., waxcoating, that serves (1) to protect perishabledrugsfromdecomposing,(2)tomaskadisagreeabletaste or odor, (3) to facilitate passageon swallowing, or (4) to permit colorcoding.Capsules usually consist of an oblong casing—generallymade of gelatin—that containsthe drug in powder or granulated form.In the matrix-type tablet,thedrugisembeddedin an inert meshwork, from which itis released by diffusion upon being moistened.In contrast to solutions, whichpermitdirect absorption of drug (A,track3),theuseof solid dosage forms initially requirestablets to break up and capsules to open(disintegration), before the drug can be dissolved(dissolution) andpassthroughthegastrointestinal mucosal lining (absorption).Because disintegration of the tabletand dissolution of the drug take time, absorptionwill occur mainly in the intestine (A,track 2). In the case of a solution, absorptionalready starts in the stomach (A, track3).For acid-labile drugs, a coating of wax or ofa cellulose acetate polymer is used to preventdisintegration of solid dosage forms inthe stomach. Accordingly, disintegration anddissolution will take place in the duodenumat normal rate (A, track 1) and drug liberationper se is not retarded.The liberation of drug, and hence the siteand time-course of absorption, are subject tomodification by appropriate productionmethods for matrix-type tablets, coated tablets,and capsules. In the case of the matrixtablet, this is done by incorporating the druginto a lattice from which it can be slowlyleached out by gastrointestinal fluids. Asthe matrix tablet undergoes enteral transit,drug liberation and absorption proceed enroute (A, track 4). In the case of coated tablets,coat thickness can be designed such thatrelease and absorption of drug occur eitherin the proximal (A, track 1) or distal (A,track5) bowel. Thus, by matching dissolution timewith small-bowel transit time, drug releasecan be timed to occur in the colon.Drug liberation and, hence, absorption canalso be spread out when the drug is presentedintheformofagranulateconsistingof pellets coated with a waxy film of gradedthickness. Depending on film thickness,gradual dissolution occurs during enteraltransit, releasing drug at variable rates forabsorption. The principle illustrated for acapsule canalsobeappliedtotablets.Inthiscase, either drug pellets coated with films ofvarious thicknesses are compressed into atablet or the drug is incorporated into a matrix-typetablet. In contrast to timed-releasecapsules slow-release tablets have the advantageof being divisible ad libitum; thusfractions of the dose contained within theentire tablet may be administered.This kind of retarded drug release is employedwhen a rapid rise in blood levels ofdrug is undesirable, or when absorption isbeing slowed in order to prolong the actionof drugs that have a short sojourn in thebody.

Oral Dosage Forms 13A. Oral administration: drug release and absorptionAdministrationEntericcoatedtabletTablet,capsuleDrops,mixture,effervescentsolutionMatrixtabletCoatedtablet withdelayedrelease

14 Drug Administration Drug Administration by InhalationInhalation in the form of an aerosol, a gas, ora mist permits drugs to be applied to thebronchial mucosa and, to a lesser extent, tothe alveolar membranes. This route is chosenfor drugs intended to affect bronchialsmooth muscle or the consistency of bronchialmucus. Furthermore, gaseous or volatileagents can be administered by inhalationwith the goal of alveolar absorption and systemiceffects (e. g., inhalational anesthetics,p. 216). Aerosols are formed when a drugsolution or micronized powder is convertedinto a mist or dust, respectively.In conventional sprays (e. g., nebulizer),the air blast required for the aerosol formationis generated by the stroke of a pump.Alternatively, the drug is delivered from asolution or powder packaged in a pressurizedcanister equipped with a valve throughwhich a metered dose is discharged. Duringuse, the inhaler (spray dispenser) is helddirectly in front of the mouth and actuatedat the start of inspiration. The effectivenessof delivery depends on the position of thedevice in front of the mouth, the size of theaerosol particles, and the coordination betweenopening the spray valve and inspiration.The size of the aerosol particles determinesthe speed at which they are sweptalong by inhaled air, and hence the depthof penetration into the respiratory tract.Particles > 100 µm indiameteraretrappedin the oropharyngeal cavity; those havingdiameters between 10 and 60 µm willbedeposited on the epithelium of the bronchialtract. Particles < 2 µm in diameter can reachthe alveoli, but they will be exhaled againunless they settle out.Drug deposited on the mucous lining ofthe bronchial epithelium is partly absorbedand partly transported with bronchial mucustoward the larynx. Bronchial mucus travelsupward owing to the orally directed undulatorybeat of the epithelial cilia. Physiologically,this mucociliary transport functionsto remove inspired dust particles.Thus, only a portion of the drug aerosol(~ 10%) gains access to the respiratory tractand just a fraction of this amount penetratesthe mucosa, whereas the remainder of theaerosol undergoes mucociliary transport tothe laryngopharynx and is swallowed. Theadvantage of inhalation (i. e., localized applicationwithout systemic load) is fully exploitedby using drugs that are poorly absorbedfrom the intestine (tiotropium, cromolyn)or are subject to first-pass elimination(p. 42); for example, glucocorticoidssuch as beclomethasone dipropionate, budesonide,flunisolide, and fluticasone dipropionateor β-agonistssuchassalbutamolandfenoterol.Even when the swallowed portion of aninhaled drug is absorbed in unchanged form,administration by this route has the advantagethat drug concentrations at the bronchiwill be higher than in other organs.The ef ciency of mucociliary transport dependson the force of kinociliary motion andthe viscosity of bronchial mucus. Both factorscan be altered pathologically (e. g., bysmoker’s cough or chronic bronchitis).

Drug Administration by Inhalation 15A. Application by inhalationDepth ofpenetrationof inhaledaerosolizeddrug solution10%90%100 µmNasopharynxDrug swept upis swallowedLarynx10 µmTrachea, bronchi>2 µmBronchioli, alveoliMucociliary transport1 cm/minAs completepresystemiceliminationas possibleAs littleenteralabsorptionas possibleLow systemic burdenSurface view of ciliatedepithelium(scanning EM photograph)

16 Drug Administration Dermatological AgentsPharmaceutical preparations applied to theouter skin are intended either to provideskin care and protection from noxious influences(A) ortoserveasavehiclefordrugsthataretobeabsorbedintotheskinor,ifappropriate, into the general circulation (B).Skin Protection (A)Protective agents are of several kinds tomeet different requirements according toskin condition (dry, low in oil, chapped vs.moist, oily, elastic), and the type of noxiousstimuli (prolonged exposure to water, regularuse of alcohol-containing disinfectants,intense solar irradiation). Distinctionsamong protective agents are based uponconsistency, physicochemical properties(lipophilic, hydrophilic), and the presenceof additives.Dusting powders are sprinkled onto theintact skin and consist of talc, magnesiumstearate, silicon dioxide (silica), or starch.They adhere to the skin, forming a low-frictionfilm that attenuates mechanical irritation.Powders exert a drying (evaporative)effect.Lipophilic ointment (oil ointment) consistsof a lipophilic base (paraf n oil, petroleumjelly, wool fat) and may contain up to10% powder materials, such as zinc oxide,titanium oxide, starch, or a mixture of these.Emulsifying ointments are made of paraf nsand an emulsifying wax, and are misciblewith water.Paste (oil paste) is an ointment containingmore than 10% pulverized constituents.Lipophilic (oily) cream is an emulsion ofwater in oil, easier to spread than oil paste oroil ointment.Hydrogel and water-soluble ointmentachieve their consistency by means of differentgel-forming agents (gelatin, methylcellulose,polyethylene glycol). Lotions areaqueous suspensions of water-insolubleand solid constituents.Hydrophilic (aqueous) cream is an oil-inwateremulsion formed with the aid of anemulsifier; it may also be considered an oilin-wateremulsion of an emulsifying ointment.All dermatological agents having a lipophilicbase adhere to the skin as a waterrepellentcoating. They do not wash off andthey also prevent (occlude) outward passageof water from the skin. The skin is protectedfrom drying, and its hydration andelasticity increase. Diminished evaporationof water results in warming of the occludedskin. Hydrophilic agents wash off easily anddo not impede transcutaneous output ofwater. Evaporation of water is felt as a coolingeffect.Dermatological Agents as Vehicles (B)In order to reach its site of action, a drugmust leave its pharmaceutical preparationand enter the skin if a local effect is desired(e. g., glucocorticoid ointment), or be able topenetrate it if a systemic action is intended(transdermal delivery system, e. g., nitroglycerinpatch, p.124). The tendency for thedrug to leave the drug vehicle is higher themore the drug and vehicle differ in lipophilicity(high tendency: hydrophilic drugand lipophilic vehicle; and vice versa).Because the skin represents a closed lipophilicbarrier (p. 22), only lipophilic drugsare absorbed. Hydrophilic drugs fail even topenetratetheouterskinwhenappliedinalipophilic vehicle. This formulation can beuseful when high drug concentrations arerequired at the skin surface (e. g., neomycinointment for bacterial skin infections).

Dermatological Agents 17A. Dermatologicals as skin protectantsPowderSolidLiquidSolutionPasteDermatologicalsAqueoussolutionAlcoholictinctureOily pasteSemi-solidHydrogelLipophilicointmentOintmentHydrophilicointmentLipophiliccreamCreamHydrophiliccreamSuspensionLotionEmulsionFat, oilWater in oilOil in waterGel, waterOcclusivePermeable,coolantPerspirationimpossible possibleDry, non-oily skinOily, moist skinB. Dermatologicals as drug vehiclesLipophilic drugin lipophilicbaseLipophilic drugin hydrophilicbaseHydrophilic drugin lipophilicbaseHydrophilic drugin hydrophilicbaseStratum corneumEpitheliumSubcutaneous fat tissue

18 Drug Administration From Application to Distribution inthe BodyAs a rule, drugs reach their target organs viathe blood. Therefore, they must first enterthe blood, usually in the venous limb of thecirculation. There are several possible sites ofentry.The drug may be injected or infused intravenously,in which case it is introduced directlyinto the bloodstream. In subcutaneousor intramuscular injection, the drug hasto diffuse from its site of application into theblood. Because these procedures entail injuryto the outer skin, strict requirementsmust be met concerning technique. For thisreason, the oral route (i. e., simple applicationby mouth) involving subsequent uptakeof drug across the gastrointestinal mucosainto the blood is chosen much more frequently.The disadvantage of this route isthat the drug must pass through the liveron its way into the general circulation. Inall of the above modes of application, thisfact assumes practical significance for anydrug that may be rapidly transformed orpossibly inactivated in the liver (first-passeffect, presystemic elimination, bioavailability;p. 42). Furthermore, a drug has to traversethe lungs before entering the generalcirculation. Pulmonary tissues may trap hydrophobicsubstances. The lungs may thenact as a buffer and thus prevent a rapid risein drug levels in peripheral blood after i.v.injection (important, for example, with i.v.anesthetics). Even with rectal administration,at least a fraction of the drug entersthe general circulation via the portal vein,because only blood from the short terminalsegment of the rectum drains directly intothe inferior vena cava. Hepatic passage iscircumvented when absorption occurs buccallyor sublingually, because venous bloodfrom the oral cavity drains into the superiorvena cava. The same would apply to administrationby inhalation (p.14). However,with this route, a local effect is usually intended,and a systemic action is intendedonly in exceptional cases. Under certain conditions,drug can also be applied percutaneouslyin the form of a transdermal deliverysystem (p.16). In this case, drug is releasedfrom the reservoir at constant rate overmany hours, and then penetrates the epidermisand subepidermal connective tissuewhere it enters blood capillaries. Only a veryfew drugs can be applied transdermally. Thefeasibility of this route is determined by boththe physicochemical properties of the drugand the therapeutic requirements (acute vs.long-term effect).Speed of absorption is determined by theroute and method of application. It is fastestwith intravenous injection, less fast with intramuscularinjection, andslowest with subcutaneousinjection. When the drug is appliedto the oral mucosa (buccal, sublingualroutes), plasma levels rise faster than withconventional oral administration becausethe drug preparation is deposited at its actualsite of absorption and very high concentrationsin saliva occur upon the dissolutionof a single dose. Thus, uptake across the oralepithelium is accelerated. Furthermore, drugabsorption from the oral mucosa avoids passagethrough the liver and, hence, presystemicelimination. The buccal or sublingualroute is not suitable for poorly water-solubleor poorly absorbable drugs. Such agentsshould be given orally because both the volumeof fluid for dissolution and the absorbingsurface are much larger in the small intestinethanintheoralcavity.

Routes of Drug Administration 19A. From application to distributionSublingualbuccalInhalationalIntravenousTransdermalOralAortaSubcutaneousDistribution in bodyIntramuscularRectal

20 Cellular Sites of Action Potential Targets of Drug ActionDrugs are designed to exert a selective influenceon vital processes in order to alleviateor eliminate symptoms of disease. Thesmallest basic unit of an organism is the cell.The outer cell membrane, or plasmalemma,effectively demarcates the cell from its surroundings,thus permitting a large degree ofinternal autonomy. Embedded in the plasmalemmaare transport proteins that serveto mediate controlled metabolic exchangewith the cellular environment. Theseincludeenergy-consuming pumps (e. g., Na + ,K + -AT-Pase, p.134), carriers (e. g., for Na + /glucoseco-transport, p.180), and ion channels (e. g.,for sodium (p.138) or calcium (p.126) (1).Functional coordination between singlecells is a prerequisite for the viability of theorganism, hence also the survival of individualcells.Cellfunctionsarecoordinatedbymeans of cytosolic contacts between neighboringcells (gap junctions, e. g., in the myocardium)and messenger substances for thetransfer of information. Included amongthese are “transmitters” released fromnerves, which the cell is able to recognizewith the help of specialized membrane bindingsites or receptors.Hormonessecretedbyendocrine glands into the blood, then intothe extracellular fluid, represent anotherclass of chemical signals. Finally, signalingsubstances can originate from neighboringcells: paracrine regulation, for instance bythe prostaglandins (p.196) and cytokines.The effect of a drug frequently resultsfrom interference with cellular function. Receptorsfor the recognition of endogenoustransmitters are obvious sites of drug action(receptor agonists and antagonists, p. 60).Altered activity of membrane transport systemsaffects cell function (e. g., cardiac glycosides,p.134; loop diuretics, p.166; calciumantagonists,p.126). Drugs may also directlyinterfere with intracellular metabolic processes,for instance by inhibiting (phosphodiesteraseinhibitors, pp. 66, 122) or activating(organic nitrates, p.124) an enzyme (2);even processes in the cell nucleus can beaffected (e. g., DNA damage by certain cytostatics).In contrast to drugs acting from the outsideon cell membrane constituents, agentsacting in the cell’s interior need to penetratethe cell membrane.The cell membrane basically consists of aphospholipid bilayer (50 Å = 5 nm in thickness),embedded in which are proteins (integralmembrane proteins, such as receptorsand transport molecules). Phospholipid moleculescontain two long-chain fatty acids inester linkage with two of the three hydroxylgroups of glycerol. Bound to the third hydroxylgroup is phosphoric acid, which,inturn, carries a further residue, e.g.,choline(phosphatidylcholine = lecithin), the aminoacid serine (phosphatidylserine), or the cyclicpolyhydric alcohol inositol (phosphatidylinositol).In terms of solubility, phospholipidsare amphiphilic: the tail region containingthe apolar fatty acid chains is lipophilic;the remainder—the polar head—ishydrophilic. By virtue of these properties,phospholipids aggregate spontaneously intoa bilayer in an aqueous medium, their polarheads being directed outward into the aqueousmedium, the fatty acid chains facingeach other and projecting into the inside ofthe membrane (3).The hydrophobic interior of the phospholipidmembrane constitutes a diffusionbarrier virtually impermeable to chargedparticles. Apolar particles, however, are betterable to penetrate the membrane. This isof major importance with respect to the absorption,distribution, and elimination ofdrugs.

Potential Targets of Drug Action 21A. Site at which drugs act to modify cell function1NeuralcontrolDNerveTransmitterReceptorIon channelHormonalcontrolHormonesDHormonereceptorsDNACellulartransportsystems forcontrolledtransfer ofsubstratesDD= DrugEnzymeDDirect actionon metabolismTransportmolecule2 3EffectDIntracellularsite of actionPhospholipidmatrixDProtein+H 3 C N CH 3O –O P OOCH 2O CHO C CH 2H 2C OH 2CH 2CH 2CH 2CH 2CH 2CH 2CCH3H2CH2CC OCH 2CH 2CH 2CH 2CH 2CH 2H2CCH 2CholinePhosphoricacidGlycerolFatty acid

22 Distribution in the Body External Barriers of the BodyPrior to its uptake into the blood (i. e., duringabsorption), the drug has to overcome barriersthat demarcate the body from its surroundings,that is, that separate the internalfrom the external milieu. These boundariesare formed by the skin and mucous membranes.When absorption takes place in the gut(enteral absorption), the intestinal epitheliumis the barrier. This single-layered epitheliumis made up of enterocytes and mucus-producinggoblet cells. On their luminalside, these cells are joined together by zonulaeoccludentes (indicated by black dots inthe inset, bottom left). A zonula occludens,ortight junction, is a region in which the phospholipidmembranes of two cells establishclose contact and become joined via integralmembrane proteins (semicircular inset, leftcenter). The region of fusion surrounds eachcell like a ring such that neighboring cells arewelded together in a continuous belt. In thismanner, an unbroken phospholipid layer isformed (yellow area in the schematic drawing,bottom left) and acts as a continuousbarrier between the two spaces separatedby the cell layer—in the case of the gut, theintestinal lumen (dark blue) and interstitialspace (light blue). The ef ciency with whichsuch a barrier restricts exchange of substancescan be increased by arranging these occludingjunctions in multiple arrays, as forinstance in the endothelium of cerebralblood vessels. The connecting proteins (connexins)furthermore serve to restrict mixingof other functional membrane proteins (carriermolecules, ion pumps, ion channels) thatoccupy specific apical or basolateral areas ofthe cell membrane.This phospholipid bilayer represents theintestinal mucosa–blood barrier that a drugmust cross during its enteral absorption. Eligibledrugs are those whose physicochemicalproperties allow permeation through thelipophilic membrane interior (yellow) orthat are subject to a special inwardly directedcarrier transport mechanism. Conversely,drugs can undergo backtransport intothe gut by means of ef ux pumps (P-glycoprotein)located in the luminal membraneof the intestinal epithelium. Absorption ofsuch drugs proceeds rapidly because the absorbingsurface is greatly enlarged owing tothe formation of the epithelial brush border(submicroscopic foldings of the plasmalemma).The absorbability of a drug is characterizedby the absorption quotient, thatis,theamount absorbed divided by the amount inthegutavailableforabsorption.In the respiratory tract, cilia-bearing epithelialcells are also joined on the luminalside by zonulae occludentes, so that thebronchial space and the interstitium are separatedby a continuous phospholipid barrier.With sublingual or buccal application, thedrug encounters the nonkeratinized, multilayeredsquamous epithelium of the oralmucosa. Here, the cells establish punctatecontacts with each other in the form of desmosomes(not shown); however, these donot seal the intercellular clefts. Instead, thecells have the property of sequestering polarlipids that assemble into layers within theextracellular space (semicircular inset, centerright). In this manner, a continuous phospholipidbarrier arises also inside squamousepithelia, although at an extracellular location,unlike that of intestinal epithelia. Asimilar barrier principle operates in the multilayeredkeratinized squamous epitheliumof the skin.Thepresenceofacontinuousphospholipidlayer again means that only lipophilicdrugs can enter the body via squamous epithelia.Epithelial thickness, which in turndependsonthedepthofthestratumcorneum,determines the extent and speed ofabsorption. Examples of drugs that can beconveyed via the skin into the blood includescopolamine (p.110), nitroglycerin (p.124),fentanyl (p. 212) and the gonadal hormones(p. 250).

External Barriers of the Body 23A. External barriers of the bodyCiliated epitheliumNonkeratinizedsquamous epitheliumEpithelium withbrush borderKeratinized squamousepithelium

24 Distribution in the Body Blood–Tissue BarriersDrugs are transported in the blood to differenttissues of the body. In order to reachtheir sites of action, they must leave thebloodstream. Drug permeation occurslargely in the capillary bed, where both surfacearea and time available for exchange aremaximal (extensive vascular branching, lowvelocity of flow). The capillary wall forms theblood–tissue barrier. Basically, this consistsof an endothelial cell layer and a basementmembrane enveloping the latter (solid blackline in the schematic drawings). The endothelialcells are “riveted” to each other bytight junctions or occluding zonulae (labeledZ in the electron micrograph, upper left)such that no clefts, gaps, or pores remainthat would permit drugs to pass unimpededfrom the blood into the interstitial fluid.Theblood–tissuebarrierisdevelopeddifferentlyin the various capillary beds. Permeabilityof the capillary wall to drugs is determinedby the structural and functional characteristicsof the endothelial cells. In manycapillary beds, e. g., those of cardiac muscle,endothelial cells are characterized by pronouncedendocytotic and transcytotic activity,as evidenced by numerous invaginationsand vesicles (arrows in the electronmicrograph, upper right). Transcytotic activityentails transport of fluid or macromoleculesfrom the blood into the interstitiumand vice versa. Any solutes trapped in thefluid, including drugs, may traverse theblood–tissue barrier. In this form of transport,the physicochemical properties ofdrugs are of little importance.In some capillary beds (e. g., in the pancreas),endothelial cells exhibit fenestrations.Although the cells are tightly connectedby continuous junctions, they possesspores (arrows in electron micrograph, lowerleft) that are closed only by diaphragms.Both the diaphragm and basement membranecan be readily penetrated by substancesof low molecular weight—the majority ofdrugs—but less so by macromolecules, e. g.,proteins such as insulin (G: insulin storagegranule). Penetrability of macromolecules isdetermined by molecular size and electriccharge. Fenestrated endothelia are found inthe capillaries of the gut and endocrineglands.In the central nervous system (brain andspinal cord), capillary endothelia lack poresand there is little transcytotic activity. Inorder to cross the blood–brain barrier,drugs must diffuse transcellularly, i. e., penetratethe luminal and basal membrane ofendothelial cells. Drug movement along thispath requires specific physicochemical properties(p. 26) or the presence of a transportmechanism (e. g., L-dopa, p.188). Thus, theblood–brain barrier is permeable only to certaintypes of drugs.Drugs exchange freely between blood andinterstitium in the liver, where endothelialcells exhibit large fenestrations (100 nm indiameter) facing Disse’s spaces (D) andwhere neither diaphragms nor basementmembranes impede drug movement.Diffusion barriers are also present beyondthe capillary wall; e. g., placental barrier offused syncytiotrophoblast cells; blood–testiclebarrier, junctions interconnecting Sertolicells; brain choroid plexus–blood barrier,occluding junctions between ependymalcells.(Vertical bars in the electron micrographsrepresent 1 µm; E, cross-sectioned erythrocyte;AM, actomyosin; G, insulin-containinggranules.)

Blood–Tissue Barriers 25A. Blood-tissue barriersCNSHeart muscleEAMZDGLiverPancreas

26 Distribution in the Body Membrane PermeationAn ability to penetrate lipid bilayers is aprerequisite for the absorption of drugs,their entry into cell or cellular organelles,and passage across the blood–brain barrier.Owing to their amphiphilic nature, phospholipidsform bilayers possessing a hydrophilicsurface and a hydrophobic interior (p. 20).Substances may traverse this membrane inthree different ways.Diffusion (A). Lipophilic substances (reddots) may enter the membrane from theextracellular space (area shown in ochre),accumulate in the membrane, and exit intothe cytosol (blue area). Direction and speedof permeation depend on the relative concentrationsin the fluid phases and the membrane.The steeper the gradient (concentrationdifference), the more drug will be diffusingper unit of time (Fick’s law). The lipidmembrane represents an almost insurmountableobstacle for hydrophilic substances(blue triangles).Transport (B). Some drugs may penetratemembrane barriers with the help of transportsystems (carriers), irrespective of theirphysicochemical properties, especially lipophilicity.As a prerequisite, the drug musthave af nity for the carrier (blue trianglematching recess on “transport system”)and, when bound to the carrier, be capableof being ferried across the membrane. Membranepassage via transport mechanisms issubject to competitive inhibition by anothersubstance possessing similar af nity for thecarrier. Substances lacking in af nity (bluecircles) are not transported. Drugs utilizecarriers for physiological substances: e. g.,L-dopa uptake by L-amino acid carrier acrossthe blood–intestine and blood–brain barriers(p.188); uptake of aminoglycosides bythe carrier transporting basic polypeptidesthrough the luminal membrane of kidneytubular cells (p. 280). Only drugs bearing sufficientresemblance to the physiological substrateof a carrier will exhibit af nity to it.The distribution of drugs in the body canbe greatly changed by transport glycoproteinsthat are capable of moving substancesout of cells against concentration gradients.The energy needed is produced by hydrolysisof ATP. These P-glycoproteins occur in theblood–brain-barrier, intestinal epithelia, andtumor cells, and in pathogens (e. g., malarialplasmodia). On the one hand, they functionto protect cells from xenobiotics; on the other,they can cause drug resistance by preventingdrugs from reaching effective concentrationsat intracellular sites of action.Transcytosis (vesicular transport, C). Whennew vesicles are pinched off, substances dissolvedin the extracellular fluid are engulfedand then ferried through the cytoplasm, unlessthe vesicles (phagosomes) undergo fusionwith lysosomes to form phagolysosomesand the transported substance is metabolized.Receptor-mediated endocytosis (C). Thedrug first binds to membrane surface receptors(1, 2) whose cytosolic domains contactspecial proteins (adaptins, 3). Drug–receptorcomplexes migrate laterally in the membraneand aggregate with other complexesby a clathrin-dependent process (4). The affectedmembrane region invaginates andeventually pinches off to form a detachedvesicle (5). The clathrin and adaptin coatsare shed (6), resulting in formation of the“early” endosome (7). Inside this, protonconcentration rises and causes the drug–receptorcomplex to dissociate. Next, the receptor-bearingmembrane portions separatefrom the endosome (8). These membranesections recirculate to the plasmalemma(9), while the endosome is delivered to thetarget organelles (10).

Membrane Permeation 27A. Membrane permeation: diffusion B. Membrane permeation: transportC. Membrane permeation: vesicular uptake, and transport19238pH 5456710LigandPlasmalemmaReceptorClathrinAdaptinsVesicular transportLysosomePhagolysosomeExtracellularIntracellularExtracellular

28 Distribution in the Body Possible Modes of Drug DistributionSolid substances andstructurally bound water40%40%Intracellular water20%Extracellular waterand erythrocytesFollowing its uptake into the body, the drugis distributed in the blood (1) andthroughitto the various tissues of the body. Distributionmay be restricted to the extracellularspace (plasma volume plus interstitial space)(2) or may also extend into the intracellularspace (3). Certain drugs may bind strongly totissue structures so that plasma concentrationsfall significantly even before eliminationhas begun (4).After being distributed in blood, macromolecularsubstances remain largely confinedto the vascular space, because theirpermeation through the blood–tissue barrier,orendothelium,isimpeded,evenwherecapillaries are fenestrated. This property isexploited therapeutically when loss of bloodnecessitates refilling of the vascular bed, forinstance by infusion of dextran solutions(p.156). The vascular space is, moreover,predominantly occupied by substancesboundwithhighaf nitytoplasmaproteins(p. 30; determination of the plasma volumewith protein-bound dyes). Unbound, freedrug may leave the bloodstream, albeit withvarying ease, because the blood–tissue barrier(p. 24) is differently developed in differentsegments of the vascular tree. These regionaldifferences are not illustrated in theaccompanying figures.Distribution in the body is determined bythe ability to penetrate membranous barriers(p.20).Hydrophilicsubstances(e.g.,inulin)are neither taken up into cells norbound to cell surface structures and can thusbe used to determine the extracellular fluidvolume (2). Lipophilic substances diffusethrough the cell membrane and, as a result,achieve a uniform distribution in body fluids(3).Bodyweightmaybebrokendownasillustratedin the pie-chart. Further subdivisionsare shown in the panel opposite.The volume ratio of interstitial: intracellularwater varies with age and body weight.On a percentage basis, interstitial fluid volumeis large in premature or normal neonates(up to 50% of body water), and smallerin the obese and the aged.The concentration (c) of a solution correspondsto the amount (D) of substance dissolvedin a volume (V); thus, c = D/V. Ifthedose of drug (D) and its plasma concentration(c) are known, a volume of distribution(V) can be calculated from V = D/c. However,this represents an apparent (notional) volumeof distribution (V app ), because an evendistribution in the body is assumed in itscalculation. Homogeneous distribution willnot occur if drugs are bound to cell membranes(5) or to membranes of intracellularorganelles (6) or are stored within organelles(7). In these cases, plasma concentration cbecomes small and V app can exceed the actualsize of the available fluid volume. Conversely,if a major fraction of drug moleculesis bound to plasma proteins, c becomes largeand the calculated value for V app may then besmaller than that attained biologically.

Possible Modes of Drug Distribution 29A. Compartments for drug distribution1 2 34IntravascularIntravascular andinterstitialExtra- andintracellularTissue bindingPlasma6%4%Interstitium25%65%ErythrocytesIntracellular spaceAqueous spaces of the organismLysosomesMitochondriaNucleus5 6 7Cellmembrane

30 Distribution in the Body Binding to Plasma ProteinsHaving entered the blood, drugs may bind tothe protein molecules that are present inabundance, resulting in the formation ofdrug–protein complexes.Protein binding involves primarily albuminand, to a lesser extent, β-globulins andacidic glycoproteins. Other plasma proteins(e. g., transcortin, transferrin, thyroxin-bindingglobulin) serve specialized functions inconnection with specific substances. The degreeof binding is governed by the concentrationof the reactants and the af nity of adrug for a given protein. Albumin concentrationin plasma amounts to 4.6 g/100 ml, or0.6 mM, and thus provides a very high bindingcapacity (two sites per molecule). As arule, drugs exhibit much lower af nity (K D~ 10 -5 –10 -3 M) for plasma proteins than fortheir specific binding sites (receptors). In therange of therapeutically relevant concentrations,protein binding of most drugs increaseslinearly with concentration (exceptions:salicylate and certain sulfonamides).The albumin molecule has different bindingsites for anionic and cationic ligands, butvan der Waals forces also contribute (p. 58).The extent of binding correlates with drughydrophobicity (repulsion of drug by water).Binding to plasma proteins is instantaneousand reversible, i. e., any change in theconcentration of unbound drug is immediatelyfollowed by a corresponding change inthe concentration of bound drug. Proteinbinding is of great importance because it isthe concentration of free drug that determinesthe intensity of the effect. At a giventotal plasma concentration (say, 100 ng/ml)the effective concentration will be 90 ng/mlfor a drug 10% bound to protein, but 1 ng/mlfor a drug 99% bound to protein. The reductionin concentration of free drug resultingfrom protein binding affects not only theintensity of the effect but also biotransformation(e. g., in the liver) and eliminationfrom the kidney, because only free drug willenter hepatic sites of metabolism or undergoglomerular filtration. When concentrationsof free drug fall, drug is resupplied frombinding sites on plasma proteins. Bindingto plasma protein is equivalent to a depotin prolonging the duration of the effect byretarding elimination, whereas the intensityof the effect is reduced. If two substanceshave af nity for the same binding site onthe albumin molecule, they may competeforthatsite.Onedrugmaydisplaceanotherfrom its binding site and thereby elevate thefree (effective) concentration of the displaceddrug (a form of drug interaction).Elevation of the free concentration of thedisplaced drug means increased effectivenessandacceleratedelimination.A decrease in the concentration of albumin(in liver disease, nephrotic syndrome,poor general condition) leads to alteredpharmacokinetics of drugs that are highlybound to albumin.Plasma protein-bound drugs that are substratesfor transport carriers can be clearedfrom blood at high velocity; e. g., p-aminohippurateby the renal tubule and sulfobromophthaleinby the liver. Clearance ratesof these substances can be used to determinerenal or hepatic blood flow.

Binding to Plasma Proteins 31A. Importance of protein binding for intensity and duration of drug effectDrug is notboundto plasmaproteinsDrug isstrongly boundto plasmaproteinsEffector cellEffectEffector cellEffectBiotransformationBiotransformationRenal eliminationRenal eliminationPlasma concentrationPlasma concentrationFree drugBound drugFree drugTimeTime

32 Drug Elimination The Liver as an Excretory OrganAsthemajororganofdrug biotransformation,the liver is richly supplied with blood, ofwhich1100mlisreceivedeachminutefromthe intestines through the portal vein and350 ml through the hepatic artery, comprisingnearly 1/3 of cardiac output. The bloodcontent of hepatic vessels and sinusoidsamounts to 500 ml. Owing to the wideningof the portal lumen, intrahepatic blood flowdecelerates (A). Moreover, the endotheliallining of hepatic sinusoids (p. 24) containspores large enough to permit rapid exit ofplasma proteins. Thus, blood and hepatic parenchymaare able to maintain intimate contactand intensive exchange of substances,which is further facilitated by microvilli coveringthe hepatocyte surfaces abutting Disse’sspaces.Thehepatocytesecretesbiliaryfluidintothe bile canaliculi (dark green), tubular intercellularclefts that are sealed off the bloodspaces by tight junctions. Secretory activityin the hepatocytes results in movement offluid toward the canalicular space (A).The hepatocyte is endowed with numerousmetabolically important enzymes thatare localized in part in mitochondria and inpart on membranes of the rough (rER) andsmooth (sER) endoplasmic reticulum. Enzymesof the sER play a most important rolein drug biotransformation. At this site, directconsumption of molecular oxygen (O 2 )takesplace in oxidative reactions. Because theseenzymes can catalyze either hydroxylationor oxidative cleavage of –N–C– or –O–C–bonds, they are referred to as “mixed-function”oxidases or hydroxylases. Theintegralcomponent of this enzyme system is theiron-containing cytochrome P450 (seep. 38). Many P450 isozymes are known andthey exhibit different patterns of substratespecificity. Interindividual genetic differencesin isozyme make-up (e. g., CYP2D6)underlie subject-to-subject variations indrug biotransformation. The same holds forother enzyme systems; hence, the phenomenonis generally referred to as genetic polymorphismof biotransformation.Compared with hydrophilic drugs notundergoing transport, lipophilic drugs aremore rapidly taken up from the blood intohepatocytes and more readily gain access tomixed-function oxidases embedded in sERmembranes.Forinstance,adrughavinglipophilicityby virtue of an aromatic substituent(phenyl ring) (B) canbehydroxylatedand thus become more hydrophilic (phase Ireaction, p. 36). Besides oxidases, sER alsocontains reductases and glucuronyltransferases.The latter conjugate glucuronic acidwith hydroxyl, carboxyl, amine, and amidegroups and hence also phenolic products ofphase I metabolism (phase II conjugation).Phase I and phase II metabolites can be transportedback into the blood—probably via agradient-dependent carrier—or actively secretedinto bile via the ABC transporter(ATP-binding cassette transporter). Differenttransport proteins are available: for instance,MRP2 (the multidrug resistance associatedprotein 2) transports anionic conjugates intothe bile canaliculi, whereas MRP3 can routethese via the basolateral membrane of thehepatocyte toward the general circulation.Prolonged exposure to substrates of one ofthe membrane-bound enzymes results in aproliferation of sER membranes in the liver(cf. C and D). The molecular mechanism ofthis sER “hypertrophy” has been elucidatedfor some drugs: thus, phenobarbital binds toa nuclear receptor (constitutive androstanereceptor) that regulates the expression of cytochromesCYP2C9 and CYP2D6. Enzyme inductionleads to accelerated biotransformation,not only of the inducing agent but also ofother drugs (a form of drug interaction).With continued exposure, it develops in afew days, resulting in an increase in reactionvelocity, maximally 2–3-fold, that disappearsafter removal of the inducing agent.

Biotransformation of Drugs 33A. Flow patterns in portal vein, Disse’s space, and hepatocyteHepatocyte Biliary capillaryDisse’s spacePortal veinIntestineGallbladderB. Fate of drugs undergoinghepatic hydroxylationRC . HepatocyteRPhase ImetaboliteBiliarycapillaryrERsEROHRABCtransportera) NormalCarrierO-GlucuronidePhase IImetaboliterERsERb) After phenobarbital administration

34 Drug Elimination Biotransformation of DrugsMany drugs undergo chemical modificationin the body (biotransformation). Most oftenthis process entails a loss of biological activityand an increase in hydrophilicity (watersolubility), thereby promoting eliminationvia the renal route (p. 40). Since rapid drugelimination improves accuracy in titratingthe therapeutic concentration, drugs areoftendesignedwithbuilt-inweaklinks.Esterbonds are such links, being subject tohydrolysis by the ubiquitous esterases.Hydrolytic cleavages, alongwithoxidations,reductions, alkylations, and dealkylations,constitute phase I reactions of drug metabolism.These reactions subsume all metabolicprocesses apt to alter drug molecules chemicallyand take place chiefly in the liver. Inphase II (synthetic) reactions, conjugationproducts of either the drug itself or its phase Imetabolites are formed, for instance, withglucuronic or sulfuric acidThe special case of the endogenous transmitteracetylcholine illustrates well the highvelocity of ester hydrolysis. Acetylcholine isbroken down so rapidly at its sites of releaseand action by acetylcholinesterase (p.106) asto negate its therapeutic use. Hydrolysis ofother esters catalyzed by various esterases isslower; though relatively fast in comparisonwith other biotransformations. The localanesthetic procaine is a case in point; it exertsits action at the site of application whilebeing largely devoid of undesirable effects atother locations because it is inactivated byhydrolysis during absorption from the site ofapplication.Esterhydrolysisdoesnotinvariablyleadto inactive metabolites, as exemplified byacetylsalicylic acid. The cleavage product,salicylic acid, retains pharmacological activity.In certain cases, drugs are administeredin the form of esters in order to facilitateuptake into the body (enalapril–enalaprilat,p.128; testosterone decanoate–testosterone,p. 248) or to reduce irritation of the gastric orintestinal mucosa (acetylsalicylic acid–salicylicacid; erythromycin succinate–erythromycin).In these cases the ester itself is notactive but its hydrolytic product is. Thus, aninactive precursor or prodrug is administeredand formation of the active moleculeoccurs only after hydrolysis in the blood.Some drugs possessing amide bonds, suchas prilocaine and of course peptides, can behydrolyzed by peptidases and inactivated inthis manner. Peptidases are also of pharmacologicalinterest because they are responsiblefor the formation of highly reactive cleavageproducts (fibrin, p.150) and potent mediators(angiotensin II, p.128; bradykinin,enkephalin,p.208)frombiologicallyinactivepeptides.Peptidases exhibit some substrate selectivityand can be selectively inhibited, asexemplified by the formation of angiotensinII, whose actions inter alia include vasoconstriction.Angiotensin II is formed from angiotensinI by cleavage of the C-terminaldipeptide histidylleucine. Hydrolysis is catalyzedby “angiotensin-converting enzyme”(ACE). Peptide analogues such as captopril(p.128) block this enzyme. Angiotensin II isdegraded by angiotensinase A, which cleavesoff the N-terminal asparagine residue. Theproduct angiotensin III lacks vasoconstrictoractivity.

Biotransformation of Drugs 35A. Examples of chemical reactions in drug biotransformation (hydrolysis)Esterases Ester Peptidases Amides AnilidesAcetylcholineOCH 3+H 3 C C O CH 2 CH 2 N CH 3CH 3OH 3 C C OHAcetic acidCH 3+HO CH 2 CH 2 N CH 3HProcaineN 2OC O CH 2 CH 2 N C 2 H 5N H 2COOHp-Aminobenzoic acidCholineCH 3C 2 H 5AspArgValO LeuLeuCCH 2HisH NCNHOC N HCH 2 C ConvertingH enzymeNHProTyrAngiotensin IIleHisAngiotensin IINH O ValCC (CH 2 ) 3H 2 N NCHHOC N HCH 2HOOC CHNH2TyrIleHisArgProValPheTyrIleHisAngiotensin IIIAngiotensinaseProPheHO CH 2 CH 2 N C 2 H 5C 2 H 5DiethylaminoethanolAspOH3CC OAcetylsalicylic acidOCOHHPrilocaineCH 3 ON CH C NHC 3 H CH73OH3CC OHAcetic acidO OHCHOSalicylic acidHCH 3 ON CH C OHHN 2C 3 H 7 CH3N-PropylalanineToluidine

36 Drug EliminationOxidation reactions can be divided into twokinds: those in which oxygen is incorporatedinto the drug molecule, and those in whichprimary oxidation causes part of the moleculeto be lost. The former include hydroxylations,epoxidations, andsulfoxidations.Hydroxylations may involve alkyl substituents(e. g., pentobarbital) or aromatic ringsystems (e. g., propranolol). In both cases,products are formed that are conjugated toan organic acid residue, e. g., glucuronic acid,in a subsequent phase II reaction.Hydroxylation may also take place at nitrogens,resulting in hydroxylamines (e. g.,acetaminophen). Benzene, polycyclic aromaticcompounds,(e.g.,benzopyrene),andunsaturated cyclic carbohydrates can beconverted by monooxygenases to epoxides,highly reactive electrophiles that are hepatotoxicand possibly carcinogenic.The second type of oxidative biotransformationcomprises dealkylations. In the caseof primary or secondary amines, dealkylationof an alkyl group starts at the carbonadjacent to the nitrogen; in the case of tertiaryamines, with hydroxylation of the nitrogen(e. g., lidocaine). The intermediaryproducts are labile and break up into thedealkylatedamineandaldehydeofthealkylgroup removed. O-dealkylation and S-dearylationproceed via an analogous mechanism(e. g., phenacetin and azathioprine, respectively).Oxidative deamination basically resemblesthe dealkylation of tertiary amines, beginningwith the formation of a hydroxylaminethat then decomposes into ammoniaand the corresponding aldehyde. The latteris partly reduced to an alcohol and partlyoxidized to a carboxylic acid.Reduction reactions may occur at oxygenor nitrogen atoms. Keto oxygens are convertedinto a hydroxyl group, as in the reductionof the prodrugs cortisone and prednisoneto the active glucocorticoids cortisoland prednisolone, respectively. N-reductionsoccur in azo or nitro compounds (e. g., nitrazepam).Nitro groups can be reduced toamine groups via nitroso and hydroxylaminointermediates. Likewise, dehalogenation is areductive process involving a carbon atom(e. g., halothane, p. 216).Methylations are catalyzed by a family ofrelatively specific methyltransferases involvingthe transfer of methyl groups to hydroxylgroups (O-methylation as in norepinephrine[noradrenaline]) or to amino groups (Nmethylationof norepinephrine, histamine,or serotonin).In thio compounds, desulfuration resultsfrom substitution of sulfur by oxygen (e. g.,parathion). This example again illustratesthat biotransformation is not always to beequated with bioinactivation. Thus, paraoxon(E600) formed in the organism fromparathion (E605) is the actual active agent(bioactivation, “toxification”, p.106)

Biotransformation of Drugs 37A. Examples of chemical reactions in drug biotransformationCH 3ON 2 NO-MethylationOOHC 2 H 5HON CH CH 2 CH 2 CH 3PropranololH OPentobarbitalOHO CH 2 CH CH 2 NH CH CH 3OHCH 3HydroxylationLidocainePhenacetinParathionOCCHO2 H 53S POC 2 H5HN CO OC 2 H 5NH C CH 2 NCH 3OCH 3C 2 H5O C 2 H 5N-DealkylationNO 2O-DealkylationDesulfurationDealkylationNorepinephrineHON NHS-DealkylationNNH3CHO C CH 2 NH2HS CH OH3NAzathioprineMethylationCH 2 CH CH 2 N2 CH 3H OClNCH 3H NNSON 2 NOOAcetaminophenSulfoxidation OH2NNitrazepamBenzpyreneChlorpromazineReductionEpoxidationOxidationHydroxylamineHOHNCOCH 3

38 Drug Elimination Drug Metabolism by CytochromeP450Cytochrome P450 enzyme. A major part ofphase I reactions is catalyzed by hemoproteins,the so-called cytochrome P450 (CYP)enzymes (A). To date about 40 genes forcytochrome P450 proteins have been identifiedin the human; among these, the proteinfamilies CYP1, CYP2, and CYP3 are importantin drug metabolism (B). The bulk of CYPenzymes are located in the liver and theintestinal wall, which explains why theseorgans are responsible for the major part ofdrug metabolism.Substrates, inhibitors, and inducers. Cytochromesareenzymeswithbroadsubstratespecificities. Accordingly, pharmaceuticals ofdiverse chemical structure can be metabolizedby a given enzyme protein. When severaldrugs are metabolized by the same isozyme,clinically important interactions mayresult. In these, substrates (drugs metabolizedby CYP) can be distinguished frominhibitors (drugs that are bound to CYP withhigh af nity, interfere with the breakdownof substrates, and are themselves metabolizedslowly) (A). The amount of hepaticCYP enzymes is a major determinant ofmetabolic capacity. An increase in enzymeconcentration usually leads to accelerateddrug metabolism. Numerous endogenousand exogenous substances, such as drugs,can augment the expression of CYP enzymesand thus act as CYP inducers (p. 32). Many ofthese inducers activate specific transcriptionfactors in the nucleus of hepatocytes, leadingto activation of mRNA synthesis and subsequentproduction of CYP isozyme protein.Some inducers also increase the expressionof P-glycoprotein transporters; as a result,enhanced metabolism by CYP and increasedmembrane transport by P-glycoprotein canact in concert to render a drug ineffective.The table in (B) provides an overview ofdifferent CYP isozymes along with their substrates,inhibitors, and inducers. Obviously,when a patient is to be exposed to polypharmaceuticregimens (especially multimorbidsubjects), it would be imprudent to starttherapy without checking whether the drugsbeing contemplated include CYP inducers orinhibitors, some of which may dramaticallyalter pharmacokinetics.Drug interaction due to CYP induction orinhibition. Life-threatening interactionshave been observed in patients taking inducersof CYP3A4 isozyme during treatmentwith ciclosporin for the prevention of kidneyand liver transplant rejection. Intake of rifampin[rifampicin] and also of St. John’swort preparations (available without prescription)may increase expression of CY-P3A4 to such an extent as to lower plasmalevels of ciclosporin below the therapeuticrange (C). As immunosuppression becomesinadequate, the risk of transplant rejectionwill be enhanced. In the presence of rifampin,other drugs that are substrates of CY-P3A4 may become ineffective. For this reason,the intake of rifampin is contraindicatedin HIV patients being treated with proteaseinhibitors. As a rule, inhibitors of CYP enzymeselevate plasma levels of drugs thataresubstratesofthesameCYPenzymes;inthis manner, they raise the risk of undesirabletoxic effects. The antifungal agent ketoconazoleenhances the nephrotoxicity of ciclosporinbysuchamechanism(C).

Drug Metabolism by Cytochrome P450 39A. Cytochrome P450 in the liverSubstratesInducerProteinsynthesisCYPInhibitorsmRNATranscriptionfactorsRXRAhRCYP geneRetinoid-XreceptorArylhydrocarbonreceptorConstitutiveandrostane receptorPregnane-X-receptorB. Cytochrome P450 isozymesInducers Cytochrome Substrates InhibitorsBarbecued meat,tobacco smoke,omeprazoleAhRArylhydrocarbonreceptorPhenobarbital,RifampicinCARConstitutiveandrostanereceptorRifampicin, carbamazepine,dexamethasone,phenytoin,St. John’s wortPXRPregnane X-receptorCYP1A2CYP2C9CYP2D6CYP3A4C. Drug interactions and cytochrome P450Clozapine, estradiol,haloperidol, theophyllineIbuprofen, LosartanCarvedilol, metoprolol,tricyclic antidepressants,neuroleptics, SSRI, codeineCiclosporin, tacrolimus,nifedipine, verapamil, statins,estradiol, progesterone,testosterone, haloperidolFluoroquinoloneIsoniazid, VerapamilQuinidine, fluoxetineHIV protease inhibitors,amiodarone, macrolides,azole antimycotics,grapefruit juiceRifampicin,St. John’s wortCiclosporinItraconazoleTransplantrejectionInductionof CYP3A4Inhibitionof CYP3A4CiclosporinnephrotoxicityAcceleratedciclosporineliminationDelayedciclosporinelimination

40 Drug Elimination The Kidney as an Excretory OrganMost drugs are eliminated in urine eitherchemically unchanged or as metabolites.The kidney permits elimination because thevascular wall structure in the region of theglomerular capillaries (B) allows unimpededpassage into urine of blood solutes havingmolecular weights (MW) < 5000. Filtration isrestricted at MW < 50 000 and ceases at MW> 70 000. With few exceptions, therapeuticallyused drugs and their metabolites havemuch smaller molecular weights and cantherefore undergo glomerular filtration,i. e., pass from blood into primary urine. Separatingthe capillary endothelium from thetubular epithelium, thebasal membranecontains negatively charged macromoleculesand acts as a filtration barrier forhigh-molecular-weight substances. The relativedensity of this barrier depends on theelectric charge of molecules that attempt topermeate it. In addition, the diaphragmaticslits between podophyte processes play apart in glomerular filtration.Apart from glomerular filtration (B),drugs present in blood may pass into urineby active secretion (C). Certain cations andanions are secreted by the epithelium of theproximal tubules into the tubular fluid viaspecial energy-consuming transport systems.These transport systems have a limitedcapacity. When several substrates arepresent simultaneously, competition for thecarrier may occur (see p. 326).During passage down the renal tubule,primary urinary volume shrinks to about1%; accordingly, there is a correspondingconcentration of filtered drug or drug metabolites(A). The resulting concentrationgradient between urine and interstitial fluidis preserved in the case of drugs incapable ofpermeating the tubular epithelium. However,with lipophilic drugs the concentrationgradient will favor reabsorption of the filteredmolecules. In this case, reabsorption isnot based on an active process but resultsinstead from passive diffusion. Accordingly,for protonated substances, the extent of reabsorptionis dependent upon urinary pH orthe degree of dissociation. The degree ofdissociation varies as a function of the urinarypH and the pK a , which represents thepH value at which half of the substance existsin protonated (or unprotonated) form.This relationship is illustrated graphically(D) with the example of a protonated aminehaving a pK a of 7. In this case, at urinary pH 7,50% of the amine will be present in the protonated,hydrophilic, membrane-impermeantform (blue dots), whereas the other half,representing the uncharged amine (reddots), can leave the tubular lumen in accordancewith the resulting concentration gradient.If the pK a of an amine is higher (pK a=7.5)orlower(pK a = 6.5), a correspondinglysmallerorlargerproportionoftheaminewill be present in the uncharged, reabsorbableform.LoweringorraisingurinarypHbyhalf a pH unit would result in analogouschanges.The same considerations hold for acidicmolecules, with the important differencethat alkalinization of the urine (increasedpH) will promote the deprotonization of–COOH groups and thus impede reabsorption.Intentional alteration of urinary pH canbe used in intoxications with proton-acceptorsubstances in order to hasten eliminationof the toxin (e. g., alkalinization † phenobarbital;acidification † methamphetamine).

The Kidney as an Excretory Organ 41A. Filtration and concentration B. Glomerular filtration180 lPrimary urineGlomerularfiltrationof drugBloodPlasmaproteinEndotheliumBasalmembraneSlitdiaphragmEpitheliumDrugPodocyteprocessesPrimaryurineD. Tubular reabsorptionpH = 7,0pK a of substance10050pK a = 7,0+R N H1,2 lFinalurineConcentrationof drugin tubule%R N6 6,5 7 7,5 8100pK a = 7,5C. Active secretion50+++++ +++++++++++++ ++++%1006 6,5 7 7,5 8pK a = 6,5Tubulartransportsystem for+ Cations–Anions----- -- - --------------pH = 7,050%6 6,5 7 7,5 8pH of urine

42 Drug Elimination Presystemic EliminationThe morphological barriers of the body areillustrated on pp. 22–25. Depending on thephysicochemical properties of drugs, intendedtargets on the surface or the insideof cells, or of bacterial organisms, may bereached to varying degrees or not at all.Whenever a drug cannot be applied locallybut must be given by the systemic route, itspharmacokinetics will be subject to yet anotherprocess. This becomes very obvious ifwe follow the route of an orally administereddrug from its site of absorption to thegeneral circulation. Any of the following mayoccur.1. The drug permeates through the epithelialbarrier of the gut into the enterocyte;however, a P-glycoprotein transports itback into the intestinal lumen. As a result,the amount actually absorbed can begreatly diminished. This counter-transportcan vary interindividually for anidentical substance and moreover maybe altered by other drugs.2. En route from the intestinal lumen to thegeneral circulation, the ingested substanceis broken down enzymatically,e. g., by cytochrome P450 oxidases.(a) Degradation may start already in theintestinal mucosa. Other drugs oragents may inhibit or stimulate theactivity of enteral cytochrome oxidases.A peculiar example is grapefruitjuice, which inhibits CYP3A4 oxidasein the gut wall and thereby causesblood concentrations of other importantdrugstorisetotoxiclevels.(b) Metabolism in the liver, throughwhich the drug must pass, plays thebiggest role. Here, many enzymes areat work to alter endogenous and exogenoussubstanceschemicallysoastopromote their elimination. Examplesof different metabolic reactions arepresented on pp. 34–39. Dependingon the quantity of drug being takenup and metabolized by the hepatocytes,only a fraction of the amountabsorbed may reach the blood in thehepatic vein. Importantly, an increasein enzyme activity (increase insmooth endoplasmic reticulum) canbe induced by other drugs.The processes referred to under (2a, b)above are subsumed under the term “presystemicelimination.”3. Parenteral administration of a drug ofcourse circumvents presystemic elimination.After i.v., s.c., or i.m. injection, thedrug travels via the vena cava, the rightheart ventricle, and the lungs to the leftventricle and, thence, to the systemic circulationand the coronary system. As alipid-rich organ with a large surface, thelungs can take up lipophilic or amphiphilicagents to a considerable extentand release them slowly after blood levelsfall again. During fast delivery of drug, thelungs act as a buffer and protect the heartagainst excessive concentrations afterrapid i.v. injection.In certain therapeutic situations, rapid presystemicelimination may be desirable. Animportantexampleistheuseofglucocorticoidsin the treatment of asthma. Because asignificant portion of inhaled drug is swallowed,glucocorticoids with complete presystemicelimination entail only a minimalsystemic load for the organism (p. 340). Theuse of acetylsalicylic acid for inhibition ofthrombocyte aggregation (see p.155) providesan example of a desirable presystemicconversion.

Presystemic Elimination 43A. Presystemic eliminationExamples of presystemic eliminationFraction of oral dose that does not reachsystemic circulation:DrugMetaboliteEstradiolTestosteroneSumatriptanBudesonideVerapamilFurosemideNifedipineAtenololDiclofenacPropranolol>95%>95%~ 85%>80%~ 80%50–70%~ 50%40–50%~ 40%20–50%Systemic bioavailability(fraction of oral dose)Lung:StorageLiver:BiotransformationIntestinal wall:BiotransformationBack-transport intolumen byefflux pumps

44 Pharmacokinetics Drug Concentration in the Body as aFunction of Time—First Order(Exponential) Rate ProcessesProcessessuchasdrugabsorptionandeliminationdisplay exponential characteristics.For absorption, this follows from the simplefact that the amount of drug being movedper unit of time depends on the concentrationdifference (gradient) between two bodycompartments (Fick’s law). In drug absorptionfrom the alimentary tract, the intestinalcontent and blood would represent the compartmentscontaining initially high and lowconcentrations, respectively. In drug eliminationvia the kidney, excretion often dependson glomerular filtration, i. e., the filteredamount of drug present in primaryurine. As the blood concentration falls, theamount of drug filtered per unit of timediminishes. The resulting exponential declineis illustrated in (A). The exponentialtime course implies constancy of the intervalduring which the concentration decreases byone-half. This interval represents the halflife(t ½ ) and is related to the elimination rateconstant k by the equation t ½ =(ln2)/k. Thetwo parameters, together with the initialconcentration c 0 , describe a first-order (exponential)rate process.The constancy of the process permits calculationof the plasma volume that would becleared of drug, if the remaining drug werenot to assume a homogeneous distributionin the total volume (a condition not met inreality). The notional plasma volume freedof drug per unit of time is termed theclearance. Depending on whether plasmaconcentration falls as a result of urinary excretionor of metabolic alteration, clearanceis considered to be renal or hepatic. Renaland hepatic clearances add up to total clearance(Cl tot ) in the case of drugs that areeliminated unchanged via the kidney andbiotransformed in the liver. Cl tot representsthe sum of all processes contributing toelimination; it is related to the half-life (t ½ )and the apparent volume of distribution V app(p. 28) by the equation:t1/2=Vappln 2CltotThe smaller the volume of distribution or thelarger the total clearance, the shorter is thehalf-life.Inthecaseofdrugsrenallyeliminatedinunchanged form, the half-life of eliminationcan be calculated from the cumulative excretionin urine; the final total amount eliminatedcorresponds to the amount absorbed.Hepatic elimination obeys exponentialkinetics because metabolizing enzymes operatein the quasi-linear region of their concentration–activitycurve, and hence theamount of drug metabolized per unit timediminishes with decreasing blood concentration.The best-known exception to exponentialkinetics is the elimination of alcohol (ethanol),which obeys a linear time course (zeroorderkinetics), at least at blood concentrations> 0.02%. It does so because therate-limiting enzyme, alcohol dehydrogenase,achieves half-saturation at very low substrateconcentrations, i. e., at about 80 mg/l(0.008%). Thus, reaction velocity reaches aplateau at blood ethanol concentrations ofabout0.02%,andtheamountofdrugeliminatedper unit time remains constant at concentrationsabove this level.

DrugConcentrationintheBody 45A. Exponential elimination of drugConcentration (c o ) of drug [amount/vol]Plasma half-lifet 1 2c t = c o· e -kt= 1 2c 1 2ln 2t 1 =2 kc oc t : Drug concentration at time tc o : Initial drug concentration afteradministration of drug dosee: base of natural logarithmk: elimination constantUnit of timeTime (t)Notional plasma volume per unit of time freed of drug = clearance [vol/t]Amount excreted per unit of time [amount/t]Totalamountof drugexcreted(Amount administered) = DoseTime (t)

46 Pharmacokinetics Time Course of Drug Concentrationin Plasma(A). Drugs are taken up into and eliminatedfrom the body by various routes. The bodythus represents an open system wherein theactual drug concentration reflects the interplayof intake (ingestion) and egress (elimination).When orally administered drug isabsorbed from the stomach and intestine,speed of uptake depends on many factors,including the speed of drug dissolution (inthe case of solid dosage forms) and of gastrointestinaltransit; the membrane penetrabilityof the drug; its concentration gradientacross the mucosa–blood barrier; and mucosalblood flow. Absorption from the intestinecauses the drug concentration in bloodto increase. Transport in blood conveys thedrug to different organs (distribution), intowhich it is taken up to a degree compatiblewith its chemical properties and rate ofbloodflowthroughtheorgan.Forinstance,well-perfused organs such as the brain receivea greater proportion than do less wellperfusedones.Uptakeintotissuecausestheblood concentration to fall. Absorption fromthe gut diminishes as the mucosa–blood gradientdecreases. Plasma concentrationreaches a peak when the amount of drugleaving the blood per unit of time equals thatbeing absorbed.Drug entry into hepatic and renal tissueconstitutes movement into the organs ofelimination. The characteristic phasic timecourse of drug concentration in plasma representsthe sum of the constituent processesof absorption, distribution, and elimination,which overlap in time. When distributiontakes place significantly faster thanelimination, there is an initial rapid and thena greatly retarded fall in the plasma level, theformer being designated the α-phase (distributionphase), the latter the β-phase (eliminationphase). When the drug is distributedfaster than it is absorbed, the time course ofthe plasma level can be described in mathematicallysimplified form by the Batemanfunction (k 1 and k 2 represent the rate constantsfor absorption and elimination, respectively).(B). The velocity of absorption depends onthe route of administration. The more rapidthe absorption, the shorter will be the time(t max ) required to reach the peak plasmalevel (c max ), the higher will be the c max ,andthe earlier will the plasma level begin to fallagain.The area under the plasma level–time curve(AUC) is independent of the route of administration,provided the doses and bioavailabilityare the same (law of correspondingareas). The AUC can thus be used to determinethe bioavailability F of a drug. Theratio of AUC values determined after oraland intravenous administrations of a givendose of a particular drug corresponds to theproportion of drug entering the systemiccirculation after oral administration. Thus,F =AUCAUCoral administrationiv administrationThe determination of plasma levels affords acomparison of different proprietary preparationscontaining the same drug in the samedosage. Identical plasma level–time curvesof different manufacturers’ products withreference to a standard preparation indicatebioequivalence with the standard ofthe preparation under investigation.

DrugConcentrationinPlasma 47A. Time course of drug concentrationAbsorptionUptake fromstomach andintestinesinto bloodDistributioninto bodytissues:α-phaseEliminationfrom body bybiotransformation(chemical alteration)excretion via kidney:β-phaseDrug concentration in blood (c)Bateman functionDose kc = x 1x (e -k 1t -e-k 2 t )V app k 2 - k 1Time (t)B. Mode of application and time course of drug concentrationDrug concentration in blood (c)IntravenousIntramuscularSubcutaneousOralTime (t)

48 Pharmacokinetics Time Course of Drug Plasma Levelsduring Repeated Dosing (A)When a drug is administered at regular intervalsover a prolonged period, the rise andfall of drug concentration in blood will bedetermined by the relationship between thehalf-life of elimination and the time intervalbetween doses. If the amount of drug administeredin each dose has been eliminatedbefore the next dose is applied, repeatedintake at constant intervals will result insimilar plasma levels. If intake occurs beforethe preceding dose is eliminated completely,the next dose will add to the residualamount still present in the body—i. e., thedrug accumulates. The shorter the dosinginterval relative to the elimination half-life,the larger will be the residual amount ofdrug to which the next dose is added andthemoreextensivelywillthedrugaccumulatein the body. However, at a given dosingfrequency, the drug does not accumulate infinitelyand a steady state (concentrationC ss )oraccumulation equilibrium is eventuallyreached. This is so because the activityof elimination processes is concentrationdependent.The higher the drug concentrationrises, the greater is the amount eliminatedper unit time. After several doses, theconcentration will have climbed to a level atwhich the amounts eliminated and taken inper unit of time become equal, i. e., a steadystateis reached. Within this concentrationrange, the plasma level will continue to rise(peak)andfall(trough)asdosingiscontinuedat regular intervals. The height of thesteady state (C ss ) depends upon the amount(D) administered per dosing interval (τ) andthe clearance (Cl):90% of the concentration plateau is about 3times the t ½ of elimination. Time Course of Drug Plasma Levelsduring Irregular Intake (B)In practice, it proves dif cult to achieve aplasma level that undulates evenly aroundthe desired effective concentration. For instance,if two successive doses are omitted(“?” in B), the plasma level will drop belowthe therapeutic range and a longer periodwill be required to regain the desired plasmalevel. In everyday life, patients will be apt toneglect to take drugs at the scheduled time.Patient compliance means strict adherenceto the prescribed regimen. Apart from poorcompliance, the same problem may occurwhen the total daily dose is divided intothree individual doses (t.i.d.) and the firstdose is taken at breakfast, the second atlunch, and the third at supper. Under theseconditions, the nocturnal dosing interval willbe twice the diurnal one. Consequently, plasmalevels during the early morning hoursmay have fallen far below the desired, orpossibly urgently needed, range.CssD= τ⋅ClThe speed at which the steady state isreached corresponds to the speed of eliminationofthedrug.Thetimeneededtoreach

Plasma Levels during Repeated/Irregular Dosing 49A. Time course of drug concentration in blood during regular intakeDosing intervalDrug concentrationDosing intervalTime (t)Time (t)Accumulation:administered drug isnot completely eliminatedduring intervalSteady state:drug intake equalselimination duringdosing intervalDrug concentrationTime (t)B. Time course of drug concentration with irregular intakeDrug concentrationDesiredtherapeuticlevel? ? ?Time (t)

50 Pharmacokinetics Accumulation: Dose, Dose Interval,and Plasma Level Fluctuation (A)Successful drug therapy in many illnesses isaccomplished only if the drug concentrationis maintained at a steady high level. Thisrequirement necessitates regular drug intakeand a dosage schedule that ensures thatthe plasma concentration neither falls belowthe therapeutically effective range nor exceedsthe minimal toxic concentration. Aconstant plasma level would, however, beundesirable if it accelerated a loss of effectiveness(development of tolerance), or if thedrug were required to be present at specifiedtimes only.A steady plasma level can be achieved bygiving the drug in a constant intravenousinfusion, the height of the steady state plasmalevel being determined by the infusionrate. This procedure is routinely used in hospitalsettings, but is generally impracticable.With oral administration, dividing the totaldaily dosage into several individual doses,e. g., four, three, or two, offers a practicalcompromise. When the daily dose is givenin several divided doses, the mean plasmalevel shows little fluctuation.In practice, it is found that a regimen offrequent regular drug ingestion is not welladhered to by patients (unreliability or lackof “compliance” by patients). The degree offluctuation in plasma level over a given dosinginterval can be reduced by a dosage formpermitting slow (sustained) release (p.12).The time required to reach steady-stateaccumulation during multiple constant dosingdepends on the rate of elimination. As arule of thumb, a plateau is reached afterapproximately three elimination half-lives(t ½ ).For slowly eliminated drugs, which tendto accumulate extensively (phenprocoumon,digitoxin, methadone), the optimal plasmalevel is attained only after a long period.Here, increasing the initial doses (loadingdose) will speed up the attainment of equilibrium,which is subsequently maintainedwith a lower dose (maintenance dose). Forslowly eliminated substances, single dailydosing may suf ce to maintain a steady plasmalevel. Change in Elimination Characteristicsduring Drug Therapy (B)With any drug taken regularly and accumulatingto the desired plasma level, it is importantto consider that conditions for biotransformationand excretion do not necessarilyremain constant. Elimination may behastened due to enzyme induction (p. 38) orto a change in urinary pH (p. 40). Consequently,the steady-state plasma level declinesto a new value corresponding to thenew rate of elimination. The drug effect maydiminish or disappear. Conversely, whenelimination is impaired (e. g., in progressiverenal insuf ciency), the mean plasma levelof renally eliminated drugs rises and mayenter a toxic concentration range.

Accumulation 51A. Accumulation: dose, dose interval, and fluctuation of plasma levelDrug concentration in blood4 x daily 50 mg2 x daily 100 mg1 x daily 200 mgDesired plasma levelSingle 50 mg612 18 24 6 12 18 24 6 12 18 24 6 12hB. Changes in elimination kinetics in the course of drug therapyInhibition of eliminationDrug concentration in bloodAccelerationof eliminationDesired plasma level6 12 18 24 6 12 18 24 6 12 18 24 6 12 18 h

52 Quantification of Drug Action Dose–Response RelationshipThe effect of a substance depends on theamount administered, i. e., the dose. If thedose chosen is below the critical threshold(subliminal dosing), an effect will be absent.Depending on the nature of the effect to bemeasured, increasing doses may cause theeffect to increase in intensity. Thus, the effectof an antipyretic or hypotensive drug can bequantified in a graded fashion, in that theextent of fall in body temperature or bloodpressure is being measured. A dose–effectrelationship is then encountered, as discussedon p. 54.The dose–effect relationship may vary dependingon the sensitivity of the individualperson receiving the drug: i. e., for the sameeffect, different doses may be required indifferent individuals. The interindividualvariation in sensitivity is especially obviouswith effects of the “all-or-none” kind.To illustrate this point, we consider anexperiment in which the subjects individuallyrespond in all-or-none fashion, as in theStraub tail phenomenon (A). Mice react tomorphine with excitation, evident in theform of an abnormal posture of the tail andlimbs. The dose dependence of this phenomenonis observed in groups of animals (e. g.,10 mice per group) injected with increasingdoses of morphine. At the low dose only themost sensitive, at increasing doses a growingproportion, and at the highest dose all of theanimals are affected (B). There is a relationshipbetween the frequency of respondinganimals and the dose given. At 2 mg/kg, 1outof10animalsreacts;at10mg/kg,5outof 10 respond. The dose–frequency relationshipresults from the different sensitivityofindividuals,which,asarule,exhibitsalog-normal distribution (C, graph at right,linear scale). If the cumulative frequency (totalnumber of animals responding at a givendose) is plotted against the logarithm of thedose (abscissa), a sigmoidal curve results (C,graph at left, semi-logarithmic scale). Theinflection point of the curve lies at the doseat which one half of the group has responded.The dose range encompassing thedose–frequency relationship reflects the variationin individual sensitivity to the drug.Although similar in shape, a dose–frequencyrelationship has, thus, a meaning differentfrom that of a dose–effect relationship.The latter can be evaluated in one individualand results from an intraindividual dependencyof the effect on drug concentration.The evaluation of a dose–effect-relationshipwithin a group of human subjects ismade more dif cult by interindividual differencesin sensitivity. To account for thebiological variation, measurements have tobe carried out on a representative sampleand the results averaged. Thus, recommendedtherapeutic doses will be appropriatefor the majority of patients, but not necessarilyfor each individual.The variation in sensitivity may be basedon pharmacokinetic differences (same dose† different plasma levels) or on differencesin target organ sensitivity (same plasma level† different effects).To enhance therapeutic safety, clinicalpharmacology has led efforts to discoverthe causes responsible for interindividualdrug responsiveness in patients. This fieldof research is called pharmacogenetics.Oftenthe underlying reason is a difference in enzymeproperty or activity. Ethnic variationsare additionally observed. Prudent physicianswill attempt to determine the metabolicstatus of a patient before prescribing aparticular drug.

Dose–Response Relationship 53A. Abnormal posture in mouse given morphineB. Incidence of effect as a function of doseDose = 0 = 2 mg/kg = 10 mg/kg= 20 mg/kg = 100 mg/kg= 140 mg/kgC. DoseÐfrequency relationship%Cumulative frequency100Frequency of dose needed806040204321mg/kg2 10 20100 1402 10 20100 140mg/kg

54 Quantification of Drug Action Concentration–Effect Relationship(A)As a rule, the therapeutic effect or toxic actionof a drug depends critically on the responseof a single organ or a limited numberof organs; for example, blood flow is affectedby a change in vascular luminal width. Byisolating critical organs or tissues from alarger functional system, these actions canbe studied with more accuracy; for instance,vasoconstrictor agents can be examined inisolated preparations from different regionsof the vascular tree, e. g., the portal or saphenousveins, or the mesentery, coronary, orbasilar arteries. In many cases, isolated organsor organ parts can be kept viable forhours in an appropriate nutrient mediumsuf ciently supplied with oxygen and heldat a suitable temperature. Responses of thepreparation to a physiological or pharmacologicalstimulus can be determined by a suitablerecording apparatus. Thus, narrowing ofa blood vessel is recorded with the help oftwowireloopsbywhichthevesselissuspendedunder tension.Experimentation on isolated organs offersseveral advantages:1. The drug concentration in the tissue isusually known.2. Reduced complexity and ease of relatingstimulus and effect.3. It is possible to circumvent compensatoryresponses that may partially cancel theprimary effect in the intact organism; forexample, the heart rate-increasing actionof norepinephrine cannot be demonstratedin the intact organism because asimultaneous rise in blood pressure elicitsa counterregulatory reflex that slows cardiacrate.4. The ability to examine a drug effect overits full range of intensities; for example, itwouldbeimpossibleintheintactorganismto follow negative chronotropic effectsto the point of cardiac arrest.Disadvantages are:1. Unavoidable tissue injury during dissection.2. Loss of physiological regulation of functionin the isolated tissue.3. The artificial milieu imposed on the tissue.These drawbacks are less important if isolatedorgan systems are used merely forcomparing the potency of different substances.The use of isolated cells offers a furthersimplification of the test system. Thus, quantitationof certain drug effects can beachieved with particular ease in cell cultures.A more marked “reduction” consists in theuse of isolated subcellular structures, such asplasma membranes, endoplasmic reticulum,or lysosomes. With increasing reduction, extrapolationto the intact organism becomesmore dif cult and less certain. Concentration–Effect Curves (B)As the concentration is raised by a constantfactor, the increment in effect diminishessteadily and tends asymptotically towardzero the closer one comes to the maximallyeffective concentration. The concentration atwhich a maximal effect occurs cannot bemeasured accurately; however, that elicitinga half-maximal effect (EC 50 ) is readily determined.This typically corresponds to the inflectionpoint of the concentration–responsecurve in a semi-logarithmic plot (log concentrationon abscissa). Full characterization of aconcentration–effect relationship requiresdetermination of the EC 50 , the maximallypossible effect (E max ), and the slope at thepoint of inflection.

Concentration–Effect Relationship 55A. Measurement of effect as a function of concentrationPortal veinMesenteric arteryCoronaryarteryBasilararterySaphenousveinVasoconstrictionActive tension1 min1251020Drug concentration304050100B. Concentration–effect relationship5040302010Effect(in mm of registration unit,e.g., tension developed%10080604020Effect(% of maximum effect)10 20 30 40 50Concentration (linear)110 100Concentration (logarithmic)

56 Drug–Receptor Interaction Concentration–Binding CurvesIn order to elicit their effect, drug moleculesmust be bound to the cells of the effectororgan. Binding commonly occurs at specificcell structures, namely, the receptors. Theanalysis of drug binding to receptors aimsto determine the af nity of ligands, the kineticsof interaction, and the characteristicsof the binding site itself.In studying the af nity and number ofsuch binding sites, use is made of membranesuspensions of different tissues. This approachis based on the expectation thatbinding sites will retain their characteristicproperties during cell homogenization.Provided that binding sites are freely accessiblein the medium in which membranefragments are suspended, drug concentrationat the “site of action” will equal that inthe medium. The drug under study is radiolabeled(enabling low concentrations to bemeasured quantitatively), added to themembrane suspension, and allowed to bindto receptors. Membrane fragments and mediumare then separated, e. g., by filtration,and the amount of bound drug (ligand) ismeasured. Binding increases in proportionto concentration as long as there is a negligiblereduction in the number of free bindingsites (c ≈ 1and B ≈ 10% of maximumbinding; c ≈ 2andB ≈ 20%). As binding sitesapproach saturation, the number of free sitesdecreases and the increment in binding is nolonger proportional to the increase in concentration(in the example illustrated, anincrease in concentration by 1 is needed toincrease binding from 10% to 20%; however,an increase by 20 is needed to raise it from70% to 80%).The law of mass action describes the hyperbolicrelationship between binding (B)andligandconcentration(c). This relationshipis characterized by the drug’s af nity (1/K D ) and the maximum binding (B max ), i. e.,the total number of binding sites per unit ofweight of membrane homogenate.B = Bmaxcc + KDK D is the equilibrium dissociation constantand corresponds to that ligand concentrationat which 50% of binding sites are occupied.The values given in (A) andusedforplotting the concentration–binding graph(B) resultwhenK D =10.The differing af nity of different ligandsfor a binding site can be demonstrated elegantlyby binding assays. Although simple toperform, these binding assays pose the dif -culty of correlating unequivocally the bindingsites concerned with the pharmacologicaleffect; this is particularly dif cult whenmore than one population of binding sites ispresent. Therefore, receptor binding mustnotbeassumeduntilitcanbeshownthat: Binding is saturable (saturability). The only substances bound are those possessingthe same pharmacological mechanismof action (specificity). Binding af nity of different substances iscorrelated with their pharmacological potency.Binding assays provide information aboutthe af nity of ligands, but they do not giveany clue as to whether a ligand is an agonistor antagonist (p. 60).Radiolabeled drugs bound to their receptorsmay be of help in purifying and analyzingfurther the receptor protein.

Concentration–Binding Curves 57A. Measurement of binding (B) as a function of concentration (c)OrgansAddition ofradiolabeleddrug indifferentconcentrationsHomogenizatonMembranesuspensionMixing and incubationCentrifugationDeterminationof radioactivityc = 1 c = 2 c = 5B = 10% B = 20% B = 30%c = 10 c = 20 c = 40B = 50% B = 70% B = 80%B. Concentration–binding relationship% Binding (B)100%100Binding (B)808060604040202010 20 30 40 50Concentration (linear)110Concentration (logarithmic)100

58 Drug–Receptor Interaction Types of Binding ForcesUnless a drug comes into contact with intrinsicstructures of the body, it cannot affectbody function.Covalent BondingTwo atoms enter a covalent bond if eachdonatesanelectrontoasharedelectronpair(cloud). This state is depicted in structuralformulas by a dash. The covalent bond is“firm,” that is, not reversible or poorly so.Few drugs are covalently bound to biologicalstructures. The bond, and possibly the effect,persist for a long time after intake of a drughas been discontinued, making therapy difficultto control. Examples include alkylatingcytostatics (p. 300) or organophosphates(p. 311). Conjugation reactions occurring inbiotransformation also represent covalentlinkages (e. g., to glucuronic acid).Noncovalent BondingIn noncovalent bonding there is no formationof a shared electron pair. The bond isreversible and is typical of most drug–receptorinteractions. Since a drug usually attachesto its site of action by multiple contacts,several of the types of bonds describedbelow may participate.Electrostatic attraction (A). A positive and anegative charge attract each other.Ionic interaction: An ion is a particlecharged either positively (cation) or negatively(anion), i. e., the atom is deficient inelectrons or has surplus electrons, respectively.Attraction between ions of oppositecharge is inversely proportional to thesquare of the distance between them; it isthe initial force drawing a charged drug to itsbinding site. Ionic bonds have a relativelyhigh stability.Dipole–ion interaction: When bondingelectrons are asymmetrically distributedover the atomic nuclei involved, one atomwill bear a negative (δ – ), and its partner apositive (δ + ) partial charge. The moleculethuspresentsapositiveandanegativepole,i. e., it has polarity or is a dipole. A partialcharge can interact electrostatically with anion of opposite charge.Dipole-dipole interaction is the electrostaticattraction between opposite partialcharges. When a hydrogen atom bearing apartial positive charge bridges two atomsbearing partial negative charges, a hydrogenbond is created.van der Waals bonds (B) are formed betweenapolar molecular groups that havecome into close proximity. Spontaneoustransient distortion of electron clouds (momentaryfaint dipole, δδ) mayinduceanoppositedipole in the neighboring molecule.The van der Waals bond, therefore, is also aform of electrostatic attraction, albeit of verylow strength (inversely proportional to 7thpower of distance).Hydrophobic interaction (C). The attractionbetween the water dipoles is strong enoughto hinder intercalation of any apolar (uncharged)molecules. By tending toward eachother, H 2 O molecules squeeze apolar particlesfrom their midst. Accordingly, in theorganism, apolar particles such as fatty acidchains of cell membranes or apolar regionsof a receptor have an increased probability ofremaining in nonaqueous, apolar surroundings.

Types of Binding Forces 59A. Electrostatic attractionDrug + Binding site ComplexHOD + N50 nm– O P OH HOHHOD + N – O P OH H OHIonIonIonic bondDOHδ – δ + δ – δ + δ – δ + δ – δ + δ +1,5 nm– OOPODOH– OOPOOHOHDipole (permanent)IonD O HD = DrugDipoleB. van der Waals’ bondingδ –0,5 nm Oδ + HDipoleDOHHydrogen bondδ –OH− Oapolar particle in polar solvent ( H O) 2 CH 2CH 2CH 2CH 2CH 2CH 2CH 2CH 2δδ + CH 2δδ – CH 2δδ – CH 2δδ + CH 2CH δδ – 2CH δδ + 2CH δδ +2CH δδ –2DDInducedtransientfluctuating dipolesC. Hydrophobic interactionδ +H H“Repulsion” of apolarδpolarPhospholipid membraneApolaracyl chainInsertion in apolar membrane interiorAdsorptionto apolar surface

60 Drug–Receptor Interaction Agonists—AntagonistsAn agonist (A) has af nity (tendency to adhere)for a receptor and affects the receptorprotein in such a manner as to cause achange in cell function—“intrinsic activity.”The biological effect of the agonist (i. e., thechange in cell function) depends on the effectivenessof signal transduction steps(p. 66) associated with receptor activation.The maximal effect of an agonist may alreadyoccur when only a fraction of the availablereceptors is occupied (B, agonist A).Another agonist (agonist B), possessingequal af nity but less ability to activate thereceptor and the associated signal transductionsteps (i. e., less intrinsic activity), willproduce a smaller maximal effect even if allreceptors are occupied—smaller ef cacy.Agonist B is a partial agonist. Thepotencyof an agonist is characterized by the concentration(EC 50 ) at which a half-maximal effectis attained.Antagonists (A) attenuate the effect ofagonists: they act “antiagonistically.” Competitiveantagonists possess af nity for thereceptors, but their binding does not elicit achange in cell function. In other words, theyare devoid of intrinsic activity. When presentsimultaneously, an agonist and a competitiveantagonist vie for occupancy of the receptor.The af nities and concentrations ofboth competitors determine whether bindingof agonist or antagonist predominates.By increasing the concentration of the agonist,blockade induced by an antagonist canbe surmounted (C): that is, the concentration–effectcurve of the agonist is shifted“right”—to higher concentrations—withpreservation of the maximal effect. Models of the Molecular Mechanismof Agonist/Antagonist Action (A)Agonist induces an active conformation.The agonist binds to the inactive receptorand thereby causes the resting conformationto change into the active state. The antagonistattaches to the inactive receptor withoutaltering its conformation.Agonist stabilizes spontaneously occurringactive conformation. The receptor mayspontaneously “flip” into the active conformation.Usually, however, the statisticalprobabilityofsuchaneventissosmallthata spontaneous excitation of the cells remainsundetectable. Selective binding of the agonistcan occur only to the active conformationand thus favors the existence of thisstate. The antagonist shows af nity only forthe inactive state, promoting existence of thelatter. If the system has little spontaneousactivity, no measurable effect will resultfrom adding an antagonist. However, if thesystem displays high spontaneous activity,the antagonist is liable to produce an effectopposite to that of an agonist: inverse agonist.A “true” antagonist without intrinsicactivity (“neutral antagonist”) displays equalaf nity for the active and inactive conformationsof the receptor and does not interferewith the basal activity of the cell. Accordingto this model, a partial agonist haslessselectivityfor the active state; however, to acertainextentitbindsalsototheinactivestate. Other Forms of AntagonismAllosteric antagonism. The antagonist isbound outside the agonist’s site of attachmentat the receptor and induces a decreasein agonist af nity. The latter is increased inthecaseofallosteric synergism.Functional antagonism. Two agonists actingvia different receptors affect the same variable(e. g., luminal diameter of bronchi) inopposite directions (epinephrine † dilation;histamine † constriction).

EC 50EC 50Agonists—Antagonists 61A. Molecular mechanisms of drug–receptor interactionAgonistAntagonist AntagonistAgonistRare spontaneoustransitionReceptorinactiveactiveAgonistinduces activeconformation ofreceptor proteinAntagonistoccupiesreceptorwithout effectsAntagonistselects inactivereceptorconformationAgonistselects activereceptorconformationB. Potency and efficacy of agonistsAgonist AReceptorsIncrease in tensionReceptor occupationEfficacyConcentration (log) of agonistSmooth-muscle cellAgonist BPotencyC. Competitive antagonismAgonist effect0 1 10 100 1000 10 000ConcentrationofantagonistAgonist concentration (log)

62 Drug–Receptor Interaction Enantioselectivity of Drug ActionMany drugs are racemates, including β-blockers, nonsteroidal anti-inflammatoryagents, as well as the anticholinergic benzetimide(A). A racemate consists of a moleculeand its corresponding mirror image which,like the left and right hands, cannot besuperimposed. Such chiral (“handed”) pairsof molecules are referred to as enantiomers.Typically, chirality is due to a single carbon(C) atom bonded to four different substituents(asymmetric carbon atom). Enantiomerismis a special case of stereoisomerism.Nonchiral stereoisomers are called diastereomers(e. g., quinidine/quinine).Bond lengths in enantiomers, but not necessarilydiastereomers, are the same. Therefore,enantiomers possess similar physicochemicalproperties (e. g., solubility, meltingpoint) and both forms are usuallyobtained in equal amounts by chemical synthesis.As a result of enzymatic activity, however,only one of the enantiomers is usuallyfound in nature.In solution, enantiomers rotate the planeof oscillation of linearly polarized light inopposite directions; hence they are referredto as “dextro-rotatory” or “levo-rotatory,”designated by the prefixes d- or(+)-andlor(–)-, respectively. The direction of rotationgives no clue concerning the spatial structureof enantiomers. The absolute configuration,as determined by certain rules, isdescribed by the prefixes (S)- and (R)-. Insome compounds, designation as the D-and L-forms is possible by reference to thestructure of D- andL-glyceraldehyde.For drugs to exert biological actions, contactwith reaction partners in the body isrequired. When the reaction favors one ofthe enantiomers, enantioselectivity is observed.of the enantiomers will have optimal fit. Itsaf nity will then be higher. Thus, dexetimidedisplays an af nity at the muscarinic AChreceptors almost 10 000 times (p.104) thatof levetimide;andatβ-adrenoceptors (S)-(–)-propranolol has an af nity 100 times that ofthe (R)-(+) form.Enantioselectivity of intrinsic activity. Themode of attachment at the receptor also determineswhether an effect is elicited; andwhether or not a substance has intrinsic activity,i. e., acts as an agonist or antagonist.For instance, (–)-dobutamine is an agonist atβ-adrenoceptors, whereas the (+)-enantiomeris an antagonist.Inverse enantioselectivity at another receptor.An enantiomer may possess an unfavorableconfiguration at one receptor thatmay, however, be optimal for interactionwith another receptor. In the case of dobutamine,the (+)-enantiomer has af nity at β-adrenoceptors that is 10 times higher thanthat of the (–)-enantiomer, both having agonistactivity. However, the α-adrenoceptorstimulant action is due to the (–)-form (seeabove).As described for receptor interactions,enantioselectivity may also be manifestedin drug interactions with enzymes andtransport proteins. Enantiomers may displaydifferent af nities and reaction velocities.Conclusion. The enantiomers of a racematecan differ suf ciently in their pharmacodynamicand pharmacokinetic properties toconstitute two distinct drugs.Enantioselectivity of af nity. If a receptorhas sites for three of the substituents (symbolizedin B by a cone, sphere, and cube) onthe asymmetric carbon to attach to, only one

Enantioselectivity of Drug Action 63A. Example of an enantiomeric pair with different affinitiesfor a stereoselective receptorRACEMATEBenzetimideENANTIOMERDexetimideHO N ON CH 2Ratio1 : 1CH 2ENANTIOMERLevetimideHO N ONPhysicochemical properties:Equal+ 125°(Dextrorotatory)Defection of polarized light:[α] 20D– 125°(Levorotatory)S = sinisterAbsolute configurationR = rectusca. 10 000 Potency (rel. affinity at m-ACh-receptors)1B. Reasons for different pharmacological properties of enantiomersCCEnzymeTransport proteinAffinityA ffinityReceptorReceptorEnzymeTransportproteinPharmacodynamicpropertiesIntrinsicactivityTurnoverratePharmacokineticproperties

64 Drug–Receptor Interaction Receptor TypesReceptors are macromolecules that operateto bind mediator substances and transducethis binding into an effect, i. e., a change incell function. Receptors differ in terms oftheir structure and the manner in whichthey translate occupancy by a ligand into acellular response (signal transduction).G-Protein coupled receptors (A) consistof an amino acid chain that weaves in andout of the membrane in serpentine fashion.The extramembranal loop regions of themolecule may possess sugar residues at differentN-glycosylation sites. The seven α-helical membrane-spanning domains probablyform a circle around a central pocketthat carries the attachment sites for the mediatorsubstance. Binding of the mediatormolecule or of a structurally related agonistmolecule induces a change in the conformationof the receptor protein, enabling thelattertointeractwithaG-protein(=guanylnucleotide-binding protein). G-proteins lieat the inner leaf of the plasmalemma andconsist of three subunits designated α, β,and γ. There are various G-proteins that differmainly with regard to their α-unit. Associationwith the receptor activates theG-protein,leadinginturntoactivationofanother protein (enzyme, ion channel). Alarge number of mediator substances actvia G-protein-coupled receptors (see p. 66for more details).An example of a ligand-gated ion channel(B) is the nicotinic cholinoceptor of themotor end plate. The receptor complex consistsof five subunits, each of which containsfour transmembrane domains. Simultaneousbinding of two acetylcholine (ACh) moleculesto the two α-subunits results in openingof the ion channel with entry of Na + (andexit of some K + ), membrane depolarization,and triggering of an action potential (p.186).The neuronal N-cholinoceptors apparentlyconsist only of α- andβ-subunits. Some ofthe receptors for the transmitter γ-aminobutyricacid (GABA) belong to this receptorfamily: the GABA A subtype is linked to achloride channel (and also to a benzodiazepinebinding site, see p. 223). Glutamate andglycine both act via ligand-gated ion channels.The insulin receptor protein represents aligand-operated enzyme (C), a catalytic receptor.When insulin binds to the extracellularattachment site, a tyrosine kinase activityis “switched on” at the intracellularportion. Protein phosphorylation leads to alteredcell function via the assembly of othersignal proteins. Receptors for growth hormonesalso belong to the catalytic receptorclass.Protein synthesis regulating receptors(D) for steroids and thyroid hormone arefound in the cytosol and in the cell nucleus,respectively. The receptor proteins are locatedintracellularly; depending on the hormone,either in the cytosol (e. g., glucocorticoids,mineralocorticoids, androgens, andgestagens) or in the cell nucleus (e. g., estrogens,thyroid hormone). Binding of hormoneexposes a normally hidden domain of thereceptor protein, thereby permitting the latterto bind to a particular DNA nucleotidesequence on a gene and to regulate its transcription.The ligand–receptor complexesthus function as transcription regulating factors.Transcription is usually initiated or enhanced,rarely blocked.The hormone–receptor complexes interactpairwise with DNA. These pairs (dimers)may consist of two identical hormone–receptorcomplexes (homodimeric form, e. g.,with adrenal or gonadal hormones). The thyroidhormone–receptor complex occurs inheterodimeric form and combines with acis-retinoic acid-receptor complex.

Receptor Types 65A. G-Protein-coupled receptorAmino acids-NH 2AgonistH 2 N3 4 5 6 7COOH34576G-ProteinCOOHEffector proteinα-HelicesTransmembrane domainsEffectB. Ligand-gated ion channel C. Ligand-regulated enzymeNa +InsulinAChγαδαβK +Na + K +AChNicotinicacetylcholinereceptorSubunitconsisting offour transmembranedomainsD. Protein synthesis-regulating receptorSS S S SSTyrosine kinasePhosphorylation oftyrosine residues in proteinsSteroidHormoneCytosolDNAReceptorNucleusmRNATranscriptionTranslationProteinHomodimericreceptors:glucocorticoidsmineralocorticoidsandrogensgestagensestrogensHeterodimericreceptors withcis-retinoic acid:triiodothyroninevitamin Dall-trans-retinoic acideicosanoids

66 Drug–Receptor Interaction Mode of Operation of G- ProteincoupledReceptorsSignal transduction at G-protein coupled receptorsuses essentially the same basicmechanism (A). Agonist binding to the receptorleads to a change in receptor proteinconformation. This change propagates to theG-protein: the α-subunit exchanges GDP forGTP, then dissociates from the two othersubunits, associates with an effector proteinand alters its functional state. In principle,the β-andγ-subunits are also able to interactwith effector proteins. The α-subunit slowlyhydrolyses bound GTP to GDP. G α -GDP hasno af nity for the effector protein and reassociateswith the β- andγ-subunits (A). G-proteins can undergo lateral diffusion in themembrane; they are not assigned to individualreceptor proteins. However, a relationexists between receptor types and G-proteintypes (B). Furthermore, the α-subunits of individualG-proteins are distinct in terms oftheir af nity for different effector proteins,as well as the kind of influence exerted onthe effector protein. G α -GTP of the G s -proteinstimulates adenylate cyclase, while G α -GTP of the G i -protein is inhibitory. TheG-protein-coupled receptor family includesmuscarinic cholinoceptors, adrenoceptorsfor norepinephrine and epinephrine, as wellas receptors for dopamine, histamine, serotonin,glutamate, GABA, morphine, prostaglandins,leukotrienes, and many other mediatorsand hormones.Major effector proteins for G-proteincoupledreceptors include adenylate cyclase(ATP † intracellular messenger cAMP),phospholipase C (phosphatidylinositol †intracellular messengers inositol trisphosphateand diacylglycerol) as well as ionchannel proteins (B). Numerous cell functionsare regulated by cellular cAMP concentration,because cAMP enhances activity ofprotein kinase A, which catalyzes the transferof phosphate groups onto functional proteins.Elevation of cAMP levels leads interalia to relaxation of smooth muscle tonus,enhanced contractility of cardiac muscle, aswell as increased glycogenolysis and lipolysis(p. 88). Phosphorylation of cardiac calciumchannel proteins increases the probabilityof channel opening during membranedepolarization. It should be noted that cAMPis inactivated by phosphodiesterase. Inhibitorsof this enzyme elevate intracellularcAMP concentration and elicit effects resemblingthose of epinephrine.The receptor protein itself may undergophosphorylation, with a resultant loss of itsability to activate the associated G-protein.This is one of the mechanisms that contributeto a decrease in sensitivity of a cell duringprolonged receptor stimulation by anagonist (desensitization).Activation of phospholipase C leads tocleavage of the membrane phospholipidphosphatidylinositol 4,5-bisphosphate intoinositol trisphosphate (IP 3 )anddiacylglycerol(DAG). IP 3 promotes release of Ca 2+from storage organelles, whereby contractionof smooth muscle cells, breakdown ofglycogen, or exocytosis may be initiated.DAG stimulates protein kinase C, whichphosphorylates certain serine- or threonine-containingenzymes.Certain G-proteins can induce opening ofchannel proteins. In this way, potassiumchannels can be activated (e. g., acetylcholineeffect on sinus node, p.104; opioid effect onneural impulse transmission, p. 208).

G-Protein-coupled Receptors 67A. G-Protein-mediated effect of an agonistReceptor G-Protein Effector protein Agonistαβ βγ α γGDPGTPβγαβγαB. G-Proteins, cellular messenger substances, and effectsG sATPAdenylate cyclase+ -cAMPProtein kinase APhosphorylation offunctional proteinsG ie.g., Relaxationof smooth muscle,glycogenolysis,lipolysis, Ca-channelactivationCa 2+Phospholipase CActivationIP 3PPPPhosphorylationof enzymesDAGProtein kinase Ce.g., Contractionof smooth muscle,glandularsecretionFacilitationof ionchannelopeningTransmembraneion movementsEffect on:e.g., Membraneaction potential,homeostasis ofcellular ions

68 Drug–Receptor Interaction Time Course of Plasma Concentrationand EffectAfter the administration of a drug, its concentrationin plasma rises, reaches a peak,and then declines gradually to the startinglevel, owing to the processes of distributionand elimination (p. 46). Plasma concentrationat a given point in time depends onthe dose administered. Many drugs exhibita linear relationship between plasma concentrationand dose within the therapeuticrange (dose-linear kinetics [A]; note differentscales on ordinate). However, the samedoes not apply to drugs whose eliminationprocesses are already suf ciently activatedat therapeutic plasma levels so as to precludefurther proportional increases in therate of elimination when the concentrationis increased further. Under these conditions,a smaller proportion of the dose administeredis eliminated per unit time.A model example of this behavior is theelimination of ethanol (p. 44). Because themetabolizing enzyme, alcohol dehydrogenase,is already saturated at low ethanolconcentrations, only the same amount perunit time is broken down despite rising concentrations.The time courses of the effect and of theconcentration in plasma are not identical,because the concentration–effect relationshipis complex (e. g., with a threshold phenomenon)and often obeys a hyperbolicfunction (B; cf. p. 54). This means that thetime course of the effect exhibits dose dependencealso in the presence of dose-linearkinetics (C).Inthelowerdoserange(example1),theplasma level passes through a concentrationrange (0–0.9) in which the change in concentrationstill correlates quasi-linearly withthechangeineffect.Thetimecoursesoftheconcentration in plasma and the effect (Aand C, left graphs) are very similar. However,after a high dose (100), the plasma level willremain in a concentration range (between90 and 20) where changes in concentrationdo not evoke significant changes in effect.Accordingly, the time–effect curve displaysa kind of plateau after high doses (100). Theeffect only begins to wane after the plasmalevel has fallen to a range (below 20) inwhich changes in plasma level are reflectedin the intensity of the effect.The dose-dependence of the time courseof the drug effect is exploited when the durationof the effect is to be prolonged byadministration of a dose in excess of thatrequired for the effect. This is done in thecase of penicillin G (p. 270), when a dosinginterval of 8 hours is recommended althoughthe drug is eliminated with a halflifeof 30 minutes. This procedure is, ofcourse, feasible only if supramaximal dosingis not associated with toxic effects.It follows that a nearly constant effect canbe achieved, although the plasma level mayfluctuate greatly during the interval betweendoses.The hyperbolic relationship between plasmaconcentration and effect explains whythetimecourseoftheeffect,unlikethatofthe plasma concentration, cannot be describedin terms of a simple exponentialfunction. A half-life can only be given forthe processes of drug absorption and elimination,hence the change in plasma levels,butgenerallynotfortheonsetordeclineofthe effect.

Plasma Concentration and Effect 69A. Dose-linear kinetics (note different ordinates)1,00,5Concentrationt 1 2105Concentration50t 1 2100Concentrationt 1 20,1110Dose = 1TimeDose = 10TimeDose = 100TimeB. Concentration–effect relationship100Effect500Concentration110 20 30 40 50 60 70 80 90 100C. Dose dependence of the time course of effectEffect100100Effect100Effect505050101010TimeTimeTimeDose = 1Dose = 10Dose = 100

70 Adverse Drug Effects Undesirable Drug Effects,Side EffectsThe desired (or intended) principal effect ofanydrugistomodifybodyfunctioninsuchamanner as to alleviate symptoms caused bythe patient’s illness. In addition, a drug mayalso elicit unwanted effects that in turn maycause complaints, provoke illness, or evenlead to death.Causes of Adverse EffectsOverdosage (A). The drug is administered ina higher dose than is required for the principaleffect; this directly or indirectly affectsother body functions.For instance, morphine (p. 208), given inthe appropriate dose, affords excellent painrelief by influencing nociceptive pathways inthe CNS. In excessive doses, it inhibits therespiratory center and makes apnea imminent.The dose-dependence of both effectscanbegraphedintheformofdose–responsecurves (DRCs). The distance between the twoDRCs indicates the difference between thetherapeutic and toxic doses. This margin ofsafety (“therapeutic index”) indicates therisk of toxicity when standard doses are exceeded.It should be noted that, apart from theamount administered, the rate of drug deliveryis important. The faster blood levels rise,the higher concentrations will climb (p. 49).Rather than being required therapeutically,the initial concentration peak following i.v.injection of morphinelike agents causes sideeffects (intoxication and respiratory depression,p. 208).“Thedosealonemakesthepoison”(Paracelsus).This holds true for both medicinesand environmental poisons. No substance assuch is toxic! In order to assess the risk oftoxicity, knowledge is required of: (1) theeffective dose during exposure; (2) the doselevel at which damage is likely to occur.Increased sensitivity (B). If certain bodyfunctions develop hyperreactivity, unwantedeffects can occur even at normaldose levels. Increased sensitivity of the respiratorycenter to morphine is found in patientswith chronic lung disease, in neonates,or during concurrent exposure to other respiratorydepressant agents. The DRC isshifted to the left and a smaller dose of morphineis suf cient to paralyze respiration.Genetic anomalies of metabolism may alsolead to hypersensitivity (pharmacogenetics,p. 78). The above forms of hypersensitivitymust be distinguished from allergies involvingthe immune system (p. 72).Lack of selectivity (C). Despite appropriatedosing and normal sensitivity, undesired effectscan occur because the drug does notspecifically act on the targeted (diseased)tissue or organ. For instance, the anticholinergicatropine is bound only to acetylcholinereceptorsofthemuscarinictype;however,these are present in many different organs.Moreover, the neuroleptic chlorpromazine isable to interact with several different receptortypes. Thus, its action is neither organspecificnor receptor-specific.The consequences of lack of selectivity canoften be avoided if the drug does not requirethe blood route to reach the target organ butis, instead, applied locally, as in the administrationof parasympatholytics in the formof eye drops or in an aerosol for inhalation.Side effects that arise as a consequence ofaknownmechanismofactionareplausibleand the connection with drug ingestion issimple to recognize. It is more dif cult todetect unwanted effects that arise from anunknown action. Some compelling examplesof these include fetal damage after intake ofa hypnotic (thalidomide), pulmonary hypertensionafter appetite depressants, and fibrosisafter antimigraine drugs.With every drug use, unwanted effectsmust be taken into account. Before prescribinga drug, the physician should therefore doa risk–benefit analysis.

Undesirable Drug Effects 71A. Adverse drug effect: overdosingDecrease in painperception(nociception)MorphineEffectDecrease inNociception RespiratoryactivitySafetymarginRespiratory depressionMorphineoverdoseDoseB. Adverse drug effect: increased sensitivityIncreasedsensitivity ofrespiratorycenterEffectSafetymarginNormaldoseDoseC. Adverse drug effect: lacking selectivityAtropinee.g., Chlorpromazine5-HTreceptormAChreceptorReceptor specificitybut lackingorgan selectivitymAChreceptorAtropineDopaminereceptorα 1 -adrenoceptorHistaminereceptorLacking receptorspecificity

72 Adverse Drug Effects Drug AllergyThe immune system normally functions toinactivate and remove high-molecularweight“foreign” matter taken up by the organism.Immune responses can, however,occur without appropriate cause or with exaggeratedintensity and may harm the organism;for instance, when allergic reactionsare caused by drugs (active ingredient orpharmaceutical excipients). Only a fewdrugs, e. g., (heterologous) proteins, have amolecular weight large enough to act as effectiveantigens or immunogens, capableby themselves of initiating an immune response.Most drugs or their metabolites (socalledhaptens) must first be converted to anantigen by linkage to a body protein. In thecase of penicillin G, a cleavage product (penicilloylresidue) probably undergoes covalentbinding to protein.During initial contact with the drug, theimmune system is sensitized: antigen-specificlymphocytes of the T-type and B-type(antibody formation) proliferate in lymphatictissue and some of them remain asso-called memory cells. Usually, these processesremain clinically silent.During the second contact,antibodiesarealready present and memory cells proliferaterapidly. A detectable immune response—theallergic reaction—occurs. This can be of severeintensity, even at a low dose of theantigen. Four types of reactions can be distinguished:Type 1, anaphylactic reaction. Drug-specificantibodies of the IgE type combine via theirFc moiety with receptors on the surface ofmast cells. Binding of the drug provides thestimulus for the release of histamine andother mediators. In the most severe form, alife-threatening anaphylactic shock develops,accompanied by hypotension, bronchospasm(asthma attack), laryngeal edema, urticaria,stimulation of gut musculature, andspontaneous bowel movements (p.118).Type 2, cytotoxic reaction. Drug–antibody(IgG) complexes adhere to the surface ofblood cells, where either circulating drugmolecules or complexes already formed inblood accumulate. These complexes mediatethe activation of complement, a family ofproteins that circulate in the blood in aninactive form, but can be activated in a cascadelikesuccession by an appropriate stimulus.“Activated complement,” normally directedagainst microorganisms, can destroythe cell membranes and thereby cause celldeath; it also promotes phagocytosis, attractsneutrophil granulocytes (chemotaxis),and stimulates other inflammatory responses.Activation of complement on bloodcells results in their destruction, evidencedby hemolytic anemia, agranulocytosis, andthrombocytopenia.Type 3, immune-complex vasculitis (serumsickness, Arthus reaction). Drug–antibodycomplexes precipitate on vascular walls, complementis activated, and an inflammatoryreaction is triggered. Attracted neutrophils,in a futile attempt to phagocytose the complexes,liberate lysosomal enzymes thatdamage the vascular walls (inflammation,vasculitis). Symptoms may include fever, exanthema,swelling of lymph nodes, arthritis,nephritis, and neuropathy.Type 4, contact dermatitis. Acutaneouslyapplied drug is bound to the surface ofT-lymphocytes directed specifically againstit. The lymphocytes release signal molecules(lymphokines) into their vicinity that activatemacrophages and provoke an inflammatoryreaction.Remarkably, virtually no drug group iscompletely free of allergic side effects. However,some chemical structures are prone tocause allergic reactions.

Drug Allergy 73A. Adverse drug effect: allergic reactionReaction of immune system to first drug exposureProteinMacromoleculeMW > 10 000Drug(= hapten)AntigenImmunesystem(lymphatictissue)recognizes:“Non-self”Production ofantibodies(Immunoglobulins)e.g., IgE,IgG, etc.Proliferation ofantigenspecificlymphocytesDistributionin bodyImmune reaction with repeated drug exposureIgEe.g., NeutrophilicgranulocyteReceptorfor IgEHistamine and other mediatorsUrticaria, asthma, shockType 1 reaction:acute anaphylactic reactionMast cell(tissue)basophilicgranulocyte(blood)IgGComplementactivationType 2 reaction:cytotoxic reactionMembraneinjuryCelldestructionDeposition onvessel wallFormation ofimmune complexesActivationof:ContactdermatitisAntigenspecificT-lymphocyteType 3 reaction:Immune complexcomplementandneutrophilsInflammatoryreactionInflammatoryreactionLymphokinesType 4 reaction:lymphocytic delayed reaction

74 Adverse Drug Effects Cutaneous ReactionsUpon systemic distribution, many drugsevoke skin reactions that are caused on animmunological basis. Moreover, cutaneousinjury can also arise from nonimmunologicalmechanisms. Cutaneous side effects vary inseverity from harmless to lethal. Cutaneousreactions are a common form of drug adversereaction. Nearly half of them are attributedto antibiotics or sulfonamides, and onethirdto nonsteroidal anti-inflammatoryagents, with many other pharmaceuticalsjoining the list.The following clinical pictures are noted: Toxic erythema with a maculopapularrash similar to that of measles and scarletfever (B, left).Urticaria with itchy swellingsas part of a Type 1 reaction includinganaphylactic shock. Fixed eruptions (drug exanthemas) withmostly few demarcated, painful lesions,usually located in intertriginous skin regions(genital area, mucous membranes).With repeated exposure, these typicallyrecur at the same sites. Steven–Johnson syndrome (SJS, erythemamultiforme) and toxic epidermal necrolysis(TEN or Lyell syndrome) withapoptosis of keratinocytes and bullous detachmentof the epidermis from the dermis.When more than 30% of the bodysurface is affected, TEN is present. Itscourse is dramatic and the outcome notrarely fatal.The aforementioned reactions are thought toinvolve the following pathogenetic mechanisms. With penicillins, opening of the β-lactambond is possible. The resulting penicilloylgroup binds as a hapten to a protein. Thismay lead to an Ig-E mediated anaphylacticreaction, manifested on the skin asurticaria. Biotransformation via cytochrome oxidasemay yield reactive products. Presumablykeratinocytes are capable of suchmetabolic reactions. In this way, thepara-amino group of sulfonamides canbe converted into a hydroxyl aminegroup, which then acts as a hapten toinduce a Type 4 reaction in the skin. Fixedmaculopapular lesions are thought toarise on this basis. Pemphiguslike manifestations with formationof blisters. The development ofcutaneous manifestations is not as ominousas in SJS or TEN, the blisters beinglocated intraepidermally. This conditioninvolves the formation of autoantibodiesdirected against adhesion proteins (desmogelin)of desmosomes, which link keratinocytesto each other. D-Penicillamineand rifampin are inducers of the raredrug-associated pemphigus (p. 308). Photosensitivity reactions result fromexposure to sunlight, in particular theUVA component. In phototoxic reactions,drug molecules absorb photic energy andturn into reactive compounds that damageskin cells at their site of production. Inphotoallergic reactions, photoreactionproducts bind covalently to proteins ashaptens and trigger Type 4 allergic responses.The type and localization are difficultto predict.

Cutaneous Reactions 75A. Adverse drug effect: cutaneous reactionSunlight (UVA)EpidermalkeratinocytesDermisDrugormetaboliteDrugMetaboliteRadical formationImmune reactionImmune reactionPhototoxicity,SunburnreactionPhotoallergy,Type 4reactionUrticariaPenicilloylgroupe.g., penicillinEdema of upper dermisType 1 reactionCH2OC NHS CH3ONHCH3COOHProteinProduction of metabolitesin keratinocytesPhotosensitizationPemphiguslikereactionIntraepidermalblistersAutoantibody againstdesmosomal adhesion proteinse.g., penicillamineStevens–Johnson syndrome, TENBlisters at the epidermis/dermisboundarye.g., sulfonamide??Type 4 reactionApoptosis of keratinocytesMaculopapular drug exanthema,fixed eruptionCell-mediated immune reactione.g., sulfonamideDrug exanthemaToxic epidermal necrolysis (TEN)

76 Adverse Drug Effects Drug Toxicity in Pregnancyand LactationDrugs taken by the mother can be passed ontransplacentally or via breast milk and canadversely affect the unborn or the neonate.Pregnancy (A). Limb malformations inducedby the hypnotic thalidomide (Contergan)first focused attention on the potential ofdrugs to cause malformations (teratogenicity).Drug effects on the unborn fall into twobasic categories:1. Predictable effects that derive from theknown pharmacological drug properties.Examples include masculinization of thefemale fetus by androgenic hormones;brain hemorrhage due to oral anticoagulants;bradycardia due to β-blockers.2. Effects that specifically affect the developingorganism and that cannot be predictedon the basis of the known pharmacologicalactivity profile.In assessing the risks attending drug useduring pregnancy, the following points haveto be considered:a Time of drug use. Thepossiblesequelaeofexposure to a drug depend on the stage offetal development, as shown in (A). Thus,the hazard posed by a drug with a specificaction is limited in time, as illustrated bythe tetracyclines, which produce effectson teeth and bones only after the thirdmonth of gestation, when mineralizationbegins.b Transplacental passage. Most drugs canpass in the placenta from the maternalinto the fetal circulation. The syncytiotrophoblastformed by the fusion of cytotrophoblastcells represents the major diffusionbarrier. It possesses a higher permeabilityto drugs than suggested by theterm “placental barrier.” Accordingly, allcentrally-acting drugs administered to apregnant woman can easily reach the fetalorganism. Relevant examples includeantiepileptics, anxiolytics, hypnotics, antidepressants,and neuroleptics.c Teratogenicity. Statistical risk estimatesare available for familiar, frequently useddrugs. For many drugs, teratogenic potencycannot be demonstrated; however,inthecaseofnoveldrugsitisusuallynotyet possible to define their teratogenichazard.Drugs with established human teratogenicityinclude derivatives of vitamin A (etretinate,isotretinoic acid [used internally in skindiseases]). A peculiar type of damage resultsfrom the synthetic estrogenic agent diethylstilbestrolfollowing its use during pregnancy:daughters of treated mothers havean increased incidence of cervical and vaginalcarcinoma at the age of about 20 years.Use of this substance in pregnancy wasbanned in the United States in 1971.In assessing the risk–benefit ratio, it is alsonecessary to consider the benefit for thechild resulting from adequate therapeutictreatment of its mother. For instance, therapywith antiepileptic drugs is indispensable,because untreated epilepsy endangersthe unborn child at least as much as doesadministration of anticonvulsants.Drug withdrawal reactions are liable tooccur in neonates whose mothers are ingestingdrugs of abuse or antidepressants of theSSRI type (p. 228).Lactation (B). Drugs present in the maternalorganism can be secreted in breast milk andthus be ingested by the infant. Evaluation ofrisksshouldbebasedonfactorslistedinB.Incase of doubt, potential danger to the infantcan be averted only by weaning.

Drug Toxicity in Pregnancy and Lactation 77A. Pregnancy: fetal damage due to drugsOvumSpermcells1 day~ 3 daysEndometriumBlastocystAge of fetus(weeks)1 21 21238DevelopmentstageNidation Embryo: organdevelopmentFetus:growthandmaturationFetal deathMalformationFunctional disturbancesArteryUterus wallVeinSequelaeofdamageby drugPlacental transfer of metabolitesB. Lactation: maternal intake of drugsTransfer ofmetabolitesCapillaryFetusSyncytiotrophoblast“Placentalbarrier”To umbilical cordMotherIntervillous spaceDrugTherapeuticeffect inmother?Unwantedeffectin childExtent oftransfer ofdrug intomilkInfant doseDrug concentration ininfant’s bloodSensitivity of site of actionDistributionof drugin infantRate ofeliminationof drugfrom infantEffect

78 Genetic Variation of Drug Effects PharmacogeneticsPharmacogenetics is concerned with the geneticvariability of drug effects. Differencesin genetic sequences that occur at a frequencyof at least 1% are designated as polymorphisms.Rare variants are observed inless than 1% of a population. Polymorphismsmay either influence the pharmacokineticsof a drug (A) or occur in the target genes thatmediate the therapeutic effect of drugs (B).Genetic variants of pharmacokinetics. Polymorphismscan occur in all genes that participatein the absorption, distribution, biotransformation,and elimination of drugs.Subjects who break down a drug moreslowly owing to a genetic defect are classifiedas “slow metabolizers” or poor metabolizers”in contrast to “normal metabolizers.”When delayed biotransformation causes anexcessive rise in plasma levels, the incidenceoftoxiceffectsincreases,asevidencedbytheexample of the immunosuppressants azathioprineand mercaptopurine. Both substancesare converted to inactive methylthiopurinesby the enzyme thiopurinemethyltransferase (TMPT). About 10% ofpatients carry a genetic polymorphism thatleads to reduced TMPT activity and in < 1%enzyme activity is undetectable. As a resultof the diminished purine methylation, theplasma level of active drug rises and, hence,the risk of toxic bone marrow damage rises.To avoid unwanted toxic effects, TMPT activitycan be determined in erythrocytes beforetherapy with mercaptopurine is started. Infact, TMPT polymorphism is the first pharmacogenetictest to be introduced into clinicalpractice. In patients with complete TMPTdeficiency, the dose of azathioprine shouldbe reduced by 90%.Other genetic variants of drug metabolismmay have a similar impact: a defect of N-acetyltransferase 2 impedes the N-acetylationof diverse drugs, including isoniazid,hydralazine, sulfonamides, clonazapam, andnitrazepam. “Slow acetylators” (50–60% ofthe population) are more likely than “fastacetylators” to develop toxic reactions andneuropathy. A genetic defect of the cytochromeP450 isozyme CYP2D6 (originallydescribed as debrisoquine–sparteine polymorphism)occurs in ~ 8% of Europeans andresults in delayed elimination of a variousdrugs, including metoprolol, flecainide, nortriptyline,desipramine, and amitriptyline.Genetic variants of pharmacodynamics. Geneticpolymorphisms can also involve genesthat directly or indirectly mediate the effectsof drugs and, hence, alter pharmacodynamics(B). In these cases, the biological effects ofa drug are changed, rather than its plasmalevels. The genetic variants of β-adrenoceptorsprovide an example. For instance, hypertensivepatients carrying an arginine atamino acid position 389 of the β 1 -receptorrespond to metoprolol with a more markedfall in blood pressure than do patients carryinga glycine residue at this position. Sinceβ 1 -blockers have a relatively large margin ofsafety and, as a rule, dosage is determined bythe observed effect, genotyping of patientsprior to administration of β-blockers wouldappear unnecessary.Future research may be expected to identifynumerous genetic polymorphisms in thetarget molecules of drugs. A genetic examinationbefore the start of drug therapy willbe a sensible precaution, particularly whendrugs with a narrow margin of safety or along half-life are to be used on a fixed dosageregimen.

Pharmacogenetics 79A. Genetic variants of pharmacokineticsDrug in plasmaAzathioprine,mercaptopurineTPMTgeneThiopurinemethyltransferaseTPMTmutantTimeEffectDamage tobonemarrowToxic“Normal”metabolizer“Slow”metabolizerTimeB. Genetic variants of pharmacodynamicsDrug in plasmaβ 1 -ReceptorantagonistTimeβ 1 -Receptor geneTimeArg389Gly389Desired hypotensiveeffectHypotensive effecttoo smallHypotensive effect

80 Drug- independent Effects Placebo (A)A placebo is a dosage form devoid of anactive ingredient—a dummy medication. Administrationof a placebo may elicit the desiredeffect (relief of symptoms) or undesiredeffects that reflect a change in the patient’spsychological situation brought aboutby the therapeutic setting.Physicians may consciously or unconsciouslycommunicate to the patientwhether or not they are concerned aboutthe patient’s problem, or are certain aboutthe diagnosis and about the value of prescribedtherapeutic measures. In the care ofa physician who projects personal warmth,competence, and confidence, the patient inturnfeelscomfortandlessanxietyandoptimisticallyanticipates recovery. The physicalcondition determines the psychic dispositionand vice versa. Consider gravelywounded combatants in war, oblivious totheir injuries while fighting to survive, onlyto experience severe pain in the safety of thefield hospital; or the patient with a pepticulcer caused by emotional stress.Clinical trials. In the individual case, it maybe impossible to decide whether therapeuticsuccess is attributable to the drug or to thetherapeutic situation. What is therefore requiredis a comparison of the effects of adrug and of a placebo in matched groups ofpatients by means of statistical procedures,i. e., a placebo-controlled trial. For seriousdiseases, the comparison group has to betreated with the best therapy known to date,rather than a placebo. To be acceptable, thetest group receiving the new medicine mustshow a result superior to that of the comparisongroup.A prospective trial is planned in advance.A retrospective (case–control) study followspatients backward in time, the decision toanalyze being made only after completion oftherapy. Patients are randomly allotted totwo groups, namely, the placebo and theactive or test drug group. In a double-blindtrial, neither the patients nor the treatingphysicians know which patient is given drugand which placebo. Finally, a switch fromdrug to placebo and vice versa can be madein a successive phase of treatment, the crossovertrial. In this fashion, drug vs. placebocomparisons can be made not only betweentwo patient groups but also within eithergroup.Homeopathy (B) is an alternative method oftherapy, developed in the 1800s by SamuelHahnemann. His idea was this: when givenin normal (allopathic) dosage, a drug (in thesenseofmedicament)willproduceaconstellationof symptoms; however, in a patientwhose disease symptoms resemble justthis mosaic of symptoms, the same drug(simile principle) would effect a cure whengiven in a very low dosage (“potentiation”).The body’s self-healing powers were to beproperly activated only by minimal doses ofthe medicinal substance. The homeopath’stask is not to diagnose the causes of morbidity,but to find the drug with a “symptomprofile” most closely resembling that of thepatient’s illness. This requires in-depth probinginto the patient’s complaints. With theaccompaniment of a prescribed (“ritualized”)shaking procedure, the drug is thenhighlydiluted(in10-foldor100-foldseries).No direct action or effect on body functionscan be demonstrated for homeopathicmedicines. Therapeutic success is due to thesuggestive powers of the homeopath and theexpectancy of the patient. When an illness isstrongly influenced by emotional (psychic)factors and cannot be treated well by allopathicmeans, a case can be made in favor ofexploiting suggestion as a therapeutic tool.Homeopathy is one of several possible methodsof doing so.

Placebo 81A. Therapeutic effects resulting from physican’s power of suggestionConsciousandunconscioussignals:language,facialexpression,gesturesConsciousandunconsciousexpectationsWellbeingcomplaintsMindPlaceboEffect:– wanted– unwantedBodyPhysicianPatientB. Homeopathy: concepts and procedure“Similia similibus curentur”“Drug”Normal, allopathic dosesymptom profileDilution“effect reversal”Very low homeopathicdose eliminationof disease symptomscorresponding to allopathicsymptom “profile”“Potentiation”increase in efficacywith progressive dilutionHomeopathPatientProfile of disease symptomsSymptom“profile”“Drug diagnosis”StocksolutionDilution1 1 1 1 1 1 1 1 1 10 10 10 10 10 10 10 10 10Homeopathicremedy (“simile”)D91 1000 000 000

Systems PharmacologyDrugs Acting on the Sympathetic Nervous System 84Drugs Acting on the Parasympathetic Nervous System 102Nicotine 112Biogenic Amines 116Vasodilators 122Inhibitors of the Renin–Angiotensin–Aldosterone System 128Drugs Acting on Smooth Muscle 130Cardiac Drugs 132Antianemics 140Antithrombotics 144Plasma Volume Expanders 156Drugs Used in Hyperlipoproteinemias 158Diuretics 162Drugs for the Treatment of Peptic Ulcers 170Laxatives 174Antidiarrheals 180Drugs Acting on the Motor System 182Drugs for the Suppression of Pain 194Antipyretic Analgesics 196Nonsteroidal Anti-inflammatory Drugs 200Local Anesthetics 202Opioids 208General Anesthetics 214Psychopharmacologicals 220Hormones 238Antibacterial Drugs 268Antifungal Drugs 284Antiviral Drugs 286Antiparasitic Drugs 292Anticancer Drugs 298Immune Modulators 304Antidotes 308

84 Drugs Acting on the Sympathetic Nervous System Sympathetic Nervous SystemInthecourseofphylogenyanef cientcontrolsystem evolved that enabled the functionsof individual organs to be orchestratedin increasingly complex life forms and permittedrapid adaptation to changing environmentalconditions. This regulatory systemconsists of the central nervous system(CNS) (brain plus spinal cord) and two separatepathways for two-way communicationwith peripheral organs, namely, the somaticand the autonomic nervous systems. Thesomatic nervous system, comprising exteroceptiveand interoceptive afferents, specialsense organs, and motor efferents, serves toperceive external states and to target appropriatebody movement (sensory perception:threat † response: flight or attack). Theautonomic (vegetative) nervous system(ANS) together with the endocrine systemcontrols the milieu interieur. It adjusts internalorgan functions to the changing needs ofthe organism. Neural control permits veryquick adaptation, whereas the endocrinesystem provides for a long-term regulationof functional states. The ANS operates largelybeyond voluntary control: it functionsautonomously. Its central components residein the hypothalamus, brainstem, and spinalcord. The ANS also participates in the regulationof endocrine functions.The ANS has sympathetic and parasympathetic(p.102) branches. Both are made upof centrifugal (efferent) and centripetal (afferent)nerves. In many organs innervated byboth branches, respective activation of thesympathetic and parasympathetic inputevokes opposing responses.In various disease states (organ malfunctions),drugs are employed with the intentionof normalizing susceptible organ functions.To understand the biological effects ofsubstances capable of inhibiting or excitingsympathetic or parasympathetic nerves, onemust first envisage the functions subservedby the sympathetic and parasympathetic divisions(A, Response to sympathetic activation).In simplistic terms, activation of thesympathetic division can be considered ameansbywhichthebodyachievesastateof maximal work capacity as required infight-or-flight situations.In both cases, there is a need for vigorousactivity of skeletal musculature. To ensureadequate supply of oxygen and nutrients,blood flow in skeletal muscle is increased;cardiac rate and contractility are enhanced,resulting in a larger blood volume beingpumped into the circulation. Narrowing ofsplanchnic blood vessels diverts blood intovascular beds in muscle.Because digestion of food in the intestinaltract is dispensable and essentially counterproductive,the propulsion of intestinal contentsis slowed to the extent that peristalsisdiminishes and sphincters are narrowed.However, in order to increase nutrient supplyto heart and musculature, glucose fromtheliverandfreefattyacidsfromadiposetissue must be released into the blood. Thebronchi are dilated, enabling tidal volumeand alveolar oxygen uptake to be increased.Sweat glands are also innervated by sympatheticfibers (wet palms due to excitement);however, these are exceptional asregards their neurotransmitter (ACh, p.110).The lifestyles of modern humans are differentfrom those of our hominid ancestors,but biological functions have remained thesame: a “stress”-induced state of maximalwork capacity, albeit without energy-consumingmuscle activity.

Sympathetic Nervous System 85A. Response to sympathetic activationCNS:drivealertnessEyes:pupillary dilationSaliva:little, viscousBronchi:dilationSkin:perspiration(cholinergic)Heart:rateforceblood pressureFat tissue:lipolysisfatty acidliberationLiver:glycogenolysisglucose releaseBladder:sphincter tonedetrusor muscleGI tract:peristalsissphincter toneblood flowSkeletal muscle:blood flowglycogenolysis

86 Drugs Acting on the Sympathetic Nervous System Structure of the SympatheticNervous SystemThe sympathetic preganglionic neurons(first neurons) project from the intermediolateralcolumn of the spinal gray matter tothe paired paravertebral ganglionic chain lyingalongside the vertebral column and tounpaired prevertebral ganglia. Thesegangliarepresent sites of synaptic contact betweenpreganglionic axons (1st neurons) andnerve cells (2nd neurons or sympathocytes)that emit axons terminating at postganglionicsynapses (or contacts) on cells invarious end organs. In addition, there arepreganglionic neurons that project either toperipheral ganglia in end organs or to theadrenal medulla.Sympathetic transmitter substances.Whereas acetylcholine (see p.104) servesas the chemical transmitter at ganglionicsynapses between first and second neurons,norepinephrine (noradrenaline) isthe mediator at synapses of the second neuron(B). This second neuron does not synapsewith only a single cell in the effectororgan; rather it branches out, each branchmaking en passant contacts with severalcells. At these junctions the nerve axonsform enlargements (varicosities) resemblingbeads on a string. Thus, excitation ofthe neuron leads to activation of a largeraggregate of effector cells, although the actionof released norepinephrine may be confinedto the region of each junction. Excitationof preganglionic neurons innervatingthe adrenal medulla causes liberation of acetylcholine.This, in turn, elicits secretion ofepinephrine (adrenaline) into the blood, bywhich it is distributed to body tissues as ahormone (A). Adrenergic SynapseWithin the varicosities, norepinephrine isstored in small membrane-enclosed vesicles(granules, 0.05–0.2 µm in diameter). In theaxoplasm, norepinephrine is formed by stepwiseenzymatic synthesis from L-tyrosine,which is converted by tyrosine hydroxylaseto L-Dopa (see p.188). L-Dopainturnisdecarboxylatedto dopamine, which is taken upinto storage vesicles by the vesicular monoaminetransporter (VMAT). In the vesicle,dopamine is converted to norepinephrineby dopamine β-hydroxylase. In the adrenalmedulla, the major portion of norepinephrineundergoes enzymatic methylation toepinephrine.When stimulated electrically, the sympatheticnerve discharges the contents of partof its vesicles, including norepinephrine, intothe extracellular space. Liberated norepinephrinereacts with adrenoceptors locatedpostjunctionally on the membrane ofeffector cells or prejunctionally on the membraneof varicosities. Activation of pre-synapticα 2 -receptors inhibits norepinephrinerelease. Through this negative feedback, releasecan be regulated.The effect of released norepinephrinewanes quickly, because ~ 90% is transportedback into the axoplasm by a specific transportmechanism (norepinephrine transporter,NAT) and then into storage vesicles by thevesicular transporter (neuronal reuptake).The NAT can be inhibited by tricyclic antidepressantsand cocaine. Moreover, norepinephrineis taken up by transporters intothe effector cells (extraneuronal monoaminetransporter, EMT). Part of the norepinephrineundergoing reuptake is enzymaticallyinactivated to normetanephrine via catecholamineO-methyltransferase (COMT,present in the cytoplasm of postjunctionalcells) and to dihydroxymandelic acid viamonoamine oxidase (MAO, present in mitochondriaof nerve cells and postjunctionalcells).The liver is richly endowed with COMTand MAO; it therefore contributes significantlyto the degradation of circulating norepinephrineand epinephrine. The end productof the combined actions of MAO andCOMT is vanillylmandelic acid.

Structure of the Sympathetic Nervous System 87A. Epinephrine as hormone, norepinephrine as transmitterPsychicstressor physicalstressFirst neuronFirst neuronAdrenalmedullaSecond neuronEpinephrineNorepinephrineB. Second neuron of sympathetic system, varicosity, norepinephrine releaseNorepinephrineEpinephrineSynthesisTyrosineL-DopaDopamineSympathetic nerveα 1G q/11Adrenal chromaffin cellVMATNorepinephrineVMAT–G iα 2α 2G iReceptorsTransport, degradationβ 1G sMAONATβ 2G sEMTCOMTMAOEffector cell

88 Drugs Acting on the Sympathetic Nervous System Adrenoceptor Subtypes andCatecholamine ActionsThe biological effects of epinephrine andnorepinephrine are mediated by nine differentadrenoceptors (α 1A,B,D , α 2A,B,C , β 1 , β 2 , β 3 ).To date, only the classification into α 1 , α 2 ,β 1 and β 2 receptors has therapeutic relevance. Smooth Muscle EffectsThe opposing effects on smooth muscle (A)of α- andβ-adrenoceptor activation are dueto differences in signal transduction. α 1 -Receptorstimulation leads to intracellular releaseof Ca 2+ via activation of the inositoltrisphosphate (IP 3 ) pathway. In concert withthe protein calmodulin, Ca 2+ can activatemyosin kinase, leading to a rise in tonus viaphosphorylation of the contractile proteinmyosin († vasoconstriction). α 2 -Adrenoceptorscan also elicit a contraction of smoothmuscle cells by activating phospholipase C(PLC) via the βγ-subunits of G 1 proteins.cAMP inhibits activation of myosin kinase.Via stimulatory G-proteins (G s ), β 2 -receptorsmediateanincreaseincAMPproduction(†vasodilation).Vasoconstriction induced by local applicationof α-sympathomimetics can be employedin infiltration anesthesia (p. 204) orfor nasal decongestion (naphazoline, tetrahydrozoline,xylometazoline; p. 94, 336,338). Systemically administered epinephrineis important in the treatment of anaphylacticshock and cardiac arrest.Bronchodilation. β 2 -Adrenoceptor-mediatedbronchodilation plays an essential partin the treatment of bronchial asthma andchronic obstructive lung disease (p. 340).For this purpose, β 2 -agonists are usually givenby inhalation; preferred agents beingthose with low oral bioavailability and lowrisk of systemic unwanted effects (e. g., fenoterol,salbutamol, terbutaline).Tocolysis. The uterine relaxant effect of β 2 -adrenoceptor agonists, such as fenoterol, canbe used to prevent premature labor. β 2 -Vasodilationin the mother with an imminentdrop in systemic blood pressure results inreflex tachycardia, which is also due in partto the β 1 -stimulant action of these drugs. CardiostimulationBy stimulating β-receptors, and hence cAMPproduction, catecholamines augment allheart functions including systolic force, velocityof myocyte shortening, sinoatrial rate,conduction velocity, and excitability. In pacemakerfibers, cAMP-gated channels (“pacemakerchannels”) are activated, whereby diastolicdepolarization is hastened and thefiring threshold for the action potential isreached sooner (B). cAMP activates proteinkinase A, which phosphorylates differentCa 2+ transport proteins. In this way, contractionof heart muscle cells is accelerated, asmore Ca 2+ enters the cell from the extracellularspace via L-type Ca 2+ channels and releaseof Ca 2+ from the sarcoplasmic reticulum(via ryanodine receptors, RyR) is augmented.Faster relaxation of heart musclecells is effected by phosphorylation of troponinand phospholamban.In acute heart failure or cardiac arrest, β-mimetics are used as a short-term emergencymeasure; in chronic failure they arenot indicated. Metabolic EffectsVia cAMP, β 2 -receptors mediate increasedconversion of glycogen to glucose (glycogenolysis)in both liver and skeletal muscle.From the liver, glucose is released into theblood. In adipose tissue, triglycerides are hydrolyzedto fatty acids (lipolysis mediated byβ 2 -andβ 3 -receptors), which then enter theblood.

+Adrenoceptor Subtypes and Catecholamine Actions 89A. Effects of catecholamines on vascular smooth muscleRelaxationContractionβ 2G sαAd-cyclaseα 1G qαPhospholipase Cα 2βγG icAMPInhibitionIP 3Ca 2+ /CalmodulinMyosin-KinaseMyosinMyosin- PB. Cardiac effects of catecholaminesCa channelPacemakerchannelsβcAMPG sProteinkinase AAd-cyclasePhosphorylationPRyRPCa 2+PPCa 2+ TroponinCa-ATPasePPhospholambanPositive chronotropicPositive inotropicC. Metabolic effects of catecholaminesβG sAd-cyclasecAMPGlycogenolysisGlycogenolysisGlucoseFatty acidsLipolysisGlucose

90 Drugs Acting on the Sympathetic Nervous System Structure–Activity Relationshipsof SympathomimeticsOwing to its equally high af nity for all α-and β-receptors, epinephrine does not permitselective activation of a particular receptorsubtype. Like most catecholamines, it isalso unsuitable for oral administration (catecholeis a trivial name for o-hydroxyphenol).Norepinephrine differs from epinephrineby its high af nity for α-receptors andlow af nity for β 2 -receptors. The converseholds true for the synthetic substance, isoproterenol(isoprenaline) (A).Norepinephrine † α, β 1Epinephrine † α, β 1 β 2Isoproterenol † β 1 , β 2Knowledge of structure–activity relationshipshas permitted the synthesis of sympathomimeticsthat display a high degree ofselectivity at adrenoceptor subtypes.Direct-acting sympathomimetics (i. e.adrenoceptor agonists) typically share aphenlethylamine structure. The side chain β-hydroxyl group confers af nity for α- andβreceptors.Substitution on the amino groupreduces af nity for α-receptors, but increasesit for β-receptors (exception: α-agonistphenylephrine), with optimal af nitybeing seen after the introduction of onlyone isopropyl group. Increasing the bulk ofamino substituents favors af nity for β 2 -receptors(e. g., fenoterol, salbutamol). Bothhydroxyl groups on the aromatic nucleuscontribute to af nity; high activity at α-receptorsis associated with hydroxyl groups atthe 3 and 4 positions. Af nity for β-receptorsis preserved in congeners bearing hydroxylgroups at positions 3 and 5 (orciprenaline,terbutaline, fenoterol).The hydroxyl groups of catecholaminesare responsible for the very low lipophilicityof these substances. Polarity is increased atphysiological pH owing to protonation of theamino group. Deletion of one or all hydroxylgroups improves the membrane penetrabilityat the intestinal mucosa–blood barrierand the blood–brain barrier. Accordingly,these noncatecholamine congeners can begiven orally and can exert CNS actions; however,this structural change entails a loss inaf nity.Absence of one or both aromatic hydroxylgroups is associated with an increase in indirectsympathomimetic activity, denotingthe ability of a substance to release norepinephrinefrom its neuronal stores withoutexerting an agonist action at the adrenoceptor(p. 92).A change in position of aromatic hydroxylgroups (e. g., in orciprenaline, fenoterol, orterbutaline) or their substitution (e. g., salbutamol)protects against inactivation by COMT(p. 87). Introduction of a small alkyl residueat the carbon atom adjacent to the aminogroup (ephedrine, methamphetamine) confersresistance to degradation by MAO (p. 87);replacement on the amino groups of themethyl residue with larger substituents(e. g., ethyl in etilefrine) impedes deaminationby MAO. Accordingly, the congeners areless subject to presystemic inactivation.Since structural requirements for high affinityon the one hand and oral applicabilityon the other do not match, choosing a sympathomimeticis a matter of compromise. Ifthe high af nity of epinephrine is to be exploited,absorbability from the intestinemust be foregone (epinephrine, isoprenaline).If good bioavailability with oral administrationis desired, losses in receptor af nitymust be accepted (etilefrine).

Structure–Activity Relationships of Sympathomimetics 91A. Interaction between epinephrine and the β 2 -adrenoceptorβ 2 Adrenoceptor6Phe 290Asn 293Ser20712PheAspSerAsn3 4 5 6 75HOHO CHCH 2+NH 2 CH 3Asp11334EpinephrineSer204Ser203OHEpinephrineB. Structure–activity relationship of epinephrineCatecholamineO-methyltransferase(COMT)Lack of penetrabilitythrough membranebarriersHOHO CHCH 2+NH 2CH 3OHMetabolicreaction sites(poor enteral absorbabilityand CNS penetrability)Monoamine oxidase(MAO)C . Direct sympathomimeticsReceptor subtype selectivity of direct sympathomimeticsα 1 α 2 β 1 β 2EpinephrineNorepinephrineDobutaminePhenylephrineClonidineBrimonidineNaphazolineOxymetazolineXylometazolineFenoterolSalbutamolTerbutalineSalmeterolFormoterol

92 Drugs Acting on the Sympathetic Nervous System Indirect SympathomimeticsRaising the concentration of norepinephrinein the synaptic space intensifies the stimulationof adrenoceptors. In principle, this canbe achieved by: Promoting the neuronal release of norepinephrine Inhibiting processes operating to lower itsintrasynaptic concentration, in particularneuronal reuptake with subsequent vesicularstorage or breakdown by monoamineoxidase (MAO)Chemically altered derivatives differ fromnorepinephrine with regard to the relativeaf nity for these systems and affect thesefunctions differentially.Inhibitors of MAO (A) block enzyme locatedin mitochondria, which serves to scavengeaxoplasmic free norepinephrine (NE). Inhibitionof the enzyme causes free NE concentrationsto rise. Likewise, dopamine catabolismis impaired, making more of it availablefor NE synthesis. In the CNS, inhibition ofMAO affects neuronal storage not only ofNE but also of dopamine and serotonin. Thefunctional sequelae of these changes includea general increase in psychomotor drive(thymeretic effect) and mood elevation (A).Moclobemide reversibly inhibits MAO A and isused as an antidepressant. The MAO B inhibitorselegiline (deprenyl) retards the catabolismofdopamine,aneffectusedinthetreatmentof Parkinsonism (p.188).Indirect sympathomimetics (B) in the narrowsense comprise amphetamine-like substancesand cocaine. Cocaine blocks the norepinephrinetransporter (NAT), besides actingas a local anesthetic. Amphetamine istaken up into varicosities via NAT, and fromthere into storage vesicles (via the vesicularmonoamine transporter), where it displacesNE into the cytosol. In addition, amphetamineblocks MAO, allowing cytosolic NEconcentration to rise unimpeded. This inducesthe plasmalemmal NAT to transportNE in the opposite direction, that is, toliberate it into the extracellular space. Thus,amphetamine promotes a nonexocytoticrelease of NE. The effectiveness of suchindirect sympathomimetics diminishesquickly or disappears (tachyphylaxis) withrepeated administration.Indirect sympathomimetics can penetratethe blood–brain barrier and evoke such CNSeffects as a feeling of well-being, enhancedphysical activity and mood (euphoria), anddecreased sense of hunger or fatigue. Subsequently,the user may feel tired and depressed.These after-effects are partly responsiblefortheurgetoreadministerthedrug (high abuse potential). To prevent theirmisuse, these substances are subject to governmentalregulations (e. g., Food and DrugsAct, Canada; Controlled Drugs Act, USA) restrictingtheir prescription and distribution.When amphetamine-like substances aremisused to enhance athletic performance(“doping”), there is a risk of dangerous physicaloverexertion. Because of the absence of asenseoffatigue,adruggedathletemaybeable to mobilize ultimate energy reserves. Inextreme situations, cardiovascular failuremay result (B).Closely related chemically to amphetamineare the so-called appetite suppressantsor anorexiants (p. 329). These may alsocausedependenceandtheirtherapeuticvalueand safety are questionable. Some ofthese (D-norpseudoephedrine, amfepramone)have been withdrawn.Sibutramine inhibits neuronal reuptake ofNE and serotonin (similarly to antidepressants,p. 226). It diminishes appetite and isclassified as an antiobesity agent (p. 328).

MAOMAOIndirect Sympathomimetics 93A. Monoamine oxidase inhibitorInhibitor: Moclobemide MAO-ASelegiline MAO-BNorepinephrineMAOMAONorepinephrinetransport systemEffector organB. Indirect sympathomimetics with central stimulant activityB. and abuse potentialH2C CH NH 2CH 3Amphetamine§§ControlledSubstancesAct regulatesuse ofcocaine andamphetaminePain stimulusH3CNCocaineLocalanestheticeffectOC O CH3OCO“Doping”Runner-up

94 Drugs Acting on the Sympathetic Nervous System α- Sympathomimetics,α-Sympatholyticsα-Sympathomimetics can be used systemicallyincertaintypesofhypotension(p.324)and locally for nasal or conjunctival decongestion(p. 336) or as adjuncts in infiltrationanesthesia (p. 204) for the purpose of delayingthe removal of local anesthetic. Withlocal use, underperfusion of the vasoconstrictedarea results in a lack of oxygen (A).In the extreme case, local hypoxia can lead totissue necrosis. The appendages (e. g., digits,toes, ears) are particularly vulnerable in thisregard, thus precluding vasoconstrictor adjunctsin infiltration anesthesia at these sites.Vasoconstriction induced by an α-sympathomimeticis followed by a phase of enhancedblood flow (reactive hyperemia, A).This reaction can be observed after applyingα-sympathomimetics (naphazoline, tetrahydrozoline,xylometazoline) to the nasal mucosa.Initially, vasoconstriction reduces mucosalblood flow and, hence, capillary pressure.Fluid exuded into the interstitial spaceis drained through the veins, thus shrinkingthe nasal mucosa. Owing to the reducedsupply of fluid, secretion of nasal mucus decreases.In coryza, nasal patency is restored.However, after vasoconstriction subsides, reactivehyperemia causes renewed exudationof plasma fluid into the interstitial space, thenose is “stuffy” again, and the patient feels aneed to reapply decongestant. In this way, avicious cycle threatens. Besides reboundcongestion, persistent use of a decongestantentails the risk of atrophic damage caused bythe prolonged hypoxia of the nasal mucosa.α-Sympatholytics (B). The interaction ofnorepinephrine with α-adrenoceptors canbe inhibited by α-sympatholytics (α-adrenoceptorantagonists, α-blockers). This inhibitioncan be put to therapeutic use in antihypertensivetreatment (vasodilation † peripheralresistance ø, blood pressure ø,p.122). The first α-sympatholytics blockedthe action of norepinephrine not only atpostsynaptic α 1 -adrenoceptors but also atpresynaptic α 2 -receptors (nonselective α-blockers, e. g., phenoxybenzamine, phentolamine).Presynaptic α 2 -adrenoceptors functionlike sensors that enable norepinephrine concentrationoutside the axolemma to bemonitored, thus regulating its release via alocal feedback mechanism. When presynapticα 2 -receptors are stimulated, furtherrelease of norepinephrine is inhibited. Conversely,their blockade leads to uncontrolledrelease of norepinephrine with an overt enhancementof sympathetic effects at β 1 -adrenoceptor-mediated myocardial neuroeffectorjunctions, resulting in tachycardia andtachyarrhythmia.Selective α 1 -Sympatholytics (α 1 -blockers,e. g., prazosin, or the longer-acting terazosinand doxazosin) do not disinhibit norepinephrinerelease.α 1 -Blockers may be used in hypertension(p. 315). Because they prevent reflex vasoconstriction,they are likely to cause posturalhypotension with pooling of blood in lowerlimb capacitance veins during change fromthesupinetotheerectposition(orthostaticcollapse, p. 324).In benign hyperplasia of the prostate, α 1 -blockers (terazosin, alfuzosin, tamsulosin)may serve to lower tonus of smooth musculaturein the prostatic region and therebyimprove micturition. Tamsulosin shows enhancedaf nity for the α 1A subtype; the riskof hypotension is therefore supposedly diminished.

α-Sympathomimetics, α-Sympatholytics 95A. Reactive hyperemia due to α-sympathomimetics, e.g., following decongestionof nasal mucosaBeforeα-AgonistAfterO 2supply = O 2demandNaphazolinNCH 2NHO 2supply < O 2demandO 2supply < O 2demandB. Autoinhibition of norepinephrine release and α-sympatholyticsα 2 α 2 α 2NENonselectiveα-blockerα 1 -blockerα 1 β 1 α 1 β 1 α 1β 1C. Indications for α 1 -sympatholyticsHigh blood pressureα 1 -blockere.g., terazosinBenignprostatic hyperplasiaONH 3 CONNOH 3 CONH 2NResistancearteriesInhibition ofα 1 -adrenericstimulation ofsmooth muscleNeck of bladder,prostate

96 Drugs Acting on the Sympathetic Nervous System β-Sympatholytics (β-Blockers)β-Sympatholytics are antagonists of norepinephrineand epinephrine at β-adrenoceptors;they lack af nity for α-receptors.Therapeutic effects. β-Blockers protect theheart from the oxygen-wasting effect ofsympathetic inotropism by blocking cardiacβ-receptors; thus, cardiac work can no longerbe augmented above basal levels (theheart is “coasting”). This effect is utilizedprophylactically in angina pectoris to preventmyocardial stress that could trigger an ischemicattack (p. 316). β-Blockers also serve tolower cardiac rate (sinus tachycardia, p.136)and protect the failing heart against excessivesympathetic drive (p. 322). β-Blockers lowerelevated blood pressure. The mechanismunderlying their antihypertensive action isunclear. Applied topically to the eye, β-blockers are used in the management ofglaucoma; they lower production of aqueoushumor (p. 346).Undesired effects. β-Blockers are used veryfrequently and are mostly well tolerated ifrisk constellations are taken into account.The hazards of treatment with β-blockersbecome apparent particularly when continuousactivation of β-receptors is needed inorder to maintain the function of an organ.Congestive heart failure. For a long time, β-blockers were considered generally contraindicatedin heart failure. Increased releaseof norepinephrine gives rise to an increase inheart rate and systolic muscle tension, enablingcardiac output to be maintained despiteprogressive cardiac disease. Whensympathetic drive is eliminated during β-receptor-blockade, stroke volume and cardiacrate decline, a latent myocardial insuf -ciency is unmasked, and overt insuf ciencyis exacerbated. Sympathoactivation not onlyhelps for some time to maintain pump functionin chronic congestive failure but itselfalso contributes to the progression of insufficiency:triggering of arrhythmias, increasedO 2 -consumption, enhanced cardiachypertrophy (A).On the other hand, convincing clinical evidencedemonstrates that, under appropriateconditions (prior testing of tolerability, lowdosage), β-blockers are able to improveprognosis in congestive heart failure. Protectionagainst heart rate increases and arrhythmiasmay be important underlying factors.Bradycardia, AV block. Elimination of sympatheticdrive can lead to a marked fall incardiacrateaswellastodisordersofimpulseconduction from the atria to the ventricles.Bronchial asthma. Increasedsympatheticactivity prevents bronchospasm in patientsdisposed to paroxysmal constriction of thebronchial tree (bronchial asthma, bronchitisin smokers). In this condition, β 2 -receptorblockade may precipitate acute respiratorydistress (B).Hypoglycemia in diabetes mellitus. Whentreatment with insulin or oral hypoglycemicsin the diabetic patient lowers bloodglucose below a critical level, epinephrineis released, which then stimulates hepaticglucose release via activation of β 2 -receptors.β-Blockerssuppressthiscounterregulation,besides masking other epinephrinemediatedwarning signs of imminent hypoglycemia,such as tachycardia and anxiety.The danger of hypoglycemic shock is thereforeaggravated.Altered vascular responses: Whenβ 2 -receptorsare blocked, the vasodilating effectof epinephrine is abolished, leaving the α-receptor-mediated vasoconstriction unaffected:“cold hands and feet.”β-Blockers exert an “anxiolytic” actionthat may be due to the suppression of somaticresponses (palpitations; trembling) toepinephrine release that is induced by emotionalstress; in turn, these responses wouldexacerbate “anxiety” or “stage-fright.” Becausealertness is not impaired by β-blockers,these agents are occasionally taken byorators and musicians before a major performance(C).

β-Sympatholytics (β-Blockers) 97A. β-Sympatholytics: effect on cardiac functionβ-Blockerblocksreceptorβ-Receptor100 mlStrokevolume1 secβ 1 -Stimulationβ 1 -BlockadeHeart is“coasting“ExercisecapacityB. β-Sympatholytics: effect on bronchial and vascular toneHealthyAsthmaticαα β 2 α β 2β 2 -Blockadeβ 2 -Stimulationβ 2 -Blockadeβ 2 -StimulationC. “Anxiolytic” effect of β-sympatholyticsβ-Blockade

98 Drugs Acting on the Sympathetic Nervous System Types of β-BlockersThebasicstructuresharedbymostβ-sympatholytics(p.11) is the side chain of β-sympathomimetics(cf. isoproterenol with the β-blockers propranolol, pindolol, atenolol). Asa rule, this basic structure is linked to anaromatic nucleus by a methylene and oxygenbridge. The side chain C-atom bearingthe hydroxyl group forms the chiral center.With some exceptions (e. g., timolol, penbutolol),all β-sympatholytics exist as racemates(p. 62).Compared with the dextrorotatory form,the levorotatory enantiomer possesses agreater than 100-fold higher af nity for theβ-receptor, and is, therefore, practicallyalone in contributing to the β-blocking effectoftheracemate.Thesidechainandsubstituentson the amino group critically affect affinityfor β-receptors, whereas the aromaticnucleus determines whether the compoundpossesses intrinsic sympathomimetic activity(ISA),thatis,actsasapartial agonistor partial antagonist. A partial agonism orantagonism is present when the intrinsicactivity of a drug is so small that, even withfull occupancy of all available receptors, theeffect obtained is only a fraction of that elicitedby a full agonist. In the presence of apartial agonist (e. g., pindolol), the ability of afull agonist (e. g., isoprenaline) to elicit amaximal effect would be attenuated, becausebinding of the full agonist is impeded.Partial agonists thus also act antagonistically,although they maintain a certain degree ofreceptor stimulation. It remains an openquestion whether ISA confers a therapeuticadvantage on a β-blocker. At any rate, patientswith congestive heart failure shouldbe treated with β-blockers devoid of ISA.As cationic amphiphilic drugs, β-blockerscan exert a membrane-stabilizing effect,asevidenced by the ability of the more lipophiliccongeners to inhibit Na + channel functionand impulse conduction in cardiac tissues.At the usual therapeutic dosage, thehigh concentration required for these effectswill not be reached.Some β-sympatholytics possess higher affinityfor cardiac β 1 -receptors than for β 2 -receptors and thus display cardioselectivity(e. g., metoprolol, acebutolol, atenolol,bisoprolol, β 1 : β 2 selectivity 20–50-fold).None of these blockers is suf ciently selectiveto permit use in patients with bronchialasthma or diabetes mellitus (p. 96).The chemical structure of β-blockers alsodetermines their pharmacokinetic properties.Except for hydrophilic representatives(atenolol), β-sympatholytics are completelyabsorbed from the intestines and subsequentlyundergo presystemic eliminationto a major extent (A).All the above differences are of little clinicalimportance. The abundance of commerciallyavailable congeners would thus appearall the more curious (B). Propranolol was thefirst β-blocker to be introduced into therapyin 1965. Thirty years later, about 20 differentcongeners were marketed in different countries(analogue preparations). This questionabledevelopment is unfortunately typical ofany drug group that combines therapeuticwith commercial success, in addition to havinga relatively fixed active structure. Variationof the molecule will create a new patentablechemical, not necessarily a drug witha novel action. Moreover, a drug no longerprotected by patent is offered as a generic bydifferent manufacturers under dozens of differentproprietary names. Propranolol alonehas been marketed in 2003 by 12 manufacturersin Germany under nine differentnames. In the USA, the drug is at presentoffered by ~ 40 manufacturers, mostly underits generic designation, and in Canada by sixmanufacturers, mostly under a hyphenatedbrand name containing its INN with a prefix.

Types of β-Blockers 99A. Types of β-sympatholyticsIsoproterenol Pindolol Propranolol Atenolol OHOHCH 2 C NH 2NHO+ OHC CH 2 NH 2CH 2OH HC CH 3HC CH 2+NH 2CH 3OH HC CH 3CH 3OCH 2+HC CH 2 NH 2OH HC CH 3CH 3OCH 2+HC CH 2 NH 2OH HC CH 3CH 3Agonistββ 1β 1β 1β 1β 1 2β 2 β 2 βCardio-2 β 2 selectivityβ-Receptor β-Receptor β-ReceptorpartialAntagonistEffectAgonistNo effectAntagonistSodium channel“membraneNa + Na +Na +blockadestabilizing”Presystemic100%50%B. Avalanche-like increase in commercially available β-sympatholytics1965 1970AlprenololPropranololOxprenololPindololBupranolol*Year introducedTertatolol NebivololCarvedilolEsmololBopindololBisoprololCeliprololBetaxololBefunololCarteololMepindololPenbutololCarazololNadololAcebutololBunitrolol*AtenololMetipranolMetoprololTimololSotalolTalinolol*No longer available commercially1975 1980 1985 1990eliminationAs of 20001995 2000

100 Drugs Acting on the Sympathetic Nervous System AntiadrenergicsAntiadrenergics are drugs capable of loweringtransmitter output from sympatheticneurons, i. e., the “sympathetic tone.” Theiraction is hypotensive (indication: hypertension,p. 314); however, being poorly tolerated,they enjoy only limited therapeuticuse.Clonidine is an α 2 -agonist whose highlipophilicity (dichlorophenyl ring) permitsrapid penetration through the blood–brainbarrier. The activation of postsynaptic α 2 -receptorsdampens the activity of vasomotorneurons in the medulla oblongata, resultingin a resetting of systemic arterial pressure ata lower level. In addition, activation of presynapticα 2 -receptors in the periphery(pp. 86, 94) leads to a decreased release ofboth norepinephrine (NE) and acetylcholine.Beside its main use as an antihypertensive,clonidine is also employed to manage withdrawalreactions in subjects being treatedfor opioid addiction.Side effects. Lassitude, dry mouth; reboundhypertension after abrupt cessation of clonidinetherapy.Methyldopa (dopa = dihydroxyphenylalanine),being an amino acid, is transportedacross the blood–brain barrier, decarboxylatedin the brain to α-methyldopamine,andthenhydroxylatedtoα-methyl-NE. Thedecarboxylation of methyldopa competes fora portion of the available enzymatic activityso that the rate of conversion of L-dopa to NE(via dopamine) is decreased. The false transmitterα-methyl-NE can be stored; however,unlike the endogenous mediator, it has ahigher af nity for α 2 - than for α 1 -receptorsand therefore produces effects similar tothose of clonidine. The same events takeplace in peripheral adrenergic neurons.Adverse effects. Fatigue,orthostatichypotension,extrapyramidal Parkinson-likesymptoms (p.188), cutaneous reactions,hepatic damage, immune-hemolytic anemia.Reserpine, analkaloidfromtheclimbingshrub Rauwolfia serpentina (native to theIndian subcontinent), abolishes the vesicularstorage of biogenic amines (NE, dopamine[DA], serotonin [5-HT]) by inhibiting the(nonselective) vesicular monoamine transporterlocated in the membrane of storagevesicles. Since the monoamines are not takenup into vesicles, they become subject tocatabolism by MAO; the amount of NE releasedper nerve impulse is decreased. To alesser degree, release of epinephrine fromthe adrenal medulla is also impaired. Athigher doses, there is irreversible damageto storage vesicles (“pharmacological sympathectomy”),days to weeks being requiredfor their re-synthesis. Reserpine readily entersthe brain, where it also impairs vesicularstorage of biogenic amines.Adverse effects. Disorders of extrapyramidalmotor function with development ofpseudo-parkinsonism (p.188), sedation, depression,stuffy nose, impaired libido, impotence;and increased appetite.Guanethidine possesses high af nity forthe axolemmal and vesicular amine transporters.It is stored instead of NE, but is unableto mimic functions of the latter. In addition,it stabilizes the axonal membrane,thereby impeding the propagation of impulsesinto the sympathetic nerve terminals.Storageandreleaseofepinephrinefromtheadrenal medulla are not affected, owing tothe absence of a reuptake process. The drugdoes not cross the blood–brain barrier.Adverse effects. Cardiovascular crises are apossible risk: emotional stress of the patientmay cause sympathoadrenal activation withepinephrine release from the adrenal medulla.The resulting rise in blood pressurecanbeallthemoremarkedaspersistentdepression of sympathetic nerve activity inducessupersensitivity of effector organs tocirculating catecholamines.

Antiadrenergics 101A. Inhibitors of sympathetic toneSuppressionof sympatheticimpulses invasomotorcenterTyrosineDOPADopamineNAFalse transmitterStimulation of central α 2 -receptorsα-Methyl-NAin brainInhibitionof DOPAdecarboxylaseα-Methyl-NAClClonidineOHHOα-MethyldopaClNNH NHCH 3αCH 2 C NH 2COOHNA5HTDACNSInhibition ofbiogenic aminestoragePeripheralsympathetic activityH 3 COReserpineNNHH 3 CO COOCH 3O C OH 3 CO OCH 3OCH 3No epinephrine fromadrenal medullaVaricosityInhibition of impulsepropagation inperipheral sympatheticnervesActive uptake andstorage instead ofnorepinephrine;not a transmitterNHN CH 2 CH 2 NH CNH 2GuanethidineRelease from adrenal medullaunaffectedVaricosity

102 Drugs Acting on the Parasympathetic Nervous System Parasympathetic Nervous SystemResponses to activation of the parasympatheticsystem. Parasympathetic nerves regulateprocesses connected with energy assimilation(food intake, digestion, absorption)and storage. These processes operatewhen the body is at rest, allowing a decreasedtidal volume (increased bronchomotortone) and decreased cardiac activity. Secretionof saliva and intestinal fluids promotesthe digestion of food stuffs; transportof intestinal contents is speeded up becauseof enhanced peristaltic activity and loweredtone of sphincteric muscles. To empty theurinary bladder (micturition), wall tensionis increased by detrusor activation with aconcurrent relaxation of sphincter tonus.Activation of ocular parasympathetic fibers(see below) results in narrowing of thepupil and increased curvature of the lens,enabling near objects to be brought into focus(accommodation).Anatomy of the parasympathetic system.The cell bodies of parasympathetic preganglionicneurons are located in the brainstemand the sacral spinal cord. Parasympatheticoutflow is channeled from the brainstem (1)through the third cranial nerve (oculomotorn.) via the ciliary ganglion to the eye; (2)through the seventh cranial nerve (facial n.)via the pterygopalatine and submaxillaryganglia to lachrymal glands and salivaryglands (sublingual, submandibular), respectively;(3) through the ninth cranial nerve(glossopharyngeal n.) via the otic ganglionto the parotid gland; and (4) via the tenthcranial nerve (vagus n.) to intramural gangliain thoracic and abdominal viscera. Approximately75% of all parasympathetic fibers arecontained within the vagus nerve. The neuronsof the sacral division innervate the distalcolon, rectum, bladder, the distal ureters,and the external genitalia.Acetylcholine (ACh) as a transmitter. AChserves as mediator at terminals of all postganglionicparasympathetic fibers, in additionto fulfilling its transmitter role at ganglionicsynapses within both the sympatheticand parasympathetic divisions andthe motor end plates on striated muscle(p.182). However, different types of receptorsare present at these synaptic junctions(see table). The existence of distinct cholinoceptorsat different cholinergic synapses allowsselective pharmacological interventions.Localization of Receptors Agonist Antagonist Receptor TypeTarget tissues of 2nd parasympatheticneurons; e. g.,smooth muscle, glandsAChMuscarineAtropineMuscarinic (M) cholinoceptor;G-protein-coupledreceptor protein with 7transmembrane domainsSympathetic & parasympatheticgangliocytesMotor end plate in skeletalmuscleAChNicotineAChNicotineTrimethaphand-Tubocurarine¸ÔÔ˝ÔÔ˛Ganglionic typeNicotinic (N) cholinoceptorligand-gated cationchannelMuscle type

Parasympathetic Nervous System 103A. Responses to parasympathetic activationEyes:Accommodationfor near vision,miosisSaliva:copious, liquidBronchi:constrictionsecretionHeart:rateblood pressureGI tract:secretionperistaltissphincter toneBladder:sphincter tonedetrusor

104 Drugs Acting on the Parasympathetic Nervous System Cholinergic SynapseAcetylcholine (ACh) is the transmitter atpostganglionic synapses of parasympatheticnerve endings. It is highly concentrated insynaptic storage vesicles densely present inthe axoplasm of the presynaptic terminal.ACh is formed from choline and activatedacetate (acetylcoenzyme A), a reaction catalyzedby the cytosolic enzyme choline acetyltransferase.The highly polar choline istaken up into the axoplasm by the specificcholine-transporter (CHT) localized to membranesof cholinergic axons terminals and asubset of storage vesicles. During persistentor intensive stimulation, the CHT ensuresthat ACh synthesis and release are sustained.The newly formed ACh is loaded into storagevesicles by the vesicular ACh transporter(VAChT). The mechanism of transmitter releaseisnotknowninfulldetail.Thevesiclesare anchored via the protein synapsin to thecytoskeletal network. This arrangement permitsclustering of vesicles near the presynapticmembrane while preventing fusionwith it. During activation of the nerve membrane,Ca 2+ is thought to enter the axoplasmthrough voltage-gated channels and to activateprotein kinases that phosphorylate synapsin.As a result, vesicles close to the membraneare detached from their anchoring andallowed to fuse with the presynaptic membrane.During fusion, vesicles discharge theircontents into the synaptic gap and simultaneouslyinsert CHT into the plasma membrane.ACh quickly diffuses through the synapticgap (the acetylcholine molecule is alittle longer than 0.5 nm; the synaptic gapas narrow as 20–30 nm). At the postsynapticeffector cell membrane, ACh reacts with itsreceptors. As these receptors can also beactivated by the alkaloid muscarine, theyare referred to as muscarinic (M-) ACh receptors.In contrast, at ganglionic and motorend plate (p.182) ACh receptors, the actionof ACh is mimicked by nicotine and, hence,mediated by nicotinic ACh receptors.Released ACh is rapidly hydrolyzed andinactivated by a specific acetylcholinesterase,localized to pre- and postjunctionalmembranes (basal lamina of motor endplates), or by a less specific serum cholinesterase(butyrylcholinesterase), a soluble enzymepresent in serum and interstitial fluid.M-ACh receptors can be divided into fivesubtypes according to their molecular structure,signal transduction, and ligand af nity.Here, the M 1, M 2 and M 3 receptor subtypesare considered. M 1 receptors are present onnerve cells, e. g., in ganglia, where they enhanceimpulse transmission from preganglionicaxon terminals to ganglion cells. M 2receptors mediate acetylcholine effects onthe heart: opening of K + channels leads toslowing of diastolic depolarization in sinoatrialpacemaker cells and a decrease inheart rate. M 3 receptors play a role in theregulation of smooth muscle tone, e. g., inthe gut and bronchi, where their activationcauses stimulation of phospholipase C,membrane depolarization, and increase inmuscle tone. M 3 receptors are also found inglandular epithelia, which similarly respondwith activation of phospholipase C and increasedsecretory activity. In the CNS, whereall subtypes are present, ACh receptors servediverse functions ranging from regulation ofcortical excitability, memory and learning,pain processing, and brainstem motor control.In blood vessels, the relaxant action of AChon muscle tone is indirect, because it involvesstimulation of M 3 -cholinoceptors onendothelial cells that respond by liberatingNO (nitrous oxid = endothelium-derivedrelaxing factor). The latter diffuses into thesubjacent smooth musculature, where itcauses a relaxation of active tonus (p.124).

Cholinergic Synapse 105A. Acetylcholine: release, effects, and degradationAcetyl-coenzyme A + cholineCholine acetyltransferaseOH 3 C CCH 3+O CH 2 CH 2 N CH 3Acetylcholine CH 3Action potentialCa 2+ influxStorage ofacetylcholinein vesiclesCa 2+activereuptake ofcholineVesiclereleaseExocytosisestericcleavageReceptoroccupationSerumcholinesteraseAcetylcholineesterase:membraneassociatedSmooth muscle cellM 3 -receptorHeart pacemaker cellM 2 -receptorSecretory cellM 3 -receptorPhospholipase C K + -channel activation Phospholipase CCa 2+ in cytosolSlowing ofdiastolicdepolarizationCa 2+ in cytosolTone Rate Secretion-30ACheffectmV0-45-70mVTimemNControlcondition-90Time

106 Drugs Acting on the Parasympathetic Nervous System ParasympathomimeticsAcetylcholine (ACh) is too rapidly hydrolyzedand inactivated by acetylcholinesterase(AChE) to be of any therapeutic use;however, its action can be replicated byother substances, namely, direct or indirectparasympathomimetics.Direct parasympathomimetics. The cholineester of carbamic acid, carbachol, activatesM-cholinoceptors, but is not hydrolyzed byAChE. Carbachol can thus be effectively employedfor local application to the eye (glaucoma)and systemic administration (bowelatonia, bladder atonia). The alkaloids pilocarpine(from Pilocarpus jaborandi) andarecoline(from Areca catechu; betel nut) also actas direct parasympathomimetics. As tertiaryamines, they moreover exert central effects.The central effect of muscarine-like substancesconsists in an enlivening, mild stimulationthat is probably the effect desired inbetel chewing, a widespread habit in SouthAsia. Of this group, only pilocarpine enjoystherapeutic use, which is almost exclusivelybylocalapplicationtotheeyeinglaucoma(p. 346).Indirect parasympathomimetics inhibit localAChE and raise the concentration of AChat receptors of cholinergic synapses. Thisaction is evident at all synapses where AChis the mediator. Chemically, these agents includeesters of carbamic acid (carbamatessuch as physostigmine, neostigmine) andofphosphoric acid (organophosphates such asparaoxon =E600,andnitrostigmine =parathion= E605, its prodrug).MembersofbothgroupsreactlikeAChwith AChE. The esters are hydrolyzed uponformation of a complex with the enzyme.The rate-limiting step in ACh hydrolysis isdeacetylation of the enzyme, which takesonly milliseconds, thus permitting a highturnover rate and activity of AChE. Decarbaminoylationfollowing hydrolysis of a carbamatetakes hours to days, the enzyme remaininginhibited as long as it is carbaminoylated.Cleavage of the phosphate residue,i. e., dephosphorylation, is practically impossible;enzyme inhibition is irreversible.Uses. The quaternary carbamate neostigmineis employed as an indirect parasympathomimeticin postoperative atonia of thebowel or bladder. Applied topically to theeye, neostigmine is used in the treatmentof glaucoma. Furthermore, it is needed toovercome the relative ACh-deficiency at themotor end plate in myasthenia gravis or toreverse the neuromuscular blockade (p.184)caused by nondepolarizing muscle relaxants(decurarization before discontinuation ofanaesthesia). Pyridostigmine has a similaruse. The tertiary carbamate physostigminecan be used as an antidote in poisoning withparasympatholytic drugs, becauseithasaccessto AChE in the brain. Carbamates andorganophosphates also serve as insecticides.Although they possess high acute toxicity inhumans, they are more rapidly degradedthan is DDT following their release into theenvironment.In the early stages of Alzheimer disease,administration of centrally acting AChE inhibitorscan bring about transient improvementin cognitive function or slow downdeterioration in some patients. Suitabledrugs include rivastigmine, donezepil, andgalantamine, which require slowly increasingdosage. Peripheral side effects (inhibitionof ACh breakdown) limit therapy. Donezepiland galantamine are not esters of carbamicacid and act by a different molecular action.Galantamine is also thought to promote theaction of ACh at nicotinic cholinoceptors byan allosteric mechanism.

Parasympathomimetics 107A. Direct and indirect parasympathomimeticsOOCH 3H 3 CO C+H 2 N C O CH 2 CH 2 N CH 3N CH3CarbacholCH 3ArecolineDirect parasympathomimeticsArecoline=OCH 3ingredient of+H 3 C C O CH 2 CH 2 N CH betel nut:3betelAcetylcholineCH 3chewingAChEH 3 CAChN CH CH 3H 3 CCH 3 IndirectOC 2 H 5H 3 CCH 3O C NRivastigmine O CH 2 CH 3CH 3O CHNH 3 CNNO CH 3H 3 CPhysostigmineAChEInhibitors ofOCH 3 C OH 3 C2 H 5+N C ON CH acetylcholinesterase3(AChE)O P ONO 2Neostigmine parasympathomimeticsParaoxon (E 600)Effector organAcetylcholine+AChECholineNeostigmine+AChEParaoxon+AChEAcetylmsCarbaminoylPhosphorylDeacetylationHoursDecarbaminoylationNitrostigmine =Parathion =E 605Dephosphorylation impossible

108 Drugs Acting on the Parasympathetic Nervous System ParasympatholyticsExcitation of the parasympathetic divisioncauses release of acetylcholine at neuroeffectorjunctionsindifferenttargetorgans.The major effects are summarized in (A)(blue arrows). Some of these effects havetherapeutic applications, as indicated bythe clinical uses of parasympathomimetics(p.106).Substances acting antagonistically at theM-cholinoceptor are designated parasympatholytics(prototype: the alkaloid atropine;actions marked red in the panels).Therapeuticuseoftheseagentsiscomplicatedby their low organ selectivity. Possibilitiesfor a targeted action include: Local application Selection of drugs with favorable membranepenetrability Administration of drugs possessing receptorsubtype selectivity.Parasympatholytics are employed for thefollowing purposes:1. Inhibition of glandular secretion.Bronchial secretion. Premedication withatropine before inhalation anesthesia preventsa possible hypersecretion of bronchialmucus, which cannot be expectorated bycoughing during anesthesia.Gastric secretion. Atropine displays aboutequally high af nity for all muscarinic cholinoceptorsubtypes and thus lacks organspecificity. Pirenzepine has preferentialaf nity for the M 1 subtype and was used toinhibit production of HCl in the gastricmucosa, because vagally mediated stimulationof acid production involves M 1 receptors.This approach has proved inadequatebecause the required dosage of pirenzepineproduced too many atropine-like sideeffects. Also, more effective pharmacologicalmeans are available to lower HCl productionin a graded fashion (H 2 -antihistaminics, protonpump inhibitors).2. Relaxation of smooth musculature. As arule, administration of a parasympatholyticagent by inhalation is quite effective inchronic obstructive pulmonary disease.Ipratropium has a relatively short lastingeffect; four aerosol puffs usually being requiredper day. The newly introduced substancetiotropium needs to be applied onlyonce daily because of its “adhesiveness.” Tiotropiumis effective in chronic obstructivelung disease; however, it is not indicated inthe treatment of bronchial asthma.Spasmolysis by N-butylscopolamine inbiliary or renal colic (p.130). Because of itsquaternary nitrogen atom, this drug does notenter the brain and requires parenteral administration.Its spasmolytic action is especiallymarked because of additional ganglionicblocking and direct muscle-relaxantactions.Lowering of pupillary sphincter tonus andpupillary dilation by local administration ofhomatropine or tropicamide (mydriatics)allows observation of the ocular fundus. Fordiagnostic uses, only short-term pupillarydilation is needed. The effect of both agentssubsides quickly in comparison with that ofatropine (duration of several days).3. Cardioacceleration. Ipratropium is usedin bradycardia and AV-block, respectively,to raise heart rate and to facilitate cardiacimpulse conduction. As a quaternary substance,it does not penetrate into the brain,which greatly reduces the risk of CNS disturbances(see below). However, it is alsopoorly absorbed from the gut (absorptionrate < 30%). To achieve adequate levels intheblood,itmustbegiveninsignificantlyhigher dosage than needed parenterally.Atropine may be given to prevent cardiacarrest resulting from vagal reflex activation,incidental to anaesthetic induction, gastriclavage, or endoscopic procedures.

Parasympatholytics 109A. Effects of parasympathetic stimulation and blockadeN. oculomotoriusN. facialisN. glossopharyngeusN. vagusDeadlynightshadeAtropabelladonnaCNCH 2 OHH 3O C CHNn. sacralesAtropineAcetylcholineOMuscarinic acetylcholine receptorSchlemmÕscanal wideIncreased blood flowfor increasingheat dissipationCiliary musclecontracted+++PhotophobiaNear vision impossibleDrainage of aqueoushumor impairedEvaporative heatlossSweat productionPupil narrowPupil wideRateAV conductionRateAV conductionÒFlusheddry skinÒ-+Bronchial secretionBronchoconstrictionBronchial secretiondecreasedBronchodilationSympatheticnerves+++++Salivary secretionGastricacidPancreatic juiceproductionBowel peristalsisBladder toneRestlessnessIrritabilityHallucinationsAntiparkinsonianeffectAntiemetic effectDry mouthAcid productiondecreasedPancreaticsecretory activitydecreasedBowel peristalsisdecreasedBladder tonedecreased

110 Drugs Acting on the Parasympathetic Nervous System4. CNS damping effects. Scopolamine is effectivein the prophylaxis of kinetosis (motionsickness, sea sickness, see p. 342); it ismostly applied by a transdermal patch. Scopolamine(pK a = 7.2) penetrates the blood–brain barrier faster than does atropine (pK a =9), because at physiological pH a larger proportionis present in the neutral, membranepermeantform.In psychotic excitement (agitation), sedationcan be achieved with scopolamine. Unlikeatropine, scopolamine exerts a calmingand amnesiogenic action that can also beused to advantage in anesthetic premedication.Symptomatic treatment in parkinsonismfor the purpose of restoring a dopaminergic-cholinergicbalance in the corpus striatum.Antiparkinsonian agents, such as benztropine(p.188) readily penetrate theblood–brain barrier. At centrally equieffectivedosages, their peripheral effects are lessmarked than those of atropine.Contraindications for parasympatholytics.Closed angle glaucoma. Since drainage ofaqueous humor is impeded during relaxationof the pupillary sphincter, intraocularpressure rises.Prostatic hyperplasia with impaired micturition:loss of parasympathetic control ofthe detrusor muscle exacerbates dif cultiesin voiding urine.Atropine poisoning. Parasympatholyticshave a wide therapeutic margin. Rarely lifethreatening,poisoning with atropine is characterizedby the following peripheral andcentral effects.Peripheral. Tachycardia; dry mouth; hyperthermiasecondary to the inhibition ofsweating. Although sweat glands are innervatedby sympathetic fibers, these are cholinergicin nature. When sweat secretion isinhibited, the body loses the ability to dissipatemetabolic heat by evaporation ofsweat. There is a compensatory vasodilationin the skin, allowing increased heat exchangethrough increased cutaneous bloodflow. Decreased peristaltic activity of the intestinesleads to constipation.Central. Motor restlessness, progressing tomaniacal agitation, psychic disturbances,disorientation and hallucinations. Itmaybe noted that scopolamine-containing herbalpreparations (especially from Datura stramonium)served as hallucinogenic intoxicantsin the Middle Ages. Accounts ofwitches’ rides to satanic gatherings and similarexcesses are likely the products of CNSpoisoning. Recently, Western youths havebeen reported to make “recreational” use ofAngel’s Trumpet flowers (several Brugmansiaspecies grown as ornamental shrubs).Plants of this genus are a source of scopolamineused by South American natives sincepre-Columbian times.Elderly subjects have an enhanced sensitivity,particularly toward the CNS toxicmanifestations. In this context, the diversityof drugs producing atropine-like side effectsshould be borne in mind: e. g., tricyclic antidepressants,neuroleptics, antihistaminics,antiarrhythmics, antiparkinsonian agents.Apart from symptomatic, general measures(gastric lavage, cooling with icewater), therapy of severe atropine intoxicationincludes the administration of theindirect parasympathomimetic physostigmine(p.106). The most common instancesof “atropine”-intoxication are observed afteringestion of the berrylike fruits of belladonna(in children). A similar picture may beseen after intentional overdosage with tricyclicantidepressants in attempted suicide.

Parasympatholytics 111A. ParasympatholyticsH 3 CNO C C OHOHHomatropineMM 1 1M 1M 1M 3M 3M3M 3H 3O C HCNBenzatropineM 2H 3 CH3OCOC+NOTiotropiumHO SCSM 1M 1MM 31M 1M 1H 3 CN“Patch”OCH 2 OHScopolamine O C CH0.2–2 mgOCH 3+NH 9 C4OO HO C C CH 2 OHN-ButylscopolamineH 3O C C CH 2 OHCC H 3CH+NCH 3ED0.5–1 mgOHIpratropiumED 10 mg+ ganglioplegic+ direct muscle relaxant

112 Nicotine Actions of NicotineAcetylcholine (ACh) is a mediator in the gangliaof the sympathetic and parasympatheticdivisions of the autonomic nervous system.Here, ACh receptors are considered that areactivated by nicotine (nicotinic receptors;NAChR, p.102) and that play a leading partin fast ganglionic neurotransmission. Thesereceptors represent ligand-gated ion channelswith a structure and mode of operationas described on p. 64. Opening of the ionpore induces Na + influx followed by membranedepolarization and excitation of thecell. NAChR tend to desensitize rapidly; thatis, during prolonged occupation by an agonistthe ion pore closes spontaneously andcannot reopen until the agonist detachesitself. Localization of Nicotinic AChReceptorsAutonomic nervous system (A, middle). Inanalogy to autonomic ganglia, NAChR arefound also on epinephrine-releasing cells ofthe adrenal medulla, which are innervatedby spinal first neurons. At all these synapses,the receptor is located postsynaptically in thesomatodendritic region of the gangliocyte.Motor end plate. Here the ACh receptorsare of the motor type (p.182).Central nervous system (CNS; A, top).NAChR are involved in various functions.They have a predominantly presynaptic locationand promote transmitter release frominnervated axon terminals by means of depolarization.Together with ganglionicNAChR they belong to the neuronal type,which differs from the motor type in termsof the composition of its five subunits.enjoyment of its central stimulant action.Nicotine activates the brain’s reward system,thereby promoting dependence. Regular intakeleads to habituation, which is advantageousin some respects (e. g., stimulation ofthe area postrema, p. 342). In habituatedsubjects, cessation of nicotine intake resultsin mainly psychological withdrawal symptoms(increased nervousness, lack of concentration).Prevention of these is an additionalimportant incentive for continuingnicotine intake. Peripheral effects caused bystimulation of autonomic ganglia may beperceived as useful (“laxative” effect of thefirst morning cigarette). Sympathoactivationwithout corresponding physical exertion(“silent stress”) may in the long term leadto grave cardiovascular damage (p.114). Aids for Smoking CessationAdministration of nicotine by means of skinpatch,chewinggum,ornasalsprayisintendedto eliminate craving for cigarettesmoking. Breaking of the habit is to beachieved by stepwise reduction of the nicotinedose. Initially this may happen; however,the long-term relapse rate is disappointinglyhigh.Bupropion (amfebutamon) shows structuralsimilarity with amphetamine (p. 329)and inhibits neuronal reuptake of dopamineand norepinephrine. It is supposed to aidsmokers in “kicking the habit,” possibly becauseit evokes CNS effects resembling thoseof nicotine. The high relapse rate after terminationof the drug and substantial sideeffects put its therapeutic value in doubt. Effects of Nicotine on Body FunctionNicotine served as an experimental tool forthe classification of acetylcholine receptors.As a tobacco alkaloid, nicotine is employeddailybyavastpartofthehumanraceforthe

Actions of Nicotine 113A. Effects of nicotine in bodyAttentivenessVigilanceAbility to concentrateStimulationof reward systemDependenceAvoidance of withdrawalsymptoms:Irritability, impatienceDifficulty concentratingDysphoriaExcitation ofarea postremaNausea, vomitingRelease oftransmittersMainly presynapticreceptorsRelease of vasopressinPostsynapticreceptors ofmotor end plateSensitization ofreceptors for pressure,temperature andpain sensationNNCH 3NicotineAdrenalmedullaPostsynapticreceptors ofautonomicgangliocytes andadrenal medullarycellsNorepinephrineEpinephrineAcetylcholineVasoconstrictionHeart rateBlood pressureGlycogenolysisLipolysis“Silent stress”Bowel peristalsisDefecationDiarrheaPresynaptic receptorsNeurotransmittersPostsynaptic receptorsNicotineNicotine

114 Nicotine Consequences of Tobacco SmokingThe dried and cured leaves of the nightshadeplant Nicotiana tabacum are known as tobacco.Tobacco is mostly smoked, less frequentlychewed or taken as dry snuff. Combustion oftobacco generates ~ 4000 chemical compoundsin detectable quantities. The xenobioticburden on the smoker depends on arange of parameters, including tobacco quality,presence of a filter, rate and temperatureof combustion, depth of inhalation, and durationof breath holding.Tobacco contains 0.2–5% nicotine. In tobaccosmoke, nicotine is present as a constituentof small tar particles. The amount ofnicotine absorbed during smoking dependson the nicotine content, the size of membranearea exposed to tobacco smoke (N.B.:inhalation), and the pH of the absorbing surface.It is rapidly absorbed through bronchiand lung alveoli when present in free baseform. However, protonation of the pyrrolidinenitrogen renders the correspondingpart of the molecule hydrophilic and absorptionis impeded. To maximize the yield ofnicotine, tobaccos of some manufacturersare made alkaline. Smoking of a single cigaretteproduces peak plasma levels in therange of 25–50 ng/ml. The effects describedon p.113 become evident. When intakestops, nicotine concentration in plasmashows an initial rapid fall, due to distributioninto tissues, and a terminal eliminationphase with a half-life of 2 hours. Nicotine isdegraded by oxidation.The enhanced risk of vascular disease(coronary stenosis, myocardial infarction,and central and peripheral ischemic disorders,such as stroke and intermittent claudication)is likely to be a consequence ofchronic exposure to nicotine. At the least,nicotine is under discussion as a factor favoringthe progression of atherosclerosis. Byreleasing epinephrine, it elevates plasmalevels of glucose and free fatty acids in theabsence of an immediate physiological needfor these energy-rich metabolites. Furthermore,it promotes platelet aggregability,lowers fibrinolytic activity of blood, and enhancescoagulability.The health risks of tobacco smoking are,however, attributable not only to nicotinebut also to various other ingredients of tobaccosmoke. Some of these promote formationof thrombogenic plaques; others possessdemonstrable carcinogenic properties(e. g., the tobacco-specific nitrosoketone).Dust particles inhaled in tobacco smoke,together with bronchial mucus, must be removedby the ciliated epithelium from theairways. However, ciliary activity is depressedby tobacco smoke and mucociliarytransport is impaired. This favors bacterialinfection and contributes to the chronicbronchitis associated with regular smoking(smoker’s cough). Chronic injury to thebronchial mucosa could be an importantcausative factor in increasing the risk insmokers of death from bronchial carcinoma.Statistical surveys provide an impressivecorrelation between the numbers of cigarettessmoked per day and the risk of deathfrom coronary disease or lung cancer. On theother hand, statistics also show that, on cessationof smoking, the increased risk ofdeath from coronary infarction or other cardiovasculardisease declines over 5–10 yearsalmost to the level of nonsmokers. Similarly,the risk of developing bronchial carcinoma isreduced.An association with tobacco use has alsobeen established for cancers of the larynx,pharynx, esophagus, stomach, pancreas, kidney,and bladder.

Consequences of Tobacco Smoking 115A. Sequelae of tobacco smokingN-H ++NHCH 3+H +NNicotianatabacumCHN3Nicotine free base“Tar”Nitrosamines,acrolein,polycyclichydrocarbons, e.g.,benzopyreneheavy metalsSum of noxiousstimuliPlateletaggregationDamage tovascularendotheliumDamage tobronchialepitheliumInhibition ofmucociliarytransportFibrinolyticactivityEpinephrineYearsDurationofexposureMonthsFreefatty acidsChronicbronchitisBronchitisCoronary diseaseAnnual deaths/1000 peopleBronchial carcinomaAnnual cases/1000 people543210 –10 –20 –40 >40 0 –15 –40 >40Number of cigarettes per dayEx-smoker

116 Biogenic Amines DopamineAs a biogenic amine, dopamine belongs to agroup of substances produced in the organismby decarboxylation of amino acids. Besidesdopamine and norepinephrine formedfrom it, this group includes many other messengermolecules such as histamine, serotonin,and γ-aminobutyric acid.Dopamine actions and pharmacologicalimplications (A). In the CNS, dopamineserves as a neuromediator. Dopamine receptorsare also present in the periphery. Neuronallyreleased dopamine can interact withvarious receptor subtypes, all of which arecoupled to G-proteins. Two groupings can bedistinguished: the family of D 1 -like receptors(comprising subtypes D 1 and D 5 )andthe family of D 2 -like receptors (comprisingsubtypes D 2 ,D 3 ,andD 4 ). The subtypes differin their signal transduction pathways. Thus,synthesis of cAMP is stimulated by D 1 -likereceptors but inhibited by D 2 -like receptors.Released dopamine can be reutilized byneuronal reuptake and re-storage in vesiclesor can be catabolized like other endogenouscatecholamines by the enzymes MAO andCOMT (p. 86).Various drugs are employed therapeuticallyto influence dopaminergic signal transmission.Antiparkinsonian agents. InParkinsondisease,nigrostriatal dopamine neurons degenerate.To compensate for the lack of dopamine,useismadeofL-dopaas the dopamineprecursor and of D 2 receptor agonists (cf.p.188).Prolactin inhibitors. Dopamine releasedfrom hypothalamic neurosecretory nervecells inhibits the secretion of prolactin fromthe adenohypophysis (p. 238). Prolactin promotesproduction of breast milk during thelactation period; moreover it inhibits thesecretion of gonadorelin. D 2 receptor agonistsprevent prolactin secretion and can beused for weaning and the treatment of femaleinfertility resulting from hyperprolactinemia.The D 2 agonists differ in their duration ofaction and, hence, their dosing interval; e. g.,bromocriptine 3 times daily, quinagolideonce daily, and cabergoline once to twiceweekly.Antiemetics. Stimulation of dopamine receptorsin the area postrema can elicit vomiting.D 2 receptor antagonists such as metoclopramideand domperidone are used asantiemetics (p. 342). In addition they promotegastric emptying.Neuroleptics.VariousCNS-permeantdrugsthat exert a therapeutic action in schizophreniadisplay antagonist properties at D 2receptors; e. g., the phenothiazines and butyrophenoneneuroleptics (p. 232).Dopamine as a therapeutic agent (B). Whengiven by infusion, dopamine causes a dilationof renal and splanchnic arteries thatresults from stimulation of D 1 receptors. Thislowers cardiac afterload and augments renalblood flow, effects that are exploited in thetreatment of cardiogenic shock. Because ofthe close structural relationship betweendopamine and norepinephrine, it is easy tounderstand why, at progressively higherdoses, dopamine is capable of activating β 1 -adrenoceptors and finally α 1 -receptors. Inparticular, α-mediated vasoconstrictionwould be therapeutically undesirable (symbolizedby red warning sign).Apomorphine is a dopamine agonist with avariegated pattern of usage. Given parenterallyas an emetic agent to aid elimination oforally ingested poisons, it is not withouthazards (hypotension, respiratory depression).In akinetic motor disturbances, it is aback-up drug. Taken orally, it supposedly isbeneficial in erectile dysfunction.

Dopamine 117A. Dopamine actions as influenced by drugsDopaminergic neuronRelease andinactivationH 3 C–ONeuronalreuptake–COOHReceptorsubtypesCOMTCatecholO-methyltransferaseHOHOCH 2 CH2NH 2DopamineD 1 -likeD 2 -likeD 1 D 5 D 2 D 3 D 4MAOMonoamineoxidaseDrugsAntiparkinson agentsInhibitors ofneurosecretionAntiemeticsNeurolepticsL-Dopa(precursor)DopamineD 2 -agonistsStriatumD 2 -agonistsAHD 2 -antagonistsAreapostremaD 2 -antagonistsS. nigraProlactin D 2 EmesisSchizophreniaB. Dopamine as a therapeutic agentCirculatoryshock withimpairedrenal bloodflowDopamineToxicDoseReceptorsD 1 β 1 α 1EffectBlood flowStimulationVasoconstriction

118 Biogenic Amines Histamine Effects and TheirPharmacological PropertiesFunctions. IntheCNShistamineservesasaneurotransmitter/modulator, promoting interalia wakefulness. In the gastric mucosa, itacts as a mediator substance that is releasedfrom enterochromaf n-like (ECL) cells tostimulate gastric acid secretion in neighboringparietal cells (p.170). Histamine stored inbloodbasophilsandtissuemastcellsplaysamediator role in IgE-mediated allergic reactions(p. 72). By increasing the tone of bronchialsmooth muscle, histamine may triggeran asthma attack. In the intestines, it promotesperistalsis, which is evidenced in foodallergies by the occurrence of diarrhea. Inblood vessels, histamine increases permeabilityby inducing the formation of gapsbetween endothelial cells of postcapillaryvenules, allowing passage of fluid into thesurrounding, tissue (e. g., wheal formation).Blood vessels are dilated because histamineinduces release of nitric oxide from the endothelium(p.124) and because of a directvasorelaxant action. By stimulating sensorynerve endings in the skin, histamine canevoke itching.Receptors. Histaminereceptorsarecoupledto G-proteins. The H 1 and H 2 receptors aretargets for substances with antagonistic actions.The H 3 receptor is localized on nervecells and may inhibit release of varioustransmitter substances, including histamineitself.Metabolism. Histamine-storing cells formhistamine by decarboxylation of the aminoacid histidine. Released histamine is degraded;no reuptake system exists as fornorepinephrine, dopamine, and serotonin.Antagonists. The H 1 and H 2 receptors can beblocked by selective antagonists.H 1 -Antihistaminics. Older substances inthis group (first generation) are rather nonspecificand also block other receptors (e. g.,muscarinic cholinoceptors). These agents areused for the symptomatic relief of allergies(e. g., bamipine, clemastine, dimetindene,mebhydroline, pheniramine); as antiemetics(meclizine, dimenhydrinate; p. 342); and asprescription-free sedatives/hypnotics (seep. 220). Promethazine represents the transitionto psychopharmaceuticals of the type ofneuroleptic phenothiazines (p. 232).Unwanted effects of most H 1 -antihistaminicsare lassitude (impaired driving skills)and atropine-like reactions (e. g., dry mouth,constipation). Newer substances (secondgenerationH 1 -antihistaminics) do not penetrateinto the CNS and are therefore practicallydevoid of sedative effects. Presumablythey are transported back into the blood by aP-glycoprotein located in the endothelium ofthe blood–brain barrier. Furthermore, theyhardly have any anticholinergic activity.Members of this group are cetirizine (a racemate)and its active enantiomer levocetirizine,aswellasloratadineanditsactivemetabolitedesloratadine. Fexofenadine is theactive metabolite of terfenadine, whichmay reach excessive blood levels when biotransformation(via CYP3A4) is too slow; andwhich can then cause cardiac arrhythmias(prolongation of QT-interval). Ebastine andmizolastine are other new agents.H 2 -Blockers (cimetidine, ranitidine, famotidine,nizatidine) inhibit gastric acid secretion,and thus are useful in the treatment ofpeptic ulcers (p.172). Cimetidine may lead todrug interactions because it inhibits hepaticcytochrome oxidases. The successor drugs(e. g., ranitidine) are of less concern in thisrespect.Mast cell stabilizers. Cromoglycate (cromolyn)and nedocromil decrease, by an as yetunknown mechanism, the capacity of mastcells to release of histamine and other mediatorsduring allergic reactions. Both agentsare applied topically (p. 338).

Histamine 119A. Histamine actions as influenced by drugsEnterochromaffinlikecellAlertnessNNHC 2 C 2 NH 2H HH 1H 2HistamineHClsecretionParietalcellHistamineCNSStomachMast cellInhibition of release:“Mast cell stabilization”;e.g., cromolynH 1 H 1 H 1 H 2 H 1BronchoconstrictionPeristalsisvia directNODilationPermeabilityItchingBronchial tree Bowel VasculatureSkinReceptor antagonistsH 1 - AntihistaminicsH 2 -Antihistaminics1. GenerationCH 3CH O CH 2 CH 2 NCH 3CNSSedationDiphenhydraminemAChreceptorantagonistHNNCH 3CimetidineInhibition ofcytochromeoxidasesCH2S(CH 2 ) 2NHC NHCH 3N C NCaution:DruginteractionCl2. GenerationH 3 CH 3 CNCH 2OCH 2S(CH 2 ) 2HCN N CH 2 CH 2 O CH 2 COOHNHCetirizineRanitidineC NHCH 3CH NO2

120 Biogenic Amines SerotoninOccurrence. Serotonin (5-hydroxytryptamine,5-HT) is synthesized from L-tryptophanin enterochromaf n cells of the intestinalmucosa. 5-HT-synthesizing neurons occuralso in the enteric nerve plexus and theCNS, where the amine fulfills a neuromediatorfunction. Blood platelets are unable tosynthesize 5-HT, but are capable of takingup,storing,andreleasingit.Serotonin receptors. Based on biochemicaland pharmacological criteria, seven receptorsclasses can be distinguished. Of majorpharmacotherapeutic importance are thosedesignated: 5-HT 1 ,5-HT 2 , each with differentsubtypes, 5-HT 4 ,and5-HT 7 ,allofwhichare G-protein-coupled, whereas the 5-HT 3subtype represents a ligand-gated nonselectivecation channel (p. 64).Serotonin actions—cardiovascular system.The responses to 5-HT are complex, becausemultiple, in part opposing, effects are exertedvia the different receptor subtypes.Thus, 5-HT 2A receptors on vascular smoothmuscle cells mediate direct vasoconstriction.Vasodilation and lowering of blood pressurecan occur by several indirect mechanisms:5-HT 1A receptors mediate sympathoinhibition(† decrease in neurogenic vasoconstrictortonus) both centrally and peripherally;5-HT 1 -like receptors on vascular endotheliumpromote release of vasorelaxant mediators(NO; prostacyclin). 5-HT released fromplatelets plays a role in thrombogenesis, hemostasis,and the pathogenesis of preeclamptichypertension.Sumatriptan is an antimigraine drug thatpossesses agonist activity at 5-HT receptorsof the 1D and 1B subtypes (p. 334). It causesa constriction of cranial blood vessels, whichmay result from a direct vascular action orfrom inhibition of the release of neuropeptidesthat mediate “neurogenic inflammation.”A sensation of chest tightness mayoccur and be indicative of coronary vasospasm.Other “triptans” are naratriptan, zolmitriptan,and rizatriptan.Gastrointestinal tract. Serotonin releasedfrom myenteric neurons or enterochromaffin(EC) cells acts on 5-HT 4 receptors to enhancebowel motility, enteral fluid secretion,and thus propulsive activity. To date, attemptsat modifying the influence of serotoninon intestinal motility by agonistic or antagonisticdrugs have not been very successful.Although the 5-HT 4 agonist cisapridewas shown to be effective in increasing propulsiveactivity of the intestinal tract, its adverseeffects were very pronounced. Since itis degraded via CYP3A4, it is liable to interactwith numerous drugs. In particular, arrhythmias(in part severe) associated with QT prolongationwere noted; the arrhythmogenicaction is caused by blockade of K + channels.Thedrugisnolongeravailable.Central nervous system. Serotoninergicneurons play a part in various brain functions,as evidenced by the effects of drugslikely to interfere with serotonin.Fluoxetine is an antidepressant which, byblocking reuptake, retards inactivation of releasedserotonin. Its activity spectrum includessignificant psychomotor stimulationand depression of appetite.Sibutramine, an inhibitor of the neuronalreuptake of 5-HT and norepinephrine, ismarketed as an antiobesity drug (pp. 329).Ondansetron, an antagonist at the 5-HT 3receptor, possesses striking effectivenessagainst cytotoxic drug-induced emesis, evidentboth at the start of and during cytostatictherapy. Tropisetron and granisetronproduce analogous effects.LSD and other psychedelics (psychotomimetics)such as mescaline and psilocybin caninduce states of altered awareness, or inducehallucinations and anxiety, probably mediatedby 5-HT 2A receptors.

Serotonin 121A. Serotonin actions as influenced by drugsSerotoninergic neuronLSDLysergic acid diethylamidePsychedelicHNH 3CSO2CH 2CH 3CH 3CH 2 CH 2 NNHHallucination5-HT 2A5-HT 1DSumatriptanAntimigraineFluoxetine5-HT-reuptake inhibitorOndansetronAntidepressant5-HT 3AntiemeticHCH CH2 CH2NOCH3EmesisNOCH CH 2 3NNF 3 C5-Hydroxy-tryptamineCH 3HONHCH 2CH2NH 2SerotoninBlood vesselIntestineEndotheliummediated Dilatation5-HT 2B5-HT 4PlateletsConstrictionPropulsivemotility5-HT 2Enterochromaffincell

122 Vasodilators Vasodilators—OverviewThe distribution of blood within the circulationis a function of vascular caliber. Venoustone regulates the volume of blood returnedto the heart and, hence, stroke volume andcardiac output. The luminal diameter of thearterial vasculature determines peripheralresistance. Cardiac output and peripheral resistanceare prime determinants of arterialblood pressure (p. 324).In (A), the clinically most important vasodilatorsare presented. Some of these agentspossess different ef cacy in affecting the venousand arterial limbs of the circulation.Possible uses. Arteriolar vasodilators are givento lower blood pressure in hypertension(p. 314), to reduce cardiac work in anginapectoris (p. 318), and to reduce ventricularafterload (pressure load) in cardiac failure(p. 322). Venous vasodilators are used to reducevenous filling pressure (preload) in anginapectoris (p. 318) or congestive heart failure(p. 322). Practical uses are indicated foreach drug group.Counterregulation in acute hypotensiondue to vasodilators (B). Increased sympatheticdrive raises heart rate (reflex tachycardia)and cardiac output and thus helps toelevate blood pressure. The patients experiencepalpitations. Activation of the renin–angiotensin–aldosterone (RAA) system servesto increase blood volume, hence cardiac output.Fluid retention leads to an increase inbody weight and, possibly, edemas.These counterregulatory processes aresusceptible to pharmacological inhibition(β-blockers, ACE inhibitors, diuretics).Mechanisms of action. The tonus of vascularsmooth muscle can be decreased by variousmeans.Protection against vasoconstricting mediators.ACE inhibitors and angiotensin receptorantagonists protect against angiotensin II(p.128); α-adrenoceptor antagonists interferewith (nor)epinephrine (p. 94); bosentan(see below) is an antagonist at receptors forendothelin, a powerful vasoconstrictor releasedby the endothelium.Substitution of vasorelaxant mediators.Analogues of prostacyclin (from vascular endothelium),such as iloprost, or of prostaglandinE 1 , such as alprostadil, stimulatethe corresponding receptors; organic nitrates(p.124) substitute for endothelial NO.Direct action on vascular smooth musclecells. Ca 2+ -channel blockers (p.126) and K +channel openers (diazoxide, minoxidil) actat the level of channel proteins to inhibitmembrane depolarization and excitation ofvascular smooth muscle cells. Phosphodiesterase(PDE) inhibitors retard the degradationof intracellular cGMP, which lowers contractiletonus. Several PDE isozymes withdifferent localization and function areknown.The following sections deal with specialaspects:Erectile dysfunction. Sildenafil, vardenafil,and tardalafil are inhibitors of PDE-5 andare used to promote erection. During sexualarousal NO is released from nerve endings inthe corpus cavernosum of the penis, whichstimulates the formation of cGMP in vascularsmooth muscle. PDE-5, which is important inthis tissue, breaks down cGMP, thus counteractingerection. Blockers of PDE-5 “conserve”cGMP.Pulmonary hypertension. This condition involvesa narrowing of the pulmonary vascularbed resulting mostly from unknowncauses. The disease often is progressive, associatedwith right ventricular overload, andall but resistant to treatment with conventionalvasodilators. The endothelin antagonist,bosentan, offers a new therapeutic approach.Administration of NO by inhalationis under clinical trial.

Vasodilators—Overview 123A. VasodilatorsCerebral bloodflow not subjectto specific interventionsVenous bed Vasodilation Arterial bedNitratesCa-antagonistsACE inhibitors, angiotensin antagonistsDihydralazineBosentanα 1 -AntagonistsNitroprusside sodiumB. Counter-regulatory responses in hypotension due to vasodilatorsSympathetic nervesVasoconstrictionVasodilationBloodpressureVasomotorcenterHeart rateBlood volumeβ-BlockerCardiacoutputBloodpressureAngiotensinconvertingenzyme(ACE)ReninAngiotensinogenAngiotensin IAldosteroneACE-inhibitorsAngiotensin IIVasoconstrictionAngiotensin II antagonistsRenin-angiotensin-aldosterone system

124 Vasodilators Organic NitratesVarious esters of nitric acid (HNO 3 )andpolyvalentalcohols relax vascular smoothmuscle, e. g., nitroglycerin (glyceryl trinitrate)and isosorbide dinitrate. The effect ismore pronounced in venous than in arterialbeds.These vasodilator effects produce hemodynamicconsequencesthatcanbeputtotherapeutic use. Owing to a decrease in bothvenous return (preload) and arterial afterload,cardiac work is decreased (p. 318). Asa result, the cardiac oxygen balance improves.Spasmodic constriction of larger coronaryvessels (coronary spasm) is prevented.Uses. Organic nitrates are used chiefly inangina pectoris (p. 316), less frequently insevere forms of chronic and acute congestiveheart failure. Continuous intake of higherdoses with maintenance of steady plasmalevels leads to loss of ef cacy, inasmuch asthe organism becomes refractory (tachyphylactic).This “nitrate tolerance” can beavoided if a daily “nitrate-free interval” ismaintained, e. g., overnight.At the start of therapy, unwanted reactionsoccur frequently in the form of a throbbingheadache, probably caused by dilationof cephalic vessels. This effect also exhibitstolerance, even when daily “nitrate pauses”are observed. Excessive dosages give rise tohypotension, reflex tachycardia, and circulatorycollapse.Mechanism of action. The reduction in vascularsmooth muscle tone is due to activationof guanylate cyclase and elevation ofcyclic GMP levels. The causative agent is nitricoxide (NO) generated from the organicnitrate. NO is a physiological messengermolecule that endothelial cells release ontosubjacent smooth muscle cells (“endothelium-derivedrelaxant factor,” EDRF). Organicnitrates thus utilize a physiological pathway;hence their high ef cacy. The enzymaticallymediated generation of NO fromorganicnitrates(viaamitochondrialaldehydedehydrogenase) within the smoothmuscle cell depends on a supply of free sulfhydryl(–SH) groups; “nitrate-tolerance” isattributed to a cellular exhaustion of SH donors.Nitroglycerin (NTG) is distinguished by ahigh membrane penetrability and very lowstability. It is the drug of choice in the treatmentof angina pectoris attacks. For this purpose,it is administered as a spray, or in sublingualor buccal tablets for transmucosaldelivery. The onset of action is between 1and 3 minutes. Due to a nearly completepresystemic elimination, it is poorly suitedfor oral administration. Transdermal delivery(nitroglycerin patch) also avoids presystemicelimination.Isosorbide dinitrate (ISDN) penetrateswell through membranes, is more stable thanNTG, and is partly degraded into the weaker,but much longer acting, 5-isosorbide mononitrate(ISMN). ISDN can also be applied sublingually;however, it is mainly administeredorally in order to achieve a prolonged effect.ISMN is not suitable for sublingual use becauseof its higher polarity and slower rate ofabsorption. Taken orally, it is absorbed and isnot subject to first-pass elimination.Molsidomine itself is inactive. After oralintake, it is slowly converted into an activemetabolite, linsidomine. The differential effectivenessin arterial vs. venous beds is lessevident compared to the drugs mentionedabove. Moreover, development of “nitratetolerance” is of less concern. These differencesin activity profile appear to reflect a differentmechanism of NO release. The same appliesto the following sodium nitroprusside.Sodium nitroprusside contains a nitroso(–NO) group, but is not an ester. It dilatesvenous and arterial beds equally. It is administeredby infusion to achieve controlled hypotensionunder continuous close monitoring.Cyanide ions liberated from nitroprussidecan be inactivated with sodium thiosulfate(p. 310).

Organic Nitrates 125A. Vasodilators: NitratesPreloadO 2 -supplyAfterloadO 2 -demandBlood pressureVenous blood returnto heartPrevention ofcoronary arteryspasmPeripheralresistanceVenous bed“Nitratetolerance”Arterial bedRoute:e.g., sublingual,transdermalRoute:e.g., sublingual,oral, transdermalH 2 C O NO 2VasodilationO 2 N OHC O NO 25 OH“Nitrates”4 3 HH 2 C O NO 2 O 21Glyceryl trinitrateHO NO 2NitroglycerinIsosorbide dinitrateNO t 1 2 ~ 2 min t 1 ~ 30 min NO2Inactivation5-Isosorbide mononitrate,an active metabolitet 1 2 ~ 240 minR – O – NO 2SH-donatorse.g., glutathioneConsumptionof SH donorsGTPSmooth mucle cellRelease of NOActivation ofguanylate cyclasecGMPRelaxationActivemetaboliteMolsidomine(precursor)N– +N NO2N1C OOC 2 H 5

126 Vasodilators Calcium AntagonistsDuring electrical excitation of the cell membraneof heart or smooth muscle, differentioniccurrentsareactivated,includinganinwardCa 2+ current. The term Ca 2+ antagonistis applied to drugs that inhibit the influx ofCa 2+ ions without affecting inward Na + oroutward K + currents to a significant degree.Other labels are calcium entry blocker orCa 2+ -channel blocker. Ca 2+ antagonists usedtherapeutically can be divided into threegroups according to their effects on heartand vasculature.I. Dihydropyridine DerivativesThe dihydropyridines, e. g., nifedipine, areuncharged hydrophobic substances. Theyparticularly induce a relaxation of vascularsmooth muscle in arterial beds. An effect oncardiac function is practically absent at therapeuticdosage. (In pharmacological experimentson isolated cardiac muscle preparations,a clear negative inotropic effect is,however, demonstrable at high concentrations.)They are thus regarded as vasoselectiveCa 2+ antagonists. Because of the dilationof resistance vessels, blood pressure falls.Cardiac afterload is diminished (p. 318) and,therefore, also oxygen demand. Spasms ofcoronary arteries are prevented.Indications. An indication for nifedipine isangina pectoris (p. 318). In angina pectoris,it is effective when given either prophylacticallyor during acute attacks. Adverse effectsare palpitation (reflex tachycardia due to hypotension),headache, and pretibial edema.The successor substances principally exertthe same effects, but have different kineticproperties (slow elimination and, hence,steady plasma levels).Nitrendipine, isradipine, andfelodipine areused in the treatment of hypertension. Nicardipineand nisoldipine are also used inangina pectoris. Nimodipine is given prophylacticallyafter subarachnoidal hemorrhageto prevent vasospasms. On its dihydropyridinering, amlodipine possesses a side chainwith a protonatable nitrogen and can thereforeexist in a positively charged state. Thisinfluences its pharmacokinetics, as evidencedby the very long half-life of elimination(~ 40 hours).II. Verapamil and Other CatamphiphilicCa 2+ AntagonistsVerapamil contains a nitrogen atom bearinga positive charge at physiological pH andthus represents a cationic amphiphilic molecule.It exerts inhibitory effects not only onarterial smooth muscle, but also on heartmuscle. Intheheart,Ca 2+ inward currentsare important in generating depolarizationof sinoatrial node cells (impulse generation),in impulse propagation through the AVjunction(atrioventricular conduction), andin electromechanical coupling in the ventricularcardiomyocytes. Verapamil thus producesnegative chronotropic, dromotropic, andinotropic effects.Indications. Verapamil is used as an antiarrhythmicdrug in supraventricular tachyarrhythmias.In atrial flutter or fibrillation, itis effective in reducing ventricular rate byvirtue of inhibiting AV conduction. Verapamilis also employed in the prophylaxis ofangina pectoris attacks (p. 318) and the treatmentof hypertension (p. 314).Adverse effects. Because of verapamil’s effectson the sinus node, a drop in bloodpressure fails to evoke a reflex tachycardia.Heart rate hardly changes; bradycardia mayeven develop. AV-block and myocardial insufciency can occur. Patients frequentlycomplain of constipation, because verapamilalso inhibits intestinal musculature.Gallopamil (= methoxyverapamil) is closelyrelated to verapamil in terms of bothstructure and biological activity.Diltiazem is a catamphiphilic benzothiazepinederivative with an activity profile resemblingthat of verapamil.

Calcium Antagonists 127A. Vasodilators: calcium antagonistsSmooth muscle cellAfterloadO 2 -demandContractionCa 2+Inhibition ofcoronary spasmArterialblood vesselBlood pressurePeripheralresistanceVasodilation in arterial bedNa + Ca 2+ 10 -3 MNO H2H 3C O CC O CH 3OOH 3C N CH 3HNifedipine(dihydropyridine derivative)Membrane depolarizationCa 2+ 10 -7 MSelectiveinhibition ofcalcium influxK +H 3COOCH 3O CH 3CH 3H 3COO CH 3HC C C NH 3C H 2CH 2CC C CH2H 2 + N H 2H 3CHVerapamil(cationic-amphiphilic)Inhibition of cardiac functionsSinus nodeImpulsegenerationHeart rateReflex tachycardiawith nifedipineCa 2+Ca 2+AV-nodeImpulseconductionAVconductionCa 2+ Ca 2+VentricularmuscleElectromechanicalcouplingContractilityHeart muscle cell

128 Inhibitors of the RAA System ACE InhibitorsAngiotensin-converting enzyme (ACE) is acomponent of the antihypotensive renin–angiotensin–aldosterone (RAA) system. Reninis produced by specialized smoothmuscle cells in the wall of the afferent arterioleof the renal glomerulus. These cellsbelong to the juxtaglomerular apparatus,the site of contact between afferent arterioleand distal tubule, which plays an importantpart in controlling nephron function. Stimulieliciting release of renin are: drop in renalperfusion pressure, decreased rate of deliveryof Na + or Cl – to the distal tubules, as wellas β-adrenoceptor-mediated sympathoactivation.The glycoprotein renin enzymaticallycleaves the decapeptide angiotensin I fromits circulating precursor substrate angiotensinogen.The enzyme ACE, in turn, producesbiologically active angiotensin II from angiotensinI.ACE is a rather nonspecific peptidase thatcan cleave C-terminal dipeptides from variouspeptides (dipeptidyl carboxypeptidase).As “kininase II,” it contributes to the inactivationof kinins, such as bradykinin. ACE isalso present in blood plasma; however, enzymelocalized in the luminal side of vascularendothelium is primarily responsible forthe formation of angiotensin II.Angiotensin II can raise blood pressure indifferent ways, including (1) vasoconstrictionin both the arterial and venous limb ofthe circulation; (2) stimulation of aldosteronesecretion, leading to increased renalreabsorption of NaCl and water, hence anincreased blood volume; (3) a central increasein sympathotonus and, peripherally,enhanced release and effects of norepinephrine.Chronically elevated levels of angiotensinII can increase muscle mass inheart and arteries (trophic effect).ACE inhibitors,suchascaptopril and enalaprilat,the active metabolite of enalapril, occupythe enzyme as false substrates. Af nitysignificantly influences ef cacy and rate ofelimination. Enalaprilat has a stronger andlonger-lasting effect than captopril.Indications are hypertension and cardiacfailure.Lowering of elevated blood pressure ispredominantly brought about by diminishedproduction of angiotensin II. Impaired degradationof kinins that exert vasodilating actionsmay contribute to the effect.In heart failure, cardiac output rises againafter administration of an ACE inhibitor becauseventricular afterload diminishes owingto a fall in peripheral resistance. Venouscongestion abates as a result of (1) increasedcardiac output and (2) reduction in venousreturn (decreased aldosterone secretion, decreasedtonus of venous capacitance vessels).Undesired effects. The magnitude of theantihypertensive effect of ACE inhibitors dependson the functional state of the RAAsystem. When the latter has been activatedby loss of electrolytes and water (resultingfrom treatment with diuretic drugs), by cardiacfailure, or by renal arterial stenosis, administrationof ACE inhibitors may initiallycause an excessive fall in blood pressure. Drycough is a fairly frequent side effect, possiblycaused by reduced inactivation of kinins inthe bronchial mucosa. In most cases, ACEinhibitors are well tolerated and effective.Newer analogues include lisinopril, perindopril,ramipril, quinapril, fosinopril, benazepril,cilazapril, and trandolapril.Antagonists at angiotensin II receptors.Two receptor subtypes can be distinguished:AT 1 , which mediates the above actions ofangiotensin II; and AT 2 ,whosephysiologicalrole is still unclear. Losartan is an AT 1 receptorantagonist whose main (antihypertensive)and side effects resemble those of ACEinhibitors. However, because it does not inhibitdegradation of kinins, it does not causedry cough. Losartan is used in the therapy ofhypertension. Other analogues are valsartan,irbesartan, eprosartan, and candesartan.

ACE Inhibitors 129A. Renin-angiotensin-aldosterone system and inhibitorsKidneyRRACE inhibitorsO OHO C C CH CH 2 SHNCH 3CaptoprilOOHOCCNNH CH CH CH 2 CH 2CH 3 C OAngiotensinogen(α 2 -globulin)COOHReninAngiotensin I (Ang I)(biologically inactive)Ang IEnalaprilatACEAngiotensinI-convertingenzymeO CH 2 CH 3EnalaprilKininaseIIDipeptidyl carboxypeptidaseKininsACEVascularendotheliumAngiotensin IIH 2 NReceptorsAng IILosartanH 3 CClNCH 2 OHNDegradationproductsHN NN NAT 1 -receptor antagonistsVenoussupplyHMVRRVenouscapacitance vesselsVasoconstrictionResistance vesselsPeripheralresistanceNaClH 2 OAldosteronesecretionSympathoactivationK +

130 Drugs Acting on Smooth Muscle Drugs Used to Influence SmoothMuscle OrgansBronchodilators. Narrowing of bronchiolesraises airway resistance, e. g., in bronchial orbronchitic asthma. Several substances thatare employed as bronchodilators are describedelsewhere in more detail: β 2 -sympathomimetics(p. 88; given by pulmonary, parenteral,or oral route), the methylxanthinetheophylline (p. 338; given parenterally ororally), and the parasympatholytics ipratropiumand tiotropium (p.108).Spasmolytics. N-butylscopolamine (p.108) isused for the relief of painful spasms of thebiliary or ureteral ducts. Its poor absorption(N.B. quaternary N; absorption rate < 10%)necessitates parenteral administration. Becausethe therapeutic effect is usually weak,a potent analgesic is given concurrently, e. g.,the opioid meperidine. Note that somespasms of intestinal musculature can be effectivelyrelieved by organic nitrates (in biliarycolic) or by nifedipine (esophageal hypertensionand achalasia).Myometrial relaxants (tocolytics). β 2 -Sympathomimeticssuch as fenoterol, given orallyor parenterally, can prevent premature laboror interrupt labor in progress when dangerouscomplications necessitate caesarean section.Tachycardia is a side effect producedreflexly because of β 2 -mediated vasodilationor a direct stimulation of cardiac β 1 -receptors.Recently, atosiban, a structurally alteredoxytocin derivative, has become available. Itacts as an antagonist at oxytocin receptors, isgiven parenterally, and lacks the cardiovascularside effects of β 2 -sympathomimetics,but often causes nausea and vomiting.Myometrial stimulants. The neurohypophysealhormone oxytocin (p. 238) is given parenterally(or by the nasal or buccal route)before, during, or after labor in order toprompt uterine contractions or to enhancethem. Certain prostaglandins or analogues ofthem (p.196; F 2 α, dinoprost; E 2 , dinoprostone,sulprostone) are capable of inducingrhythmic uterine contractions and cervicalrelaxation at any time. They are mostly employedas abortifacients (local or parenteralapplication).Ergot alkaloids are obtained from Secale cornutum(ergot), the sclerotium of a fungus(Claviceps purpurea) parasitizing rye. Consumptionof flour from contaminated grainwas once the cause of epidemic poisonings(ergotism) characterized by gangrene of theextremities (St. Anthony’s fire) and CNS disturbances(hallucinations).Ergot alkaloids contain lysergic acid (seeergotamine formula in A). They act on uterineand vascular muscle. Ergometrine particularlystimulates the uterus. It readilyinduces a tonic contraction of the myometrium(tetanus uteri). This jeopardizes placentalblood flow and fetal oxygen supply.Ergometrine is not used therapeutically. Thesemisynthetic derivative methylergometrineis used only after delivery for uterine contractionsthat are too weak.Ergotamine, as well as the ergotoxinealkaloids (ergocristine, ergocryptine, ergocornine),have a predominantly vascular action.Depending on the initial caliber, constrictionor dilation may be elicited. Themechanism of action is unclear; a partialagonism at α-adrenoceptors may be important.Ergotamine is used in the treatment ofmigraine (p. 334). Its derivative, dihydroergotamine,is furthermore employed in orthostaticcomplaints (p. 324).Other lysergic acid derivatives are the 5-HTantagonist methysergide, the dopamineagonist bromocriptine (p.116), and the hallucinogenlysergic acid diethylamide (LSD,p. 236).

Drugs Acting on Smooth Muscle 131A. Drugs used to alter smooth-muscle functionBronchial asthmaBiliary/renal colicO 2Spasmsmooth muscleBronchodilationβ 2 -Sympathomimeticse.g., salbutamolOH3CNO NCH3TheophyllineIpratropiumHNNSpasmolysisN-ButylscopolamineCH3H3C CH2 CH2 CH2 N +ScopolamineNitratese.g., nitroglycerinInhibition of laborβ 2 -Sympathomimeticse.g., fenoterolOxytocin antagonistAtosibanInduction of laborOxytocinProstaglandinsF 2α , E 2Secale cornutum(ergot)Fungus:Claviceps purpureaSecale alkaloidsTonic contraction of uteruse.g., ergometrineOxygen supplydiminishedContraindicationbefore deliveryIndication:postpartumuterine atoniaEffect onvasomotor tonee.g., ergotamineOH C NH RNCH 3HNFixation of lumen at intermediate caliber

132 Cardiac Drugs Cardiac DrugsPossible ways of influencing heart function(A). The pumping capacity of the heart dependson different factors: with increasingheart rate, the force of contraction increases(“positive staircase”); the degree of diastolicfilling regulates contraction amplitude (Starling’slaw of the heart). The sympathetic innervationwith its transmitter norepinephrineand the hormone epinephrine promotecontractile force generation (but also oxygenconsumption), and raise beating rate andexcitability (p. 88). The parasympathetic innervationlowers beat frequency becauseacetylcholine inhibits pacemaker cells(p.104).From the influence of the autonomic nervoussystem it follows that all sympatholyticor sympathomimetic and parasympatholyticor parasympathomimetic drugs can producecorresponding effects on cardiac performance.These possibilities are exploited therapeutically:for instance, β-blockers for suppressingexcessive sympathetic drive (p. 96);ipratropium for treating sinus bradycardia(p.108). An unwanted activation of the sympatheticsystem can result from anxiety,pain, and other emotional stress. In thesecases, the heart can be protected from harmfulstimulation by psychopharmaceuticalssuch as benzodiazepines (diazepam andothers; important in myocardial infarction).Cardiac work furthermore dependsstrongly on the state of the circulation system:physical rest or work demand appropriatecardiac performance; the level ofmean blood pressure is an additional decisivefactor. Chronic elevation of afterloadleads to myocardial insuf ciency. Therefore,all blood pressure-lowering drugs can havean important therapeutic influence on themyocardium. Vasodilator substances (e. g.,nitrates) lower the venous return and/or peripheralresistance and, hence, exert a favorableeffect in angina pectoris or heart failure.The heart muscle cells can also be reacheddirectly. Thus, cardiac glycosides bind to theNa + /K + -ATPases,(p.134),theCa-antagoniststo Ca 2+ channels (p.126), and antiarrhythmicsof the local anaesthetic type to Na +channels (p.136) in the plasmalemma.Events underlying contraction and relaxation(B). The signal triggering contraction isa propagated action potential (AP) generatedin the sinoatrial node. Depolarization of theplasmalemma leads to a rapid rise in cytosolicCa 2+ levels, which causes contraction(electromechanical coupling). The level ofCa 2+ concentration attained determines thedegree of shortening, i. e., the force of contraction.Sources of calcium are: (a) extracellularcalcium entering the cell throughvoltage-gated Ca 2+ channels; (b) calciumstored in the sarcoplasmic reticulum (SR);(c) calcium bound to the inside of the plasmalemma.The plasmalemma of cardiomyocytesextends into the cell interior in theform of tubular invaginations (transverse tubuli).The trigger signal for relaxation is the returnof the membrane potential to its restinglevel. During repolarization Ca 2+ levels fallbelow the threshold for activation of themyofilaments (3 × 10 –7 M): the plasmalemmalCa binding sites regain their Ca-bindingcapacity; calcium ions are pumped back intothe SR lumen and the plasmalemmal ATPasesmove Ca 2+ that entered during systole backout of the cell under expenditure of energy.Additionally, Ca 2+ is extruded from the cell inexchange for Na + (Na/Ca exchanger).

Cardiac Drugs 133A. Possible mechanisms for influencing heart functionDrugs withindirect actionDrugs with direct actionNutrient solutionPsychotropicdrugsParasympatheticForceRateSympatheticEpinephrineDrugs alteringpre- and afterloadB. Processes in myocardial contraction and relaxationβ-SympathomimeticsCardiac Phosphodiesterase inhibitorsglycosidesForceRateParasympathomimeticsCatamphiphilicCa-antagonistsLocal anestheticsContractionElectricalexcitationCa-channelSarcoplasmicreticulumTransverse tubulePlasmalemmalbinding sitesRelaxationNa/CaexchangePlasmalemmalbinding sitesNa+Ca 2 +10 -3 M0Ca 2+10 -5 M-80Na +Ca 2+ Ca-ATPaseCa 2 +10 -3 MCa 2+Ca 2+10 -7 MCa2+Na+Heart muscle cellHeart muscle cellMembrane potential[mV]ForceAction potentialtContraction300 mst

134 Cardiac Drugs Cardiac GlycosidesDiverse plants are sources of sugar-containingcompounds (glycosides) that also containa steroid ring system (structural formulas,A) and augment the contractile force ofheart muscle: cardiotonic glycosides, cardiosteroids,“digitalis.”The cardiosteroids possess a small therapeuticmargin, signs of intoxication are arrhythmiaand contracture (B). This therapeuticdrawback can be explained by the mechanismofaction.Cardiac glycosides (CG) bindtotheextracellulardomain of Na + /K + -ATPases andexclude this enzyme molecule for a timefrom further ion transport activity. Thehigh-af nity binding of CG is restricted to aparticular conformation that the enzymeadopts during its transport cycle. In the restingstate, Na + /K + -ATPase molecules are notbinding partners. Under normal conditionsonly a fraction of the Na + /K + -ATPase transportactivity is required to maintain the highgradients of Na + and K + across the plasmalemma.Low therapeutic concentrations ofCG occupy only a fraction of Na + /K + -ATPases;the decrease of the resulting pump activitycan easily be compensated for by recruitmentof resting ATPase molecules via a smallincrease of the intracellular Na + concentration.Attached to the ATPases there are Na +channels which, upon binding of CG to theenzyme, lose their specificity for Na + and areconverted to nonselective, promiscuouschannels: during systole, Ca 2+ will easilypass through this channel owing to its hugegradient (almost 4 orders of magnitude!).This results in an increased Ca 2+ -influx andaugmented contractile force. It should, however,benotedthatthemodeofactionofcardiosteroids is still a matter of debate.Mobilization of edema (weight loss) andlowering of heart rate are simple but decisivecriteria for achieving optimal dosing. IfATPase activity is inhibited too much, K + andNa + homeostasisisdisturbed:themembranepotential declines, arrhythmias occur. Intracellularflooding with Ca 2+ prevents relaxationduring diastole: contracture.The CNS effects of CGs (C) arealsoduetobinding to Na + /K + -ATPases. Enhanced vagalnerve activity causes a decrease in sinoatrialbeating rate and velocity of atrioventricularconduction. In patients with heart failure,improved circulation also contributes to thereduction in heart rate. Stimulation of thearea postrema leads to nausea and vomiting.Indications for CGs are:1 chronic congestive heart failure,2 atrial fibrillation or flutter, whereinhibitionof AV conduction protects the ventriclesfrom excessive atrial impulse activityand thereby improves cardiac performance(D).Signs of intoxication are:1 Cardiac arrhythmias, whichundercertaincircumstances are life-threatening, e. g., sinusbradycardia, AV-block, ventricular extrasystoles,ventricular fibrillation (ECG);2 CNS disturbances: characteristically, alteredcolor vision (xanthopsia), and alsofatigue, disorientation, hallucinations;3 anorexia, nausea, vomiting, diarrhea;4 renal: loss of electrolytes and water; thismust be differentiated from mobilizationof edema fluid accumulated in front of theheart during congestive failure, an effectexpected with therapeutic dosage.Therapy of intoxication: administration ofK + ,whichinter alia reduces binding of CG,but may impair AV-conduction; administrationof antiarrhythmics, such as phenytoin orlidocaine (p.136); oral administration of colestyramine(p.160) for binding and preventingabsorption of digitoxin present in theintestines (enterohepatic cycle), and mostimportantly injection of antibody (Fab) fragmentsthat bind and inactivate digitoxin anddigoxin. Compared with full antibodies, fragmentshave superior tissue penetrability,more rapid renal elimination, and lowerantigenicity.

Cardiac Glycosides 135A. Cardiac glycosidesEnteral absorptionEliminationDigoxinCH 3OHOOH3COHOCH 3OHO~ 80%t1 2: 2–3 daysprolonged withdecreased renalfunctionbetter controlOH3ODigitoxinCH 3OHOOHH3CO 33CH 314OHO100%t1 2: 5–7 daysindependentof renalfunctionSlow waningof intoxicationB. Therapeutic and toxic effects of cardiac glycosides (CG)ContractionArrhythmiaContractureTime “therapeutic” “toxic” Dose of cardiac glycoside (CG)Na/K-ATPaseNa + CGCGNa + Na + Na +Coupling-Ca 2+K + K +K + Ca 2+K + Ca 2+CGHeart muscle cellCGCGC. Cardiac glycoside effects on the CNSDisturbanceof color visionD. Cardiac glycoside effects inatrial fibrillation“Re-entrant”excitation inatrialfibrillationArea postrema:nausea, vomitingExcitation ofN. vagus:Heart rateCardiacglycosideDecrease inventricularrate

136 Cardiac Drugs Antiarrhythmic DrugsThe electrical impulse for contraction(propagated action potential; p.138) originatesin pacemaker cells of the sinoatrialnode and spreads through the atria, atrioventricular(AV) node, and adjoining partsof the His–Purkinje fiber system to the ventricles(A). Irregularities of heart rhythm caninterfere dangerously with cardiac pumpingfunction.I. Drugs for Selective Control of Sinoatrialand AV NodesIn some forms of arrhythmia, certain drugscan be used that are capable of selectivelyfacilitating and inhibiting (green and red arrows,respectively) the pacemaker functionof sinoatrial or atrioventricular cells.Sinus bradycardia. An abnormally low sinoatrialimpulse rate (< 60/min) can beraised by parasympatholytics. The quaternaryipratropium is preferable to atropine,becauseitlacksCNSpenetrability(p.108).Sympathomimetics also exert a positivechronotropic action; they have the disadvantageof increasing myocardial excitability(and automaticity) and, thus, promoting ectopicimpulse generation (tendency to extrasystolicbeats). In cardiac arrest, epinephrine,given by intrabronchial instillation orintracardiac injection, can be used to reinitiateheart beat.Sinus tachycardia (resting rate > 100 beats/min). β-Blockers eliminate sympatho-excitationand lower cardiac rate. Sotalol is noteworthybecause of its good antiarrhythmicaction (caution: QT-prolongation)Atrial flutter or fibrillation. An excessiveventricular rate can be decreased by verapamil(p.126) or cardiac glycosides (p.134).These drugs inhibit impulse propagationthrough the AV node, so that fewer impulsesreach the ventricles.II. Nonspecific Drug Actions on ImpulseGeneration and PropagationIn some types of rhythm disorders, antiarrhythmicsof the local anesthetic, Na + -channel blocking type are used for bothprophylaxis and therapy. These substancesblock the Na + channel responsible for thefast depolarization of nerve and muscle tissues.Therefore, the elicitation of action potentialsis impeded and impulse conductionis delayed. This effect may exert a favorableinfluence in some forms of arrhythmia, butcan itself act arrhythmogenically. Unfortunately,antiarrhythmics of the local anesthetic,Na + -channel blocking type lack suf -cient specificity in two respects: (1) otherion channels of cardiomyocytes, such as K +and Ca + channels, are also affected (abnormalQT prolongation); and (2) their action isnot restricted to cardiac muscle tissue butalso impacts on neural tissues and braincells. Adverse effects on the heart includeproduction of arrhythmias and lowering ofheart rate, AV conduction, and systolic force.CNS side effects are manifested by vertigo,giddiness, disorientation, confusion, motordisturbances, etc.Some antiarrhythmics are rapidly degradedinthebodybycleavage(seearrowsin B); these substances are not suitable fororal administration but must be given intravenously(e. g., lidocaine).Irrespective of the cause underlying atrialfibrillation, formation of a thrombus mayoccur in the atria, because blood stagnatesin the auricles. From such a thrombus anembolus may be dislodged and carried intothe arterial supply of the brain, precipitatinga stroke. It is therefore imperative to instituteanticoagulant therapy in atrial fibrillation.For immediate effect, heparin preparationsare indicated; subsequently, changeover tovitamin K antagonists (e. g., phenprocoumon)may be made. As long as episodes ofarrhythmia occur, therapy must be continued.

Antiarrhythmic Drugs 137A. Cardiac impulse generation and conductionSinus nodeAtriumAV-nodeParasympatholyticsβ-SympathomimeticsBundle of HisTawara (AV node)bundle branchesPurkinjefibersVentricleβ-BlockerVerapamilCardiacglycosideVagalstimulationB. Antiarrhythmics of the Na+-channel blocking typeMain effectAntiarrhythmiceffectAntiarrhythmics of the local anesthetic(Na+-channel blocking) type:Inhibition of impulse generation and conductionEsterasesProcaineO C 2 H 5+H 2 NC O CH 2 CH 2 NHC 2 H 5Adverse effectsProcainamideO C 2 H 5+H 2 NC N CH 2 CH 2 NHHC 2 H 5CNS disturbancesCH 3CH 3NHOCCH 2LidocaineC 2 H 5+NHC 2 H 5ArrhythmiaCardiodepressionCH 3H+O CH 2 CH NHHCHCH 33Mexiletine

138 Cardiac Drugs Electrophysiological Actions ofAntiarrhythmics of the Na + - ChannelBlocking TypeAction potential and ionic currents. Thetransmembrane electrical potential ofcardiomyocytes can be recorded throughan intracellular microelectrode. Upon electricalexcitation, the resting potential showsa characteristic change—the action potential(AP). Its underlying cause is a sequence oftransient ionic currents. During rapid depolarization(phase 0), there is a short-livedinflux of Na + through the membrane. A subsequenttransient influx of Ca 2+ (aswellasofNa + ) maintains the depolarization (phase 2,plateau of AP). A delayed ef ux of K + returnsthe membrane potential (phase 3, repolarization)to its resting value (phase 4). Thevelocity of depolarization determines thespeed at which the AP propagates throughthe myocardial syncytium.The transmembrane ionic currents involveproteinaceous membrane pores: Na + ,Ca 2+ , and K + channels. In (A), the phasicchange in the functional state of Na + channelsduring an action potential is illustrated.Na+-channel blocking antiarrhythmics reducethe probability of Na + channels to openupon membrane depolarization (“membranestabilization”). The potential consequencesare (A, bottom): (1) A reduction inthe velocity of depolarization and a decreasein the speed of impulse propagation; aberrantimpulse propagation is impeded. (2)Depolarization is entirely absent; pathologicalimpulse generation, e. g., in the marginalzone of an infarction, is suppressed. (3) Thetime required until a new depolarization canbe elicited, i. e., the refractory period, is increased;prolongation of the AP (see below)contributes to the increase in refractory period.Consequently, premature excitationwith risk of fibrillation is prevented.Mechanism of action. Na + -channel blockingantiarrhythmics resemble most local anestheticsin being cationic amphiphilic molecules(p. 206; exception: phenytoin, p.191).Possible molecular mechanisms of their inhibitoryeffects are outlined on p. 202 inmore detail. Their low structural specificityis reflected by a low selectivity toward differentcation channels. Besides the Na + channel,Ca 2+ and K + channels are also likely to beblocked. Accordingly, cationic amphiphilicantiarrhythmics affect both the depolarizationand repolarization phases. Dependingon the substance, AP duration can be increased(Class IA), decreased (Class IB), orremain the same (Class IC). Antiarrhythmicsrepresentative of these categories include:Class IA—quinidine, procainamide, ajmaline,disopyramide; Class IB—lidocaine, mexiletine,tocainide; Class IC—flecainide, propafenone.K 2+ –channel blocking antiarrhythmics. Thedrug amiodarone and the β-blocker sotalolhave been assigned to Class III, comprisingagents that cause marked prolongation of APwith less effect on the velocity of depolarization.Note that Class II is representedby β-blockersandClassIVbytheCa 2+ -channelblockers verapamil and diltiazem (seep.126).Therapeutic uses. Because of their narrowtherapeutic margin, antiarrhythmics are onlyemployed when rhythm disturbances are ofsuch severity as to impair the pumping actionof the heart, or when there is a threat ofother complications. Combinations of differentantiarrhythmics are not recommended(e. g., quinidine plus verapamil). Someagents, such as amiodarone, are reservedfor special cases. This iodine-containing substancehas unusual properties: its eliminationhalf-life is 50–70 days; depending on itselectrical charge, it is bound to apolar andpolar lipids, stored in tissues (corneal opacification,pulmonary fibrosis); and it interfereswith thyroid function.

Antiarrhythmics of Na+-Channel Blocking Type 139A. Effects of antiarrhythmics of the Na+-channel blocking typeMembrane potential [mV]0-80001Action potential2Rate ofdepolarizationRefractory period32504Time [ms]Heart muscle cellNa + Ca 2+ (+Na + )K +Phase 0 Phases 1,2Phase 3 Phase 4FastNa + Slow Ca-entry2+ -entryIonic currents during action potentialNa +Na+-channelsOpen (active)ClosedOpening impossible(inactivated)States of Na+-channels during an action potentialClosedOpening possible(resting, can beactivated)Inhibition ofNa+-channel openingAntiarrhythmics of theNa+-channel blocking typeInexcitabilityStimulusRate ofdepolarizationSuppressionof AP generationProlongation of refractory period =duration of inexcitability

140 Antianemics Drugs for the Treatment of AnemiasAnemia denotes a reduction in red blood cellcount or hemoglobin content, or both.Erythropoiesis (A)Blood corpuscles develop from stem cellsthrough several cell divisions (n =17!).Hemoglobinis then synthesized and the cellnucleus is extruded. Erythropoiesis is stimulatedby the hormone erythropoietin (a glycoprotein),which is released from the kidneyswhen renal oxygen tension declines. Anephrogenic anemia can be ameliorated byparenteral administration of recombinanterythropoietin (epoetin alfa) or hyperglycosylatederythropoietin (darbepoetin; longerhalf-life than epoetin).Even in healthy humans, formation of redblood cells and, hence, the oxygen transportcapacity of blood, is augmented by erythropoietin,.This effect is equivalent to high-altitudetraining and is employed as a dopingmethod by high-performance athletes.Erythropoietin is inactivated by cleavage ofsugar residues, with a biological half-life of~ 5 hours after intravenous injection and a t ½> 20 hours after subcutaneous injection.Given adequate production of erythropoietin,a disturbance of erythropoiesis isdue to two principal causes. (1) Cell multiplicationis inhibited because DNA synthesisis insuf cient. This occurs in deficienciesof vitamin B 12 or folic acid (macrocytic hyperchromicanemia). (2) Hemoglobin synthesisis impaired. This situation arises in iron deficiency,sinceFe2+ is a constituent of hemoglobin(microcytic hypochromic anemia).Vitamin B 12 (B)Vitamin B 12 (cyanocobalamin) isproducedby bacteria; vitamin B 12 generated in thecolon, however, is unavailable for absorption.Liver, meat, fish, and milk productsare rich sources of the vitamin. The minimalrequirement is about 1 µg/day. Enteral absorptionof vitamin B 12 requires the so-called“intrinsic factor” from parietal cells of thestomach. The complex formed with this glycoproteinundergoes endocytosis in theileum. Bound to its transport protein, transcobalamin,vitamin B 12 is destined for storagein the liver or uptake into tissues.A frequent cause of vitamin B 12 deficiencyis atrophic gastritis leading to a lackof intrinsic factor. Besides megaloblastic anemia,damage to mucosal linings and degenerationof myelin sheaths with neurologicalsequelae will occur (pernicious anemia).The optimal therapy consists in parenteraladministration of cyanocobalamin or hydroxycobalamin(vitamin B 12a ;exchangeof–CN for –OH group). Adverse effects, in theform of hypersensitivity reactions, are veryrare.Folic Acid (B)Leafy vegetables and liver are rich in folicacid (FA). The minimal requirement is~ 50 µg/day. Polyglutamine-FA in food is hydrolyzedto monoglutamine-FA prior tobeing absorbed. Causes of deficiency includeinsuf cient intake, malabsorption,and increased requirements during pregnancy(hence the prophylactic administrationduring pregnancy). Antiepileptic drugsand oral contraceptives may decrease FA absorption,presumably by inhibiting the formationof monoglutamine-FA. Inhibition ofdihydro-FA reductase (e. g., by methotrexate,p. 300) depresses the formation of the activespecies, tetrahydro-FA. Symptoms of deficiencyare megaloblastic anemia and mucosaldamage. Therapy consists in oral administrationof FA.Administration of FA can mask a vitaminB 12 deficiency. Vitamin B 12 is required for theconversion of methyltetrahydro-FA to tetrahydro-FA,which is important for DNA-synthesis(B). Inhibition of this reaction due tovitamin B 12 deficiency can be compensatedby increased FA intake. The anemia is readilycorrected; however, nerve degenerationprogresses unchecked and its cause is mademore dif cult to diagnose by the absence ofhematological changes. Indiscriminate use ofFA-containing multivitamin preparationscan, therefore, be harmful.

Drugs for the Treatment of Anemias 141A. Erythropoiesis in bone marrowInhibition of DNAsynthesis(cell multiplication)Vit. B 12 deficiencyFolate deficiencyErythropoetinInhibition ofhemoglobin synthesisIron deficiencyVery few largehemoglobin-richerythrocytesFew smallhemoglobin-poorerythrocytesB. Vitamin B 12 and folate metabolismFolic acid H 4DNAsynthesisVit. B 12Folic acidH 3C- Folic acid H 4H 3C- Vit. B 12Vit. B 12H 3C-Storage supply for3 yearsVit. B 12TranscobalaminIIIntrinsicfactorHClParietal celli.m.Streptomycesgriseus

142 Antianemics Iron CompoundsNot all iron ingested in food is equally absorbable.Trivalent Fe 3+ is virtually not takenup from the neutral milieu of the small bowel,where the divalent Fe 2+ is markedly betterabsorbed. Uptake is particularly ef cientin the form of heme (present in hemoglobinand myoglobin). Within the mucosal cells ofthe gut, iron is oxidized and either depositedas ferritin (see below) or passed on to thetransport protein, transferrin. The amountabsorbed does not exceed that needed tobalance losses due to epithelial sheddingfrom skin and mucosae or hemorrhage (socalled“mucosal block”). In men this amountis ~ 1mg/day,inwomenitis~ 2mg/day(becauseof menstrual blood loss); it correspondsto about 10% of the dietary intake.The transferrin–iron complex undergoes endocytoticuptake into erythrocyte precursorsto be utilized for hemoglobin synthesis.About 70% of the total body store of iron(~ 5 g) is contained within erythrocytes.When these are degraded by macrophagesof the mononuclear phagocyte system, ironis liberated from hemoglobin. Fe 3+ can bestored as ferritin (= protein apoferritin+Fe 3+ )orbereturnedtoerythropoiesissitesvia transferrin.A frequent cause of iron deficiency ischronic blood loss due to gastric/intestinalulcers or tumors. One liter of blood contains500mgofironinhealthycondition.Despitea significant increase in absorption rate, absorptionis unable to keep up with losses andthe body store of iron falls. Iron deficiencyresults in impaired synthesis of hemoglobinand anemia.The treatment of choice (after the causeof bleeding has been found and eliminated)consists in the oral administration of Fe 2+compounds,e. g., ferrous sulfate (daily dose100 mg of iron, equivalent to 300 mg ofFeSO 4 , divided into multiple doses). Replenishingof iron stores may take severalmonths. Oral administration, however, is advantageousin that it is impossible to overloadthe body with iron through an intactmucosa because of its demand-regulated absorption(mucosal block).Adverse effects. The frequent gastrointestinalcomplaints (epigastric pain, diarrhea,constipation) necessitate intake of iron preparationswith or after meals, although absorptionis higher from the empty stomach.Interactions. Antacids inhibit iron absorption.Combination with ascorbic acid (vitaminC) to protect Fe 2+ from oxidation to Fe 3+is theoretically sound but practically is notneeded.Parenteral administration of Fe 3+ salts isindicated only when adequate oral replacementis not possible. There is a risk of overdosage,with iron deposition in tissues(hemosiderosis). The binding capacity oftransferrin is limited and free Fe 3+ is toxic.Therefore, Fe 3+ complexes are employed thatcan donate Fe 3+ directly to transferrin or canbe phagocytosed by macrophages, enablingiron to be incorporated into the ferritinstore. Possible adverse effects are: with i.m.injection, persistent pain at the injection siteand skin discoloration; with i.v. injection,flushing, hypotension, anaphylactic shock.

Iron Compounds 143A. Iron: possible routes of administration and fate in the organismFe(III) salts nonabsorbableOralintakeFe(II) saltsHeme-FeFe(III)AbsorptionDuodenumupper jejunumFe(III)FerritinTransportPlasmaFe(III)TransferrinFe(III)Parenteraladministrationi.v.i.m.Uptake intoerythroblastbone marrowHemoglobinFe(III) complexesFe(III)ErythrocytebloodFerritinHemosiderin= aggregatedferritinLoss throughbleedingUptake into macrophagesspleen, liver, bone marrow

144 Antithrombotics Prophylaxis and Therapy ofThrombosesUpon vascular injury, the coagulation systemis activated: thrombocytes and fibrin moleculescoalesce into a “plug” that seals thedefect and halts bleeding (hemostasis). Unnecessaryformation of an intravascularclot—a thrombosis—can be life-threatening.If the clot forms on an atheromatous plaquein a coronary artery, myocardial infarction isimminent; a thrombus in a deep leg vein canbe dislodged and carried into a lung arteryand can cause pulmonary embolism.Drugs that decrease the coagulability ofblood, suchascoumarins and heparin (A)are employed for the prophylaxis ofthromboses. In addition, attempts are directed,by means of acetylsalicylic acid, atinhibiting the aggregation of blood platelets,which are prominently involved in intra-arterialthrombogenesis (p.152). For thetherapy of thrombosis, drugs are used thatdissolve the fibrin meshwork—fibrinolytics(p.150).An overview of the coagulation cascadeand sites of action for coumarins and heparinis shown in (A). There are two ways to initiatethe cascade (B): (1) conversion of factorXII into its active form (XII a , intrinsic system)at intravascular sites denuded of endothelium;(2) conversion of factor VII into VII a(extrinsic system) under the influence of atissue-derived lipoprotein (tissue thromboplastin).Both mechanisms converge via factorX into a common final pathway.The clotting factors are protein molecules.“Activation” mostly means proteolysis(cleavage of protein fragments) and, with theexception of fibrin, conversion into proteinhydrolyzingenzymes (proteases). Some activatedfactors require the presence of phospholipids(PL) and Ca 2+ for their proteolyticactivity. Conceivably, Ca 2+ ions cause the adhesionof factor to a phospholipid surface, asdepicted in (B). Phospholipids are containedin platelet factor 3 (PF3), which is releasedfrom aggregated platelets, and in tissuethromboplastin (A). The sequential activationof several enzymes allows the aforementionedreactions to “snowball” (symbolizedin C by increasing number of particles),culminating in massive production of fibrin.Ca 2+ -chelators (B) prevent the enzymaticactivity of Ca 2+ -dependent factors; they containCOO – groups that bind Ca 2+ ions (C):citrate and EDTA (ethylenediaminetetraaceticacid) form soluble complexes with Ca 2+ ;oxalate precipitates Ca 2+ as insoluble calciumoxalate. Chelation of Ca 2+ cannot be usedin vivo for therapeutic purposes becauseCa 2+ concentrations would have to be loweredto a level incompatible with life (hypocalcemictetany). These compounds (sodiumsalts) are, therefore, used only for renderingblood incoagulable outside the body. Thiseffect can be reversed at any time by additionof Ca 2+ ions.In vivo, the progression of the coagulationcascade can be inhibited as follows (C):1. Coumarin derivatives decrease the bloodconcentrations of inactive factors II, VII, IXand X, by inhibiting their synthesis in theliver.2. The complex consisting of heparin andantithrombin III neutralizes the proteaseactivity of activated factors; unlike unfractionatedheparin, low-molecular-weightheparin fragments or the “minimal molecularsubunit of heparin,” fondaparinux,inhibitonly activated factor Xa when complexedwith antithrombin III.3. Hirudin and its derivatives (bivalirudin,lepirudin) block the active center ofthrombin.

Prophylaxis and Therapy of Thromboses 145A. Activation of clotting B. Inhibition of clotting by removal of Ca 2+PlateletsEndothelial defectClotting factorCOO –XIICOO –Tissue+thrombokinase+XIIa–PF 3 VIIa VII– – – – –CaVesselrupturePhospholipids,e.g., PF 3FibrinCa 2+ chelationCitrateEDTAOxalateonly in vitroC. Inhibition of clotting cascade in vivoXIIXIIaXIXIaSynthesis susceptible toinhibition by coumarinsReaction susceptible toinhibition by heparin–antithrombin complexIXVIII + Ca 2+ + PlIXaVIIaCa 2+ + Pl (phospholipids)VIIXV + Ca 2+ + PlXaSusceptible to inhibition alsoby low-molecular-weightheparin and fondaparinuxProthrombin IIIIa ThrombinHirudinFibrinogen IIa Fibrin

146 Antithrombotics Vitamin K Antagonists and Vitamin KVitamin K promotes the hepatic γ-carboxylationof glutamate residues on the precursorsof factors II, VII, IX, and X. Carboxylgroups are required for Ca 2+ -mediated bindingto phospholipid surfaces (p.144). Thereare several vitamin K derivatives of differentorigins: K 1 (phytomenadione) from chlorophyllousplants; K 2 from gut bacteria; and K 3(menadione) synthesized chemically. All arehydrophobic and require bile acids for absorption.Oral anticoagulants. Structurally related tovitamin K, 4-hydroxycoumarins act as”false” vitamin K and prevent regenerationof reduced (active) vitamin K from vitamin Kepoxide, hence the synthesis of vitamin K-dependent clotting factorsCoumarins are well absorbed after oraladministration. Their duration of actionvaries considerably. Synthesis of clotting factorsdepends on the intrahepatocytic concentrationratio between coumarins and vitaminK. The dose required for an adequateanticoagulant effect must be determined individuallyfor each patient (monitoring ofthe International Normalized Ratio, INR).Indications. Hydroxycoumarins are used forthe prophylaxis of thromboembolism as, forinstance, in atrial fibrillation or after heartvalve replacement.The most important adverse effect isbleeding. With coumarins, this can be counteractedby giving vitamin K 1 . However, coagulabilityof blood returns to normal onlyafter hours or days, when the liver has resumedsynthesis and restored suf cientblood levels of carboxylated clotting factors.In urgent cases, deficient factors must bereplenished directly (e. g., by transfusion ofwhole blood or of prothrombin concentrate).Other notable adverse effects include: atthe start of therapy, hemorrhagic skin necrosesand alopecia; with exposure in utero,disturbances of fetal cartilage and bone formationand CNS injury (due to bleeding);enhanced risk of retroplacental bleeding. Possibilities for Interference (B)Adjusting the dosage of a hydroxycoumarincalls for a delicate balance between the opposingrisks of bleeding (effect too strong)and of thrombosis (effect too weak). Afterthe dosage has been titrated successfully,loss of control may occur if certain interferingfactors are ignored. If the patient changesdietary habits and consumes more vegetables,vitamin K may predominate over thevitamin K antagonist. If vitamin K-producinggut flora is damaged in the course of antibiotictherapy, the antagonist may prevail.Drugs that increase hepatic biotransformationvia enzyme induction (p. 38) may accelerateelimination of a hydroxycoumarin andthus lower its blood level. Inhibitors of hepaticbiotransformation (e. g., the H 2 blockercimetidine) augment the action of hydroxycoumarins.Apart from pharmacokinetic alterations,pharmacodynamic interactionsmust be taken into account. Thus, acetylsalicylicacid is contraindicated because (a) itretards hemostasis by inhibiting platelet aggregationand (b) it may cause damage to thegastric mucosa with erosion of blood vessels.

Vitamin K Antagonists and Vitamin K 147A. Vitamin K-antagonists of the coumarin type and vitamin KDuration of action/daysVit. K 1CH 3 CH 3R =3PhytomenadioneCH3R =CHCH 2 CH 3PhenprocoumonVit. K 2R =CH 3 CH 3CH 31–12R =CHCH 2 C CH 3OWarfarinVit. K 3R = HMenadioneR =CHNO 2CH 2 C CH 3OAcenocoumarolOCarboxylation of glutamine residuesH 2 NCCHII, VII, IX, XCH 2OCHHOOC COOHCH 3Vit. K-EpoxidOOOHRVit. K derivatesVit. K4-HydroxycoumarinderivativesOHRB. Possible interactionsRisk of thrombosisOptimal adjustmentRisk of bleedingIncreased intake ofvitamin K-rich foodIncreaseVitamin KeffectDamage to vitamin K-producingintestinal bacteria by antibioticsDecreaseDecreaseInhibition of enteral coumarin absorptionby adsorbents, e.g., antacids, medicinalcharcoalAcceleration of hepatic coumarinmetabolism: enzyme induction, e.g.,by carbamazepine, rifampicinHydroxycoumarineffectInhibition of hepatic coumarinmetabolism, e.g., by cimetidine,metronidazoleIncrease

148 Antithrombotics Heparin (A)Occurrence and structure. Heparin can beobtained from porcine gut, where it ispresent (together with histamine) in storagevesicles of mast cells. Heparin molecules arechains of amino sugars bearing –COO – and–SO 3 – groups. Chain length is not constantand anticoagulant ef cacy varies with chainlength. The potency of a preparation isstandardized in international units of activity(IU)bybioassayandcomparisonwithareference preparation. The molecular weight(MW) for unfractionated heparin ranges from4000 to 40 000, with a peak around 15 000.Low-molecular-weight fractionated heparincanbeproducedbycleavageofnativeheparin;molecular size is less heterogeneous,withameanMWof5000(e.g.,certoparin,dalteparin, enoxaparin).The synthetic fondaparinux(MW 1728) resembles the basic pentasaccharidesubunit of heparin, essential foractivity. The numerous negative charges aresignificant in several respects: (1) they contributeto complex formation with antithrombinIII that underlies the anticoagulanteffect; (2) they permit binding of heparin toits antidote, protamine (a polycationic proteinfrom salmon sperm); (3) they conferpoor membrane penetrability, necessitatingadministration of heparin by injection.Mechanism of action. Antithrombin III (ATIII) is a circulating glycoprotein capable ofinhibiting activated clotting factors by occupationand irreversible blockade of the activecenter. Heparin acts to inhibit clotting byaccelerating formation of this complex morethan 1000-fold. Activated clotting factorshave differing requirements for optimalchain length of heparin. For instance, to inactivatethrombin, the heparin moleculemust simultaneously contact the factor andAT III. With factor Xa, however, contact betweenheparin and AT III is suf cient forspeeding up inactivation.Indications. Heparin is used for the prophylaxisand therapy of thrombosis. For theformer, low dosages, given subcutaneously,are suf cient. Unfractionated heparin mustbe injected about three time daily, fractionatedheparins and fondaparinux can beadministered once daily. For treatment ofthrombosis, heparin must be infused intravenouslyin an increased daily dose.Adverse effects. When bleeding is inducedby heparin, the heparin action can be instantlyreversed by protamine. Against fractionatedheparins and fondaparinux, protamineislessornoteffective.Heparin-inducedthrombocytopenia type II (HIT II) is adangerous complication. It results from formationof antibodies that precipitate withbound heparin on platelets. The plateletsaggregate and give rise to vascular occlusions.Because of the thrombocytopenia,hemorrhages may occur. Fondaparinux is alsocontraindicated in HIT II.The drug danaparoid consists mostly ofthe heparinoid heparan sulfate. Its chainsare composed of a part of the heparin molecule(indicated by blue color underlay). Itseffect is mediated by AT III. Hirudin and Derivatives (B)The polypeptide hirudin from the saliva ofthe European medicinal leech inhibits clottingof the leech’s blood meal by blockade oftheactivecenterofthrombin.ThisactionisindependentofATIIIandthusalsooccursinpatients with AT III deficiency. Lepirudin anddesrudin are yeast-derived recombinant analogues.They can be used in patients withHIT II.Ximelagatran is a modified thrombin antagonistsuitable for oral use.

Heparin 149A. Heparins: origin, structure, and mechanism of actionMast cellOCH2 OSO3 –OCOO –OOHOOHHN C CH3 OHOPentasaccharide basic unitOCH2 OSO3 –OOHN SO3 –OSO3 –OCOO –OH OOSO3 –CH2 OSO3 –OOHOHN SO3 –Standard heparinunfractionatedmeanMW ~ 15 000Low-MW heparinfractionatedmean MW ~ 5000Antidote protamine~ 3x daily s.c. ~once daily s.c.ActivatedclottingfactorIIaThrombinAccelerationof inactivationXaInactivationAntithrombin IIIStandard heparinrequiredLow-MW heparinsufficientHeparin-induced thrombocytopenia type IIAntibodyHeparinPlateletaggregationPlateletThromboembolismB. Hirudin and derivativesLeucine Isoleucine: LepirudinH 2 NHirudinIIaThrombinDirectselectiveinhibitionHirudo medicinalis

150 Antithrombotics FibrinolyticsThe fibrin meshwork of a blood clot can becleaved by plasmin. As a protease, plasmincan break down not only fibrin but also fibrinogenand other proteins. Plasmin derivesfrom an inactive precursor, plasminogen,present in blood. Under physiological conditions,specificity of action for fibrin isachieved because, among other things, activationtakes place on the fibrin clot.The tissue plasminogen activator (t-PA)is released into the blood from endothelialcells when blood flow stagnates. Next to itscatalytic center, this protease possesses otherfunctional domains, including dockingsites for fibrin. During contact with fibrin,plasminogen–plasmin conversion rate isseveral-fold higher than in streaming blood.Plasminogen also contains a binding domainfor fibrin.Plasminogen activators available fortherapeutic use are designated as fibrinolytics;they are infused intravenously inmyocardial infarction, stroke, deep leg veinthrombosis, pulmonary embolism, and otherthrombotic vascular occlusions. The earliertreatment is started after thrombus formation,the better is the chance of achievingpatency of the occluded vessel.The desired effect carries with it the risk ofbleeding as the most important adverse effect,because, apart from the intravascularfibrin clot forming the thrombus, other fibrincoagula sealing defects in the vascular wallare dissolved as well. Moreover, use of fibrinolyticsentails the risk that fibrinogen andother clotting factors circulating in blood willundergo cleavage (“systemic lytic state”).Streptokinase is the oldest available fibrinolytic.By itself it lacks enzymatic activity;only after binding to a plasminogen moleculeis a complex formed that activates plasminogen.Streptokinase is produced bystreptococcal bacteria. Streptokinase antibodiesmay be present as a result of previousstreptococcal infections and may lead to incompatibilityreactions.Urokinase is an endogenous plasminogenactivator that occurs in different organs. Urokinaseused therapeutically is obtained fromhuman cultured kidney cells. Circulatingantibodies are not expected. The substanceis more expensive than streptokinase andalso does not depend on fibrin in its action.Alteplase is a recombinant tissue plasminogenactivator (rt-PA). As a result of itsproduction in eukaryotic Chinese hamsterovary (CHO) cells, carbohydrate residuesarepresentasinthenativesubstance.Atthe therapeutically used dosage, alteplaseloses its “fibrin dependence” and thus alsoactivates circulating plasminogen. In freshmyocardial infarctions, alteplase appears toproduce better results than does streptokinase.Tenecteplase is a variant of alteplase thathas been altered by six point mutations, resultingin a significant prolongation of itsplasma half-life (tenecteplase t ½ = 20 minutes;alteplase t ½ = 3–4 minutes). Tenecteplaseis dosed according to body weight andgiven by intravenous bolus injection.Reteplase is a deletion variant of t-PA thatlacks both fibrin-binding domains and oligosaccharideside chains (manufactured inprokaryotic E. coli). It is eliminated moreslowly than alteplase. Whereas alteplase isgiven by infusion, reteplase can be administeredintwobolusinjectionsspaced30minutesapartPlasmin inhibitors. ε-Aminocaproic acid aswell as tranexamic acid and p-aminomethylbenzoicacid (PAMBA) are plasmin inhibitorsthat can be useful in bleeding complications.They exert an inhibitory effect by occupyingthe fibrin binding site of plasminogen orplasmin.

Fibrinolytics 151A. FibrinolyticsFibrint-PAFibrinolysisPlasminogenPlasminEndotheliumt-PA: tissueplasminogen activatorPlasminogen activatorsActive centerAlteplase =recombinant t-PACHOcellsStreptokinaseStreptococciFevers, chills,inactivationUrokinaseAntibodiesfrom priorinfectionsPlasmin inhibitorH 2 NCOOHε-Aminocaproic acidcDNATenecteplase =t-PA with 6 aminoacid mutationsReteplase =nonglycosylatedvariant of t-PAHuman kidney cell cultureBlockade ofplasminogen/plasminbinding site on fibrinE. coliTruncated cDNA

152 Antithrombotics Intra- arterial ThrombusFormation (A)Activation of platelets, e. g., upon contactwith collagen of the extracellular matrixafter injury to the vascular wall, constitutesthe immediate and decisive step in initiatingthe process of primary hemostasis,i.e.,cessationof bleeding. However in the absenceof vascular injury, platelets can be activatedas a result of damage to the endothelial celllining of blood vessels. Among the multiplefunctions of the endothelium, the productionof prostacyclin and nitric oxide (NO)plays an important role because both substancesinhibit the tendency of platelets toadhere to the endothelial surface. Impairmentof endothelial function, e. g., due tochronic hypertension, chronic elevation ofplasma LDL levels or of blood glucose, andcigarette smoking, increases the probabilityof adhesion between thrombocytes and endothelium.The deceleration of fast flowingplateletsoccursthroughaninteractionbetweenthe glycoprotein Ibα (GP I) in the plateletmembrane and von Willebrand factorin the endothelium and basal membrane(denuded after endothelial injury). For theproper activation of the platelet, interactionwith subendothelial collagen of an additionalplatelet glycoprotein (GP IV) is necessary.As soon as platelets are activated (see p.154),they change their shape and gain af nity forfibrinogen. This results from a conformationalchange of glycoprotein IIb/IIIa in the plateletmembrane. Platelets can now be linkedto each other via fibrinogen bridges (A).Platelet aggregation proceeds like an avalanchebecause, once activated, one plateletcan activate other platelets. On the injuredendothelial cell a thrombus is formed, whichobstructs blood flow. Ultimately, the vascularlumen is occluded by the thrombus as thelatter is solidified by vasoconstriction promotedby the release of serotonin andthromboxane A 2 from the aggregated plateletsand by locally activated thrombin.Thrombin plays a twofold part in thrombusformation: as a protease, thrombin cleavesfibrinogen and thus initiates the formationof fibrin clot (blood coagulation, p.144). Theeffects of thrombin on platelets and endothelialcells, however, involve a proteolyticactivation of receptors coupled to G-proteins(so-called protease-activated receptors).When these events occur in a larger, functionallyimportant artery, myocardial infarctionor stroke may be the result.Von Willebrand factor plays a key role inthrombogenesis. Lack of this factor is thecause of thrombasthenia, the inability tostaunch bleeding by platelet aggregation. Arelative deficiency of von Willebrand factorcan be transiently relieved by injection ofthe vasopressin analogue desmopressin, becausethis substance makes factor availablefrom stored supplies. Formation, Activation, andAggregation of Platelets (B)Platelets are fragments of multicellularmegakaryocytes. They constitute the smallestformed elements of blood (diameter1–4 µm) and, devoid of a cell nucleus, areno longer capable of protein synthesis.Platelets can be activated by various stimuli,leading to: Change in shape Conversion of integrin GP IIb/IIIa into itsactive conformation Releaseofactivesubstancessuchasserotonin,platelet-activating factor (PAF),ADP, and thromboxane A 2 .Allthesesubstancesactivate other platelets.

Intra-arterial Thrombus Formation 153A. Thrombogenesis1. Adhesion2. Activation 3. AggregationEndothelial defectPlateletnot activatedActivatedplateletvon WillebrandfactorCollagenFibrinogenB. Aggregation of platelets by the integrin GPIIb/IIIaMegakaryocyteActivationFibrinogenbinding:GlycoproteinIIb/IIIaContact withcollagenADPThrombinThromboxane A 2SerotoninPlateletPlateletFibrinogenGlycoproteinIIb/IIIaAggregationimpossiblepossible

154 Antithrombotics Inhibitors of PlateletAggregation (A)Collagen, thrombin, ADP, and thromboxaneA 2 are the most important mediators thatinduce maximal activation and aggregationof platelets. The first essential step in plateletactivation is mediated by direct contact withcollagen, which can bind to different proteinsin the platelet membrane. The mostimportant “collagen receptor” in the plateletmembrane is glycoprotein VI (GP VI). Activationinduces a change in platelet shape andtriggers secretion of substances stored inintracellular platelet granula (e. g., ADP, serotonin).In addition, GP VI stimulates cyclooxygenase(COX-1), causing thromboxane A 2to be produced and released from arachidonicacid (p.196).The propensity of platelets to aggregatecan be inhibited by various pharmacologicalinterventions.Acetylsalicylic acid (ASA) prevents COX-1-mediated synthesis of thromboxane. Lowdaily doses (75–100 mg) may be suf cient.Indications include prophylaxis of re-infarctionafter myocardial infarction and ofstroke. Despite the low dosage, adverse effectssuch as gastric mucosal damage orprovocation of asthma attacks cannot beruled out.Available alternatives to ASA are the ADPreceptor antagonists ticlopidine and clopidrogel,which can also be given orally. Similarlyto ASA, ticlopidine and clopidrogelcause an irreversible inhibition of plateletfunction. Both substances are inactive precursorsthat are converted by hepatic cytochromeP450 to an active metabolite thatbinds covalently to a subtype (P2Y 12 ) ofADP receptors on platelets. Consequently,ADP-mediated platelet aggregation is inhibitedfor the duration of the platelet life cycle(~ 7–10 days). Ticlopidine may cause seriousadverse effects, including neutropenia andthrombopenia. The successor substance, clopidrogel,is better tolerated.Antagonists at the integrin glycoproteinIIb/IIIa. Available agents are suitable onlyfor parenteral administration and, in clinicalsettings, are used in percutaneous coronaryballoon distension or in unstable angina pectoris.They block the fibrinogen cross-linkingprotein and thus decrease fibrinogen-mediatedmeshing of platelets independently ofthe precipitating cause. Abciximab is a chimericFab-antibody fragment directedagainst GP IIb/IIIa protein. Tirofiban and eptifibatideact as competitive antagonists atthe fibrinogen binding site. Because abciximabadheres to GPIIb/IIIa for a long time,24–48 hours are required after injection ofthedrugbeforeplateletaggregationagainbecomes possible. The effects of eptifibatideand tirofiban dissipate within a few hours.Because GP IIb/IIIa antagonists inhibit thecommon final pathway in platelet activation,they pose a risk of bleeding during treatment. Presystemic Effect of ASAThe inhibition of platelet aggregation by ASAresults from acetylation and blockade of plateletCOX-1 (B). The specificity of this reactionis achieved in the following manner:irreversible acetylation of the enzyme alreadyoccurs in the blood of the splanchnicregion, that is, before the liver is reached.Since ASA is subject to extensive presystemicdeacetylation, cyclooxygenases located posthepatically(e. g., in endothelial cells) arehardly affected. Confinement of COX-1 inhibitionto platelets is further accentuatedbecause enzyme can be re-synthesized innormal cells having a nucleus but not inthe anuclear platelets.

Inhibitors of Platelet Aggregation 155A. Inhibitors of platelet aggregationASAAbciximabAcetylsalicylic acidEptifibatide,a peptideThromboxaneA 2Tirofiban,nonpeptideGPIIb/IIIa antagonistsTPFibrinogenGPIIb/IIIaCox1CH 3SecretionClopidogrelADPG iP2Y 12GPVIOOCollagenNS ClADP-receptor antagonistsB. Presystemic inhibition of platelet aggregation by acetylsalicylic acidPlateletsLow doseOHCOOHH 3 COCOAcetylsalicylicacidCOOHAcetylation ofCOX in platelets

156 Plasma Volume Expanders Plasma Volume ExpandersMajor blood loss entails the danger of lifethreateningcirculatory failure, i. e., hypovolemicshock. The immediate threat resultsnot so much from the loss of erythrocytes,i. e., oxygen carriers, as from the reduction involume of circulating blood.To eliminate the threat of shock, replenishmentof the circulation is essential. Withmoderate loss of blood, administration of aplasma volume expander may be suf cient.Blood plasma consists basically of water,electrolytes, and plasma proteins. However,aplasmasubstituteneednotcontainplasmaproteins. These can be suitably replacedwith macromolecules (“colloids”) that, likeplasma proteins, (1) do not readily leave thecirculation and are poorly filtrable in the renalglomerulus; and (2) bind water along with itssolutes owing to their colloid osmotic properties.In this manner, they will maintain circulatoryfilling pressure for many hours. Onthe other hand, complete elimination ofthese colloids from the body is clearly desirable.Compared with whole blood or plasma,plasma substitutes offer several advantages:they can be produced more easily and atlower cost, have a longer shelf-life, and arefree of pathogens such as hepatitis B and C orAIDS viruses.Three colloids are currently employed asplasma volume expanders—the two polysaccharidesdextran and hydroxyethyl starch,and the polypeptide gelatin.Dextran is a polymer formed by bacteriaand consisting of atypically linked (1†6 insteadof 1†4 bond) glucose molecules. Commerciallyavailable plasma substitutes containdextran of a mean molecular weight(MW) of 70 or 75 kDa (dextran 70 or 75)or 40 kDa (dextran 40 or low-molecularweightdextran). The chain length of singlemolecules varies widely, however. Smallerdextran molecules can be filtered at the glomerulusand slowly excreted in urine; thelarger ones are eventually taken up and degradedby cells of the mononuclear phagocytesystem. Apart from restoring blood volume,dextran solutions are used for hemodilutionin the management of blood flow disorders.As for microcirculatory improvement, it isoccasionally emphasized that low -molecular-weightdextran, unlike dextran 70, maydirectly reduce the aggregability of erythrocytesby way of altering their surface properties.With prolonged use, larger moleculeswill accumulate owing to the more rapidrenal excretion of the smaller ones. Consequently,the molecular weight of dextrancirculating in blood will tend toward a highermean molecular weight with the passageof time.The most important adverse effect resultsfrom the antigenicity of dextrans, which maylead to an anaphylactoid reaction. Dextranantibodies can be intercepted without animmuneresponsebyinjectionofsmalldextranmolecules (MW 1000), thus obviatingany incompatibility reaction to subsequentinfusion of the dextran plasma substitutesolution.Hydroxyethyl starch (hetastarch) is producedfrom starch. By virtue of its hydroxyethylgroups, it is metabolized more slowlyand retained significantly longer in bloodthan would be the case with infused starch.Hydroxyethyl starch resembles dextrans interms of its pharmacological properties andtherapeutic applications. A particular adverseeffect is pruritus of prolonged durationwith deposition of the drug in peripheralnerves.Gelatin colloids consist of cross-linkedpeptide chains obtained from collagen. Theyare employed for blood replacement but notfor hemodilution in circulatory disturbances.

Plasma Volume Expanders 157A. Plasma subtitutesCirculationGelatin colloids= cross-linked peptide chainsMW 35 000Peptides MW ~ 15 000Gelatin MW ~ 100 000Collagen MW ~ 300 000Blood lossPlasmaDanger of shockOCH 2OCH 2OHOHOOOHO HO OCH 2OHROOHCH 2OHOOOHO RO ORO OCH 2OHOR = HO–CH 2 –CH 2 –Hydroxyethyl starchRO O(hetastarch)mean MW 670 000Plasmasubstitutewith colloidsHOCH2OOHOHHOODextranMW 70 000MW 40 000CH2OOHErythrocytesOOH CH2OOHO6HOOH CH25 O4 OH3 1HOOHOPlasmaproteinsHydroxyethylationstarchSucroseFructoseBacteriumLeuconostocmesenteroides

158 Drugs Used in Hyperlipoproteinemias Lipid- lowering AgentsTriglycerides and cholesterol are essentialconstituents of the organism. Among otherthings, triglycerides represent a form of energystore and cholesterol is a basic buildingblock of biological membranes. Both lipidsarewaterinsolubleandrequireappropriate“packaging” for transport in the aqueousmedia of lymph and blood. To this end, smallamounts of lipid are coated with a layer ofphospholipids, embedded in which are additionalproteins—the apolipoproteins (A). Accordingto the amount and the compositionof stored lipids, as well as the type of apolipoprotein,one distinguishes four transportforms (see table).Origin Density (g/ml) Mean time inblood plasma (h)Diameter (nm)Chylomicron Gut epithelium > 1.006 0.2 500 or moreVLDL particle Liver 0.95–1.006 3 100–200LDL particle (Blood) 1.006–1.063 50 25HDL particle Liver 1.063–1.210 — 5–10Lipoprotein metabolism. Enterocytes releaseabsorbed lipids in the form of triglyceride-richchylomicrons. Bypassing the liver,these enter the circulation mainly via thelymph and are hydrolyzed by extrahepaticendothelial lipoprotein lipases to liberatefatty acids. The remnant particles move oninto liver cells and supply these with cholesterolof dietary origin.The liver meets the larger part (60%) of itsrequirement for cholesterol by synthesis denovo from acetyl-coenzyme A. Synthesisrate is regulated at the step leading fromhydroxymethylglutaryl-CoA (HMG-CoA) tomevalonic acid (p.161A), with HMG-CoA reductaseas the rate-limiting enzyme.The liver requires cholesterol for synthesizingVLDL particles and bile acids. Triglyceride-richVLDL particles are released intothe blood and, like the chylomicrons, supplyother tissues with fatty acids. Left behind areLDL particles that either return into the liveror supply extrahepatic tissues with cholesterol.LDL particles carry the apolipoprotein B-100, by which they are bound to receptorsthat mediate uptake of LDL into the cells,including the hepatocytes (receptor-mediatedendocytosis, p. 26).HDL particles are able to transfer cholesterolfrom tissue cells to LDL particles. In thisway, cholesterol is transported from tissuesto the liver.Hyperlipoproteinemias can be causedgenetically (primary hyperlipoproteinemia)or can occur in obesity and metabolic disorders(secondary hyperlipoproteinemia). ElevatedLDL-cholesterol serum concentrationsare associated with an increased risk of atherosclerosis,especially when there is a concomitantdecline in HDL concentration (increasein LDL : HDL quotient).Treatment. Various drugs are available thathave different mechanisms of action and effectson LDL (cholesterol) and VLDL (triglycerides)(A). Their use is indicated in thetherapy of primary hyperlipoproteinemias.In secondary hyperlipoproteinemias, the immediategoalshouldbetolowerlipoproteinlevels by dietary restriction, treatment of theprimary disease, or both.

Lipid-lowering Agents 159A. Lipoprotein metabolismDietary fatsCell metabolismCholesterolChylomicronFat tissueLDLHDLHeartSkeletal muscleVLDLHDLLDLChylomicronremnantLipoproteinsynthesisCholesterolTriglyceridesCholesterolFatty acidsLipoproteinLipaseLiver cellCholesterolesterTriglyceridesApolipoproteinOHOHOHCholesterolB. Cholesterol metabolism in liver cell and cholesterol-lowering drugsColestyramineGut: bindingandexcretionof bileacids (BA)Liver:BA synthesisCholesterolconsumptionBile acidsCholesterolstoreLipoproteinsLiver cellEzetimibGut:CholesterolabsorptionSynthesisLDLHMG-CoA-Reductase inhibitors

160 Drugs Used in HyperlipoproteinemiasDrugs. As nonabsorbable anion-exchangeresins, colestyramine and colestipol can bindbile acids in the gut lumen, which are thusremoved from cholesterol metabolism. Therequired dosage is rather high (15–30 g/day)and liable to produce gastrointestinal disturbances.Consequently, patient compliance islow. Moreover, the resins trap needed drugsand vitamins. A more promising approach tolowering absorption of cholesterol derivesfrom a novel mechanism of action probablybased on the specific inhibition of intestinalcholesterol transporters that are required forabsorption of cholesterol. An inhibitor of thistype is ezetimibe.β-Sitosterin is a plant steroid that is notabsorbed after oral administration; in suf -ciently high dosage it impedes enteral absorptionof cholesterol. Treatment with sitosterinhas become obsolete. The drug is nolonger on the market.The statins lovastatin and fluvastatin inhibitHMG-CoA reductase. They contain amolecular moiety that chemically resemblesthe physiological substrate of the enzyme(A). Lovastatin is a lactone that is rapidlyabsorbed by the enteral route, subjected toextensive first-pass extraction in the liver,and there hydrolyzed to active metabolites.Fluvastatin represents the active form and,as an acid, is actively transported by a specificanion carrier that moves bile acids frombloodintoliverandalsomediatestheselectiveuptake of the mycotoxin amanitin (A).Normally viewed as presystemic elimination,ef cient hepatic extraction serves toconfine the action of statins to the liver. Despitethe inhibition of HMG-CoA reductase,hepatic cholesterol content does not fall becausehepatocytes compensate any drop incholesterol levels by increasing the synthesisof LDL receptor protein (along with the reductase).Since, in the presence of statins, thenewly-formed reductase is inhibited as well,the hepatocyte must meet its cholesteroldemand entirely by uptake of LDL from theblood (B). Accordingly, the concentration ofcirculating LDL falls. As LDL remains in bloodfor a shorter time, the likelihood of LDL beingoxidized to its proatherogenic degradationproduct decreases pari passu.Other statins include simvastatin (also alactone prodrug), pravastatin, atorvastatin,and cerivastatin (activeformwithopenring).The statins are the most important therapeuticsfor lowering cholesterol levels. Theirnotable cardiovascular protective effect,however, appears to involve additional actions.The combination of a statin with an inhibitorof cholesterol absorption (e. g., ezetimibe)can lower LDL levels even further.A rare but dangerous adverse effect ofstatins is damage to skeletal muscle (rhabdomyolysis).This risk is increased by combineduse of fibric acid agents (see below).Cerivastatin has proved particularly toxic.Besides muscle damage associated withmyoglobinuria and renal failure, severehepatotoxicity has also been noted, promptingwithdrawal of the drug.Nicotinic acid and its derivatives (pyridylcarbinol,xanthinol nicotinate, andacipimox)activate endothelial lipoprotein lipase andthereby mainly lower triglyceride levels. Atthe start of therapy, a prostaglandin-mediatedvasodilation occurs (flushing, hypotension)that can be prevented by low doses ofacetylsalicylic acid.Clofibrate and derivatives (bezafibrate, fenofibrate,and gemfibrozil) lower concentrationsof VLDL (triglycerides) along with LDL(cholesterol). They may cause damage to liverand skeletal muscle (myalgia, myopathy,rhabdomyolysis with myoglobinemia andrenal failure). The mechanism of action offibrates is not completely understood. Theybind to a peroxisome proliferator-activatedreceptor (PPARα) and thereby influencegenes regulating lipid metabolism.

Lipid-lowering Agents 161A. Accumulation and effect of HMG-CoA reductase inhibitors in liverLow systemic availabilityHO–COOCH3OSCoA3-Hydroxy-3-methylglutaryl-CoAHMG-CoA-ReductaseMevalonateHO–COOCH3OHCholesterolBioactivationHOR–COOOHActive formExtractionof lipophiliclactoneActiveuptake ofanionH 3 CHOOOH 3 COOCH 3OraladministrationFHOCOO –OHCH 3N CH 3H 3 CLovastatinFluvastatinB. Regulation by cellular cholesterol concentration of HMG-CoA reductase andLDL-receptorsInhibition ofHMG-CoA reductaseLDL-ReceptorHMG-CoAreductaseGeneexpressionGeneexpressionCholesterolLDLin bloodIncreased receptormediateduptake of LDL

162 Diuretics Diuretics—An OverviewDiuretics (saluretics) elicit increased productionof urine (diuresis). In the strict sense,the term is applied to drugs with a directrenal action. The predominant action of suchagents is to augment urine excretion by inhibitingthe reabsorption of NaCl and water.The most important indications for diureticsare the following.Mobilization of edemas (A). In edemathere is swelling of tissues owing to accumulationof fluid, chiefly in the extracellular(interstitial) space. When a diuretic is given,increased renal excretion of Na + and H 2 Ocauses a reduction in plasma volume withhemoconcentration. As a result, plasma proteinconcentration rises along with oncoticpressure. As the latter operates to attractwater, fluid will shift from interstitium intothecapillarybed.Thefluidcontentoftissuesthus falls and the edemas recede. The decreasein plasma volume and interstitial volumemeans a diminution of the extracellularfluid volume (EFV). Depending on the condition,use is made of thiazides, loop diuretics,aldosterone antagonists, and osmoticdiuretics.Antihypertensive therapy. Diuretics havebeen used as drugs of first choice for loweringelevated blood pressure (p. 314). Evenat low dosage, they decrease peripheral resistance(without significantly reducing EFV)and thereby normalize blood pressure.Therapy of congestive heart failure. Bylowering peripheral resistance, diuretics aidthe heart in ejecting blood (reduction inafterload, p. 322); cardiac output and exercisetolerance are increased. Owing to theincreased excretion of fluid, EFV and venousreturn decrease (reduction in preload).Symptoms of venous congestion, such as ankleedema and hepatic enlargement, subside.The drugs principally used are thiazides(possibly combined with K + -sparing diuretics)and loop diuretics.Prophylaxis of renal failure. In circulatoryfailure (shock), e. g., secondary to massivehemorrhage, renal production of urinemay cease (anuria). By means of diuretics, anattempt is made to maintain urinary flow.Use of either osmotic or loop diuretics isindicated.Massive use of diuretics entails a hazard ofadverse effects (A):1. Thedecreaseinbloodvolumecanleadtohypotension and collapse.2. Blood viscosity rises owing to the increasein erythrocyte and thrombocyte concentrations,bringing an increased risk of intravascularcoagulation or thrombosis.When depletion of NaCl and water (EFV reduction)occurs as a result of diuretictherapy, the body can initiate counterregulatoryresponses (B), namely, activation ofthe renin–angiotensin–aldosterone system(p.128). Because of the diminished bloodvolume, renal blood flow is jeopardized. Thisleads to release from the kidneys of the hormonerenin, which enzymatically catalyzesthe formation of angiotensin I. Angiotensin Iis converted to angiotensin II by the action of“angiotensin-converting enzyme” (ACE). AngiotensinII stimulates release of aldosterone.The mineralocorticoid promotes renalreabsorption of NaCl and water and thuscounteracts the effect of diuretics. ACE inhibitors(p.128) and angiotensin II antagonistsaugment the effectiveness of diuretics bypreventing this counterregulatory response.

Diuretics—An Overview 163A. Mechanism of edema fluid mobilization by diureticsProtein moleculesEdemaHemoconcentrationColloidosmoticpressureMobilization ofedema fluidCollapse,danger ofthrombosisDiureticB. Possible counter-regulatory responses during long-term diuretic therapySalt andfluid retentionDiureticDiureticEFV:Na + , Cl - ,H 2 OAngiotensinogenReninAngiotensin IACEAngiotensin IIAldosterone

164 Diuretics NaCl Reabsorption in the Kidney (A)The smallest functional unit of the kidney isthe nephron. In the glomerular capillaryloops, ultrafiltration of plasma fluid intoBowman’s capsule yields primary urine. Inthe proximal tubules (pT), ~ 70% of the ultrafiltrateis retrieved by iso-osmotic reabsorptionof NaCl and water. Downstream, in thethick portion of the ascending limb ofHenle’s loop, NaCl is absorbed unaccompaniedby water. The differing properties of thelimbs of Henle’s loop, together with the parallelarrangement of vasa recta, are the prerequisitesfor the hairpin countercurrentmechanism that allows build-up of a veryhigh NaCl concentration in the renal medulla.NaCl is again reabsorbed in the distalconvoluted tubules, the connecting segment,and the collecting ducts, accompanied by acompensatory secretion of K + in the (cortical)collecting tubules. In the connecting tubulesand collecting ducts, vasopressin (antidiuretichormone, ADH) increases the epithelialpermeability for water by insertionof aquaporin molecules into the luminalplasmalemma. The driving force for the passageof water comes from the hyperosmolarmilieu of the renal medulla. In this manner,water is retained in the body, and concentratedurine can leave the kidney. The ef -cient mechanisms of reabsorption permitthe production of ~ 1 l/day of final urinefrom 150–180 l/day of primary urine.Na + transport through the tubular cellsbasically occurs in similar fashion in all segmentsof the nephron. The intracellular concentrationof Na + is significantly below thatin primary urine because the Na + /K + -ATPaseof the basolateral membrane continuouslypumps Na + fromthecell into the interstitium.Along the resulting luminal–intracellularconcentration gradient, movement of sodiumions across the membrane proceeds by a carriermechanism. All diuretics inhibit Na + reabsorption.This effect is based on two mechanisms:either the inward movement is diminishedor the outward transport impaired. Aquaporins (AQP)By virtue of their structure, cell membranesare water-impermeable. Therefore, specialpores are built into the membrane to allowpermeation of water. These consist of proteinscalled aquaporins that, of necessity,occur widely and with many variations inboth the plant and animal kingdoms. In thehuman kidney, the following types exist: AQP-1 localized in the proximal tubulusand the descending limb of Henle’s loop. AQP-2 localized in the connecting tubuliand collecting ducts; its density in theluminal plasmalemma is regulated byvasopressin. AQP-3 and AQP-4 present in the basolateralmembrane region to allow passage ofwater into the interstitium. Osmotic Diuretics (B)These include mannitol and sorbitol whichact mainly in the proximal tubules to preventreabsorption of water. These polyhydricalcohols cannot be absorbed and thereforebind a corresponding volume of water. Sincebody cells lack transport mechanisms forthese substances (structure on p.175), theyalso cannot be absorbed through the intestinalepithelium and thus need to be givenby intravenous infusion. The result of osmoticdiuresisisalargevolumeofdiluteurine, as in decompensated diabetes mellitus.Osmotic diuretics are indicated in theprophylaxis of renal hypovolemic failure,the mobilization of brain edema, and thetreatment of acute glaucoma attacks (p. 346).

NaCl Reabsorption in the Kidney 165A. Renal actions of diureticsReabsorptionof Na + , H 2 O andmany otherconstituents ofprimary urineNa + , Cl - transport(thiazide diuretics)21546Inward Na +current linkedto K + channel(amiloride)outward currentAldosteroneincreasessynthesis ofchannels12 Prox. tubule3 Distal tubulepars recta456GlomerulusDist. tubulepars contortaConnecting tubuleCollecting ductCarbonic anhydrasemechanism(acetazolamide)Na + , K + ,2Cl - cotransport(loop diuretics)3Aquaporin 2(vasopressin increasesexpression): H 2 O uptakeLumenInterstitiumNa + , Cl -Na+“carrier”Na +Na+Na/K-ATPaseNa + , Cl - + H 2 OH 2 ODiureticsB. NaCl reabsorption in proximal tubule and effect of mannitolMannitol[Na + ] inside = [Na + ] outside[Na + ] inside < [Na + ] outside

166 Diuretics Diuretics of the Sulfonamide TypeThese drugs contain the sulfonamide group–SO 2 NH 2 and are suitable for oral administration.In addition to being filtered at theglomerulus, they are subject to tubular secretion.Their concentration in urine is higherthan in blood. They act on the tubule cellsfrom the luminal side. Loop diuretics havethe highest ef cacy. Thiazides are most frequentlyused. The carbonic anhydrase inhibitorsno longer serve as diuretics but haveimportant other therapeutic uses; accordingly,their mode of action is considered here.Acetazolamide is a carbonic anhydrase(CAH) inhibitor that acts predominantly inthe proximal convoluted tubules. Its mechanismof action can be summarized as follows.Reabsorption of Na + is decreased becausefewer H + ions are available for the Na + /H +antiporter. As a result, excretion of Na + andH 2 O increases. CAH accelerates attainmentofequilibriumofCO 2 hydration/dehydrationreactions:(1) (2)H + +HCO 3 – ⇌ H 2 CO 3 ⇌ H 2 O+CO 2Cytoplasmic enzyme is used in tubulus cellsto generate H + (reaction1),whichissecretedinto the tubular fluid in exchange for Na + .There, H + captures HCO 3 − . CAH localized inthe luminal membrane catalyzes reaction 2(dehydration) to yield again H 2 OandCO 2 ,which can easily permeate through the cellmembrane. In the tubulus cell, H + and HCO 3−are regenerated. When the enzyme is inhibited,these reactions occur too slowly, so thatless Na + ,HCO 3 – and water are reabsorbedfrom the fast-flowing tubular fluid. Loss ofHCO 3 – leads to acidosis. The diuretic effectivenessof CAH inhibitors decreases withprolonged use. CAH is also involved in theproduction of ocular aqueous humor.Present indications for drugs in this classinclude: acute glaucoma, acute mountainsickness, and epilepsy.Dorzolamide can be applied topically tothe eye to lower intraocular pressure in glaucoma(p. 346).Loop diuretics include furosemide (frusemide),piretanide, and others. After oral administrationof furosemide, a strong diuresisoccurs within 1 hour but persists for onlyabout 4 hours. The site of action of theseagents is the thick ascending limb of Henle’sloop, where they inhibit Na + /K + /2Cl − cotransport.As a result, these electrolytes, togetherwith water, are excreted in largeramounts. Excretion of Ca 2+ and Mg 2+ alsoincreases. Special adverse effects include (reversible)hearing loss and enhanced sensitivityto nephrotoxic agents. Indications:pulmonaryedema (added advantage of i.v. injectionin left ventricular failure: immediatedilation of venous capacitance vessels, †preload reduction); refractoriness to thiazidediuretics; e. g., in renal failure with creatinineclearance reduction (< 30 ml/min);prophylaxis of acute renal hypovolemic failure.Ethacrynic acid is classed in this groupalthough it is not a sulfonamide.Thiazide diuretics (benzothiadiazines)include hydrochlorothiazide, trichlormethiazideand butizide. Chlorthalidone is a longactinganalogue. These drugs affect the distalconvoluted tubules, where they inhibit Na + /Cl − cotransport in the luminal membrane oftubulus cells. Thus, reabsorption of NaCl andwater is inhibited. Renal excretion of Ca 2+decreases, that of Mg 2+ increases. Indicationsare hypertension, congestive heart failure,and mobilization of edema. Frequently, theyare combined with the K + sparing diureticstriamterene or amiloride (p.168)Unwanted effects of sulfonamide-typediuretics: (a) hypokalemia is a consequenceof an increased secretion of K + in the connectingtubule and the collecting duct becausemoreNa+ becomes available for exchangeagainst K + ;(b)hyperglycemia; (c)increasein serum urate levels (hyperuricemia),which may precipitate gout in predisposedpatients. Sulfonamide diuretics competewithurateforthetubularorganicanionsecretorysystem.

Diuretics of the Sulfonamide Type 167A. Diuretics of the sulfonamide typeSulfonamidediureticsK +NormalstateNa + Na +AnionsecretorysystemNa +Na + K +K + lossinducedbydiureticUric acidCollectingductThiazidesGoutNa +Cl -e.g., hydrochlorothiazideHNClHNSOS NH 2O OOCarbonic anhydrase inhibitorsLoop diureticsNa +H +HCO - 3H 2 OCO 2H + HCO - 3CAHCO 2 H 2 ONa +HCO - 3Na +K +2 Cl –e.g., acetazolamidee.g., furosemideCH 3 N N OO N S S NH 2HOOCH 2NHHOOCClOS NH 2O

168 Diuretics Potassium-sparing Diuretics (A)Theseagentsactintheconnectingtubulesand the proximal part of the collecting ductswhere Na + is reabsorbed and K + is secreted.Their diuretic effectiveness is relatively minor.In contrast to sulfonamide diuretics(p.166), there is no increase in K + secretion;rather, there is a risk of hyperkalemia. Thesedrugs are suitable for oral administration.a Triamterene and amiloride, in addition toglomerular filtration, undergo secretion inthe proximal tubule. They act on corticalcollecting tubule cells from the luminalside. Both inhibit the entry of Na + intothe cell, whereby K + secretion is diminished.They are mostly used in combinationwith thiazide diuretics, e. g., hydrochlorothiazide,because the opposing effectson K + excretion cancel each other,while the effects on secretion of NaCland water complement each other.b Aldosterone antagonists. The mineralocorticoidaldosterone increases synthesis ofNa-channel proteins and Na + /K + -ATPasesin principal cells of the connecting tubulesand the cortical collecting ducts, therebypromoting the reabsorption of Na + (Cl –and H 2 O follow), and simultaneously enhancingsecretion of K + . Spironolactone,aswell as its metabolite canrenone, areantagonistsat the aldosterone receptor andattenuate the effect of the hormone. Thediuretic effect of spironolactone developsfully only with continuous administrationfor several days. Two possible explanationsare: (1) the conversion of spironolactoneinto and accumulation of the moreslowly eliminated metabolite canrenone;(2) an inhibition of aldosterone-stimulatedprotein synthesis would become noticeableonly if existing proteins had becomenonfunctional and needed to be replacedby de-novo synthesis.Aparticularadverse effect results from interferencewith gonadal hormones, as evidencedby the development of gynecomastia.Clinical uses include conditions ofincreased aldosterone secretion (e. g., livercirrhosis with ascites) and congestive heartfailure. Vasopressin and Derivatives (B)Vasopressin (ADH), a nonapeptide, is releasedfrom the posterior pituitary glandand promotes reabsorption of water in thekidney.Thisresponseismediatedbyvasopressinreceptors of the V 2 subtype. AVP enhancesthe permeability of connecting tubulesand medullary collecting duct epitheliumfor H 2 O (but not electrolytes) in thefollowing manner: H 2 O-channel proteins(type 2 aquaporins) are stored in tubuluscells within vesicles. When AVP binds to V 2receptors,thesevesiclesfusewiththeluminalcell membrane, allowing influx of H 2 Oalong its osmotic gradient (the medullaryzone is hyperosmolar). AVP thus causesurine volume to shrink from 15 l/day at thispoint of the nephron to the final 1.5 l/day.This aquaporin type can be reutilized afterinternalization into the cell. Nicotine augments(p.112) and ethanol decreases releaseof AVP. At concentrations above those requiredfor antidiuresis, AVP stimulatessmooth musculature, including that of bloodvessels (“vasopressin”). The latter responseis mediated by V 1 receptors. Blood pressurerises; coronary vasoconstriction can precipitateangina pectoris.Lypressin (8-L-lysine-vasopressin) acts likeAVP. Other derivatives may display only oneof the two actions.Desmopressin is used for the therapy ofdiabetes insipidus (AVP deficiency), primarynocturnal enuresis and von Willebrand disease(p.152); it is given by injection or viathe nasal mucosa (as “snuff”).Felypressin and ornipressin serve as adjunctivevasoconstrictors in infiltration localanesthesia (p. 204).

Potassium- sparing Diuretics and Vasopressin 169A. Potassium-sparing diureticsH 2 NNNNa + K + Na +NNNH 2HOOHCCH 2 OHC ONH 2TriamtereneAmilorideH 2HH 2 N NNH 2OK + orH +Protein synthesisTransport capacitySpironolactoneAldosteroneAldosteroneantagonistsOCanrenoneOClNNNNHOO76SCCH 3OB. Antidiuretic hormone (ADH) and derivativesNicotineNeurohypophysisEthanolVasoconstrictionH 2Opermeabilityof collectingductV 2 Adiuretin = VasopressinV 1Cys Tyr Phe Gln Asn Cys Pro Arg Gly NH 2DesmopressinOrnipressinOrnCH2 CCH2 OSD-ArgFelypressinPheLys

170 Drugs for the Treatment of Peptic Ulcers Drugs for Gastric and DuodenalUlcersIn the area of a gastric or duodenal pepticulcer, the mucosa has been attacked by digestivejuices to such an extent as to exposethe subjacent connective tissue layer (submucosa).This “self-digestion” occurs whenthe equilibrium between the corrosive hydrochloricacid and acid-neutralizing mucus,which forms a protective cover on the mucosalsurface, is disturbed. Mucosal damagecan be promoted by Helicobacter pylori bacteriathat colonize the gastric mucus.Drugs are employed with the followingtherapeutic aims: (a) to relieve pain; (b) toaccelerate healing; and (c) to prevent ulcerrecurrence. Therapeutic approaches arethreefold : (I) to reduce aggressive forcesby lowering H + output,(II)toincreaseprotectiveforces by means of mucoprotectants;and (III) to eradicate Helicobacter pylori.I. Lowering of Acid ConcentrationIa. Agents for acid neutralization (A). H + -bindinggroupssuchasCO 3 2- ,HCO 3 − or OH − ,together with their counter ions, are containedin antacid drugs. Neutralization reactionsoccurring after intake of CaCO 3 andNaHCO 3 ,respectively,areshownin(A). Withnonabsorbable antacids, the counter ion isdissolved in the acidic gastric juice in theprocess of neutralization. Upon mixture withthe alkaline pancreatic secretion in the duodenum,it is largely precipitated again bybasic groups, e. g., as CaCO 3 or AlPO 4 ,andexcreted in feces. Therefore, systemic absorptionof counter ions or basic residues isminor. In the presence of renal insuf ciency,however, absorption of even small amountsmay cause an increase in plasma levels ofcounter ions (e. g., magnesium intoxicationwith paralysis and cardiac disturbances).Precipitation in the gut lumen is responsiblefor other side effects, such as reduced absorptionof other drugs due to their adsorptionto the surface of precipitated antacid; orphosphate depletion of the body with excessiveintake of Al(OH) 3 .Na + ions remain in solution even in thepresence of HCO 3 − -rich pancreatic secretionsand are subject to absorption, like HCO 3 − .Because of the uptake of Na + ,useofNaHCO 3must be avoided in conditions requiring restrictionof NaCl intake, such as hypertension,cardiac failure, and edema.Since food has a buffering effect, antacidsare taken between meals (e. g., 1 and 3 hoursafter meals and at bedtime). Nonabsorbableantacids are preferred. Because Mg(OH) 2produces a laxative effect (cause: osmoticaction, p.174, release of cholecystokinin byMg 2+ , or both) and Al(OH) 3 produces constipation(cause: astringent action of Al 3+ ,p.180), these two antacids are frequentlyused in combination (e. g., magaldrate).Ib. Inhibitors of acid production (B). Actingon their respective receptors, the transmitteracetylcholine, the hormone gastrin, and histaminereleased intramucosally stimulatethe parietal cells of the gastric mucosa toincrease output of HCl. Histamine comesfrom enterochromaf n-like (ECL) cells; itsrelease is stimulated by the vagus nerve(via M 1 receptors) and hormonally by gastrin.The effects of acetylcholine and histaminecan be abolished by orally applied antagoniststhat reach parietal cells via theblood. Proton pump inhibitors are drugs offirst choice for promoting healing of ulcers.Infection with H. pylori should be treatedresolutely (p.172) to lower the risk of ulcerrecurrence, chronic gastritis, gastric carcinomas,and gastric lymphomas.The cholinoceptor antagonist pirenzepinepreferentially blocks cholinoceptors of theM 1 type; its use in peptic ulcer therapy isnow obsolete.

Drugs for Gastric and Duodenal Ulcers 171A. Drugs used to neutralize gastric acidNaHCO 3AbsorbableAntacidsNonabsorbableCaCO 3Mg(OH) 2Al(OH) 3Na + HCO- 3H +H +H 2 CO 3H 2 CO 3H 2 OH 2 OCO 2CO 2Na +PancreasPancreasCaCO 3CaCO 3Ca 2+ H + M 1HCO 3-AbsorptionNa + HCO 3-HCO - 3B. Drugs used to lower gastric acid productionN. vagusAcid-resistantcoatingInactive formATPaseParietal cellM 3AChActive formof omeprazoleH+K+H 2HistamineECL cellGastrinProton pump inhibitorsH 3 COHNNOSCH 2H 2 -AntihistaminicsH 3 CN CH 2 OH 3 CCH 2S(CH 2 ) 2OmeprazoleH 3 CNCH 3OCH 3RanitidineNHC NHCH 3CH NO 2

172 Drugs for the Treatment of Peptic UlcersHistamine receptors on the parietal cells belongto the H 2 typeandareblockedbyH 2antihistaminics (p.118). Because histamineplays a pivotal role in the activation of parietalcells, H 2 antihistaminics also diminishresponsivity to other stimulants, e. g., gastrin(in gastrin-producing pancreatic tumors,Zollinger–Ellison syndrome). The first H 2 -blocker used clinically, cimetidine, onlyrarely produces adverse effects (CNS disturbancessuch as confusion; endocrine effectsinthemalesuchasgynecomastia,decreasedlibido, impotence); however, it inhibits thehepatic biotransformation of many otherdrugs. The more recently introduced substancesranitidine, nizatidine, and famotidineare effective at lower dosages. Evidently,inhibition of microsomal enzymesdecreases with reduced drug load; thus,these substances are less likely to interferewith the therapeutic use of other pharmaceuticals.Omeprazole (p.171) can cause maximal inhibitionof HCl secretion. Given orally in gastricjuice-resistant capsules, it reaches parietalcells via the blood. In the acidic milieu ofthe mucosa, an active metabolite is formedand binds covalently to the ATP-driven protonpump (H + /K + -ATPase) that transports H +in exchange for K + into the gastric juice.Lansoprazole, pantoprazole, andrabeprazoleproduce analogous effects. Omeprazole is aracemate. With respect to dosage, the nowavailable (S)-omeprazole (esomeprazole) representsthe more potent enantiomer, butthis offers no therapeutic advantage.II. Protective DrugsSucralfate (A) contains numerous aluminumhydroxide residues. However, it is not anantacid because it fails to lower the overallacidity of gastric juice. After oral intake, sucralfatemolecules undergo cross-linking ingastric juice, forming a paste that adheres tomucosal defects and exposed deeper layers.Here sucralfate intercepts H + .Protectedfromacid, and also from pepsin, trypsin, and bileacids, the mucosal defect can heal more rapidly.Sucralfate is taken on an empty stomach(1 hour before meals and at bedtime). It iswell tolerated, but released Al 3+ ions cancause constipation.Misoprostol (B) isasemisyntheticprostaglandinderivative with greater stabilitythan natural prostaglandin, permitting absorptionafter oral administration. Locallyreleased prostaglandins (PGF 2α, PGE 2 )promotemucus production in superficial cellsandinhibitacidsecretionofparietalcells(B).Inhibition of physiological PG synthesis bydrugs (e. g., NSAIDS, p. 200) explains the mucosalinjury from these pharmaceuticals:protection by the mucus layer is diminishedand acid production is enhanced. Misoprostolmimics the action of the prostaglandinson the mucosal tunic and thus can attenuatethe adverse effects produced by inhibitors ofPG synthesis, at least as regards the gastricmucosa. Additional systemic effects (frequentdiarrhea; risk of precipitating contractionsof the gravid uterus) significantly restrictits therapeutic utility.III. Eradication of Helicobacter pylori (C)This organism plays an important role in thepathogenesis of chronic gastritis and pepticulcer disease. The combination of antibacterialdrugs and omeprazole has proved effective.If amoxicillin (p. 272) or clarithromycin(p. 278) cannot be tolerated, metronidazole(p. 276) may serve as a substitute. Colloidalbismuth compounds are also effective; however,as they entail the problem of heavymetalexposure, this treatment can no longerbe recommended.

Drugs for Gastric and Duodenal Ulcers 173A. Chemical structure and protective effect of sucralfateHROCH 2 ORHORHOHORORH 2 CHOROOHROCH 2 ORHSucralfate– SO 3-R = – SO 3 [Al 2 (OH) 5 ]H +R = – SO 3 [Al 2 (OH) 4 ] +Conversionin acidicenvironmentpH < 4Cross-linkingand formationof pasteCoating ofmucosaldefectsB. Structure and protective effect of misoprostolMucusSurface epithelial cellsOOSupporting cellsCH 3OCH 3CH 3H+Cl-HOOOHMisoprostolCOOHCH 3LumenParietal cellswith protonpumpsPepsinproducingchiefcellsHOOHProstaglandin E 2C. Helicobacter eradicationHelicobacterpyloriEradicatione.g., short-term triple therapyRefluxesophagitisGastritisPeptic ulcerAmoxicillin*Clarithromycin*Omeprazole(2 x 1000 mg/day) 7 days(2 x 500 mg/day) 7 days(2 x 20 mg/day) 7 days*if intolerable,metronidazole (2 x 500 mg/day) 7 days

174 Laxatives LaxativesLaxatives promote and facilitate bowel evacuationby acting locally to stimulate intestinalperistalsis, to soften bowel contents, or both.1. Bulk LaxativesDistension of the intestinal wall by bowelcontents stimulates propulsive movementsof the gut musculature (peristalsis). Activationof intramural mechanoreceptors inducesa neurally mediated ascending reflexcontraction (red in A) and descending relaxation(blue) whereby the intraluminal bolusis moved in the anal direction.Hydrophilic colloids or bulk gels (B)comprise insoluble and nonabsorbable substancesthat expand on taking up water inthe bowel. Vegetable fibers in the diet act inthis manner. They consist of the indigestibleplant cell walls containing homoglycans thatare resistant to digestive enzymes, e. g., cellulose(1 † 4β-linked glucose molecules vs.1 † 4α-glucoside bond in starch; p.157).Bran, a grain milling waste product, and linseed(flaxseed) are both rich in cellulose.Other hydrophilic colloids derive from theseeds of Plantago species or karaya gum. Ingestionof hydrophilic gels for the prophylaxisof constipation usually entails a low riskof side effects. However, when fluid intake isvery low and a pathological stenosis exists inthe bowel, mucilaginous viscous materialscould cause an ileus.Osmotically active laxatives (C) aresolublebut nonabsorbable particles that retainwater in the bowel by virtue of their osmoticaction. The osmotic pressure of bowel contentsalways corresponds to that of the extracellularspace because the intestinal mucosais unable to maintain a higher or lowerosmotic pressure of the luminal contents.Therefore, absorption of molecules (e. g., glucose,NaCl) occurs iso-osmotically, i. e., solutemolecules are followed by a correspondingamount of water. Conversely, water remainsin the bowel when molecules cannot be absorbed.With Epsom salt (MgSO 4 ) and Glauber’ssalt (Na 2 SO 4 ), the SO 4 2- anion is hardly absorbableand retains cations to maintainelectroneutrality. Mg 2+ ions are also believedto promote release of cholecystokinin/pancreozymin,a polypeptide that also stimulatesperistalsis, from the duodenal mucosa.These so-called saline cathartics elicit awatery bowel discharge 1–3 hours after administration(preferably in isotonic solution).They are used to purge the bowel(e. g., before bowel surgery) or to hastenthe elimination of ingested poisons. Contraindicationsarise because a small part of cationsis absorbed. Thus, Glauber’s salt is contraindicatedin hypertension, congestiveheart failure, and edema because of its highNa + content. Epsom salt is contraindicated inrenal failure (risk of Mg 2+ intoxication).Osmotic laxative effects are also producedby the polyhydric alcohols mannitol and sorbitol,which unlike glucose cannot be transportedthrough the intestinal mucosa.Since the disaccharide lactulose cannot behydrolyzed by digestive enzymes, it also actsas an osmotic laxative. Fermentation of lactuloseby colon bacteria leads to acidificationof bowel contents and a reduced number ofbacteria. Lactulose is used in liver failure toforestall hepatic coma by preventing bacterialproduction of ammonia and its subsequentabsorption (absorbable NH 3 † nonabsorbableNH 4 + ). Another disaccharide, lactitol,produces a similar effect.

Laxatives 175A. Stimulation of persistalsis by an intraluminal bolusStretch receptorsContractionRelaxationB. Bulk laxativesH 2 OH 2 OCellulose, agar-agar, bran, linseedC. Osmotically active laxativesH 2 ONa + , Cl -H 2 OH 2 ONa + , Cl -H 2 OH 2 ONa + , Cl -H 2 OH 2 ONa + , Cl -H 2 OH 2 ONa + , Cl -H 2 OH 2 ONa + , Cl -H 2 OH 2 ONa + , Cl -H 2 OIso-osmoticabsorptionGH 2 OH 2 O GHHOCHCHCHCCHOOHOHOHH 2C OHG = GlucoseH 2 OGH 2 ONa + , Cl -H 2 OH 2 ONa + , Cl -H 2 OH 2 ONa + , Cl -H 2 OH 2 ONa + , Cl -H 2 OH 2 ONa + , Cl -H 2 OH 2 ONa + , Cl -H 2 OH 2 ONa + , Cl -H 2 OGH 2 OG H 2OGH 2 OH 2C OHH 2 O2 Na + 2-SO 4 H2 O H 2 OH 2 OHO CHHO CHHC OHHC OHH 2C OHMannitolH 2 O

176 Laxatives2. Irritant LaxativesLaxativesinthisgroupexertanirritantactionon the enteric mucosa (A). Consequently,less fluid is absorbed than is secreted.The increased filling of the bowelpromotes peristalsis; excitation of sensorynerve endings elicits enteral hypermotility.According to the site of irritation, one distinguishesthe small-bowel irritant castor oilfrom the large-bowel irritants anthraquinoneand diphenylmethane derivatives (fordetails see p.178).Misuse of laxatives. It is a widely held beliefthat at least one bowel movement per day isessential for health; yet three bowel evacuationsper week is quite normal. The desire forfrequent bowel emptying probably stemsfrom the time-honored, albeit mistaken, notionthat absorption of colon contents isharmful. Thus, purging has long been partof standard therapeutic practice. Nowadaysit is known that intoxication from intestinalsubstances is impossible as long as the liverfunctions normally. Nonetheless, purgativescontinue to be sold as remedies to “cleansethe blood” or to rid the body of “corrupthumors.”There can be no objection to the ingestionof bulk substances for the purpose of supplementinglow-residue “modern diets.” However,use of irritant purgatives or cathartics isnot without hazards. Specifically, there is arisk of laxative dependence, i. e., the inabilityto do without them. Chronic intake of irritantpurgatives disrupts the water and electrolytebalance of the body and can thuscause symptoms of illness (e. g., cardiac arrhythmiassecondary to hypokalemia).Accordingly, a longer period is needed untilthe next natural defecation can occur. Fearingconstipation, the user becomes impatientand again resorts to the laxative, whichthen produces the desired effect as a resultof emptying out the upper colonic segments.Thus, a “compensatory pause” following cessationof laxative use must not give cause forconcern (B).In the colon, semifluid material enteringfrom the small bowel is thickened by absorptionof water and salts (from about 1000 mlto 150 ml per day). If, owing to the action ofan irritant purgative, the colon empties prematurely,anenterallossofNaCl,KClandwater will be incurred. In order to forestalldepletion of NaCl and water, the bodyresponds with an increased release of aldosterone(p.168), which stimulates theirreabsorption in the kidney. However, theaction of aldosterone is associated with increasedrenal excretion of KCl. The enteraland renal K + losses add up to K + depletion ofthe body, evidenced by a fall in serum K +concentration (hypokalemia). This conditionis accompanied by a reduction in intestinalperistalsis (bowel atonia). The affected individualinfers “constipation” and again partakesof the purgative, and the vicious circleis closed.Causes of purgative dependence (B). Thedefecation reflex is triggered when the sigmoidcolon and rectum are filled. A naturaldefecation empties the descending colon.The interval between natural stool evacuationsdepends on the speed with which thiscolon segment is refilled. A large-bowel irritantpurgativeclearsouttheentirecolon.

Laxatives 177A. Stimulation of peristalsis by mucosal irritationReflexIrritationof mucosaFillingPeristalsisAbsorption Secretionof fluidB. Causes of laxative habituationIntervalneeded torefill colonNormal fillingdefecation reflexAfter normalevacuation of colonLonger interval neededto refill rectum1Laxative“Constipation”Renal retentionof Na + , H 2 OLaxativeBowel inertiaAldosteroneHypokalemiaEnteralloss of K +Renallossof K +2Na + , H 2 O

178 Laxatives2a. Small-Bowel Irritant PurgativeRicinoleic acid. Castor oil comes from Ricinuscommunis (castor bean; panel A: sprig,panicle, seed). The oil is obtained from thefirst cold-pressing of the seed (shown innatural size). Oral administration of10–30 ml of castor oil is followed within0.5–3 hours by discharge of a watery stool.Ricinoleic acid, but not the oil itself, is active.Theacidarisesasaresultoftheregularprocesses involved in fat digestion: the duodenalmucosa releases the enterohormonecholecystokinin/pancreozymin into theblood. The hormone elicits contraction of thegallbladder and discharge of bile acids viathe bile duct, as well as release of lipase fromthe pancreas (intestinal peristalsis is alsostimulated). Lipase liberates ricinoleic acidsfrom castor oil; these irritate the small boweland thus stimulate peristalsis. Because of itsmassive effect, castor oil is hardly suitablefor the treatment of ordinary constipation. Itcan be employed after oral ingestion of atoxin in order to hasten elimination and toreduce absorption of toxin from the gut.Castor oil is not indicated after the ingestionof lipophilic toxins likely to depend on bileacids for their absorption.2b. Large-Bowel Irritant PurgativesAnthraquinone derivatives are of plant origin.They occur in the leaves (Folia sennae)orfruits (Fructus sennae)ofthesenna plant, thebark of Rhamnus frangulae and Rh. purshiana(Cortex frangulae, Cascara sagrada), the rootsof rhubarb (Rhizoma rhei), or the leaf extractfrom Aloë species. The structural features ofanthraquinone derivatives are illustrated bythe prototype structure depicted in panel(B). Amongothersubstituents, theanthraquinonenucleus contains hydroxyl groups, oneof which is bound to a sugar (glucose, rhamnose).Following ingestion of galenical preparationsor of the anthraquinone glycosides,discharge of soft stool occurs after a latency of6–8 hours. The anthraquinone glycosidesthemselvesareinactivebutareconvertedbycolon bacteria to the active free aglycones.Diphenolmethane derivatives were developedfrom phenolphthalein, an accidentallydiscovered laxative, use of which hadbeen noted to result in rare but severe allergicreactions. Bisacodyl and sodium picosulfateare converted by gut bacteria into theactive colon-irritant principle. Given by theenteral route, bisacodyl is subject to hydrolysisof acetyl residues, absorption, conjugationin liver to glucuronic acid (or also tosulfate), and biliary secretion into the duodenum.Oral administration is followed after~ 6–8 hours by discharge of soft formedstool. When given by suppository, bisacodylproduces its effect within one hour.Indications for colon-irritant purgativesare the prevention of straining at stool followingsurgery, myocardial infarction, orstroke; and provision of relief in painful diseasesoftheanus,e.g.,fissure,hemorrhoids.Purgatives must not be given in abdominalcomplaints of unclear origin.3. Lubricant laxativesLiquid paraf n (paraf num subliquidum) isalmost nonabsorbable and makes fecessofter and passed easier. It interferes withthe absorption of fat-soluble vitamins bytrapping them. The few absorbed paraf nparticles may induce formation of foreignbodygranulomas in enteric lymph nodes(paraf nomas). Aspiration into the bronchialtract can result in lipoid pneumonia. Becauseof these adverse effects, its use is not advisable.Antiflatulents (carminatives) serve to alleviatemeteorism (excessive accumulation ofgas in the gastrointestinal tract). Aboral propulsionof intestinal contents is impededwhen these are mixed with gas bubbles. Defoamingagents, such as dimeticone (dimethylpolysiloxane)and simethicone,incombinationwith charcoal, are given orally to promoteseparation of gaseous and semisolidcontents.

Laxatives 179A. Plants containing laxative substancesRicinuscommunsChineseRhubarbSennaB. Large-bowel irritant laxatives: anthraquinone derivativesOOH O O-sugare.g., 1,8-DihydroxyanthraquinoneglycosideOH O OH1,8-DihydroxyanthroneOH OH OHAnthranolReductionSugar cleavageBacteriaAnthraquinoneglycoside

180 Antidiarrheals Antidiarrheal AgentsCauses of diarrhea. Many bacteria (e. g., Vibriocholerae) secrete toxins that inhibit theability of mucosal enterocytes to absorb NaCland water and, at the same time, stimulatemucosal secretory activity. Bacteria or virusesthat invade the gut wall cause inflammationcharacterized by increased fluid secretioninto the lumen. The enteric musculaturereacts with increased peristalsis.The aims of antidiarrheal therapy are (1) toprevent dehydration and electrolyte depletion(exsiccosis) of the body, and (2) to preventthe distressing, though nonthreatening,frequent bowel movements. The differenttherapeutic approaches listed are variouslysuited for these purposes.Adsorbent powders are nonabsorbablematerials with a large surface area. Thesebind diverse substances including toxins,permitting them to be inactivated and eliminated.Medicinal charcoal has a particularlylarge surface because of the preserved cellstructures. The recommended effective antidiarrhealdoseisintherangeof4–8g.Kaolin(hydrated aluminum silicate) is another adsorbent.Oral rehydration solution (in g/l of boiledwater: NaCl 3.5, glucose 20, NaHCO 3 2.5, KCl1.5). Oral administration of glucose-containingsalt solutions enables fluids to be absorbedbecause toxins do not impair theco-transport of Na + and glucose (as well asof H 2 O) through the mucosal epithelium. Inthis manner, although frequent discharge ofstool is not prevented, dehydration is successfullycorrected (important in therapy ofcholera).respiratory depression, physical dependence),derivatives with mainly peripheralactions have been developed. Whereasdiphenoxylate can still produce clear CNS effects,loperamide does not affect brain functionsat normal dosage because it is pumpedback into the blood by a P-glycoprotein locatedin capillary endothelial cells of theblood–brain barrier.Loperamide is, therefore, the opioid antidiarrhealof first choice. The prolonged contacttime for intestinal contents and mucosamay also improve absorption of fluid. Withoverdosage, there is a hazard of ileus. Thedrug is contraindicated in infants below age2years.Antibacterial drugs. Use of these agents(e. g., co-trimoxazole, p. 274) is only rationalwhen bacteria are the cause of diarrhea. Thisis rarely the case. Note that antibiotics alsodamage the intestinal flora, which in turncan give rise to diarrhea.Astringents such as tannic acid (home remedy:black tea) or metal salts precipitate surfaceproteins and are thought to help “seal”the mucosal epithelium. Protein denaturationmust not include cellular proteins, forthis would mean cell death. Although astringentsinduce constipation (cf. Al 3+ salts,p.170), a therapeutic effect in diarrhea isdoubtful.Demulcents, e. g., pectin (home remedy:grated apples) are carbohydrates that expandon absorbing water. They improve theconsistency of bowel contents; beyond thatthey are devoid of any favorable effect.Opioids. Activation of opioid receptors in theenteric nerve plexus results in inhibition ofpropulsive motor activity and enhancementof segmentation activity. This antidiarrhealeffect was formerly induced by applicationof opium tincture (paregoric) containing morphine.Because of the CNS effects (sedation,

Antidiarrheal Agents 181A. Antidiarrheals and their sites of actionToxinsNa +Cl -Fluid secretionNa +GlucoseAdsorptione.g., tomedicinalcharcoalToxinsOralrehydrationsolution:salts andglucoseAntibacterialdrugs: e.g., cotrimoxazoleResidentmicrofloraPathogenicbacteriaMucosal injuryVirusesOpium tincturewith morphineDiphenoxylateCNSEnhanced peristalsisProteincontainingmucusAstringents:e.g., tannic acidLoperamideInhibition ofpropulsiveperistalsisOpioidreceptorsPrecipitation ofsurface proteins,sealing ofmucosaDiarrheaFluid loss

182 Drugs Acting on the Motor System Drugs Affecting Motor FunctionThe smallest structural unit of skeletal musculatureis the striated muscle fiber. It contractsin response to an impulse of “its” motornerve. In executing motor programs, thebrain sends impulses to the spinal cord.These converge on α-motoneurons in theanterior horn of the spinal medulla. Bundledin motor nerves, efferent axons course toskeletal muscles. Simple reflex contractionsto sensory stimuli, conveyed via the dorsalroots to the motoneurons, occur withoutparticipation of the brain. Neural circuitsthat propagate afferent impulses into thespinal cord contain inhibitory interneurons.These serve to prevent a possible overexcitationof motoneurons (or excessive musclecontractions) due to the constant barrage ofsensory stimuli.Neuromuscular transmission (B) of motornerve impulses to the striated muscle fibertakes place at the motor end plate. The nerveimpulse liberates acetylcholine (ACh) fromthe axon terminal. ACh binds to nicotiniccholinoceptors at the motor end plate. Thiscauses depolarization of the postsynapticmembrane, which in turn elicits a propagatedaction potential (AP) in the surroundingsarcolemma. The AP triggers a release ofCa 2+ from its storage organelles, the sarcoplasmicreticulum (SR), within the musclefiber; the rise in Ca 2+ concentration inducesa contraction (electromechanical coupling).Meanwhile, ACh is hydrolyzed by acetylcholinesterase(p.104); excitation of the endplate subsides. If no AP follows, Ca 2+ is takenup again by the SR and the myofilamentsrelax.Centrally-acting muscle relaxants (A)lowermuscletonebyaugmentingtheactivityof intraspinal inhibitory interneurons.They are used in the treatment of painfulmuscle spasms, e. g., in spinal disorders. Benzodiazepinesenhance the effectiveness of theinhibitory transmitter GABA (p. 222) at *$%$ $receptors, which are ligand-gated ion channels.Baclofen stimulates GABA B receptors,which are G-protein coupled.The convulsants toxins tetanus toxin(cause of wound tetanus) and strychnine,diminish the ef cacy of interneuronal synapticinhibition mediated by the amino acidglycine (A). As a consequence of an unrestrainedspread of impulses in the spinalcord, motor convulsions develop. Spasms ofrespiratory muscle groups endanger life.Botulinus toxin from Clostridium botulinumis the most potent poison known. Theestimated lethal dose for 50% of an exposedhuman population is ~ 1 × 10 –9 g/kg (i. e.,about 75 nanograms for an adult individual).The toxin, a zinc endopeptidase, blocks exocytosisof ACh in motor (and also parasympathetic)nerve endings. Death is caused byparalysis of respiratory muscles.Targeted intramuscular injection of thetoxin can produce a long-lasting localizedparalysis. This procedure is used to treatpathological or painful muscle spasms (e. g.,blepharospasm, esophageal achalasia, cervicaldystonia). The same method is increasinglypracticed in cosmetic surgery for removaloffacialwrinkles(“facelift”).Infocalhyperhidrosis (palmar, axillary, plantar), localinjection of the toxin disrupts cholinergicsympathetic innervation, the effect of a singletreatment lasting for several weeks.Apathologicalriseinserum Mg 2+ levelsalso causes inhibition of neuromusculartransmission.Dantrolene interferes with electromechanicalcoupling in the muscle cell by inhibitingCa 2+ release from the SR. It is used totreat painful muscle spasms attending spinaldiseases and skeletal muscle disorders involvingexcessive release of Ca 2+ (malignanthyperthermia).

Drugs Affecting Motor Function 183A. Mechanisms for influencing skeletal muscle toneAntiepilepticsAntiparkinsonian drugsMyotonolytics DantroleneMuscle relaxantsMyotonolyticsIncreased inhibitionInhibitoryneuronBenzodiazepinesallostericenhancement ofGABAGlycineGABA effectAgonistStrychnineCl – Baclofen Receptorantagonist Cl -ConvulsantsAttenuatedinhibitionInhibitoryinterneuronTetanusToxinInhibitionof releaseGABA A receptor GABA B receptor Glycine receptorB. Inhibition of neuromuscular transmission and electromechanical couplingMotoraxonMg 2+Botulinum toxininhibitACh-releaseMuscle relaxantsinhibit generationof actionpotentialAction potentialSarcoplasmicreticulumt-TubuleMotorend plateAChDepolarizationMembrane potentialDantroleneinhibitsCa 2+ releaseMyofilamentsACh receptor(nicotinic)Muscle tonems 10 20Ca2+Contraction

184 Drugs Acting on the Motor System Muscle RelaxantsMuscle relaxants cause a flaccid paralysis ofskeletal musculature by binding to motor endplate cholinoceptors, thus blocking neuromusculartransmission (p.182). According towhether receptor occupancy leads to ablockade or an excitation of the end plate,one distinguishes nondepolarizing from depolarizingmuscle relaxants (p.186). As adjunctsto general anesthetics, muscle relaxantshelp to ensure that surgical proceduresare not disturbed by muscle contractions ofthe patient (p. 214). Nondepolarizing Muscle RelaxantsCurare is the term for plant-derived arrowpoisons of South American natives. Whenstruck by a curare-tipped arrow, an animalsuffers paralysis of skeletal musculaturewithin a short time after the poison spreadsthrough the body; death follows becauserespiratory muscles fail (“peripheral respiratoryparalysis”). Killed game can be eatenwithout risk because absorption of the poisonfrom the gastrointestinal tract is virtuallynil. The curare ingredient of greatestmedicinal importance is d-tubocurarine.This compound contains a quaternary nitrogenatom (N) and, at the opposite end of themolecule, a tertiary N that is protonated atphysiological pH. These two positivelycharged N atoms are common to all othermuscle relaxants. The fixed positive chargeof the quaternary N accounts for the poorenteral absorbability. d-Tubocurarine is givenby i.v. injection (average dose ~ 10 mg). Itbinds to the end-plate nicotinic cholinoceptorswithout exciting them, acting as a competitiveantagonist toward ACh. By preventingthe binding of released ACh, it blocksneuromuscular transmission. Muscular paralysisdevelops within about 4 minutes. d-Tubocurarine does not penetrate into theCNS. The patient would thus experience motorparalysis and inability to breathe, whileremaining fully conscious but incapable ofexpressing anything. For this reason, caremust be taken to eliminate consciousnessby administration of an appropriate drug(general anesthesia) before using a musclerelaxant. The effect of a single dose lastsabout 30 minutes.The duration of the effect of d-tubocurarinecan be shortened by administering anacetylcholinesterase inhibitor, such as neostigmine(p.106). Inhibition of ACh breakdowncauses the concentration of ACh releasedat the end plate to rise. Competitive“displacement” by ACh of d-tubocurarinefrom the receptor allows transmission to berestored.Unwanted effects produced by d-tubocurarineresult from a non-immune-mediatedrelease of histamine from mast cells leadingto bronchospasm, urticaria, and hypotension.More commonly, a fall in blood pressurecan be attributed to ganglionic blockadeby d-tubocurarine.Pancuronium is a synthetic compoundnowfrequentlyusedandnotlikelytocausehistamine release or ganglionic blockade. Increasedheart rate and blood pressure areattributed to blockade of cardiac M 2 -cholinoceptors.Other nondepolarizing muscle relaxantsinclude the pancuronium congeners vecuroniumand rocuronium, inadditionto alcuroniumderived from the alkaloid toxiferin.Atracurium is remarkable because itundergoes spontaneous nonenzymaticcleavage; termination of its effect thereforedoes not depend on hepatic or renal elimination.Mivacurium is structurally related toalcuronium; it is rapidly cleaved by cholinesterasesand, hence, is short-acting like thedepolarizing blocker succinylcholine(p.186). Rocuronium possesses the fastestonset of action (90 seconds) in this groupof substances. The onset of action of nondepolarizingmuscle relaxants can be shortenedby giving a small nonrelaxant dose minutesbefore the intubation dose (“primingprinciple”).

Nondepolarizing Muscle Relaxants 185A. Nondepolarizing muscle relaxantsArrow poison of indigenous South Americansd-Tubocurarine(no enteral absorption)PancuroniumOCCH 3OHCH 3H CHO3C+ 3N CH ON+2HC 3OOOCH 3+NOOHCH 3CH2+NCH3HOCCH 3AChBlockade of ACh receptorsNo depolarization ofend plateRelaxation of skeletal muscles(Respiratory paralysis)Artificialventilationnecessary(plus generalanesthesia!)Antidote:cholinesteraseinhibitorse.g., neostigmine

186 Drugs Acting on the Motor System Depolarizing Muscle RelaxantsIn this drug class, only succinylcholine (succinyldicholine,suxamethonium, A)isofclinicalimportance. Structurally, it can be describedas a double ACh molecule. Like ACh,succinylcholine acts as agonist at end-platenicotinic cholinoceptors, yet it producesmuscle relaxation. Unlike ACh, it is not hydrolyzedby acetylcholinesterase. However,it is a substrate of nonspecific plasma cholinesterase(serum cholinesterase, p.104).Succinylcholine is degraded more slowlythan is ACh and therefore remains in thesynaptic cleft for several minutes, causingan end plate depolarization of correspondingduration. This depolarization initially triggersa propagated action potential (AP) inthe surrounding muscle cell membraneleading to contraction of the muscle fiber.After i.v. injection, fine muscle twitches (fasciculations)can be observed. A new AP canbe elicited near the end plate only if themembrane has been unexcited for a suf -cient interval and allowed to repolarize.TheAPisduetoopeningofvoltage-gatedNa-channel proteins, allowing Na + ions toflow through the sarcolemma and to causedepolarization. After a few milliseconds, theNa + channels close automatically (“inactivation”),the membrane potential returns toresting levels, and the AP is terminated. Aslong as the membrane potential remains incompletelyrepolarized, renewed opening ofNa + channels, hence a new AP, is impossible.In the case of released ACh, rapid breakdownby ACh esterase allows repolarization of theendplateandthusareturnofNa + channelexcitability in the adjacent sarcolemma.With succinylcholine, however, there is apersistent depolarization of the end plateand adjoining membrane regions. Becausethe Na + channels remain inactivated, an APcannot be triggered in the adjacent membrane.The effect of a standard dose of succinylcholinelasts only about 10 minutes. It isoften given at the start of anesthesia to facilitateintubation of the patient. As expected,cholinesterase inhibitors are unable to counteractthe effect of succinylcholine. In thefew patients with a genetic deficiency inpseudocholinesterase (= nonspecific cholinesterase),the succinylcholine effect is significantlyprolonged.Since the persistent depolarization of endplates is associated with an ef ux of K + ions,hyperkalemia can result (risk of cardiac arrhythmias).Only in a few muscle types (e. g.,extraocular muscle) are muscle fibers suppliedwith multiple end plates and thereforecapable of a graded response. Here succinylcholinecauses depolarization distributedovertheentirefiber,whichrespondswitha contracture. Intraocular pressure rises,which must be taken into account duringeye surgery.In skeletal muscle fibers whose motornerve has been severed, ACh receptorsspreadovertheentirecellmembraneaftera few days. In this case, succinylcholinewould evoke a persistent depolarizationwith contracture and hyperkalemia. Theseeffects are likely to occur in polytraumatizedpatients undergoing follow-up surgery. Theuse of succinylcholine is waning because ofits marked adverse effects (rhabdomyolysis;hyperkalemia; cardiac arrest)Clinical use of muscle relaxants. Among theavailable neuromuscular blockers, succinylcholinedisplays the fastest onset of action.The patient can be intubated as early as30–60 seconds after intravenous injection(“rapid sequence intubation”), which is importantin emergency situations with an increasedrisk of aspiration (e. g., ileus, fullstomach, head trauma). Postoperativemuscle pain due to succinylcholine can beprevented by preinjection of a small dose ofa nondepolarizing blocker (“precurarization”).In combination with propofol p. 218),rocuronium (p.184) creates intubation conditionscomparable to those obtained withsuccinylcholine.

Depolarizing Muscle Relaxants 187A. Action of the depolarizing relaxant succinylcholineOCH 3+C O CH 2 CH 2 N CH 3H 3 CCH 3AcetylcholineH 3 C CHN + 3H 3 C CH2OH 2 C O C CH 2 CH 2 CSuccinylcholineOO CH 2H 2 C CHN + 3H 3 C CH3DepolarizationDepolarizationAChPropagation ofaction potential (AP)Succinylcholine1ContractionRapid ACh cleavage byacetylcholine esterasesSkeletalmusclecellContractionSuccinylcholine not degradedby acetylcholine esterases2Repolarization of end platePersistent depolarization of end plateACh3New APand contraction elicitedNew AP andcontraction cannot be elicitedMembrane potentialNa+-channelMembrane potential0 [mV]OpenClosed(opening not possible)RepolarizationClosed(opening possible)Membrane potential0 [mV]Persistent depolarizationNo repolarization,renewed opening ofNa+-channelimpossible

188 Drugs Acting on the Motor System Antiparkinsonian DrugsThe central nervous programming of purposivemovements depends on neuronal circuitsinterconnecting cortical regions, thethalamus, the cerebellum, and the basal ganglia(corpus striatum; subthalamic nucleus).The basal ganglia, in particular, play an importantpart in the initiation and scaling ofmovement as well as the programming oftarget acquisition. A disorder primarily involvingbasal ganglionic motor function isknown as idiopathic Parkinson disease(shaking palsy). The disease typically manifestsat an advanced age and is characterizedby poverty of movement (akinesia), musclestiffness (rigidity), tremor at rest, posturalinstability, gait disturbance, and a progressiveimpairment in the quality of life. Theprimary cause of this disease and its syndromalforms is a degeneration of dopamineneurons in the substantia nigra that projectto the corpus striatum (specifically, the caudatenucleus and putamen) and exert an inhibitoryinfluence. Cholinergic interneuronsin the striatum promote neuronal excitation.Pharmacotherapeutic measures are aimedat compensating striatal dopamine deficiencyor suppressing unopposed cholinergicactivity.L-Dopa. Dopamine itself cannot penetratethe blood–brain barrier; however, its naturalprecursor, L-dihydroxyphenylalanine (levodopa),is effective in replenishing striataldopamine levels, because it is transportedacross the blood–brain barrier via an aminoacid carrier and is subsequently decarboxylatedby dopa decarboxylase, present instriatal tissue. Decarboxylation also takesplace in peripheral organs where dopamineis not needed and is likely to cause undesirableeffects (vomiting; hypotension; p.116).Extracerebral production of dopamine canbe prevented by inhibitors of dopa decarboxylase(carbidopa, benserazide) that do notpenetrate the blood–brain barrier, leavingintracerebral decarboxylation unaffected.Excessive elevation of brain dopamine levelsmay lead to undesirable reactions such asinvoluntary movements (dyskinesias) andmental disturbances.Dopamine receptor agonists. Striatal dopaminedeficiency can be compensated by lysergicacid derivatives such as bromocriptine(p.116), lisuride, cabergoline, and pergolideand by the non-ergot compounds ropiniroleand pramipexole.Inhibitors of monoamine oxidase-B(MAO B ). Monoamine oxidase occurs in theform of two isozymes: MAO A and MAO B .Thecorpus striatum is rich in MAO B .Thisisozymecan be inhibited by selegiline. Degradation ofbiogenic amines in peripheral organs is notaffected because MAO A remains functional.Inhibitor of catecholamine O-methyltransferase(COMT). The CNS-impermeant entacaponeinhibits peripheral degradation of L-dopa and thus enhances availability of L-dopa for the brain. Accordingly, it is suitablyonly for combination therapy with L-dopa.Anticholinergics. Antagonists at muscariniccholinoceptors such as benztropine and biperiden(p.110) can be used to suppress thesequelae of the relative predominance ofcholinergic activity in the striatum (in particular,tremor). Atropine-like peripheral sideeffects and impairment of cognitive functionlimit the tolerable dosage. Complete disappearanceof symptoms cannot be achieved.Amantadine. Early or mild parkinsonianmanifestations may be relieved temporarilyby amantadine. The underlying mechanismsof action may involve, inter alia, blockade ofligand-gated ion channels of the glutamate/NMDA subtype, ultimately leading to diminishedrelease of acetylcholine.Treatment of advanced Parkinson diseaserequires combined administration ofthe above drugs for ameliorating the symptomsof this grave condition. Commonly, additionalsigns of central degeneration developas the disease progresses.

Antiepileptics 189A. Antiparkinsonian drugsSelegilineCH 2CH 3N CH 2 C CHCH CH 3Inhibition ofdopamine degradationby MAO-B in CNSCortexMotorcontrolloopGABAergicCholinergicPallidumAmantadineNH 2NMDA receptor:Blockadeof ionophore:attenuation ofcholinergic neuronsDopaminergicS. nigraStriatumDegeneration inParkinson diseaseInhibition of cholinergictransmissionBlood-brain barrierHOCarbidopaHOCH3CH2 C NH NH2COOHInhibition of dopadecarboxylaseDOPAdecarboxylaseDopamineStimulation ofperipheral dopaminereceptorsAdverse effectsDopamine substitution2000 mg 200 mgEntacaponeHOHOCOMTNO 2OCN 2 H 5C 2 HCN5Inhibition of theperipheral catechol-O-methyltransferaseBromocriptineCH 3C H CH 3L-DOPABenzatropineOOHH 3 CONNH C NHHONOO H CH 2HOCH2 CH NHN2CH3CHCOOHO C HH 3C CH 3MuscarinicHN Dopamine-receptoracetylcholineBr agonistDopamine precursorantagonist

190 Drugs Acting on the Motor System AntiepilepticsEpilepsy is a chronic brain disease of diverseetiology; it is characterized by recurrent paroxysmalepisodes of uncontrolled excitationof brain neurons. Involving larger or smallerparts of the brain, the electrical discharge isevident in the electroencephalogram (EEG)as synchronized rhythmic activity and manifestsitself in motor, sensory, psychic, andvegetative (visceral) phenomena. As boththe affected brain region and the cause ofabnormal excitability may differ, epilepticseizurescantakeonmanyforms.Fromapharmacotherapeutic viewpoint, these maybe classified as: Generalized vs. partial (focal) seizures Seizures with or without loss of consciousness Seizures with or without specific modes ofprecipitationThe brief duration of a single epileptic fitmakes acute drug treatment unfeasible. Instead,antiepileptics are used to prevent seizuresand therefore need to be given chronically.Only in the case of status epilepticus(succession of several tonic-clonic seizures),is acute anticonvulsant therapy indicated—usually with benzodiazepines given i.v. or, ifneeded, rectally.The initiation of an epileptic attack involves“pacemaker” cells; these differ fromother nerve cells by their unstable restingmembrane potential; i. e., a depolarizingmembrane current persists after the actionpotential terminates.Therapeutic interventions aim to stabilizeneuronal resting potential and, hence, tolower excitability. In specific forms of epilepsy,initially a single drug is tried toachieve control of seizures, valproate usuallybeing the drug of first choice in generalizedseizures, and carbamazepine being preferredfor partial (focal), especially partial complex,seizures. Dosage is increased until seizuresare no longer present or adverse effects becomeunacceptable. Only when monotherapywith different agents proves inadequatecan change-over to a second-line drug orcombined use (“add on”) be recommended(B), provided that the possible risk of pharmacokineticinteractions is taken into account(see below). The precise mode of actionof antiepileptic drugs remains unknown.Some agents appear to lower neuronalexcitability by several mechanisms ofaction. In principle, responsivity can be decreasedby inhibiting excitatory or activatinginhibitory neurons. The transmitters utilizedby most excitatory and inhibitory neuronsare glutamate and γ-aminobutyric acid (GA-BA), respectively (p.193A).Glutamate receptors comprise three subtypes,of which the NMDA subtype has thegreatest therapeutic importance. (N-methyl-D-aspartate is a synthetic selective agonist.)This receptor is a ligand-gated ion channelthat, upon stimulation with glutamate, permitsentry of both Na + and Ca 2+ into the cell.Valproic acid inhibits both Na + and Ca 2+channels. The antiepileptics lamotrigine,phenytoin, andphenobarbital inhibit, amongother things, the release of glutamate. Felbamateis a glutamate antagonist.Benzodiazepines and phenobarbital augmentthe activation of the GABA A receptorby physiologically released amounts of GABA(B) (see pp.193, 222). Chloride influx is increased,counteracting depolarization. Progabideis a direct GABA-mimetic but not anapproved drug. Tiagabine blocks removal ofGABA from the synaptic cleft by decreasingits reuptake. Vigabatrin inhibits GABA catabolism.Gabapentin augments the availabilityof glutamate as a precursor in GABA synthesis(B).

Antiepileptics 191A. Epileptic attack, EEG, and antiepilepticsDrugs used in the treatment of status epilepticus:Benzodiazepines, e.g., diazepamWaking statemV15010050EEGEpileptic attackmV1501005001 s01 sDrugs used in the prophylaxis of epileptic seizuresOHHNOCH 3N CCCN 5 C 2 H 2 H 55 O CO CO CCNNOCN CHHHO NH 2OCarbamazepine PhenobarbitalPhenytoin EthosuximideCH 2H 3 C CH 3H2CCH 2H 2 C H CH 2CCOOHValproic acidCH 2 NH 2CCH 2COOHGabapentinHCHC NH 2CH 2CH 2COOHVigabatrinH 2 C NH 2CH 2CH 2COOHGABAB. Indications for antiepilepticsFocalseizuresGeneralizedattacksSimpleseizuresComplex orsecondarilygeneralizedTonic-clonicattack (grand mal)Tonic attackClonic attackMyoclonic attackAbsenceseizureCarbamazepineValproic acidI. II.Valproic acid,PhenytoinCarbamazepine,PhenytoinEthosuximideIII. ChoicePrimidone,Phenobarbital+ Lamotrigine or Vigabatrin or GabapentinLamotrigine,Primidone,Phenobarbital+ Lamotrigine or Vigabatrin or Gabapentin+ Lamotrigine or Clonazepam

192 Drugs Acting on the Motor SystemThe tricyclic carbamazepine, its analogueoxycarbazepine, andphenytoin enhance inactivationof voltage-gated sodium and calciumchannels and limit the spread of electricalexcitation by inhibiting sustainedhigh-frequency firing of neurons.Ethosuximide blocks a neuronal T-type Ca 2+channel (A); and represents a special classbecauseit iseffectiveonlyin absenceseizures.All antiepileptics are likely, albeit in differentdegrees, to produce adverse effects. Sedation,dif culty concentrating, and slowingof psychomotor drive encumber practically allantiepileptic therapy. Moreover, cutaneous,hematological, and hepatic changes may necessitatea change in medication. Phenobarbital,primidone, and phenytoin may lead toosteomalacia (vitamin D prophylaxis) ormegaloblastic anemia (folate prophylaxis).During treatment with phenytoin, gingivalhyperplasia may develop in ~ 20% of patients.Valproic acid (VPA) islesssedatingthan other anticonvulsants. Tremor, gastrointestinalupset, and weight gain are frequentlyobserved; reversible hair loss is ararer occurrence. Its hepatotoxicity shouldbe kept in mind.Adverse reactions to carbamazepine includenystagmus, ataxia, and diplopia, particularlyif the dosage is raised too fast. Gastrointestinalproblems and skin rashes arefrequent. It exerts an antidiuretic effect (sensitizationof collecting ducts to vasopressin).Valproate, carbamazepine, and other anticonvulsantspose teratogenic risks. Despitethis, treatment should continue during pregnancy,as the potential threat to the fetus bya seizure is greater. However, it is mandatoryto apply the lowest dose affording safe andeffective prophylaxis. Concurrent high-doseadministration of folate may prevent neuraltube defects.Carbamazepine, phenytoin, phenobarbital,and other anticonvulsants induce hepaticenzymes responsible for drug biotransformation;valproate is a potent inhibitor. Combinationsbetween anticonvulsants or withother drugs may result in clinically importantinteractions (plasma level monitoring!).Carbamazepine is also used to treat trigeminalneuralgia and neuropathic pain.For the often intractable childhood epilepsies,various other agents are used includingACTH and the glucocorticoid dexamethasone.Multiple (mixed) seizures associatedwith the slow spike-wave (Lennox–Gastaut) syndrome may respond to valproate,lamotrigine, and felbamate, the lastbeing restricted to drug resistant seizuresowingtoitspotentiallyfatalliverandbonemarrow toxicity.Benzodiazepines are the drugs of choicefor status epilepticus (see above); however,development of tolerance renders them lesssuitable for long-term therapy. Clonazepamis used for myoclonic and atonic seizures.Clobazam, a 1,5-benzodiazepine exhibitingan increased anticonvulsant/sedative activityratio, has a similar range of clinical uses.Personality changes and paradoxical excitementare potential side effects.Clomethiazole can also be effective forcontrolling status epilepticus but is usedmainly to treat agitated states, especiallyalcoholic delirium tremens and associatedseizures.Topiramate, derived from D-fructose, hascomplex, long-lasting anticonvulsant actionsthat cooperate to limit the spread of seizureactivity; it is effective in partial and generalizedseizures and as add-on in Lennox–Gastautsyndrome.It should be noted that certain drugs (e. g.,neuroleptics, isoniazid, and high-dose β-lactamantibiotics) lower seizure threshold andare therefore contraindicated in epileptic patients.Outlook: Among the newer antiepileptics,gabapentin, oxycarbazepine, lamotrigine,andtopiramatearenowendorsedasprimarymonotherapeutics for both partial and generalizedseizures. Their pharmacokinetic characteristicsare generally more desirable thanthose of the older drugs.

Antiepileptics 193A. Neuronal sites of action of antiepilepticsNa + Ca 2+Ca 2+ -channelNMDAreceptorNMDA-receptorantagonistfelbamate,valproic acidExcitatory neuronGlutamateInhibition ofglutamaterelease:phenytoin,lamotriginephenobarbitalT-Typecalciumchannel blockerethosuximide,(valproic acid)GABAAreceptorCI -InhibitoryneuronGABAVoltagedependentNa + -channelGabamimetics:benzodiazepinebarbituratesvigabatrintiagabinegabapentinInhibition ofactionpotentialscarbamazepinevalproic acidphenytoinB. Sites of action of antiepileptics in GABAergic synapseBenzodiazepinesAllostericenhancementofGABAactionαγβαβGABA A -receptorαγβαβChloridechannelTiagabineInhibitionof GABAreuptakeBarbituratesEnding ofinhibitoryneuronGlutamicacidVigabatrinInhibitorof GABAtransaminaseProgabideGABAmimeticGABAGlutamic aciddecarboxylaseGABAtransaminaseSuccinicsemialdehydeSuccinic acidGabapentinImproved utilizationof GABA precursor:glutamate

194 Drugs for the Suppression of Pain (Analgesics) Pain Mechanisms and PathwaysPain is a designation for a spectrum of sensationsof highly divergent character and intensityranging from unpleasant to intolerable.Pain stimuli are detected by physiologicalreceptors (sensors, nociceptors) leastdifferentiated morphologically, viz., freenerve endings. The body of the bipolar afferentfirst-order neuron lies in the dorsal rootganglia. Nociceptive impulses are conductedvia unmyelinated (C-fibers, conductionvelocity 0.2–2 m/s) and myelinated axons(Aδ-fibers,10–30m/s).ThefreeendingsofAδ-fibers respond to intense pressure orheat, those of C-fibers respond to chemicalstimuli (H + ,K + ,histamine,bradykinin,etc.)arising from tissue trauma.Irrespective of whether chemical, mechanical,or thermal stimuli are involved,they become significantly more effective inthe presence of prostaglandins (p.196).Chemical stimuli also underlie painsecondary to inflammation or ischemia (anginapectoris, myocardial infarction). The intensepain that occurs during overdistensionor spasmodic contraction of smooth muscleabdominal organs may be maintained bylocal anoxemia developing in the area ofspasm (visceral pain).Aδ- and C-fibers enter the spinal cord viathe dorsal root, ascend in the dorsolateralfuniculus, and then synapse on second-orderneurons in the dorsal horn. The axons of thesecond-order neurons cross the midline andascend to the brain as the anterolateral pathwayor spinothalamic tract. Based on phylogeneticage, a neospinothalamic tract and apalaeospinothalamic tract are distinguished.The second-order (projection) neurons ofboth tracts lie in different zones (laminae)of the dorsal horn. Lateral thalamic nucleireceiving neospinothalamic input project tocircumscribed areas of the postcentral gyrus.Stimuli conveyed via this path are experiencedas sharp, clearly localizable pain. Themedial thalamic regions receiving palaeospinothalamicinput project to the postcentralgyrus as well as the frontal, limbic cortex andmost likely represent the pathway subservingpainofadull,aching,orburningcharacter,i. e., pain that can be localized onlypoorly.Impulse traf c in the neospinothalamicand palaeospinothalamic pathways is subjectto modulation by descending projectionsthat originate from the reticular formationand terminate at second-order neurons,at their synapses with first-order neurons orspinal segmental interneurons (descendingantinociceptive system). This system caninhibit substance P-mediated impulse transmissionfrom first- to second-order neuronsvia release of endogenous opiopeptides (enkephalins)or monoamines (norepinephrine,serotonin).Pain sensation can be influenced ormodified as follows: Elimination of the cause of pain Lowering of the sensitivity of nociceptors(antipyretic analgesics, local anesthetics) Interrupting nociceptive conduction insensory nerves (local anesthetics) Suppression of transmission of nociceptiveimpulses in the spinal medulla(opioids) Inhibition of pain perception (opioids,general anesthetics) Altering emotional responses to pain, i. e.,pain behavior (antidepressants as co-analgesics)

Pain Mechanisms and Pathways 195A. Pain mechanisms and pathwaysGyrus postcentralisPerception:sharpquicklocalizablePerception:dulldelayeddiffuseAnestheticsThalamusAntidepressantsLocal anestheticsOpioidsNeospinothalamictractPaleospinothalamictractReticularformationDescendingantinociceptivepathwayOpioidsNitrous oxideNociceptorsCyclooxygenaseinhibitorsProstaglandinsInflammationCausation of pain

196 Antipyretic Analgesics EicosanoidsUnder the influence of cyclooxygenases(COX-1, COX-2, and their splice variants),the extended molecule of arachidonic acid(eicosatetraenoic acid 1 ) is converted intocompounds containing a central ring withtwo long substituents: prostaglandins, prostacyclin,and thromboxanes. Via the action ofa lipoxygenase, arachidonic acid yields leukotrienes,in which ring closure in the centerofthemolecule(A) does not occur. The productsformed from arachidonic acid are inactivatedvery rapidly; they act as local hormones.The groups of prostaglandins andleukotrienes each comprise a large numberof closely related compounds. In the presentcontext, only the most important prostaglandinsand their constitutive actions areconsidered.Prostaglandin (PG)E 2 inhibits gastric acidsecretion, increases production of mucus(mucosa-protective action), and elicits bronchoconstriction.PGF 2α stimulates uterinemotility. PGI 2 (prostacyclin) produces vasodilatationand promotes renal excretion ofNa + . In addition, prostaglandins synthesizedby COX-2 participate in inflammatory processesby sensitizing nociceptors, thus loweringpain threshold; by promoting inflammatoryresponses by release of mediatorssuch as interleukin-1 and tumor-necrosisfactor α; and by evoking fever.Prostacyclin is produced in vascular endotheliumand plays a role in the regulationof blood flow. It elicits vasodilation and preventsaggregation of platelets (functional antagonistof thromboxane).Thromboxane A 2 is a local hormone ofplatelets; it promotes their aggregation.Small defects in the vascular or capillary wallelicit the formation of thromboxane._1 Name derived from Greek eikosi =twentyforthe number of carbon atoms and tetra =4forthenumber of double bondsLeukotrienes 2 are produced mainly inleukocytes and mast cells. Newly formedleukotrienes can bind to glutathione. Fromthis complex, glutamine and glycine can becleaved, resulting in a larger number of localhormones. Leukotrienes are pro-inflammatory;they stimulate invasion of leukocytesand enhance their activity. In anaphylacticreactions, they produce vasodilation,increase vascular permeability, and causevasoconstriction.Therapeutic uses of synthetic eicosanoids.Efforts to synthesize stable derivatives ofprostaglandins for therapeutic applicationshave not been very successful to date. Dinoprostone(PGE 2 ), carboprost (15-methyl-PGF 2α) and mifeprostone are uterine stimulants(p.130, 254). Misoprostol is meant toafford protection of the gastric mucosa buthas pronounced systemic side effects. Allthese substances lack organ specificity._2 Note the change in chemical nomenclature: -triene (tri=three), although leukotrienes possessfour double bonds; however, of these only theconjugated ones are counted

Eicosanoids 197A. Origin and actions of prostaglandinsPhospholipase A 2H 3 CH 3 CProstaglandin F 2αand othersCOOHArachidonic acidThromboxane A 2COOHProstacyclin Leukotriene A 4CyclooxygenasesLipoxygenasesand othersCH3H 3 CH 3 CCOOHHOHOHOOCHOHOOHHOOO OStomach[H + ]MucusInhibitionof plateletaggregationStimulationof plateletaggregationOKidneyBlood flowAdaptation to:salt loadlack of H 2 OVasodilationVasoconstrictionCOOHUterusMotilityImplantationNociceptionSensitizationInflammatoryprocessesincreasedThermoregulatorycenterFever producingconstitutiveinducibleInflammatoryprocessesaugmentedVascularpermeabilityincreasedBronchoconstriction

198 Antipyretic Analgesics Antipyretic AnalgesicsThe large and important family of drugs forthe treatment of pain, inflammation, andfever has to be subdivided into two groupsthat differ in their mechanism of action andspectrum of activity, namely,1. Antipyretic analgesics2. Nonsteroidal anti-inflammatory drugs(NSAIDs)all of which have the chemical character ofacids.Antipyretic analgesics represent p-aminophenolor pyrazolone derivatives withclinically useful analgesic and antipyretic efficacy.Their mechanism of action is not completelyunderstood but thought to be mediatedvia inhibition of prostanoid formationby variants of COX enzymes. Acetaminophen(paracetamol), phenazone, and dipyrone belongin this group.Acetaminophen has good analgesic ef -cacy in commonplace pain, such as toothacheand headaches, but is of less use ininflammatory and visceral pain. It exerts astrong antipyretic effect. The adult dosage is0.5–1.0 g up to 4 times daily; the eliminationhalf-life is about 2 hours. Acetaminophen iseliminated renally after conjugation to sulfuricor glucuronic acid. A small portion ofthedoseisconvertedbyhepaticCYP450toareactive metabolite that requires detoxificationby coupling to glutathione. In suicidal oraccidental poisoning with acetaminophen(10 g), the depleted store of thiol groupsmust be replaced by administration of acetylcysteine.This measure can be life-saving.Long-term therapy with pure acetaminophenpreparations does not cause renaldamage, reported earlier after use of stimulantcombination preparations. Fixed combinationswith codeine may be used withhardly any reservation.Dipyrone (metamizole) is a pyrazolonederivative. It produces strong analgesia, evenin pain of colic, and has an additional spasmolyticeffect. The antipyretic effect ismarked. The usual dosage is about 500 mgorally. Higher doses (up to 2.5 g) are neededfor biliary colic. The effect of a standard doselasts ~ 6hours.Use of dipyrone is compromised by a veryrare but serious adverse reaction, viz., bonemarrow depression. The incidence of agranulocytosisremains controversial; probably,one case occurs in > 100 000 treatments.Hypotension may occur after intravenousinjection. Dipyrone is not for routine use;however, short-term administration is recommendedfor appropriate individual cases. Nonsteroidal Anti- inflammatoryDrugs (NSAIDs)This term subsumes drugs other than COX-2inhibitors that (a) are characterized chemicallyby an acidic moiety linked to an aromaticresidue; and that (b) by virtue of inhibitingcyclooxygenases, are effective insuppressing inflammation, alleviating pain,and lowering fever. Cyclooxygenases (COX)localized to the endoplasmic reticulum areresponsible for the formation from arachidonicacid of a group of local hormones comprisingthe prostaglandins, prostacyclin, andthromboxanes. NSAIDs (except ASA) are reversibleinhibitors of COX enzymes. Theseenzymes possess an elongated pore intowhich the substrate arachidonic acid is insertedand converted to an active product.NSAIDs penetrate into this pore and thusprevent access for arachidonic acid, leadingto reversible blockade of the enzyme.

Antipyretic Analgesics vs. NSAIDs 199A. Comparison of antipyretic analgesics with a nonsteroidal anti-inflammatory drugToothacheHeadacheFeverInflammatorypainEffectiveLess effectivePain of colicAcetaminophen Acetylsalicylic acid DipyroneOOHCOOHH 2 C S OHO C CH 3H 3 C NOCH 3OOHN CON N CH 3CH 3AcutemassiveoverdoseonlywithChronicabuseveryrarely>10gAgranulocytosisBronchoconstrictionImpairedhemostasis withrisk of bleedingIrritationofgastrointestinalmucosaHepatotoxicityNephrotoxicityRisk ofanaphylactoidshock

200 Nonsteroidal Anti-inflammatory Drugs Cyclooxygenase (COX) InhibitorsTwo principal types of COX can be distinguished:COX-1 is constitutive, that is, always presentand active; it contributes to the physiologicalfunction of organs. Inhibition inevitably producesunwanted effects, such as mucosal injury,renaldamage,hemodynamicchanges,and disturbances of uterine function.COX-2 is induced by inflammatory processesand produces prostaglandins that sensitizenociceptors, evoke fever, and promote inflammationby causing vasodilation and anincrease in vascular permeability. However,in some organs, COX-2 is also expressed constitutively(kidney, vascular endothelium,uterus, and CNS).Nonselective COX inhibitors derive fromsalicylic acid. The majority are carbonicacids, such as ibuprofen, naproxene, diclofenac,indometacin, and many more; or enolicacids, such as azapropazone and meloxicam.All these drugs inhibit both COX enzymes.The molecules of COX-1 and COX-2 reveala pharmacologically important difference:the enzymatic pore width of COX-2 exceedsthat of COX-1. The nonselective COX inhibitorscan also enter the narrower pores andthus inhibit both cyclooxygenases.Efforts have succeeded to develop inhibitorsthat readily enter the slightly widerpores of COX-2 but not the COX-1 pores,giving rise to the specific COX-2 inhibitors(denoted coxibs). These drugs consist of ahetero-aromatic ring bearing two phenylring substituents, one of which contains a−SO 2 group (see formulas in A). The advantageofcoxibsliesintheirlesserpropensitytocause mucosal injury. This effect has beenreported in large clinical trials (but subsequentlyqueried). However, a number of adversereactions are now known that are consistentwith COX-2 also serving constitutivefunctions. Furthermore, one needs to considerthat COX-1 functions may be more or lessaffected at suf ciently large dosages. Selectivityfactors (COX-1/COX-2 ratio) determinedbiochemically in vitro range from 30to 400.Coxibs available at present include: celecoxib(daily dosage 200–400 mg), valdecoxib(10–20 mg) (no longer available in the US)and its prodrug parecoxib (40 mg i.v.!).Coxibs are not drugs for routine use andshould only be employed in a targeted manner,in particular when antiarthritis treatmentwith nonselective NSAIDs has led togastrointestinal mucosal damage (bleeding,gastritis, ulcerations). Contraindicationsmust be heeded, in particular, advanced congestiveheart failure, hepatic and renal diseases,inflammatory bowel diseases, andasthma. Concern over an increased risk ofstroke and myocardial infarction in vulnerablepatient populations has led to withdrawalof rofecoxib (Sept. 2004), raisingstrong suspicion that this represents a coxibclass effect.Acetylsalicylic acid (ASA) meritsaseparatecomment. Acetylation of salicylic acidsignificantly reduces its ability to induce mucosalinjury. After absorption of ASA, theacetyl moiety is cleaved with a t ½ of 15–20minutes, salicylic acid then being present invivo. For anti-inflammatory therapy, the requireddosage of ASA lies above 3 g daily. Fortreatment of ordinary pain, a dose of~ 500 mg is needed. At low dosage(100–200 mg daily), following absorptioninto the portal circulation, ASA causes along-lasting blockade of COX-1-mediatedthromboxane synthesis in platelets becauseof an irreversible acetylation of the enzyme.Since platelets represent anuclear cell fragments,theyareunabletosynthesizenewCOX molecules.

Nonsteroidal Anti-inflammatory Drugs 201A. Nonsteroidal anti-inflammatory drugs (NSAIDs)0.3 – 6.0 gNonselective COX inhibitors200 – 400 mgAcetylsalicylicacidCOO –OHSalicylic acidCOO –Cl–CH 2 COONHCl0.05 – 0.15 gOH 2 NSOCelecoxibO C CH3ON N CF 3CH 3HDiclofenac3 C CH CH 2CH 3CHCOOHH 3 CIbuprofenH 3 COSRofecoxib*NaproxenCH3CH– COOOOH3CO0.6 – 2.4 g12.5 – 25 mgOCOX-2 inhibitors0.5 – 1.0 g daily dosesB. Adverse effects of nonsteroidal anti-inflammatory drugsCyclooxygenasesNonselectiveCOX inhibitorsCOX -2inhibitorsArachidonic acidLipoxygenasesProstaglandins decreasedLeukotrienes increasedGastric mucosaldamage withulcer formation,bleeding, andperforationLowerincidence ofgastropathy(depending onsupply of arachidonicacid)Nephropathy, decreased excretion of NaCl andH 2 O, edemas, increased blood pressure, impairedwound healing, diarrhea, disturbed uterine motilityBronchoconstriction,bronchial asthma,proinflammatory effect

202 Local Anesthetics Local AnestheticsLocal anesthetics reversibly inhibit impulsegeneration and propagation in nerves. Insensory nerves, such an effect is desiredwhen painful procedures must be performed,e. g., surgical or dental operations.Mechanism of action. Axonal impulse conductionoccurs in the form of an action potential.The change in potential involves arapid influx of Na + (A) throughamembranechannel protein that, upon being opened(activated), permits rapid inward movementof Na + down a chemical gradient ([Na + ] outside~ 150 mM, [Na + ] inside ~ 7 mM). Local anestheticsare capable of inhibiting this rapidinflux of Na + ; initiation and propagation ofexcitation are therefore blocked (A).Most local anesthetics exist in part in thecationic amphiphilic form (cf. p. 206). Thisphysicochemical property favors incorporationinto membrane interphases betweenpolar and apolar domains. These are foundin phospholipid membranes and also in ionchannel proteins. Some evidence suggeststhat Na + -channel blockade results frombinding of local anesthetics to the channelprotein. It appears certain that the site ofaction is reached from the cytosol, implyingthat the drug must first penetrate the cellmembrane (p. 204).Local anesthetic activity is also shown byuncharged substances, suggesting a bindingsite in apolar regions of the channel proteinor the surrounding lipid membrane.Mechanism-specific adverse effects. Sincelocal anesthetics block Na + influx not onlyin sensory nerves but also in other excitabletissues (A and p. 206), they are applied locally.Depression of excitatory processes inthe heart, while undesired during local anesthesia,can be put to therapeutic use in cardiacarrhythmias (p.138).Forms of local anesthesia. Local anestheticsare applied via different routes, includinginfiltration of the tissue (infiltration anesthesia)or injection next to the nerve branchcarrying fibers from the region to be anesthetized(conduction anesthesia of thenerve, spinal anesthesia of segmental dorsalroots), or by application to the surface of theskin or mucosa (surface anesthesia). In eachcase, the local anesthetic drug is required todiffuse to the nerves concerned from a depotplacedinthetissueorontheskin.High sensitivity of sensory, low sensitivityof motor nerves. Impulse conduction in sensorynerves is inhibited at a concentrationlower than that needed for motor fibers. Thisdifference may be due to the higher impulsefrequency and longer action potential durationin nociceptive as opposed to motor fibers.Alternatively, it may relate to the thicknessof sensory and motor nerves, as well asthe distance between nodes of Ranvier. Insaltatory impulse conduction, only the nodalmembrane is depolarized. Because depolarizationcan still occur after blockade of threeor four nodal rings, the area exposed to adrug concentration suf cient to cause blockademustbelargerformotorfibers(p.203B).This relationship explains why sensorystimuli that are conducted via myelinatedAδ-fibers are affected later and to a lesserdegree than are stimuli conducted via unmyelinatedC-fibers. Since autonomic postganglionicfibers lack a myelin sheath, theyare susceptible to blockade by local anesthetics.As a result, vasodilation ensues inthe anesthetized region, because sympatheticallydriven vasomotor tone decreases.This local vasodilation is undesirable (seeopposite).

Local Anesthetics 203A. Effects of local anestheticsLocal anestheticNa + -entryPropagatedimpulseActivatedNa + -channelNa +insideinsidePeripheral nerveCNSBlockedNa + -channelNa +PerineuriumConductionblockRestlessness,convulsions,respiratoryparalysisBlockedNa + -channelNa +HeartLocalapplicationImpulseconductioncardiac arrestpolar+apolarCationicamphiphiliclocalanestheticUnchargedlocalanestheticB. Inhibition of impulse conduction in different types of nerve fibersLocal anestheticAα motor0.8–1.4 mmAδ sensory0.3–0.7 mmC sensory andpostganglionic

204 Local AnestheticsDiffusion and effect. During diffusion fromthe injection site (i. e., the interstitial space ofconnective tissue) to the axon of a sensorynerve, the local anesthetic must traverse theperineurium. The multilayered perineuriumis formed by connective tissue cells linked byzonulae occludentes (p. 22) and thereforeconstitutes a closed lipophilic barrier.Local anesthetics in clinical use are usuallytertiary amines; at the pH of interstitial fluidthese exist partly as the neutral lipophilicbase (symbolized by particles marked withtwo red dots) and partly as the protonatedform, i. e., amphiphilic cation (symbolized byparticles marked with one blue and one reddot). The uncharged form can penetrate theperineurium and enters the endoneuralspace, where a fraction of the drug moleculesregains a positive charge in keepingwith the local pH. The same process repeatsitself when the drug penetrates through theaxonal membrane (axolemma) into the axoplasmfrom which it exerts its action on thesodium channel; and again when it diffusesout of the endoneural space through theunfenestrated endothelium of capillaries intothe blood.The concentration of local anesthetic atthe site of action is, therefore, determinedby the speed of penetration into the endoneuriumand axoplasm and the speed of diffusioninto the capillary blood. To enable asuf ciently fast build-up of drug concentrationatthesiteofaction,theremustbeacorrespondingly large concentration gradientbetween drug depot in the connectivetissue and the endoneural space. Injection ofsolutions of low concentration will fail toproduce an effect; however, too high concentrationsmust also be avoided becauseof the danger of intoxication resulting fromtoo rapid systemic absorption into the blood.To ensure a reasonably long-lasting localeffect with minimal systemic action, a vasoconstrictor(epinephrine, less frequentlynorepinephrine or vasopressin derivatives)is often co-administered in an attempt toconfine the drug to its site of action. As bloodflow is diminished, diffusion from the endoneuralspace into the capillary blood decreases.Addition of a vasoconstrictor, moreover,helps to create a relative ischemia inthe surgical field. Potential disadvantages ofcatecholamine-type vasoconstrictors includethe reactive hyperemia followingwashout of the constrictor agent (p. 94) andcardiostimulation when epinephrine entersthe systemic circulation. In lieu of epinephrine,the vasopressin analogue felypressincan be used as adjunctive vasoconstrictor(less pronounced reactive hyperemia, noarrhythmogenic action, but danger of coronaryconstriction). Vasoconstrictors must notbe applied in local anesthesia involving theappendages (e. g., fingers, toes).

Local Anesthetics 205A. Disposition of local anesthetics in peripheral nerve tissue0.1 mmCross section through peripheralnerve (light microscope)PerineuriumAxonEndoneuralspaceCapillarywallInterstitiumAxolemmaAxoplasmVasoconstrictione.g., with epinephrinelipophilicamphiphilicAxolemmaAxoplasm

206 Local AnestheticsCharacteristics of chemical structure. Localanesthetics possess a uniform structure.Generally they are secondary or tertiaryamines. The nitrogen is linked through anintermediary chain to a lipophilic moiety—most often an aromatic ring system.The amine function means that local anestheticsexist either as the neutral amine or asthe positively charged ammonium cation,depending upon their dissociation constant(pK a value) and the actual pH value. The pK aof typical local anesthetics lies between 7.5and 9. In its protonated form, the moleculepossesses both a polar hydrophilic moiety(protonated nitrogen) and an apolar lipophilicmoiety (ring system)—it is amphiphilic.Depending on the pK a ,from50%to5%ofthe drug may be present at physiological pHin the uncharged lipophilic form. This fractionis important because it represents thelipid membrane-permeable form of the localanesthetic (p. 26), which must take on itscationic amphiphilic form in order to exertits action (p. 202).Clinically used local anesthetics are eitheresters or amides. Even drugs containing amethylene bridge, such as chlorpromazine(p. 233) or imipramine (p. 229) would exerta local anesthetic effect with appropriateapplication. Ester-type local anesthetics aresubject to inactivation by tissue esterases.This is advantageous because of the diminisheddanger of systemic intoxication. On theother hand, the high rate of bioinactivationand, therefore, shortened duration of actionis a disadvantage.Procaine cannot be used as surface anestheticbecause it is inactivated faster than itcan penetrate the dermis or mucosa. In mepivacaine,the nitrogen atom usually locatedat the end of the side chain forms part of acyclohexane ring.Lidocaine is broken down primarily in theliver by oxidative N-dealkylation. This stepcan occur only to a restricted extent in prilocaineand carticaine because both carry asubstituent on the C-atom adjacent to thenitrogen group. Carticaine possesses a carboxymethylgroup on its thiophene ring. Atthis position, ester cleavage can occur, resultingin the formation of a polar COO –group, loss of the amphiphilic character,and conversion to an inactive metabolite.Benzocaine is a member of the group oflocal anesthetics lacking a nitrogen atomthat can be protonated at physiological pH.It is used exclusively as a surface anesthetic.Other agents employed for surface anesthesiainclude the uncharged polidocanoland the catamphiphilic tetracaine and lidocaine(e. g. as a 5% gel).Adverse effects of local anesthetics (LAs).The cellular point of attack of LAs is a “fast“Na + channel, opening of which initiates theaction potential. LAs block this channel. Fastsodium channels also operate in other excitabletissues including nerve cells of the brainand muscle or specialized conducting tissuesoftheheart.TheactionofLAsisthusnotconfined to nerve tissue; it is not organ-specific.Accordingly, serious adverse effects occurwhenLAsenterthecirculationtoorapidlyor in too high concentrations. In theheart, impulse conduction is disrupted, asevidenced by atrioventricular block or, atworst, ventricular arrest. In the CNS, differentregions are perturbed with a resultantloss of consciousness and development ofseizures. Since no specific LA antidote isavailable, symptomatic countermeasuresneed to be taken immediately. If signs ofcardiac inhibition predominate, epinephrinemust be given intravenously. If CNS toxicityis present, anticonvulsant drugs have to beadministered (e. g., diazepam i.v.).

Local Anesthetics 207A. Local anesthetics and pH valueH 2 NCOOH 5 C 2+NC 2 H 5(CH 2 ) 2HCH3 H 5 C 2CNH OCH2CH3+ C 2 H 5NHNHCH3COHN + C 3 H 7CH HCH3Procaine Lidocaine PrilocaineCH 3 HC 3 HC7N +SNH OCH HC CH3O OCH 3CH3N C HN+H OCH3 H3CH2NCOOCH2 CH3Carticaine Mepivacaine Benzocaine[H + ] Proton concentration1008060402002040608001006 7 8 9 10pH valueActive formcationicamphiphilicMembranepermeablelipophilic formR'+R N HR''RR'NR''PoorAbility to penetratelipophilicbarriers andcell membranesGood

208 Opioids Opioid Analgesics—Morphine TypeSources of opioids. Morphine is an opiumalkaloid (p. 4). Besides morphine, opiumcontains alkaloids devoid of analgesic activity,e. g., the spasmolytic papaverine. Allsemisynthetic derivatives (hydromorphone)and fully synthetic derivatives (pentazocine,pethidine = meperidine, l-methadone, andfentanyl) that possess the analgesic effectof morphine are collectively referred to asopiates and opioids, respectively.Thehighanalgesic effectiveness of xenobiotic opioidsderives from their af nity for receptors normallyacted upon by endogenous opioids(enkephalins, β-endorphin, dynorphins; A).Opioid receptors occur on nerve cells. Theyare found in various brain regions and thespinal medulla, as well as in intramural nerveplexuses that regulate the motility of thealimentary and urogenital tracts. There areseveral types of opioid receptors, designatedµ, δ, κ, which mediate the various opioideffects, and all belong to the superfamily ofG-protein coupled receptors (p. 66).Endogenous opioids are peptides that arecleaved from the precursors, proenkephalin,pro-opiomelanocortin, and prodynorphin.All contain the amino acid sequence of thepentapeptides [Met]- or [Leu]-enkephalin(A). The effects of the opioids can be abolishedby antagonists (e. g., naloxone; A), withthe exception of buprenorphine.Mode of action of opioids. Most neuronsreact to opioids with a hyperpolarization,reflecting an increase in K + conductance.Ca 2+ influx into nerve terminals during excitationis decreased, leading to a decreasedrelease of transmitters and decreased synapticactivity (A). Depending on the cell populationaffected, this synaptic inhibition translatesinto a depressant or excitant effect (B).Effects of opioids (B). The analgesic effectresults from actions at the level of the spinalcord (inhibition of nociceptive impulsetransmission) and the brain (disinhibitionof the descending antinociceptive system,attenuationofimpulsespread,andinhibitionof pain perception). Attention and abilityto concentrate are impaired. There is amood change, thedirectionofwhichdependson the initial condition. Aside fromthe relief associated with the abatement ofstrong pain, there is a feeling of detachment(floating sensation) and a sense of wellbeing(euphoria), particularly after intravenousinjection and, hence, rapid build-up ofdrug levels in the brain. The desire to reexperiencethis state by renewed administrationof drug may become overpowering: developmentof psychological dependence.The attempt to quit repeated use of thedrug results in withdrawal signs of bothphysical (e. g., cardiovascular disturbances)and psychological (e. g., restlessness, anxiety,depression) nature.Opioids meet the criteria of drugs producingdependence, that is, a psychological andphysiological need to continueuseof the drugas wellas the compulsion to increase the dose.For these reasons, prescription of opioidsis subject to special rules (Controlled SubstancesAct, USA; Narcotic Control Act, Canada;etc). Certain opioid analgesics such ascodeine and tramadol may be prescribed inthe usual manner, because of their lesserpotential for abuse and development of dependence.Differences among opioids in ef -cacy and liability to cause dependence probablyreflect differing patterns of af nity andintrinsic activity at individual receptor subtypes,as well as genetic variation of opioidreceptors. A given substance does not necessarilyact as an agonist or antagonist at eachsubtype; instead, it may behave as an agonistat one subtype and as a partial agonist/antagonistat another, or even as a pure antagonist(p. 212). In particular, the addictive potentialis determined by kinetic properties;only with rapid drug entry into the brain canthe euphoriant “rush” be experienced. Allhigh-potency opioids pose the risk of respiratorydepression (paralysis of the respiratorycenter) after overdosage. The maximally

Opioid Analgesics 209A. Action of endogenous and exogenous opioids at opioid receptorsProopiomelanocortinProenkephalinMorphineNCH 336β-LipotropinHOO OHEnkephalinβ-EndorphinOpioid receptorsCH 2 CH CH 2K+-permeabilityCa 2+ -influxExcitabilityNRelease oftransmittersHOHOOOAntagonistnaloxoneB. Effects of opioidsStimulant effectsMediated byopioid receptorsDampening effectsVagal centers,Chemoreceptorsof area postremaOculomotorcenter (Edinger–Westphal nucleus)Pain sensationMoodalertnessAnalgesicAnalgesicAntinociceptivesystemSmooth musculaturestomachbowelspasticconstipationRespiratory centerCough centerEmetic centerAntitussiveAntidiarrhealUrinary tractpossibleimpairment ofmicturition

210 Opioidspossible extent of respiratory depression isthought to be less for partial agonists/antagonists(pentazocine, nalbuphine).The cough-suppressant (antitussive) effectproduced by inhibition of the cough reflexis independent of the effects on nociceptionor respiration (antitussives: codeine, noscapine).Stimulation of chemoreceptors in the areapostrema (p. 342) results in vomiting, particularlyafter first-time administration or in theambulant patient. The emetic effect disappearswith repeated use because a direct inhibitionof the emetic center then predominates.Opioids elicit pupillary narrowing (miosis)by stimulating the parasympathetic portion(Edinger–Westphal nucleus) of the oculomotornucleus.The peripheral effects concern the motilityand tonus of gastrointestinal smooth muscle;segmentation is enhanced but propulsiveperistalsisisinhibited.Thetonusofsphinctermuscles is markedly raised (spastic constipation).The antidiarrhetic effect is usedtherapeutically (loperamide, p.180).Gastricemptying is delayed (pyloric spasm) anddrainage of bile and pancreatic juice is impededbecause the sphincter of Oddi contracts.Likewise, bladder function is affected;specifically bladder emptying is impairedowing to an increased tone of the vesicularsphincter.Kinetics of opioids. The endogenous opioids(e. g., metenkephalin, leuenkephalin, β-endorphin)cannot be used therapeutically because,owing to their peptide nature, theyare rapidly degraded or excluded from passagethrough the blood–brain barrier, thuspreventing access to their sites of actioneven after parenteral administration (A).Morphine can be given orally or parenterally,as well as epidurally or intrathecally in thespinal cord. Fentanyl is of such potency andhigh tissue penetrability as to permit applicationin the form of a patch (transdermaldelivery system) (A). In opiate abuse, drug(“stuff,” “junk,” “smack,” “jazz,” “Chinawhite”; mostly heroin = diacetylmorphine)is injected intravenously (“mainlining”) toachievethefastestpossiblerateofriseinbrain concentration. Evidently, psychic effects(“kick,” “buzz,” “rush”) are especiallyintense with this route of delivery. The usermay also resort to other more unusualroutes: opium is smoked; heroin can be takenas snuff (B).Metabolism (C). Like other opioids bearing afree hydroxyl group, morphine is conjugatedto glucuronic acid and excreted renally. Glucuronidationof the OH group at position 6,unlike that at position 3, does not affectaf nity for the receptors.Tolerance. With repeated administration ofopioids, their CNS effects undergo habituation(adaptation). In the course of therapy,progressively larger doses are thus neededto achieve the same degree of pain relief. Theperipheral effects are less altered by the developmentof tolerance, so that persistentconstipation during prolonged use may forcea discontinuation of analgesic therapy howeverurgently needed. Frequently laxativesmust be prescribed.Morphine antagonists and partial agonists.The effects of opioids can be abolished by theantagonists naloxone or naltrexone (A), irrespectiveof the receptor type involved. Givenby itself, neither has any effect in normalsubjects; however, in opioid-dependent subjects,both precipitate acute withdrawalsigns. Because of its rapid presystemic elimination,naloxone is only suitable for parenteraluse. Naltrexone is metabolically morestable and can be given orally. Naloxone iseffective as antidote in the treatment ofopioid-induced respiratory paralysis. Sinceit is more rapidly eliminated than mostopioids, repeated doses may be needed. Naltrexonemay be used as adjunct in withdrawaltherapy.

Opioids 211A. Opioids: mode of application and bioavailabilityMet-EnkephalinTyr Gly Gly Phe MetMorphineNCH 3FentanylCarfentanylCH 2 CH 2O NH 3 C CHOOOHN CH 3C CH 2OB. Application and rate of dispositionC. Metabolism of morphineNasalmucosa,e.g., heroinsniffingOpioidOralapplicationMorphineIntravenousapplication“Mainlining”Morphine 6-glucuronideMorphine 3-glucuronideBronchialmucosae.g., opiumsmoking

212 OpioidsBuprenorphine behaves like a partial agonist/antagonistat µ-receptors. Pentazocineis an antagonist at µ-receptors and an agonistat κ-receptors (A). Both are classified as“low-ceiling” opioids (B), because neither iscapable of eliciting the maximal analgesiceffect obtained with morphine or meperidine.Intoxication with buprenorphine cannotbe reversed with antagonists, becausethe drug dissociates too slowly from theopioid receptors. Tramadol is a moderatelypotent opioid with supposedly less potentialfor abuse. Its dosage (oral or parenteral) isabout 10 times that of morphine (i. e.,50–100 mg; maximum 400 mg/day). Respiratorydepression is unlikely to occur at thisdose level. The mechanism of its analgesiceffect is complex and extends beyond agonismat opioid receptors. Tramadol is a racemate.The (+)-enantiomer has preferentialaf nity for µ-receptors and is more potentin this regard than the (–)-enantiomer. TheO-desmethyl metabolite possesses still higheraf nity. Moreover, transport systems forthe neuronal reuptake of norepinephrineand serotonin are inhibited—actually withinverse enantioselectivity. The most prominentadverse effect is vomiting (~ 10% ofcases). Tramadol cannot alleviate cravingfor morphine in addicts but can reinitiatephysical dependence.Fentanyl merits special mention, being~ 20-times more potent than morphine. Itis administered in the form of a skin patch(transdermal delivery system) for chronicpain management. Specific effectiveness isgreatly augmented by introduction into themolecule of a side chain (see p. 211A), leadingto carfentanyl. Carfentanyl has a potency5000 times that of morphine and along duration of action. The drug is approvedfor veterinary tranquilization of large animals.In aqueous solution it can be appliedas an aerosol. Its action can be surmountedby morphine antagonists; however, unusuallyhigh doses are required.Uses. Two conditions must be distinguished:(1) Acute severe pain after trauma (accidents),myocardial infarction, etc. and lifethreateningpulmonary edema requiring inhibitionof the respiratory center. For theseindications, administration of morphine (intravenouslyor subcutaneously) in suf cientamounts is appropriate. With short-termuse, development of tolerance or dependenceis of no concern.(2) Severe chronic pain, especially in cancerpatients. In these cases, the aim is to establisha constant plasma level of opioid for aprolonged period. Drug must be given beforethe appearance of pain, not after the patienthas begun to suffer from intolerable pain.Like some of the other opioids (hydromorphone,meperidine, pentazocine, codeine),morphine is rapidly eliminated; its durationof action is about 4 hours. To achieve continuousanalgesia, these substances wouldhave to be given every 4 hours. For treatmentof severe chronic pain states, use ofmorphine (or oxycodone) in controlled releaseform isthemostadvantageousregimenbecause (a) the slow rise in serum levelsavoids the subjective “rush” sensation and,hence, the development of “addiction” (psychologicaldependence); (b) the effect is prolonged;(c) under this condition, an increasedproportion of morphine is converted to the 6-glucuronide and contributes to the centraleffect; and (d) the patient can independentlycontrolintakeofmorphine(i.e.,nextsustained-releasetablet before severe pain reemerges).If a cancer patient has reached aterminal state, development of tolerance isquite acceptable and can easily be compensated.In a moribund person, a certain degreeof euphoria, possibly associated with diminishedvigilance, appears ethically acceptable.Under special conditions (oral routeunavailable; intolerable peripheral side effects),opioids may be administered by continuousinfusion (pump) or applied near thespinal cord under control by the patient. Theadvantage is much lower dosage (300-fold)and constant therapeutic level; the disadvantageis the need for a catheter.

Opioids 213A. Opioids: µ- and κ-receptor ligands B. Opiods: dose-response relationshipHONCOCH 3NO OHCH 2 CH 2NCH 3CH 2µκMorphineMeperidineFentanylNCOH 3 CCH 3 CCH 3CH 2OCHCH 2NCH 3Analgesic effectFentanylBuprenorphineMorphinePentazocine MeperidineH 2 CCHCH 2NPentazocineHOCH 3HOµκµκµκµκCH 30.1 1 10 100HOOONaloxoneDose (mg)C. Enantioselective effects of tramadolRacemate of tramadolAgonistat µ-opioidreceptorsSerotoninreuptakeinhibitorH 3COHOCH 2CH 3NCH 3Norepinephrinereuptake inhibitor,α 2 -AgonistD. Morphine and methadone during chronic intakeMorphineReleaseMorphineHigh doseevery 12 hLow doseevery 4 hTimedreleaseformulationDrug concentration in plasmaIntoxicationAnalgesia12 24 36 hours4 8 12 16 20 24 hoursMethadonet 1/2 = 55 hhigh doseMethadonelow dose1 2 3 45 days

214 General Anesthetics General Anesthesia and GeneralAnesthetic DrugsGeneral anesthesia is a state of drug-inducedreversible inhibition of central nervous function,during which surgical procedures canbe carried out in the absence of consciousness,responsiveness to pain, defensive orinvoluntary movements, and significantautonomic reflex responses (A).The required level of anesthesia dependson the intensity of the pain-producing stimuli,i. e., the degree of nociceptive stimulation.The skillful anesthetist, therefore, dynamicallyadapts the plane of anesthesia tothedemandsofthesurgicalsituation.Originally,anesthesia was achieved with a singleanesthetic agent (e. g., diethyl ether, firstsuccessfully demonstrated in 1846 by W. T.G. Morton, Boston). To suppress defensivereflexes, such a “monoanesthesia” necessitatesa dosage in excess of that needed tocause unconsciousness, thereby increasingthe risk of paralyzing vital functions, suchas cardiovascular homeostasis (B). Modernanesthesia employs a combination of differentdrugs to achieve the goals of surgicalanesthesia (balanced anesthesia). This approachreduces the hazards of anesthesia. In(C) are listed examples of drugs that are usedconcurrently or sequentially as anesthesiaadjuncts. Neuromuscular blocking agentsare covered elsewhere in more detail. Recallthat “curarization” of the patient necessitatesartificial ventilation. However, the useof neuromuscular blockers is making an essentialcontribution to risk reduction inmodern anesthesia. In the following, somespecial methods of anesthesia are consideredbefore presentation of the anestheticagents.Neuroleptanalgesia can be considered aspecial form of combination anesthesia: theshort-acting opioid analgesic fentanyl iscombined with a strongly sedating and affect-bluntingneuroleptic. Because of majordrawbacks, including insuf cient eliminationof consciousness and extrapyramidalmotor disturbances, this procedure has becomeobsolete.In regional anesthesia (spinal anesthesia)with a local anesthetic (p. 202), nociceptiveconduction is interrupted. Since consciousnessis preserved, this procedure does notfall under the definition of anesthesia.According to their mode of application,general anesthetics in the narrow senseare divided into inhalational (gaseous, volatile)and injectable agents.Inhalational anesthetics are administeredin and, for the most part, eliminated viarespired air. They serve especially to maintainanesthesia (p. 216)Injectable anesthetics (p. 218) are frequentlyemployed for induction. Intravenousinjection and rapid onset of action are clearlymore agreeable to the patient than is breathinga stupefying gas. The effect of most injectableanesthetics is limited to a few minutes.This allows brief procedures to becarried out or preparation of the patient forinhalational anesthesia (intubation). Administrationof the volatile anesthetic must thenbe titrated in such a manner as to counterbalancethe waning effect of the injectableagent. Increasing use is now being made ofinjectable, instead of inhalational, anestheticsduring prolonged combined anesthesia(e. g., propofol; total intravenous anaesthesia—TIVA).

General Anesthesia and General Anesthetic Drugs 215A. Goals of surgical anesthesiaMuscle relaxation Loss of consciousness Automatic stabilizationMotorreflexesPain andsufferingAutonomicreflexesNociceptionAnalgesiaPain stimulusB. Traditional monoanesthesia vs. modern balanced anesthesiaMonoanesthesiae.g., diethyl etherReduced pain sensitivity,analgesiaLoss of consciousnessMuscle relaxationParalysis ofvital centersFormusclerelaxatione.g., pancuroniumForunconsciousness:e.g., halothaneor propofolForanalgesiae.g., N 2 Oor fentanylIf needed,autonomicstabilization:atropine,esmololC. Regimen for balanced anesthesiaPremedicationInduction Maintenance RecoveryNeostigmine reversal ofneuromuscular blockFentanyl analgesiaMuscle relaxation, intubationMidazolam unconsciousnessN2OIsofluranePancuroniumFentanyl AnalgesiaDiazepam anxiolysisMuscle relaxationAnalgesiaUnconsciousness

216 General Anesthetics Inhalational AnestheticsThe mechanism of action of inhalationalanesthetics is not known in detail. In the firstinstance, the diversity of chemical structures(inert gas xenon; hydrocarbons; halogenatedhydrocarbons) possessing anestheticactivity appeared to argue against the involvementof specific sites of action. Thecorrelation between anesthetic potency andlipophilicity of anesthetic drugs (A) pointedto a nonspecific uptake into the hydrophobicinterior of the plasmalemma, with a resultantimpairment of neuronal function.Meanwhile, several lines of evidence supportan interaction with membrane proteins;among these ligand-gated ion channel proteinsassume special importance. Experimentalstudies favor the idea that anestheticsenhance the effectiveness of inhibitoryGABA and glycine receptors, while attenuatingresponsiveness to stimulation ofexcitatory glutamate receptors.Anesthetic potency can be expressed interms of the minimal alveolar concentration(MAC) at which 50% of patients remain immobilefollowing a defined painful stimulus(skin incision). Whereas the poorly lipophilicnitrous oxide must be inhaled in high concentrations,much smaller concentrationsare required in the case of the more lipophilichalothane.The rates of onset and cessation of actionvary widely among different inhalationalanesthetics and also depend on the degreeof lipophilicity. In the case of nitrous oxide,elimination from the body is rapid when thepatient is ventilated with normal air. Owingto the high partial pressure in blood, thedriving force for transfer of the drug intoexpired air is large and, since tissue uptakeis minor, the body can be quickly cleared ofnitrous oxide. In contrast, with halothane,partial pressure in blood is low and tissueuptake is high, resulting in a much slowerelimination.Given alone, nitrous oxide (N 2 O, “laughinggas”) is incapable of producing anesthesia ofsuf cient depth for surgery, even when takingup 80% of the inspired air volume (O 220% vol. is necessary!). It has good analgesicef cacy that can be exploited when it is usedin conjunction with other anesthetics. As agas, N 2 O can be administered directly; it isnot metabolized appreciably and is clearedentirely by exhalation (B).Halothane (boiling point [BP] 50 ο C), enflurane(BP 56 ο C), isoflurane (BP 48 ο C) andthe newer substances, desflurane and sevoflurane,have to be vaporized by specialdevices. Part of the administered halothane(up to 20%) is converted into hepatotoxicmetabolites (B). Liver damage may resultfrom halothane anesthesia. With a singleexposure, the risk involved is unpredictable;however, the risk increases with the frequencyof exposure and the shortness ofthe interval between successive exposures(estimated incidence 1 in 35 000 procedures).Degradation products of enflurane or isoflurane(fraction biotransformed < 2%) probablydo not play any role in anesthetic action.Halothane exerts a hypotensive effect(vasodilation and negative inotropic effect).Enflurane and isoflurane cause less circulatorydepression. Halothane sensitizes themyocardium to catecholamines. This effectis much less pronounced with enflurane andisoflurane. Unlike halothane, enflurane andisoflurane have a muscle-relaxant effect thatis additive with that of nondepolarizing neuromuscularblockers.Desflurane is a close structural relative ofisoflurane, but has low lipophilicity and alow rate of biotransformation (0.02%). Thispermits rapid induction and recovery as wellas good control of anesthetic depth. Thenewest member of this group, sevoflurane,is similarly fast-acting and convenient tocontrol but has a higher rate of biotransformation(up to 5%) and lower incidence oflaryngospasm and cough.

Inhalational Anesthetics 217A. Lipophilicity, potency and elimination of N 2 O and halothaneLow potencyhigh partial pressure neededrelatively little binding to tissueAnesthetic potencyNitrous oxideN 2 OXenonHalothaneChloroformIsofluraneEnfluraneDiethyl etherCyclopropaneLipophilicityN 2 OPotential effectsEnhancementInhibitionCl - Cl - Na+, Ca 2+GABA AreceptorGlycinereceptorNMDAreceptorPartial pressure in tissueHalothaneTermination of intakeHigh potencylow partial pressure sufficientrelatively high binding in tissueTimeB. Elimination routes of different volatile anestheticsMetaboliteMetabolite15 – 20% 0.2%F BrF H FN 2 O Nitrous oxideF C C HF C C O C HH 5 C 2 OC 2 H 5 EtherF Cl HalothaneF Cl F Isoflurane

218 General Anesthetics Injectable AnestheticsSubstances from different chemical classessuspend consciousness when given intravenouslyand can be used as injectable anesthetics(A). Like inhalational agents, most ofthese drugs affect consciousness only and aredevoid of analgesic activity (exception: ketamine).The effect appears to arise from aninteraction with ligand-gated ion channels.Channels mediating neuronal excitation(NMDA receptor, see below) are blocked,while the function of channels dampeningexcitation (GABA A receptor, p. 222; and, forthree drugs, additionally also the glycine receptor)is enhanced allosterically.Most injectable anesthetics are characterizedby a short duration of action. The rapidcessation of action is largely due to redistribution:after intravenous injection, brainconcentration climbs rapidly to effectiveanesthetic levels because of the high cerebralblood flow; the drug then distributesevenly in the body, i. e., concentration risesin the periphery, but falls in the brain—redistributionand cessation of anesthesia (A).Thus, the effect subsides before the drughas left the body. A second injection of thesame drug would encounter “presaturated”body compartments and thus be dif cult topredict in terms of effect intensity. Only etomidateand propofol may be given by infusionover a longer period to maintain unconsciousness.If no additional inhalationalagent is employed, the procedure is referredto as total intravenous anesthesia (TIVA).Thiopental and methohexital belong to thebarbiturates, which, depending on dose, producesedation, sleepiness, or anesthesia. Barbiturateslower pain threshold and therebyfacilitate defensive reflex movements; theyalso depress central inspiratory drive. Barbituratesare frequently used for induction ofanesthesia.Ketamine has analgesic activity that persistsup to 1 hour after injection, well beyondthe initial period of unconsciousness (~ 15minutes only). On regaining consciousness,the patient may experience a disconnectionbetween outside reality and inner mentalstate (dissociative anesthesia). Frequentlythere is memory loss for the duration of therecovery period; however, adults in particularcomplain about distressing dreamlike experiences.These can be counteracted by administrationof a benzodiazepine (e. g., midazolam).The CNS effects of ketamine arise, inpart, from an interference with excitatoryglutamatergic transmission via ligand-gatedcation channels of the NMDA subtype, atwhich ketamine acts as a channel blocker.The nonnatural excitatory amino acid N-methyl D-aspartate (NMDA) is a selectiveagonistatthisreceptor.Ketaminecaninducerelease of catecholamines with a resultantincrease in heart rate and blood pressure.Propofol has a remarkably simple structureresembling that of phenol disinfectants.Because the substance is water-insoluble, aninjectable emulsion is prepared by means ofsoy oil, phosphatide, and glycerol. The effecthas a rapid onset and decays quickly, beingexperienced by the patient as fairly pleasant.The intensity of the effect can be well controlledduring prolonged administration.Possible adverse reactions include hypotensionand respiratory depression, and a potentiallyfatal syndrome of bronchospasm,hypotension, and erythema.The anesthetic effect of (+)-etomidate subsideswithin a few minutes owing to redistributionof the drug. Etomidate can provokemyoclonic movements that can be preventedby premedication with a benzodiazepineor an opioid. Because it has little effecton the autonomic nervous system, it is suitablefor induction in combination anesthesia.Etomidate inhibits cortisol synthesis insubanesthetic doses and can therefore beused in the long-term treatment of adrenocorticaloveractivity (Cushing disease).Midazolam is a rapidly metabolized benzodiazepine(p. 224) that is used for inductionof anesthesia. The longer-acting lorazepamis preferred as an adjunctive anestheticin prolonged cardiac surgery with cardiopulmonarybypass; its amnesiogenic effect ispronounced.

Injectable Anesthetics 219A. Termination of drug effect by redistributionCNS:relativelyhighblood flowHigh concentrationin tissueRelatively largeamount of drugi.v. injectionPeriphery:relativelylow blood flowml bloodmin x g tissueRelatively smallamount of drugmg drugmin x g tissue1. Initial situation2. Preferential accumulationof drug in brainDecreasein tissueconcentrationLow concentrationin peripheryFurtherincreasein tissueconcentration3. Redistribution 4. Steady state of distributionB. Intravenous anestheticsON CH2 CH3NaSN CH (CH 2)2 CH3H O CH3Sodium thiopentalNNaONH3COCH2CHO CH3CH CH2C C CH2Sodium methohexitalCH3ClONHCH3NMDA receptorblockadeKetamineCH3OHCH3H3C CHCH CH3Activation ofglycine receptorsPropofolOCCH3NCHOCH2NActivation ofGABA A receptorsCH3EtomidateClH3CNNNMidazolamF

220 Psychopharmacologicals Sedatives, HypnoticsDuring sleep, the brain generates a patternedrhythmic activity that can be monitoredby means of the electroencephalogram(EEG). Internal sleep cycles recur 4–5 timespernight,eachcyclebeinginterruptedbyarapid eye movement (REM) sleep phase (A).The REM stage is characterized by EEG activitysimilar to that seen in the waking state,rapid eye movements, vivid dreams, and occasionaltwitches of individual musclegroups against a background of generalizedatonia of skeletal musculature. Normally, theREM stage is entered only after a precedingnon-REM cycle. Frequent interruption ofsleep will, therefore, decrease the REM portion.Shortening of REM sleep (normally~ 25% of total sleep duration) results in increasedirritability and restlessness duringthe daytime. With undisturbed night rest,REM deficits are compensated by increasedREM sleep on subsequent nights (B).Hypnotic drugs can shorten REM sleepphases (B). With repeated ingestion of a hypnoticon several successive days, the proportionof time spent in REM vs. non-REM sleepreturns to normal despite continued drugintake. Withdrawal of the hypnotic drug resultsin REM rebound, which tapers off onlyover many days (B). Since REM stages areassociated with vivid dreaming, sleep withexcessively long REM episodes is experiencedas unrefreshing. Thus, the attempt todiscontinue use of hypnotics may result inthe impression that refreshing sleep calls fora hypnotic, probably promoting hypnoticdrug dependence.Benzodiazepines and benzodiazepine-likesubstances are the hypnotics of greatesttherapeutic importance. They display a positiveallosteric action at the GABA A receptor(p. 222). The formerly popular barbiturateshave become obsolete because of their narrowmargin of safety (respiratory arrest afteroverdosage). Barbiturates can also activateGABA A receptors allosterically; however, thisaction does not occur at benzodiazepinebinding sites. At high dosage, barbituratescan apparently produce an additional directGABA agonist effect.Depending on their blood levels, bothbenzodiazepines and barbiturates producecalming and sedative effects. At higher dosage,both groups promote the onset of sleepor induce it (C). At low doses, benzodiazepineshave a predominantly anxiolytic effect.Unlike barbiturates, benzodiazepine derivativesadministered orally lack a generalanesthetic action; cerebral activity is notglobally inhibited (the virtual impossibilityof respiratory paralysis negates suicidal misuse)and autonomic functions, such as bloodpressure, heart rate, or body temperature,are unimpaired. Thus, benzodiazepines possessa therapeutic margin considerablywider than that of barbiturates.Zolpidem (an imidazopyridine), zaleplone(a pyrazolopyrimidine) and zopiclone(a cyclopyrrolone) are hypnotics that,despite their different chemical structure,can bind to the benzodiazepine site on theGABA A receptor (p. 222). However, their effectsdo not appear to be identical to those ofbenzodiazepines. Thus, compared with benzodiazepines,zolpidem exerts a weaker effecton sleep phases, supposedly carries alower risk of dependence, and appears tohave less anxiolytic activity. Heterogeneityof GABA A receptors may explain these differencesin activity. GABA A receptors consist offive subunits that exist in several subtypes.Antihistaminics are popular as nonprescription(over-the-counter) sleep remedies(e. g., diphenhydramine, doxylamine, p.118),in which case their sedative side effect isused as the principal effect. The hypnoticeffect is weak; adverse effects (e. g., atropine-like)and corresponding contraindicationsneed to be taken into account.

Benzodiazepines 221A. Succession of different sleep phases during night restWakingstateSleepstage IREMSleepstage IISleepstage IIISleepstage IVREM-sleep = Rapid Eye Movement sleepB. Influence of hypnotics on sleep phasesNREM = No Rapid Eye Movement sleepREMNREMProportionNightswithouthypnotic5 10 15 20 25 30Nights Nights afterwithwithdrawalhypnotic of hypnoticC. Concentration dependence of effectsBarbiturates:PentobarbitalON C2H5HON CH CH3H O C3H7BrotizolamH3CBrSNNNNEffectPentobarbitalZolpidemParalyzingAnesthetizingHypnogenicBenzodiazepines:Imidazopyridines:ZolpidemNNCH3ClCH2C ON CH3CH3 CH3TriazolamHypnagogicSedatingAnxiolyticConcentration in blood

222 Psychopharmacologicals BenzodiazepinesBalanced CNS activity requires inhibitoryand excitatory mechanisms. Spinal and cerebralinhibitory interneurons chiefly utilizeγ-aminobutyric acid (GABA) as transmittersubstance, which decreases the excitabilityof target cells via GABA A receptors. Bindingof GABA to the receptor leads to opening of achloride (Cl – )ion channel, chloride influx,neuronal hyperpolarization, and decreasedexcitability. The pentameric subunit assemblymaking up the receptor/ion channel containsa high-af nity binding site for benzodiazepines,in addition to the GABA bindinglocus. Binding of benzodiazepine agonistsallosterically enhances binding of GABAand its action on the channel. The prototypicalbenzodiazepine is diazepam. Barbituratesalso possess an allosteric binding siteon the Cl − -channel protein; their effect is toincrease the channel mean open-time duringGABA stimulation.Benzodiazepines exhibit a broad spectrumof activity: they exert sedating, sleep-inducing,anxiolytic, myorelaxant, and anticonvulsanteffects and can be used for induction ofanesthesia. Of special significance for the useof benzodiazepines is their wide margin ofsafety. At therapeutic dosages, neither centralrespiratory control nor cardiovascularregulation are affected. By virtue of thesefavorable properties, benzodiazepines haveproved themselves for a variety of indications.At low dosage, they calm restless oragitated patients and allay anxiety, thoughwithout solving problems. Use of benzodiazepinesas sleep remedies is widespread.Here, preference is given to substances thatare completely eliminated during the nighthours(tetracycliccompoundssuchastriazolam,brotizolam, alprazolam). For longerlastinganxiolytic therapy, compoundsshould be selected that are eliminatedslowly and ensure a constant blood level(e. g., diazepam).In psychosomatic reactions, benzodiazepinescan exert an uncoupling effect. Theyare therefore of great value in hyperacutedisease states (e. g., myocardial infarction,p. 320) or severe accidents. Status epilepticusisanecessaryindicationforparenteraladministration (p.190); however, benzodiazepinescan also be used for the long-termtreatment of certain forms of epilepsy, ifnecessary in combination with other anticonvulsants.Rapidly eliminated benzodiazepinesare suitable for the intravenous inductionof anesthesia.Use of benzodiazepines may lead to personalitychanges characterized by flatteningof affect. Subjects behave with indifferenceand fail to react adequately. Any tasks requiringprompt and target-directed action—notonly driving a motor vehicle—should be leftundone.Benzodiazepine AntagonistThe drug flumazenil binds with high af nityto the benzodiazepine receptor but lacks anyagonist activity. Consequently, the receptoris occupied and unavailable for binding ofbenzodiazepine agonists. Flumazenil is aspecific antidote and is used with successfor reversal of benzodiazepine toxicity or toterminate benzodiazepine sedation. Whenpatients suffering from benzodiazepine dependenceare given flumazenil, withdrawalsymptoms are precipitated.Flumazenil is eliminated relatively rapidlywith a t ½ of ~ 1 hour. Therefore, the requireddose of 0.2–1.0 mg i.v. must be repeated acorresponding number of times when toxicityis due to long-acting benzodiazepines.

Benzodiazepines 223A. Action of benzodiazepinesGABAergicneuronBenzodiazepinebinding siteαCl -βGABAbindingsiteBarbituratebinding siteAnxiolyisβγαPlasmalemmaCl -Plus anticonvulsant effect,sedation, muscle relaxationGABAbindingsiteBinding site forBenzodiazepinesBarbituratesPositive allosteric modulators of GABA effect increasein Cl - conductance hyperpolarizationdecreased excitabilityGABA A receptorwith allosteric binding sitesBenzodiazepinesCH 3ONCH 2OCNNCH 3OFFlumazenilBenzodiazepine antagonistNormalGABAergic inhibitionEnhancedGABAergic inhibition

224 Psychopharmacologicals Pharmacokinetics ofBenzodiazepinesA typical metabolic pathway for benzodiazepines,as exemplified by the drug diazepam,is shown in panel (A): first the methyl groupon the nitrogen atom at position 1 is removed,with a concomitant or subsequenthydroxylation of the carbon at position 3.The resulting product is the drug oxazepam.These intermediary metabolites are biologicallyactive. Only after the hydroxyl group(position 3) has been conjugated to glucuronicacid is the substance rendered inactiveand, as a hydrophilic molecule, readily excretedrenally. The metabolic degradation ofdesmethyldiazepam (nordiazepam) is theslowest step (t ½ = 30–100 hours). This sequenceof metabolites encompasses otherbenzodiazepines that may be consideredprecursors of desmethyldiazepam, e. g., prazepamand chlordiazepoxide (the first benzodiazepine= Librium®). A similar metabolitepattern is seen in benzodiazepines inwhich an −NO 2 group replaces the chlorineatom on the phenyl ring and in which thephenyl substituent on carbon 5 carries a fluorineatom (e. g., flurazepam). With the exceptionof oxazepam, all these substancesare long-acting. Oxazepam represents thosebenzodiazepines that are inactivated in asingle metabolic step; nevertheless, itshalf-life is still as long as 8 ± 2hours.Substanceswith a short half-life result only fromintroduction of an additional nitrogen-containingring (see A) bearing a methyl groupthat can be rapidly hydroxylated. Midazolam,brotizolam, and triazolam are membersof such tetracyclic benzodiazepines; the lattertwo are used as hypnotics, whereas midazolamgiven intravenously is employed foranesthesia induction.Another possible way of obtaining compoundswith an intermediate duration ofaction is to replace the chlorine atom indiazepam with an NO 2 residue (rapidly reducedto an amine group with immediateacetylation) or with a bromine atom (whichcauses ring cleavage in the organism). Inthese cases, biological inactivation againconsists of a one-step reaction.Dependence potential. Prolonged regularuse of benzodiazepines can lead to physicaldependence. With the long-acting substancesmarketed initially, this problem was lessobvious in comparison with other dependence-producingdrugs, because of the delayedappearance of withdrawal symptoms(the decisive criterion for dependence).Symptoms manifested during withdrawalinclude restlessness, irritability, nervousness,anxiety, insomnia, and, occasionally orin susceptible patients, convulsions. Thesesymptoms are hardly distinguishable fromthose considered indications for the use ofbenzodiazepines. Benzodiazepine withdrawalreactions are more likely to occurafter abrupt cessation of prolonged or excessivedosage and are more pronounced inshorter-acting substances, but may also beevident after discontinuance of therapeuticdosages administered for no longer than 1–2weeks.Administration of a benzodiazepine antagonistwould abruptly provoke abstinencesigns. Benzodiazepines exhibit cross-dependencewith ethanol and can thus be usedin the management of delirium tremens.There are indications that substances withintermediate elimination half-lives have thehighest abuse potential. Withdrawal of benzodiazepinesshould be done gradually andcautiously. A long-acting substance such asdiazepam is the drug of choice for controlledtapering of withdrawal.

Pharmacokinetics of Benzodiazepines 225A. Biotransformation of benzodiazepinesClH 3 CNNNMidazolamDiazepamClH 3 C1 ON35 NFHOH 2 C NNNInactiveOHas glucuronideHNNOOGlucHNNOOHHNNNordiazepamOOxazepamActive metabolitesB. Rate of elimination of benzodiazepinesPrecursorTriazolamBrotizolamOxazepamLormetazepamBromazepamFlunitrazepamLorazepamCamazepamNitrazepamClonazepamDiazepamTemazepamPrazepam0 10 20 30 40 50 60>60 hoursRange of plasma t 1/2i.v. induction of anesthesiaApplied drugHypnagogic effectAnxiolysisActive metaboliteMidazolam

226 Psychopharmacologicals Therapy of Depressive IllnessThe term “depression” is used for a variety ofstates that are characterized by downswingsin mood varying from slight to most severe.The principal types are: Endogenous depression, ranging from itssevere form (major depression) to lightercases (minor depression) Dysthymia (neurotic depression) Reactive depression as (overshooting) reactionto psychic insults or somatic illnessEndogenous depression generally follows aphasic course with intervals of normal mood.When mood swings do not change direction,unipolar depression is said to be present.Bipolar illness designates an alternation betweendepressive states and manic episodes.Besides devitalizing melancholia with its attendantburden of suffering, the behavior ofpatients in depression may vary fromstrongly inhibited to anxious, agitated,guilt-ridden, presuicidal, and so on. Depressivestates are frequently associated withsomatic symptoms; the patients projecttheir mood disturbance into a physical ailment.Accordingly, many depressive patientsinitially visit a family physician or internist.The pharmacotherapy of depression is adif cult undertaking. At the outset, it is necessaryto determine the type of depression.For instance, in neurotic depression, psychotherapymay be suf cient. A reactive mooddisorder calls for attempts to establish thecausal link. In either condition, temporaryuse of antidepressants may be warranted.The proper indication for thymoleptics isendogenous depression. However, even forthis endogenous psychosis, it is dif cult toevaluate the effectiveness of this drug class.One fundamental reason is the lack of experimentalanimal models of depression: theef cacy of drugs cannot be tested in experimentson animals. Moreover, depression isperiodic in nature; spontaneous remissionnearly always occurs. Intensive psychologicalsupport may also sometimes be effectivein improving the condition of patients. Accordingto some estimates, one-third of therapeuticsuccess in moderately severe depressioncan be attributed to a placebo effect,one-third to intensive support, and theremaining one-third to use of antidepressantagents. In severe depression, pharmacotherapymay achieve somewhat more favorableresults. Because objective documentation oftherapeutic success is extraordinarily dif -cult, it is hardly surprising that no specificantidepressant has proved superior in comparisonwith others. About 30% of patientsare resistant to currently available drugtreatments. A workable general rule wouldbe to prescribe tricyclic compounds (andvenlafaxine) for severe depression, and selectiveserotonin reuptake inhibitors (SSRI)for moderately severe to mild cases. No scientificallyconvincing evidence is availablefor the “alternative” phytomedicinal, St.John’s wort (Hypericum perforatum),although drug interactions are well documented.It would be a major therapeutic error toadminister a drive-enhancing drug such asamphetamine to a depressed patient withpsychomotor inhibition (A). Suicide wouldbe an expected consequence.The antidepressant effect of thymolepticsmanifests after a prolonged latency; usually1–3 weeks pass before subjective or objectiveimprovement becomes noticeable (A). Incontrast, somatic effects are immediatelyevident; specifically, the interference withneuronal transmitter/modulator systems(norepinephrine, serotonin, acetylcholine,histamine, dopamine). Reuptake of releasedserotonin, norepinephrine, or both is impaired(† elevated concentration in synapticcleft) and/or receptors are blocked (examplein A).Theseeffectsaredemonstrableinanimalstudies and are the cause of acute adverseeffects.The importance of these phenomena forthe antidepressant effect remains unclear.Presumably, adaptation of receptor systemsto altered concentrations or actions of transmitter/modulatorsubstances plays a role.

Therapy of Depressive Illness 227A. Effect of antidepressantsEndogenousdepressionDeficient driveWeek 9 Week 7 Week 5 Week 3ImipramineNCH 3CH 2 CH 2 CH 2 N5 HT orNAInhibition ofre-uptakeCH 3M, H1, α1Blockade ofreceptorsAmphetamineImmediateNormalmoodNormal drive

228 PsychopharmacologicalsThe thymoleptic mechanism of action remainsto be elucidated.Antidepressants can be divided into fourgroups:1. Tricyclic antidepressants (A), suchasdesipramine,amitriptyline, and many analoguesubstances, possess a hydrophobic ring system.The central 7-membered ring increasesthe annelation angle between the outerflanking rings. This moiety can also be tetracyclic(e. g., maprotiline). The ring systembears a side chain with a secondary or tertiaryamine that can be protonated dependingon its pK a value. These substances canthus take on an amphiphilic character, permittinginsertion into lipid membranes andenrichment in cellular structures. The basicstructure of tricyclic antidepressants also explainstheir af nity for receptors and transmittertransport mechanisms. Receptorblockade is the chief cause of the adverseeffectsinthisdruggroup,including:tachycardia,inhibition of glandular secretion (drymouth), constipation, dif culty in micturition,blurred vision, and orthostatic hypotension(A upper). A sedative action probablyarising from antagonism at CNS H 1 histaminereceptors, as obtained with amitriptyline,can be desirable.2. Selective serotonin reuptake inhibitors(SSRI). These substances (e. g., fluoxetine)also possess a protonatable nitrogen atomand, instead of a larger ring system, containsimpler aromatic moieties. They also haveamphiphilic character. Because their af nityfor receptors is much less (no blockade ofacetylcholine or norepinephrine receptors),acute adverse effects are less marked thanthose of tricyclic thymoleptics. Blockade ofreuptake is confined to serotonin (5-HT).Antidepressant potency is equal to orslightly inferior to that of tricyclics. Fluoxetinehas a long duration of action. Togetherwith its active metabolite, it is eliminatedwith a half-life of several days. The SSRIgroup includes several other substancessuch as citalopram, paroxetine, sertralineand fluvoxamine. Besides depression, thesesubstances are also marketed for variousother psychiatric indications, including anxietydisorders, posttraumatic stress, and obsessive-compulsivedisorder.Labeling of most drugs in this group wasrecently revised to include a warning statementconcerning a worsening of depressionand treatment-emergent suicidality in bothadult and pediatric patients.3. Inhibitors of monoamine oxidase A (thymeretics).Moclobemide is the only representativeof this group. It produces a reversibleinhibition of MAO A , which is responsiblefor inactivation of the amines norepinephrine,dopamine, and serotonin (A).Enzyme inhibition results in an increasedconcentration of these neurotransmitters inthe synaptic cleft. Moclobemide is less effectiveas an antidepressant than as a psychomotorstimulant. It is indicated only in depressionswith extreme psychomotor slowingand is contraindicated in patients at riskof suicide.Tranylcypromine causes irreversible inhibitionof the two isozymes MAO A and 0$2 %Therefore, presystemic elimination in theliver of biogenic amines, such as tyramine,that are ingested in food (e. g., in aged cheeseand Chianti) is impaired (with danger of adiet-induced hypertensive crisis). The compoundisobsoleteinsomecountries.4. Atypical antidepressants represent a heterogeneousgroup comprising agents thatinterfere only weakly or not at all withmonoamine reuptake (trazodone, nefazodone,bupropion, mirtazapine), preferentiallyblock reuptake of norepinephrine (reboxetine),or act as dual inhibitors of 5-HTand norepinephrine reuptake (venlafaxine,milnacipran, duloxetine). Venlafaxine appearstobeaseffectiveastricyclicantidepressantsin severe depression.

Antidepressant Drugs 229A. Antidepressants: activity profilesSerotonin5-HT-ReceptorDopamine D-ReceptorIndicationAdverse effectsNorepinephrineα-AdrenoceptorTricyclic AntidepressantsAmitriptylinePatient:Parasympatholyticeffects:Psychomotordampening,anxiolyticHistaminecentralH 1 -ReceptorCH3HC CH2 CH2NCH3Anxious,agitatede.g., tachycardia,dry mouth,constipation,difficult urinationCaution: closedangleglaucomaImipraminePatient:α1-Blockade:NCH3H2C CH2 CH2NCH3DrivenormalorthostatichypotensionDesipraminePatient:PsychomotoractivationNHH2C CH2 CH2NCH3PsychomotorinhibitionIn high dose:cardiodepressionSelective Serotonin Reuptake Inhibitors (SSRI)F3COFluoxetineCH CH2CH2HNCH3Patient:PsychomotorinhibitionAkathisia,insomnia,loss of appetite,weight loss,suicidal ideationMAO A InhibitorsMAOMAOMAOClOCNHMoclobemideCH2CH2NOPatient:PsychomotorinhibitionIn hypertonicpatients:Caution: biogenicamines in food

230 Psychopharmacologicals ManiaThe manic phase is characterized by exaggeratedelation,flightofideas,andapathologicallyincreased psychomotor drive. Thisis symbolically illustrated in (A) byadisjointedstructure and aggressive color tones.The patients are overconfident, continuouslyactive, show progressive incoherence ofthought and loosening of associations, andact irresponsibly (financially, sexually, etc.).Lithium. Lithium is the lightest of the alkalimetal atoms (A), of which family sodium andpotassium have special significance for theorganism. Lithium ions (Li + )distributenearlyevenly in the extracellular and intracellularfluid compartments and thus build up only asmall concentration gradient across the cellmembrane. The lithium ion cannot be transportedby the membranal Na + /K + -ATPase. Intracellularly,lithium ions interfere in transductionmechanisms. For instance, they reducethe hydrolysis of inositol phosphate,leading to a reduced sensitivity to transmitterof nerve cells. In addition, the metabolismof transmitters is thought to be alteredin the presence of lithium ions. These andother biochemical findings observed afteradministration of lithium do not provide asatisfactory explanation for the therapeuticeffect of this “simple” pharmaceutical, particularlyso because the somatic disturbanceunderlying mania remains unknown. As inendogenous depression, it is surmised thatimbalances between different transmittersystems are at fault. Remarkably, Li + ionsdo not exert psychotropic effects in healthyhumans, although they elicit the typical adverseeffects.Indications for lithium therapy.1. Acute treatment of manic phase; therapeuticresponse develops only in thecourse of several days (A).2. Long-term administration (6–12 monthsuntil full effect reached) for the prophylaxisof both manic and depressive phasesof bipolar illness (A).3. Adjunctive therapy in severe therapy-resistantdepressions.Lithium therapy of acute mania is dif cultbecause of the narrow margin of safety andbecause the patient being treated lacks insight.Therapeutic levels should be closelymonitored and kept between 0.8 and1.2 mM in fasting morning blood samples.For prevention of relapse, slightly lowerblood levels of 0.6–0.8 mM are recommended.Adverse effects that occur at therapeuticserum concentration during longtermintake of lithium salts include renal(diabetes insipidus) and endocrine manifestations(goiter and/or hypothyroidism,glucose intolerance, hyperparathyroidism,sexual dysfunction). At concentrations> 1.2–1.5 mM, signs of mild toxicity are evident,including a fine hand tremor, weakness,fatigue, and abdominal complaints. Asblood levels rise further, decreased ability toconcentrate, agitation, confusion, and cerebellarsigns are noted. In the most severecases of poisoning, seizures may occur andthe patient may lapse into a comatose state.During lithium therapy, fluctuations in bloodlevel are quasi expected because changes indietary daily intake of NaCl or fluid losses(diarrhea, diuretics) can markedly alter renalelimination of lithium. Lithium therapy thusrequires special diligence on the part of thephysician and cooperation on the part of thepatientorhisorherrelatives.

Therapy of Manic States 231A. Effect of lithium salts in maniaManiaHDay 8 Day 6 Day 4 Day 2DepressionLi+LithiumNaKRbCsManiaBeMgCaSrBaNormalstateNormal driveDay 10Normal state

232 Psychopharmacologicals Therapy of SchizophreniaSchizophrenia is an endogenous psychosis ofepisodic character; in most cases, recovery isincomplete (residual defects, burned-outend stage). The different forms of schizophrenicillness will not be considered here.From a therapeutic perspective, it is relevantto differentiate between Positive signs including delusions, hallucinations,disorganized speech, behaviordisturbance; and Negative signs, such as social isolation,affective flattening, avolition, poverty ofspeech, and anhedoniasince both symptom complexes respond differentlyto antipsychotic drugs.NeurolepticsAfter neuroleptic treatment of a psychoticepisode is initiated, the antipsychotic effectproper manifests following a latent period.Acutely, psychomotor damping with anxiolysisand distancing is noted. Tormentingparanoid ideas and hallucinations lose theirsubjective importance (A, dimming of flashycolors); initially, however, the psychoticprocess persists but then wanes graduallyoverthecourseofseveralweeks.Complete normalization often cannot beachieved. Even though a “cure” is unrealizable,these changes signify success because(a) the patient obtains relief from the tormentof psychotic personality changes; (b) care ofthe patient is facilitated; and (c) return into afamiliar community environment is accelerated.Neuroleptic therapy utilizes differentdrug classes, namely phenothiazines, butyrophenones,and the atypical neuroleptics.The phenothiazines were developedfrom the H 1 -antihistamine promethazine:prototype chlorpromazine and congenerswith a tricyclic ring system and a side chaincontaining a protonatable nitrogen atom.Phenothiazines exhibit af nity for variousreceptors and exert corresponding antagonisticactions. Blockade of dopamine receptors,specifically in the mesolimbic prefrontalsystem, appears important for the antipsychoticeffect. The latency of the antipsychoticeffect suggests that adaptiveprocesses induced by receptor blockade playa role in the therapeutic response. Besidesaf nity for D 2 dopamine receptors, neurolepticsalso exhibit varying af nity to otherreceptors, including M-ACh receptors, α 1 -adrenoceptors, and histamine H 1 and 5-HTreceptors. Antagonism at these receptorscontributes to the adverse effects. Af nityprofiles of “classical” neuroleptics (phenothiazineand butyrophenone derivatives)differ significantly from those of newer atypicaldrugs (see p. 235B), in which af nity for5-HT receptors predominates.Neuroleptics do not have anticonvulsantactivity. Because they inhibit the thermoregulatorycenter, neuroleptics can be employedfor controlled hypothermia (“artificial hibernation”).Chronic use of neuroleptics can on occasiongive rise to hepatic damage associated withcholestasis. A very rare, but dramatic, adverseeffect is the malignant neuroleptic syndrome(skeletal muscle rigidity, hyperthermia,stupor),whichcanhaveafataloutcomein the absence of intensive countermeasures(including treatment with dantrolene).With other phenothiazines (e. g., fluphenazinewith a piperazine side chain substituent),antagonism at other receptor typestends to recede into the background vis-àvisthe blockade of D 2 dopamine receptors.In panel (B)onp.235theD 2 receptor af nityof the drugs concerned is defined as ++,while the differences in absolute af nity forthe other receptors are ignored.The butyrophenones (prototype haloperidol)were introduced after the phenothiazines.With these agents, blockade of D 2 receptorspredominates entirely (p. 235B).Antimuscarinic and antiadrenergic effectsare attenuated. The “extrapyramidal” motordisturbances that result from D 2 receptorblockade are, however, preserved and constitutethe clinically most important adversereactions that often limit therapy.

Therapy of Schizophrenia 233A. Effects of neuroleptics in schizophreniaNeurolepticsWeek 3after start of therapySNCl CH 3H 2 C CH 2 CH 2 NCH 3DesiredPhenothiazine type:ChlorpromazineUndesired effectAntipsychotic effectD 2ProlactinWeek 9 Week 7 Week 5D2MDyskinesiasGlaucomaMMMα 1SedationAntiemeticInhibition of salivarysecretionHypotensionTachycardiaArrhythmiaCholestasisBowel atoniaH 1D 2MDisturbance ofmicturitionButyrophenone type:Antipsychotic effectDyskinesiasD 2Antiemetic D 2

234 PsychopharmacologicalsEarly dyskinesias occur immediately afterneuroleptization and are manifested by involuntaryabnormal movements in the headneck and shoulder region. After treatment ofseveral weeks to months, a parkinsoniansyndrome (pseudoparkinsonism) (p.188) orakathisia (motor restlessness) may develop.All these disturbances can be treated by administrationof antiparkinsonian drugs ofthe anticholinergic type, such as biperiden.As a rule, these disturbances disappear afterwithdrawal of neuroleptic medication. Tardivedyskinesia may become evident afterchronic neuroleptization for several years,particularly when the drug is discontinued.Its postulated cause is a hypersensitivity ofthe dopamine receptor system. The conditionis exacerbated by administration ofanticholinergics.The butyrophenones carry an increasedrisk of adverse motor reactions because theylack anticholinergic activity and, hence, areprone to upset the balance between striatalcholinergic and dopaminergic activity.Atypical neuroleptics differ in structure andpharmacological properties from the aforementioneddrug groups. Extrapyramidalmotor reactions are absent or less prevalent.The antipsychotic effect involves not onlythepositivebutalsothenegativesymptoms.Inthecaseofclozapine, it was assumed atfirst that the drug acted as a selective antagonistat D 4 dopamine receptors. Subsequently,however, the drug was recognizedas a high-af nity ligand and antagonist atother receptors (B). Clozapine can be usedwhenotherneurolepticshavetobediscontinuedbecause of extrapyramidal motor reactions.Clozapine may cause agranulocytosis,necessitating close hematological monitoring.It produces marked sedation.Olanzapine is structurally related to clozapine;thus far the risk of agranulocytosisappears to be low or absent.Risperidone differs in structure from theaforementioned drugs; it possesses relativelylower af nity for all “non–D 2 -receptors.”Ziprasidone shows high af nity for 5-HT 2A receptors. Remarkably, this new substancealso stimulates 5-HT 1A receptors,which translates into an antidepressant effect.Ziprasidone particularly influences negativesymptoms, its effect on positive symptomsreportedly being equivalent to that ofclassical neuroleptics. Adverse effects due toblockade of M-ACh, H 1 and α 1 -receptors arecomparatively weak. Central disturbances(giddiness, ataxia, etc.) may occur. Moreover,QT interval prolongation has been observed;concurrent administration of QT-prolongingdrugs must therefore be avoided.Uses. Management of acute psychotic phasesrequires high-potency neuroleptics. Inhighly agitated patients, i.v. injection of haloperidolmay be necessary. The earlier therapyis started, the better is the clinical outcome.Most schizophrenic patients requiremaintenance therapy for which a low dosagecan be selected. For stabilization and preventionof relapse, atypical neuroleptics are especiallysuited since they improve negativesymptoms in responsive patients. The patientsneed good care and, if possible, integrationinto a suitable milieu. Dif cultiesarise because patients do not take their prescribedmedication (N.B.: counseling of bothpatient and caregivers). To circumvent lackof compliance, depot preparations have beendeveloped, e. g., fluphenazine decanoate(i.m. every 2 weeks) and haloperidol decanoate(i.m. every 4 weeks), which yield stableblood levels for the period indicated.

Therapy of Schizophrenia 235A. Conventional and atypical neurolepticsPositive symptoms– Hallucinations– Delusions– DisorganizedthoughtsSchizophreniaNegative symptoms– Avolition– Affective flattening– Social isolationButyrophenone derivativeHHFONOHClClNNNNN SNNNCH 3HaloperidolCH 3ClozapineCH 3OlanzapinePhenothiazine derivativeSN CH 3NCF 3NNFluphenazineOHNONNORisperidoneFB. Receptor affinity profile with reference to D 2 -dopamine receptorD 2MACh α 1 H 1 5-HT 2A5-HT 1AChlorpromazine+++++++++++Fluphenazine+++++Haloperidol++++++ClozapineOlanzapineRisperidoneZiprasidone++ +++ +++ +++ +++++ ++ ++ +++ +++++ ++ ++ ++++ ++ + +++ !++!The receptor affinities of each drug are compared in relation to its D 2 -receptor affinity,arbitrarily set at (++); antagonistic effects, except for ziprasidone (5-HT 1A agonism)

236 Psychopharmacologicals Psychotomimetics (Psychedelics,Hallucinogens)Psychotomimetics are able to elicit psychicchanges like those manifested in the courseof a psychosis, such as illusionary distortionof perception and hallucinations. Thisexperiencemay be dreamlike in character; itsemotionalorintellectualtranspositionappearsincomprehensible to the outsider.A psychotomimetic effect is pictorially recordedin the series of portraits drawn by anartist under the influence of lysergic aciddiethylamide (LSD). As the intoxicated statewaxes and wanes wavelike, he reports seeingthe face of the portrayed subject turninto a grimace, phosphoresce bluish-purple,and fluctuate in size as if viewed through amoving zoom lens, creating the illusion ofabstruse changes in proportion and grotesquemotion sequences. The diabolic caricatureis perceived as threatening.Illusions also affect the senses of hearingand smell; sounds (tones) are “experienced”as floating beams and visual impressions asodors(“synesthesia”). Intoxicated individualssee themselves temporarily from the outsideand pass judgment on themselves and theircondition. The boundary between self and theenvironment becomes blurred. An elatingsense of being one with the other and thecosmos sets in. The sense of time is suspended;there is neither present nor past. Objectsare seen that do not exist, and experiencesare felt that transcend explanation, hencethe term “psychedelic” (Greek delosis = revelation)implying expansion of consciousness.The contents of such illusions and hallucinationscan occasionally become extremelythreatening (a “bad trip” or “bum trip”); theindividual may feel provoked to turn violentor to commit suicide. Intoxication is followedby a phase of intense fatigue, feelingsof shame, and humiliating emptiness.The mechanism of the psychotogenic effectremains unclear. LSD and some naturalhallucinogens such as psilocin, psilocybin(from fungi), bufotenin (the cutaneous glandsecretion of a toad), and mescaline (from theMexican cactus Anhalonium lewinii—peyote)bear structural resemblance to 5HT (p.120)and chemically synthesized amphetaminederivedhallucinogens (4-methyl-2,5-dimethoxyamphetamine,3,4-dimethoxyamphetamine,2,5-dimethoxy-4-ethylamphetamine)that are thought to interact withthe agonist recognition site of the 5-HT 2Areceptor. Conversely, most of the psychotomimeticeffects are annulled by neurolepticshaving 5-HT 2A antagonist activity (e. g., clozapine,risperidone). The structures of otheragents such as tetrahydrocannabinol (fromthe hemp plant, Cannabis sativa—hashish,marihuana), muscimol (from the fly agaric,Amanita muscaria), or phencyclidine (formerlyused as injectable general anesthetic)do not reveal a similar connection. Hallucinationsmay also occur as adverse effects afterintake of other substances, e. g., scopolamine(medieval witches’ ointment) and other centrally-activeparasympatholytics. Naturallyoccurring hallucinogens are employed bypriests (shamans) of nature religions toachieve a trance state. SyntheticLSDwaspopular among artists in the 1960s; “psychedelicart” denotes pictorial representation ofexperiential spaces and hallucinatory signsthat elude rational comprehension.In addition, other drugs that do not act asprimary hallucinogens, such as methylenedioxyamphetaminederivatives (e. g., 3,4-dimethylene-dioxymethamphetamine, “Ecstasy”)and cocaine pose a health risk. Theacute intoxication is associated with a misperceptionof reality, a period of exhaustionfollows. After prolonged use, dependencedevelops associated with intellectual degradationand physical decay. Withdrawal therapyisverydifcult.Marihuanafrequentlyserves as an entry-level recreational substancefor hard drugs.Psychotomimetics are devoid of therapeuticvalue; however, since their use leads totoxic effects and permanent damage, theirmanufacture and commercial distributionare prohibited (Schedule I, Controlled Drugs).

Psychotomimetics 237A. Psychotomimetic effect of LSD in a portrait artistOCC 2 H 5NC 2 H 5NCH 3Lysergic aciddiethylamide0.0001 g/70 kgHN

238 Hormones Hypothalamic and HypophysealHormonesThe endocrine system is controlled by thebrain. Nerve cells of the hypothalamussynthesize and release messenger substancesthat regulate adenohypophyseal (AH)hormone release or that are themselvessecreted into the body as hormones. Thelatter comprise the so-called neurohypophyseal(NH) hormones.The axonal processes of hypothalamicneurons project to the neurohypophysis,where they store the nonapeptides vasopressin(= antidiuretic hormone, ADH) and oxytocinand release them on demand into theblood. Therapeutically (ADH, p.168, oxytocin,p.130), these peptide hormones are givenparenterally or via the nasal mucosa.The hypothalamic releasing hormonesare peptides. They reach their target cells inthe AH lobe by way of a portal vascular routeconsisting of two serially connected capillarybeds. The first of these lies in the hypophysealstalk, the second corresponds to thecapillary bed of the AH lobe. Here, the hypothalamichormones diffuse from the blood totheir target cells, whose activity they control.Hormones released from the AH cells enterthe blood, in which they are distributed toperipheral organs (1).Nomenclature of releasing hormones.(RH – releasing hormone; RIH – release-inhibitinghormone.)GnRH, gonadotropin-RH = gonadorelin:stimulates the release of FSH (follicle-stimulatinghormone) and LH (luteinizing hormone).TRH, thyrotropin-RH (protirelin): stimulatesthe release of TSH (thyroid-stimulatinghormone = thyrotropin).CRH, corticotropin-RH: stimulates the releaseof ACTH (adrenocorticotropic hormone= corticotropin).GRH, growth hormone-RH = somatorelin:stimulates the release of GH (growth hormone= STH, somatotropic hormone).GRIH = somatostatin: inhibits release ofSTH (and also other peptide hormones includinginsulin, glucagon and gastrin).PRIH inhibits the release of prolactin andis identical with dopamine.Therapeutic control of AH cells. GnRH isused in hypothalamic infertility in women tostimulate FSH and LH secretion and to induceovulation. For this purpose, it is necessaryto mimic the physiological intermittentrelease (“pulsatile,” approximately every 90minutes) by means of a programmed infusionpump.Gonadorelin superagonists are GnRHanalogues that bind with very high aviditytoGnRHreceptorsofAHcells.Asaresultofthe nonphysiological uninterrupted receptorstimulation, initial augmentation of FSH andLH output is followed by a prolonged decrease.Buserelin, leuprorelin, goserelin, andtriptorelin are used to shut down gonadalfunction in this manner (“chemical castration,”e. g., in advanced prostatic carcinoma).Gonadorelin receptor antagonists,such as cetrorelix and ganirelix, block theGnRHreceptorsofAHcellsandthuscausecessation of gonadotropin release (2).The dopamine D 2 agonists, bromocriptineand cabergoline (p.116), inhibit prolactin-releasingAH cells (indications: suppressionof lactation, prolactin-producing tumors).Excessive, but not normal, growthhormone release can also be inhibited (indication:acromegaly).Octreotide is a somatostatin analogue; itis used in the treatment of somatostatinsecretingpituitary tumors.Growth hormone requires mediation bysomatomedins for many of its actions. Theseare chiefly formed in the liver, including theimportant somatomedin C (= insulin-likegrowth factor 1, IGF-1). Pegvisomant is anewly developed antagonist at the GH receptorand inhibits the production of IGF-1.

Hypothalamic and Hypophyseal Hormones 239A. Hypothalamic and hypophyseal hormonesHypothalamicreleasing hormonesSynthesisReleaseintobloodHypothalamusADHOxytocinSynthesisReleaseintobloodControlofsynthesisandreleaseofAHhormonesGnRH TRH CRH GRHGRIHPRIHApplicationparenteralNeurohypophysisAdenohypophysis (AH)AH-cellsnasalFSH, LHTSHACTHSTH(GH)ProlactinADHOxytocinOvummaturation;Estradiol,ProgesteroneSomatomedinsH 2 O1Spermatogenesis;TestosteroneThyroxineCortisolGrowthLactationLaborMilk ejectionAltered AAReleased amountGnRHPulsatile releaseBuserelinSuperagonistCetrorelixGnRH receptorantagonist90 minRhythmic stimulationAHcellPersistent stimulationGnRH receptor sensitivity2FSHLHCessation of hormone secretion

240 Hormones Thyroid Hormone TherapyThyroid hormones accelerate metabolism.Their release (A) isregulatedbythehypophysealglycoprotein TSH, whose release, inturn, is controlled by the hypothalamic tripeptideTRH. Secretion of TSH declines as theblood level of thyroid hormones rises; bymeans of this negative feedback mechanism,hormone production is “automatically” adjustedto demand.The thyroid releases predominantly thyroxine(T 4 ). However, the active form appearstobetriiodothyronine(T3 ); T 4 is convertedin part to T 3 , receptor af nity in targetorgans being 10-fold higher for T 3 .Theeffectof T 3 develops more rapidly and has a shorterduration than does that of T 4 . Plasmaelimination t ½ for T 4 is about 7 days; thatfor T 3 , however, is only 1.5 days. Conversionof T 4 to T 3 releases iodide; 150 µgT 4 contains100 µg ofiodine.For therapeutic purposes, T 4 is chosen,although T 3 is the active form and betterabsorbed from the gut. With T 4 administration,more constant blood levels can beachieved because T 4 degradation is so slow.Since T 4 absorption is maximal from anempty stomach, T 4 is taken about half anhour before breakfast.Replacement therapy of hypothyroidism.Whether primary, i. e., caused by thyroid disease,or secondary, i. e., resulting from TSHdeficiency, hypothyroidism is treated by oraladministration of T 4 . Since too rapid activationof metabolism entails the hazard of cardiacoverload (angina pectoris, myocardialinfarction), therapy is usually started withlowdosesandgraduallyincreased.Thefinalmaintenance dose required to restore a euthyroidstate depends on individual needs(~ 150 µg/day).Thyroid suppression therapy of euthyroidgoiter (B). The cause of goiter (struma) isusually a dietary deficiency of iodine. Owingto increased TSH action, the thyroid is activatedto raise utilization of the little iodineavailable to a level at which hypothyroidismis averted. Accordingly, the thyroid increasesin size. In addition, intrathyroid depletion ofiodine stimulates growth.Because of the negative feedback regulationof thyroid function, thyroid activationcan be inhibited by administration of T 4doses equivalent to the endogenous dailyoutput (~ 150 µg/day). Deprived of stimulation,the inactive thyroid regresses in size.If a euthyroid goiter has not persisted fortoo long, increasing iodine supply (with potassiumiodide tablets) can also be effectivein reversing overgrowth of the gland.In older patients with goiter due to iodinedeficiency, there is a risk of provoking hyperthyroidismby increasing iodine intake(p. 243B). During chronic maximal stimulation,thyroid follicles can become independentof TSH stimulation (“autonomic tissue”containing TSH receptor mutants with spontaneous“constitutive activity”). If the iodinesupply is increased, thyroid hormone productionincreases while TSH secretion decreasesowing to feedback inhibition. Theactivity of autonomic tissue, however, persistsat a high level; thyroxine is released inexcess, resulting in iodine-induced hyperthyroidism.Iodized salt prophylaxis. Goiter is endemicin regions where soils are deficient in iodine.Use of iodized table salt allows iodine requirements(150–300 µg/day) to be metand effectively prevents goiter.

Thyroid Hormone Therapy 241A. Thyroid hormones – release, effects, degradationHypothalamusTRHHypophysisDecrease insensitivityto TRHII5' 6' 5 64'4HO O CH1'1 2 CH COOH3' 2'3 2NH2IIL-Thyroxine, Levothyroxine,3,5,3´,5´-Tetraiodothyronine, T 4IThyroidTSHHO O CH2CH COOHNH2IILiothyronine3,5,3´-Triiodothyronine, T 3~ 90 µg/day ~ 9 µg/dayThyroxineTriiodothyronineEffector cell:receptor affinityT 3 10=T 4 1Deiodinase~ 25 µg/dayDuration2. 9.DayI - I - I - I -Deiodinationcoupling“reverse T 3 ”3,3´,5´-Triiodothyronine Urine FecesT 3T 410 20 30 40 DaysB. Endemic goiter and its treatment with thyroxineHypophysisTSHTSHInhibitionNormalI - stateT 4 , T 3 T 4 , T 3 T 4Therap.administration

242 Hormones Hyperthyroidism and AntithyroidDrugsThyroid overactivity in Graves disease (A)results from formation of IgG antibodies thatbind to and activate TSH receptors. Consequently,there is overproduction of hormonewith cessation of TSH secretion. Graves diseasecan abate spontaneously after 1–2years; therefore, initial therapy consists inreversible suppression of thyroid activity bymeans of antithyroid drugs. In other forms ofhyperthyroidism, such as hormone-producing(morphologically benign) thyroid adenoma,the preferred therapeutic method is removalof tissue, either by surgery or by administrationof iodine-131 ( 131 I) in suf cientdosage. Radioiodine is enriched in thyroidcells and destroys tissue within a sphere ofa few millimeters by emitting β-particles(electrons) during its radioactive decay.Antithyroid drugs inhibit thyroid function.Release of thyroid hormone (C) isprecededby a chain of events. A membrane Na + /I − symporter actively accumulates iodide inthyroid cells (the required energy comesfrom a Na + /K + -ATPaselocatedinthebasolateralmembrane region); this is followedby oxidation to iodine, iodination of tyrosineresidues in thyroglobulin, conjugation of twodiiodotyrosine groups, and formation of T 4moieties. These reactions are catalyzed bythyroid peroxidase, which is localized inthe apical border of the follicular cell membrane.T 4 -containing thyroglobulin is storedinside the thyroid follicles in the form ofthyrocolloid. Upon endocytotic uptake, colloidundergoes lysosomal enzymatic hydrolysis,enabling thyroid hormone to be releasedas required. A “thyrostatic” effectcan result from inhibition of synthesis orrelease.Whensynthesisisarrested,theantithyroideffect develops after a delay, asstored colloid continues to be utilized.Antithyroid drugs for long-term therapy(C). Thiourea-derivatives (thioamides) inhibitperoxidase and, hence, hormone synthesis.To restore a euthyroid state, two therapeuticprinciples can be applied in Gravesdisease: (a) monotherapy with a thioamide,with gradual dose reduction as the diseaseabates; (b) administration of high doses of athioamide, with concurrent administrationof thyroxine to offset diminished hormonesynthesis. Adverse effects of thioamides arerare, but the possibility of agranulocytosishas to be kept in mind.Perchlorate, given orally as the sodiumsalt, inhibits the iodide pump. Adverse reactionsinclude aplastic anemia. Comparedwith thioamides, its therapeutic importanceis low.Short-term thyroid suppression (C). Iodinein high dosage (> 6000 µg/day) exerts a transient“thyrostatic” effect in hyperthyroid, butusually not in euthyroid, individuals. Sincerelease is also blocked, the effect developsmore rapidly than does that of thioamides.Clinical applications include preoperativesuppression of thyroid secretion accordingto Plummer with Lugol’s solution (5% iodine+ 10% potassium iodide, 50–100 mg iodine/dayforamaximumof10days).Inthyrotoxiccrisis, Lugol’s solution is given together withthioamides and β-blockers. Adverse effects:allergies. Contraindications: iodine-inducedthyrotoxicosis.Lithium ions inhibit thyroxine release.Lithium salts can be used instead of iodinefor rapid thyroid suppression in iodine-inducedthyrotoxicosis. Regarding administrationof lithium in manic-depressive illness,see p. 230.

Hyperthyroidism and Antithyroid Drugs 243A. Graves' disease B. Iodine hyperthyroidosis in endemic goiterHypophysisTSHAutonomoustissueTSHlikeantibodiesI -I -T 4 , T 3T 4 , T 3 T 4 , T 3C. Antithyroid drugs and their modes of actionThioamidesH3C CH2CH2N SNHOHPropylthiouracilCH3NSNHThiamazoleMethimazoleConversionduringabsorptionCH3NSNC O CH2 CH3OCarbimazoleI - T 4 -ClO 4-SynthesisPeroxidaseI -eTyrosineI TGIIodine inhigh doseReleaseTyrosineIT 4 -T 4Storagein colloidLysosomeLithiumions

244 Hormones Glucocorticoid TherapyI. Replacement TherapyThe adrenal cortex (AC) produces the glucocorticoidcortisol (hydrocortisone) in the zonafasciculata and the mineralocorticoid aldosteronein the zona glomerulosa. Both steroidhormones are vitally important in adaptationresponses to stress situations, such asdisease, trauma, or surgery. Cortisol secretionis stimulated by hypophyseal ACTH; aldosteronesecretion by angiotensin II in particular(p.128). In AC failure (primary adrenocorticalinsuf ciency; Addison disease),both cortisol and aldosterone must be replaced;whenACTHproductionisdeficient(secondary adrenocortical insuf ciency), cortisolalone needs to be replaced. Cortisol iseffective when given orally (30 mg/day, 2/3a.m., 1/3 p.m.). In stress situations, the dose israised 5- to 10-fold. Aldosterone is poorly effectivevia the oral route; instead, the mineralocorticoidfludrocortisone (0.1 mg/day) isgiven.II. Pharmacodynamic Therapy withGlucocorticoids (A)In unphysiologically high concentrations,cortisol or other glucocorticoids suppressall phases (exudation, proliferation, scar formation)of the inflammatory reaction, i. e.,the organism’s defensive measures againstforeign or noxious matter. This effect ismediated by multiple components, all ofwhich involve alterations in gene transcription(p. 64) Thus, synthesis of the anti-inflammatoryprotein lipocortin (macrocortin)is stimulated. Lipocortin inhibits the enzymephospholipase A 2 .Consequently,releaseofarachidonic acid is diminished, along withthe formation of inflammatory mediators ofthe prostaglandin and leukotriene series(pp.196, 200). Conversely, glucocorticoidsinhibit synthesis of several proteins that participatein the inflammatory process, includinginterleukins (p. 304) and other cytokines,phospholipase A 2 (p.196), and cyclooxygenase-2(p. 200). At very high dosage, nongenomiceffects via membrane-bound receptorsmay also contribute.Desired effects. As antiallergics, immunosuppressants,oranti-inflammatorydrugs, glucocorticoidsdisplay excellent ef cacy against“undesired” inflammatory reactions, such asallergy, rheumatoid arthritis, etc.Unwanted effects. With short-term use,glucocorticoidsare practically free of adverseeffects, even at the highest dosage. Longtermuse islikelytocausechangesmimickingthe signs of Cushing syndrome (endogenousoverproduction of cortisol). Sequelae of theanti-inflammatory action are lowered resistancetoinfectionanddelayedwoundhealing.Sequelaeofexaggeratedglucocorticoidactionare (a) increased gluconeogenesis and releaseof glucose, insulin-dependent conversion ofglucose to triglycerides (adiposity mainly noticeablein the face, neck, and trunk), and “steroid-diabetes”ifinsulin releaseisinsuf cient;(b)increasedproteincatabolismwithatrophyof skeletal musculature (thin extremities), osteoporosis,growth retardation in infants, andskin atrophy. Sequelae of the intrinsicallyweak, but now manifest, mineralocorticoidaction of cortisol are salt and fluid retention,hypertension, edema; and KCl loss with dangerof hypokalemia. Psychic changes, chieflyintheformofeuphoricormanicmoodswings,also need to be taken into account duringchronic intake of glucocorticoids.Measures for attenuating or preventingdrug-induced Cushing syndrome. (a) Useof cortisol derivatives with less (e. g.,prednisolone) or negligible mineralocorticoidactivity (e. g., triamcinolone, dexamethasone).Glucocorticoid activity of these congenersis more pronounced. Glucocorticoid,anti-inflammatory, and feedback-inhibitory(p. 246) actions on the hypophysis are correlated.An exclusively anti-inflammatorycongener does not exist. The “glucocorticoid”-relatedCushinglike symptoms cannotbe avoided. The table opposite lists relative

Glucocorticoid Therapy 245A. Glucocorticoids: principal and adverse effectsInflammationredness,swelling heat,pain;scarUnwantedWantede.g., allergyautoimmune disease,transplant rejectionHealing oftissue injurydue to bacteria,viruses, fungi, traumaHypertensionNa +H 2 OMineralocorticoidactionK +Unphysiologicallyhigh concentrationCortisolOHOCH OH 2COOHGlucocorticoidactionDiabetesmellitusGlucoseGluconeogenesisAmino acidsProtein catabolismPotency10.8003000CortisolPrednisoloneTriamcinoloneDexamethasoneAldosterone147.5300.3MuscleweaknessOsteoporosisGrowth inhibitionTissue atrophySkinatrophyHOOHCCH OH 2COHHOCH OH 2COOHOAldosteroneOPrednisoloneCH OH 2CH OH 2HOCOOHOHHOCOOHCH 3OFTriamcinoloneOFDexamethasone

246 Hormonesactivity (potency) with reference to cortisol,whose mineralocorticoid and glucocorticoidactivities are assigned a value of 1.0. Alllisted glucocorticoids are effective orally.(b) Local application. This enables therapeuticallyeffective concentrations to be builtup at the site of application without a correspondingsystemic exposure. Glucocorticoidsthat are subject to rapid biotransformationand inactivation following diffusion fromthesiteofactionarethepreferredchoice.Thus, inhalational administration employsglucocorticoids with a high presystemicelimination such as beclomethasone dipropionate,budesonide, flunisolide, or fluticasonepropionate (p.14). Adverse effects, however,also occur locally: e. g., with inhalationaluse, oropharyngeal candidiasis (thrush) andhoarseness; with cutaneous use, skin atrophy,striae, telangiectasias and steroid acne;and with ocular use, cataracts and increasedintraocular pressure (glaucoma).(c) Lowest dosage possible. Forlong-termmedication, a just-suf cient dose should begiven. However, in attempting to lower thedose to the minimally effective level, it isnecessary to take into account that administrationof exogenous glucocorticoids willsuppress production of endogenous cortisolowing to activation of an inhibitory feedbackmechanism. In this manner, a very low dosecould be “buffered,” so that unphysiologicallyhigh glucocorticoid activity and theanti-inflammatory effect are both prevented.Effect of glucocorticoid administration onadrenocortical cortisol production (A). Releaseof cortisol depends on stimulation byhypophyseal ACTH, which in turn is controlledby hypothalamic corticotropin-releasinghormone (CRH). In both in the hypophysisand hypothalamus there are cortisolreceptors through which cortisol can exert afeedback inhibition of ACTH or CRH release.By means of these cortisol “sensors,” theregulatory centers can monitor whetherthe actual blood level of the hormone correspondsto the “set-point.” If the blood levelexceeds the set-point, ACTH output is decreasedand thus also the cortisol production.In this way, cortisol level is maintainedwithin the required range. The regulatorycenters respond to synthetic glucocorticoidsas they do to cortisol. Administration ofexogenous cortisol or any other glucocorticoidreduces the amount of endogenous cortisolneeded to maintain homeostasis. Releaseof CRH and ACTH declines (“inhibitionof higher centers by exogenous glucocorticoid”)and, hence, cortisol secretion (“adrenocorticalsuppression”). After weeks ofexposure to unphysiologically high glucocorticoiddoses, the cortisol-producing portionsof the adrenal cortex shrink (“adrenocorticalatrophy”). Aldosterone-synthesizing capacityremains unaffected, however. Whenglucocorticoid medication is suddenly withheld,the atrophic cortex is unable to producesuf cient cortisol and a potentially lifethreateningcortisol deficiency may develop.Therefore, glucocorticoid therapy should alwaysbe tapered off by gradual reduction ofthe dosage.Regimens for prevention of adrenocorticalatrophy. Cortisol secretion is high in theearly morning and low in the late evening(circadian rhythm). Accordingly, sensitivityto feedback inhibition must be high in thelate evening.(a) Circadian administration: The dailydose of glucocorticoid is given in the morning.Endogenous cortisol production will alreadyhave begun, the regulatory centersbeing relatively insensitive to inhibition. Inthe early morning hours of the next day, CRF/ACTH release and adrenocortical stimulationwill resume.(b) Alternate day therapy: Twicethedailydose is given on alternate mornings. On the“off” day, endogenous cortisol production isallowed to occur.The disadvantage with either regimen is arecrudescence of disease symptoms duringthe glucocorticoid-free interval.

Glucocorticoid Therapy 247A. Cortisol release and its modification by glucocorticoidsHypothalamusCRHHypophysisACTHAdrenocorticalatrophyAdrenalcortexCortisol30 mg/dayExogenousadministrationCortisolproduction undernormalconditionsDecrease incortisol productionwith cortisol dose< daily productionCessation ofcortisol productionwith cortisol dose> daily productionCortisol deficiencyafter abruptcessation ofadministrationCortisolconcentrationGlucocorticoid-inducedinhibition of cortisol productionnormal circadian time-course0 4 8 12 16 20 24 4 8hMorning doseInhibition ofendogenouscortisolproductionElimination ofexogenousglucocorticoidduring daytimeStart of earlymorningcortisolproductionGlucocorticoidconcentration0 4 8 12 16 20 24 4 8h

248 Hormones Androgens, Anabolic Steroids,AntiandrogensAndrogens are masculinizing substances.The endogenous male gonadal hormone isthe steroid testosterone from the interstitialLeydig cells of the testis. Testosterone secretionis stimulated by hypophyseal luteinizinghormone (LH), whose release is controlledby hypothalamic GnRH (gonadorelin,p. 238). Release of both hormones is subjectto feedback inhibition by circulating testosterone.Reduction of testosterone to dihydrotestosteroneoccurs in most target organs(e. g., the prostate gland); the latter possesseshigher af nity for androgen receptors.Rapid intrahepatic degradation (plasmat ½ ~ 15 minutes) yields androsterone amongother metabolites (17-ketosteroids) that areeliminated as conjugates in the urine. Becauseof rapid hepatic metabolism, testosteroneis unsuitable for oral use. Although it iswell absorbed, it undergoes virtually completepresystemic elimination.Testosterone (T.) derivatives for clinicaluse. Because of its good tissue penetrability,testosterone is well suited for percutaneousadministration in the form of a patch (transdermaldelivery system, p.18). T. esters for i.m. depot injection are T. propionate and T.heptanoate (or enanthate). These are givenin oily solution by deep intramuscular injection.Upondiffusionoftheesterfromthedepot, esterases quickly split off the acylresidue to yield free T. With increasing lipophilicity,esters will tend to remain in thedepot, and the duration of action thereforelengthens. A T. ester for oral use is the undecanoate.Owing to the fatty acid nature ofundecanoic acid, this ester is absorbed intothelymph,enablingittobypasstheliverandenter the general circulation via the thoracicduct. 17-α Methyltestosterone is effective bythe oral route owing to its increased metabolicstability, but because of the hepatotoxicityof C17-alkylated androgens (cholestasis,tumors) its use should be avoided.Orally active mesterolone is 1-α-methyldihydrotestosterone.Indication: for hormone replacement indeficiency of endogenous T. production.Anabolics are testosterone derivatives(e. g., clostebol, metenolone, nandrolone, stanozolol)that are used in debilitated patients,and are misused by athletes, because of theirprotein anabolic effect. They act via stimulationof androgen receptors and, thus, alsodisplay androgenic actions (e. g., virilizationin females, suppression of spermatogenesis).Inhibitory PrinciplesGnRH superagonists (p. 238), such as buserelin,leuprolin, goserelin, and triptorelin, areused in patients with metastasizing prostatecancer to inhibit production of testosteronewhich promotes tumor growth. Following atransient stimulation, gonadotropin releasesubsides within a few days and testosteronelevels fall as low as after surgical removal ofthe testes.Androgen receptor antagonists. The antiandrogencyproterone is a competitive antagonistof testosterone. By virtue of an additionalprogestin action, it decreases secretionof gonadotropins. Indications: in themale, dampening of sexual drive in hypersexuality,prostatic cancer; in the female,treatment of virilization phenomena, if necessary,with concomitant utilization of thegestagen contraceptive effect.Flutamide and bicalutamide are structurallydifferent androgen receptor antagonistslacking progestin activity.Finasteride and dutasteride inhibit 5αreductase,theenzymeresponsibleforconvertingT. to dihydrotestosterone (DHT).Thus, androgenic stimulation is reduced inthosetissueswhereDHTistheactivespecies(e. g., the prostate). T.-dependent tissues andfunctions are not or hardly affected: e. g.,skeletal musculature, feedback inhibition ofgonadotropin release, or libido. Both can beused in benign prostatic hyperplasia toshrink the gland and to improve micturition.

Androgens, Anabolic Steroids, Antiandrogens 249A. TestosteroneHypothalamusGnRHSubstitutiontransdermalOOCTestosteroneundecanoatep.o.HypophysisLHi.m.Testosterone esterIntestinal lymphTestosteroneOHe.g., skeletal muscle fiberAndrogen receptorOGene expressione.g., Prostaticgland cell5α-ReductaseOConjugation withsulfate, glucuronate17-KetosteroidODihydrotestosteroneH HHOHHAndrosteroneInhibitory PrinciplesReceptor antagonistsGnRH superagonists5α-Reductase inhibitorOCNHCH 3CH 3 CCH 3H 2COClCH 3C OO C CH 3OCyproteroneacetateONHFinasterideF 3CO 2NFlutamideCH 3NH C C HO CH 3

250 Hormones Follicular Growth and Ovulation,Estrogen and Progestin ProductionFollicular maturation and ovulation, as wellas the associated production of female gonadalhormones, are controlled by the hypophysealgonadotropins FSH (follicle-stimulatinghormone) and LH (luteinizing hormone).In the first half of the menstrualcycle, FSH promotes growth and maturationof ovarian tertiary follicles that respond withaccelerating synthesis of estradiol. Estradiolstimulates endometrial growth and increasesthe permeability of cervical mucusfor sperm cells. When the estradiol bloodlevel approaches a predetermined set-point,FSH release is inhibited owing to feedbackaction on the anterior hypophysis. Since folliclegrowth and estrogen production arecorrelated, hypophysis and hypothalamuscan “monitor” the follicular phase of theovariancyclethroughtheirestrogenreceptors.Immediately prior to ovulation, whenthenearlymaturetertiaryfolliclesareproducinga high concentration of estradiol, thecontrol loop switches to positive feedback.LH secretion transiently surges to peak levelsand triggers ovulation. Within hours afterovulation, the tertiary follicle develops intothe corpus luteum, which then also releasesprogesterone in response to LH. This initiatesthesecretoryphaseoftheendometrialcycleand lowers the permeability of cervical mucus.Nonruptured follicles continue to releaseestradiol under the influence of FSH.After two weeks, production of progesteroneand estradiol subsides, causing the secretoryendometrial layer to be shed (menstruation).The natural hormones are unsuitable fororal application because they are subject topresystemic hepatic elimination. Estradiol isconverted via estrone to estriol; by conjugation,all three can be rendered water-solubleand amenable to renal excretion. The majormetabolite of progesterone is pregnanediol,which is also conjugated and eliminated renally.Estrogen preparations. Depot preparationsfor i.m. injection are oily solutions of estersof estradiol (3- or 17-OH group). The hydrophobicityof the acyl moiety determines therate of absorption, hence the duration ofeffect. Released ester is hydrolyzed to yieldfree estradiol.Orally used preparations. Ethinylestradiol(EE) is more stable metabolically, passes theliver after oral intake and mimics estradiol atestrogen receptors. Mestranol itself is inactive;however, cleavage of the C3 methoxygroup again yields EE. In oral contraceptives,one of the two agents forms the estrogencomponent (p. 252). (Sulfate-) Conjugated estrogens(excretory products) can be extractedfrom equine urine and are used inthe therapy of climacteric complaints. Theireffectiveness is a matter of debate. Estradioltransdermal delivery systems are available.Progestin preparations. Depot formulationsfor i.m. injection are 17-α-hydroxyprogesteronecaproate and medroxyprogesteroneacetate. Preparations for oral useare derivatives of ethinyltestosterone =ethisterone (e. g., norethisterone, dimethisterone,lynestrenol, desogestrel, gestoden),or of 17α-hydroxyprogesterone acetate(e. g., chlormadinone acetate or cyproteroneacetate).Indications for estrogens and progestins includehormonal contraception (p. 252); hormonereplacement, as in postmenopausalwomen for prophylaxis of osteoporosis;bleeding anomalies; menstrual and severeclimacteric complaints.Adverse effects. After long-term intake ofestrogen/progestin preparations, increasedrisks have been reported for breast cancer,coronary heart disease, stroke, and thromboembolism.Although the incidence of bonefractures also decreases, the risk–benefit relationshipis unfavorable. Concerning the adverseeffects of oral contraceptives, see p. 252.

Estrogens and Progestins 251A. Estradiol, progesterone, and derivativesO EstradiolO C-valerate173 weeksOC O 3-benzoate1 2 weekDuration of effectHypothalamusGnRHHypophysisFSH LHOvaryHydroxyprogesteronecaproateH3COC O17OCMedroxyprogesteroneacetate1 week8 – 12 weeksDuration of effectOHH3CC17OHO3EstradiolOProgesteroneCH3HCOHOHOOHOHHOEstriol Estrone EstradiolPregnanediolConjugation with sulfate, glucuronateConjugationInactivationInactivationEstradiolOHC CHProgesteroneOHCCHEthinylestradiol (EE)OEthinyltestosterone,a gestagenConjugatedestrogensH3C3OMestranol =3-Methylether of EE

252 Hormones Oral ContraceptivesInhibitors of ovulation. Negative feedbackcontrol of gonadotropin release can be utilizedto inhibit the ovarian cycle. Administrationof exogenous estrogens (ethinylestradiolor mestranol) during the first half ofthe cycle permits FSH production to be suppressed(as it is by administration of progestinsalone). Owing to the reduced FSH stimulationof tertiary follicles, maturation offollicles and hence ovulation are prevented.In effect, the regulatory brain centersare deceived, as it were, by the elevatedestrogen blood level, which signals normalfollicular growth and a decreased requirementfor FSH stimulation. If estrogens alonearegivenduringthefirsthalfofthecycle,endometrial and cervical responses, as wellas other functional changes, will occur in thenormal fashion. By adding a progestin(p. 250) during the second half of the cycle,the secretory phase of the endometrium andassociated effects can be elicited. Discontinuanceof hormone administration would befollowed by menstruation.The physiological time course of estrogenprogesteronerelease is simulated in the socalledbiphasic (sequential) preparations(A). In monophasic preparations, estrogenand progestin are taken concurrently. Earlyadministration of progestin reinforces theinhibition of CNS regulatory mechanisms,prevents both normal endometrial growthand conditions for ovum implantation, anddecreases penetrability of cervical mucus tosperm cells. The two latter effects also act toprevent conception. According to the stagingof progestin administration, one distinguishes(A): one-, two-, and three-stagepreparations. Even with one-stage preparations,“withdrawal bleeding” occurs whenhormone intake is discontinued (if necessary,by substituting dummy tablets).Unwanted effects. An increased risk ofthromboembolism is attributed to the estrogencomponent in particular but is also associatedwith certain progestins (gestodenand desogestrel). The risk of myocardial infarction,stroke, and benign liver tumors iselevated. Nonetheless, the absolute prevalenceof these events is low. Predisposingfactors (family history, cigarette smoking,obesity,andage)havetobetakenintoaccount.The overall risk of malignant tumorsdoes not appear to be increased. In addition,hypertension, fluid retention, cholestasis,nausea, and chest pain, are reported.Minipill. Continuous low-dose administrationof progestin alone can prevent pregnancy.Ovulations are not suppressed regularly;the effect is then due to progestininducedalterations in cervical and endometrialfunction. Because of the need for constantintake at the same time of day, a lowersuccess rate, and relatively frequent bleedinganomalies, these preparations are nowrarely employed.“Morning- after” pill. This refers to administrationof a high dose of estrogen and progestin,preferably within 12–24 hours, butno later than 72 hours after coitus. Themechanism of action is unclear.Stimulation of ovulation. Gonadotropin secretioncan be increased by pulsatile deliveryof GnRH (p. 238). Regarding clomifene, seep. 254; whereas this substance can be givenorally, the gonadotropins presented belowmust be given parenterally. HMG is humanmenopausal gonadotropin extracted fromthe urine of postmenopausal women. Owingto the cessation of ovarian function, gonadotropinsshow elevated blood levels and passinto urine in utilizable quantities. HMG (menotropins)consists of FSH and LH. HCG ishuman chorionic gonadotropin; it is obtainedfrom the urine of pregnant womenand acts like LH. Recombinant FSH (follitropin)and LH are available.

Oral Contraceptives 253A. Oral contraceptivesHypophysisHypophysisFSHLH17 14 21 28InhibitionMinipillOvulationOvaryOvulationOvaryEstradiolEstradiolProgesteroneIntake ofestradiolderivativeIntake ofprogestinProgesteronePenetrabilityby sperm cells17 14 21 28Day of cycleReadinessfornidationNo ovulationBiphasic preparationDays of cycle7 14 21 28Monophasic preparationsOne-stage regimenTwo-stage regimenThree-stage regimen

254 Hormones Antiestrogen and AntiprogestinActive PrinciplesSelective estrogen receptor modulators(SERMs) (A). Estrogen receptors belong tothe group of transcription-regulating receptors(p. 64). The female gonadal hormoneestradiol is an agonist at these receptors.Several drugs are available that can produceestrogen-antagonistic effects. Interestingly,these are associated with estrogen-agonisticeffects in certain tissues. A tentative explanationderives from the idea that each ligandinduces a specific conformation of the estrogenreceptor. The ligand–estrogen receptorcomplexes combine with co-activators or repressorsat specified gene sequences. Thepattern of co-regulators differs from tissueto tissue, allowing each SERM to generate atissue-specific activity. It is of therapeuticsignificance that the patterns of estrogenicand antiestrogenic effects differ in a substance-specificmanner among the drugs ofthis class.It is useful to compare the activity profileof a SERM with that of estradiol, particularlyin relation to effects seen postmenopausally.During chronic administration of estradiol,the risk of endometrial cancer rises; co-administrationof a progestin prevents this effect.Breast cancers occur more frequently,likewise thromboembolic diseases. Estradioleffectively alleviates climacteric hot flashesand sweating. After chronic treatment it reducesthe incidence of osteoporotic bonefractures by preventing the loss of an estrogen-dependentportion of bone mass. Nonetheless,estrogens can no longer be recommendedfor this purpose because of the unfavorablebenefit–risk constellation (p. 330).Clomifene is a stilbene derivative usedorally for the therapy of female infertility.Owing to its antagonistic action at estrogenreceptors in the adenohypophysis, feedbackinhibition by estradiol of gonadotropin secretionis suppressed. The resulting increasein release of FSH induces augmented maturationof oocyte follicles. For instance, clomifenecan be used for the treatment of lutealphase defects associated with disturbancesof follicular maturation or the treatment ofpolycystic ovary syndrome. Since its use isconfined to a few selected days during theovarian cycle, chronic effects need not beconsidered.Tamoxifen is a stilbene derivative that isused in metastasizing breast cancer to blockthe estrogenic stimulus for tumor cellgrowth. As a mixed estrogenic antagonist/partial agonist, tamoxifen promotes ratherthan ameliorates climacteric complaints; atthe same time it displays agonistic featuresthat are of concern as a potential risk factorwhen use of the drug for the prophylaxis ofbreast cancer is being considered.Raloxifene is approved for use in thetreatment and prophylaxis of osteoporosis.Asshowninthetableopposite,ithasotherbeneficial as well as adverse effects.The estrogen receptor antagonist fulvestrantis devoid of agonist activities and, givenas a monthly injection may be used todelay progression of breast cancer. It causesdownregulation and degradation of the estrogenreceptor protein.Progestin receptor antagonist (B). Approximatelyone week after conception, the embryoimplants itself into the endometrium inthe form of the blastocyst. By secreting humanchorionic gonadotropin (HCG, mainlyLH), the trophoblast maintains the corpusluteum and secretion of progesterone andthereby prevents menstrual bleeding. Mifepristoneis an antagonist at progestin receptorsand prevents maintenance of the endometriumduring early pregnancy. Consequently,it acts as an abortifacient in earlypregnancy. Its use has provoked medical debates(comparison of adverse reactions tomifepristone vs. surgical intervention) andaroused ethical-ideological conflicts.

Antiestrogens and Antiprogestins 255A. Selective estrogen receptor modulators (SERM)ClClomifeneO CH2 CH2CH3C 2HNCH2NOHORaloxifeneOOHSCH3TamoxifenHypophysisFSHCH2CH3EstrogenCH3O CH2 CH2 NCH3OvaryEstradiolif no gestagen addedEndometrialcancer riskBreast cancer riskOvulationEstradiolAdvanced breast cancerTamoxifenQuestionable therapyand prophylaxisof osteoporosis inpostmenopauseRaloxifeneThromboembolismRelief of climactericcomplaintsBone massB. Gestagen receptor antagonistH 3 CCH 3NMifepristoneCH 3CCOHEmbryoHCGProgesteroneCorpusluteumMaintenance of endometriumOAbortion

256 Hormones Aromatase InhibitorsAromatase inhibitors constitute an additionalantiestrogenic principle that is basedupon inhibition of estrogen formation. Theyare used chiefly in the therapy of advancedbreast cancer when the tumor has becomeinsensitive to estrogen and the patient hascompleted menopause. However, one agentin this class (anastrozole) was recently licensedfor use in early breast cancer.Aromatase. The enzyme converts androgenssuch as testosterone and androstenedioneinto the estrogens estradiol and estrone. Thisreaction involves cleavage of the methylgroup at C10 and aromatization of ring A.Aromatase is a cytochrome P450-containingenzyme (isozyme CYP19). During the femalereproductive phase, the major portion of circulatingestrogens originates from the ovaries,where estradiol is synthesized in thegranulosa cells of the maturing tertiary follicles.Theca cells surrounding the granulosacells supply androgen precursors. FSH stimulatesformation of estrogens by inducingthe synthesis of aromatase in granulosa cells.An isoform of the enzyme 17β-hydroxysteroiddehydrogenase (17β-HSD 1) catalyzesthe conversion of androstenedione to testosteroneand of estrone to estradiol. Aftermenopause, ovarian function ceases. However,estrogens do not disappear completelyfrom the blood because they continue toenter the circulation from certain other tissues,in particular the subcutaneous adiposetissue, which produces estrone. In hormonedependentbreast cancers, tumor growth isthereby promoted. In addition, breast cancercells themselves may be capable of producingestrogens via aromatase.gonadal hormones. A drop in blood estradiolconcentration would lead to increased releaseof FSH with a compensatory increasein synthesis of aromatase and estrogens.Two groups of inhibitors can be distinguishedon the basis of chemical structureand mechanism of action. Steroidal inhibitors(formestane, exemestane) attach to the androgenbinding site on the enzyme and intheformofintermediaryproductsgiveriseto an irreversible inhibition of the enzyme.Nonsteroidal inhibitors (anastrozole, letrozole)attach to a different binding site ofthe enzyme; via their triazole ring they interactreversibly with the heme iron of cytochromeP450.Among the adverse effects, climacteric-likecomplaints predominate, reflecting the declineinestrogenlevels.UnliketheSERMs,tamoxifen, which is used for the same indication,aromatase inhibitors do not promoteendometrial growth and do not increase therisk of thromboembolic complications.Aromatase inhibitors serve to eliminate extraovariansynthesis of estrogens in breastcancer patients. This can be achieved effectivelyonly in postmenopause because, as anFSH-dependent enzyme, ovarian aromataseis subject to feedback regulation of female

Aromatase Inhibitors 257A. Aromatase inhibitorsTestosteroneOHOvariesFeedback-regulatedgonadotropin-dependentexpression in granulosa cellsEstradiolOHOAromataseHOOCYP 19OOAndrostenedioneExtragonadaltissues;expression also aftermenopauseHOEstroneBreast carcinomae.g.,Subcutaneousadipose tissueEstrogenstimulatedgrowthI n h i b i t o r si.m.FormestaneSteroidalONonsteroidalNAnastrozoleN N C NC CH 3CH 3OOHH 3 CC CCH 3NExemestaneONN NLetrozolep.o.OCH 2NCCN

258 Hormones Insulin FormulationsInsulin is synthesized in the B- (or β-) cells ofthe pancreatic islets of Langerhans. It is aprotein (MW 5800) consisting of two peptidechains linked by two disulfide bridges;the A chain has 21 and the B chain 30 aminoacids. Upon ingestion of carbohydrates, insulinis released into the blood and promotesuptake and utilization of glucose in specificorgans, namely, the heart, adipose tissue,and skeletal muscle.Insulin is used in the replacement therapyof diabetes mellitus.Sources of therapeutic insulin preparations(A). Porcine insulin differs from human insulinbyoneB-chainaminoacid.Owingtotheslightness of this difference, its biologicalactivity is similar to that of human hormone.Human insulin is produced by two methods:biosynthetically from porcine insulin,by exchanging the wrong amino acid; or bygene technology involving synthesis in E. colibacteria.Recombinant insulin is produced to modifypharmacokinetic properties (see below). It isimportant in these insulin analogues thatspecificity for the insulin receptor is preserved(e. g., also toward the receptor forIGF-1 = somatomedin C, which promotesproliferation of cells; p. 238).Control of delivery from injection site intoblood (B). As a peptide, insulin is unsuitablefor oral administration (owing to destructionby gastrointestinal proteases) and thusneeds to be given parenterally. Usually, insulinpreparations are injected subcutaneously.The duration of action depends onthe rate of absorption from the injection site.Variations in Dosage FormInsulin solution. Dissolved insulin is dispensedas a clear neutral solution known asregular (R) insulin or crystalline zinc insulin.In emergencies, such as hyperglycemic coma,it can be given intravenously (mostly by infusionbecause i.v. injections have too shortan action; plasma t ½ ~ 9 minutes). With theusual subcutaneous application, the effect isevident within 15–20 minutes, reaches apeak after ~ 3hours,andlastsfor~ 6hours.Insulin suspensions. When it is injected as asuspension of insulin-containing particles,dissolution and release of the hormone insubcutaneous tissue is retarded (extendedactioninsulins). Suitable particles can beobtained by precipitation of apolar, poorlywater-soluble complexes consisting ofanionic insulin and cationic partners, e. g.,the polycationic protein protamine. In thepresence of zinc ions, insulin crystallizes;crystal size determines the rate of dissolution.Intermediate-acting insulin preparations(NPH or isophane; Lente) act for 18–26hours, slow-acting preparations (protaminezinc, ultralente) for up to 36 hours.Variation in Amino Acid SequenceRapidly acting insulin analogues. After injectionof a regular insulin solution, insulinmolecules exist at the injection site in theform of hexameric aggregates. Only afterdisintegration into monomers can rapid diffusioninto the bloodstream occur. In insulinlispro, two amino acids are exchanged, resultingin a diminished propensity towardaggregate formation. Thus, diffusion fromthe injection site is faster, with rapid onsetand short duration of action. Insulin asparthassimilarproperties. Fast-actinginsulinsareinjected immediately before a meal, whereasregular insulin requires a 15–30 minute intervalbetween injection and food intake.Long-acting insulin analogues. The moreextensive alteration of amino acids in insulinglargine changes the electric charge of themolecule. At pH 4 of the injectate, it is dissolved;however, at the pH of tissue it ispoorly water-soluble and precipitates. Resolubilizationand diffusion into the bloodstreamtake about one day.

Insulin Formulations 259A. Human insulinB-chainPro Lys Thr29 3028C-terminusSubcutaneous insulin injectionSSAsn 21A-chainB. Control of release from injection site into bloodstreamHuman insulin solutionBloodstreamVariation in amino acid sequenceThr30Lys29Pro28InsulinsolutionHexamerDimersInsulin lisprosolutionThr30Pro29Lys28MonomersNo aggregateformationInsulin concentration in bloodInsulin concentration in blood0 6 12 18 h 0 6 12 18 hVariation in formulationVariation in amino acid sequenceInsulinsuspensionCrystalformationAdditionof zinc ionsInsulin concentration in bloodPrecipitationof crystalsTissue(pH 7)Insulinglarginesolution(pH 4)Gly21Arg32Arg31Thr30Lys29Pro280 6 12 18 h

260 Hormones Treatment of Insulin-dependentDiabetes MellitusPathogenesis and complications (A). Type Idiabetes mellitus typically manifests in childhoodor adolescence (juvenile onset diabetesmellitus); it is caused by the destruction ofinsulin-producing B cells in the pancreas. Agenetic predisposition together with a precipitatingfactor (viral infection) could startan autoimmune reaction against B-cells. Replacementof insulin (daily dose ~ 40 U,equivalent to ~ 1.6 mg) becomes necessary.Therapeutic objectives. (1) prevention oflife-threatening hyperglycemic (diabetic)coma; (2) prevention of diabetic sequelaearising from damage to small and largeblood vessels, precise “titration” of the patientbeing essential to avoid even shorttermspells of pathological hyperglycemia;(3) prevention of insulin overdosage leadingto life-threatening hypoglycemic shock (CNSdisturbance due to lack of glucose).Therapeutic principles. In healthy subjects,the amount of insulin is “automatically”matched to carbohydrate intake, hence toblood glucose concentration. The critical secretorystimulusistheriseinplasmaglucoselevel. Food intake and physical activity (increasedglucose uptake into musculature, decreasedinsulin demand) are accompanied bycorresponding changes in insulin secretion.Methods of insulin replacement (B). In thediabetic, insulin can be administered as it isnormally secreted. For instance, administrationof a long-acting insulin in the late eveninggenerates a basal level, whereas a fastacting insulin is used before meals. The doseneeded is determined on the basis of theactual blood glucose concentration measuredby the patient and the meal-dependentdemand. This regimen (so-called intensifiedinsulin therapy) provides the patient withmuch flexibility in planning daily activities.A well-educated, cooperative, and competentpatient is a precondition. In other cases,a fixed-dosage schedule (conventional insulintherapy) will be needed, e. g., with morningand evening injections of a combinationinsulin (a mixture of regular insulin plus insulinsuspension) in constant respective dosage(A). To avoid hypoglycemia or hyperglycemia,dietary carbohydrate (CH) intakemust be synchronized with the time courseof insulin absorption from the s.c. depot: dietcontrol!Caloricintakeistobedistributed(50% CH, 30% fat, 20% protein) in smallmealsoverthedaysoastoachieveasteadyCH supply—snacks, late night meal. Rapidlyabsorbable CH (sweets, cakes) must beavoided (hyperglycemic peaks) and replacedwith slowly digestible ones.Undesirable EffectsHypoglycemia is heralded by warning signs:tachycardia, unrest, tremor, pallor, profusesweating. Some of these are due to the releaseof glucose-mobilizing epinephrine.Counter-measures: glucose administration,rapidly absorbed CH orally (diabetics shouldalways have a suitable preparation withinreach) or 10–20 g glucose i.v. in case of unconsciousness;if necessary, injection of glucagon,the pancreatic hyperglycemic hormone.Allergic reactions are rare; locally, rednessmay occur at the injection site and atrophy ofadipose tissue; lipodystrophy). A possible locallipohypertrophy can be avoided by alternatinginjection sites.Even with optimal control of blood sugar, s.c. administration of insulin cannot fully replicatethe physiological situation. In healthysubjects, absorbed glucose and insulin releasedfrom the pancreas simultaneouslyreach the liver in high concentrations,whereby effective presystemic eliminationof both substances is achieved. In the diabetic,s.c. injected insulin is uniformly distributedin the body. Since insulin concentrationin blood supplying the liver cannot rise,less glucose is extracted from portal blood. Asignificant amount of glucose enters extrahepatictissues, where it has to be utilized.

Treatment of IDDM 261A. Diabetes mellitus type I: pathogenesis and complicationsGeneticdispositionEnvironmentalfactors, e.g.,viral infectionDiabetic comaDiabetic micro- andmacroangiopathyLate organ damageRetinopathyStroke!Autoimmunedestruction ofB-cells in isletsof LangerhansAbsolute insulindeficiencyHyperglycemiaNephropathyNeuropathyMyocardialinfarctionPeripheral obliteratingarterial diseaseB. Methods of insulin replacementExtended-actioninsulinBlood glucose measurementRapid-acting insulin:flexible time and dose22 244 8 121620 22Breakfast Lunch DinnerFood intake:flexible1. Intensified insulin therapyCombinationinsulinInsulin administration:fixed schedule4 8 12 16 20 244Breakfast Lunch Dinner& snacks2. Conventional insulin therapySupper8Food intake:fixed scheduleC. Presystemic and systemic insulin action in healthy and diabetic subjectsInsulinGlucoseHealthy subjectGlucoseDiabeticInsulin

262 Hormones Treatment of Maturity-Onset(Type II) Diabetes MellitusIn overweight adults, a diabetic metaboliccondition may develop (type II or non-insulin-dependentdiabetes) whenthereisarelativeinsulin deficiency—enhanced demandcannot be met by a diminishing insulin secretion.The cause of increased insulin requirementis an insulin resistance of target organs.The decrease in the effectiveness ofinsulin is due to a reduction in the densityof insulin receptors in target tissues and adecreased ef ciency of signal transduction ofinsulin-receptor complexes. Conceivably,obesity with increased storage of triglyceridescauses a decrease in insulin sensitivityof target organs. The loss in sensitivity can becompensated by enhancing insulin concentration.In panel (A), this situation is representedschematically by the decreased receptordensity. In the obese patient, themaximum binding possible (plateau ofcurve) is displaced downward, indicative ofthe reduction in receptor numbers. At lowinsulin concentrations, correspondingly lessbinding of insulin occurs, compared with thecontrol condition (normal weight). For a givenmetabolic effect (say, utilization of carbohydratescontained in a piece of cake), acertain number of receptors must be occupied.As shown by the binding curves(dashed lines), this can still be achieved witha reduced receptor number; although only ata higher concentration of insulin.Development of adult diabetes (B). Asubjectwith normal body weight (left) ingests aspecified amount of carbohydrate; to maintainblood glucose concentration within thephysiological range, the necessary amount ofinsulin is released into the blood. Comparedwith a normal subject, the overweight patientwith insulin resistance requires a continuallyelevated output of insulin (orangecurves) to avoid an excessive rise of bloodglucose levels (green curves) during anequivalent carbohydrate load. When the insulinsecretory capacity of the pancreasdecreases,thisisfirstnotedasariseinbloodglucose during glucose loading (latent diabetesmellitus). As insulin secretory capacitydeclines further, not even the fasting bloodlevel can be maintained (manifest, overt diabetes).Treatment. Caloric restriction to restorebody weight to normal is associated withan increase in insulin responsiveness, evenbefore a normal weight is reached. Moreover,physical activity is important becauseit enhances peripheral utilization of glucose.When changes in lifestyle are insuf cient incorrecting the diabetic condition, therapywith oral antidiabetics is indicated (p. 264).Therapy of first choice is weight reduction,not administration of drugs!A metabolic syndrome is said to bepresentwhenatleastthreeofthefollowingfive risk factors can be identified in a patient:1. Elevated blood glucose levels2. Elevated blood lipid levels3. Obesity4. Lowered HDL levels5. HypertensionOverweight and resistance to insulin appearto play pivotal roles in the pathophysiologicalprocess. The resulting hyperinsulinemiainduces a rise in systemic arterial blood pressureand probably also a hyperglyceridemiaassociated with an unfavorable LDL/HDLquotient. This combination of risk factorslowers life expectancy and calls for therapeuticintervention. The metabolic syndromehas a high prevalence; in industrializedcountries, up to 20% of adults are believedto suffer from it.

Treatment of Maturity-Onset Diabetes Mellitus 263A. Insulin concentration and binding in normal and overweight subjectsInsulin bindingNormal receptor numberInsulin receptorbindingneededfor euglycemiaNormaldietDecreasedreceptornumberInsulin concentrationObesityB. Development of maturity-onset diabetesOralantidiabeticGlucose in blood Insulin releaseTimeWeight reductionTherapy of 1st choiceDiagnosis:latentovertDiabetes mellitusTherapy of 2nd choice

264 Hormones Oral AntidiabeticsIn principle, the blood concentration of glucoserepresents a balance between influxinto the bloodstream (chiefly from liverandintestines)andegressfrombloodintoconsuming tissues and organs. In (A), drugsavailable for lowering an elevated level ofglucose are grouped schematically in relationto these two processes.Metformin is a biguanide derivative thatcan normalize an elevated blood glucose level,provided that insulin is present. Themechanism underlying this effect is notcompletely understood. Decreased glucoserelease from the liver appears to play anessential part. Metformin does not increaserelease of insulin and therefore does notpromote hyperinsulinemia. The risk of hypoglycemiais relatively less common. Triglycerideconcentrations can decrease. Metforminhas proved itself as a monotherapeuticinobesetypeIIdiabetics.Itcanbecombinedwith other oral antidiabetics as well as insulin.Frequent adverse effects include anorexia,nausea, and diarrhea. Overproductionof lactic acid (lactate acidosis) is a rare, potentiallyfatal reaction. It is contraindicatedin renal insuf ciency and therefore shouldbe avoided in elderly patients.Oral antidiabetics of the sulfonylureatype increase the release of insulin frompancreatic B-cells. They inhibit ATP-gatedK + channels and thereby cause depolarizationof the B-cell membrane. Normally, thesechannels are closed when intracellular levelsof glucose, and hence of ATP, increase. Thisdrug class includes tolbutamide (500–2000 mg/day) and glyburide (glibenclamide)(1.75–10.5 mg/day). In some patients,it is not possible to stimulate insulin secretionfrom the outset; in others, therapy failslater. Matching of dosage of the oral antidiabeticandcaloricintakeisnecessary.Hypoglycemiais the most important unwantedeffect. Enhancement of the hypoglycemic effectcan result from drug interactions: displacementof antidiabetic drug from plasmaprotein binding sites, for example, by sulfonamidesor acetylsalicylic acid.Repaglinide possesses the same mechanismof action as the sulfonylureas but differsin chemical structure. After oral administration,the effect develops rapidly andfades away quickly. Therefore, repaglinidecan be taken immediately before a meal.“Glitazone” is an appellation referring tothiazolidinedione derivatives such as rosiglitazoneand pioglitazone. These substancesaugment the insulin sensitivity of target tissues.They are agonists at the peroxisomeproliferator-activated receptor of the γ subtype(PPARγ), a transcription-regulating receptor.As a result, they (a) promote thematuration of preadipocytes into adipocytes,(b) increase insulin sensitivity, and (c) enhancecellular glucose uptake. Besides fattissue, skeletal muscle is also affected.Rosiglitazone and pioglitazone are approvedonly for combination therapy whenadequate glycemic control cannot beachieved with either metformin or a sulfonylureaalone. A combination with insulin iscontraindicated. Adverse effects includeweight gain and fluid retention (thus contraindicationfor any stage of congestive heartfailure). Hepatic function requires closemonitoring (withdrawal of troglitazone becauseof fatal liver failure).Acarbose is an inhibitor of α-glucosidase(localized in the brush border of intestinalepithelium), which liberates glucose fromdisaccharides. It retards breakdown of carbohydrates,and hence absorption of glucose.Owing to increased fermentation of carbohydratesby gut bacteria, flatulence and diarrheamay develop. Miglitol has a similar effectbut is absorbed from the intestine.

Oral Antidiabetics 265A. Oral antidiabeticsMetformin, a biguanide derivativeLiverH 3CNCH 3HN CNHC NHNH 2Inhibition ofhepatic glucose releaseLactic acidosisOCGlibenclamide, a sulfonylurea derivativeONHNHB-cellsof pancreasK+HypoglycemiaSO 2 CH 2 CH 2 NH CBlockadeInsulin secretionInsulinATPH 3COGlucoseClATP-gatedK+-channelK+Membranepotential depolarizedInfluxGlucoseconcentrationin bloodEgressIntestinesAcarbose, a “false”tetrasaccharideDisaccharideGlucoseα-GlucosidaseRosiglitazone, a thiazolidinedione derivativeNNH 3CCH 2CH 2PPARγOC 2HOSPre-adipocytesNHAdipocytesInsulin sensitivityOretards enteralabsorption of glucoseFatty tissueDNAGlucose uptakeIntestinal complaintsWeight gainContraindication in congestiveheart failure, NYHA 1–4

266 Hormones Drugs for Maintaining CalciumHomeostasisAt rest, the intracellular concentration of freecalcium ions (Ca 2+ )iskeptat0.1µm (seep.132 for mechanisms involved). During excitation,a transient rise of up to 10 µm elicitscontraction in muscle cells (electromechanicalcoupling) and secretion in glandular cells(electrosecretory coupling). The cellular contentof Ca 2+ is in equilibrium with the extracellularCa 2+ concentration (~ 1000 µm), as isthe plasma protein-bound fraction of calciumin blood. Ca 2+ may crystallize with phosphateto form hydroxyapatite, the mineral of bone.Osteoclasts are phagocytes that mobilize Ca 2+by resorption of bone. Slight changes in extracellularCa 2+ concentration can alter organfunction: thus, excitability of skeletal muscleincreases markedly as Ca 2+ is lowered (e. g., inhyperventilationtetany).Threehormonesareavailable to the body for maintaining a constantextracellular Ca 2+ concentration.Vitamin D hormone is derived from vitaminD (cholecalciferol).VitaminDcanalsobeproduced in the body; it is formed in the skinfrom dehydrocholesterol during irradiationwith UV light. When there is lack of solarradiation, dietary intake becomes essential,cod liver oil being a rich source. Metabolicallyactive vitamin D hormone results from twosuccessive hydroxylations: in the liver at position25 (†calcifediol) and in the kidney atposition 1 (†calcitriol = vitamin D hormone).1-Hydroxylation depends on the level of calciumhomeostasis and is stimulated byparathormone and a fall in plasma levels ofCa 2+ and phosphate. Vitamin D hormone promotesenteral absorption and renal reabsorptionof Ca 2+ and phosphate. As a result of theincreased Ca 2+ and phosphate concentrationin blood, there is an increased tendency forthese ions to be deposited in bone in the formof hydroxyapatite crystals. In vitamin D deficiency,bone mineralization is inadequate(rickets, osteomalacia). Therapeutic useaims at replacement. Mostly, vitamin D is given;in liver disease, calcifediol may be indicated,in renal disease, calcitriol. Effectiveness,aswellasrateofonsetandcessationofaction increase in the order vitamin D < 25-OH-vitamin D < 1,25-di-OH vitamin D. Overdosagemay induce hypercalcemia with depositsof calcium salts in tissues (particularlyin kidney and blood vessels): calcinosis.The polypeptide parathormone is releasedfrom the parathyroid glands whenthe plasma Ca 2+ level falls. It stimulates osteoclaststo increase bone resorption; in thekidneys it promotes calcium reabsorption,while phosphate excretion is enhanced. Asblood phosphate concentration diminishes,the tendency of Ca 2+ to precipitate as bonemineral decreases. By stimulating the formationof vitamin D hormone, parathormonehas an indirect effect on the enteral uptakeof Ca 2+ and phosphate. In parathormone deficiency,vitamin D can be used as a substitutethat, unlike parathormone, is effectiveorally. Teriparatide is a recombinant shortenedparathormone derivative containingthe portion required for binding to the receptor.It can be used in the therapy of postmenopausalosteoporosis and promotesbone formation. While this effect seems paradoxicalin comparison with hyperparathyroidism,it obviously arises from the specialmode of administration: the once daily s.c.injection generates a quasi-pulsatile stimulation.Additionally, adequate intake of calciumand vitamin D must be ensured.The polypeptide calcitonin is secreted bythyroid C-cells during imminent hypercalcemia.It lowers elevated plasma Ca 2+ levels byinhibiting osteoclast activity. Its uses includehypercalcemia and osteoporosis. Remarkably,calcitonin injection may produce a sustainedanalgesic effect that alleviates painassociated with bone diseases (Paget disease,osteoporosis, neoplastic metastases)or Sudek syndrome.Hypercalcemia can be treated by (1) administering0.9% NaCl solution plus furosemide(if necessary) † renal excretion ⁄; (2)the osteoclast inhibitors calcitonin and clodronate(a biphosphonate) † bone Ca mobilizationø;(3) glucocorticoids.

Drugs for Maintaining Calcium Homeostasis 267A. Calcium homeostasis of the bodyMuscle cellCa 2+Electricalexcitability~ 1 x 10-7 MGland cell~ 10-5 MEffect on cell function1 x 10 -3 M Ca 2+ + PO 43-Ca~ 1 x 10-3 MBone trabeculaeHydroxyapatite crystalsCa 10 (PO 4 ) 6 (OH) 2Osteoclast2525OHOHCa 2+ Ca 2+ContractionSecretionAlbuminGlobulinSkinParathyroid hormone, Ca 2 + , PO 43-17HO7-DehydrocholesterolCH 2CH 2H 2 CHO1HOOHCholecalciferol(vitamin D 3 )50 – 5000 µg/day25-Hydroxycholecalciferol(calcifediol)50 – 2000 µg/day1,25-Dihydroxycholecalciferol(calcitriol)0.5 – 2 µg/dayCod liver oilVit. D-HormoneParafollicularcells ofthyroidParathyroidglandsCalcitoninParathyroidhormoneCa 2 + + PO43-

268 Antibacterial Drugs Drugs for Treating BacterialInfectionsWhen bacteria overcome the cutaneous ormucosal barriers and penetrate into bodytissues, a bacterial infection is present. Frequentlythe body succeeds in removing theinvaders, without outward signs of disease,by mounting an immune response. However,certain pathogens have evolved a sophisticatedcounterstrategy. Although they aretaken up into host cells via the regularphagocytotic pathway, they are able to forestallthe subsequent fusion of the phagosomewith a lysosome and in this mannercan escape degradation. Since the wall of thesheltering vacuole is permeable to nutrients(amino acids, sugars), the germs are able togrow and multiply until the cell dies and thereleased pathogens can infect new host cells.This strategy is utilized, e. g., by Chlamydiaand Salmonella species, Mycobacterium tuberculosis,Legionella pneumophila, Toxoplasmagondii, andLeishmania species. It is easyto see that targeted pharmacotherapy is especiallydif cult in such cases because thedrug cannot reach the pathogen until it hassurmounted first the cell membrane andthen the vacuolar membrane. If bacteriamultiply faster than the body’s defensescan destroy them, infectious disease develops,with inflammatory signs, e. g., purulentwound infection or urinary tract infection.Appropriate treatment employs substancesthat injure bacteria and thereby preventtheir further multiplication, without harmingcells of the host organism (1).Specific damage to bacteria is particularlyfeasible when a substance interferes with ametabolic process that occurs in bacterialbut not in host cells. Clearly this applies toinhibitors of cell wall synthesis, since humanor animal cells lack a cell wall. The points ofattack of antibacterial agents are schematicallyillustrated in a grossly simplified bacterialcell, as depicted in (2).In the following sections, plasmalemmadamagingpolymyxins and tyrothricin arenot considered further. Because of their poortolerability, they are suitable only for topicaluse.The effect of antibacterial drugs can beobserved in vitro (3). Bacteria multiply in agrowth medium under controlled conditions.If the medium contains an antibacterialdrug, two results can be discerned: (a)bacteria are killed—bactericidal effect; or(b) bacteria survive, but do not multiply—bacteriostatic effect. Although variationsmay occur under therapeutic conditions,the different drugs can be classified accordingto their primary mode of action (colortone in 2 and 3).When bacterial growth remains unaffectedby an antibacterial drug, bacterial resistanceis present. This may occur becauseof certain metabolic characteristics that confera natural insensitivity to the drug on aparticular strain of bacteria (natural resistance).Dependingonwhetheradrugaffectsonly few or numerous types of bacteria, theterms narrow-spectrum (e. g., penicillin G)or broad-spectrum (e. g., tetracyclines)antibiotic are applied. Naturally susceptiblebacterial strains can be transformed underthe influence of antibacterial drugs into resistantones (acquired resistance), when arandom genetic alteration (mutation) givesrise to a resistant bacterium. Under the influenceof the drug, the susceptible bacteriadieoff,whereasthemutantmultipliesunimpeded.The more frequently a given drugisapplied,themoreprobabletheemergenceof resistant strains (e. g., hospital strains withmultiple resistance)!Resistance can also be acquired when DNAresponsible for nonsusceptibility (so-calledresistance plasmid) ispassedonfromotherresistant bacteria by conjugation or transduction.

Drugs for Treating Bacterial Infections 269A. Principles of antibacterial therapyBacterialinvasion:infectionAntibacterialdrugs1.ImmunedefensesSelectiveantibacterialtoxicityBody cellsBacteriaPenicillinsCephalosporinsBacitracinVancomycinPolymyxinsTyrothricinCell wallTetrahydrofolatesynthesisDNARNAProteinCellmembrane2.BacteriumSulfonamidesTrimethoprim“Gyrase-inhibitors”NitroimidazolesRifampicinTetracyclinesAminoglycosidesChloramphenicolErythromycinClindamycin1 dayResistanceAntibioticInsensitive strainBactericidal3.BacteriostaticSensitive strain withresistant mutantSelection

270 Antibacterial Drugs Inhibitors of Cell Wall SynthesisIn most bacteria, a cell wall surrounds thecell like a rigid shell that protects againstnoxious outside influences and preventsrupture of the plasma membrane from ahigh internal osmotic pressure. The structuralstability of the cell wall is due mainly tothe murein (peptidoglycan) lattice. Thisconsists of basic building blocks linked togetherto form a large macromolecule. Eachbasic unit contains the two linked aminosugarsN-acetylglucosamine and N-acetylmuramicacid; the latter bears a peptidechain. The building blocks are synthesizedin the bacterium, transported outwardthrough the cell membrane, and assembledas illustrated schematically. The enzymetranspeptidase cross-links the peptidechains of adjacent aminosugar chains.Inhibitors of cell wall synthesis are suitableantibacterial agents because animal, includinghuman, cells lack a cell wall. Theseagents exert a bactericidal action on growingormultiplyinggerms.Membersofthisclass include β-lactam antibiotics such as thepenicillins and cephalosporins, in addition tobacitracin and vancomycin.Penicillins (A). The parent substance of thisgroup is penicillin G (benzylpenicillin).Itisobtained from cultures of mold fungi, originallyfrom Penicillium notatum. Penicillin Gcontains the basic structure common to allpenicillins, 6-aminopenicillanic acid (6-APA; p. 273) comprising a thiazolidine anda4-memberedβ-lactam ring. 6-APAitselflacks antibacterial activity. Penicillins disruptcell wall synthesis by inhibiting transpeptidase.When bacteria are in theirgrowth and replication phase, penicillinsare bactericidal; as a result of cell wall defects,the bacteria swell and burst.Penicillins are generally well tolerated;with penicillin G, the daily dose can rangefrom approx. 0.6 g i.m. (= 10 6 internationalunits, 1 Mega IU [MIU]) to 60 g by infusion.The most important adverse effects are dueto hypersensitivity (incidence up to 5%), withmanifestations ranging from skin eruptionsto anaphylactic shock (in less than 0.05% ofpatients). Known penicillin allergy is a contraindicationfor these drugs. Because of anincreased risk of sensitization, penicillinsmust not be used locally. Neurotoxic effects,mostly convulsions due to GABA antagonism,may occur if the brain is exposed toextremely high concentrations, e. g., afterrapid i.v. injection of a large dose or intrathecalinjection.Penicillin G undergoes rapid renal eliminationmainly in unchanged form (plasmat ½ ~ 0.5 hours). The duration of the effectcan be prolonged by:1. Use of higher doses, enabling plasma levelsto remain above the minimally effectiveantibacterial concentration.2. Combination with probenecid. Renal eliminationof penicillin occurs chiefly via theanion (acid)-secretory system of the proximaltubule (–COOH of 6-APA). The acidprobenecid (p. 326) competes for thisroute and thus retards elimination of penicillin.3. Intramuscular administration in depotform. In its anionic form (–COO – )penicillinG forms poorly water-soluble saltswith substances containing a positivelycharged amino group (procaine; clemizole,an antihistaminic; benzathine, dicationic).Depending on the substance, releaseofpenicillinfromthedepotoccursover a variable interval.

Inhibitors of Cell Wall Synthesis 271A. Penicillin G: structure and origin; mode of action of penicillins; methodsfor prolonging duration of actionCell wallCell membraneBacteriumCross-linked bytranspeptidaseInhibition ofcell wall synthesisAmino acidchainSugarCell wallbuilding blockOHumanC 2 CHNHSCH 3AntibodyPenicillin GONCH 3COOHPenicillinallergyFungusPenicillium notatumNeurotoxicityat veryhigh dosagePlasma concentration3 x DosePenicillinProcainePenicillin+-MinimalbactericidalconcentrationTimeIncreasing the doseProbenecidAnionsecretorysystemCombination with probenecidDuration of action (d)+-~ 1 ~ 2~ 7–28ClemizolePenicillin++-Benzathine2 PenicillinsDepot preparations

272 Antibacterial DrugsAlthough very well tolerated, penicillin Ghas disadvantages (A) that limit its therapeuticusefulness: (1) it is inactivated bygastric acid, which cleaves the β-lactam ring,necessitating parenteral administration. (2)The β-lactam ring can also be opened bybacterial enzymes (β-lactamases); in particular,penicillinase, which can be produced bystaphylococcal strains, renders them resistantto penicillin G. (3) The antibacterialspectrum is narrow; although it encompassesmany Gram-positive bacteria, Gramnegativecocci, and spirochetes, many Gramnegativepathogens are unaffected.Derivatives with a different substituenton 6-APA possess advantages (B):1. Acid resistance permits oral administration,provided that enteral absorption ispossible. All derivatives shown in (B) canbe given orally. Penicillin V (phenoxymethylpenicillin)exhibits antibacterial propertiessimilar to those of penicillin G.2. Owing to their penicillinase resistance,isoxazolylpenicillins (oxacillin, dicloxacillin,floxacillin) are suitable for the (oral) treatmentof infections caused by penicillinase-producingstaphylococci.3. Extended-activity spectrum: The aminopenicillinamoxicillin is active againstmany Gram-negative organisms, e. g.,colibacteria or Salmonella typhi. Itcanbeprotected from destruction by penicillinaseby combination with inhibitors ofpenicillinase (clavulanic acid, sulbactam,tazobactam).The structurally close congener ampicillin(no 4-hydroxy group) has a similar activityspectrum. However, because it is poorly absorbed(

Inhibitors of Cell Wall Synthesis 273A. Disadvantages of penicillin G6-Aminopenicillanic acidOPenicillin GAcid sensitivityCH 2CNHONSCH 3CH 3COOHPenicillinasesensitivityPenicillinaseStaphylococciSalmonella typhiNarrow-action spectrumE. coliTreponemapallidumActiveGram-positive Gram-negativeNot activeGonococciPneumococciStreptococciB. Derivatives of penicillin GAcidPenicillinaseSpectrumConcentration neededto inhibit penicillin G-sensitive bacteriaOO CH2 C NHPenicillin VOS CH3NCH3COOHResistantSensitiveNarrowNOCH3OC NHOxacillinONSCH3CH3COOHResistantResistantNarrowHOOCH C NHNH 2OAmoxicillinNSCH3CH3COOHH + Cl - Resis-ResistantSensitiveBroadC. CephalosporinOCH CNH 2CefalexinNHOSNCH3COOHtantResistant,but sensitive tocephalosporinaseBroad

274 Antibacterial Drugs Inhibitors of TetrahydrofolateSynthesisTetrahydrofolic acid (THF) is a coenzyme inthe synthesis of purine bases and thymidine.These are constituents of DNA and RNA andare required for cell growth and replication.Lack of THF leads to inhibition of cell proliferation.Formation of THF from dihydrofolate(DHF) is catalyzed by the enzyme dihydrofolatereductase. DHF is made from folicacid, a vitamin that cannot be synthesized inthe body but must be taken up from exogenoussources. Most bacteria do not have arequirement for folate, because they are capableof synthesizing it—more preciselyDHF—from precursors. Selective interferencewith bacterial biosynthesis of THF canbe achieved with sulfonamides and trimethoprim.Sulfonamides structurally resemble p-aminobenzoic acid (PABA), a precursor inbacterial DHF synthesis. As false substrates,sulfonamides competitively inhibit utilizationof PABA, and hence DHF synthesis. Becausemostbacteriacannottakeupexogenousfolate, they are depleted of DHF. Sulfonamidesthus possess bacteriostatic activityagainst a broad spectrum of pathogens.Sulfonamides are produced by chemical synthesis.The basic structure is shown in (A).Residue R determines the pharmacokineticproperties of a given sulfonamide. Most sulfonamidesare well absorbed via the enteralroute. They are metabolized to varying degreesand eliminated through the kidney.Rates of elimination, hence duration of effect,may vary widely. Some members arepoorly absorbed from the gut and are thussuitable for the treatment of bacterial bowelinfections. Adverse effects may include allergicreactions, sometimes with severe skindamage (p. 74), and displacement of otherplasma protein-bound drugs or bilirubin inneonates (danger of kernicterus, hence contraindicationfor the last weeks of gestationand in the neonate). Because of the frequentemergence of resistant bacteria, sulfonamidesare now rarely used. Introduced in1935, they were the first broad-spectrumchemotherapeutics.Trimethoprim inhibits bacterial DHF reductase,the human enzyme being significantlyless sensitive than the bacterial one(rarely, bone marrow depression). A 2,4-diaminopyrimidine, trimethoprim has bacteriostaticactivity against a broad spectrumof pathogens. It is used mostly as a componentof co-trimoxazole.Co-trimoxazole is a combination of trimethoprimand the sulfonamide sulfomethoxazole.Since THF synthesis is inhibited at twosuccessive steps, the antibacterial effect ofco-trimoxazole is better than that of the individualcomponents. Resistant pathogensare infrequent; a bactericidal effect may occur.Adverse effects correspond to those ofthe components.Sulfasalazine. Although originally developedas an antirheumatic agent (p. 332),sulfasalazine (salazosulfapyridine) is usedmainly in the treatment of inflammatorybowel disease (ulcerative colitis and terminalileitis or Crohn disease). Gut bacteriasplit this compound into the sulfonamidesulfapyridine and mesalazine (5-aminosalicylicacid). The latter is probably the antiinflammatoryagent (inhibition of prostaglandinand leukotriene synthesis, of chemotacticsignals for granulocytes, and of H 2 O 2formationinmucosa),butmustbepresenton the gut mucosa in high concentrations.Coupling to the sulfonamide prevents prematureabsorption in upper small-bowelsegments. The cleaved-off sulfonamide canbe absorbed and may produce typical adverseeffects (see above). Delayed release(prodrug) formulations of mesalazine withoutthe sulfonamide moiety are available.

Inhibitors of Tetrahydrofolate Synthesis 275A. Inhibitors of tetrahydrofolate synthesisHOHOHNCNSNHOHHORp-Aminobenzoic acidSulfonamidesFolic acidR determinespharmacokinetics(Vitamin)Dihydrofolicacid(DHF)HONCH H 2 CNHH N NHOOC CHCH 2N OHHOOCNCH 2H 2 NOCH 3H 3 COOCH 3Duration of effectSulfisoxazole6 hoursSulfamethoxazole12 hoursSulfalene7 daysDosing intervalDHF-ReductaseCH 2Co-trimoxazole =Tetrahydro- folic acidHHNH H 2 CHNNH 2 NSynthesis ofpurinesThymidineNNHOHNH 2 NBacteriumNNH 2TrimethoprimCombination ofTrimethoprim andSulfamethoxazoleSulfasalazine(not absorbable)HOOCO HHO N N S NOCleavage byintestinal bacteriaNHuman cellMesalamine Sulfapyridine(absorbable)

276 Antibacterial Drugs Inhibitors of DNA FunctionDeoxyribonucleic acid (DNA) serves as atemplate for the synthesis of nucleic acids.Ribonucleic acid (RNA) executes protein synthesisand thus permits cell growth. Synthesisof new DNA is a prerequisite for celldivision. Substances that inhibit reading ofgenetic information at the DNA templatedamage the regulatory center of cell metabolism.The substances listed below are usefulas antibacterial drugs because they do notaffect human cells.Gyrase inhibitors. Theenzymegyrase(topoisomeraseII) permits the orderly accommodationof a ~ 1000 µmlongbacterialchromosomein a bacterial cell of ~ 1 µm. Withinthe chromosomal strand, double-strandedDNA has a double helical configuration. Theformer, in turn, is arranged in loops that areshortened by supercoiling. The gyrase catalyzesthisoperation,asillustrated,byopening,underwinding, and closing of the DNAdouble strand such that the full loop neednot be rotated.Derivatives of 4-quinolone-3-carboxylicacid (green portion of ofloxacin formula)are inhibitors of bacterial gyrases. They appearto prevent specifically the resealing ofopened strands and thereby act bactericidally.These agents are absorbed after oralingestion. The older drug nalidixic acid affectsexclusively Gram-negative bacteriaand attains effective concentrations only inurine; it is used as a urinary tract antiseptic.Norfloxacin has a broader spectrum. Ofloxacin,ciprofloxacin, enoxacin, and others, alsoyield systemically effective concentrationsand are used for infections of internal organs.Besides gastrointestinal problems and allergy,adverse effects particularly involve theCNS (confusion, hallucinations, and seizures).Since they can damage epiphysealchondrocytes and joint cartilages in laboratoryanimals, gyrase inhibitors should not beused during pregnancy, lactation, and periodsof growth. Tendon damage includingrupture may occur in elderly or glucocorticoid-treatedpatients. In addition, hepaticdamage, prolongation of the QT-intervalwith risk of arrhythmias, and phototoxicityhave been observed.Nitroimidazole derivatives, suchasmetronidazole,damage DNA by complex formationor strand breakage. This occurs in obligateanaerobic bacteria. Under these conditions,conversion to reactive metabolitesthat attack DNA takes place (e. g., the hydroxylamineshown). The effect is bactericidal.A similar mechanism is involved in theantiprotozoal action on Trichomonas vaginalis(causative agent of vaginitis and urethritis)and Entamoeba histolytica (causativeagent of large-bowel inflammation, amebicdysentery, and hepatic abscesses). Metronidazoleis well absorbed via the enteral route;it is also given i.v. or topically (vaginal insert).Because metronidazole is consideredpotentially mutagenic, carcinogenic, and teratogenicin humans, it should not be used forlongerthan10days,ifpossible,andshouldbe avoided during pregnancy and lactation.Timidazole may be considered equivalent tometronidazole.Rifampin (rifampicin) inhibits the bacterialenzyme that catalyses DNA template-directedRNA transcription, i. e., DNA-dependentRNA polymerase. Rifampin acts bactericidallyagainst mycobacteria (Mycobacteriumtuberculosis, M. leprae), as well as manyGram-positive and Gram-negative bacteria.It is well absorbed after oral ingestion. Becauseresistancemaydevelopwithfrequentusage, it is restricted to the treatment oftuberculosis and leprosy (p. 282). Rifampinis contraindicated in the first trimester ofgestation and during lactation.Rifabutin resembles rifampin but may beeffective in infections resistant to rifampin.

Inhibitors of DNA Function 277A. Antibacterial drugs acting on DNA1234Twisting byopening, underwinding,and closureof DNA strandH3 CNFNOONCH 3COOHGyrase inhibitors4-Quinolone-3-carboxylatederivatives, e.g.,ofloxacinGyraseDNA double helixIndication: TBBacterialchromosomeDNA-dependentRNA polymeraseRifampicinStreptomycesspeciesDamageto DNARNATrichomonas infectionHOHNNNCH 3CH 2 CH 2OHNitroimidazoleNO 2 NNCH 3CH 2 CH 2Amebic infectionAnaerobicbacteriaOHe. g., metronidazole

278 Antibacterial Drugs Inhibitors of Protein SynthesisProtein synthesis means translation into apeptide chain of a genetic message first transcribedinto mRNA. Amino acid (AA) assemblyoccurs at the ribosome. Delivery of aminoacidstomRNAinvolvesdifferenttransferRNAmolecules (tRNA), each of which binds a specificAA. Each tRNA bears an “anticodon” nucleobasetriplet that is complementary to aparticular mRNA coding unit (codon, consistingof three nucleobases).Incorporation of an AA normally involvesthe following steps (A):1. The ribosome “focuses” two codons onmRNA; one (at the left) has bound itstRNA–AA complex, the AA having alreadybeen added to the peptide chain; the other(at the right) is ready to receive thenext tRNA–AA complex.2. After the latter attaches, the AAs of the twoadjacent complexes are linked by the actionof the enzyme peptide synthetase(peptidyltransferase). Concurrently, AAand tRNA of the left complex disengage.3. The left tRNA dissociates from mRNA. Theribosome can advance along the mRNAstrand and focus on the next codon.4. Consequently, the right tRNA–AA complexshifts to the left, allowing the next complexto be bound at the right.Theseindividualstepsaresusceptibletoinhibitionby antibiotics of different groups.The examples shown originate primarilyfrom Streptomyces species, some of the aminoglycosidesalso being derived from Micromonosporabacteria. 11a. Tetracyclines inhibit the binding oftRNA–AA complexes. Their action is bacteriostaticand affects a broad spectrum ofpathogens._1 A note on spelling: the termination -mycindenotes origin from Streptomyces species; -micin(e. g., gentamicin) denotes origin from Micromonosporaspecies.1b. Aminoglycosides induce the binding of“wrong” tRNA–AA complexes, resulting insynthesis of false proteins. Aminoglycosidesare bactericidal. Their activity spectrum encompassesmainly Gram-negative organisms.Streptomycin and kanamycin are usedpredominantly in the treatment of tuberculosis.2. Chloramphenicol inhibits peptide synthetase.It has bacteriostatic activity against abroadspectrumofpathogens.Thechemicallysimple molecule is now produced synthetically.3. Macrolides suppresses advancement ofthe ribosome. Their action is predominantlybacteriostatic and is directed mainly againstGram-positive organisms. Intracellulargerms such as chlamydias and mycoplasmsare also affected. Macrolides are effectiveorally. The prototype of this group is erythromycin.Among other uses, it is suitable as asubstitute in allergy or resistance to penicillin.Clarithromycin, roxithromycin and azithromycinare erythromycin derivatives withsimilar activity; however, their elimination isslower and, therefore, permits reduction indosage and less frequent administration.Gastrointestinal disturbances may occur. Becauseof inhibition of CYP isozymes (CY-P3A4) the risk of drug interactions ispresent. Telithromycin is a semisyntheticmacrolide with a modified structure (“ketolide”).Ithasadifferentpatternofresistancethat is attributed to interaction with an additionalribosomal binding site.Lincosamides. Clindamycin has antibacterialactivity similar to that of erythromycin. Itexerts a bacteriostatic effect mainly onGram-positive aerobic, as well as on anaerobicpathogens. Clindamycin is a semisyntheticchloro analogue of lincomycin, whichderives from a Streptomyces species. Takenorally, clindamycin is better absorbed thanlincomycin, has greater antibacterial ef cacyandisthuspreferred.Bothpenetratewellinto bone tissue.

Inhibitors of Protein Synthesis 279A. Protein synthesis and modes of action of antibacterial drugsRibosomemRNATetracyclinesH3CCH3H3CHO NOHOCOH O HO O H ONH 2DoxycyclinetRNAAmino acidInsertion ofincorrectamino acidHOH2CNH2OOH2NOHHOOONH2NH2OHCH2OHPeptide chainAminoglycosidesNH2TobramycinOHO2NCHCH CH2 OHNHOCCHCl2ChloramphenicolPeptidesynthetaseChloramphenicolCH3HOH3CNCH3MacrolidesH3C OCH3 OOHOOHOHH3C O CH3H3COCH3H3C H2C O O H3C OHCH3 OCH3ErythromycinStreptomyces species

280 Antibacterial Drugs4. Oxazolidinones, suchaslinezolide, areanewly discovered drug group (p. 281). Theyinhibit initiation of synthesis of a new peptidestrand at the point where ribosome,mRNA, and the “start-tRNA–AA” complexaggregate. Oxazolidinones exert a bacteriostaticeffect on Gram-positive bacteria. Sincebone marrow depression has been reported,hematological monitoring is necessary.Tetracyclines are absorbed from the gastrointestinaltract to differing degrees, dependingon the substance, absorption beingnearly complete for doxycycline and minocycline.Intravenous injection is rarely needed(rolitetracycline is available only for i.v. administration).The most common unwantedeffect is gastrointestinal upset (nausea, vomiting,diarrhea, etc.) due to (1) a direct mucosalirritant action of these substances and(2) damage to the natural bacterial gut flora(broad-spectrum antibiotics) allowing colonizationby pathogenic organisms, includingCandida fungi. Concurrent ingestion of antacidsor milk would, however, be inappropriatebecause tetracyclines form insolublecomplexes with plurivalent cations (e. g., Ca 2+ ,Mg 2+ ,Al 3+ ,Fe 2+/3+ ) resulting in their inactivation;that is, absorbability, antibacterialactivity, and local irritant action are abolished.The ability to chelate Ca 2+ accountsfor the propensity of tetracyclines to accumulatein growing teeth and bones. As aresult, there occurs an irreversible yellowbrowndiscoloration of teeth and a reversibleinhibition of bone growth. Because of theseadverse effects, tetracycline should not begiven after the second month of pregnancyand not prescribed to children aged 8 yearsand under. Other adverse effects are increasedphotosensitivity of the skin and hepaticdamage, mainly after i.v. administration.brain barrier. Despite these advantageousproperties, use of chloramphenicol is onlyrarely indicated (e. g., in CNS infections) becauseof the danger of bone marrow damage.Two types of bone marrow depression canoccur: (1) a dose-dependent, toxic, reversibleform manifested during therapy, and (2)a frequently fatal form that may occur after alatency of weeks and is not dose-dependent.Owing to high tissue penetrability, the dangerof bone marrow depression must be takeninto account even after local use (e. g., eyedrops).Aminoglycoside antibiotics consist of glycoside-linkedamino sugars (cf. gentamicin C 1a ,a constituent of the gentamicin mixture).They contain numerous hydroxyl groupsand amino groups that can bind protons.Hence,thesecompoundsarehighlypolar,poorly membrane permeable and not absorbedenterally. Neomycin and paromomycinare given orally in order to eradicateintestinal bacteria (prior to bowel surgeryorforreducingNH 3 formation by gut bacteriain hepatic coma). Aminoglycosides for thetreatment of serious infections must beinjected (e. g., gentamicin, tobramycin, amikacin,netilmicin, sisomycin). In addition, localinlays of a gentamicin-releasing carriercan be used in infections of bone or softtissues. Aminoglycosides gain access to thebacterial interior via bacterial transport systems.In the kidney, they enter the cells of theproximal tubules via an uptake system foroligopeptides. Tubular cells are susceptibleto damage (nephrotoxicity, mostly reversible).In the inner ear, sensory cells of thevestibular apparatus and Corti’s organ maybe injured (ototoxicity, in part irreversible).Chloramphenicol. The broad-spectrum antibioticchloramphenicol is completely absorbedafter oral ingestion. It undergoeseven distribution in the body and readilycrossesdiffusionbarrierssuchastheblood–

Inhibitors of Protein Synthesis 281A. Aspects of the therapeutic use of tetracyclines, chloramphenicol, and aminoglycosidesTetracyclinesChloramphenicolInactivation bychelation ofCa 2+ , Al 3+ etc.Advantage:good penetrationthrough barriersIrritation ofmucousmembranesAbsorptionAntibacterialeffect ongut floracomplex formationONFDisadvantage:bone marrowtoxicityLinezolideNOH 3 C COONHe.g.,neomycinAminoglycoside2 CNHH + 22ONH + HOONHH + CH 3NHOHCHH +NH HOHOO3H H 2 2Gentamicin C 1aHigh hydrophilicityno passive diffusionthrough membranes,therefore parenteraluseH +H +HBasic+oligopeptidesTransport systemCochlear andvestibularototoxicityBacteriumNephrotoxicityNo absorption“bowel sterilization”

282 Antibacterial Drugs Drugs for Treating MycobacterialInfectionsIn the past 100 years, advances in hygienehave led to a drastic decline in tuberculardiseases in central Europe. Infection withMycobacterium tuberculosis could be diagnosedincreasingly earlier and in most casesbe cured by a systematic long-term therapy(6–12 months) with effective chemotherapeutics.Worldwide, however, tuberculosishas remained one of the most threateningdiseases. In developing countries, long-termcombination therapy is scarcely realizable.Therapeutic success is thwarted by a lack ofadequate (medical) infrastructure and financialresources, and insuf cient compliance ofpatients; as a result, millions of persons dieannually of tuberculosis infections. The insufcient treatment entails an additionalbad consequence: more and more mycobacterialstrains develop resistance and cannotbe adequately treated. Patients sufferingfrom immune deficiency are affected moreseverely by infections with M. tuberculosis.Antitubercular drugs (1)Drugs of choice are isoniazid, rifampin, andethambutol, along with streptomycin andpyrazinamide. Less well tolerated, secondlineagents include p-aminosalicylic acid, cycloserine,viomycin, kanamycin, amikacin,capreomycin, and ethionamide.Isoniazid is bactericidal against growingM. tuberculosis. Itsmechanismofactionremainsunclear. In the bacterium it is convertedto isonicotinic acid, which is membraneimpermeable and hence likely to accumulateintracellularly. Isoniazid is rapidlyabsorbed after oral administration. In theliver, it is inactivated by acetylation. Notableadverse effects are peripheral neuropathy,optic neuritis preventable by administrationof vitamin B 6 (pyridoxine), and liver damage.Rifampin. Source, antibacterial activity,and routes of administration are describedon p. 276. Although mostly well tolerated,this drug may cause several adverse effectsincluding hepatic damage, hypersensitivitywith flulike symptoms, disconcerting butharmless red/orange discoloration of bodyfluids, and enzyme induction (failure of oralcontraceptives). Concerning rifabutin, seep. 276.Pyrazinamide exerts a bactericidal actionby an unknown mechanism. It is given orally.Pyrazinamide may impair liver function; hyperuricemiaresults from inhibition of renalurate elimination.Streptomycin must be given i.v. like otheraminoglycoside antibiotics (p. 280). It damagesthe inner ear and the labyrinth. Itsnephrotoxicity is comparatively minorEthambutol. The cause of ethambutol’sspecific antitubercular action is unknown. Itis given orally. It is generally well tolerated,but may cause dose-dependent reversibledisturbances of vision (red/green blindness,visual field defects).Antileprotic drugs (2)Rifampin is frequently given in combinationwith one or both of the following two agents.Dapsone is a sulfone that, like sulfonamides,inhibits dihydrofolate synthesis(p. 274). It is bactericidal against susceptiblestrains of M. leprae. Dapsone is given orally.The most frequent adverse effect is methemoglobinemiawith accelerated erythrocytedegradation (hemolysis).Clofazimine is a dye with bactericidal activityagainst M. leprae and anti-inflammatoryproperties. It is given orally but is incompletelyabsorbed. Because of its highlipophilicity, it accumulates in adipose andother tissues and leaves the body only ratherslowly (t ½ ~ 70 days). Red-brown skin pigmentationis an unwanted effect, particularlyin fair-skinned patients.

Drugs for Treating Mycobacterial Infections 283A. Drugs used to treat infections with mycobacteria (1. tuberculosis, 2. leprosy)Combination therapyReduced risk ofbacterial resistanceReduction of dose and ofrisk of adverse reactionsIsoniazidOCNHN (CH2)2 NHH3C OHH3CCOOOHH3C OH OH O CH3CH3H3CONHONHCH3CH2HO CH2 CHOCH3NH2CNS damageand peripheralneuropathy(Vit. B 6 administration)Liver damageEthambutolOptic nerve damageRifampicinH3CCH3O OHHCCH3CH2Liver damageand enzyme inductionCHCH2OHN N N CH3MycobacteriumtuberculosisNIsonicotinic acidNH 2 NOCOCOHOHNicotinic acidCOOHp-Aminobenzoic acid1.2.PyrazinamideNNLiver damageH2NCNHNHHOOHNH2HON C NHHOHN CH3OOOHH3CH C OH OOHOCH2OHClOCStreptomycinan aminoglycosideantibioticVestibular andcochlearototoxicityClofazimineNH2CH3DapsoneOFolatesynthesisNNN CHCH3NHH2N S NH2HemolysisOMycobacteriumlepraeSkin discolorationCl

284 Antifungal Drugs Drugs Used in the Treatment ofFungal InfectionsInfections due to fungi are usually confinedto the skin or mucous membranes: local orsuperficial mycosis. However, in immune deficiencystates, internal organs may also beaffected: systemic or deep mycosis.Mycoses are most commonly due to dermatophytes,which affect the skin, hair, andnails following external infection, and toCandida albicans, a yeast organism normallyfound on body surfaces, which may causeinfections of mucous membranes, less frequentlyof the skin or internal organs whennatural defenses are impaired (immunosuppression,or damage of microflora by broadspectrumantibiotics).Imidazole derivatives inhibit synthesis ofergosterol, an integral constituent of cytoplasmicmembranes of fungal cells. Fungistop growing (fungistatic effect) or die (fungicidaleffect). The spectrum of affected fungiis very broad. Because they are poorly absorbedand poorly tolerated systemically,most imidazoles are suitable only for topicaluse (clotrimazole, econazole, oxiconazole andother azoles). Fluconazole and itroconazoleare newer orally effective triazole derivatives.Owing to its hydroxyl group, fluconazoleis suf ciently water-soluble to allowformulation as an injectable solution. Bothsubstances are slowly eliminated (plasma t ½~ 30 hours). The topically active allyl aminenaftidine and the morpholine amorolfine alsoinhibit ergosterol synthesis, albeit at adifferent step. Both are for topical use.The polyene antibiotics amphotericin Band nystatin are of bacterial origin. They insertthemselves into fungal cell membranes(probably next to ergosterol molecules) andcause formation of hydrophilic channels.Amphotericin B is active against most organismsresponsible for systemic mycoses. Becausepolyene antimycotics are nonabsorbable,itmustbegivenbyinfusion,whichis,however, poorly tolerated (chills, fever, CNSdisturbances, impaired renal function, andphlebitis at the infusion site). Applied topicallyto skin or mucous membranes, amphotericinB is useful in the treatment of candidalmycosis. Because of the low rate of enteralabsorption, oral administration in intestinalcandidiasis can be considered a topicaltreatment. Likewise, nystatin is only usedtopically (e. g., oral cavity, gastrointestinaltract) against candidiasis.Flucytosine is converted in candidal fungito 5-fluorouracil by the action of a specificfungal cytosine deaminase. As an antimetabolite,thiscompounddisruptsDNAandRNAsynthesis (p. 300), resulting in a fungicidaleffect. Given orally, flucytosine is rapidly absorbed.It is often combined with amphotericinB to allow dose reduction of the latter.Caspofungin is a cyclic polypeptide thatinhibits synthesis of the fungal cell wall. Itcan be used in systemic mycoses due to aspergillusfungi when amphotericin B or itroconazolecannot be employed. It is given byinfusion and causes various adverse effects.Griseofulvin originates from molds andhas activity only against dermatophytes. Itpresumably acts as a spindle poison to inhibitfungal mitosis. Although targetedagainst local mycoses, griseofulvin must beused systemically. It is incorporated intonewly-formed keratin. “Impregnated” in thismanner, keratin becomes unsuitable as afungal nutrient. The time required for theeradication of dermatophytes correspondsto the renewal period of skin, hair, or nails.Griseofulvin may cause uncharacteristic adverseeffects. Because of its cumbersome application,this antimycotic is becoming obsolete.

Drugs Used in the Treatment of Fungal Infections 285A. Antifungal drugsCell wallCytoplasmic membraneErgosterolCaspofunginAzolesImidazoles topical,e.g., clotrimazoleInhibition ofcell wall synthesisSynthesisNNCClTriazoles systemic,e.g., fluconazoleNNNOHCH 2 C CH 2FNNNMitotic spindleDNA/RNAmetabolismGriseofulvinFOHFNHO NHO5-FluorouracilOHNNUracilIncorporation intogrowing skin, hair, nails“Impregnation effect”Mold fungiFungal cellCytosinedeaminasePolyene AntibioticsNH 2NH 2NFNHONHONStreptomyces bacteriaAmphotericin BNystatinFlucytosine

286 Antiviral Drugs Chemotherapy of Viral InfectionsViruses essentially consist of genetic material(nucleic acids) and a capsular envelopemade up of proteins, often with a coat of aphospholipid (PL) bilayer with embeddedproteins. They lack a metabolic system anddepend on the infected cell for their growthand replication. Targeted therapeutic suppressionof viral replication requires selectiveinhibition of those metabolic processesthat specifically serve viral replication in infectedcells.Viral replication as exemplified by herpessimplex viruses (A).1. The viral particle attaches to the host cellmembrane (adsorption) viaenvelopeglycoproteinsthat make contact with specificstructures of the cell membrane.2. The viral coat fuses with the plasmalemmaof host cells and the nucleocapsid (nucleicacidpluscapsule)entersthecellinterior(penetration).3. The capsule opens (“uncoating”) near thenuclear pores and viral DNA moves intothe cell nucleus. The genetic material ofthe virus can now direct the cell’s metabolicsystem.4a. Nucleic acid synthesis: The genetic material(DNA in this instance) is replicatedand RNA is produced for the purposeof protein synthesis.4b. The proteins are used as “viral enzymes”catalyzing viral multiplication(e. g., DNA polymerase and thymidinekinase), as capsomers, or as coat components,or are incorporated into thehost cell membrane.5. Individual components are assembled intonew virus particles (maturation).6. Release of daughter viruses results inspread of virus inside and outside the organism.With herpesviruses, replication entails hostcell destruction and development of diseasesymptoms.Antiviral mechanisms (A). The organism candisrupt viral replication with the aid of cytotoxicT-lymphocytes that recognize and destroyvirus-producing cells (presenting viralproteins on their surface, p. 304) or by meansof antibodies that bind to and inactivate extracellularvirus particles. Vaccinations aredesigned to activate specific immunedefenses.Interferons (IFN) are glycoproteins that,among other products, are released fromvirus-infected cells. In neighboring cells, interferonstimulates the production of “antiviralproteins.” These inhibit the synthesis ofviral proteins by (preferential) destruction ofviral DNA or by suppressing its translation.Interferons are not directed against a specificvirus, but have a broad spectrum of antiviralaction that is, however, species-specific.Thus, interferon for use in humans must beobtained from cells of human origin, such asleukocytes (IFN-α), fibroblasts (IFN-β), orlymphocytes (IFN-γ). Interferons are usedin the treatment of certain viral diseases, aswell as malignant neoplasias and autoimmunediseases; e. g., IFN-α for the treatmentof chronic hepatitis C and hairy cell leukemia;and IFN-β in severe herpes virus infectionsand multiple sclerosis.Virustatic antimetabolites are “false”DNA building blocks (B) ornucleosides.Anucleoside (e. g., thymidine) consists of anucleobase (e. g., thymine) and the sugar deoxyribose.In antimetabolites, one of thecomponents is defective. In the body, theabnormal nucleosides undergo bioactivationby attachment of three phosphate residues(p. 289).Idoxuridine and congeners are incorporatedinto DNA with deleterious results. Thisalso applies to the synthesis of human DNA.Therefore, idoxuridine and analogues aresuitable only for topical use (e. g., in herpessimplex keratitis).

Chemotherapy of Viral Infections 287A. Virus multiplication and modes of action of antiviral agentsVirusinfectedcell1. AdsorptionGlycoproteinInterferonProteins withantigenic propertiesSpecific immunedefensee.g., cytotoxicT-lymphocytes2. Penetration3. UncoatingDNAAntiviralproteins4a. Nucleic acidsynthesisRNA4b. Protein synthesisViral DNApolymerase6. ReleaseCapsuleEnvelopeDNA5. MaturationB. Chemical structure of virustatic antimetabolitesCorrect:ThymidineThymineDesoxyriboseOHNO NHOCH 2 OOHCH3Antimetabolites = incorrect DNA building blocksOincorrect base HNO NHOCH 2 Oincorrect sugarOHRR: -I Idoxuridine-CF 3 TrifluridineInsertion intoDNA insteadof thymidineNH 2 O CH 2 OH3C CH CH C H2CCH 2CH 3Valaciclovir,prodrugOGuanineAcyclovirHNOH2NNHOCH 2 OH2NInhibition of viral DNA polymeraseNNHNONHOCH 2 OOHGanciclovirNNGuanine

288 Antiviral DrugsAmong virustatic antimetabolites, aciclovir(A) has both specificity of the highest degreeand optimal tolerability because it undergoesbioactivation only in infected cells,where it preferentially inhibits viral DNAsynthesis. (1) A virally coded thymidine kinase(specific to herpes simplex and varicella-zosterviruses) performs the initial phosphorylationstep; the remaining two phosphateresidues are attached by cellular kinases.(2) The polar phosphate residuesrender aciclovir triphosphate membraneimpermeableand cause it to accumulate ininfected cells. (3) Aciclovir triphosphate is apreferred substrate of viral DNA polymerase;it inhibits enzyme activity and, following itsincorporation into viral DNA, induces strandbreakagebecauseitlacksthe3′-OH group ofdeoxyribose that is required for the attachmentof additional nucleotides. The hightherapeutic value of aciclovir is evident insevere infections with herpes simplex viruses(e. g., encephalitis, generalized infection)and varicella-zoster viruses (e. g., severeherpes zoster). In these cases, it can begiven by i.v. infusion. Aciclovir may also begiven orally despite its incomplete (15–30%)enteral absorption. In addition, it has topicaluses. Because host DNA synthesis remainsunaffected, adverse effects do not includebone marrow depression.In valaciclovir, thehydroxylgroupisesterifiedwith the amino acid L-valine(p. 287B). This allows utilization of an enteraldipeptide transporter, leading to an enteralabsorption rate almost double that of aciclovir.Subsequent cleavage of the valine residueyields aciclovir.Famciclovir is an antiherpetic prodrug(active species penciclovir) with good oralbioavailability.Ganciclovir (structure on p. 287B) isusedin the treatment of severe infections withcytomegaly viruses (also belonging to theherpes group); these do not form thymidinekinase, phosphorylation being initiated by adifferent viral enzyme. Ganciclovir is lesswell tolerated and, not infrequently, producesleukopenia and thrombopenia. It is infusedor administered orally as a valine ester(valganciclovir).Foscarnet represents a diphosphate analogue.Incorporation of nucleotide into aDNA strand entails cleavage of a diphosphateresidue. Foscarnet inhibits DNA polymeraseby interacting with its binding site for thediphosphate group. Indications: systemictherapy in severe cytomegaly infections inAIDS patients; local therapy of herpes simplexinfections.Drugs against influenza viruses (C). Amantadinespecifically affects the replication ofinfluenza A (RNA) viruses, the causativeagents of true influenza. These viruses areendocytosed into the cell. Release of viralRNA requires protons from the acidic contentof endosomes to penetrate into the virus.Amantadine blocks a channel protein inthe viral coat that permits influx of protons.Thus, “uncoating” is prevented. The drug isused for prophylaxis and, hence, must betaken before the outbreak of symptoms. Itis also an antiparkinsonian drug (p.188).Neuraminidase inhibitors prevent the releaseof influenza A and B viruses. Normally,the viral neuraminidase splits off N-acetylneuraminic(sialic) acid residues on the cellularsurface coat, thereby enabling newlyformed viral particles to be detached fromthe host cell. Zanamivir is given by inhalation;oseltamivir is suitable for oral administrationbecause it is an ester prodrug. Possibleuses include treatment and prophylaxisof influenza virus infections.

Chemotherapy of Viral Infections 289A. Activation of acyclovir and inhibition of viral DNA synthesisAcyclovirInfected cell:herpes simplexor varicella-zosterCellular kinasesViralthymidinekinaseHOOPO –OViral DNA templateOO OHNH2NNP O PO CH 2OO – O – H 2 CActive antimetaboliteNNCH 2OBase5'CH 2 OOBaseCH 2 OOBaseCH 2 ODNA-chainterminationP 3' P3'PODNAsynthesisHOPPViralDNA polymeraseInhibitionB. Inhibitor of DNA-polymerase:B. FoscarnetC. Prophylaxis for viral fluInfluenza A virusBaseOPOPO CH2O3´HOOEndosomeViral channelproteinH +ONH 2OPOOOCOViralDNA polymeraseInhibition ofuncoatingAmantadineOPOOFoscarnetInhibition ofreleaseNeuraminidaseinhibitors

290 Antiviral Drugs Drugs for the Treatment of AIDSReplication of the human immunodeficiencyvirus (HIV), the causative agent ofAIDS, is susceptible to targeted interventionsbecause it entails several obligatory steps invirus-specific metabolism (A). First, the virusdocks at the CD4 complex of T-helper lymphocytesby means of a glycoprotein in theviral coat (p. 304). A fusion protein is thenextruded from the viral coat, by which fusionof the latter and the cell membrane is initiated.Next, viral RNA is transcribed into DNA,a step catalyzed by viral “reverse transcriptase.”Double-stranded DNA is incorporatedinto the host genome with the help of viralintegrase. Under control by viral DNA, viralreplication can then be initiated, with synthesisof viral RNA and proteins (includingenzymessuchasreversetranscriptaseandintegrase, and structural proteins such as thematrix protein lining the inside of the viralenvelope). These proteins are not assembledindividually but in the form of polyproteins.An N-terminal fatty acid (myristoyl) residuepromotes their attachment to the interiorface of the plasmalemma. As the virus particlebudsoffthehostcell,itcarrieswithitthe affected membrane area as its envelope.During this process, a protease containedwithin the polyprotein cleaves the latter intoindividual functionally active proteins.I. Inhibitors of Reverse Transcriptase—Nucleoside AgentsRepresentatives of this group include zidovudine,stavudine, zalcitabine, didanosine,and lamivudine. They are nucleosides containingan abnormal sugar moiety and requirebioactivation by phosphorylation (cf.zidovudine in A). As triphosphates, they inhibitreverse transcriptase and cause strandbreakage following incorporation into viralDNA. The substances are administered orally.In part, they differ in their spectrum ofadverse effects (e. g., leukopenia with zidovudine;peripheral neuropathy and pancreatitiswith the others) and in the mechanismsresponsible for development of resistance.AIDS therapy mostly employs combinationsof two members of this group plus either anonnucleoside inhibitor (see below) or oneto two protease inhibitors (see below).Nonnucleoside InhibitorsNevirapine and efavirenz areactiveinhibitorsof reverse transcriptase, that is, they donot require phosphorylation. Adverse reactionsinclude rashes and interactions involvingcytochrome P450 isozymes (CYP).II. HIV protease InhibitorsInhibitors of viral protease prevent cleavageof inactive precursor proteins, and henceviral maturation. They are administeredorally.Saquinavir could be considered an abnormalpeptide. Its bioavailability is low. Ritonavir,indinavir, nelfinavir, andamprenavirare other protease inhibitors that in partexhibit markedly higher bioavailability. Biotransformationof these drugs involves CYPenzymes and is therefore subject to interactionwith various other drugs metabolizedvia this route. Prolonged administrationmay be associated with a peculiar redistributionof adipose tissue and metabolicdisturbances (hyperlipidemia, insulin resistance,hyperglycemia).III. Fusion InhibitorsEnfuvirtide is a peptide that binds to theviral fusion protein in such a manner as toprevent the necessary change in conformation.It is a reserve drug.

Drugs for the Treatment of AIDS 291A. AIDS drugsRNAEnvelopeFusion glycoproteinMatrix proteinReversetranscriptaseIntegraseFusion inhibitor Enfuvirtide,a peptide, s.c. administrationViral RNAInhibitors ofreversetranscriptaseODNAOH NNCH 3HOCH 2ONN+ N –e.g., zidovudineViral RNAPolyproteinsInhibitors ofHIV proteaseONNHH 2NOH NOProteaseHOPolyproteincleavageNOH 3CN HCH 3Mature viruse.g., saquinavirCH 3

292 Antiparasitic Drugs Drugs for Treating Endoparasiticand Ectoparasitic InfestationsAdverse hygienic conditions favor human infestationwith multicellular organisms (referredto here as parasites). Skin and hairare colonization sites for arthropod ectoparasites,such as insects (lice, fleas) and arachnids(mites). Against these, insecticidal andarachnicidal agents, respectively, can be used.Endoparasites invade the intestines or eveninternal organs and are mostly members ofthe phyla of flatworms and roundworms.They are combated with anthelmintics.Antihelmintics. As shown in the table, thenewer agents, praziquantel and mebendazole,are adequate for the treatment of diverseworm diseases. They are generally welltolerated, as are the other agents listed.Insecticides. Whereas fleas can be effectivelydealt with by disinfection ofclothesand livingquarters, lice and mites require the topicalapplication of insecticides tothe infested subject.The following agents act mainly by interferingwith the activation or inactivation ofneural voltage-gated insect sodium channels.Chlorphenothane (DDT) kills insects afterabsorption of a very low amount, e. g., via footcontact with sprayed surfaces (contact insecticide).The cause of death is nervous systemdamage and seizures. In humans DDT causesacute neurotoxicity only after absorption ofvery large amounts. DDT is chemically stableand is degraded in the environment and thebody at extremely slow rates. As a highlylipophilic substance, it accumulates in fat tissues.Widespread use of DDT in pest controlhas led to its accumulation in food chains toalarming levels. For this reason its use hasnow been banned in many countries.Lindane is the active γ-isomer of hexachlorocyclohexane.It also exerts a neurotoxicactiononinsects(aswellashumans).Irritation of skin or mucous membranes mayoccur after topical use. Lindane is active alsoagainst intradermal mites (Sarcoptes scabiei,causative agent of scabies), besides lice andfleas. Although it is more readily degradedthan DDT, it should be used only as a secondlineagent with appropriate precautions. Inthe United Kingdom its use for head lice hasbeen banned; in the United States it is notrecommended in young children and is contraindicatedin premature infants.Permethrin, a synthetic pyrethroid, exhibitssimilar antiectoparasitic activity andmay be the drug of choice owing to its slowercutaneous absorption, fast hydrolytic inactivation,and rapid renal elimination.Therapy of Worm InfestationsWorms (helminths)Flatworms (platyhelminths)Tape worms (cestodes)Flukes (trematodes),e. g., Schistosoma species (bilharziasis)Roundworms (nematodes)Pinworm (Enterobius vermicularis)Whipworm (Trichuris trichiura)Ascaris lumbricoidesTrichinella spiralis bStrongyloides stercoralisHookworms (Necator americanus,Ancylostoma duodenale)Anthelminthic Drug of ChoicePraziquantel a or niclosamidePraziquantelMebendazole or pyrantel pamoateMebendazoleMebendazole or pyrantel pamoateMebendazole and thiabendazoleThiabendazoleMebendazole or pyrantel pamoatea Not for ocular or spinal cord cysticercosis.b Thiabendazole in intestinal phase; mebendazole in tissue phase.

Drugs against Endo- and Ectoparasites 293A. Endoparasites and ectoparasites: therapeutic agentsTapewormse.g., beeftapewormLouseSpasm,injury ofintegumentClRoundworms,e.g.,ascarisOCOCNNMebendazoleOPinwormPraziquantelNHN NH COOCH3Damage to nervous system: convulsions, deathChlorphenothane(DDT)FleaClClClHC C ClClClClClClClHexachlorocyclohexane(Lindane)TrichinellalarvaeScabies mite

294 Antiparasitic Drugs AntimalarialsThe causative agents of malaria are plasmodia,unicellular organisms (Order Hemosporidia,Class Protozoa). The infective form, thesporozoite, is inoculated into skin capillarieswhen infected female Anopheles mosquitoes(A) suck blood from humans. The sporozoitesinvade liver parenchymal cells, wherethey develop into primary tissue schizonts.Thesegiverisetonumerousmerozoitesthatenter the blood. The preerythrocytic stage isasymptomatic. In blood, the parasite enterserythrocytes (erythrocytic stage), where itagain multiplies by schizogony, resulting inthe formation of more merozoites. Ruptureof the infected erythrocytes releases themerozoites and pyrogens. A fever attack ensuesand more erythrocytes are infected. Thegeneration period for the next crop of merozoitesdetermines the interval between feverattacks. With Plasmodium vivax and P.ovale, there can be a parallel multiplicationin the liver (paraerythrocytic stage). Moreover,some sporozoites may become dormantin the liver as “hypnozoites” beforeentering schizogony.Different antimalarials selectively kill theparasite’s different developmental forms.The mechanism of action is known for someagents: Chloroquine and quinine accumulatewithin the acidic vacuoles of blood schizontsand inhibit polymerization of heme releasedfrom digested hemoglobin, free heme beingtoxic for the schizonts. Pyrimethamine inhibitsprotozoal dihydrofolate reductase(p. 274), as does chlorguanide (proguanil)via its active metabolite cycloguanil. The sulfonamidesulfadoxine inhibits synthesis ofdihydrofolic acid (p. 274). Dihydrofolate reductaseis also blocked by cycloguanil, theactive form of proguanil. Atoquavone suppressessynthesis of pyrimidine bases, probablyby interfering with mitochondrial electrontransport. Artemesinin derivatives (artemether,artesunate) originate from the EastAsian plant Qinghaosu (Artemisia sp.) Itsantischizontal effect appears to involve a reactionbetween heme iron and the epoxidegroup of these compounds.Antimalarial drug choice takes tolerabilityand plasmodial resistance into account.Tolerability. The oldest antimalarial, quinine,has the smallest therapeutic margin.All newer agents are rather well tolerated.Plasmodium falciparum, responsibleforthemostdangerousformofmalaria,isparticularlyprone to develop drug resistance. Theprevalence of resistant strains rises with increasingfrequencyof drug use. Resistance hasbeen reported for chloroquine and also thecombination pyrimethamine/sulfadoxine.Drug choice for antimalarial chemoprophylaxis.In areas with a risk of malaria, continuousintake of antimalarials affords the bestprotection against the disease, though notagainst infection. Primaquine would be effectiveagainst primary tissue schizonts of allplasmodial species; however, it is not usedfor long-term prophylaxis because of unsatisfactorytolerability and the risk of plasmodialresistance. Instead, prophylactic regimensemploy agents against blood schizonts.Depending on the presence of resistantstrains, use can be made of chloroquine,and/or proguanil, mefloquine, the tetracyclinedoxycycline, as well as the combinationof atoquavone and proguanil.These drugs do not prevent the (symptom-free)hepatic infection but only the disease-causinginfection of erythrocytes (“suppressiontherapy”). On a person’s returnfrom an endemic malaria region, a two-weekcourse of primaquine is adequate for eradicationof the late hepatic stages (P. vivax andP. ovale).Protection from mosquito bites (with nets,skin-covering clothes, etc.) is a very importantprophylactic measure.Therapy. Antimalarial therapy employs thesame agents, in addition to the combinationsof artemether plus lumefantrine or pyrimethamineplus sulfadoxine.

Antimalarials 295A. Malaria: stages of the plasmodial life cycle in the human: therapeutic optionsSporozoitesHepatocytePrimary tissue schizontPrimaquineHypnozoitePreerythrocytic cycle1-4 weeksP. falciparumMerozoitesProguanilPyrimethamineOnlyP. vivaxP. ovaleErythrocytic cycleErythrocyteBloodschizontChloroquineMefloquineQuinineLumefantrineArtemetherAtovaquoneProguanilPyrimethamineSulfadoxineFeverFeverPrimaquine2 days :Tertian malariaP. vivax, P. ovale3 days:Quartan malariaP. malariaeNo feverperiodicity:Pernicious malaria:P. falciparumnot P. falciparumGametocytesChloroquineQuinineFever

296 Antiparasitic Drugs Other Tropical DiseasesIn addition to malaria, other tropical diseasesand their treatment will be considered forthe following reasons. (1) Owing to the tremendousgrowthinglobaltravel,inhabitantsof temperate climatic zones have becomeexposed to the hazard of infection with tropicaldisease pathogens. (2) The spread ofsome tropical diseases is of unimaginabledimensions, with humans victims numberingin the millions. The pharmacotherapeuticpossibilities known to date will be presented.Amebiasis. The causative agent, Entamoebahistolytica, livesandmultipliesinthecolon(symptom: diarrhea), its cyst form residingalso in the liver among other sites. In tropicalregions, up to half the population can beinfested, transmission occurring by the fecal–oralroute. The most effective treatmentagainst both intestinal infestation and systemicdisease is administration of metronidazole.If monotherapy fails, combinationtherapy with chloroquine, emetine or tetracyclinesmay be indicated.Leishmaniasis. The causative agents are flagellatedprotozoa that are transmitted bysand flies to humans. The parasites are takenup into phagocytes, where they remain inphagolysosomes and multiply until the celldies and the parasites can infect new cells.Symptoms: A visceral form, known as kalaazar,and cutaneous or mucocutaneousforms exist (A). An estimated 12 million humansare affected. Therapy is dif cult; pentavalentantimonial compounds, such as stibogluconate,must be given for extendedperiods. Adverse effects are pronounced.Trypanosomiasis. The pathogens, Trypanosomabrucei (sleeping sickness) and T. cruzi(Chagas disease), are flagellated protozoa. T.brucei (C) is transmitted by the tsetse fly,distributed in West and East Africa. An initialstage (swelling of lymph nodes, malaise,hepatosplenomegaly, among others) is followedby invasion of the CNS with lethargy,extrapyramidal motor disturbances, Parkinson-likesigns, coma, and death. Therapy:Long-term suramine i.v. or pentamidine (lesseffective); arsenicals (e. g., melarsoprol,highly toxic), when the CNS is involved.T. cruzi is confined to Central and SouthAmerica and transmitted by blood-suckingreduviid bugs. These parasites preferentiallyinfiltrate the cardiac musculature, wherethey cause damage to muscle fibers and thespecialized conducting tissue. Death resultsfrom cardiac failure. Therapy: unsatisfactory.Schistosomiasis (bilharziasis) (see alsop. 292). The causative organisms are trematodeswith a complex life cycle that need(aquatic)snailsasintermediatehosts.Freeswimminglarval cercariae penetrate the intactskin of humans. The adult worms (Schistosomamansoni, D) live in the venous vasculature.Occurrence: tropical countries rich inaquatic habitats. About 200 million humansare af icted. Therapy: praziquantel, 10–40 mg/kg, single dose, is highly effective withminimal adverse effects. Substances releasedfrom decaying worms may cause problems.Filariasis. In its microform, Wuchereria bancroftiis transmitted by mosquitoes; the adultparasites live in the lymph system and causeinflammations and blockage of lymph drainageleading to elephantiasis in extreme cases(B). Therapy: diethylcarbamazepine for severalweeks; adverse reactions are chiefly dueto products from disintegrating worms.Onchocerciasis (“River Blindness”). Thecausative organism is Onchocerca volvulus,a filaria transmitted by black flies (genusSimulium). The adult parasites (several centimeterslong) form tangles and proliferatingnodules (onchocercomas) in the skin andhave a particular propensity for invadingthe eyeball, resulting in blindness. About 20million people inhabiting banks of fast-flowingrivers are af icted with river blindness.Therapy: ivermectin (0.15 mg/kg, singledose); adverse reactions are in part causedby disintegrating worms.

Other Tropical Diseases 297A. Cutaneous leishmaniasisCausative agent: Leishmania majorB. ElephantiasisCausative agent: Wuchereria bancroftiC. Trypanosoma bruceiCausative agent of sleeping sicknessD. Schistosoma mansoniCausative agent of bilharziasis

298 Anticancer Drugs Chemotherapy of MalignantTumorsA tumor (neoplasm) consists of cells thatproliferate independently of the body’s inherent“building plan.” A malignant tumor(cancer) is present when the tumor tissuedestructively invades healthy surroundingtissue or when dislodged tumor cells formsecondary tumors (metastases) in other organs.A cure requires the elimination of allmalignant cells (curative therapy). Whenthis is not possible, attempts can be madeto slow tumor growth and thereby prolongthe patient’s life or improve quality of life(palliative therapy). Chemotherapy is facedwith the problem that the malignant cellsare endogenous and almost lacking in specificmetabolic properties.Cytostatics (A) are cytotoxic substances thatparticularly affect proliferating or dividing(mitotic) cells. Rapidly dividing malignantcells are preferentially injured. Damage tomitotic processes not only retards tumorgrowth but also may initiate apoptosis (programmedcell death). Tissues with a lowmitosis rate are largely unaffected; likewise,most healthy tissues. This, however, also appliesto malignant tumors consisting ofslowly dividing differentiated cells.Tissues that have a physiologically highmitosis rate are bound to be affected bycytostatic therapy. Thus, typical adverse effectsoccur. Loss of hair results from injury tohair follicles; gastrointestinal disturbances,such as diarrhea, from inadequate replacementof enterocytes whose lifespan is limitedto a few days; nausea and vomiting fromstimulation of area postrema chemoreceptors(p. 342); and lowered resistance to infectionfrom weakening of the immune system(p. 304). In addition, cytostatics cause bonemarrow depression. Resupply of blood cellsdepends on the mitotic activity of bone marrowstem and daughter cells. When myeloidproliferation is arrested, the short-livedgranulocytes are the first to be affected (neutropenia),then blood platelets (thrombopenia)and, finally, the more long-lived erythrocytes(anemia). Infertility is caused by suppressionof spermatogenesis or follicle maturation.Most cytostatics disrupt DNAmetabolism. This entails the risk of a potentialgenomic alteration in healthy cells (mutageniceffect). Conceivably, the latteraccounts for the occurrence of leukemiasseveral years after cytostatic therapy (carcinogeniceffect). Furthermore, congenitalmalformations are to be expected when cytostaticsmust be used during pregnancy(teratogenic effect).Cytostatics possess different mechanismsof action.Damagetothemitoticspindle(B).The contractileproteins of the spindle apparatusmust draw apart the replicated chromosomesbefore the cell can divide. This processis prevented by the so-called spindle poisons(see also colchicine, p. 326) that arrest mitosisat metaphase by disrupting the assemblyinto spindle threads of microtubuli. Theseconsist of the proteins α-and β-tubulin. Surplustubuli are broken down, enabling thetubulin subunits to be recycled.The vinca alkaloids, vincristine and vinblastine(from the periwinkle plant, Vincarosea), inhibit the polymerization of tubulinsubunits into microtubuli. Damage to thenervoussystemisapredictedadverseeffectarising from injury to microtubule-operatedaxonal transport mechanisms.Paclitaxel,fromthebarkofthepacificyew(Taxus brevifolia), inhibits disassembly of microtubulesand induces formation of atypicalones, and thus impedes the reassemblage oftubulins into properly functioning microtubules.Docetaxel is a semisynthetic derivative.

Chemotherapy of Malignant Tumors 299A. Chemotherapy of tumors: principal and adverse effectsMalignant tissuewith numerous mitosesCytostatics inhibitcell divisionHealthy tissuewith few mitosesWanted effect:inhibition oftumor growthLittle effectHealthy tissue withnumerous mitosesLymph nodeDamage to hair follicleHair lossInhibition ofephithelial renewalUnwanted effectsInhibition oflymphocytemultiplication:immuneweaknessLowered resistanceto infectionBone marrowInhibition ofgranulo-,thrombocyto-,and erythropoiesisDiarrheaGerminal cell damageB. Cytostatics: inhibition of mitosisInhibition offormationVinca alkaloids,e.g., vinblastineMicrotubulesof mitotic spindleTaxoids,e.g., paclitaxelInhibition ofdegradationVinca roseaWestern yew tree

300 Anticancer DrugsInhibition of DNA and RNA synthesis (A).Mitosis is preceded by replication of chromosomes(DNA synthesis) and increasedprotein synthesis (RNA synthesis). ExistingDNA(gray)servesasatemplateforthesynthesisof new (blue) DNA or RNA. De-novosynthesis may be inhibited by the followingmechanisms.Damagetothetemplate(1).Alkylating cytostaticsarereactivecompoundsthattransferalkyl residues into a covalent bond withDNA. For instance, mechlorethamine (nitrogenmustard) is able to cross-link doublestrandedDNA on giving off its chlorineatoms. Correct reading of genetic informationis thereby rendered impossible. Otheralkylating agents are chlorambucil, melphalan,thio-TEPA, cyclophosphamide, ifosfamide,lomustine, and busulfan. Specificadverse reactions include irreversible pulmonaryfibrosis due to busulfan and hemorrhagiccystitis caused by the cyclophosphamidemetabolite acrolein (preventable bythe uro-protectant mesna = sodium 2-mercaptoethanesulfonate).The platinum-containingcompounds cisplatin and carboplatinrelease platinum, which binds to DNA.Cystostatic antibiotics insert themselvesinto the DNA double strand; this may lead tostrand breakage (e. g., with bleomycin). Theanthracycline antibiotics daunorubicin andadriamycin (doxorubicin) may induce cardiomyopathy.Bleomycin can also cause pulmonaryfibrosis.Induction of strand breakage may resultfrom inhibition of topoisomerase. The epipodophyllotoxinsetoposide and tenoposideinteract with topoisomerase II, which functionsto split, transpose, and reseal DNAstrands (p. 276); these agents cause strandbreakage by inhibiting resealing. The “tecans”topotecan and irinotecan are derivativesofcamptothecinfromthefruitsofaChinesetree(Camptotheca acuminata). Theyinhibit topoisomerase I, which inducesbreaks in single-strand DNA.Inhibition of nucleobase synthesis (2). Tetrahydrofolicacid (THF) is required for thesynthesis of both purine bases and thymidine.Formation of THF from folic acid involvesdihydrofolate reductase (p. 274). Thefolate analogues aminopterin and methotrexate(amethopterin) inhibit enzyme activity.Cellular stores of THF are depleted. The effectof these antimetabolites can be reversed byadministration of folinic acid (5-formyl-THF,leucovorin, citrovorum factor). Hydroxyurea(hydroxycarbamide) inhibits ribonucleotidereductase that normally converts ribonucleotidesinto deoxyribonucleotides subsequentlyused as DNA building blocks.Incorporation of false building blocks (3).Unnatural nucleobases (6-mercaptopurine;5-fluorouracil) or nucleosides with incorrectsugars (cytarabine) act as antimetabolites.They inhibit DNA/RNA synthesis or lead tosynthesis of missense nucleic acids.6-Mercaptopurine results from biotransformationof the inactive precursor azathioprine(p. 37). The uricostatic allopurinol(p. 327) inhibits the degradation of 6-mercaptopurinesuch that coadministration ofthe two drugs requires dose reduction ofthe latter.Combination therapy. Cytostatics are frequentlyadministered in complex therapeuticregimens designed to improve ef cacyand tolerability of treatment.Supportive therapy. Cancer chemotherapycan be supported by adjunctive medications.Thus, 5-HT 3 serotonin receptor antagonists(e. g., ondansetron, p. 342) afford effectiveprotection against vomiting induced byhighly emetogenic drugs such as cisplatin.Bone marrow depression can be counteractedby granulocyte and granulocyte/macrophagecolony-stimulating factors (filgrastimand lenograstim and molgramostim, respectively).

Chemotherapy of Malignant Tumors 301A. Cytostatics: alkylating agents and cytostatic antibiotics (1),inhibitors of tetrahydrofolate synthesis (2), antimetabolites (3)DNADamageto templatePtAlkylation,e.g., bymechlorethamineBindingof platinumInsertioninto DNA, e.g.,doxorubicinH 2 NNNCl CH 2 CH 2N CH 3Cl CH 2 C 2NHMechlorethamineHO+NCH 2 CH 2 CH 3NH 2 C1Induction ofstrand breaksTopoisomeraseinhibitors:epipodophyllotoxins,tecansH 2 C +NOHNNNNH 2Inhibition of nucleotide synthesisBuilding blocksPurinesThyminenucleotideTetrahydrofolateDihydrofolatereductaseFolic acidRNAInhibition byH 2N NNOHNNCH 2NHMethotrexateNH 2CH 32DNADNAPurine antimetaboliteSHHNNN N6-Mercaptopurinefrom azathioprineInsertion of incorrect building blocksinstead ofNH2HNNN NAdenine3Pyrimidine antimetabolite5-Fluorouracilinstead of UracilCytarabine Cytosine CytosineArabinoseinstead of Desoxyribose

302 Anticancer Drugs Targeting of Antineoplastic DrugAction (A)When degenerating neoplastic cells displayspecial metabolic properties which are differentfrom those of normal cells, targetedpharmacotherapeuticintervention becomes possible.Imatinib. Chronic myelogenous leukemia(CML) results from a genetic defect in thehematopoietic stem cells of the bone marrow.Nearly all CML patients possess thePhiladelphia chromosome. It results fromtranslocation between chromosomes 9 and22 of the c-abl protooncogene, leading to thehybrid bcr-abl fusion gene on chromosome22. The recombinant gene encodes a tyrosinekinase mutant with unregulated (constitutive),enhanced activity that promotes cellproliferation. Imatinib is a tyrosine kinaseinhibitor that specifically affects this mutantbut also interacts with some other kinases. Itcan be used orally in Philadelphia chromosome-positiveCML.Asparaginase cleaves the amino acid asparagineinto aspartate and ammonia. Certaincells, in particular the tumor cells inacute lymphatic leukemia, require asparaginefor protein synthesis and must take itup from the extracellular space, whereasmany other cell types are themselves ableto synthesize asparagine. Supply of the aminoacid can be disrupted by administrationof the asparagine-hydrolyzing enzyme. Consequently,protein synthesis and proliferationof neoplastic cells are inhibited. Asparaginaseis obtained from E. coli bacteria ormay be of plant origin (Erwinia chrysanthemi),when it is also named crisantaspase.Allergic reactions against the exogenousprotein occur after parenteral administration.Trastuzumab exemplifies a growingnumber of monoclonal antibodies that havebecome available for antineoplastic therapy.These are directed against cell surface proteinsthat are strongly expressed by cancercells. Trastuzumab binds to HER2, the receptorfor epidermal growth factor. The densityof this receptor is greatly increased in sometypes of breast cancer. When the tumor cellshave bound antibody, immune cells can recognizethem as elements to be eliminated.Trastuzumab is indicated in advanced casesunder certain conditions. The antibody iscardiotoxic; it is likely that cardiomyocytesalso express HER2. Mechanisms of Resistance toCytostatics (B)Initial success can be followed by loss ofeffect because of the emergence of resistanttumor cells. Mechanisms of resistance aremultifactorial. Diminished cellular uptake may resultfrom reduced synthesis of a transport proteinthat may be needed for membranepenetration (e. g., methotrexate). Augmented drug extrusion: increased synthesisof the P-glycoprotein that extrudesdrugs from the cell (e. g., anthracyclines,vinca alkaloids, epipodophyllotoxins, andpaclitaxel) is responsible for multidrugresistance (mdr1 gene amplification). Diminished bioactivation of a prodrug,e.g.,cytarabine, which requires intracellularphosphorylation to become cytotoxic. Change in site of action: e. g., increasedsynthesis of dihydrofolate reductase mayoccur as a compensatory response to methotrexate. Damage repair: DNA repair enzymes maybecome more ef cient in repairing defectscaused by cisplatin. Inhibition of apoptosisdue to activation of antiapoptotic cellularmechanisms.

Targeting of Antineoplastic Drugs 303A. Targeting of antineoplastic drug actionChronic myelogenousleukemiaPhiladelphiachromosomeAcute lymphatic leukemiaNormal cellsBreast carcinomain 1/4 of cases:Overexpressionof HER2Tyrosinekinasemutant withconstitutivelyenhancedactivityCell proliferationImatinibUptake ofL-asparagineNH 3L-AspartateEndogenoussynthesisof L-asparagineAsparaginaseH HumanE Epidermal growth factorR ReceptorTrastuzumabB. Mechanisms of cytostatic resistanceCytostatic drugUptakeDecreaseMutationand selectionof resistantcellsEfflux pumpingIncreaseBioactivationDecreaseSite of actionChangeEffectDamageRepairApoptosisInhibition

304 Immune Modulators Inhibition of Immune ResponsesBoth the prevention of transplant rejectionand the treatment of autoimmune disorderscall for a suppression of immune responses.However, immune suppression also entailsweakened defenses against infectious pathogensand a long-term increase in the risk ofneoplasms.A specific immune response begins withthe binding of antigen by lymphocytes carryingspecific receptors with the appropriateantigen-binding site. B-lymphocytes “recognize”antigen surface structures by means ofmembrane receptors that resemble the antibodiesformed subsequently. T-lymphocytes(and naive B cells) require the antigen to bepresented on the surface of macrophages orother cells in conjunction with the majorhistocompatibility complex (MHC); the latterpermits recognition of antigenic structuresby means of the T-cell receptor. T-helper(T H ) cells carry adjacent CD3 and CD4complexes, cytotoxic T cells a CD8 complex.The CD proteins assist in docking to theMHC. Besides recognition of antigen, stimulationby cytokines plays an essential part inthe activation of lymphocytes. Interleukin-1is formed by macrophages, and various interleukins(IL), including IL-2, are made by T-helper cells. As antigen-specific lymphocytesproliferate, immune defenses are set intomotion.I. Interference with antigen recognition.Muromonab CD3 is a monoclonal antibodydirected against mouse CD3 that blocks antigenrecognition by T-lymphocytes (use ingraft rejection).Glatirameracetate consists of peptides ofvarying lengths, polymerized in random sequencefrom the amino acids glutamine, lysine,alanine, and tyrosine. It can be used inthe treatment of multiple sclerosis besides β-interferon. This disease is caused by a T-lymphocyte-mediatedautoaggression directedagainst oligodendrocytes that form myelinsheaths of CNS axons. The culprit antigenappears to be myelin basic protein. Glatiramerresembles the latter; by blocking antigenreceptors, it interferes with antigen recognitionby lymphocytes.II. Inhibition of cytokine production andaction. Glucocorticoids modulate the expressionof numerous genes; thus, the productionof IL-1 and IL-2 is inhibited, whichexplains the suppression of T-cell-dependentimmune responses. In addition, glucocorticoidsinterfere with inflammatory cytokinesand signaling molecules at various othersites. Glucocorticoids are used in organtransplantations, autoimmune diseases, andallergic disorders. Systemic use carries therisk of iatrogenic Cushing syndrome (p. 244).Ciclosporin and related substances inhibitthe production of cytokines, in particularinterleukin-2. In contrast to glucocorticoids,the plethora of accompanying metabolic effectsisabsent(seep.306formoredetails).Daclizumab and basiliximab are monoclonalantibodies against the receptor for IL-2. They consist of murine Fab fragments andahumanFc-segment.Theyareusedtosuppresstransplant rejection reactions.Anakinra is a recombinant form of anendogenous antagonist at the interleukin-1receptor; it is used in rheumatoid arthritis(p. 332).III. Disruption of cell metabolism with inhibitionof proliferation. At dosages belowthose needed to treat malignancies, somecytostatics are also employed for immunosuppression;e. g., azathioprine, methotrexate,and cyclophosphamide. The antiproliferativeeffect is not specific for lymphocytesand involves both T and B cells.Mycophenolate mofetil has a more specificeffect on lymphocytes than on other cells. Itinhibits inosine monophosphate dehydrogenase,which catalyzes purine synthesis inlymphocytes. It is used in acute tissue rejectionresponses.

Inhibition of Immune Responses 305A. Immune reaction and immunosuppressivesAntigenMacrophagePhagocytosisDegradationPresentationVirus-infected cell,transplanted cell.tumor cellSynthesis of"foreign" proteinsPresentationGlucocorticoidsInhibition ofcytokinesynthesis,e. g.,IL-1IL-2UptakeDegradationPresentationMHC IIMHC IICD4T-HelpercellIL-1CD3MHC IT-cellreceptorCD8CD3Muromonab-CD3monoclonalantibodyCalcineurininhibitorsB-LymphocyteInterleukinsIL-2T-LymphocyteInhibition ofcytokinesynthesisIL-2ProliferationandDaclizumabBasiliximabIL-2 receptorblockadedifferentiationinto plasma cellsSirolimusSuppressionof IL-2 effectCytotoxicT-lymphocytesAntibody-mediatedimmune reactionLymphokinesChemotaxisImmune reaction:delayedhypersensitivityElimination of“foreign” cellsCytotoxicantiproliferativesubstancesAzathioprineMethotrexateCyclophosphamideMycophenolatemofetil

306 Immune ModulatorsIV. Anti-T-cell immune serum is obtainedfrom animals immunized with human T-lymphocytes. The antibodies bind to anddamage T cells and can thus be used to attenuatetissue rejection.Ciclosporin is of fungal origin; it is a cyclicpeptide composed of 11, in part atypical,amino acids. Therefore, orally administeredciclosporin is not degraded by gastrointestinalproteases. In T-helper cells, it inhibits theproduction of interleukin-2 by interfering atthe level of transcriptional regulation. Normally,“nuclear factor of activated T cells,”(NFAT) promotes the expression of interleukin-2.This requires dephosphorylation of theprecursor, phosphorylated NFAT, by the phosphatasecalcineurin, enabling NFAT to enterthe cell nucleus from the cytosol. Ciclosporinbinds to the protein cyclophilin in the cellinterior; the complex inhibits calcineurin,hence the production of interleukin-2.The breakthroughs in modern transplantationmedicine are largely attributable to theintroduction of ciclosporin. It is now alsoemployed in certain autoimmune diseases,atopic dermatitis, and other disorders.The predominant adverse effect of ciclosporinis nephrotoxicity. Its dosage must betitrated so that blood levels are neither toohigh (risk of renal injury) nor too low (rejectionreaction). To complicate the problem,ciclosporin is a substance dif cult to managetherapeutically. Oral bioavailability is incomplete.Back-transport of the drug into the gutlumen occurs via the P-glycoprotein ef uxpump, in addition to metabolization by cytochromeoxidases of the 3A subfamily. HepaticCYP3A4 enzymes contribute to presystemicelimination and are responsible forelimination of systemically available ciclosporin.Diverse drug interactions may occurby interference with CYP3A and P-glycoprotein.For optimal dosage adjustment, monitoringof plasma levels is mandatory.Drug-mediated suppression of transplantrejection entails long-term treatment. Protractedimmunosuppression carries an increasedrisk of malignomas. Risk factors forcardiovascular diseases may be adversely affected—acritical and important concern inlong-term prognosis.Tacrolimus is a macrolide antibiotic fromStreptomyces tsukubaensis. In principle, itacts like ciclosporin. At the molecular level,however, its “receptor” is not cyclophilin buta so-called FK-binding protein. Tacrolimus islikewise used to prevent allograft rejection.Its epithelial penetrability is superior to thatof ciclosporin, allowing topical application inatopic dermatitis.Sirolimus (rapamycin) isanothermacrolide,produced by Streptomyces hydroscopicus.Its immunosuppressant action, evidently,does not appear to involve inhibitionof calcineurin. It forms a complex with theFK protein, imparting a special conformationon it; and the complex then inhibits themTOR (mammalian target of rapamycin)phosphatase. The latter operates in the signalingpath leading from the interleukin-2receptor to activation of mitosis in lymphocytes.Thus, sirolimus inhibits lymphocyteproliferation. It is approved for the preventionof transplant rejection.

Inhibition of Immune Responses 307A. Calcineurin inhibitors and sirolimus (rapamycin)Activated T-helper lymphocyteCyclophilinCiclosporinCalcineurinNFATPImmunophilin/drugcomplexH3CH3CH 3CNCOCH CH 2 CHCH 3CHCH 2CHCOH 3CH 3CNCH 3CHCHCOHCHCHOH3CCH 3CH 2CH CH 3CHCH 3CH 2N CH CO N CH CH OCH 3CH 2NCON CH 3PH 3CNOCDCHCH 3NHCOHCH N CO CHCH 3H 3 CCH 2CHON CCH 3CHHN COCH CH 3CH 3CHCH 2CH CH3CH 3CH 3DNANFATSynthesisCiclosporinMeasurement!IL-2and otherlymphokinesIL-2receptorCYP3AP-glycoproteinPlasmaconcentrationCYP3AInhibition oftransplantrejectionNephrotoxicitymTORFK-binding proteinSirolimusLong-term adverse effectsNeoplasia, hypertension,hyperlipidemia, hyperglycemiaLymphocyteproliferationFK-binding proteinTacrolimus

308 Antidotes Antidotes and Treatment ofPoisoningsDrugs used to counteract drug overdosageareconsideredundertheappropriateheadings;e. g., physostigmine with atropine; naloxonewith opioids; flumazenil with benzodiazepines;antibody (Fab fragments) withdigitalis; and N-acetylcysteine with acetaminophenintoxication.Chelating agents (A) serve as antidotes inpoisoning with heavy metals. They act tocomplex and, thus, “inactivate” heavy metalions. Chelates (from Greek: chele =pincer[ofcrayfish]) represent complexes between ametal ion and molecules that carry severalbinding sites for the metal ion. Because oftheir high af nity, chelating agents “attract”metal ions present in the organism. The chelatesare nontoxic, are excreted predominantlyvia the kidney, and maintain a tightorganometallic bond in the concentrated,usually acidic, milieu of tubular urine andthus promote the elimination of metal ions.Na 2 Ca-EDTA is used to treat lead poisoning.This antidote cannot penetrate throughcell membranes and must be given parenterally.Because of its high binding af nity,the lead ion displaces Ca 2+ from its bond.The lead-containing chelate is eliminated renally.Nephrotoxicity predominates amongthe unwanted effects. Na 3 Ca-pentetate is acomplex of diethylenetriaminopentaaceticacid (DPTA) and serves as antidote in leadand other metal intoxications.Dimercaprol (BAL, British Anti-Lewisite)was developed in World War II as an antidoteagainst vesicant organic arsenicals (B).It is able to chelate various metal ions. Dimercaprolforms a liquid, rapidly decomposingsubstance that is given intramuscularlyin an oily vehicle. A related compound, bothin terms of structure and activity, is dimercaptopropanesulfonicacid, whosesodiumsalt is suitable for oral administration. Shivering,fever, and skin reactions are potentialadverse effects.Deferoxamine derives from Streptomycespilosus. The substance possesses a very highiron-binding capacity but does not withdrawiron from hemoglobin or cytochromes. It ispoorly absorbed enterally and must be givenparenterally to cause increased excretion ofiron. Oral administration is indicated only ifenteralabsorptionofironistobecurtailed.Unwanted effects include allergic reactions.It should be noted that bloodletting is themost effective means of removing iron fromthe body; however, this method is unsuitablefor treating conditions of iron overloadassociated with anemia.D-Penicillamine can promote the eliminationof copper (e. g., in Wilson disease)and of lead ions. It can be given orally. Twoadditional indications are cystinuria andrheumatoid arthritis. In cystinuria, formationof cystine stones in the urinary tract isprevented because the drug can form a disulfidewith cysteine that is readily soluble.In rheumatoid arthritis, penicillamine can beused as a basal regimen (p. 332). The therapeuticeffect may result in part from a reactionwith aldehydes, whereby polymerizationof collagen molecules into fibrils is inhibited.Unwanted effects are cutaneousdamage (diminished resistance to mechanicalstress with a tendency to form blisters;p. 74), nephrotoxicity, bone marrow depression,and taste disturbances.Apart from specific antidotes (if they exist),the treatment of poisonings also calls forsymptomatic measures (control of bloodpressure and blood electrolytes; monitoringof cardiac and respiratory function; preventionof toxin absorption by activated charcoal).An important step is early emptying ofthestomachbygastriclavageand,ifnecessary,administration of an osmotic laxative.Use of emetics (saturated NaCl solution, ipecacsyrup, apomorphine s.c.) is inadvisable.

Antidotes and Treatment of Poisonings 309A. Chelation of lead ions by EDTANa 2 Ca-EDTA2Na +Ca2+CH 2CH 2N CH 2CO - ONCH 2COO -O -CH 2COCH 2EDTA: Ethylenediamine tetra acetateCOO -B. ChelatorsH 2 CDimercaprol (i.m.)H 2 CCHSH SHCHSH SHCH 2CH 2Arsenic, mercury,gold ionsDMPSOSOOHDimercaptopropanesulfonateDeferoxamineNCO–O O HND-PenicillamineCH*CH 3NHHS NH2OFe 3 +–OONβ, β-DimethylcysteineC –OOC chelation withNCHNH 3Cu 2+ and Pb 2+3H +2O – Na +H 3 CCCOOHDissolution of cystinestones:Cysteine-S-S-CysteineInhibition ofcollagenpolymerization

310 AntidotesReactivators of phosphorylated acetylcholinesterase(AChE). Certain organic phosphoricacid compounds bind with high af n-ity to a serine OH group in the active centerof AChE and thus block the hydrolysis ofacetylcholine. As a result, the organism ispoisoned with its own transmitter substance,acetylcholine. This mechanism operatesnot only in humans and warm-bloodedanimals but also in lower animals, ACh havingbeen “invented” early in evolution. Thus,organophosphates enjoy widespread applicationas insecticides. Time and again, theiruse has led to human poisoning becausethese toxicants can enter the body throughthe intact skin or inhaled air. Depending onthe severity, signs of poisoning include excessiveparasympathetic tonus, ganglionicblockade, and inhibition of neuromusculartransmission leading to peripheral respiratoryparalysis. Specific treatment of the intoxicationconsists in administration of extremelyhigh doses of atropine and reactivationof acetylcholinesterase with pralidoximeor obidoxime (A).Unfortunately, the organophosphateshave been misused as biological weapons.In World War II, they were stockpiled on bothsides but not deployed. The ef cacy of thepoisons was subsequently “demonstrated” insmaller local armed conflicts in developingcountries. In the present global situation, thefear has arisen that organophosphates maybe used by terrorist groups. Thus, understandingthe signs of poisoning and the principlesof treatment are highly important.Tolonium chloride (toluidine blue). Browncoloredmethemoglobin, containing trivalentinstead of divalent iron, is incapable ofcarrying O 2 . Under normal conditions,methemoglobin is produced continuously,but reduced again with the help of glucose-6-phosphate dehydrogenase. Substancesthat promote formation of methemoglobin(B) may cause a lethal deficiency of O 2 . Toloniumchloride is a redox dye that can begiven i.v. to reduce methemoglobin.Antidotes for cyanide poisoning (B). Cyanideions (CN – )entertheorganismintheform of hydrocyanic acid (HCN); the lattercan be inhaled, released from cyanide saltsin the acidic stomach juice, or enzymaticallyliberated from bitter almonds in the gastrointestinaltract. The lethal dose of HCN canbe as low as 50 mg. CN – binds with highaf nity to trivalent iron and thereby arrestsutilization of oxygen via mitochondrial cytochromeoxidases of the respiratory chain.Internal asphyxiation (histotoxic hypoxia)ensues while erythrocytes remain chargedwith O 2 (venous blood colored bright red).In small amounts, cyanide can be convertedto the relatively nontoxic thiocyanate(SCN – ) by hepatic “rhodanese” or sulfurtransferase.As a therapeutic measure, sodiumthiosulfate can be given i.v. to promoteformation of thiocyanate, which is eliminatedin urine. However, this reaction is slowin onset. A more effective emergency treatmentis the i.v. administration of the methemoglobinforming agent 4-dimethylaminophenol,which rapidly generates trivalentiron from divalent iron in hemoglobin. Competitionbetween methemoglobin and cytochromeoxidase for CN – ions favors the formationof cyanmethemoglobin. Hydroxycobalamin(= vitamin B 12a )isanalternative,very effective antidote because its centralcobalt atom binds CN – with high af nity togenerate cyanocobalamin (= vitamin B 12 ).Ferric ferrocyanide (“Berlin blue” [B]) isused to treat poisoning with thallium salts(e. g., in rat poison), initial symptoms ofwhich are gastrointestinal disturbances, followedbynerveandbraindamage,aswellashair loss. Thallium ions present in the organismare secreted into the gut but undergoreabsorption. The insoluble, nonabsorbablecolloidal Berlin blue binds thallium ions. It isgiven orally to prevent absorption of acutelyingested thallium or to promote clearancefrom the organism by intercepting thalliumthat is secreted into the intestines (B).

Antidotes and Treatment of Poisonings 311A. Reactivation of ACh-esterase by an oximeC H 3O Acetylcholine CH 3C O CH 2 CH 2+N CH 3CH 3HONH 3 CHCPralidoximeN+CH 3 CH 3CH 2 CH 2O OCH 3 CH 3CH 2 CH 2O OP OOParaoxon residueHOPOONHCH 3 CN+AldoximeSerineACh-esterasemoleculeInhibition ofACh-esteraseby paraoxonSerineACh-esteraseOxime-phosphonateformationRelease ofactive centerB. Poisons and antidotesH 2 NO 2 NSubstances formingmethemoglobine.g., NO 2Fe III -HbNitriteAnilineNitrobenzeneFe II -HbSCNsynthetaseNa 2 S 2 O 3CN - Fe III -HbHCNDMAPTolonium chlorideFe III 4 [Fe II (CN) 6 ] 3(toluidine blue)Tl + =ThalliumionTl + Tl +CH3NH3C+SNNH2Cl –CH3Fe3+Vitamin B 12Tolonium chloride(toluidine blue)Arrest of O 2utilizationVitamin B 12aTl excretion

Therapy of Selected DiseasesHypertension 314Angina Pectoris 316Antianginal Drugs 318Myocardial Infarction 320Congestive Heart Failure 322Hypotension 324Gout 326Obesity 328Osteoporosis 330Rheumatoid Arthritis 332Migraine 334Common Cold 336Atopy and Antiallergic Therapy 338Bronchial Asthma 340Emesis 342Alcohol Abuse 344Local Treatment of Glaucoma 346

314 Therapy of Selected Diseases HypertensionCardiovascular diseases are the leadingcause of death in the Western world. Basically,atherosclerosis manifests itself in threemajor organs and thereby leads to severesecondary diseases. Coronary disease resultsfrom atherosclerosis of the coronary arteriesand culminates in myocardial infarctionwhen vessels are occluded by a thrombus.In the brain, atherosclerosis gives rise to arterialthrombi or ruptures that result in astroke. Atherosclerosis in the kidney leadsto renal failure. Since these diseases significantlylower life expectancy, early recognitionand elimination of risk factors (hypertension,diabetes mellitus, hyperlipidemia,and smoking) that promote atherosclerosisare essential.Hypertension is considered to be presentwhen systolic blood pressure exceeds140 mmHg and the diastolic value liesabove 90 mmHg. Since cardiovascular riskincreases over a wide range with increasingblood pressure, no “threshold value” existsthat defines hypertension unequivocally. Ifother risk factors are present, blood pressureshould be brought down to an evenlower level (in diabetes mellitus below130/80 mmHg). Therapeutic objectives comprisethe prevention of organ damage andreduction of mortality. Because these targetparameters cannot be measured in individualpatients, the “surrogate parameter” of loweringof blood pressure is defined as theimmediate goal. Before drug therapy is instituted,the patient has to be instructed tolower body weight (BMI < 30), to reduceconsumption of alcohol (in men < 20–30 gethanol/day; in women 10–20 g/day), to stopsmoking, and to restrict the daily intake ofNaCl (to 6 g/day).The drugs of first choice in antihypertensivetherapy are those that have been unambiguouslyshown in clinical studies to reducemortality of hypertension—diuretics, ACE inhibitorsand AT 1 antagonist, β-blockers, andcalcium antagonists.Among the diuretics, thiazides are particularlyrecommended for treatment of hypertension.To avoid undue loss of K + ,combinationwith triamterene or amiloride is oftenadvantageous.ACE inhibitors prevent the formation ofangiotensin II by angiotensin-converting enzyme(ACE) and thereby reduce peripheralvascular resistance and blood pressure. Inaddition, ACE inhibitors prevent the effectof angiotensin II on protein synthesis inmyocardial and vascular muscle cells, andthus diminish ventricular hypertrophy. Asadverse effects, ACE inhibitors may provokedry cough, impaired renal function, and hyperkalemia.When ACE inhibitors are poorlytolerated, an AT 1 -receptor antagonist can begiven.From the group of antagonists at β-adrenoceptors,β 1 -selective blockers are mainlyused (e. g., metoprolol). Owing to blockade ofβ 2 -receptors, β-blockers can impair pulmonaryfunction, particularly in patients withchronic obstructive lung disease.Among calcium antagonists, dihydropyridineswith long half-lives are advantageousbecause short-acting drugs, which rapidlylower blood pressure, are prone to elicit reflextachycardia.Fewer that 50% of hypertensive patientsare adequately managed by monotherapy. Ifthe monotherapy fails, either the drugshould be discontinued or two agents shouldbe combined in reduced dosage (thiazideand β-blocker, or/and ACE inhibitor, or/andcalcium-antagonist). Combinations thatabolish the counterregulation against theprimary antihypertensive drug are especiallyeffective. For instance, diuretic-induced lossof Na + and water leads to a compensatoryactivation of the renin–angiotensin systemthat can be eliminated by ACE inhibitors orAT 1 -antagonists.

Hypertension 315A. Risk factors of atherosclerosis and secondary diseasesBrainR i s k f a c t o r sHypertension, hypercholesterolemia,diabetes mellitus, smokingAtherosclerosisHeartStroke:InfarctionHemorrhageKidneyRenalfailureCoronaryheart diseaseMyocardialinfarctionCongestiveheart failureDiminished life expectancyB. Therapy of hypertensionHypertension > 140/90 mmHgHealthy diet (low NaCl),weight reduction, no smoking,alcohol restriction, exerciseThiazide diureticsIf antihypertensive effect insufficient, add:β-Blocker or ACE inhibitor,angiotensin receptor antagonist or calcium antagonistIf still not sufficient:Combination therapy:+ clonidine or α 1 -antagonists or vasodilatorsTherapeutic aim:Lowering of blood pressure(< 140/90, in diabetes < 130/80 mmHg);and, hence, reduction in cardiovascular mortality

316 Therapy of Selected Diseases Angina PectorisAn anginal pain attack signals a transienthypoxiaofthemyocardium.Asarule,theoxygen deficit results from inadequate myocardialblood flow due to narrowing of largercoronary arteries. The underlying causes aremost commonly an atherosclerotic change ofthe vascular wall (coronary sclerosis withexertional angina); very infrequently a spasmodicconstriction of a morphologicallyhealthy coronary artery (coronary spasmwith angina at rest; variant angina); or moreoften a coronary spasm occurring in an atheroscleroticvascular segment.The goal of treatment is to prevent myocardialhypoxia either by raising blood flow(oxygen [O 2 ] supply) orbyloweringmyocardialoxygen demand (O 2 demand) (A).Factors determining oxygen supply. Theforce driving myocardial blood flow is thepressure difference between the coronary ostia(aortic pressure) and the opening of thecoronary sinus (right atrial pressure). Bloodflow is opposed by coronary flow resistance,which includes three components:1. Owing to their large caliber, the proximalcoronary segments do not normally contributesignificantly to flow resistance.However, in coronary sclerosis or spasm,pathological obstruction of flow occurshere. Whereas the more common coronarysclerosis cannot be overcome pharmacologically,the less common coronaryspasm can be relieved by appropriate vasodilators(nitrates, nifedipine).2. The caliberofarteriolarresistancevesselscontrols blood flow through the coronarybed. Arteriolar caliber is determined bymyocardial O 2 tension and local concentrationsof metabolic products, and is “automatically”adjusted to the requiredblood flow (B, healthysubject).Thismetabolicautoregulation explains why anginalattacks in coronary sclerosis occur onlyduring exercise (B, patient). At rest, thepathologically elevated flow resistance iscompensated by a corresponding decreasein arteriolar resistance, ensuringadequate myocardial perfusion. Duringexercise, further dilation of arterioles isimpossible. As a result, there is ischemiaassociated with pain. Pharmacologicalagents that act to dilate arterioles wouldthus be inappropriate because at rest theymay divert blood from underperfused intohealthy vascular regions on account ofredundant arteriolar dilation. The resulting“steal effect” could provoke an anginalattack.3. The intramyocardial pressure, i. e., systolicsqueeze, compresses the capillary bed.Myocardial blood flow is halted duringsystole and occurs almost entirely duringdiastole. Diastolic wall tension (“preload”)depends on ventricular volume and fillingpressure. The organic nitrates reduce preloadby decreasing venous return to theheart.Factors determining oxygen demand. Theheart muscle cell consumes the most energyto generate contractile force. O 2 demand riseswith an increase in (1) heart rate, (2)contractionvelocity, (3) systolic wall tension(“afterload”). The last depends on ventricularvolume and the systolic pressure neededto empty the ventricle. As peripheral resistanceincreases, aortic pressure rises and,hence, the resistance against which ventricularblood is ejected. O 2 demand is loweredby β-blockers and calcium-antagonists, aswell as by nitrates (p. 318).

Angina Pectoris 317A. O 2 supply and demand of the myocardiumO 2-supplyduringdiastoleO 2-demandduringsystoleFlow resistance:Left atrium1. Heart rate1. Coronary arterialcaliberCoronary artery2. Contractionvelocity2. Arteriolarcaliber3. Diastolicwall tension= PreloadRightatriumPressure pLeft ventriclePressure pp-force3. Systolic walltension= AfterloadTimeVenoussupplyVol.Vol.AortaPeripheralresistanceVenousreservoirB. Pathogenesis of exertion angina in coronary sclerosisHealthy subjectPatient with coronary sclerosisNarrowRestWideCompensatorydilatation ofarteriolesRateContractionvelocityAfterloadExerciseWideWideAdditionaldilatationnot possibleAnginapectoris

318 Therapy of Selected Diseases Antianginal DrugsAntianginal agents derive from three druggroups, the pharmacological properties ofwhich have already been presented in moredetail: the organic nitrates (p.124), the calciumantagonists (p.126), and the β-blockers(p. 96).Organic nitrates (A) increase blood flow,hence O 2 supply, because diastolic wall tension(preload)declinesasvenousreturntothe heart is diminished. Thus, the nitratesenable myocardial flow resistance to be reducedeven in the presence of coronary sclerosiswith angina pectoris. In angina due tocoronary spasm, arterial dilation overcomesthe vasospasm and restores myocardial perfusionto normal. O 2 demand falls because ofthe ensuing decrease in the two variablesthat determine systolic wall tension (afterload):ventricular filling volume and aorticblood pressure.Calcium antagonists (B) decreaseO 2 demandby lowering aortic pressure, one of thecomponents contributing to afterload. Thedihydropyridine nifedipine, is devoid of acardiodepressant effect, but may give riseto reflex tachycardia and an associated increasein O 2 demand. The catamphiphilicdrugs verapamil and diltiazem are cardiodepressant.Reduced beat frequency and contractilitycontribute to a reduction in O 2 demand;however, AV-block and mechanicalinsuf ciency can dangerously jeopardizeheart function. In coronary spasm, calciumantagonists can induce spasmolysis and improveblood flow.β-Blockers (C) protect the heart againstthe O 2 -wasting effect of sympathetic driveby inhibiting β 1 -receptor-mediated increasesin cardiac rate and speed of contraction.Uses of antianginal drugs (D). For relief ofthe acute anginal attack, rapidly absorbeddrugs devoid of cardiodepressant activity arepreferred. The drug of choice is nitroglycerin(NTG, 0.8–2.4 mg sublingually; onset of actionwithin 1–2 minutes; duration of effect~ 30 minutes). Isosorbide dinitrate (ISDN)can also be used (5–10 mg sublingually);compared with NTG, its action is somewhatdelayed in onset but of longer duration. Finally,nifedipine may be useful in chronicstable, or in variant angina (5–20 mg, capsuleto be bitten and the content swallowed).For sustained daytime angina prophylaxis,nitrates are of limited value because“nitrate pauses” of about 12 hoursareappropriateifnitratetoleranceistobeavoided. If attacks occur during the day,ISDN, or its metabolite isosorbide mononitrate,maybegiveninthemorningandatnoon (e. g., ISDN 40 mg in extended-releasecapsules). Because of hepatic presystemicelimination, NTG is not suitable for oral administration.Continuous delivery via atransdermal patch would also not seem advisablebecause of the potential developmentof tolerance. With molsidomine, thereis less risk of a nitrate tolerance; however, itsclinical use is restricted owing to its potentialcarcinogenicity.The choice between calcium antagonistsmust take into account the differential effectof nifedipine versus verapamil or diltiazemon cardiac performance (see above). Whenβ-blockers are given, the potential consequencesof reducing cardiac contractility(withdrawal of sympathetic drive) must bekept in mind. Since vasodilating β 2 -receptorsare blocked, an increased risk of vasospasmcannot be ruled out. Therefore, monotherapywith β-blockers is recommended only in anginadue to coronary sclerosis, but not invariant angina.

Antianginal Drugs 319A. Effects of nitratesp Diastole SystolepVolVolVenouscapacitancevesselsPreloadNitratetoleranceAfterloadO 2 -demandResistancevesselsO 2 -supplyVasorelaxationRelaxation ofcoronary spasmNitrates, e.g., nitroglycerin (GTN), isosorbide dinitrate (ISDN)B. Effects of Ca-antagonistsC. Effects of β-blockerspCaantagonistsRestRelaxationofresistancevesselsβ-BlockerSympatheticsystemAfterloadRateO 2 -demandRelaxation ofcoronary spasmContractionvelocityExerciseD. Clinical uses of antianginal drugsTherapy of attackCoronary sclerosisAngina pectorisGTN, ISDNNifedipineCoronary spasmAnginal prophylaxisβ−BlockersLong-acting nitratesCa-antagonists

320 Therapy of Selected Diseases Acute Coronary Syndrome—Myocardial InfarctionMyocardial infarction (MI) is caused by theacute thrombotic occlusion of a coronary artery.The myocardial region that has been cutoff from its blood supply dies within a shorttime owing to the lack of O 2 and glucose. Theloss in functional muscle tissue results inreduced cardiac performance. In the infarctborder zone, spontaneous pacemaker potentialsmay develop, leading to fatal ventricularfibrillation. The patient experiences severepain, a feeling of annihilation, and fear ofdying.MI usually develops after rupture or erosionof an atherosclerotic plaque within acoronary blood vessel. At this site, the clottingcascade is activated and the resultantthrombus occludes the lumen. In all patientsunder suspicion of MI, immediate therapyhas to be initiated by the emergency physician.To relieve the patient from severe painand anxiety, morphine and a benzodiazepineneed to be given. Antiplatelet drugs and heparinare necessary for preventing further formationof thrombi. Nitroglycerin can be usedto reduce cardiac load. When blood pressureand heart rate have stabilized, a β-blockercan be administered to lower cardiac O 2 consumptionand the risk of arrhythmias. Infusionof lidocaine is required to counter thethreat of arrhythmias. The chance of survivalof the MI patient depends on the intervalbetween the onset of infarction and the startof therapy.In the hospital, ECG and laboratory testsare performed promptly to determine thesubsequent treatment strategy. When cardiomyocytesdie, contractile proteins (troponin)or myocardial enzymes (creatine kinase,CK-MB) are liberated and can be detected inblood for diagnostic purposes. Marked elevationof the ST segment in the ECG raisesthe strong suspicion of a complete occlusionof a coronary artery (ST elevation MI, STEMI).In these MI patients, reperfusion of the affectedarea as early and as completely aspossible may be life-saving. In this situation,removal of the coronary stenosis with a ballooncatheter combined with implantationof a stent offers the best chance of survivalbut can be performed only in specializedcardiac centers. As dilatation of the vascularstenosis by the heart catheter liberates manythrombogenic mediators, platelet aggregationmust be prevented by administrationof glycoprotein IIb/IIIa receptor antagonists(p.154).If the MI patient cannot be transported toa cardiac center in time, fibrinolytic treatmentof the coronary thrombus is instituted.For this purpose, fibrinolytics (streptokinaseor recombinant tissue plasminogen activators)are given intravenously. Fibrinolysis isassociated with an increased risk of bleeding;cerebral hemorrhages are of particularconcern. A coronary bypass operation isavailable as a third therapeutic option.Patients with persistent angina pectoriswho lack an elevated ST segment in theECG but show an elevated blood level oftroponin may have a non-STEMI (“NSTEMI”).The most frequent cause is thrombi thathave moved from the larger coronary arteriesinto smaller branches to produce ablockage there. If neither ST segment elevationnor biochemical MI markers can be ascertained,unstable angina pectoris ispresent, which is initially treated with antiplateletdrugs.Post-MI management calls for strict adherenceto a program of secondary prevention.Cardiac risk factors have to be excludedor modified, for instance, by reduction ofoverweight, cessation of smoking, optimalcontrol of diabetes mellitus, and physicalexercise (a dog that loves to run is an idealtraining partner). Supportive pharmacotherapeuticmeasures include administration ofplatelet aggregation inhibitors, β-blockers,and ACE inhibitors.

Myocardial Infarction 321A. Myocardial infarction: pharmacotherapeutic approachesPatientAcute symptoms:severe painsense of impendingdoomfear of dyingAcute care measures– Nitroglycerin (reduction ofpre- and afterload)– Acetylsalicylic acid(if needed i.v.)(inhibition of plateletaggregation)– Morphine (analgesia, sedation)– Oxygen via nasal tubeHospitalizationwith minimal delayAcute coronary syndromeAngina pectoris > 20 minThrombusPlaque ruptureDistalthrombusECGST-elevationTNo ST-elevationSLaboratoryCK-MBTroponin-I, -TTroponin-I, -T–DiagnosisMyocardial infarction(“STEMI”)Myocardial infarction(“NSTEMI”)Unstableangina pectorisTherapyGeneral: O 2 , acetylsalicylic acid,heparin, nitrates, β-blocker, morphineAcetylsalicylic acid,clopidrogelPTCA (Stent)GPIIb/IIIa-Antagonistorfibrinolysisorbypass surgeryPTCA (Stent)GPIIb/IIIa-AntagonistCardiaccatheterizationSecondary preventionDischarge– Acetylsalicylic acid– β-Blocker– ACE inhibitorpossibly:– Clopidrogel– Phenprocoumon– Statins

322 Therapy of Selected Diseases Congestive Heart FailureIn chronic congestive heart failure, cardiacpump performance falls below a level requiredby the body’s organs for maintainingfunction and metabolism. The most commonprimary causes of heart failure are coronarydisease, hypertension, volume overload, orcardiomyopathies. Diminished cardiac performanceleads to a precardial congestionof venous blood. Congestion in front of theleft ventricle causes dyspnea and pulmonaryedema. Ankle edemas, enlarged liver, andascites signal congestion in front of the rightventricle.The degree of severity of myocardial failureis categorized according to the New YorkHeart Association (NYHA) Functional ClassificationSystem. Stages I—IV reflect an increasinglevel of disability.The decrease in cardiac function activatesseveral compensatory mechanisms thatoperate to maintain perfusion of organs.These include activation of the sympatheticnerve system and of the renin–angiotensinsystem. Increased release of norepinephrineraises cardiac rate and evokes peripheralvasoconstriction. Increased production ofangiotensin II promotes both vasoconstrictionand release of aldosterone from theadrenals. These compensations increase cardiacafterload and plasma volume is expandedbecause the kidney retains waterand sodium. Although such “auxiliary” countermeasuresafford transient help in maintainingcardiac output, (nor)epinephrine, aldosterone,and angiotensin II promote theprogression of myocardial insuf ciency: hypertrophyand fibrosis are the outcome. Successfultherapy of chronic congestive failureis therefore contingent on inhibition ofcompensation mechanisms.Although β-blockers were formerly heldto be contraindicated, this drug class hasbeen used successfully since the mid-1990sin the management of heart failure. A prerequisiteis to begin therapy with very smalldaily doses. Every 2–3 weeks, the daily dosecan be increased in small increments, as longas the patient does not develop bradycardia.Since bisoprolol, metoprolol, and carvedilolhave proved effective in large clinical trials,these β-blockers would be the preferredchoice for this indication.ACE inhibitors are the appropriate agentsfor inhibiting the renin–angiotensin II system;they prevent the production of angiotensinII. The effect of angiotensin II receptorantagonistsisequivalenttothatofACEinhibitors.Both interventions for attenuatingcompensatory mechanisms improve theclinical state of patients (less hospitalization)and increase life expectancy.In edemas, dyspnea, and advanced myocardialinsuf ciency, diuretics are indispensable.Digitalis glycosides augment contractileforceandarelikewiseusedinsevereformsof insuf ciency, specifically in the presenceof concomitant atrial fibrillation. Because ofthe narrow margin of safety, the digoxindose must be adjusted individually in eachpatient.Drugswithanacutepositiveinotropicaction(e. g., catecholamines or phosphodiesteraseinhibitors) may be of transient helpin sudden decompensation but must not begiveninchroniccongestivefailure.

Congestive Heart Failure 323A. Congestive heart failurePerformancedecreaseCongestionHeart failureCardiac outputDiureticsDyspneaEdemasNa+, H 2 O retentionpreloadSpironolactoneAT 1 -blockersACE inhibitorsAldosteroneAngiotensin IIFibrosisHypertrophyDigitalisPositiveinotropicTachycardiaInotropismVasoconstrictionAfterloadβ-BlockerACE inhibitorsRenin–Angiotensin SystemCompensatory mechanismsSympathetic SystemB. Classification and drug therapy of congestive heart failureImpairment of cardiac functionNYHAFunctional ClassI II III IVClinical symptoms slight marked at restACE inhibitorsAT 1 blockerβ-BlockerDiureticsAldosteroneantagonistswhen ACE inhibitors cause adverse effects, e.g., coughInfarctionHypertensionHypertensionEdemasHypokalemiaDigitalis Atrial fibrillation Atrial fibrillation

324 Therapy of Selected Diseases HypotensionThe venous side of the circulation accommodates~ 85% of the total blood volume;because of the low venous pressure (mean~ 15 mmHg), it is referred to as the low-pressuresystem. The arterial vascular beds, representingthe high-pressure system (meanpressure ~ 100 mmHg), contain ~ 15%. Thearterial pressure generates the driving forcefor perfusion of tissues and organs. Blooddraining from these collects in the low-pressuresystem and is pumped back by the heartinto the high-pressure system.The arterial blood pressure (ABP) dependson: (1) the volume of blood per unit of timethat is forced by the heart into the highpressuresystem—cardiac output correspondingto the product of stroke volumeand heart rate (beats/min), stroke volumebeing determined by, inter alia, venous fillingpressure; (2) the counterforce opposingthe flow of blood, i. e., peripheral resistance,which is a function of arteriolar caliber.Chronic hypotension (recumbent systolic BP< 105 mmHg). Primary idiopathic hypotensiongenerally has no clinical importance. Ifsymptoms such as lassitude and dizzinessoccur, a program of physical exercise insteadofdrugsisadvisable.Secondary hypotension is a sign of anunderlying disease that should be treatedfirst. If stroke volume is too low, as in heartfailure, a cardiac glycoside can be given toincrease myocardial contractility and strokevolume. When stroke volume is decreasedowing to insuf cient blood volume, plasmasubstitutes will be helpful in treating bloodloss, whereas aldosterone deficiency requiresadministration of a mineralocorticoid(e. g., fludrocortisone). The latter is the drugof choice for orthostatic hypotension due toautonomic failure. A parasympatholytic (orelectrical pacemaker) can restore cardiacrate in bradycardia.Acute hypotension. Failure of orthostaticregulation. A change from the recumbent tothe erect position (orthostasis) will causeblood within the low-pressure system tosink toward the feet because the veins inbody parts below the heart will be distended,despite a reflex venoconstriction,by the weight of the column of blood in theblood vessels. The fall in stroke volume ispartly compensated by a rise in heart rate.The remaining reduction of cardiac outputcan be countered by elevating the peripheralresistance, enabling blood pressure and organperfusion to be maintained. An orthostaticmalfunction is present when counterregulationfails and cerebral blood flow falls,with resultant symptoms, such as dizziness,“black-out,” or even loss of consciousness. Inthe sympathotonic form, sympatheticallymediatedcirculatory reflexes are intensified(more pronounced tachycardia and rise inperipheral resistance, i. e., diastolic pressure);however, there is failure to compensatefor the reduction in venous return. Prophylactictreatment with sympathomimeticswould therefore hold little promise. Instead,cardiovascular fitness training would appearmore important. An increase in venous returnmay be achieved in two ways. IncreasingNaCl intake augments salt and fluid reservesand, hence, the blood volume (contraindications:hypertension, heart failure).Constriction of venous capacitance vesselsmight be produced by dihydroergotamine.Whether this effect could also be achievedby an α-sympathomimetic, remains debatable.In the very rare asympathotonic form,use of sympathomimetics would certainly bereasonable.

Hypotension 325A. Treatment of hypotensionLow-pressuresystemBrainHigh-pressuresystemLungVenousreturnHeartβ-SympathomimeticsCardiacglycosidesStroke vol. x rate= cardiac outputKidneyBlood pressure (BP)Peripheral resistanceIntestinesArteriolarcaliberSkeletal muscleInitial conditionIncrease of blood volumeBP0.9%NaClSALTNaCl + H 2 OBPRedistribution of blood volumeBPNaCl+ H 2 OConstriction of venous capacitancevessels, e.g., dihydroergotamine ifappropriate, α-sympathomimeticsα-SympathomimeticsParasympatholyticsMineralocorticoid

326 Therapy of Selected Diseases GoutGout is an inherited metabolic disease thatresults from hyperuricemia, an elevation inthe blood of uric acid, the end-product ofpurine degradation. Uric acid is not readilywater-soluble; it therefore tends to crystallizeat unphysiologically elevated concentrations,predominantly in bradytrophic tissues(such as the metatarsophalangeal joint). Likeother crystals, urate crystals provide a strongstimulus for neutrophilic granulocytes andmacrophages. Neutrophils are attracted (1)and phagocytose (2) this indigestible material.In the process, neutrophils release (3)proinflammatory cytokines. Macrophagesalso phagocytose the crystals, injure themselves,and liberate lysosomal enzymes thatlikewise promote inflammation and attacktissues. As a result, an acute and very painfulgout attack may develop (4).The therapy of gout is twofold: (1) treatmentof the acute attack; and (2) chroniclowering of hyperuricemia.1. The acute attack demands prompt actionto relieve the patient from his painfulstate. The classical remedy (already usedby Hippocrates) is colchicine, analkaloidfrom the autumn crocus (Colchicum autumnale).This substance binds with highaf nity to microtubular proteins and impairstheirfunction,causing interaliaarrestof mitosis at metaphase (“spindle poison”).Its acute antigout activity is due to inhibitionof neutrophil and macrophage reactions.The details of these mechanisms arenot completely clear; at any rate, release ofproinflammatory cytokines is prevented.Colchicine is usually given orally (e. g.,0.5 mg hourly up to a maximum daily doseof 8 mg). Colchicine therapy is limited byinjury to the gastrointestinal epithelium,which divides rapidly and therefore reactswith high sensitivity to the spindle poison.Nonsteroidal anti-inflammatory drugs, suchas diclofenac and indometacin, are also effective;on occasion, glucocorticoids may beof additional help.2. Chronic lowering of urate levels below6 mg/l blood requires (a) an appropriatediet that avoids purine (cell nuclei)-richfoods (e. g., organ offal); and (b) uricostaticsfor decreasing uric acid production.Allopurinol, as well as its accumulating metabolite,oxypurinol (“alloxanthine”), inhibitsxanthine oxidase, which catalyzes urateformation from hypoxanthine via xanthine.These precursors are readily eliminated viathe urine. Allopurinol is given orally(300–800 mg/day). Apart from infrequentallergic reactions, it is well tolerated and isthe drug of choice for gout prophylaxis. Goutattacks may occur at the start of therapy butthey can be prevented by concurrent administrationof colchicine (0.5–1.5 mg/day).Uricosurics, suchasprobenecid or benzbromarone(100 mg/day), promote renalexcretion of uric acid. They saturate the organicacid transport system in the proximalrenal tubules, making it unavailable for uratereabsorption. When underdosed, they inhibitonly the acid secretory system, which has asmaller transport capacity. Urate eliminationis then inhibited and a gout attack is possible.In patients with urate stones in the urinarytract, uricosurics are contraindicated.Uricolytics. Nonprimates are able, via theenzyme urate oxidase, to metabolize uricacid to allantoin, a product with better watersolubility and faster renal elimination. Rasburicase,a recombinant urate oxidase, canbegivenbyinfusioninpatientswithmalignantneoplasias, in whom chemotherapy isliable to generate a massive amount of uricacid.

Gout 327A. Gout and its therapyOHOHNNNNHNNNNHAllopurinolHypoxanthineAlloxanthineXanthineOxidaseXanthineColchicineUricostaticUricosuricProbenecidOHNN–O H+HO N NHUric acidNucleusLysosome1H7C3ON S– COO H+H7C3O2NeutrophilgranulocyteChemotacticfactors3Anion (urate)reabsorption4Anion secretionGout attack

328 Therapy of Selected Diseases Obesity—Sequelae andTherapeutic ApproachesIn industrialized nations, a significant portionof the population is overweight. TheBody-Mass-Index (BMI) provides a reliableand simple quantitative criterion for assessingthiscondition;itiscalculatedasfollows:BMIbody weight in kg=square of body height in mNormal values range from 22 to 28. Values> 30 are indicative of an overweight condition.Obesity is always the consequence of adisturbed energy balance: caloric intake exceedsconsumption. Almost unavoidably, excessbody weight and obesity lead to diseasesand a shortened lifespan.The most important secondary disordersinclude development of type II diabetes mellitus,which alone shortens life, and hypertension,which together with disturbed lipidmetabolism gives rise to atherosclerosis (anginapectoris, inadequate cerebral bloodflow, etc.). Owing to the constant mechanicalstress, weight-bearing joints suffer, resultingin arthrotic complaints. Finally, obesity givesrise to psychological problems that mayoverwhelm the coping ability of both adultsand children.The treatment of obesity—and it shouldbe treated to safeguard normal life expectancy—isextraordinarily dif cult. Althoughthe principle “eat much less, move muchmore” is so simple, no more than a depressinglylow percentage of patients can be relievedof their condition. Not until the obeseindividual, after suf cient counseling, realizesthat he or she needs to make a change inlifestyle and can then muster suf cient selfdisciplineto stick to the “new life,” will areturn to normal body weight and protectionfrom secondary diseases be achieved. Requisitechanges include a diet low in fat withreduced caloric content (~ 1000 kcal/day),no snacks (sweets, potato chips, lemonades,beer, etc.), and plenty of physical exercise(sports, hiking, swimming, tennis, etc. insteadof the TV easy-chair). Under these conditions,body weight will drop slowly; dramaticchanges of several kilograms in a fewdays are not to be expected. This reductiontherapy must be kept up for months.Regrettably, the pharmacologist mustconfessthatnodrugsexistthatcanberecommendedfor the purpose of weight reduction.The so-called appetite suppressants(anorexiants)actonly,ifatall,foralimitedperiod and are fraught with side effects.Most anorexiants are derivatives of methamphetaminethathavebeenwithdrawnfromthe market. A different mechanism of actionis involved in the case of an inhibitor ofpancreatic lipase, which is required in theintestines for fat absorption. This inhibitor(orlistat) diminishes fat absorption so thatfats reach the lower bowel, where they cancause disturbances: flatulence, steatorrhea,and frequent need to relieve the bowels occurin about 30% of affected subjects. Thesesymptoms correspond exactly to those seenin pancreatic hypofunction which are thenusually treated with pancreatic lipase. Beforean obese person submits to treatment withorlistat, he or she should voluntarily reducethe food fat content by one half to live free ofsuch unpleasant adverse effects.In summary, the obese individual has nochoice but to normalize the energy balanceunder sympathetic guidance and by strengthof will, and thus evade any secondary diseases.

Obesity 329A. Obesity: Sequelae and therapeutic approachesEnergy balanceConsumptionConsumption BMI 25 - 27 IntakeBMI >> 30IntakeTherapyCaloric restrictionIntensive psychological counseling,much exerciseDrugsAnorexiantsMethamphetaminederivativesSibutramineLipase inhibitor orlistatConsequences: life expectancyDiabetes mellitusHyperlipoproteinemiaHypertensionJoint mechanical stressPsychosocial problemsCF 3CH 2 CH NHClCH 3CH 2CH 3HCH 2 CH NCH 3CH 3Fenfluramine(discontinued)Methamphetamine (controlled substance)N CH 3C CHH 2 C CHCH 32CH CH 3CH CH 2 CH 22 CH 3Sibutramine

330 Therapy of Selected Diseases OsteoporosisOsteoporosis is defined as a generalized decreasein bone mass (osteopenia) thatequally affects bone matrix and mineral contentand is associated with a change in spongiosalarchitecture. This condition predisposesto collapse of vertebral bodies andbone fractures with trivial trauma (e. g., hipfractures).Bone substance is subject to continual remodeling.The equilibrium between boneformation and bone resorption is regulatedin a complex manner: a remodeling cycle isinitiated by osteoblasts when these stimulateuninucleated osteoclast precursor cellsto fuse into large multinucleated cells. Stimulationoccurs by direct cell-to-cell contactbetween osteoblasts and osteoclast precursorcells and is mediated by the RANK ligandon the surface of osteoblasts and its receptoron the osteoclasts (or their precursors), aswell as cytokines secreted by osteoblasts.These processes are inhibited by estrogensand a protein secreted by osteoblasts (osteoprotegerin).The osteoclast creates an acidicmilieu, enabling minerals to be solubilized,and then phagocytoses the organic matrix.Hormones regulate these events.In hypocalcemia, the parathyroid increasesits secretion of parathormone, resultingin enhanced liberation of Ca 2+ . Calcitonintransfers active osteoclasts into a restingstate. Calcitonin given therapeuticallyrelieves pain associated with neoplasticbone metastases and vertebral body collapse.Estrogens diminish bone resorptionby (a) inhibiting activation of osteoclasts byosteoblasts and (b) promoting apoptosis ofosteoclasts.Idiopathic osteoporosis cannot be preventedby prophylactic therapy, but its developmentcan be delayed. This requires: ahealthy lifestyle with plenty of physical exercise(sports, hiking), daily intake of calcium(1000 mg/day Ca 2+ ) and of vitamin D(1000 IU/day). The same principle holds forpostmenopausal osteoporosis. Hormonereplacement therapy in postmenopausalwomen has not been successful because ofan increased incidence of breast cancers,thromboembolism, and other adverse effects(p. 250). Long-term hormone replacementtherapy should no longer be carried out.If osteoporosis has become clinicallymanifest, attempts can be made at improvingthe condition by means of drugs, or atleast slowing down further deterioration.Besides administration of calcium and vitaminD, the following options are available.Bisphosphonates (N-containing) structurallymimic endogenous pyrophosphate(see formulae), and like the latter are incorporatedinto the mineral substance of bone.During phagocytosis of the bone matrix, theyare taken up by osteoclasts. There, the N-containing bisphosphonates inhibit prenylationof G-proteins and thus damage the cells.Accordingly, osteoclast activity levels arelowered by alendronate and risedronate,while osteoclast apoptosis is promoted. Theresult is a reduction in bone resorption and adecreased risk of bone fractures.Raloxifene exerts an estrogen-like effecton bone, while acting as an estrogen antagonistin the uterus and breast tissue (p. 254).In terms of fracture prophylaxis, its effectivenessappears inferior to that of bisphosphonates.Thromboembolism and edemaare reported as adverse effects.It should also be mentioned that intermittentslight elevation in the plasma concentrationof parathormone leads to increasedformation of bone substance. The likely explanationis that, under this condition, stimulationof osteoblasts is suf cient to inducesynthesis of bone matrix but not strongenough to activate osteoclasts. This strategyis applied therapeutically by administrationof a fragment (amino acids 1–34) of recombinanthuman parathormone (teriparatide,s.c.).

Osteoporosis 331A. Bone: normal state and osteoporosisNormal stateOsteoporosisOrganic bone matrixBone mineral: hydroxyapatiteB. Regulation of bone remodelingParathyroid hormoneEstrogensProgenitorcellsFusionBiphosphonatesEstrogensRANKLApoptosisOPGRANKLActivation(Pre)OsteoblastsOPGCalcitoninOsteoclastsOHHO P OOOHRANK = receptor activating NF-Κ-BOH OH OHP OH RANKL = RANK-LigandHO P C P OHOOPG = OsteoprotegerinO CH 2 OPyrophosphateBone resorptionStimulationInhibition(CH 2 ) 2AlendronateNH 2

332 Therapy of Selected Diseases Rheumatoid ArthritisRheumatoid arthritis or chronic polyarthritis(A) is a progressive inflammatory jointdisease that intermittently attacks more andmore joints, predominantly those of the fingersand toes. The probable cause of rheumatoidarthritis is a pathological reaction of theimmune system. This malfunction can be promotedor triggered by various conditions, includinggenetic disposition, age-related wearand tear, hypothermia, and infection. An initialnoxiousstimuluselicitsaninflammationof synovial membranes that, in turn, leadsto release of antigens through which theinflammatory process is maintained.The antigen is taken up by synovial antigen-presentingcells; lymphocytes, includingT-helper cells (p. 304), are activated andstart to proliferate. In the process of interactionbetween lymphocytes and macrophages,the intensity of inflammation increases.Macrophages release proinflammatorymessengers; among these, interleukin-1and tumor necrosis factor α (TNFα) areimportant.TNFα is able to elicit a multiplicity ofproinflammatory actions (B) that benefit defenseagainst infectious pathogens but aredetrimental in rheumatoid arthritis. The cytokinesstimulate gene expression for COX-2; inflammation-promoting prostanoids areproduced. The inflammatory reaction increasesactivity of lymphocytes and macrophages,initiating a vicious circle. Synovialfibroblasts proliferate and release destructiveenzymes; the inflamed characteristicpannus tissue develops and destructively invadesjoint cartilage and subjacent bone. Ultimately,ankylosis (loss of joint motion orbone fusion) with connective tissue scar formationoccurs. Concomitant extra-articulardisease may be superimposed. The diseaseprocess is associated with strong pain andrestriction of mobility.Pharmacotherapy. Acutereliefofinflammatorysymptoms can be achieved by prostaglandinsynthase inhibitors (p. 200; nonselectiveCOX inhibitors or COX-2 inhibitors)and by glucocorticoids (p. 244). The inevitablychronic use of both groups of substancesis likely to cause significant adverse effects.Neither can halt the progressive destructionof joints.Substances that are able to reduce therequirement for nonsteroidal anti-inflammatorydrugs and to slow disease progressionare labeled disease-modifying agents.Early use of these drugs is recommended.Their effect develops only after treatmentfor several weeks. Proliferation of lymphocytescan be slowed by methotrexate(p. 304) and leflunomide, which reducesthe availability of pyrimidine nucleotides inlymphocytes (via inhibition of dihydroorotatedehydrogenase). For ciclosporin, seep. 306. In addition, use is made of immunesuppressants such as azathioprine and cyclophosphamide.Intralysosomal accumulationandimpairedphagocyticfunctionmaybe involved in the action of chloroquine orhydroxychloroquine, aswellasgold compounds(i.m.: aurothioglucose or aurothiomalate;oral: auranofin, less effective). Theantibodies, infliximab and adalimumab, aswell as the fusion protein etanercept interceptTNF-α molecules, preventing them frominteracting with membrane receptors of targetcells. Anakinra is a recombinant analogueof the endogenous interleukin-1 antagonist.The mechanisms of action of D-penicillamineand sulfasalazine are unknown.Same of the drugs mentioned possess considerablepotential for adverse effects. Sulfasalazineand methotrexate exhibit a relativelyfavorable risk–benefit ratio. Combinationof disease-modifying drugs is possible.Surgical removal of the inflamed synovialmembrane (synovectomy) frequently provideslong-term relief. If feasible, this approachis preferred because all pharmacotherapeuticmeasures entail significant adverseeffects.

Rheumatoid Arthritis 333A. Rheumatoid ArthritisGenetic predispositionEnvironmental factorsPrecipitatingcausesInfectionTraumaImmune system: reactive against autologous joint tissueSulfasalazine?ProstaglandinsynthesisCOX inhibitorsIL-1 receptorCox-2AnakinraNClCytokines, etc.IL-1, TNFαInfliximabNH2NNH2N N NMethotrexateCH2NCH3NHC2H5EtanerceptH CNOHC 3CHCH2CH2CH2NHOOC (CH2)2CHCOOHChloroquineGold,chloroquine?C2H5MacrophagesAntigen (unknown)LymphocytesÐMethotrexate(purinesynthesis )ÐLeflunomide(pyrimidinesynthesis )ÐCiclosporin(IL-2 synthesisin T-helper cells )D-Penicillamine?B. Tumor necrosis factor α and inhibitorsInfliximab(chimericIgG antibody)Murineportion (Fab)Humanportion (Fc)HomotrimerTNF αEtanercept(fusion protein)TNF αreceptorpartsFc portionTNF αreceptorTumor cellsÐ LysisVessels:Ð ProliferationÐ Adhesion ofblood cellsActivationMacrophages:ÐActivationÐ ChemotaxisSynovial membrane:Ð ProliferationÐ Pannus formationBone:ÐResorption

334 Therapy of Selected Diseases MigraineMigraine is a syndrome characterized by recurrentattacks of intense headache and nauseathat occur at irregular intervals and lastfor several hours. In classical migraine, theattack is typically heralded by an “aura” accompaniedby spreading homonymous visualfield defects with colored sharp edges(“fortification” spectra). In addition, the patientcannotfocusoncertainobjects,hasaravenous appetite for particular foods, and ishypersensitive to odors (hyperosmia) orlight (photophobia). The exact cause of thesecomplaints is unknown; conceivably, theunderlying pathogenetic mechanisms involvelocal release of proinflammatory mediatorsfrom nociceptive primary afferents(neurogenic inflammation) or a disturbancein cranial blood flow. In addition to an ofteninherited predisposition, precipitating factorsare required to provoke an attack, e. g.,psychic stress, lack of sleep, certain foods.Pharmacotherapy of migraine has two aims:stopping the acute attack and preventingsubsequent ones.Treatment of the attack. For symptomaticrelief, headaches are treated with analgesics(acetaminophen, acetylsalicylic acid), andnausea is treated with metoclopramide(pp.116, 342) or domperidone. Since thereis delayed gastric emptying during the attack,drug absorption can be markedly retardedand hence effective plasma levels arenot obtained. Because metoclopramide stimulatesgastric emptying, it promotes absorptionof ingested analgesic drugs and thusfacilitates pain relief.If acetylsalicylic acid is administered i.v. asthe lysine salt, its bioavailability is complete.Therefore, i.v. injection may be advisable inacute attacks.Should analgesics prove insuf ciently effective,sumatriptan (prototype of the triptans)or ergotamine may help prevent animminent attack in many cases. Both substancesare effective in migraine and clusterheadaches but not in other forms of headache.The probable common mechanism ofaction is a stimulation of serotonin receptorsof the 5-HT 1D subtype. Moreover, ergotaminehas af nity for dopamine receptors(†nausea, emesis), as well as α-adrenoceptorsand 5-HT 2 receptors (⁄ vascular tone, ⁄platelet aggregation). With frequent use, thevascular side effects may give rise to severeperipheral ischemia (ergotism). Paradoxically,overuse of ergotamine (> once perweek) may provoke “rebound” headaches,thoughttoresultfrompersistentvasodilation.Though different in character (tensiontypeheadache), these prompt further consumptionof ergotamine. Thus, a viciouscircle develops with chronic abuse of ergotamineor other analgesics that may end withirreversible disturbances of peripheral bloodflow and impairment of renal function.Administered orally, ergotamine and sumatriptanhave only limited bioavailability.Dihydroergotamine may be given by i.m. orslow i.v. injection, sumatriptan subcutaneously,by nasal spray, or as a suppository.When given orally, other triptans such aszolmitriptan, naratriptan, andrizatriptanhave higher bioavailability than sumatriptan.Prophylaxis. Taken regularly over a longerperiod, a heterogeneous group of drugs comprisingpropranolol, nadolol, atenolol, andmetoprolol (β-blockers), flunarizine (H 1 -histamine,dopamine, and calcium antagonist),pizotifen (pizotyline, 5-HT antagonist withstructural resemblance to tricyclic antidepressants),and methysergide (partial 5-HTantagonist) may decrease the frequency, intensity,and duration of migraine attacks.The drug of first choice is one of the β-blockersmentioned.

Migraine 335A: Migraine and its treatmentAcetylsalicylic acid 1000 mgor acetaminophen 1000 mgWhen therapeutic effect inadequateSumatriptanand other triptansor(Dihydro)-Ergotamine6 mg 50–100 mg 1 mg 1–2 mgMigraineMetoclopramideMigraine attack:HeadacheHypersensitivity ofolfaction, gustation,audition, vision,nausea, vomitingNeurogenicinflammation,local edema,vasodilationinhibiteddelayedGastric emptyingDrugabsorptionacceleratedimproved5-HT 1B/1DRelief of migraine5-HT 1B/1D5-HT 1APsychosis5-HT 1ASumatriptanand other triptansD 25-HT 2Nausea,vomitingPlatelet aggregationD 25-HT 2Ergotamineα 1 + α 2Vasoconstrictionα 1 + α 2

336 Therapy of Selected Diseases Common ColdThe common cold—colloquially the flu, catarrh,or grippe (strictly speaking the rarerinfection with influenza viruses)—is an acuteinfectious inflammation of the upper respiratorytract. Its symptoms—sneezing, runningnose (due to rhinitis), hoarseness (laryngitis),dif culty in swallowing and sorethroat (pharyngitis and tonsillitis), cough associatedwith first serous then mucous sputum(tracheitis, bronchitis), sore muscles,and general malaise—can be present individuallyorconcurrentlyinvaryingcombinationor sequence. The term stems from an oldpopular belief that these complaints arecaused by exposure to chilling or dampness.The causative pathogens are different viruses(rhino-, adeno-, and parainfluenza viruses)that may be transmitted by aerosol dropletsproduced by coughing and sneezing.Therapeutic measures. Causal treatmentwith a virustatic is not possible at present.Since cold symptoms abate spontaneously,there is no compelling need to use drugs.However, conventional remedies are intendedfor symptomatic relief.Rhinitis. Nasal discharge could be preventedby parasympatholytics; however,other atropine-like effects (p.108) wouldhave to be accepted. Parasympatholyticsare threfore hardly ever used, although acorresponding action is probably exploitedinthecaseofH 1 -antihistaminics, aningredientof many cold remedies. Locally applied(nasal drops), vasoconstricting α-sympathomimeticsdecongest the nasal mucosa anddry up secretions, clearing the nasal passage.Long-term use may cause damage to nasalmucous membranes (p. 94).Sore throat, swallowing problems. Demulcentlozenges containing surface anestheticssuch as lidocaine (caveat: benzocaineand tetracaine contain an allergenic p-aminophenylgroup; p. 207) may provide shorttermrelief; however, the risk of allergic reactionsshould be kept in mind.Cough. Since coughing serves to expel excesstracheobronchial secretions, suppressionof this physiological reflex is justifiedonly when coughing is dangerous (after surgery)or unproductive because of absent secretions.Codeine and noscapine (p. 210) suppresscough by a central action. A different,though incompletely understood, mechanismof action is evident in antitussives suchas clobutinol, which do not derive from opium.The available clinical studies concerningthebenefitsofantitussivesincommoncoldsdo not present a convincing picture.Mucous airway obstruction. Expectorantsare meant to promote clearing of bronchialmucus by a liquefying action thatinvolves either cleavage of mucous substances(mucolytics) or stimulation of productionof watery mucus (e. g., hot beverages).Whether mucolytics are indicated in thecommon cold and whether expectorantssuch as bromohexine or ambroxole effectivelylower viscosity of bronchial secretionsmay be questioned. In clinical studies ofchronic obstructive bronchitis (but not commoncold infections), N-acetylcysteine wasshown to have clinical effectiveness, as evidencedby a lowered incidence of exacerbationsduring chronic intake.Fever. Antipyretic analgesics (acetylsalicylicacid, acetaminophen, p.198) are indicatedonly when there is high fever. Fever isa natural response and useful in monitoringtheclinicalcourseofaninfection.Muscle aches and pains, headache. Antipyreticanalgesics are effective in relievingthese symptoms.

Common Cold 337A. Drugs used in common coldLocal use ofα-sympathomimetics(nasal drops or spray)Acetylsalicylic acidAcetaminophenSorenessHeadacheFeverH 1 -AntihistaminesCaution: sedationViral infectionMucosal decongestionNose breathing facilitatedCaution: habituationSniffles, runny noseCommon coldFluCausal therapyimpossibleSurface anestheticsCaution:risk of sensitizationSore throatAntitussive:CH 3NCodeineH3COOOHCoughMucolyticsONH C CH 3Givewarm fluidsElderberryteaAcetylcysteineBromhexineHS CH 2 C COOHBrHNH 2CH 3Br CH 2 NAirway congestionAccumulation in airwaysof mucus, inadequateexpulsion by cough

338 Therapy of Selected Diseases Atopy and Antiallergic TherapyAtopy denotes a hereditary predisposition forIgE-mediated allergic reactions. Clinical picturesinclude allergic rhinoconjunctivitis(“hay fever”), bronchial asthma, atopic dermatitis(neurodermatitis, atopic eczema) andurticaria.Evidently,differentiationofT-helper(TH) lymphocytes toward the TH 2 phenotypeis the common denominator. Therapeutic interventionsare aimed at different levels toinfluence pathophysiological events (A).1. Specific immune therapy (“hyposensitization”)with intracutaneous antigen injectionsis intended to shift TH cells in the directionof TH 1 .2. Inactivation of IgE can be achieved bymeans of the monoclonal antibody, omalizumab.This is directed against the Fc portion ofIgE and prevents its binding to mast cells.3. Stabilization of mast cells. Cromolyn preventsIgE-mediated release of mast cell mediators,although only after chronic treatment.Itisappliedlocally to conjunctiva, nasalmucosa, the bronchial tree (inhalation),and intestinal mucosa (absorption is almostnil with oral intake). Indications: prophylaxisof hay-fever, allergic asthma, andfood allergies.Nedocromil acts similarly.4. Blockade of histamine receptors. Allergicreactions are predominantly mediated by H 1receptors. H 1 -antihistaminics (p.118) aremostly used orally. Their therapeutic effectis often disappointing. Indications: allergicrhinitis (hay fever).5. Blockade of leukotriene receptors. Montelukastis an antagonist at receptors for(cysteinyl) leukotriene. Leukotrienes evokeintense bronchoconstriction and promote allergicinflammation of the bronchial mucosa.Montelukast is used for oral prophylaxis ofbronchial asthma. It is effective in analgesiainducedasthma (pp. 200, 340) and exerciseinducedbronchospasm.6. Functional antagonists of mediatorsof allergy.a α-Sympathomimetics, suchasnaphazoline,oxymetazoline, and tetrahydrozoline,are applied topically to the conjunctivaland nasal mucosa to produce local vasoconstriction.Their use should be shorttermat most.b Epinephrine, given i.v., is the most importantdrug in the management of anaphylacticshock: it constricts blood vessels,reduces capillary permeability, and dilatesbronchi.c β 2 -Sympathomimetics, suchasterbutaline,fenoterol, and albuterol, are employedin bronchial asthma, mostlybyinhalation,and parenterally in emergencies.Even after inhalation, effective amountscan reach the systemic circulation andcause side effects (e. g., palpitations, tremulousness,restlessness, hypokalemia).Thedurationofactionofbothsalmeteroland formoterol, given by inhalation, is 12hours. These long-acting β 2 -mimetics areincluded in the treatment of severe asthma.Given at nighttime, they can preventattacks that preferentially occur in theearly morning hours.d Theophylline belongs to the methylxanthines.Its effects are attributed to bothinhibition of phosphodiesterase (cAMP increase,p. 66) and antagonism at adenosinereceptors. In bronchial asthma, theophyllinecan be given orally for prophylaxisor parenterally to control the attack.Manifestations of overdosage include tonic-clonicseizuresandcardiacarrhythmias(blood level monitoring).e Glucocorticoids (p. 244) have significantantiallergic activity and probably interferewith different stages of the allergic response.Indications: hay fever, bronchialasthma (preferably local application ofanalogues with high presystemic elimination,e. g., beclomethasone dipropionate,budesonide, flunisolide, fluticasone propionate);and anaphylactic shock (i.v. in highdosage)—a probably nongenomic action ofimmediate onset.

Antiallergie Therapy 339A. Atopy and antiallergic therapyTH 1 TH 0 TH 2AntigenSkinSpecificimmunotherapyAllergenIgEAtopyMast cellstabilization bycromolynOHIgEOmalizumabMast cell- OOCOOCH 2OCHCH 2OOOCOO -GlucocorticoidsH 1-AntihistaminicsHistamineLeukotrienesAntileukotriene,e.g., montelukastHistaminereceptorLeukotrienereceptorReaction of target cellsVascular smooth muscle, permeabilityBronchial musculatureVasodilation Edema ContractionBronchial asthmaα-Sympathomimetics:e. g.,naphazolineMucous membranesof nose and eye:redness, swelling,secretionβ2-Sympathomimetics:e. g., terbutalineHOCH3VasoconstrictionEpinephrineSkin:wheal formationCirculation:anaphylactic shockBronchodilationHOCH CH2 N C CH3HOHCH3TheophyllineOH3CNO NHNNCH3

340 Therapy of Selected Diseases Bronchial AsthmaDefinition. A recurrent, episodic shortness ofbreath caused by bronchoconstriction arisingfrom airway inflammation and hyperreactivity.Pathophysiology. One of the main pathogeneticfactors is an allergic inflammation ofthe bronchial mucosa. For instance, leukotrienesthat are formed during an IgE-mediatedimmune response (p. 72) exert a chemotacticeffect on inflammatory cells. As theinflammation develops, bronchi becomeglobally hyperreactive to spasmogenic stimuli.Thus, stimuli other than the original antigen(s)can act as triggers (A); e. g., breathingof cold air is an important trigger in exerciseinducedasthma. Cyclooxygenase inhibitors(p. 200) exemplify drugs acting as asthmatriggers.Management. Avoidance of asthma triggersis an important prophylactic measure,thoughnotalwaysfeasible.Drugsthatinhibitallergic inflammatory mechanisms or reducebronchial hyperreactivity (glucocorticoids,“mast-cell stabilizers,” and leukotrieneantagonists) attack crucial pathogeneticlinks. Bronchodilation is achieved by inhalationof β 2 -sympathomimetics (with highpresystemic elimination) or, in the case ofchronic obstructive lung disease, the anticholinergic,tiotropium (long-acting; singledaily dose).The step scheme (B) illustrates successivelevels of pharmacotherapeutic managementat increasing degrees of disease severity.Step 1. Medications of first choice for theacute attack are short-acting, aerosolized β 2 -sympathomimetics, e. g., salbutamol or fenoterol.Their action occurs within minutesafter inhalation and lasts for 4–6 hours.Step 2. If β 2 -mimetics have to be usedmore frequently than once a week, moresevere disease is present. At this stage, managementincludes anti-inflammatory drugs,preferably an inhalable glucocorticoid(p. 246). Inhalational treatment with glucocorticoidsmust be administered regularly,improvement being evident only afterseveral weeks. With proper inhalationaluse of glucocorticoids undergoing high presystemicelimination, concern about systemicadverse effects (“cortisone fear”) isunwarranted. Possible local adverse effectsare oropharyngeal candidiasis and dysphonia.To minimize the risk of candidiasis, drugadministration should occur before morningor evening meals. Alternatively, a “mast-cellstabilizer” (p.118)givenbyinhalationmayprove adequately successful. Oral administrationof timed-release theophylline(p. 338) is considered a further alternative,particularly so since the effect of theophyllineis thought to possess an additional inflammation-inhibitingcomponent, apartfrom bronchodilation. The margin of safetyis narrow (cardiac or CNS stimulation; plasmalevel controls!). A leukotriene antagonist(montelukast, p. 338) may also merit consideration.Anti-inflammatory therapy is the moresuccessful the less use is made of asneededβ 2 -mimetic medication.Step 3. Continuous bronchodilator treatmentis added to the low-dose glucocorticoidregimen. Preference is given to local useof a long-acting inhalable β 2 -mimetic (salmeterolor formoterol; p. 338). If this provesinsuf cient, the glucocorticoid dose is increased.Instead of a long-acting β 2 -mimetic,oral administration of timed-release theophylline,ofacontrolledreleaseβ2 -agonist,or of a leukotriene antagonist would be possible.Step 4. The dose of inhalable glucocorticoidis increased further. When this provesunsatisfactory, the active principles shownin (B) can be added on, including systemicadministration of a glucocorticoid.

Bronchial Asthma 341A. Asthma bronchiale, pathophysiology and therapeutic approachAllergensInflammationAntigens,infections,ozone,SO 2 , NO 2Bronchial hyperreactivityNoxious stimuliBronchialspasmDust,cold air,drugsAvoidexposureTreatinflammationDilatebronchiB. Bronchial asthma treatment algorithmPreferred substancesfor adultsafter: Global Strategyfor Asthma Managementand Prevention 2002If needed (orally):Glucocorticoidβ 2 -MimeticMontelukastTheophyllineMaintained bronchodilationLong-acting β 2 -mimetic by inhalationAntiinflammatory treatment, inhalative, chronicallyGlucocorticoid with high presystemic eliminationlow dose medium dose high doseBronchodilation as needed: short-acting inhalative β 2 -mimetics< 1 x /weekMild asthma

342 Therapy of Selected Diseases EmesisIn emesis the stomach empties in a retrogrademanner. The pyloric sphincter isclosed while cardia and esophagus relax toallow gastric contents to be propelled oradby a forceful synchronous contraction of abdominalwall muscles and diaphragm. Closureof the glottis and elevation of the softpalate prevent entry of vomitus into the tracheaand the nasopharynx. As a rule, there isprodromal salivation or yawning. Coordinationbetween these different stages dependson the medullary center for emesis, whichcanbeactivatedbydiversestimuli.Theseareconveyed via the vestibular apparatus, visual,olfactory,andgustatory inputs,aswellas viscerosensory afferents from the upperalimentary tract. Psychic stress may alsoactivate the emetic center. The mechanismsunderlying motion sickness (kinetosis, seasickness) and vomiting during pregnancy arestill unclear.Polar substances cannot reach the emeticcenter itself because it is protected by theblood–brain barrier. However, they can indirectlyexcite the center by activating chemoreceptorsin the area postrema or receptorson peripheral vagal nerve endings.Antiemetic therapy. Vomiting can be a usefulreaction enabling the body to eliminatean orally ingested poison. Antiemetic drugsare used to prevent kinetosis, pregnancyvomiting, cytotoxic drug-induced or postoperativevomiting, as well as vomiting due toradiation therapy.Motion sickness. Effective prophylaxiscan be achieved with the parasympatholyticscopolamine (p.110) and H 1 -antihistaminics(p.118)ofthediphenylmethanetype(e.g.,diphenhydramine, meclizine). Antiemeticactivity is not a property shared by all parasympatholyticsor antihistaminics. The ef -cacy of the drugs mentioned depends on theactual situation of the individual (gastric filling,ethanol consumption), environmentalconditions (e. g., the behavior of fellow travelers),andthetypeofmotionexperienced.The drugs should be taken 30 minutes beforethe start of travel and repeated every 4–6hours. Scopolamine applied transdermallythrough an adhesive patch 6–8 hours beforetravel can provide effective protection for upto 3 days.Pregnancy vomiting is prone to occur inthe first trimester; thus, pharmacotherapywould coincide with the period of maximalfetal vulnerability to chemical injury. Accordingly,antiemetics (antihistaminics, orneuroleptics if required; p. 232) should beused only when continuous vomiting threatensto disturb electrolyte and water balancetoadegreethatplacesthefetusatrisk.Drug-induced vomiting. To prevent vomitingduring anticancer chemotherapy (especially,with cisplatin), effective use can bemade of 5-HT 3 receptor antagonists (e. g.,ondansetron, granisetron, and tropisetron),alone or in combination with glucocorticoids(methylprednisolone, dexamethasone). Anticipatorynausea and vomiting, resultingfrom inadequately controlled nausea andemesis in patients undergoing cytotoxic chemotherapy,can be attenuated by a benzodiazepinesuch as lorazepam. Dopamineagonist-inducednausea in parkinsonian patients(p.188) can be counteracted with D 2 -receptor antagonists that penetrate poorlyinto the CNS (e. g., domperidone, sulpiride).Metoclopramide is effective in nausea andvomiting of gastrointestinal origin (5-HT 4receptor agonism) and at high dosage alsoin chemotherapy- and radiation-inducedsickness (low potency antagonism at 5-HT 3and D 3 -receptors). Phenothiazines (e. g., levomepromazine,trimeprazine, andperphenazine)or metoclopramide may suppress nausea/emesisthat follows certain types of surgeryor is due to opioid analgesics, gastrointestinalirritation, uremia, and diseasesaccompanied by elevated intracranial pressure.The synthetic cannabinoids dronabinoland nabilone have antiemetic effects thatmay benefit AIDS and cancer patients.

Emesis 343A. Emetic stimuli and antiemetic drugsPregnancyvomitingKinetosese.g., sea sicknessChemoreceptorsPsychogenicvomitingEmetic centerSightOlfactionVestibularsystemArea postremaTasteIntramucosal sensory nerveendings in mouth, pharynx,and stomachChemoreceptors(drug-inducedvomiting)CParasympatholyticsNDopamine D 2 antagonistsOOH 3CH N N CH 2CH 3CH 2 OHO C CHO ScopolamineH 1 -AntihistaminesHNONNNN H ClDomperidoneClCH 3CH O CH 2 CH 2 NCH 3DiphenhydramineMeclozineH 2NOCH 3C 2H 5ClC NH CH 2 CH 2 NOC 2H 5MetoclopramideOCH 2 CH 3NNNOndansetronCH 35-HT 3 -antagonist

344 Therapy of Selected Diseases Alcohol AbuseSince prehistoric times, ethanol-containingbeverages have enjoyed widespread use asa recreational luxury. What applies to anymedicinal substance also holds for alcohol:thedosealonemakesthepoison(seep.2).Excessive, long-term consumption of alcoholicdrinks, or alcohol abuse, isharmfulto the affected individual. Alcoholism mustbe considered a grave disorder that plays amajor role in terms of numbers alone; forinstance, in Germany 1 000 000 people areaffected by this self-inflicted illness.Ethanol is miscible with water and is welllipid-soluble, enabling it to penetrate easilythrough all barriers in the organism; theblood–brain barrier and the placental barrierare no obstacles. In liver cells, alcohol is brokendowntoaceticacidviaacetaldehyde(A).Ethyl alcohol is never ingested as a chemicallypure substance but in the form of analcoholic beverage that contains flavoringagents and higher alcohols, depending onits origin. The effect desired by the consumertakes place in the brain: ethanol acts as astimulant, it disinhibits, and it enhances sociability,as long as the beverage is enjoyedin moderate quantities. After higher doses,self-critical faculties are lost and motor functionis impaired–the familiar picture of thedrunk. Still higher doses induce a comatosestate (caution: hypothermia and respiratoryparalysis). The complex effects on the CNScannot be ascribed to a simple mechanism ofaction. An inhibitory effect on the NMDAsubtype of glutamate receptor appears topredominate.In chronic alcohol abuse, mainly two organsare damaged:1. In the liver, hepatocytes may initiallyundergo fatty degeneration, this processbeing reversible. With continued exposure,liver cells die and are replaced byconnective tissue newly formed from myofibroblasts:liver cirrhosis. Hepatic bloodflow is greatly reduced; the organ becomesunable to fulfill its detoxificationfunction (danger of hepatic coma). Collateralcirculation routes develop (bleedingfrom esophageal varicose veins) with productionof ascites. Alcoholic liver cirrhosisis a severe, mostly progressive disease thatpermits only symptomatic therapy (B).2. The functional capacity of the brain isimpaired. Irreversible damage may manifestin a measurable fallout of neuronal cellbodies. Often delirium tremens develops(usually triggered by alcohol withdrawal),which can be managedwith intensive therapy(clomethiazole, haloperidol, amongothers). In addition, alcoholic hallucinationsand Wernicke–Korsakow syndromeoccur. All of these are desolate states.It must be pointed out specifically that alcoholabuse during pregnancy leads to (embryo–fetalalcohol syndrome (malformations,persistent intellectual deficits). Thisintrauterine intoxication is relatively common:one case per 1000 births (C).Chronic alcohol abuse is an expression oftrue dependence. Thus, therapy of this addictionis dif cult and frequently withoutsuccess. There is no pharmacotherapeuticsilver bullet (the NMDA receptor antagonistacamprosate may be worth trying). Aboveall, psychotherapeutic care, a change in milieu,and supportive treatment with benzodiazepinesare important.

Alcohol Abuse 345A. AlcoholismEthanol Acetaldehyde Acetic acid Quotient NADH/NAD+H 3 CH 3 CH 3 CFatty acid oxidationFatty acid synthesisTriglyceride synthesisH COH 2 HC=O COOHFatty liverNAD+ NADH NAD+ NADHCell necrosesMain catabolic pathway of ethanol in liver cellCirrhosisB. Liver cirrhosisHepaticencephalopathyInsufficientpresystemiceliminationof NH 3Esophageal andgastric varicesPortalhypertensionLiver cirrhosisAscitesC. Embryo-fetal alcohol syndrome

346 Therapy of Selected Diseases Local Treatment of GlaucomaCurrently, glaucoma therapy remains focusedon mechanisms designed to decreaseintraocular pressure (IOP) and this approachis considered effective also in normal tensionglaucoma.Normal values of IOP lie between 15 and20 mmHg, that is, above the venous pressure.IOP reflects the ratio of productionand outflow of aqueous humor. Aqueous humoris secreted by the epithelial cells of theciliary body and, following passage throughthe trabecular meshwork, is drained via thecanal of Schlemm (blue arrows in A). Thisroute is taken by 85–90% of aqueous humor;a smaller portion enters the uveoscleral vesselsand, thus, the venous system. In the socalledopen-angle glaucoma, passage ofaqueous humor through the trabecularmeshwork is impeded so that drainagethrough Schlemm’s canal becomes inef -cient. The much rarer primary angle-closureglaucoma features a narrowed iridocornealangle or a tight contact between iris and lens(‘pupillary block’). Secondarily, blockade bythe iris of the trabecular meshwork may bedue to various causes (e. g., synechiae). Topographicalrelationships in the chamber angleareshownenlargedintheredbox.For topical therapy of open-angle glaucoma,the following groups of drugs can beused: for reducing production of aqueoushumor, β-blockers (e. g., timolol), α 2 -agonists(clonidine, brimonidine), and inhibitors ofcarbonic anhydrase (dorzolamide, brinzolamide).For promoting drainage through the trabecularmeshwork, parasympathomimetics(e. g., pilocarpine) are effective, and throughthe uveoscleral route, prostaglandin derivatives.Pilocarpine excites the ciliary muscleand the pupillary sphincter. The contractionof both muscles widens the geometrical arrangementof trabeculae, resulting in improveddrainage of aqueous humor. Uveoscleraldrainage is augmented by the prostaglandinderivatives lanatoprost and bimatoprost.Both substances can be used fortopical monotherapy or combined with otheractive principles. A peculiar side effect isnotable: dark pigmentation of iris and eyelashes.The therapy of angle-closure glaucomainvolves chiefly reduction of aqueous humorproduction (osmotic agents, β-blockers) andsurgical procedures.The topical application of pharmaceuticalsintheformofeye-dropsishamperedbyapharmacokinetic problem. The drug mustpenetrate from the ocular surface (corneaand conjunctiva) to its target sites, namely,the smooth muscle of the ciliary body or theiris, the secretory epithelium of the ciliarybody, or the uveoscleral vessels (B). The applieddrug concentration is diluted by lacrimalfluid and drains via the tear duct to thenasal mucosa, where the drug may be absorbed.During permeation through the cornea,transport through blood vessels takesplace. The drug concentration reaching theanterior chamber is diluted by aqueous humorand, finally, drug molecules are alsotransported away via Schlemm’s canal. Inorder to reach the required concentrationsatthetargetsite(10 –8 to 10 –6 M, dependingon the substance), the concentration neededin the eye drops is ~ 10 –2 M(equivalentto~ 0.5 mg per droplet, depending on molecularweight). The amount of drug contained ina single drop is large enough to elicit a generalreaction with systemic use. Even whenapplied properly, eye drops can thereforeevoke side effects in the cardiovascular systemor the bronchial space. This possibilityleads to corresponding contraindications.Thus, in patients with severe congestiveheart failure, bradycardia, or obstructivelung disease, eye drops containing β-blockersmust be avoided at all times.

Local Treatment of Glaucoma 347A. Local pharmacotherapy of glaucomaConjunctivaScleraIncreased drainagePilocarpineProstaglandin derivativesM. ciliarisProc. ciliarisSchlemm’s canalCorneaInhibitors of aqueous humorproduction: β-Blocker,CAH-inhibitors, α 2 -agonistAqueous humorIrisSchlemm’s canal(drainage intovenous system)ScleraM. ciliarisLensB. Diffusion barriers for eye dropsTrabecularlabyrinthConcentration:~ 10 -7MTearfilmCorneaAqueous humorIrisPotential targetorgans:Eye dropsConcentration:~ 10 -2MRemoval throughSchlemm’s canalM. sphincter pup.M. dilatator pup.Ciliary epitheliumM. ciliaristo nasalmucosaRemoval throughblood vessels

Further Reading

350 Further Reading and Picture Credits Further ReadingFoundations and Basic Principles ofPharmacologyForeman JC, Johansen T. Textbook of ReceptorPharmacology. 2nd ed. New York:McGraw-Hill; 2002.Hardman JG, Limbird LE, Gilman A. Goodman& Gilman’s The Pharmacological Basisof Therapeutics. 10th ed. New York:McGraw-Hill; 2001.Katzung BG. Basic and Clinical Pharmacology.9th ed. New York: Lange Medical Books/McGraw-Hill; 2004.Page CR, Curtis MJ, Sutter MC, Walker MJA,Hoffman BB. Integrated Pharmacology.2nd ed. London: Mosby; 2002.Pratt WB, Taylor P. Principles of Drug Action—TheBasis of Pharmacology. 3rd ed.New York: Churchill Livingstone; 1990.Rang HP, Dale MM, Ritter JM, Moore PK.Pharmacology.5thed.NewYork:ChurchillLivingstone; 2003.Clinical PharmacologyBennett PN, Brown MJ. Clinical Pharmacology.9th ed. Edinburgh: Churchill Livingstone;2003.Caruthers SG, Hoffman BB, Melmon KL, NierenbergDW. Melmon and Morelli’s ClinicalPharmacology—Basic Principles in Therapeutics.4th ed. New York: McGraw-Hill;2000.Clinical Pharmacology—Electronic Drug Reference.Tampa, Florida: Gold StandardMultimedia Inc. [Updated every 4 months].Dipiro JT, Talbert RL, Yee GC, Matzke GR,Wells BG, Posey LM. Pharmacotherapy—APathophysiological Approach. New York:McGraw-Hill/Appleton and Lange; 2002.Grahame-Smith D, Aronson J. Oxford Textbookof Clinical Pharmacology and DrugTherapy. 3rd ed. Oxford: Oxford UniversityPress; 2002.Drug Interactions and Adverse EffectsDavies DM, Ferner RE, de Glanville H. Davies’Textbook of Adverse Drug Reactions. 5thed. London: Chapman and Hall; 1998.Hansten PD, Horn JR. Drug interactions, Analysisand Management. Vancouver, WA:Applied Therapeutics Inc. [Updated every4months].WebsitesUSA. FDA:www.fda.gov/medwatch/index.htmlUK. NHS: http://www.nhsdirect.nhs.uk/Drugs in Pregnancy and LactationBriggs GG, Freeman RK, Yaffe SJ. Drugs inPregnancy and Lactation: a ReferenceGuide to Fetal and Neonatal Risk. 6th ed.Baltimore: Williams and Wilkins; 2002.PharmacokineticsBauer LA. Applied Clinical Pharmacokinetics.New York: McGraw-Hill Med. Publ. Div.;2001.Boroujerdi M. Pharmacokinetics—Principlesand Applications. New York: McGraw-HillMed. Publ. Div.; 2002.Shargel L, Yu A. Applied Biopharmaceuticsand Pharmacokinetics. 4th ed. New York:McGraw-Hill Med. Publ. Div.; 1999.ToxicologyKlaassen CD, Watkins J. Casarett and Doull’sToxicology: The Basic Science of Poisons.7th ed. New York: McGraw-Hill; 2003. Picture Creditsp. 75 Permission to use the two photographsin the plate on p. 75 was kindly granted byProfessor Enno Christophers, Head of theDepartment of Dermatology, Venereologyand Allergology at the University of Kiel.p. 297 A and B taken from: Lang W, LöschnerT. Tropenmedizin in Klinik und Praxis. 3rded. Stuttgart: Thieme; 1999.p. 297 C taken from: Hof H, Dörries R. MedizinischeMikrobiologie. 2nd ed. Stuttgart:Thieme: 2002.p. 297 D taken from: Kayser F, Bienz KA, EckertJ, Zinkernagel RM. Medizinische Mikrobiologie.10th ed. Stuttgart: Thieme; 2001.p. 345 C taken from: Murken J, Clevett. Humangenetik.6th ed. Stuttgart: Enke; 1996.

Drug Indexes

352 Drug IndexTrade Name – Drug Name(* denotes investigational status in theUnited States)AAbbokinase ®Acantex ®Accolate ®Accupril ®Acediur ®Acephen ®Acepril ®Achromycin ®AcipHex ®Acnex ®Acthar ®®Acti-B 12Actilyse ®Actimmune ®Actiprophen ®Activase ®Actonel ®Actos ®Actulin ®Acular ®Adalat ®Adcortyl ®ADH ®Adicort ®Adrenalin ®Adriamycin ®Adriblastin ®Adrucil ®Advil ®Aegrosan ®Aerius ®Aerobid ®Aerolate ®Afibrin ®Afrin ®Agenerase ®Aggrastat ®Agopton ®Airbron ®Ak Pred ®Akarpine ®Akineton ®Akinophyl ®Alazine ®Albalon ®Albego ®Albiotic ®Albuterol ®Alcoban ®Aldactone ®Aldecin ®Aldinamide ®Aldocorten ®UrokinaseCeftriaxoneZafirlukastQuinaprilCaptoprilAcetaminophen(= paracetamol)CaptoprilTetracyclineRabeprazoleSalicylic acidCorticotropinHydroxocobalaminAlteplaseInterferon gammaIbuprofent-PA (= alteplase)RisedronatePioglitazoneRepaglinideKetorolacNifedipineTriamcinoloneVasopressinTriamcinolone acetonideEpinephrineDoxorubicinDoxorubicinFluorouracilIbuprofenDimeticoneDesloratadineFlunisolideTheophyllineε-Aminocaproic acidOxymetazolineAmprenavirTirofibanLansoprazoleAcetylcysteinePrednisolonePilocarpineBiperidenBiperidenHydralazineNaphazolineCamazepamLincomycinSalbutamolFlucytosineSpironolactoneBeclometasonePyrazinamideAldosteroneAldomet ®Aldrox ®Aleve ®Alexan ®Alfenta ®Alflorone ®Alfoten ®Algocalmin ®Algocor ®Alkeran ®Allegra ®Allerdryl ®Allerest ®Alloferin ®Alloprin ®Allvoran ®Almocarpine ®Almodan ®Alocort ®Alophen ®Alopresin ®Alphagan ®Alpha-redisol ®Altace ®Altracin ®Alu-Cap ®Aludrin ®Alupent ®Alu-Tab ®Alzapam ®Ambaxine ®Ambien ®Ambril ®Amcill ®Amen ®Americaine ®Amfebutamon(e) ®Amicar ®Amidate ®Amidonal ®Amikin ®Aminomux ®Aminopan ®Amitril ®Ammuno ®Amoban ®Amodopa ®Amovane ®Amoxil ®Amphipen ®Amphojel ®Amphozone ®Amycor ®MethyldopaAluminum hydroxideNaproxenCytarabineAlfentanilFludrocortisoneAlfuzosinDipyroneGallopamilMelphalanFexofenadineDiphenhydramineOxymetazolineAlcuroniumAllopurinolDiclofenacPilocarpineAmoxicillinHydrocortisone (cortisol)PhenolphthaleinCaptoprilBrimonidineHydroxocobalaminRamiprilBacitracinAluminum hydroxideIsoprenaline(= isoproterenol)Metaproterenol(orciprenaline)Aluminum hydroxideLorazepamAmantadineZolpidemAmbroxolAmpicillinMedroxyprogesteroneacetateBenzocaineBupropionε-Aminocaproic acidEtomidateAprindineAmikacinPamidronateSomatostatinAmitriptylineIndometacinZopicloneMethyldopaZopicloneAmoxicillinAmpicillinAluminum hydroxideAmphotericin BBifonazole

TradeName–DrugName 353Anabactyl (A) ®Anabolin ®Anacaine ®Anacin-3 ®Anacobin ®Anaesthesin ®Anamid ®Anaprox ®Ancotil ®Andriol ®Andro ®Androcur ®Androcyp ®Android ®Androlone ®Andronate ®Androviron ®Anectine ®Anergan ®Anethaine ®Anexate ®Angettes ®Angionorm ®Ang-O-Span ®Antagon ®Antepsin ®Antilirium ®Antiminth ®Antipressan ®Antivert ®Antocin ®Antrizine ®Apaurin ®Apocretin ®Apresoline ®Aprobal ®Aprozide ®Apsin VK ®Apsolox ®Aptine ®Aralen ®Aranesp ®Arava ®Arduan ®Aredia ®Arelix ®Arfonad ®Arhythmol ®Aricept ®Arimidex ®Aristocort ®Arixtra ®Armazid ®Arsumax ®Arteoptic ®Arterenol ®Arthrisin ®Articulose ®CarbenicillinNandroloneBenzocaineAcetaminophen(= paracetamol)CyanocobalaminBenzocaineKanamycinNaproxenFlucytosineTestosteroneundecanoateTestosterone enantateCyproterone-acetateTestosterone cypionateMethyltestosteroneNandroloneTestosterone cypionateMesteroloneSuccinylcholinePromethazineTetracaineFlumazenilAcetylsalicylic acidDihydroergotamineNitroglycerin(glyceryl trinitrate)GanirelixSucralfatePhysostigminePyrantel pamoateAtenololMeclizine (meclozine)AtosibanMeclizine (meclozine)DiazepamEtilefrineHydralazineAlprenololHydrochlorothiazidePencillin VOxprenololAlprenololChloroquineDarbepoetinLeflunomidePipecuroniumPamidronatePiretanideTrimetaphanPropafenoneDonepezilAnastrozoleTriamcinoloneFondaparinuxIsoniazidArtesunateCarteololNorepinephrine(noradrenaline)Acetylsalicylic acidPrednisoloneArumil ®AmilorideAsacol ®Mesalamine (mesalazine)Asadrine ®Acetylsalicylic acidAscotop ®ZolmitriptanAspenon ®AprindineAspirin ®Acetylsalicylic acidAstramorph ® Morphine sulfateAtabrine ®QuinacrineAtacand ®CandesartanAtempol ®NitrazepamAtensine ®DiazepamAtivan ®LorazepamAtridox ®DoxycyclineAtromid-S ®ClofibrateAtropisol ®AtropineAtrovent ®IpratropiumAugmentan ®Amoxicillin + clavulanicacidAugmentin ® Clavulanic acid +amoxicillinAureotan ®AurothioglucoseAuromyose ®AurothioglucoseAurorix ®MoclobemideAvandia ®RosiglitazoneAvapro ®IrbesartanAvicel ®CelluloseAvinza ®Morphine sulfateAvloclor ®ChloroquineAvlosulfone ®DapsoneAvodart ®DutasterideAvomine ®PromethazineAzaline ®Salazosulfapyridine(sulfasalazine)Azanin ®AzathioprineAzlin ®AzlocillinAzmacort ®Triamcinolone acetonideAzopt ®BrinzolamideAzulfidine ®Salazosulfapyridine(sulfasalazine)BBaciguent ®BacitracinBactidan ®EnoxacinBactocill ®OxacillinBactrim ®Co-trimoxazoleBAL in oil ®DimercaprolBarbita ®PhenobarbitalBay-Bee ® Vitamin B 12Baycol ®CerivastatinBayer 205 ®SuramineBayotensin ®NitrendipineBaypress ®NitrendipineBecloforte ®BeclometasoneBecodisks ®BeclometasoneBeconase ®BeclometasoneBecotide ®BeclometasoneBedoz ®CyanocobalaminBee Six ® Vitamin B 6Bee-six ®PyridoxineBefizal ®Bezafibrate

354 Drug IndexBenadryl ®DiphenhydramineBenemid ®ProbenecidBentos ®BefunololBerkaprine ®AzathioprineBerkatens ®VerapamilBerkolol ®PropranololBerofor alpha 2 ® Interferon alfa2Berotec ®FenoterolBerubigen ® Vitamin B 12Bestcall ®CefmenoximeBetaclar ®BefunololBetadran ®BupranololBetadrenol ®BupranololBetagon ®MepindololBetalin 12 ® Vitamin B 12Betaloc ®MetoprololBetapen-VK ® Pencillin VBetimol ®TimololBetoptic ®BetaxololBetriol ®BunitrololBextra ®BucindololBextra ®ValdecoxibBezalip ®BezafibrateBezatol ®BezafibrateBiaxin ®ClarithromycinBicalm ®ZolpidemBicillin ®Penicillin GBicol ®BisacodylBiltricide ®PraziquantelBlack Draught ® SennaBlenoxane ®BleomycinBlocadren ®TimololBofedrol ®EphedrineBonamine ®Meclizine (meclozine)Bonpyrin ®DipyroneBopen-VK ®Pencillin VBorotropin ®AtropineBotox ®Botulinum toxin type ABrethine ®TerbutalineBrevibloc ®EsmololBrevital ®MethohexitalBricanyl ®TerbutalineBriclin ®AmikacinBromo-Seltzer ® Acetaminophen(= paracetamol)Bronalide ®FlunisolideBronchaid ®EpinephrineBronchopront ® AmbroxolBronkodyl ®TheophyllineBroxalax ®BisacodylBrufen ®IbuprofenBumex ®BumetanideBuprene ®BuprenorphineBurinex ®BumetanideBuscopan ®ButylscopolamineBuscopan ®Hyoscine butyl bromideBuspar ®BuspironeButylone ®PentobarbitalCCabadon ® Vitamin B 12Cabaseril ®CabergolineCacit ®Calcium carbonateCalabren ®Glibenclamide(= glyburide)Calan ®VerapamilCalchichew ®Calcium carbonateCalcidrink ®Calcium carbonateCalciferol ®Vitamin DCalcimer ®CalcitoninCalcimux ®EtidronateCalciparin ®HeparinCalcitare ®CalcitoninCalderol ®CalcifediolCalpol ®Acetaminophen(= paracetamol)Calsan ®Calcium carbonateCalsynar ®CalcitoninCaltidren ®CarteololCaltrate ®Calcium carbonateCalvepen ®Pencillin VCamcolit ®Lithium carbonateCamoquin ®AmodiaquineCampral ®AcamprosateCampto ®IrinotecanCanasa ®Mesalamine (mesalazine)Cancidas ®CaspofunginCanesten ®ClotrimazoleCapastat ®CapreomycinCaplenal ®AllopurinolCapoten ®CaptoprilCapramol ® ε-Aminocaproic acidCaprolin ®CapreomycinCarace ®LisinoprilCarafate ®SucralfateCarbex ®SelegelineCarbocaine ®MepivacaineCarbolite ®Lithium carbonateCardene ®NicardipineCardinol ®PropranololCardioqin ®QuinidineCardiorhythmino ® AjmalineCardizem ®DiltiazemCardura ®DoxazosinCarduran ®DoxazosinCaridian ®MepindololCarindapen ®CarbenicillinCarteol ®CarteololCartrol ®CarteololCasodex ®BicalutamideCatapres ®ClonidineCCNU ®LomustineCedocard ®Isosorbide dinitrateCedur ®BezafibrateCeeNu ®LomustineCefmax ®CefmenoximeCelance ®PergolideCelebrex ®Celecoxib = ColecoxibCelevac ®Methylcellulose

TradeName–DrugName 355Celexa ®CitalopramCeliomycin ®ViomycinCellCept ®Mycophenolate mofetilCemix ®CefmenoximeCentrax ®PrazepamCephulac ®LactuloseCerebid ®PapaverineCerespan ®PapaverineCerubidine ®DaunorubicinCesamet ®NabiloneCesplon ®CaptoprilChloraminophene ® ChlorambucilChlorohist ®XylometazolineChloromycetin ® ChloramphenicolChloroptic ®ChloramphenicolCholestabyl ®ColestipolCholestid ®ColestipolCholoxin ®ThyroxineChronulac ®LactuloseCialis ®TadalafilCibacalcin ®CalcitoninCidomycin ®GentamicinCillimycin ®LincomycinCiloxan ®CiprofloxacinCimetrin ®ErythromycinpropionateCin-Quin ®QuinidineCipro ®CiprofloxacinCiprobay ®CiprofloxacinCiprox ®CiprofloxacinCiproxin ®CiprofloxacinCircupon ®EtilefrineCitanest ®PrilocaineCitaprim ®CitalopramCitrucell ®MethylcelluloseClaforan ®CefotaximeClamoxyl ®AmoxicillinClaripex ®ClofibrateClaritin ®LoratadineClasteon ®ClodronateCleocin ®ClindamycinClexane ®EnoxaparinClomid ®ClomifeneClonopin ®ClonazepamClont ®MetronidazoleClopra ®MetoclopramideClotrimaderm ® ClotrimazoleClovapen ®CloxacillinClozan ®ClotiazepamClozaril ®ClozapineCobalin-H ®HydroxocobalaminCobex ® Vitamin B 12Cocillin-VK ®Pencillin VCodelsol ®PrednisoloneCodicept ®CodeineCogentin ®BenztropineCognex ®TacrineColchicine ®ColchicineColeb ®Isosorbide mononitrateColectril ®AmilorideCollyrium ®Tetryzoline(= tetrahydrozoline)Cologel ®MethylcelluloseCombactam ® SulbactamCombantrin ® Pyrantel pamoateComplamin ®Xanthinol nicotinateComplementContinus ®PyridoxineComprecin ®EnoxacinComtan ®EntacaponeComtess ®EntacaponeConcor ®BisoprololConducton ®CarazololConstant-T ®TheophyllineContergan ®ThalidomideCopaxone ®Glatimer acetateCoracten ®NifedipineCoradus ®Isosorbide dinitrateCordanum ®TalinololCordarex ®AmilorideCordarex ®AmiodaroneCordarone ®AmiodaroneCordilox ®VerapamilCoreg ®CarvedilolCorgal ®GallopamilCorgard ®NadololCoricidin ®OxymetazolineCorindolan ®MepindololCoronex ®Isosorbide dinitrateCorrectol ®PhenolphthaleinCortalone ®PrednisoloneCortate ®Hydrocortisone (cortisol)Cortef ®Hydrocortisone (cortisol)Cortelan ®CortisoneCortenema ®Hydrocortisone (cortisol)Cortigel ®CorticotropinCortistab ®CortisoneCortogen ®CortisoneCortone ®CortisoneCortrophin ®CorticotropinCorvaton ®MolsidomineCoscopin ®Narcotine (= noscapine)Coscopin ®Noscapine (= narcotine)Coscotab ®Narcotine (= noscapine)Coscotab ®Noscapine (= narcotine)Cosmegen ®DactinomycinCoumadin ®WarfarinCoversum ®PerindoprilCoversyl ®PerindoprilCozaar ®LosartanC-Pak ®DoxycyclineCrixivan ®IndinavirCryspen ®Penicillin GCrystapen ®Penicillin GCrystodigin ®DigitoxinCuemid ®CholestyramineCuprimine ®D-PenicillamineCutivate ®FluticasoneCuvalit ®LisurideCyanoject ® Vitamin B 12Cyclogest ®ProgesteroneCyklokapron ® Tranexamic acidCymevene ®GanciclovirCyomin ® Vitamin B 12

356 Drug IndexCyprostat ®Cytacon ®Cytamen ®Cytomel ®Cytomel ®Cytosar ®Cytotec ®Cytovene ®Cytoxan ®DD.E.H.45 ®Dagenan ®Daktarin ®Dalacin ®Dalcaine ®Dalmane ®Daneral ®Dantrium ®Daonil ®Daraprim ®Datril ®Daunoblastin ®DDAVP ®Decadron ®Deca-Durabolin ®Decapeptyl ®Decapryn ®Dedrogyl ®Degest-2 ®Delapav ®Delatestryl ®Delestrogen ®Delta-Cortef ®Deltapen ®Deltastab ®Demerol ®Dendrid ®Depakene ®Depen ®Deponit ®Depo-Provera ®Deprenyl ®Dermonistat ®Deronil ®Deseril ®Desferal ®Desoxyn ®Desuric ®Desyrel ®Detensiel ®Detensol ®DiaBeta ®Diabex ®Diamox ®Diapid ®Diaqua ®Diarsed ®Diastabol ®Diastat ®Dibenyline ®Dibenzyline ®Diclocil ®Diclophlogont ®Diflucan ®Digacin ®Digibind ®Digicor ®Digimerck ®Digitaline ®Dihydergot ®Dihyzin ®Dilantin ®Dilaudid ®Dimaval ®Dimetab ®Dinaplex ®Diodronel ®Dioval ®Diovan ®Diphenasone ®Diphos ®Diprivan ®Dirythmin ®Distaquaine V-K ®Distraneurin ®Diuchlor ®Diumax ®Divarine ®Divegal ®Dixarit ®Dizac ®Dobutrex ®Dolantine ®Dolophine ®Domical ®Donnagel-MB ®Dopamet ®Dopar ®Dopastat ®Dopergin ®Doral ®Doryl ®Doryx ®Dostinex ®Dowmycin ®Doxicin ®Dramamine ®Drisdol ®Drisdol ®Dristan ®Drogenil ®Droleptan ®Droxia ®Cyproterone-acetateCyanocobalaminCyanocobalaminTriiodthyronine(= liothyronine)LiothyronineCytarabineMisoprostolGanciclovirCyclophosphamideDihydroergotamineSulfapyridineMiconazoleClindamycinLidocaineFlurazepamPheniramineDantroleneGlibenclamide(= glyburide)PyrimethamineAcetaminophen(= paracetamol)DaunorubicinDesmopressinDexamethasoneNandroloneTriptorelinDoxylamineCalcifediolNaphazolinePapaverineTestosterone enantateEstradiol-valeratePrednisolonePenicillin GPrednisoloneMeperidine (pethidine)IdoxuridineValproic acidD-PenicillamineNitroglycerin(glyceryl trinitrate)MedroxyprogesteroneacetateSelegelineMiconazoleDexamethasoneMethysergideDeferoxamineMethamphetamineBenzbromaroneTrazodoneBisoprololPropranololGlibenclamide(= glyburide)MetforminAcetazolamideLypressinHydrochlorothiazideDiphenoxylateMiglitolDiazepamPhenoxybenzaminePhenoxybenzamineDicloxacillinDiclofenacFluconazoleDigoxinDigoxin immune FABDigitoxinDigitoxinDigitoxinDihydroergotamineDihydralazinePhenytoinHydromorphoneDimercaptopropanesulfonicacidDimenhydrinateFlunarizineEtidronateEstradiol-valerateValsartanDapsoneEtidronatePropofolDisopyramidePencillin VClomethiazoleHydrochlorothiazidePiretanideDipyroneDihydroergotamineClonidineDiazepamDobutamineMeperidine (pethidine)MethadoneAmitriptylineKaolin + pectin(= attapulgite)MethyldopaLevodopaDopamineLisurideQuazepamCarbacholDoxycyclineCabergolineErythromycin-estolateDoxycyclineDimenhydrinateVitamin DErgocalciferolOxymetazolineFlutamideDroperidolHydroxyurea

TradeName–DrugName 357Droxomin ®Dryptal ®D-Tabs ®Dulcolax ®Duoralith ®Duphalac ®Duracoron ®Duralutin ®Duramorph ®Duratest ®Durazanil ®Durolax ®D-Vi-sol ®Dymenate ®DynaCirc ®Dynapen ®Dynaprin ®Dynastat ®Dyneric ®Dyrenium ®Dyspamet ®Dytac ®EE605 ®Ebastel ®Econopred ®Ecostatin ®Ecotrin ®Edecrin ®Edronax ®EES ®Efedron ®Eferox ®Effectin ®Effexor ®Effontil ®Effortil ®Effudex ®Effurix ®Elantan ®Elavil ®Eldepryl ®Eligard ®Elimite ®Elixophyllin ®Eltroxin ®Emcor ®Emex ®E-mycin ®Enbrel ®Endak ®Endep ®Endophleban ®Endoxan ®Enoram ®Enovil ®Enoxor ®Entocort EC ®Entromone ®Entrophen ®Epanutin ®Epifin ®Epimorph ®Epinal ®EpiPen ®Epitol ®Epitrate ®Epivir ®Epogen ®Eporal ®Eprex ®Epsicapron ®Ergocalm ®Ergomar ®Ergotrate Maleate ®Eridan ®Ermalate ®Erwinase ®Eryc ®Erymax ®Erymycin ®Erythrocin ®Erythrocin ®Erythromid ®Erythroped ®Esidrix ®Eskalith ®Espotabs ®Estinyl ®Estrace ®Ethrane ®Ethyl Adrianol ®Etibi ®Etopophos ®Euciton ®Eudemine ®Euglucon ®Euhypnos ®Eulexin ®Eunal ®Euthyrox ®Evac-U-gen ®Evac-U-Lax ®Evastel ®Everone ®Evipan ®Evista ®Evoxin ®Exanta ®Exelon ®Ex-Lax ®HydroxocobalaminFurosemideColecalciferol(vitamin D 3 )BisacodylLithium carbonateLactuloseMolsidomineHydroxyprogesteronecaproateMorphine sulfateTestosterone cypionateBromazepamBisacodylVitamin DDimenhydrinateIsradipineDicloxacillinImipramineParecoxibClomifeneTriamtereneCimetidineTriamtereneNitrostigmineEbastinePrednisoloneEconazoleAcetylsalicylic acidEthacrynic acidReboxetineErythromycin-ethylsuccinateEphedrineLevothyroxineBitolterolVenlafaxineEtilefrineEtilefrineFluorouracilFluorouracilIsosorbide mononitrateAmitriptylineSelegelineLeuprolide (leuprorelin)PermethrinTheophyllineThyroxineBisoprololMetoclopramideErythromcyinEtanerceptCarteololAmitriptylineDihydroergotamineCyclophosphamideEnoxacinAmitriptylineEnoxacinBudesonideChorionic gonadotropin(HCG)Acetylsalicylic acidPhenytoinEpinephrineMorphine sulfateEpinephrineEpinephrineCarbamazepineEpinephrineLamivudineErythropoietin(= epoetin alfa)DapsoneEpoetinε-Aminocaproic acidLormetazepamErgotamineErgometrine(= ergonovine)DiazepamErgometrine(= ergonovine)AsparaginaseErythromcyinErythromcyinErythromycin-stearateErythromycin-ethylsuccinateErythromycin-stearateErythromcyinErythromcyinHydrochlorothiazideLithium carbonatePhenolphthaleinEthinylestradiolEstradiolEnfluraneEtilefrineEthambutolEtoposideDomperidoneDiazoxideGlibenclamide(= glyburide)TemazepamFlutamideLisurideLevothyroxinePhenolphthaleinPhenolphthaleinEbastineTestosterone enantateHexobarbitalRaloxifeneDomperidoneXimelagatranRivastigminePhenolphthalein

358 Drug IndexFFabrol ®AcetylcysteineFactrel ®GonadorelinFalcigo ®ArtesunateFamvir ®FamciclovirFansidar ® Pyrimethamine +sulfadoxineFansidar ® Sulfadoxine +pyrimethamineFarlutal ®MedroxyprogesteroneacetateFasigyn(CH) ® TinidazolFaslodex ®FulvestrantFastject ®EpinephrineFasturtec ®RasburicaseFaverin ®FluvoxamineF-Cortef ®FludrocortisoneFelbatol ®FelbamateFemara ®LetrozoleFemazole ®MetronidazoleFeminone ®EthinylestradiolFemogex ®Estradiol-valerateFemotrone ®ProgesteroneFemovan ®Gestoden + ethinylestradiolFenbid ®IbuprofenFenestil ®DimetindeneFertodur ®CyclofenilFeverall ®DipyroneFiblaferon 3 ® Interferon betaFibocil ®AprindineFiboran ®AprindineFlagyl ®MetronidazoleFlavoquine ®AmodiaquineFletcher’s Castoria ® SennaFlixonase ®FluticasoneFlomax ®TamsulosinFlonase ®FluticasoneFlorinef ®FludrocortisoneFlovent ®FluticasoneFloxapen ®Flucloxacillin(floxacilline)Floxifral ®FluvoxamineFluagel ®Aluminum hydroxideFluctin ®FluoxetineFlugeral ®FlunarizineFluothane ®HalothaneFoldine ®Folic acidFolex ®MethotrexateFollutein ®Chorionicgonadotropin (HCG)Folvite ®Folic acidFontego ®BumetanideForadil ®FormoterolForane ®IsofluraneFordiuran ®BumetanideFortaz ®CeftazidimeForteo ®TeriparatideFortovase ®SaquinavirFortral ®PentazocineFortum ®Fosamax ®Foscavir ®Fragmin ®Fragmin ®Fraxiparin ®Frisium ®Fulcin ®Fulvicin ®Fungilin ®Fungizone ®Fusid ®Fuzeon ®GGabitril ®Gabren(e) ®Gamazole ®Ganal ®Ganphen ®Gantanol ®Gantrisin ®Garamycin ®Gardenal ®Gas.X ®Gastrozepin ®Gelafundin ®Gengraf ®Genna ®Genotropin ®Genticin ®Gentle Nature ®Geodon ®Geopen ®Germanin ®Gestafortin ®Gesterol L.A. ®Gestone ®GHRH-Ferring ®Gilurytmal ®Gladem ®Glauconex ®Glaupax ®Glivec ®Glucophage ®Granocyte ®Grisovin ®Gubernal ®Gulfasin ®Gumbix ®Gyne-Lotrimin ®Gynergen ®Gyno-Pevaryl ®Gyno-Travogen ®CeftazidimeAlendronateFoscarnetDalteparinHeparin, low molecularHeparin, low molecularClobazamGriseofulvinGriseofulvinAmphotericin BAmphotericin BFurosemideEnfuvirtideTiagabineProgabideSulfamethoxazoleFenfluraminePromethazineSulfamethoxazoleSulfisoxazoleGentamicinPhenobarbitalSimethiconePirenzepineGelatin-colloidsCiclosporin(= cyclosporine A)SennaSomatotropinGentamicinSennaZiprasidoneCarbenicillinSuramineChlormadinone acetateHydroxyprogesteronecaproateProgesteroneSomatorelinAjmalineSertralineBefunololAcetazolamideImatinibMetforminLenograstim (G-CSF)GriseofulvinAlprenololSulfisoxazoleAminomethylbenzoicacidClotrimazoleErgotamineEconazoleIsoconazole

TradeName–DrugName 359HHaemaccel ®Gelatin-colloidsHalcion ®TriazolamHaldol ®HaloperidolHalfan ®HalofantrineHamarin ®AllopurinolHemineurin ® ClomethiazoleHepalean ®HeparinHepsal ®HeparinHerceptin ®TrastuzumabHerpid ®IdoxuridineHerplex ®IdoxuridineHespan ®Hetastarch (HES)Hespan ®Hydroxyethyl starchHetrazan ®DiethylcarbamazepineHexa-Betalin ® Vitamin B 6Hexa-Betalin ® PyridoxineHexadrol ®DexamethasoneHexit ®LindaneHibanil ®ChlorpromazineHidroferol ®CalcifediolHismanal ®AstemizoleHivid ®ZalcitabineHomapin ®HomatropineHonvol ®DiethylstilbestrolHumalog ®InsulinHumatin ®ParomomycinHumira ®AdalimumabHumulin ®InsulinHybalamine ® HydroxocobalaminHybolin Decanoate ® NandroloneHycamtin ®TopotecanHydeltrasol ®PrednisoloneHyderm ®Hydrocortisone (cortisol)Hydrea ®HydroxyureaHydromal ®HydrochlorothiazideHydromedin ® Ethacrynic acidHydrosaluric ® HydrochlorothiazideHydrotricin ®TyrothricinHygroton ®ChlorthalidoneHylutin ®HydroxyprogesteronecaproateHymorphan ® HydromorphoneHyocort ®Hydrocortisone (cortisol)Hyperstat ®DiazoxideHypertensin ® AngiotensinamideHypertil ®CaptoprilHypnomidate ® EtomidateHypnosedon ® FlunitrazepamHypnovel ®MidazolamHypovase ®PrazosinHyroxon ®HydroxyprogesteronecaproateHyskon ®DextranHytrin ®TerazosinIIletin ®Ilomedin ®Ilosone ®Ilosone ®Imbrilon ®Imdur ®Imitrex ®Imodium ®Imovane ®Importal ®Impril ®Imuran ®Imurek ®Inapsine ®Inderal ®Indocid ®Indocin ®Indomee ®Indomod ®Inflamase ®Infumorph ®Inhibace ®Inhiston ®Innovace ®Innovar ®Inocor ®Insommal ®Intal ®Integriline ®Intron A ®Intropin ®Invirase ®I-Pilopine ®Ipral ®Isicom ®Ismelin ®Ismo ®Isocaine ®Isocillin ®Isoket ®Isoptin ®Isopto-Carpine ®Isordil ®Isotamine ®Isoten ®Isotol ®Isotrate ®Isuprel ®Itracol ®Itrop ®JJanimine ®Jexin ®InsulinIloprostErythromycin-estolateErythromcyinIndometacinIsosorbide mononitrateSumatriptanLoperamideZopicloneLactitolImipramineAzathioprineAzathioprineDroperidolPropranololIndometacinIndometacinIndometacinIndometacinPrednisoloneMorphine sulfateCilazaprilPheniramineEnalapril/enalaprilatFentanyl + droperidolAmrinoneDiphenhydramineCromoglycate (cromolyn)EptifibatideInterferon alfa-2bDopamineSaquinavirPilocarpineTrimethoprimCarbidopa + levodopaGuanethidineIsosorbide mononitrateMepivacainePhenoxybenzylpenicillinIsosorbide dinitrateVerapamilPilocarpineIsosorbide dinitrateIsoniazidBisoprololMannitolIsosorbide mononitrateIsoprenaline(= isoproterenol)ItraconazoleIpratropiumImipramineTubocurarineIfex ®Iktorivil ®IfosfamideClonazepam

360 Drug IndexKKabikinase ®Kabolin ®Kadian ®Kaletra ®Kannasyn ®Kanrenol ®Kantrex ®Kaopectate ®Kaopectate II ®Karil ®Keflex ®Keftab ®Kemicetine ®Kenacort ®Kenalog ®Kenalone ®Kerecid ®Kerlone ®Kertasin ®Kestine ®Ketalar ®Key-Pred ®Kiditard ®Kineret ®Kinidin ®Klebcil ®Klot ®Konakion ®Korostatin ®Kryptocur ®Kwell ®Kwilldane ®Kytril ®LLacril ®Ladropen ®Lamiazid ®Lamictal ®Lampren ®Lanacillin ®Lanacillin-VK ®Lanicor ®Lanoxin ®Lantus ®Lanzor ®Largactil ®Lariam ®Larodopa ®Lasix ®Lasma ®Laxabene ®Laxanin ®Lectopam ®Ledercillin VK ®Ledercort ®StreptokinaseNandroloneMorphine sulfateLopinavirKanamycinCanrenoneKanamycinKaolin + pectin(= attapulgite)LoperamideCalcitoninCefalexinCefalexinChloramphenicolTriamcinoloneTriamcinolone acetonideTriamcinolone acetonideIdoxuridineBetaxololEtilefrineEbastineKetaminePrednisoloneQuinidineAnakinraQuinidineKanamycinTolonium chloridePhytomenadioneNystatinGonadorelinLindaneLindaneGranisetronMethylcelluloseFlucloxacillin(floxacilline)IsoniazidLamotrigineClofaziminePenicillin GPencillin VDigoxinDigoxinInsulin glargineLansoprazoleChlorpromazineMefloquineLevodopaFurosemideTheophyllineBisacodylBisacodylBromazepamPencillin VTriamcinoloneLembrol ®Lendorm(A) ®Lendormin ®Lenoxin ®Lentin ®Lentizol ®Lescol ®Leucomax ®Leucovorin ®Leukeran ®Leukomycin ®Levate ®Levatol ®Levitra ®Levophed ®Levoprome ®Lexotan ®Librium ®Lidifen ®Lidopen ®Likuden ®Lincocin ®LingraineMedihaler ®Lioresal ®Lipitor ®Lipo-Merz ®Lipostat ®Liquamar ®Liquemin ®Lisino ®Liskonum ®Litec ®Lithane ®Lithobid ®Lithotabs ®Lixil ®Loceryl ®Lomotil ®Longum ®Loniten ®Looser ®Lopid ®Lopirin ®Lopressor ®Loramet ®Loraz ®Lorinal ®Losec ®Lotensin ®Lovelco ®Lovenox ®Ludiomil ®Lumigan ®Lupron ®Luvox ®Lyclear ®Lynoral ®Lyophrin ®Lysenyl ®DiazepamBrotizolamBrotizolamDigoxinCarbacholAmitriptylineFluvastatinMolgramostimFolic acidChlorambucilChloramphenicolAmitriptylinePenbutololVardenafilNorepinephrine(noradrenaline)MethotrimeprazineBromazepamChlordiazepoxideIbuprofenLidocaineGriseofulvinLincomycinErgotamineBaclofenAtorvastatinEtofibratePravastatinPhenprocoumonHeparinLoratadineLithium carbonatePizotifen = pizotylineLithium carbonateLithium carbonateLithium carbonateBumetanideAmorolfinDiphenoxylateSulfalenMinoxidilBupranololGemfibrozilCaptoprilMetoprololLormetazepamLorazepamChloral hydrateOmeprazoleBenazeprilProbucolEnoxaparinMaprotilineBimatoprostLeuprolide (leuprorelin)FluvoxaminePermethrinEthinylestradiolEpinephrineLisuride

TradeName–DrugName 361MMacrobin ®ClostebolMadopar ®Levodopa + benserazideMalarone ®Atoquavone + proguanilMallergan ®PromethazineMarcumar ®PhenprocoumonMarevan ®WarfarinMarinol ®DronabinolMarmine ®DimenhydrinateMarvelon ® Desogestrel +ethinylestradiolMavik ®TrandolaprilMaxalt ®RizatriptanMaxeran ®MetoclopramideMaxidex ®DexamethasoneMaxolan ®MetoclopramideMaxtrex ®MethotrexateMazepine ®CarbamazepineMectizam ®IvermectinMegacillin ®Penicillin GMegacillin ®PhenoxybenzylpenicillinMegaphen ®ChlorpromazineMegestat ®MegestrolMelarsen Oxide-BAL ®MelarsoprolMelB ®MelarsoprolMelipramin ®ImipramineMenogon ®MenotropinMenophase ®MestranolMepron ®AtoquavoneMercazol ®Methimazole(thiamazole)Mercuval ®DimercaptopropanesulfonicacidMesacal ®Mesalamine (mesalazine)Mesnex ®MesnaMestinon ®PyridostigmineMetacen ®IndometacinMetahydrin ®TrichlormethiazideMetalone ®PrednisoloneMetalyse ®TenecteplaseMetandren ®MethyltestosteroneMetaprel ®Metaproterenol(orciprenaline)Metenarin ®Methylergometrine(methylergonovine)Meteosan ®DimeticoneMethadose ®MethadoneMethampex ® MethamphetamineMethanoxanol ® SulfamethoxazoleMethergine ®Methylergometrine(methylergonovine)Methofane ®MethoxyfluraneMethylergobrevin ® Methylergometrine(methylergonovine)Meticorten ®PrednisoneMetilon ®DipyroneMetreton ®PrednisoloneMetronid ®MetronidazoleMevacor ®LovastatinMeval ®DiazepamMevaril ®AmitriptylineMevinacor ®LovastatinMexate ®MethotrexateMexitil ®MexiletinMezlin ®MezlocillinMicardis ®TelmisartanMicatin ®MiconazoleMicronase ®Glibenclamide(= glyburide)Micronor ®Norethindrone(norethisterone)Midamor ®AmilorideMielucin ®BusulfanMifegyne ®MifepristoneMigril ®ErgotamineMinipress ®PrazosinMinirin ®DesmopressinMinprog ® Alprostadil (= PGE 1 )Minprostin F2α ® DinoprostMintezol ®ThiabendazoleMiocarpine ®PilocarpineMiostat ®CarbacholMistamine ®MizolastineMitosan ®BusulfanMitoxana ®IfosfamideMivacron ®MivacuriumMizollen ®MizolastineMobenol ®TolbutamideMobic ®MeloxicamModane ®PhenolphthaleinModiten ®FluphenazineModuret ® Amiloride +hydrochlorothiazideMogadon ®NitrazepamMolsidolat ®MolsidomineMonistat ®MiconazoleMonitan ®AcebutololMonocor ®BisoprololMonodox ®DoxycyclineMonomycin ® Erythromycin-succinateMonopril ®FosinoprilMonotrim ®TrimethoprimMoronal ®Amphotericin BMorphitec ®Morphine hydrochlorideMosegor ®Pizotifen = pizotylineMotilium ®DomperidoneMotrin ®IbuprofenMoxacin ®AmoxicillinMSIR ®Morphine sulfateMST Continus ® MorphineMucomyst ®AcetylcysteineMucosolvan ® AmbroxolMurine ®Tetryzoline(= tetrahydrozoline)Murocel ®MethylcelluloseMustargen ®MechlorethamineMutabase ®DiazoxideMyambutol ®EthambutolMycelex ®ClotrimazoleMycifradin ®NeomycinMyciguent ®NeomycinMycobutin ®Rifabutin

362 Drug IndexMycospor ®Mycosporan ®Mycostatin ®Myidone ®Mykinac ®Myleran ®Mylicon ®Myobid ®Myobloc ®Mysoline ®Nacom ®NNadopen-V ®Naftin ®Nalador ®Nalcrom ®Nalorex ®Naprelan ®Napron ®Naprosyn ®Naqua ®Naramig ®Narcan ®Narcaricin ®Narcozep ®Narkotan ®Nasalide ®Nautamine ®Nauzelin ®Navoban ®Naxen ®Nebcin ®Nefaclar ®Negram ®Nemasol Sodium ®Nembutal ®Neo-Codema ®Neo Epinin ®Neo-Mercazole ®Neoral ®Neo-Synephrine ®Neosynephrine II ®Neo-Thyreostat ®Nepresol ®Netillin ®Netromycin ®Neupogen ®NeuroBloc ®Neurontin ®Nexium ®Niclocide ®Nigalax ®Nilstat ®Nilurid ®Nimotop ®Nipride ®BifonazoleBifonazoleNystatinPrimidoneNystatinBusulfanSimethiconePapaverineBotulinum toxin type BPrimidoneCarbidopa + levodopaPencillin VNaftifinSulprostoneCromoglycate(Cromolyn)NaltrexoneNaproxenNaproxenNaproxenTrichlormethiazideNaratriptanNaloxoneBenzbromaroneFlunitrazepamHalothaneFlunisolideDiphenhydramineDomperidoneTropisetronNaproxenTobramycinNefazodoneNalidixic acid4-Aminosalicylic acidPentobarbitalHydrochlorothiazideIsoprenaline(= isoproterenol)CarbimazoleCiclosporin(= cyclosporine A)OxymetazolineXylometazolineCarbimazoleDihydralazineNetilmicinNetilmicinFilgrastimBotulinum toxin type BGabapentinEsomeprazoleNiclosamideBisacodylNystatinAmilorideNimodipineNitroprusside sodiumNitrocap ®Nitrogard ®Nitronal ®Nitropress ®Nivaquine ®Nivemycin ®Nix ®Nizoral ®Noan ®Nocinan ®Noctamid ®Noctec ®Nogram ®Nolvadex ®Norcuron ®Nordox ®Noriday ®Norlutin ®Normiflo ®Normison ®Normodyne ®Normurat ®Noroxin ®Norpace ®Norpramin ®Norprolac ®Nor-Q D ®Norquen ®Norvasc ®Norvir ®Novalgin ®Novamin ®Novamoxin ®Novarectal ®Novocaine ®Novoclopate ®Novodigoxin ®Novolin ®Novolog ®Novomedopa ®NovoNorm ®Novopen-VK ®Novopurol ®Novorythro ®Novotrimel ®Nubain ®Nu-Cal ®Nuelin ®Nulicaine ®Nuprin ®Nuromax ®Nydrazid ®Nystan ®Nystex ®Nytilax ®Nitroglycerin(glyceryl trinitrate)Nitroglycerin(glyceryl trinitrate)Nitroglycerin(glyceryl trinitrate)Nitroprusside sodiumChloroquineNeomycinPermethrinKetoconazolDiazepamMethotrimeprazineLormetazepamChloral hydrateNalidixic acidTamoxifenVecuroniumDoxycyclineNorethindrone(norethisterone)Norethindrone(norethisterone)ArdeparinTemazepamLabetalolBenzbromaroneNorfloxacinDisopyramideDesipramineQuinagolideNorethindrone(norethisterone)MestranolAmlodipineRitonavirDipyroneAmikacinAmoxicillinPentobarbitalProcaineClorazepateDigoxinInsulinInsulin aspartMethyldopaRepaglinidePencillin VAllopurinolErythromycin-estolateCo-trimoxazoleNalbuphineCalcium carbonateTheophyllineLidocaineIbuprofenDoxacuriumIsoniazidNystatinNystatinSenna

TradeName–DrugName 363OOctapressin ®Octostim ®Oculinum ®Ocupress ®Ocusert ®Olbemox ®Olbetam ®Omifin ®Omnipen ®Oncovin ®Ondena ®Ondogyne ®Ondonid ®Opticrom ®Optipranolol ®Oragest ®Oramide ®Oramorph ®Orasone ®Oretic ®Orgalutran ®Orgametril ®Orgaran ®Orinase ®Orthoclone OKT3 ®Osmitrol ®Ossiten ®Ostac ®Otrivin ®O-V Statin ®Ovastol ®Oxi ®Oxistat ®Oxpam ®PPaludrine ®Pamba ®Pamelor ®Panadol ®Panasol ®Panimit ®Panwarfin ®Papacon ®Paralgin ®Paraplatin ®Parathion ®Paraxin ®Parcillin ®Paregoric ®Pariet ®Parlodel ®Parnate ®Parsitan ®FelypressinDesmopressinBotulinum toxin type ACarteololPilocarpineAcipimoxAcipimoxClomifeneAmpicillinVincristineDaunorubicinCyclofenilCyclofenilCromoglycate (cromolyn)MetipranololMedroxyprogesteroneacetateTolbutamideMorphinePrednisoneHydrochlorothiazideGanirelixLynestrenolDanaparoidTolbutamideMuromonab-CD3MannitolClodronateClodronateXylometazolineNystatinMestranolFormoterolOxiconazoleOxazepamProguanilAminomethylbenzoicacidNortriptylineAcetaminophen(= paracetamol)PrednisoneBupranololWarfarinPapaverineDipyroneCarboplatinNitrostigmineChloramphenicolPenicillin GOpium tincture(laudanum)RabeprazoleBromocriptineTranylcypromineEthopropazineParsitol ®EthopropazinePartergin ®Methylergometrine(methylergonovine)Partusisten ®FenoterolParvolex ®AcetylcysteinePathocil ®DicloxacillinPavabid ®PapaverinePavadur ®PapaverinePaveral ®CodeinePavulon ®PancuroniumPaxil ®ParoxetinePectokay ®Kaolin + pectin(= attapulgite)Pediapred ®PrednisolonePemavit ® Vitamin B 12Penapar VK ®Pencillin VPenapar-VK ®Pencillin VPenbec-V ®Pencillin VPenbritin ®AmpicillinPensorb ®Penicillin GPentacarinat ® PentamidinePentanca ®PentobarbitalPentasa ®Mesalamine (mesalazine)Pentazine ®PromethazinePenthrane ®MethoxyfluranePentids ®Penicillin GPentostam ®Stibogluconate sodiumPentothal ®ThiopentalPen-VEE K ®Pencillin VPepcid ®FamotidinePepdul ®FamotidinePepto-Bismol ® Bismuth subsalicylatePeptol ®CimetidinePergotime ®ClomifenePeridon ®DomperidonePeriostat ®DoxycyclinePermanone ®PermethrinPermapen ®Penicillin GPermax ®PergolidePertofran ®DesipraminePethidine ®MeperidinePetinimid ®EthosuximidePevaryl ®EconazolePfizerpen VK ® Pencillin VPfizerpin ®Penicillin GPhazyme ®SimethiconePhenazine ®PromethazinePhenergan ®PromethazinePhyseptone ®MethadonePilokair ®PilocarpinePipracil ®PiperacillinPitocin ®OxytocinPitressin ®VasopressinPlaquenil ®HydroxychloroquinePlasmotrim ®ArtesunatePlatet ®Acetylsalicylic acidPlatinex ®CisplatinPlatinol ®CisplatinPlavix ®ClopidogrelPlendil ®FelodipinePolamidon ®LevomethadonePolycillin ®Ampicillin

364 Drug IndexPonderal ®Ponderax ®Pondimin ®Pontocaine ®POR 8 ®Pradin ®Pravachol ®Pravidel ®Precose ®Predate ®Predcor ®Predenema ®Predfoam ®Prednesol ®Preferid ®Pregnesin ®Pregnyl ®Prelone ®Prenalex ®Prepidil ®Presinol ®Pressunic ®Prevacid ®Prevalite ®Priadel ®Primabolan ®Primaquine ®Primolut Depo ®Primolut N ®Primperan ®Principen ®Prinivil ®Privine ®Probalan ®Procan SR ®Procardia ®Procorum ®Procrit ®Procytox ®Pro-Depo ®Progestasert ®Proglicem ®Prograf ®Progynon ®Progynova ®Prolixan ®Prolixin ®Prolopa ®Proloprim ®Prometh ®Promine ®Pronestyl ®Propaderm ®Propasa ®Propecia ®FenfluramineFenfluramineFenfluramineTetracaineOrnipressinRepaglinidePravastatinBromocriptineAcarbosePrednisolonePrednisolonePrednisolonePrednisolonePrednisoloneBudesonideChorionic gonadotropin(HCG)Chorionic gonadotropin(HCG)PrednisoloneTertatololDinoprostoneMethyldopaDihydralazineLansoprazoleCholestyramineLithium carbonateMetenolonePrimaquineHydroxyprogesteronecaproateNorethindrone(norethisterone)MetoclopramideAmpicillinLisinoprilNaphazolineProbenecidProcainamideNifedipineGallopamilErythropoietin(= epoetin alfa)CyclophosphamideHydroxyprogesteronecaproateProgesteroneDiazoxideTacrolimusEstradiol-benzoateEstradiol-valerateAzapropazoneFluphenazineLevodopa + benserazideTrimethoprimPromethazineProcainamideProcainamideBeclometasoneMesalamine (mesalazine)FinasterideProphasi ®Chorionic gonadotropin(HCG)Propulsid(discontinued) ® CisapridePropyl-Thyracil ® PropylthiouracilProrex ®PromethazineProscar ®FinasterideProstaphlin ®OxacillinProstarmon ®DinoprostProstigmin ®Neostigmine®Prostin E 2 DinoprostoneProstin F 2 Alpha, ® DinoprostProstin VR ® Alprostadil (= PGE 1 )Protonix ®PantoprazoleProtopam Chloride ® PralidoximeProtostat ®MetronidazoleProtrin ®Co-trimoxazoleProvas ®ValsartanPro-Vent ®TheophyllineProvera ®MedroxyprogesteroneacetateProvigan ®PromethazineProviron ®MesteroloneProzac ®FluoxetinePrulet ®PhenolphthaleinPulmicort ®BudesonidePulsamin ®EtilefrinePurinethol ®MercaptopurinePurodigin ®DigitoxinPyopen ®CarbenicillinPyrilax ®BisacodylPyronoval ®Acetylsalicylic acidPyroxine ® Vitamin B 6Pyroxine ®PyridoxineQQuelicin ®Quellada ®Questran ®Quibron-T ®Quinachlor ®Quinalan ®Quinaminoph ®Quinamm ®Quine ®Quinidex ®Quinite ®Quinora ®Qvar ®RRapamune ®Rapilysin ®Rastinon ®Rebetol ®Rebif ®Reclomide ®SuccinylcholineLindaneCholestyramineTheophyllineChloroquineQuinidineQuinineQuinineQuinineQuinidineQuinineQuinidineBeclometasoneSirolimusReteplaseTolbutamideRibavirinInterferon beta-1aMetoclopramide

TradeName–DrugName 365Recormon ®EpoetinRectocort ®Hydrocortisone (cortisol)Redisol ® Vitamin B 12Reductil ®SibutramineRedux ®FenfluramineRefludan ®LepirudinRefobacin ®GentamicinRegaine ®MinoxidilRegitin ®PhentolamineReglan ®MetoclopramideRegonol ®PyridostigmineRehibin ®CyclofenilRelefact ®GonadorelinRelenza ®ZanamivirRelpax ®EletriptanRemergil ®MirtazepineRemeron SolTab ® MirtazepineRemicade ®InfliximabReminyl ®GalantamineRemsed ®PromethazineReomax ®Ethacrynic acidReoPro ®AbciximabReQuip ®RopiniroleRescriptor ®DelavirdineRescudose ®Morphine sulfateRestandol ®TestosteroneRestoril ®TemazepamRetardin ®DiphenoxylateRetrovir ®ZidovudineRevasc ®DesirudinReverin ®RolitetracyclineRezipas ®Mesalamine (mesalazine)Rezulin ®TroglitazoneRheumox ®AzapropazoneRhinalar ®FlunisolideRhinocort ®BudesonideRhumalgan ®DiclofenacRhythmin ®ProcainamideRhythmol ®PropafenoneRiamet ® Artemether +lumefantrineRidaura ®AuranofinRifadin ®Rifampin (rifampicin)Rimactan ®Rifampin (rifampicin)Rimifon ®IsoniazidRinatec ®IpratropiumRiopan ®MagaldrateRisperdal ®RisperidoneRivotril ®ClonazepamRize ®ClotiazepamRobicillin-VK ® Pencillin VRocaltrol ®CalcitriolRocephin ®CeftriaxoneRoferon A3 ®Interferon alpha-2aRogaine ®MinoxidilRogitin ®PhentolamineRohypnol ®FlunitrazepamRomazicon ®FlumazenilRoniacol ®PyridylcarbinolRonicol ®PyridylcarbinolRowasa ®Mesalamine (mesalazine)Roxanol ®Morphine sulfateRU 486 ®MifepristoneRubesol ® Vitamin B 12Rubion ®CyanocobalaminRubramin ®CyanocobalaminRulid ®RoxithromycinRyegonovin ®Methylergometrine(methylergonovine)Rynacrom ®Cromoglycate (cromolyn)Rythmodan ®DisopyramideSS.A.S.-500 ®Salazosulfapyridine(sulfasalazine)Sabril ®VigabatrinSaizen ®SomatotropinSalazopyrin ®Salazosulfapyridine(sulfasalazine)Saltucin ®ButizidSandimmune ® Ciclosporin(= cyclosporine A)Sandomigran ® Pizotifen = pizotylineSandostatin ®OctreotideSandril ®ReserpineSang-35 ®Ciclosporin(= cyclosporine A)SangCya, ®Ciclosporin(= cyclosporine A)Sanocrisin ®CyclofenilSansert ®MethysergideSatric ®MetronidazoleSaventrine ®Isoprenaline(= isoproterenol)Scabene ®LindaneScopoderm TTS ® ScopolamineSebcur ®Salicylic acidSectral ®AcebutololSecuron ®VerapamilSecuropen ®AzlocillinSeguril ®FurosemideSeldane ®TerfenadineSelectol ®CeliprololSembrina ®MethyldopaSempera ®ItraconazoleSenokot ®SennaSenolax ®SennaSepram ®CitalopramSeptra ®Co-trimoxazoleSerax ®OxazepamSerenace ®HaloperidolSerevent ®SameterolSerlect ®Sertindole*Sernyl ®PhencyclidineSeromycin ®CycloserineSerono-Bagren ® BromocriptineSerophene ®ClomifeneSerpalan ®ReserpineSerpasil ®ReserpineSertan ®PrimidoneSerzone ®NefazodoneSevorane ®Sevoflurane

366 Drug IndexSexovid ®Sibelium ®Sifrol ®Silain ®Simplene ®Simplotan ®Simulect ®Sinarest ®Sinemet ®Singulair ®Sinthrome ®Sintrom ®Sinutab ®Sirtal ®Skleromexe ®Slo-bid ®Slo-Phylli ®Sno Phenicol ®Sobelin ®Sofarin ®Soldactone ®Solfoton ®Solganal ®Solprin ®Solu-Contenton ®Soluver ®Solvex ®Somavert ®Somnite ®Somnos ®Somophyllin-T ®Sonata ®Sopamycetin ®Soprol ®Sorbitrate ®Sorquetan ®Sotacor ®Spametrin-M ®Spersadex ®Spersanicol ®Spiriva ®Spirocort ®Spiroctan ®Sporanox ®Sprecur ®Stabillin V-K ®Stafoxil ®Stas Surfactal ®Statex ®Steranabol ®Stesolid ®Stilnox ®Stilphostrol ®Stimate ®Stoxil ®Strepolin ®Streptase ®Streptosol ®CyclofenilFlunarizinePramipexoleSimethiconeEpinephrineTinidazolBasiliximabOxymetazolineCarbidopa + levodopaMontelukastAcenocoumarin(= nicoumalone)Acenocoumarin(= nicoumalone)XylometazolineCarbacholClofibrateTheophyllineTheophyllineChloramphenicolClindamycinWarfarinCanrenonePhenobarbitalAurothioglucoseAcetylsalicylic acidAmantadineSalicylic acidReboxetinePegvisomantNitrazepamChloral hydrateTheophyllineZaleploneChloramphenicolBisoprololIsosorbide dinitrateTinidazolSotalolMethylergometrine(methylergonovine)DexamethasoneChloramphenicolTiotropiumBudesonideSpironolactoneItraconazoleBuserelinPencillin VFlucloxacillin(floxacilline)AmbroxolMorphine sulfateClostebolDiazepamZolpidemDiethylstilbestrolDesmopressinIdoxuridineStreptomycinStreptokinaseStreptomycinStresson ®BunitrololStromectol ®IvermectinSuacron ®CarazololSublimaze ®FentanylSuccostrin ®SuccinylcholineSufenta ®SufentanilSulcrate ®SucralfateSulfabutin ®BusulfanSulmycin ®GentamicinSulpyrin ®DipyroneSupasa ®Acetylsalicylic acidSupramycin ® TetracyclineSuprane ®DesfluraneSuprarenin ®EpinephrineSuprefact ®BuserelinSustac ®Nitroglycerin(glyceryl trinitrate)Sustaine ®XylometazolineSustaire ®TheophyllineSustanon ®TestosteroneSustiva ®EfavirenzSuxamethonium ® SuccinylcholineSuxinutin ®EthosuximideSymmetrel ®AmantadineSynflex ®NaproxenSynkayvit ®MenadioneSynovir ®ThalidomideSyntocinon ®OxytocinSyntopressin ® LypressinSytobex ®CyanocobalaminSytobex ® Vitamin B 12TTacef ®CefmenoximeTacicef ®CeftazidimeTactocile ®AtosibanTagamet ®CimetidineTalwin ®PentazocineTambocor ®FlecainideTamiflu ®OseltamivirTamofen ®TamoxifenTapazole ®Methimazole(thiamazole)Tardigal ®DigitoxinTarivid ®OfloxacinTasmar ®TolcaponeTauredon ®Aurothiomalate sodiumTavegil ®ClemastineTavist ®ClemastineTavor ®LorazepamTaxol ®PaclitaxelTaxotere ®DocetaxelTebrazid ®PyrazinamideTeebaconin ®IsoniazidTegison ®EtretinateTegopen ®CloxacillinTegretol ®CarbamazepineTelemin ®BisacodylTelfast ®FexofenadineTemgesic ®Buprenorphine

TradeName–DrugName 367Tempra ®Tenalin ®Tenormin ®Tensium ®Tensobon ®Teoptic ®Testex ®Testoject ®Testone ®Testred ®Teveten ®Theelol ®Theolair ®Thesit ®Thevier ®Thiotepa Lederle ®Thorazine ®Thrombinar ®Thrombostat ®Thyrogen ®Ticar ®Ticlid ®Tienor ®Tigason ®Tilade ®Tildiem ®Timentin ®Timonil ®Timoptic ®Timoptol ®Timox ®Toazul ®Tobralex ®Tobrex ®Tofranil ®Tonocard ®Topamex ®Topitracin ®Toposar ®Toradol ®Tornalate ®Totacillin ®Totamol ®Toxogonin ®Tracleer ®Tracrium ®Tramal ®Trandate ®Transcycline ®Transderm Scop ®Trans-Ver-Sal ®Tranxene ®Tranxilium N ®Trapanal ®Trasicor ®Travogen ®Travogyn ®Trecalmo ®Trecator ®Trelstar Depot ®Tremblex ®Acetaminophen(= paracetamol)CarteololAtenololDiazepamCaptoprilCarteololTestosterone propionateTestosterone cypionateTestosterone enantateMethyltestosteroneEprosartanEstratriol = estriolTheophyllinePolidocanolLevothyroxineThio-TEPAChlorpromazineThrombinThrombinThyrotropinTicarcillinTiclopidineClotiazepamEtretinateNedocromilDiltiazemTicarcillinCarbamazepineTimololTimololOxcarbazepineTolonium chlorideTobramycinTobramycinImipramineTocainideTopiramateBacitracinEtoposideKetorolacBitolterolAmpicillinAtenololObidoximeBosentanAtracuriumTramadolLabetalolRolitetracyclinScopolamineSalicylic acidClorazepateNordazepamThiopentalOxprenololIsoconazoleIsoconazoleClotiazepamEthionamideTriptorelinDexetimideTrendar ®Trental ®Trexan ®Trialodine ®Triam-A ®Trichlorex ®Tricor ®Tridil ®Trileptal ®Triludan ®Trimpex ®Trimysten ®Triostat ®Triptone ®Trusopt ®Tryptizol ®Tubarine ®Tubasal ®Tus ®Tylenol ®Typramine ®Tyrozets ®Tyzine ®UUdicil ®Udolac ®Ukidan ®Ulcolax ®Ultair ®Unacid ®Unasyn ®Unicort ®Uniparin ®Uniphyl ®Univer ®Uricovac ®Uritol ®Uromitexan ®Urosin ®UroXatral ®Uticillin-VK ®Utinor ®VValadol ®Valcyte ®Valium ®Valorin ®Valtrex ®Vancocin ®Vaponefrine ®Vasal ®IbuprofenPentoxifyllineNaltrexoneTrazodoneTriamcinolone acetonideTrichlormethiazideFenofibrateNitroglycerin(glyceryl trinitrate)OxcarbazepineTerfenadineTrimethoprimClotrimazoleLiothyronineScopolamineDorzolamideAmitriptylineTubocurarine4-Aminosalicylic acidAmbroxolAcetaminophen(= paracetamol)ImipramineTyrothricinTetryzoline(= tetrahydrozoline)CytarabineDapsoneUrokinaseBisacodylPranlukastAmpicillin + sulbactamAmpicillin + sulbactamHydrocortisone (cortisol)HeparinTheophyllineVerapamilBenzbromaroneFurosemideMesnaAllopurinolAlfuzosinPencillin VNorfloxacinAcetaminophen(= paracetamol)ValganciclovirDiazepamAcetaminophen(= paracetamol)ValaciclovirVancomycinEpinephrinePapaverine

368 Drug IndexVascardin ®Isosorbide dinitrateVasocon ®NaphazolineVasotec ®Enalapril/enalaprilatVatran ®DiazepamVa-tro-nol ®EphedrineV-Cillin K ®Pencillin VVectavir ®PenciclovirVeetids ®Pencillin VVegesan ®NordazepamVelacycline ®RolitetracyclinVelban ®VinblastineVelbe ®VinblastineVelosulin ®InsulinVenactone ®CanrenoneVePesid ®EtoposideVeratran ®ClotiazepamVerelan ®VerapamilVermox ®MebendazoleVersed ®MidazolamVestra ®ReboxetineViagra ®SildenafilVibal ® Vitamin B 12Vibal L.A. ®HydroxocobalaminVibramycin ®DoxycyclineVidex ®DidanosineVidopen ®AmpicillinVigantol ®Colecalciferol(vitamin D 3 )Vigorsan ®Colecalciferol(vitamin D 3 )Vinactane ®ViomycinViocin ®ViomycinVionactane ®ViomycinVioxx ®RofecoxibVira-A ®VidarabineViracept ®NelfinavirViramune ®NevirapineVirazole ®RibavirinVirilon ®MethyltestosteroneVirofral ®AmantadineVisine ®Tetryzoline(= tetrahydrozoline)Visken ®PindololVistacrom ®Cromoglycate (cromolyn)Visutensil ®Guanethidine®Vitamine B 1 Thiamin(e)Vitrasert ®GanciclovirVivol ®DiazepamVolon ®TriamcinoloneVoltaren ®DiclofenacVoltarol ®DiclofenacVP-16 ®EtoposideVumon ®TeniposideWWandonorm ® BopindololWelcovorin ®LeucovorinWellbatrin ®BupropionWellbutrin ®BupropionWelldorm Elixir ®Whevert ®Wincoram ®Wingom ®Winpred ®Wyamycin ®XXalaten ®Xanax ®Xanef ®Xenical ®Xolair ®Xusal ®Xylocain ®Xylocard ®Xylonest ®YYal ®Yomesan ®ZZadstat ®Zantac ®Zapex ®Zarontin ®Zebeta ®Zeldox ®Zemuron ®Zenapax ®Zepine ®Zerit ®Zestril ®Zetria ®Ziagen ®Zimovane ®Zinamide ®Zithromax ®Zocor ®Zofran ®Zoladex ®Zolim ®Zoloft ®Zomig-ZMT ®Zosyn ®Zovirax ®Zyban ®Zyloprim ®Zyloric ®Zyprexa ®Zyvoxid ®Chloral hydrateMeclizine (meclozine)AmrinoneGallopamilPrednisoneErythromycin-ethylsuccinateLanatoprostAlprazolamEnalapril/EnalaprilatOrlistatOmalizumabLevocetirizineLidocaineLidocainePrilocaineSorbitolNiclosamideMetronidazoleRanitidineOxazepamEthosuximideBisoprololZiprasidoneRocuroniumDaclizumabReserpineStavudineLisinoprilEzetimibeAbacavirZopiclonePyrazinamideAzithromycinSimvastatinOndansetronGoserelinMizolastineSertralineZolmitriptanTazobactam + piperacillinAciclovirBupropionAllopurinolAllopurinolOlanzapineLinezolide

Drug Name –TradeName 369Drug Name – Trade Name(* denotes investigational status in theUnited States)AAbacavir Ziagen ®Abciximab ReoPro ®Acamprosate Campral ®Acarbose Precose ®Acebutolol Monitan ® , Sectral ®Acenocoumarin Sinthrome ® , Sintrom ®(= nicoumalone)Acetaminophen(= paracetamol)Virofral ® Plasmotrim ®Ambroxol Ambril ® , Bronchopront ® ,Mucosolvan ® ,StasSurfactal® ,Tus ®Amfebutamon(e) see Bupropion ®Amikacin Amikin ® ,Briclin ® ,Novamin ®Amiloride Arumil ® ,Colectril ® ,Cordarex ® ,Midamor ® ,Nilurid ®Acephen ® , Anacin-3 ® ,Bromo-Seltzer ® ,Calpol ® ,Datril ® , Panadol ® ,Tempra,Tylenol ® ,Valadol ® ,Valorin ®Amiloride + hydrochlorothiazideε-Aminocaproic acidAminomethylModuret ®Afibrin ® ,Amicar ® ,Capramol,Epsicapron ®Gumbix ® ,Pamba ®benzoic acid4-Aminosalicylic acid Nemasol Sodium ® ,Tubasal ®5-Aminosalicylic acid see Mesalamine(mesalazine) ®Amiodarone Cordarex ® ,Cordarone ®Amitriptyline Amitril ® ,Domical ® ,Elavil® ,Endep ® ,Enovil ® ,Lentizol ® ,Levate ® ,Mevaril ® ,Tryptizol ®Amlodipine Norvasc ®Amodiaquine Camoquin ® ,Flavoquine ®Amorolfin Loceryl ®Amoxicillin Almodan ® ,Amoxil ® ,Clamoxyl ® ,Moxacin ® ,Novamoxin ®Amoxicillin + Augmentan ®clavulanic acidAmphetamine see Dextroamphetamine®Amphotericin B Amphozone ® ,Fungilin ® ,Fungizone ® , Moronal ®Ampicillin Amcill ® ,Amphipen ® ,Omnipen ® ,Penbritin ® ,Polycillin ® ,Principen ® ,Totacillin ® ,Vidopen ®Ampicillin +Unacid ® ,Unasyn ®sulbactamAmprenavir Agenerase ®Amrinone Inocor ® ,Wincoram ®Anakinra Kineret ®Anastrozole Arimidex ®Angiotensinamide Hypertensin ®Aprindine Amidonal ® ,Aspenon ® ,Fibocil ® ,Fiboran ®Ardeparin Normiflo ®Artemether + Riamet ®lumefantrineArtesunate Arsumax ® ,Falcigo ® ,Asparaginase Erwinase ®Astemizole Hismanal ®Acetazolamide Diamox ® ,Glaupax ®Acetylcysteine Airbron ® ,Fabrol ® ,Mucomyst® ,Parvolex ®Acetylsalicylic acid Angettes ® , Arthrisin ® ,Asadrine ® ,Aspirin ® ,Ecotrin® ,Entrophen ® ,Platet® , Pyronoval ® ,Solprin® ,Supasa ®Aciclovir (Acyclovir) Zovirax ®Acipimox Olbemox ® ,Olbetam ®ACTH see Corticotropin ®Actinomycin D see Dactinomycin ®ADH see Vasopressin ®Adalimumab Humira ®Adrenaline see Epinephrine ®Adriamycin see Doxorubicin ®Ajmaline Cardiorhythmino ® ,Gilurytmal ®Albuterol see Salbutamol ®Alcuronium Alloferin ®Aldosterone Aldocorten ®Alendronate Fosamax ®Alfentanil Alfenta ®Alfuzosin Alfoten ® ,UroXatral ®Allopurinol Alloprin ® ,Caplenal ® ,Hamarin ® , Novopurol ® ,Urosin ® ,Zyloprim ® ,Zyloric ®Alprazolam Xanax ®Alprenolol Aprobal ® ,Aptine ® ,Gubernal ®AlprostadilMinprog ® ,ProstinVR ®(= PGE 1 )Alteplase Actilyse ®Aluminum hydroxide Aldrox ® ,Alu-Cap ® ,Alu-Tab ® ,Amphojel ® ,Fluagel®AmantadineAmbaxine ® ,Solu-Contenton® , Symmetrel ® ,

370 Drug IndexAspirin see Acetylsalicylic acid ® Bleomycin Blenoxane ®Bitolterol Effectin ® ,Tornalate ®AtenololAntipressan ® ,TenorminBopindolol Wandonorm ®® , Totamol ®Bosentan Tracleer ®Atoquavone Mepron ®Botulinum toxin Botox ® ,Oculinum ®Atoquavone + Malarone ®type AproguanilBotulinum toxin Myobloc ® , NeuroBloc ®Atorvastatin Lipitor ®type BAtosiban Antocin ® ,Tactocile ® Brimonidine Alphagan ®Atracurium Tracrium ®Brinzolamide Azopt ®Atropine Atropisol ® , Borotropin ® Bromazepam Durazanil ® ,Lectopam ® ,Auranofin Ridaura ®Lexotan ®Aurothioglucose Aureotan ® ,Auromyose ® ,Solganal ®Bromocriptine Parlodel ® ,Pravidel ® ,Serono-Bagren ®Aurothiomalate Tauredon ®BrotizolamLendorm(A) ® ,Lendorminsodium®Azapropazone Prolixan ® ,Rheumox ® Bucindolol Bextra ®Azathioprine Azanin ® ,Berkaprine ® ,Imuran ® ,Imurek ®Budesonide Entocort EC ® , Preferid ® ,Pulmicort ® ,Rhinocort ® ,Azidothymidine see Zidovudine ®Spirocort ®(AZT)Azithromycin Zithromax ®BumetanideBumex ® ,Burinex ® ,Fontego,Fordiuran ® ,Lixil ®Azlocillin Azlin ® , Securopen ® Bunitrolol Betriol ® , Stresson ®Bupranolol Betadran ® ,Betadrenol ® ,Looser ® , Panimit ®BBuprenorphine Buprene ® ,Temgesic ®Bacitracin Altracin ® ,Baciguent ® ,BupropionWellbatrin ® ,Wellbutrin,Zyban ®Topitracin ®Buserelin Sprecur ® ,Suprefact ®Baclofen Lioresal ®Buspirone Buspar ®Basiliximab Simulect ®Busulfan Mielucin ® ,Mitosan ® ,Beclometasone Aldecin ® , Becloforte ® ,Myleran ® ,Sulfabutin ®Becodisks ® ,Beconase ® , Butizid Saltucin ®Becotide ® , Propaderm ® , Butylscopolamine Buscopan ®Qvar ®Befunolol Bentos ® ,Betaclar ® ,Glauconex ®CBenazepril Lotensin ®BenserazideMadopar (plusCabergoline Cabaseril ® ,Dostinex ®levodopa) ®Calcifediol Calderol ® ,Dedrogyl ® ,Benzbromarone Desuric ® , Narcaricin ® ,Hidroferol ®Normurat ® ,Uricovac ® Calcitonin Calcimer ® , Calcitare ® ,Benzocaine Americaine ® ,Anacaine ® ,Anaesthesin ®Calsynar ® , Cibacalcin ® ,Karil ®Benztropine Cogentin ®Calcitriol Rocaltrol ®Betaxolol Betoptic ® ,Kerlone ® Calcium carbonate Cacit ® ,Calchichew ® ,Bezafibrate Befizal ® ,Bezalip ® ,Bezatol ® ,Cedur ®Calcidrink ® ,Calsan ® ,Caltrate ® ,Nu-Cal ®Bicalutamide Casodex ®Camazepam Albego ®Bifonazole Amycor ® ,Mycospor ® , Candesartan Atacand ®Mycosporan ®Canrenone Kanrenol ® , Soldactone ® ,Bimatoprost Lumigan ®Venactone ®Biperiden Akineton ® ,Akinophyl ® Capreomycin Capastat ® ,Caprolin ®BisacodylBicol ® ,Broxalax ® ,Dulcolax,Durolax ® ,Laxabene, Laxanin ® ,Nigalax,Pyrilax ® ,Telemin ® ,Captopril Acediur ® ,Acepril ® ,Alopresin ® ,Capoten ® ,Cesplon ® ,Hypertil ® ,Lopirin ® ,Tensobon ®Ulcolax ®Carazolol Conducton ® ,Suacron ®Bismuth subsalicylate Pepto-Bismol ®CarbacholDoryl ® ,Lentin ® ,MiostatBisoprololConcor ® , Detensiel ® ,Emcor® , Sirtal ®® ,Isoten ® , Monocor ® ,Soprol ® ,Zebeta ®Carbamazepine Epitol ® ,Mazepine ® ,Tegretol ® , Timonil ®

Drug Name –TradeName 371Clarithromycin Biaxin ®Carbenicillin Anabactyl (A) ® ,Sepram ® Udicil ®Carindapen ® ,Geopen ® , Clavulanic acid + Augmentin ®Pyopen ®amoxicillinCarbidopa + levodopa Isicom ® ,Nacom ® ,Clemastine Tavegil ® ,Tavist ®Sinemet ®Clindamycin Cleocin ® , Dalacin ® ,Carbimazole Neo-Mercazole ® ,Sobelin ®Neo-Thyreostat ®Clobazam Frisium ®Carboplatin Paraplatin ®Clodronate Clasteon ® ,Ossiten ® ,Carteolol Arteoptic ® ,Caltidren ® ,Ostac ®Carteol ® , Cartrol ® ,Clofazimine Lampren ®Endak ® ,Ocupress ® ,Tenalin ® ,Teoptic ®Clofibrate Atromid-S ® ,Claripex ® ,Skleromexe ®Carvedilol Coreg ®Clomethiazole Distraneurin ® ,Caspofungin Cancidas ®Hemineurin ®Cefalexin Keflex ® ,Keftab ®Clomifene Clomid ® ,Dyneric ® ,Cefmenoxime Bestcall ® ,Cefmax ® ,Cemix ® ,Tacef ®Omifin ® ,Pergotime ® ,Serophene ®Cefotaxime Claforan ®Clonazepam Clonopin ® ,Iktorivil ® ,Ceftazidime Fortaz ® , Fortum ® ,Rivotril ®Tacicef ®Clonidine Catapres ® , Dixarit ®Ceftriaxone Acantex ® ,Rocephin ® Clopidogrel Plavix ®Celecoxib =Celebrex ®Clorazepate Novoclopate ® ,Tranxene ®colecoxibClostebol Macrobin ® , Steranabol ®Celiprolol Selectol ®Clotiazepam Clozan ® ,Rize ® ,Tienor ® ,Cellulose Avicel ®Trecalmo ® ,Veratran ®Cerivastatin Baycol ®ClotrimazoleCanesten ® , ClotrimadermChloral hydrate Lorinal ® ,Noctec ® ,Somnos, Welldorm Elixir ®® ,Gyne-Lotrimin ® ,Mycelex ® ,Trimysten ®Chlorambucil Chloraminophene ® ,LeukeranCloxacillin Clovapen ® ,Tegopen ®®Clozapine Clozaril ®Chloramphenicol Chloromycetin ® ,ChloropticCodeine Codicept ® , Paveral ®® , Kemicetine Leu-Colchicine Colchicine ®komycin ® , Paraxin ® ,SnoPhenicol ® ,Sopamycetin ® ,Colecalciferol (vitaminD 3 )D-Tabs ® ,Vigantol ® ,Vigorsan ®Spersanicol ®Colecoxib see Celecoxib ®Chlordiazepoxide Librium ®Colestipol Cholestabyl ® ,Cholestid ®Chlormadinone acetateGestafortin ®Corticotropin Acthar ® , Cortigel ® ,Cortrophin ®ChloroquineAralen ® ,Avloclor ® ,NivaquineCortisol see Hydrocortisone ®® ,Quinachlor ® Cortisone Cortelan ® , Cortistab ® ,Chlorpromazine Hibanil ® ,Largactil ® ,Cortogen ® ,Cortone ®Megaphen ® ,Thorazine ® Co-trimoxazole Bactrim ® , Novotrimel ® ,Chlorthalidone Hygroton ®Protrin ® ,Septra ®Cholestyramine Cuemid ® ,Prevalite ® ,Questran ®Cromoglycate(cromolyn)Intal ® ,Nalcrom ® ,Opticrom,Rynacrom ® ,Chorionic gonadotropinEntromone ® ,Follutein ® ,Vistacrom ®(HCG)Pregnesin ® ,Pregnyl ® ,Prophasi ®Cyanocobalamin Anacobin ® ,Bedoz ® ,Cytacon ® ,Cytamen ® ,Ciclosporin(= cyclosporine A)Gengraf ® ,Neoral ® ,Sandimmune,SangCya ® ,Rubion ® ,Rubramin ® ,Sytobex ®Sang-35 ®Cyclofenil Fertodur ® ,Ondogyne ® ,Cilazapril Inhibace ®Ondonid ® ,Rehibin ® ,Cimetidine Dyspamet ® ,Peptol ® ,Sanocrisin ® ,Sexovid ®Tagamet ®Cyclophosphamide Cytoxan ® ,Endoxan ® ,Ciprofloxacin Ciloxan ® ,Cipro ® ,CiprobayProcytox ®® ,Ciprox ® ,Ciproxin ® Cycloserine Seromycin ®CisapridePropulsid (discontinued)Cyclosporine A see Ciclosporin ®®Cyproterone-Androcur ® ,Cyprostat ®Cisplatin Platinex ® ,Platinol ® acetateCitalopram Celexa ® ,Citaprim ® , Cytarabine Alexan ® ,Cytosar ® ,

372 Drug IndexDDimercaprol BAL in oil ® Ephedrine Bofedrol ® ,Efedron ® ,DimercaptopropanesulfonicDimaval ® ,Mercuval ®acidDaclizumab Zenapax ®Dimethylaminophenol4-DMAP ®Dactinomycin Cosmegen ®Dalteparin Fragmin ®Dimeticone Aegrosan ® , Meteosan ®Danaparoid Orgaran ®Dimetindene Fenestil ®Dantrolene Dantrium ®DinoprostMinprostin F2α ® ,ProstarmonDapsone Avlosulfone ® ,Eporal ® ,Diphenasone ® ,Udolac ®® ,ProstinF 2Alpha ®Darbepoetin Aranesp ®Dinoprostone Prepidil ® ®,ProstinE 2Daunorubicin Cerubidine ® ,DaunoblastinDiphenhydramine Allerdryl ® ,Benadryl ® ,® ,Ondena ®Insommal ® ,Nautamine ®Deferoxamine Desferal ®Diphenoxylate Diarsed ® , Lomotil ® ,Delavirdine Rescriptor ®Retardin ®Desflurane Suprane ®Dipyrone Algocalmin ® ,Bonpyrin ® ,Desipramine Norpramin ® , Pertofran ®Divarine ® , Feverall ® ,Desirudin Revasc ®Metilon ® ,Novalgin ® ,Desloratadine Aerius ®Paralgin ® ,Sulpyrin ®Desmopressin DDAVP ® , Minirin ® , Disopyramide Dirythmin ® ,Norpace ® ,Octostim ® ,Stimate ®Rythmodan ®Desogestrel + ethinylestradiolDocetaxel Taxotere ®Marvelon ®Dobutamine Dobutrex ®Dexamethasone Decadron ® ,Deronil ® , Domperidone Euciton ® ,Evoxin ® ,Hexadrol ® ,Maxidex ® ,Spersadex ®Motilium ® , Nauzelin ® ,Peridon ®Dexetimide Tremblex ®Donepezil Aricept ®Dextran Hyskon ®Dopamine Dopastat ® ,Intropin ®Diazepam Apaurin ® ,Atensine ® , Dorzolamide Trusopt ®Diastat ® ,Dizac ® ,Eridan ® , Doxacurium Nuromax ®Lembrol ® ,Meval ® , Doxazosin Cardura ® ,Carduran ®Noan ® ,Stesolid ® ,Doxorubicin Adriamycin ® ,Tensium ® ,Adriblastin ®Valium ® , Vatran ® ,Vivol ® Doxycycline Atridox ® ,C-Pak ® ,Diazoxide Eudemine ® ,Hyperstat ® ,Mutabase ® ,Proglicem ®Doryx ® , Doxicin ® ,Monodox ® ,Nordox ® ,DiclofenacAllvoran ® ,Diclophlogont,Rhumalgan ® ,Periostat ® ,Vibramycin ®Voltaren ® , Voltarol ® Doxylamine Decapryn ®Dicloxacillin Diclocil ® ,Dynapen ® , Dronabinol Marinol ®Pathocil ®Droperidol Droleptan ® ,Inapsine ®Didanosine Videx ®Dutasteride Avodart ®DiethylcarbamazepineHetrazan ®Diethylstilbestrol Honvol ® , Stilphostrol ® EDigitoxin Crystodigin ® , Digicor ® ,Digimerck ® , Digitaline ® ,Purodigin ® ,Tardigal ®Ebastine Ebastel ® ,Evastel ® ,Kestine ®Digoxin Digacin ® ,Lanicor ® ,Lanoxin ® ,Lenoxin ® ,EconazoleEcostatin ® ,Gyno-Pevaryl ® ,Pevaryl ®Novodigoxin ®Efavirenz Sustiva ®Digoxin immune FAB Digibind ®Eletriptan Relpax ®Dihydralazine Dihyzin ® ,Nepresol ® ,Pressunic ®Enalapril/enalaprilatInnovace ® ,Vasotec ® ,Xanef ®Dihydroergotamine Angionorm ® , D.E.H.45 ® , Enflurane Ethrane ®Dihydergot ® ,Divegal ® , Enfuvirtide Fuzeon ®Endophleban ®Enoxacin Bactidan ® ,Comprecin ® ,Diltiazem Cardizem ® ,Tildiem ®Enoram ® ,Enoxor ®Dimenhydrinate Dimetab ® , Dramamine ® , Enoxaparin Clexane ® ,Lovenox ®Dymenate ® ,Marmine ® Entacapone Comtan ® ,Comtess ®Va-tro-nol ®

Drug Name –TradeName 373Epinephrine Adrenalin ® , Bronchaid ® , FEzetimibe Zetria ®Epifin ® ,Epinal ® ,EpiPen ® ,Epitrate ® ,Fastject ® ,Lyophrin ® ,Simplene ® ,Suprarenin ® ,Vaponefrine ®Epoetin Eprex ® ,Recormon ®Eprosartan Teveten ®Eptifibatide Integriline ®Ergocalciferol Drisdol ®Ergometrine(= ergonovine)Ergotrate Maleate ® ,Ermalate ®Ergotamine Ergomar ® ,Gynergen ® ,Lingraine Medihaler ® ,Migril ®Erythromcyin E-mycin ® ,Eryc ® ,Erymax, Erythromid ® ,Erythroped ® ,Ilosone ®ErythromycinestolateDowmycin ® ,Ilosone ® ,Novorythro ®ErythromycinethylsuccinateEES ® , Erythrocin ® ,Wyamycin ®ErythromycinpropionateCimetrin ®ErythromycinstearateErymycin ® ,Erythrocin ®ErythromycinsuccinateMonomycin ®Erythropoietin Epogen ® ,Procrit ®(=epoetin alfa)Esmolol Brevibloc ®Esomeprazole Nexium ®Estradiol Estrace ®Estradiol-benzoate Progynon ®Estradiol-valerate Delestrogen ® ,Dioval ® ,Femogex ® , Progynova ®Estratriol (= estriol) Theelol ®Etanercept Enbrel ®Ethacrynic acid Edecrin ® ,Hydromedin ® ,Reomax ®Ethambutol Etibi ® ,Myambutol ®Ethinylestradiol Estinyl ® ,Feminone ® ,Lynoral ®Ethionamide Trecator ®Ethopropazine Parsitan ® ,Parsitol ®Ethosuximide Petinimid ® , Suxinutin ® ,Zarontin ®Etidronate Calcimux ® ,Diodronel ® ,Diphos ®Etilefrine Apocretin ® ,Circupon ® ,Effontil ® , Effortil ® ,EthylAdrianol ® ,Kertasin ® ,Pulsamin ®Etofibrate Lipo-Merz ®EtomidateAmidate ® ,HypnomidateGEtoposide Etopophos ® ,Toposar ® ,VePesid ® ,VP-16 ®Etretinate Tegison ® ,Tigason ®Famciclovir Famvir ®Famotidine Pepcid ® ,Pepdul ®Felbamate Felbatol ®Felodipine Plendil ®Felypressin Octapressin ®Fenfluramine Ganal ® ,Ponderal ® ,Ponderax ® ,Pondimin ® ,Redux ®Fenofibrate Tricor ®Fenoterol Berotec ® , Partusisten ®Fentanyl Sublimaze ®Fentanyl +Innovar ®droperidolFexofenadine Allegra ® ,Telfast ®Filgrastim Neupogen ®Finasteride Propecia ® ,Proscar ®Flecainide Tambocor ®Flucloxacillin(floxacilline)Floxapen ® ,Ladropen ® ,Stafoxil ®Fluconazole Diflucan ®Flucytosine Alcoban ® ,Ancotil ®Fludrocortisone Alflorone ® , F-Cortef ® ,Florinef ®Flumazenil Anexate ® , Romazicon ®Flunarizine Dinaplex ® ,Flugeral ® ,Sibelium ®Flunisolide Aerobid ® ,Bronalide ® ,Nasalide ® ,Rhinalar ®FlunitrazepamHypnosedon ® ,Narcozep® ,Rohypnol ®Fluorouracil Adrucil ® ,Effudex ® ,Effurix ®Fluoxetine Fluctin ® ,Prozac ®Fluphenazine Moditen ® ,Prolixin ®Flurazepam Dalmane ®Flutamide Drogenil ® , Eulexin ®Fluticasone Cutivate ® ,Flixonase ® ,Flonase ® ,Flovent ®Fluvastatin Lescol ®Fluvoxamine Faverin ® ,Floxifral ® ,Luvox ®Folic acid Foldine ® ,Folvite ® ,Leucovorin ®Fondaparinux Arixtra ®Formoterol Foradil ® ,Oxi ®Foscarnet Foscavir ®Fosinopril Monopril ®Fulvestrant Faslodex ®Furosemide Dryptal ® ,Fusid ® ,Lasix ® ,Seguril ® , Uritol ®Gabapentin Neurontin ®Galantamine Reminyl ®Gallopamil Algocor ® ,Corgal ® ,Procorum ® ,Wingom ®

374 Drug IndexHydroxyurea Droxia ® ,Hydrea ®Ganciclovir Cymevene ® ,Cytovene ® ,Pro-Depo ®Vitrasert ®Hyoscine butyl Buscopan ®Ganirelix Antagon ® , Orgalutran ® bromideGelatin-colloids Gelafundin ® ,Haemaccel ®Gemfibrozil Lopid ®IGentamicin Cidomycin ® ,Garamycin ® ,Genticin ® ,Refobacin ® ,Sulmycin ®Ibuprofen Actiprophen ® ,Advil ® ,Brufen ® ,Fenbid ® , LidifenGestoden + ethinyl Femovan ®® , Motrin ® ,Nuprin ® ,estradiolTrendar ®Glatimer acetate Copaxone ®Idoxuridine Dendrid ® ,Herpid ® ,Glibenclamide(= glyburide)Calabren ® ,Daonil ® ,DiaBeta ® , Euglucon ® ,Herplex ® , Kerecid ® ,Stoxil ®Micronase ®Ifosfamide Ifex ® ,Mitoxana ®Glyceryl trinitrate see Nitroglycerin ®Iloprost Ilomedin ®Gonadorelin Factrel ® ,Kryptocur ® , Imatinib Glivec ®Relefact ®Imipramine Dynaprin ® ,Impril ® ,Goserelin Zoladex ®Janimine ® ,Melipramin ® ,Granisetron Kytril ®Tofranil ® ,Typramine ®Griseofulvin Fulcin ® ,Fulvicin ® ,Indinavir Crixivan ®Grisovin ® ,Likuden ® Indometacin Ammuno ® ,Imbrilon ® ,Guanethidine Ismelin ® ,Visutensil ®Indocid ® ,Indocin ® ,Indomee ® , Indomod ® ,HMetacen ®Infliximab Remicade ®Insulin Humalog ® , Humulin ® ,Halofantrine Halfan ®Iletin ® ,Novolin ® ,Haloperidol Haldol ® , Serenace ®Velosulin ®Halothane Fluothane ® ,Narkotan ® Insulin aspart Novolog ®HCGsee ChorionicInsulin glargine Lantus ®gonadotropin ®Interferon alfa-2 Berofor alpha 2 ®Heparin Calciparin ® , Hepalean ® , Interferon alfa-2a Roferon A3 ®Hepsal ® ,Liquemin ® , Interferon alfa-2b Intron A ®Uniparin ®Interferon beta Fiblaferon 3 ®Heparin ® ,low Fragmin ® , Fraxiparin ® Interferon beta-1a Rebif ®molecularInterferon gamma Actimmune ®Hetastarch (HES) Hespan ®Ipratropium Atrovent ® , Itrop ® ,Hexachlorophane see Lindane ®Rinatec ®Hexobarbital Evipan ®Irbesartan Avapro ®Homatropine Homapin ®Irinotecan Campto ®Hydralazine Alazine ® ,Apresoline ® Isoconazole Gyno-Travogen ® ,Hydrochlorothiazide Aprozide ® ,Diaqua ® ,DiuchlorTravogen ® ,Travogyn ®® ,Esidrix ® ,Hydro-Isoflurane Forane ®mal ® , Hydrosaluric ® ,Neo-Codema ® , Oretic ®Isoniazid Armazid ® ,Isotamine ® ,Lamiazid ® ,Nydrazid ® ,Hydrocortisone Alocort ® , Cortate ® ,Rimifon ® ,Teebaconin ®(cortisol)Cortef ® ,Cortenema ® ,Hyderm ® ,Hyocort ® ,Rectocort ® ,Unicort ®Isoprenaline(= isoproterenol)Aludrin ® ,Isuprel ® ,Neo Epinin ® ,Saventrine ®Hydromorphone Dilaudid ® ,Hymorphan ® Isosorbide dinitrate Cedocard ® ,Coradus ® ,Hydroxocobalamin Acti-B ® 12 ,Alpha-redisol,Cobalin-H ® ,Droxomin,Hybalamine ® ,Coronex ® ,Isoket ® ,Isordil ® ,Sorbitrate ® ,Vascardin ®Vibal L.A. ®Isosorbide mononitrateColeb ® ,Elantan ® ,Hydroxychloroquine Plaquenil ®Imdur ® ,Ismo ® , Isotrate ®Hydroxyethyl starch Hespan ®Isradipine DynaCirc ®HydroxyprogesteronecaproateDuralutin ® , Gesterol L.A. ® ,Hylutin ® ,Hyroxon ® ,Itraconazole Itracol ® , Sempera ® ,Sporanox ®Primolut Depo ® ,Ivermectin Mectizam ® , Stromectol ®

Drug Name –TradeName 375KLopinavir Kaletra ® Methoxyflurane Methofane ® ,Penthrane ®Loratadine Claritin ® ,Lisino ®Lorazepam Alzapam ® ,Ativan ® ,Kanamycin Anamid ® ,Kannasyn ® ,Loraz ® ,Tavor ®Kantrex ® ,Klebcil ® Lormetazepam Ergocalm ® ,Loramet ® ,Kaolin + pectin Donnagel-MB ® ,Noctamid ®(=attapulgite) Kaopectate ® ,Losartan Cozaar ®Pectokay ®Lovastatin Mevacor ® ,Mevinacor ®Ketamine Ketalar ®Lumefantrine see Artemether ®Ketoconazole Nizoral ®(= benflumetol)Ketorolac Acular ® , Toradol ®Lynestrenol Orgametril ®Lypressin Diapid ® ,Syntopressin ®LMLabetalol Normodyne ® ,Trandate ®Lactitol Importal ®Magaldrate Riopan ®Lactulose Cephulac ® ,Chronulac ® , Mannitol Isotol ® , Osmitrol ®Duphalac ®Maprotiline Ludiomil ®Lamivudine Epivir ®Mebendazole Vermox ®Lamotrigine Lamictal ®Mechlorethamine Mustargen ®Lanatoprost Xalaten ®MeclizineAntivert ® , Antrizine ® ,Lansoprazole Agopton ® , Lanzor ® , (meclozine)Bonamine ® ,Whevert ®Prevacid ®Medroxyprogesterone-acetateAmen ® , Depo-Provera ® ,Leflunomide Arava ®Farlutal ® ,Oragest ® ,Lenograstim (G-CSF) ® ,Granocyte ®Provera ®Lepirudin Refludan ®Mefloquine Lariam ®Letrozole Femara ®Megestrol Megestat ®Leucovorin Welcovorin ®MelarsoprolMelB ® ,MelarsenOxide-LeuprolideEligard ® ,Lupron ®BAL ®(leuprorelin)Meloxicam Mobic ®Levocetirizine Xusal ®Melphalan Alkeran ®Levodopa Dopar ® ,Larodopa ®Menadione Synkayvit ®Levodopa +Madopar ® ,Prolopa ®Menotropin Menogon ®benserazideMeperidineDemerol ® ,Dolantine ®Levodopa +Sinemet ®(pethidine)carbidopaLevomethadone Polamidon ®Mepindolol Betagon ® ,Caridian ® ,Corindolan ®Levothyroxine Eferox ® , Euthyrox ® , Mepivacaine Carbocaine ® ,Isocaine ®Thevier ®Mercaptopurine Purinethol ®Lidocaine Dalcaine ® ,Lidopen ® ,Nulicaine ® ,Xylocain ® ,Xylocard ®Mesalamine (mesalazine)Asacol ® ,Canasa ® ,Mesacal,Pentasa ® ,Propasa ® ,Rezipas ® ,Rowasa ®Lincomycin Albiotic ® ,Cillimycin ® , Mesna Mesnex ® , Uromitexan ®Lincocin ®Mesterolone Androviron ® , Proviron ®LindaneHexit ® ,Kwell ® ,Kwilldane,Quellada ® ,Mestranol Menophase ® ,Norquen ® ,Ovastol ®Scabene ®Metamizol see Dipyrone ®Linezolide Zyvoxid ®Metaproterenol (orciprenaline)Alupent ® ,Metaprel ®Liothyronine Cytomel ® , Triostat ®LisinoprilCarace ® ,Prinivil ® ,ZestrilMetenolone Primabolan ®®Metformin Diabex ® ,Glucophage ®Lisuride Cuvalit ® ,Dopergin ® ,Eunal ® ,Lysenyl ®MethadoneDolophine ® ,Methadose,Physeptone ®Lithium carbonate Camcolit ® ,Carbolite ® , Methamphetamine Desoxyn ® , Methampex ®Duoralith ® ,Eskalith ® , Methimazole Tapazole ® , Mercazol ®Liskonum ® ,Lithane ® ,Lithobid ® ,Lithotabs ® ,(thiamazoleMethohexital Brevital ®Priadel ®Methotrexate Folex ® ,Maxtrex ® ,Lomustine CCNU ® , CeeNu ®Mexate ®Loperamide Imodium ® , Kaopectate II ®Methotrimeprazine Levoprome ® ,Nocinan ®

376 Drug IndexMethylcellulose Celevac ® , Citrucell ® ,CologelNalbuphine Nubain ®Naftifin Naftin ® Olanzapine Zyprexa ®® ,Lacril ® ,Murocel ® Nalidixic acid Negram ® ,Nogram ®Methyldopa Aldomet ® ,Amodopa ® , Naloxone Narcan ®Dopamet ® , NovomedopaNaltrexone Nalorex ® ,Trexan ®® ,Presinol ® , Sembri-na ®Nandrolone Anabolin ® , Androlone ® ,Deca-Durabolin ® ,Methylergometrine(methylMetenarin ® ,Methergine,MethylergobrevinHybolin Decanoate ® ,Kabolin ®ergonovine)® , Partergin Ryegono-vin ® ,Spametrin-M ®Naphazoline Albalon ® ,Degest-2 ® ,Privine ® , Vasocon ®Methyltestosterone Android ® , Metandren ® ,Testred ® , Virilon ®Naproxen Aleve ® ,Anaprox ® ,Naprelan ® ,Napron ® ,Methysergide Deseril ® ,Sansert ®Naprosyn ® ,Naxen ® ,Metipranolol Optipranolol ®Synflex ®Metoclopramide Clopra ® ,Emex ® ,MaxeranNaratriptan Naramig ®® , Maxolan ® ,Primper-NarcotineCoscopin ® ,Coscotab ®an ® ,Reclomide ® ,Reglan ® (= noscapine)Metoprolol Betaloc ® , Lopressor ® Nedocromil Tilade ®Metronidazole Clont ® ,Femazole ® , Nefazodone Nefaclar ® , Serzone ®Flagyl ® , Metronid ® , Nelfinavir Viracept ®Protostat ® ,Satric ® ,Zadstat ®NeomycinMycifradin ® ,Myciguent,Nivemycin ®Mexiletin Mexitil ®Neostigmine Prostigmin ®Mezlocillin Mezlin ®Netilmicin Netillin ® , Netromycin ®Miconazole Daktarin ® ,Dermonistat ® , Nevirapine Viramune ®Micatin ® ,Monistat ® Nicardipine Cardene ®Midazolam Hypnovel ® ,Versed ® Niclosamide Niclocide ® ,Yomesan ®Mifepristone RU 486 ® ,Mifegyne ® Nifedipine Adalat ® ,Coracten ® ,Miglitol Diastabol ®Procardia ®Minoxidil Loniten ® ,Regaine ® , Nimodipine Nimotop ®Rogaine ®Nitrazepam Atempol ® , Mogadon ® ,MirtazepineRemergil ® ,RemeronSomnite ®SolTab ®Nitrendipine Bayotensin ® ,Baypress ®Misoprostol Cytotec ®Nitroglycerin Ang-O-Span ® ,Deponit ® ,Mivacurium Mivacron ®Nitrocap ® , Nitrogard ® ,Mizolastine Mistamine ® , Mizollen ® ,Zolim ®Nitronal ® ,Sustac ® ,Tridil ®Moclobemide Aurorix ®Nitroprusside Nipride ® , Nitropress ®Molgramostim Leucomax ®sodiumMolsidomine Corvaton ® ,Duracoron ® , Nitrostigmine E605 ® ,Parathion ®Molsidolat ®Nordazepam Tranxilium N ® , Vegesan Montelukast Singulair ®Norepinephrine Arterenol ® ,Levophed®Morphine MST Continus ® ,(noradrenaline)Oramorph ®Norethindrone Micronor ® ,Noriday ® ,Morphine hydrochlorideMorphitec ®(norethisterone) Norlutin ® ,Nor-QD ® ,Primolut N ®Morphine sulfate Astramorph ® ,Avinza ® , Norfloxacin Noroxin ® ,Utinor ®Duramorph ® ,EpimorphNortriptyline Pamelor ®® ,Infumorph ® , NoscapineCoscopin ® ,Coscotab ®Kadian ® ,MSIR ® ,Roxanol,Rescudose ® ,Statex ®(= narcotine)NystatinKorostatin ® ,Mycostatin,Mykinac ® ,Nilstat ® ,Muromonab-CD3 Orthoclone OKT3 ®Nystan ® ,Nystex ® ,O-VMycophenolate CellCept ®Statin ®mofetilNOObidoxime Toxogonin ®Nabilone Cesamet ®Octreotide Sandostatin ®Nadolol Corgard ®Ofloxacin Tarivid ®

Drug Name –TradeName 377Omalizumab Xolair ®Perindopril Coversum ® ,Coversyl ®Pergolide Celance ® ,Permax ® Pronestyl ® ,Rhythmin ®Omeprazole Losec ®Permethrin Elimite ® ,Lyclear ® ,Nix ® ,Ondansetron Zofran ®Permanone ®Opium tincture Paregoric ®Pethidine see Meperidine ®(laudanum)Phencyclidine Sernyl ®Orciprenaline see Metaproterenol ® Pheniramine Daneral ® ,Inhiston ®Orlistat Xenical ®Phenobarbital Barbita ® ,Gardenal ® ,Ornipressin POR 8 ®Solfoton ®Oseltamivir Tamiflu ®Phenolphthalein Alophen ® , Correctol ® ,Oxacillin Bactocill ® ,Prostaphlin ®Espotabs ® , Evac-U-gen ® ,Oxazepam Oxpam ® , Serax ® ,Zapex ®Evac-U-Lax ® ,Ex-Lax ® ,Oxcarbazepine Timox ® ,Trileptal ®Modane ® ,Prulet ®Oxiconazole Oxistat ®Phenoxybenzamine Dibenyline ® ,DibenzylineOxprenolol Apsolox ® ,Trasicor ®®Oxymetazoline Afrin ® , Allerest ® , CoricidinPhenoxybenzyl Isocillin ® , Megacillin ®® ,Dristan ® ,Neo-Syn-ephrine ® ,Sinarest ®penicillinPhenprocoumon Liquamar ® ,Marcumar ®Oxytocin Pitocin ® ,Syntocinon ® Phentolamine Regitin ® , Rogitin ®Phenytoin Dilantin ® ,Epanutin ®PPhysostigmine Antilirium ®Phytomenadione Konakion ®PilocarpineAkarpine ® ,AlmocarpinePaclitaxel Taxol ®® , I-Pilopine ® ,Pamidronate Aminomux ® ,Aredia ®Isopto-Carpine ® ,Pancuronium Pavulon ®Miocarpine ® ,Ocusert ® ,Pantoprazole Protonix ®Pilokair ®Papaverine Cerebid ® , Cerespan ® , Pindolol Visken ®Delapav ® ,Myobid ® , Pioglitazone Actos ®Papacon ® , Pavabid ® , Pipecuronium Arduan ®Pavadur ® , Vasal ®Piperacillin Pipracil ®Paracetamol see Acetaminophen ® Pirenzepine Gastrozepin ®Parecoxib Dynastat ®Piretanide Arelix ® ,Diumax ®Paromomycin Humatin ®Pizotifen =Litec ® , Mosegor ® ,Paroxetine Paxil ®pizotylineSandomigran ®Pegvisomant Somavert ®Polidocanol Thesit ®Penbutolol Levatol ®Pralidoxime Protopam Chloride ®Penciclovir Vectavir ®Pramipexole Sifrol ®D-Penicillamine Cuprimine ® , Depen ® Pranlukast Ultair ®Penicillin GBicillin ® ,Cryspen ® ,CrystapenPravastatin Lipostat ® ,Pravachol ®® ,Deltapen ® , Prazepam Centrax ®Lanacillin ® ,Megacillin ® , Praziquantel Biltricide ®Parcillin ® ,Pensorb ® , Prazosin Hypovase ® , Minipress ®Pentids ® ,Permapen ® ,Pfizerpin ®Prednisolone Ak Pred ® ,Articulose ® ,Codelsol ® , Cortalone ® ,PenicillinV ApsinVK ® , Betapen-VK ® ,Bopen-VK ® ,Calvepen ® ,Cocillin-VK ® ,DistaquaineV-K ® , Lanacillin-VK ® ,LedercillinVK ® ,Nadopen-V ® , Novopen-VK ® ,Pen-Vee K ® , Pen-VEE K PenaparVK ® ,Penapar-VK ® ,Delta-Cortef ® ,Deltastab,Econopred ® ,Hydeltrasol ® ,Inflamase ® ,Key-Pred ® ,Metalone ® ,Metreton ® ,Pediapred ® ,Predate ® ,Predcor ® ,Predenema ® ,Predfoam ® ,Prednesol ® ,Prelone ®Penbec-V ® ,PfizerpenVK ® , Robicillin-VK ® ,StabillinPrednisone Meticorten ® ,Orasone ® ,Panasol ® ,Winpred ®V-K ® ,Uticillin-VK ® , Prilocaine Citanest ® ,Xylonest ®V-Cillin K ® , Veetids ® Primaquine Primaquine ®Pentamidine Pentacarinat ®Primidone Myidone ® ,Mysoline ® ,Pentazocine Fortral ® ,Talwin ®Sertan ®Pentobarbital Butylone ® ,Nembutal ® , Probenecid Benemid ® ,Probalan ®Novarectal ® ,Pentanca ® Probucol Lovelco ®Pentoxifylline Trental ®Procainamide Procan SR ® ,Promine ® ,

378 Drug IndexProcaine Novocaine ®Rifampin (rifampicin) Rifadin ® ,Rimactan ®Rifabutin Mycobutin ® Sulfalen Longum ®Progabide Gabren(e) ®Risedronate Actonel ®Progesterone Cyclogest ® , Femotrone ® , Risperidone Risperdal ®Gestone ® ,Progestasert ® Ritonavir Norvir ®Proguanil Paludrine ®Rivastigmine Exelon ®Promethazine Anergan ® ,Avomine ® , Rizatriptan Maxalt ®Ganphen ® , Mallergan ® , Rocuronium Zemuron ®Pentazine ® , Phenazine ® , Rofecoxib Vioxx ®Phenergan ® , Prometh ® ,Prorex ® , Provigan ® ,Rolitetracycline Reverin ® ,Transcycline ® ,Velacycline ®Remsed ®Ropinirole ReQuip ®Propafenone Arhythmol ® ,Rhythmol ® Rosiglitazone Avandia ®Propofol Diprivan ®Roxithromycin Rulid ®Propranolol Berkolol ® ,Cardinol ® ,Detensol ® ,Inderal ®Propylthiouracil Propyl-Thyracil ® SPyrantel pamoate Antiminth ® ,CombantrinSalazosulfapyridine Azaline ® , Azulfidine ® ,S.Pyrazinamide Aldinamide ® ,Tebrazid ® , (sulfasalazine) A.S.-500 ® ,Salazopyrin ®Zinamide ®Salbutamol see Albuterol ®Pyridostigmine Mestinon ® , Regonol ® Salicylic acidAcnex ® , Sebcur ® ,SoluverPyridoxineBee-six ® , Complement® ,Trans-Ver-Sal ®Continus ® ,Hexa-BetalinSameterol Serevent ®® ,Pyroxine ®Saquinavir Fortovase ® ,Invirase ®Pyridylcarbinol Roniacol ® , Ronicol ® ScopolamineScopoderm TTS ® ,TransdermPyrimethamine Daraprim ®Scop ® ,Pyrimethamine + Fansidar ®Triptone ®sulfadoxineSelegeline Carbex ® ,Deprenyl ® ,Eldepryl ®QSennaBlack Draught ® ,Fletcher’sCastoria ® , Genna ® ,Quazepam Doral ®Gentle Nature ® ,Nytilax ® ,Senokot ® , Senolax ®Quinacrine Atabrine ®Sertindole* Serlect ®Quinagolide Norprolac ®Sertraline Gladem ® , Zoloft ®Quinapril Accupril ®Sevoflurane Sevorane ®Quinidine Cardioqin ® ,Cin-Quin ® , Sibutramine Reductil ®Kiditard ® , Kinidin ® , Sildenafil Viagra ®Quinalan ® ,Quinidex ® ,Quinora ®Simethicone Gas.X ® ,Mylicon ® ,Phazyme ® ,Silain ®Quinine Quinaminoph ® ,Simvastatin Zocor ®Quinamm ® ,Quine ® , Sirolimus Rapamune ®Quinite ®Somatorelin GHRH-Ferring ®Somatostatin Aminopan ®RSomatotropin Genotropin ® , Saizen ®Sorbitol Yal ®Sotalol Sotacor ®Rabeprazole AcipHex ® ,Pariet ®Spironolactone Aldactone ® ,Spiroctan ®Raloxifene Evista ®Stavudine Zerit ®Ramipril Altace ®Stibogluconate Pentostam ®Ranitidine Zantac ®sodiumRapamycin see Sirolimus ®Streptokinase Kabikinase ® , Streptase ®Rasburicase Fasturtec ®Streptomycin Strepolin ® , Streptosol ®Reboxetine Edronax ® ,Solvex ® ,Vestra ®Succinylcholine Anectine ® ,Quelicin ® ,Succostrin ®Repaglinide Actulin ® , NovoNorm ® ,Pradin ®Sucralfate Antepsin ® , Carafate ® ,Sulcrate ®Reserpine Sandril ® , Serpalan ® , Sufentanil Sufenta ®Serpasil ® ,Zepine ® Sulbactam Combactam ®Reteplase Rapilysin ®Sulfadoxine + pyrimethamineFansidar ®Ribavirin Rebetol ® ,Virazole ®

Drug Name –TradeName 379Sulfamethoxazole Gamazole ® ,Gantanol ® , Thyroxine Choloxin ® , Eltroxin ®Thyrotropin Thyrogen ® Vardenafil Levitra ®Methanoxanol ®Tiagabine Gabitril ®Sulfapyridine Dagenan ®Ticarcillin Ticar ® ,Timentin ®Sulfisoxazole Gantrisin ® ,Gulfasin ® Ticlopidine Ticlid ®Sulfasalazine see Salazosulfapyridine ® Timolol Betimol ® ,Blocadren ® ,Sulprostone Nalador ®Timoptic ® ,Timoptol ®Sumatriptan Imitrex ®TinidazolFasigyn(CH) ® ,SimplotanSuramine Bayer 205 ® ,Germanin ®® ,Sorquetan ®Suxamethonium see Succinylcholine ® Tiotropium Spiriva ®Tirofiban Aggrastat ®TTobramycin Nebcin ® ,Tobralex ® ,Tobrex ®Tocainide Tonocard ®t-PA (= alteplase) Activase ®Tolbutamide Mobenol ® ,Oramide ® ,Tacrine Cognex ®Orinase ® ,Rastinon ®Tacrolimus Prograf ®Tolcapone Tasmar ®Tadalafil Cialis ®Tolonium chloride Klot ® , Toazul ®Talinolol Cordanum ®Topiramate Topamex ®Tamoxifen Nolvadex ® ,Tamofen ® Topotecan Hycamtin ®Tamsulosin Flomax ®Tramadol Tramal ®Tazobactam + Zosyn ®Trandolapril Mavik ®piperacillinTranexamic acid Cyklokapron ®Telmisartan Micardis ®Tranylcypromine Parnate ®Temazepam Euhypnos ® ,Normison ® , Trastuzumab Herceptin ®Restoril ®Trazodone Desyrel ® ,Trialodine ®Tenecteplase Metalyse ®Triamcinolone Adcortyl ® , Aristocort ® ,Teniposide Vumon ®Kenacort ® , Ledercort ® ,Terazosin Hytrin ®Volon ®Terbutaline Brethine ® ,Bricanyl ® Triamcinolone Adicort ® , Azmacort ® ,Terfenadine Seldane ® ,Triludan ® acetonideKenalog ® ,Kenalone ® ,Teriparatide Forteo ®Triam-A ®Tertatolol Prenalex ®Triamterene Dyrenium ® ,Dytac ®Testosterone Restandol ® ,Sustanon ® Triazolam Halcion ®TestosteronecypionateAndrocyp ® , Andronate ® ,Duratest ® ,Testoject ®Trichlormethiazide Metahydrin ® ,Naqua ® ,Trichlorex ®TestosteroneAndro ® ,Delatestryl ® , Triiodthyronine Cytomel ®enantateEverone ® ,Testone ® (= liothyronine)TestosteroneTestex ®Trimetaphan Arfonad ®propionateTestosteroneAndriol ®Trimethoprim Ipral ® , Monotrim ® ,Proloprim ® ,Trimpex ®undecanoateTetracaine Anethaine ® ,Pontocaine ®TriptorelinDecapeptyl ® ,TrelstarDepot ®TetracyclineAchromycin ® ,SupramycinTroglitazone Rezulin ®®Tropisetron Navoban ®TetryzolineCollyrium ® ,Murine ® , Tubocurarine Jexin ® ,Tubarine ®(= tetrahydrozoline) Tyzine ® ,Visine ®Tyrothricin Hydrotricin ® ,Tyrozets ®Thalidomide Contergan ® ,Synovir ®Theophylline Aerolate ® ,Bronkodyl ® ,Constant-T ® ,ElixophyllinU® ,Lasma ® ,Nuelin ® ,Pro-Vent ® ,Quibron-T ® , Urokinase Abbokinase ® ,Ukidan ®Slo-bid ® , Slo-Phylli ® ,Somophyllin-T,Sustaire ® ,Theolair ® ,Uniphyl ® VThiabendazole Mintezol ®Thiamazole see Methimazole ®Valaciclovir Valtrex ®Thiamine®Vitamine B 1 Valdecoxib Bextra ®Thiopental Pentothal ® ,Trapanal ® Valganciclovir Valcyte ®Thio-TEPA Thiotepa Lederle ®Valproic acid Depakene ®Thrombin Thrombinar ® ,Valsartan Diovan ® ,Provas ®Thrombostat ®Vancomycin Vancocin ®

380 Drug IndexVasopressin Pitressin ®Vecuronium Norcuron ®Venlafaxine Effexor ®VerapamilBerkatens ® ,Calan ® ,Cordilox® ,Isoptin ® , Securon® ,Univer ® , Verelan ®Vidarabine Vira-A ®Vigabatrin Sabril ®Vinblastine Velban ® ,Velbe ®Vincristine Oncovin ®Viomycin Celiomycin ® ,Vinactane ® ,Viocin ® ,Vionactane ®Vitamin B 6 Bee Six ® ,Hexa-Betalin ® ,Pyroxine ®Vitamin B 12 Bay-Bee ® , Berubigen ® ,Betalin 12 ® ,Cabadon ® ,Cobex ® ,Cyanoject ® ,Cyomin® ,Pemavit ® ,Redisol® ,Rubesol ® ,Sytobex ® ,Vibal ®Vitamin D Calciferol ® ,Drisdol ® ,D-Vi-sol ®XXanthinol nicotinate Complamin ®Ximelagatran Exanta ®Xylometazoline Chlorohist ® ,NeosynephrineII ® , Otrivin ® ,Sinutab ® ,Sustaine ®ZZafirlukast Accolate ®Zalcitabine Hivid ®Zaleplone Sonata ®Zanamivir Relenza ®Zidovudine Retrovir ®Ziprasidone Geodon ® ,Zeldox ®Zolmitriptan Ascotop ® ,Zomig-ZMT ®Zolpidem Ambien ® ,Bicalm ® ,Stilnox ®Zopiclone Amoban ® ,Amovane ® ,Imovane ® ,Zimovane ®WWarfarin Coumadin ® ,Marevan ® ,Panwarfin ® ,Sofarin ®

Subject Index

382 Subject IndexSubject IndexAAbciximab, 154Absorbent powders, 180Absorption, 46enteral, 22Absorption quotient, 22Acamprosate, 344Acarbose, 264Accumulation equilibrium, 48Acebutolol, 98ACE inhibitors, 128, 314cardiac failure, 128congestive heart failure, 322hypertension, 128indicators, 128kinins, 128myocardial infarction, 320undesired effects, 128Acetaldehyde, 344Acetaminophen, 198, 334, 336suicide and poisoning, 198Acetic acid, 344Acetylcholine, 86, 104motor function, 182nicotine, 112parasympathetic transmitter, 102parasympathomimetics, 106Acetylcholinesterase, 104, 310parasympathomimetics, 106Acetylcoenzyme A, 104, 158N-Acetylcysteine, 336N-acetylneuramininic acid, 288Acetylsalicylic acid (ASA), 6, 154, 200common cold, 336migraine, 334presystemic effect, 154N-Acetyltransferase 2 defects, 78Aciclovir, 288Acid neutralization agents, 170Acid production inhibitors, 170Acipimox, 160Acrolein, 300ACTH, 192, 244Action potential, 138muscle relaxants, 186Active secretion, 40Acute coronary syndrome, 320Acylaminopenicillins, 272Adalimumab, 332Addictive potentialamphetamine, 92opioids, 208Addison disease, 244Adenohypophyseal hormone, 238Adenohypophyseal lobe, 238Adenosine-5-diphosphate (ADP), 154Adenosine triphosphatases (ATPases), 134Adenylate cyclase, 66Aδ fibers, pain, 194Administration routes, 12buccal, 18dermatological, 16cream, 16dusting powder, 16hydrogel, 16lotions, 16ointment, 16inhalation, 14intramuscular injection, 18intravenous, 18oral, 12subcutaneous injection, 18sublingual, 18transdermal, 18Adrenaline see EpinephrineAdrenergic synapses, 86Adrenocortical suppression, 246Adrenocorticotrophic hormone(ACTH), 192, 244Adrenoreceptors, 86metabolic effects, 88smooth muscle effects, 88subtypes, 88α-Adrenoreceptors, 334α 2 - agonists, 346α-blockers, nonselective, 94β-Adrenoreceptors, 314β 2 -adrenoreceptors, 314, 318antagonists see β-blockersAdriamycin, 300Adverse drug effects, 70–76drug allergy, 72hypersensitivity, 70non selectiveness of drugs, 70overdose, 70Adverse drug reactions, 74Aglycones, 178Agranulocytosis, 242AIDS treatment, 290Akathisia, 234Albumin, 30Albuterol, 338

Subject Index 383Alcohol abuse, 344brain, 344CNS effects, 344liver, 344Alcoholic hallucinations, 344Alcuronium, 184Aldosterone antagonists, 168Alendronate, 330Allergic reactions, 72anaphylactic reaction, 72contact dermatitis, 72cytotoxic reaction, 72immune-complex vasculitis, 72Allergic rhinoconjunctivitis, 338Allopurinol, 300, 326Allosteric antagonism, 60Alloxanthine, 326Aloë species, 178Alprazolam, 222Alteplase, 150Alzheimer disease, 106Amanita muscaria, 236Amantadine, 188, 288Ambroxole, 336AMDE (absorption, distribution,metabolism, excretion), 46Amebiasis, 296Amethopterin, 300Amfebutamon, 112Amikacin, 280, 282Amiloride, 168, 314p-Aminobenzoic acid, 274γ-Aminobutyric acid (GABA) seeGamma-aminobutyric acid (GABA)ε-Aminocaproic acid, 150Aminoglycoside antibiotics, 278, 280p-Aminohippurate, 30p-Aminomethylbenzoic acid, 1506-Aminopenicillanic acid, 270Aminopterin, 300p-Aminosalicyclic acid, 282Amlodipine, 126Amorolfine, 284Amoxicillin, 272Helicobacter pylori eradication, 172Amphetamine, 92Amphiphilic property, local anesthetic, 206Amphotericin B, 284Ampicillin, 272Amprenavir, 290Anabolic steroids, 248Anakinra,304,332Analgesics, 194antipyretic, 198, 336Analogous drugs, 10Anaphylactic reaction, 72, 338penicillins, 74Anaphylactic shock, 338Anaphylactoid reaction, 156Anastrozole, 256Androgens, 248Anemia, 142Anesthesiabalanced, 214conduction, 202general see General anesthesiainfiltration, 202injectable see Injectable anestheticslocal see Local anestheticsspinal,202,214surface, 202, 336Anesthetics, inhalation, 214, 216Angina pectoris, 316acute attack, 318β-blockers, 96cardiac drugs, 132organic nitrates, 124pain, 194prophylaxis, 318Angiotensin-converting enzyme (ACE), 34, 128,162, 314inhibitors see ACE inhibitorsAngiotensin II, 314Angle-closure glaucoma, 346Anhalonium lewinii, 236Anopheles mosquitoes, 294Anorexiants, 92, 328Antacid drugs, 170Antagonismallosteric, 60functional, 60Antagonists, 60competitive, 60natural, 60Anthracycline antibiotics, 300Anthraquinone derivatives, 178Antiadrenergics, 100Antiallergic therapy, 338Antiandrogens, 248Antianemics, 140adverse effects, 142interactions, 142Antianginal drugs, 318Antiarrhythmic drugs, 136of local anesthetic type, 136Antibacterial drugs, 268bactericidal effect, 268bacteriostatic effect, 268broad-spectrum, 268diarrhea, 180Helicobacter pylori, 172narrow-spectrum, 268see also specific antibioticsAntibiotic resistance, 268

384 Subject IndexAnticancer drugs, 298, 300mechanism of action, 302see also ChemotherapyAnticholinergics, 188Anticoagulants, oral, 146Antidepressantsatypical, 228selective serotonin reuptakeinhibitors, 226, 228tricyclic, 228Antidiabetics, oral, 264Antidiarrheal agents/therapy, 180Antidiuretic hormone, 164Antidotes, 308Antiemetics, 116, 342Antiepileptics, 190adverse effects, 192psychomotor drive, 192Antiestrogen, 254Antiflatulents, 178Antigen recognition interference, 304Antigens, 72Antihelmintics, 292Antihistamines, 220H 1 -antihistaminics see H 1 antihistaminicsH 2 -antihistamines, 17Antihypertensive therapy, 162Antileprotic drugs, 282Antimalarials, 294chemoprophylaxis, 294tolerability, 294Antineoplastic drugs see Anticancer drugsAntiparasitic drugs, 292Antiparkinisonism agents, 116, 188Antiplatelet drugs, 320Antiprogestin, 254Antipyretic analgesics, 198, 336Anti-T-cell immune serum, 306Antithrombin III, 148Antithrombotics, 144Antithyroid drugs, 242Antitubercular drugs, 282Antitussive effect, opioids, 210Antiviral mechanisms, 286Anxiolytic effect, sedatives, 220Anxiolytics, 220Aortic pressure, 316Apomorphine, 116, 308Apoptosis, 298Appetite suppressants, 92, 328Aquaporins, 164type 2, 168Aquaporins, type 2, 168Arachidonic acid, 196Area under curve (AUC), 46Areca catechu, 106Arecoline, 106Aromatase, 256female reproductive phase, 256inhibitors, 256Arrhythmias, 134Artemesinin, 294Arteriolar vasodilators, 122Asparaginase, 302Asthma see Bronchial asthmaAstringents, 180AT 1 receptor antagonist, 314Atenolol, 98, 334Atherosclerosis, 314Atopic dermatitis, 338Atopic eczema, 338Atopy, 338Atoquavone, 294Atorvastatin, 160Atosiban, 130Atracurium, 184Atrial fibrillation, 134, 136Atrioventricular node, 136Atropa belladonna, 6, 7Atropine, 108, 310poisoning, 110Atypical antidepressants, 228Atypical neuroleptics, 234extrapyramidal motor reactions, 234Auranofin, 332Aurothioglucose, 332Aurothiomalate, 332Autacoids, 190, 196Autonomic nervous system, 84nicotine, 112Autonomic reflex responses,general anesthesia, 214Autumn crocus, 6AV block, bradycardia, 96Axoplasm, 204Azapropazone, 200Azathioprine, 300, 304, 332Azithromycin, 278Azlocillin, 272BBacitracin, 270, 272Baclofen, 182Bacterial diarrhea, 180Bacterial infections, 268Bacterial protein synthesis, 278Bactericidal effect, 268Bacteriostatic effect, 268Bad trip, lysergic acid diethylamide(LSD), 236Balanced anesthesia, 214Balloon catheter, 320

Subject Index 385Barbiturates, 220Basiliximab, 304Bateman function, 46Beclomethasone dipropionate, 246, 338Benserazide, 188Benzobromarone, 326Benzocaine, 206, 336Benzodiazepines, 132, 182, 220, 222alcohol abuse, 344antagonists, 222effects, 222emesis, 342myocardial infarction, 320pharmacokinetics, 224status epilepticus, 192Benzothiadiazines, 166Benztropine, 188Benzylpenicillin, 270Berlin blue, 310β-blockers, 10, 318angina pectoris, 316anxiolytic action, 96bronchial asthma, 96, 98cardioselectivity, 98congestive heart failure, 322glaucoma, 346membrane stabilizing effect, 98migraine, 334myocardial infarction, 320patentable chemical, 98β 1 -selective blockers, 314structures, 11therapeutic effects, 96types, 98undesired effects, 96vascular response, 96Bezafibrate, 160Bicalutamide, 248Biguanide, 264Bilharziasis, 296Biliary colic, 108Bimatoprost, 346Bioavailability (F), 46Biogenic amines, 116Biosoprolol, 98Biotransformation, 74phase I, 34phase II (synthetic) reactions, 34Biperiden, 188Bipolar illness, 226Bisacodyl, 178Bisphosphonates, 330Bivalirudin, 144Bladder emptying, opioids, 210Bleomycin, 300Blood-brain barrier, 24Bloodletting, 308Blood-tissue barrier, 24brain, 24cardiac muscle, 24pancreas, 24B max (maximum drug binding), 56Body-mass-index (BMI), 328Bone marrow depression, 198Botulinus toxin, 182Bowel atonia, 176Bradycardia, AV block, 96Bradykinin, 128pain, 194Breast cancers, 254Brimonidine, 346Brinzolamide, 346British Anti-Lewisite (BAL), 308Broad-spectrum antibiotics, 268Bromocriptine, 130, 188Bromohexine, 336Bronchial asthma, 338, 340anti-inflammatory therapy, 340β-blockers, 96, 98Bronchitis, chronic obstructive, 336Bronchodilation, 88Bronchodilators, 130, 340Brotizolam, 222Brugmansia species, 110Buccal administration route, 18Buchheim, Rudolf, 3Budesonide, 246, 338Bufotenin, 236Bulk gels, 174Bulk laxatives, 174Buprenorphine, 212Bupropion, 112, 228Buserelin, 248Busulfan, 300Butizide, 166N-Butylscopolamine, 130Butyrophenone derivatives, 232Butyrophenones, 232extrapyramidal disturbance, 232CCa 2+- chelators, 144Cabergoline, 188Calcinosis, 266Calcitonin, 266, 330Calcitriol, 266Calcium, 330electromechanical coupling, 266electrosecretory coupling, 266homeostasis, 266

386 Subject IndexCalcium antagonists, 126, 314, 318adverse effects, 126angina pectoris, 316catamphiphilic, 126dihydropyridines, 314migraine, 334Calmodulin, 88Caloric restriction, diabetes, 262cAMP, 88Camptothecin, 300Cancer, 298see also Anticancer drugsCandida, 280Candida albicans, 284Cannabis sativa, 236Capreomycin, 282Capsules, 12Captopril, 128Carbamates, 106Carbamazepine, 190, 192Carbenicillin, 272Carbidopa, 188Carbonic anhydrase inhibitors, 346Carboplatin, 300Cardiac arrest, 108Cardiac arrhythmias, 134Cardiac drugs, 132Cardiac failureACE inhibitors, 128congestive see Congestive heart failureCardiac glycosides, 134, 324atrial flutter, 136Cardiac inhibition, local anesthetics, 206Cardiogenic shock, dopamine, 116Cardiostimulation, 88Cardiovascular disease, 314Cardiovascular system, 120Cardipine, 126Carfentanyl, 212Carminatives, 178Carticaine, 206Caspofungin, 284Catamphiphilic calcium antagonists, 126Catarrh, 336Catecholamine O-methyltransferase (COMT),86, 116inactivation, 90inhibitors, 188Catecholamines, 90, 322actions, 88Cefalexin, 272Cefmenoxin, 272Cefotaxime, 272Ceftazidime, 272Ceftraxone, 272Celecoxib, 200Cell membrane, drug targets, 20Cell metabolism disruption, 304Cell proliferation, inhibition, 304Cell wall synthesis, inhibitors, 270Centrally-acting muscle relaxants, 182Central nervous system, 84disturbances, 134nicotine, 112serotonin, 120Cephalosporins, 270, 272Cerivastatin, 160Cetirizine, 118Cetrorelix, 238Cheese, monoamine oxidase inhibitors, 228Chelating agents, 308Chemotherapycytotoxic, 342sickness induced by, 342see also Anticancer drugsChianti, monoamine oxidase inhibitors, 228China white, opiate abuse, 210Chinese hamster ovary cells, 150Chiral stereoisomers, 62Chlamydia species, 268Chlorambucil, 300Chloramphenicol, 278, 280Chlordiazepoxide, 224Chlorguanide, 294Chloroquine, 294Chlorphenothane (DDT), 292Chlorpromazine, 206Chlorthalidone, 166Cholecalciferol, 266Cholecystokinin, 178Choline acetyltransferase, 104Cholinergic synapse, 104Cholinesterase, plasma, 186Choline-transporter, 104Cholinoreceptors, pirenzepine, 170Chronic obstructive bronchitis, 336Chronic obstructive pulmonary disease, 108Chylomicron, 158Ciclosporin, 38, 304, 306nephrotoxicity, 306rheumatoid arthritis, 332Cimetidine,118,172Ciprofloxacin, 276Cisplatin, 300, 342Citalopram, 228Citrate, 144Clarithromycin, 172, 278Clathrin, 26Claviceps purpurea, 130Clavulanic acid, 272Clearance, 44total (Cl tot ), 44Clindamycin, 278Clinical trials, 80

Subject Index 387Clobazam, 192Clobutinol, 336Clofazimine, 282Clofibrate, 160Clomethiazole, 192, 344Clomifene, 252, 254Clonazepam, 192drug metabolism, 78Clonidine, 100, 346Clopidogrel, 154Closed angle glaucoma, 110Clostebol, 248Clostridium botulinum, 182Clotrimazole, 284Clozapine, 234, 236Coagulation cascade, 144Cocaine, 92, 236Codeine, 208, 210, 212, 336Colchicine, 326Colchicum autumnale, 6, 7, 326Colestipol, 160Colestyramine, 160Colicbiliary, 108renal, 108Collagenplatelet aggregation, 154receptor, 154Colloidal bismuth, 172Colon-irritant purgatives, 178Common cold, 336Competitive antagonists, 60Complement, 72Concentration-binding curves, 56Concentration-effect curves, 54Concentration-effect relationship, 54in vitro experimentation, 54Conduction anesthesia, 202Congeneric names, 10Congestive heart failure, 322, 346β-blockers, 96chronic, 134, 322diuretics, 162Constipation, parasympatholytics, 110Contact dermatitis, allergic reactions, 72Contraceptives, oral, 252Convallaria majalis, 6Convulsant toxins, 182Coronary sclerosis, 316Coronary spasm, 316Corpus striatum, 188Corticotropin releasing hormone, 238, 246Cortisol, 244Coryza, 94Co-trimoxazole, 274Coumarins, 144, 146derivatives, 144Counteregulatory responses, diuretics, 162Covalent bonding, 58COX-1, 200COX-2, 200COX-2 inhibitors, 332, 340Coxibs, 200COX inhibitors, nonselective, 332Creatine kinase, 320Crohn disease, 274Cromolyn, 338Crystalline zinc insulin, 258Curare, 184Curarization, general anesthetics, 214Cushing syndrome, 244, 304Cutaneous reactions, 74Cyanide poisoning, 310Cyanmethemoglobin, 310Cyanocobalamin, 140, 310Cyclic adenosine monophosphate(cAMP), 88Cyclooxygenase, 154, 196COX-1, 200COX-2, 200inhibitors, 332, 340Cyclophilin, 306Cyclophosphamide,300,304,332Cycloserine, 282Cyproterone, 248Cystinuria, 308Cytarabine, 300Cytochrome 3A4, 118Cytochrome P450, 32, 38, 42inducers, 38inhibitors, 38isoenzyme CYP2D6, 78role in drug interaction, 38substrates, 38Cytokine inhibition, 304Cytostatics, 298, 304mechanism of resistance, 302Cytotoxic chemotherapy, 342Cytotoxic reaction, allergic reactions, 72DD 2 agonists, 238D 2 -receptor antagonists, 342Daclizumab, 304Danaparoid, 148Dantrolene, 182Darbepoetin, 140Datura stramonium, 110Daunorubicin, 300DDT, 106Deadly nightshade, 6Dealkylation, 36

388 Subject IndexO-Dealkylation, 36S-Dealkylation, 36Deamination, 36Decarbaminoylation, indirectparasympathomimetics, 106Deferoxamine, 308Dehalogenation, 36Demulcent lozenges, 336Demulcents, 180Dephosphorylation, indirectparasympathomimetics, 106Depolarizing muscle relaxants, 186Depression, 228bipolar, 226unipolar, 226Dermatological administration routes, 16Dermatophytes, 284Desflurane, 216Desmethyldiazepam, 224Desmopressin, 152, 168Desogestrel, 252Desrudin, 148Desulfuration, 36Dexamethasone, 192, 244, 342Dextran, 28, 156Diabetes mellitus, 258β-blockers, 98caloric restriction, 262hypoglycemia, 96insulin-dependent, treatment, 260juvenile onset, 260maturity onset (Type II), 262obesity, 262Diacetylmorphine, 210Diacylglycerol (DAG), 66Diarrheaantidiarrheal agents/therapy, 180causes, 180viruses, 180Diastereomers, 62Diazepam, 222Diazoxide, 122Diclofenac,200,326Dicloxacillin, 272Didanosine, 290Diethylenetriaminopentaacetic acid, 308Diethylstilbestrol, 76Digitalis, 6Digitalis glycosides, 322Digitalis purpurea, 7Digitoxin, 50, 134Digoxin, 6, 134Dihydroergotamine, 324, 334Dihydrofolate, 274Dihydrofolate reductase, 302Dihydropyridine derivatives, 126Dihydropyridines, 314L-Dihydroxyphenylalanine, 188Diltiazem, 126, 318Dimercaprol, 308Dimercaptopropanesulfonic acid, 3084-Dimethylaminophenol, 310Dinoprost, 130Dinoprostone, 130, 196Diphenhydramine, 342Diphenolmethane derivatives, 178Dipole-dipole, 58Dipole-ion interaction, 58Dipyrone, 198Disease-modifying agents, 332Disorientation, parasympatholytics, 110Disse's spaces, 24Dissociation constant pK a ,40Distribution (drug), 46accumulation, 48, 50Bateman function, 46diffusion, 26drugs in the body, 22–30possible modes, 28receptor-mediated endocytosis, 26transcytosis, 26transport, 26volume of, 28Diuretics, 162congestive heart failure, 322counteregulatory responses, 162extracellular fluid volume, 162hypertension, 314potassium-sparing, 168sulfonamide type, 166thiazide, 166, 314DNA function inhibitors, 276DNA synthesis inhibition, 300Docetaxel, 298Domperidone, 334, 342Donepezil, 106L-Dopa, 26, 188Dopa decarboxylase, 188Dopamine, 116actions and pharmacologicalimplications, 116cardiogenic shock, 116migraine, 334therapeutic use, 116Dopamine agonist induced nausea, 342Dopamine β-hydroxylase, 86Dopamine D 2 agonists, 238Dopamine D 2 -receptor antagonists, 342Dopamine receptor, 334agonists, 188, 238Doping, sympathomimetics, indirect, 92Dorzolamide, 346Dose-effect relationship, 52Dose-frequency relationship, 52

Subject Index 389Dose-linear kinetics, 68Dose response relationship, 52interindividual differences, 52Dosing frequency, 48Doxazosin, 94Doxorubicin, 300Doxycycline, 280, 294Dronabinol, 342Drug(s)acting on smooth muscle, 130elimination see Elimination of drugsmotor system, 182peptic ulcers, 170sources, 4Drug allergy, 72Drug-dependent effects, 80Drug development, 8–11approval, 8clinical testing, 8preclinical testing, 8presystemic elimination, 42synthesis to approval, 9Drug eruptions, fixed, 74Drug-induced vomiting, 342Drug interaction, 32role of cytochrome P450's, 38Drug metabolismhydralazine, 78nitrazepam, 78Drug-receptor interaction, 56–70agonists, antagonists vs., 60binding forces, 58plasma concentration over time, 68Drug targets, 20cell membrane, 20receptors, 20transport proteins, 20Drug toxicitylactation, 76pregnancy, 76Duodenal ulcers, 170Dutasteride, 248Dynorphins, 208EEbastine, 118EC 50 ,54Econazole, 284Ecstasy, 236Ectoparasitic infestations, 292Edinger-Westphal nucleus, opioids, 210Efavirenz, 290Ef cacy, 60Eicosanoids, 196Electroencephalogram, 190, 220Elimination of drugs, 32–42change over time course of treatment, 50E max ,54Emesis, 342Emetics, 308Enalaprilat, 128Enantiomers, 62Enantioselectivity, 62of af nity, 62of intrinsic activity, 62Endogenous opioids, 208Endoneural space, 204Endoparasitic infestations, 292β-Endorphin, 208Endothelium-derived relaxant factor(EDRF), 124Enflurane, 216Enfuvirtide, 290Enkephalins, 194, 208Enoxacin, 276Entamoeba histolytica, 276Enterochromaf n cells, 120Enterochromaf n-like cells, 118, 170Epilepsy, 190Epinephrine (adrenaline), 86, 338cardiac arrest, 136Epipodophyllotoxins, 300Epoxidation, 36Epsom salt, 174Equilibrium dissociation constant (KD), 56Erectile dysfunction, 122Ergocornine, 130Ergocristine, 130Ergocryptine, 130Ergometrine, 130Ergot alkaloids, 130Ergotamine, 130, 334Ergotism, 130Erythromycin, 278Erythropoiesis, 140Erythropoietin, 140Esomeprazole, 172Estradiol, 250, 254Estrogenantagonist, 330production, 250Estrous cycle, 250Etanercept, 332Ethambutol, 282Ethanol, 68, 344Ethinylestradiol, 250, 252Ethionamide, 282Ethosuximide, 192Ethylenediaminetetraacetic acid (EDTA), 144Etomidate, 218Etoposide, 300

390 Subject IndexEuphoriaindirect sympathomimetics, 92opioids, 208Euthyroid goiter, thyroid suppressiontherapy, 240Evonymus europaeus, 6Excretion of drugs, kidney, 40Exemestane, 256Expectorants, 336Extended release drugs, 12Extracellular fluid volume, diuretics, 162Ezetimib, 160Follicular growth, 250Follitropin, 252Fondaparinux, 148Formestane, 256Formoterol, 338, 340Foscarnet, 288Fructus sennae, 178Fulvestrant, 254Functional antagonism, 60Fungal infections, 284Furosemide, 166Fusion inhibitors, 290FFamciclovir, 288Famotidine,118,172Felbamate, 192Felodipine, 126Felypressin, 168, 204Female reproductive phase, aromatase, 256Fenofibrate, 160Fenoterol, 130, 338, 340Fentanyl,22,212,214Ferric ferrocyanide, 310Fetal alcohol syndrome, 344Fexofenadine, 118Fibrinogen bridges, thrombus formation, 152Fibrinolytics, 150, 320adverse effect, 150Fick's law, 26, 44Fight or flight response, 84Filariasis, 296Filgrastim, 300Finasteride, 248Fixed eruptions, 74Fleas, 292Floxacillin, 272Flu, 336Fluconazole, 284Flucytosine, 284Fludrocortisone, 244, 324Flumazenil, 222Flunarizine, 334Flunisolide, 246, 3385-Fluorouracil, 300Fluoxetine, 120, 228Flurazepam, 224Flutamide, 248Fluticasone propionate, 246, 338Fluvastatin, 160Fluvoxamine, 228Folia sennae, 178Folic acid, 140Follicle-stimulating hormone (FSH), 250production, 252GGabapentin, 190Galantamine, 106Galen, Claudius, 2Gallopamil, 126Gamma-aminobutyric acid (GABA), 116, 220benzodiazepines, 222epilepsy, 190Ganciclovir, 288Ganglia, 86Ganirelix, 238Gastric acid concentration lowering, 170Gastric/intestinal ulcer/tumor, iron deficiency, 142Gastric ulcers, 142, 170Gastrointestinal tract, serotonin, 120Gelatin, 156Gelatin colloids, 156Gemfibrozil, 160General anesthesiaanesthetic agents, 212autonomic reflex responses, 214Genetic polymorphismsof biotransformation, 32in drug metabolism, 32Genetic variants, of pharmacodynamics, 78Gentamicin, 280Gestoden, 252Gingival hyperplasia, 192Glatiramer acetate, 304Glauber's salt, 174Glaucoma, 96, 246, 346angle-closure, 110, 346open-angle, 346Glitazone, 264Glomerular filtration, 30, 40Glucocorticoids, 244, 304, 326antiallergenics, 338bronchial asthma, 340emesis, 342rheumatoid arthritis, 332Glucose intolerance, lithium, 230α-Glucosidase, 264

Subject Index 391Glutamate, 190Glycogenolysis, 88Glycoprotein Ibα,152Glycoprotein IIb receptor antagonists, 320Glycoprotein Illa receptor antagonists, 320Goitereuthyroid, thyroid suppressiontherapy, 240lithium, 230Gold compounds, 332Gonadorelin, 116, 248superagonists, 238, 248Gonadotropin, 252Gonadotropin releasing hormone, 238Goserelin, 248Gout, 326acute attack, 326G-protein coupled receptors, 64mode of action, 66Granisetron, 342Granulocyte/macrophage colony stimulatingfactors, 300Graves disease, 242Gravid uterus, 172Grippe, 336Griseofulvin, 284Guanethidine, 100Gyrase inhibitors, 276HH 1 antihistaminics, 118, 336, 338emesis, 342H 1 receptors, 338H 2 antihistamines, 17, 118Half life (t 1/2 ), 44Hallucinations, 110alcoholic, 344Hallucinogens, 236Haloperidol, 344decanoate, 234Halothane, 216Haptens, 72Hay fever, 338Heart failure see Cardiac failureHelicobacter pylori, 170eradication, 172Helleborus niger, 6Hemogloblin synthesis, 140Hemostasis, 144Henle's loop, 164Heparin, 144, 148adverse effects, 148indications, 148mechanism of action, 148occurrence and structure, 148Heparinoid, 148Hepatic damage, 280Hepatic elimination, 32, 44HER2, 302Heroin, 210Herpes simplex, viral replication, 286High density lipoprotein (HDL), 158Hirudin, 144, 148derivatives, 148His-Purkinje system, 136Histamine, 116antagonists, 118effects and pharmacologicalproperties, 118metabolism, 118migraine, 334pain, 194receptor blockade, 338receptors, 118see also H 1 antihistaminics; H 2 antihistaminesHistory, pharmacology, 2–3Histotoxic hypoxia, 310HIV protease inhibitors, 290HIV replication, 290Hohenhiem, Theophrastus von, 2Homeopathy, 80Hormone replacement therapy, 330Hormones, 2385-HT 2 receptors, 3345-HT 3 receptor antagonists, 342Human chorionic gonadotropin (hCG), 252Human insulin, 258Human parathormone, recombinant, 330Hydralazine, drug metabolism, 78Hydrochlorothiazide, 166Hydrocortisone, 244Hydromorphone, 212Hydrophilic colloids, 174Hydrophobic interaction, 58Hydroxycarbamide, 300Hydroxychloroquine, 332Hydroxycobalamin, 140, 3104-Hydroxycoumarins, 146Hydroxyethyl starch, 156Hydroxylation, 36Hydroxymethylglutaryl-Co A, 15817-α-Hydroxyprogesterone caproate, 25017β-Hydroxysteroid dehydrogenase, 256Hydroxyurea, 300Hypercalcemia, 266Hyperglyceridemia, 262Hyperhydrosis, 182Hyperkalemia, 186Hyperlipoproteinemias, treatment, 158Hyperparathyroidism, 230Hypersensitivity to drugs, adverse drugeffects, 70

392 Subject IndexHypertension, 314ACE inhibitors, 128risk factors, 314Hyperthermia, parasympatholytics, 110Hyperthyroidism, 242Hyperuricemia, 326Hyperventilation tetany, 266Hypnotic drug dependence, 220Hypnotics, 220Hypoglycemia, diabetes mellitus, 96, 260Hypoglycemic shock, 260Hypokalemia, 176, 244Hypophyseal hormones, 238Hypotension, 324Hypothalamic hormones, 238Hypothalamus nerve cells, 238Hypothyroidismlithium, 230replacement therapy, 240Hypoxiahistotoxic, 310myocardial, 316IIbuprofen, 200Idoxuridine, 286Ifosfamide, 300IgE inactivation, 338Imatinib, 302Imidazole derivatives, 284Imipramine, 206Immune-complex vasculitis, allergicreactions, 72Immune response, 304inhibition, 304Immunogens, 72Indinavir, 290Indirect sympathomimetics,tachyphylaxis, 92Indometacin, 200, 326Infectious disease, 268Infiltration anesthesia, 202Inflammation, pain, 194Infliximab, 332Influenza, 336Inhalational administration, 14Inhalation anesthetics, 214, 216Injectable anesthetics, 214, 218redistribution, 218Inositol phosphate, 230Inositol triphosphate (IP 3 ), 66, 88Insecticides, 292Insulin, 258aspart, 258formulations, 258amino acid variation, 258dosage variations, 258glargine, 258human, 258intensified insulin therapy, 260lispro, 258recombinant, 258resistance, 262solution, 258suspension, 258Insulin-dependent treatment, diabetesmellitus, 260Intensified insulin therapy, 260Interferon-α, 286Interferon-β, 286Interferon-γ, 286Interferons, 286Interleukin-2, 306International Nonproprietary Names(INNs), 10International Normalized Ratio, oral anticoagulants,146Intra-arterial thrombus formation, 152Intramuscular injection, 18Intravenous administration route, 18Intrinsic sympathomimetic activity, 98Ionic interaction, 58Ipecac syrup, 308Ipratropium, 130, 132, 136Irinotecan, 300Iron compounds, 142Iron deficiency, 142Iron salts, parental administration, 142Irritant laxatives, 176Ischemia, 194Isoflurane, 216Isoniazid, 192, 282drug metabolism, 78Isophane, 258Isoprenaline, 98Isosorbide dinitrate, 124, 318Isosorbide mononitrate, 124, 318Isoxazolylpenicillins, 272Isradipine, 126Itroconazole, 284JJazz,opiateabuse,210Junk,opiateabuse,210Juvenile onset diabetes mellitus, 260KKanamycin, 278, 282Karaya gum, 174

Subject Index 393KD, 30Kernicterus, 274Ketamine, 218Kidney, 40sodium chloride reabsorption, 164Kininase II, 128Kinins, ACE inhibitors, 128Lβ-Lactam antibiotics, 192β-Lactamases, 272β-Lactam ring, 270Lactate acidosis, 264Lactation, drug toxicity, 76Lactitol, 174Lactulose, 174Laminae, pain, 194Lamivudine, 290Lamotrigine,190,192Lansoprazole, 172Lantoprost, 346Large bowel irritant purgatives, 178Law of mass action, 56assumptions, 56Laxatives, 174bulk, 174irritant, 176misuse, 176Lead poisoning, 308Leflunomide, 332Legionella pneumophilia, 268Leishmaniasis, 296Leishmania species, 268Lennox-Gastaut syndrome, 192Lenograstim, 300Lente, 258Lepirudin, 144, 148Letrozole, 256Leukotrienes, 196antagonists, 338, 340Leuprolin, 248Levodopa (L-dopa), 26, 188Levomepromazine, 342Leydig cells, 248Lice, 292Lidocaine, 206, 320, 336Ligand gated ion channels, 64Ligand operated enzyme, 64Lincomycin, 278Lincosamides, 278Lindane, 292Linezolide, 280Lipid-lowering agents, 158Lipocortin, 244Lipohypertrophy, 260Lipoprotein metabolism, 158Lisuride, 188Lithium, 230glucose intolerance, 230goiter, 230indicators, 230sexual dysfunction, 230Lithium ions, 242Liver, as an excretory organ, 32Loading dose, 50Local anesthetics, 202amphiphilic property, 206cardiac inhibition, 206chemical structure, 206forms, 202mechanism of action, 202nodes of Ranvier, 202perineurium, 204tissue esterases, 206vasoconstrictors, 204Local hormones, 196Lomustine, 300Loop diuretics, 166Loperamide, 180Loratadine, 118Lorazepam, 218, 342Losartan, 128Lovastatin, 160Low density lipoprotein (LDP), 158Low-molecular-weight heparin fragments, 144,148LSD, 120Lubricant laxatives, 178Lugol's solution, 242Lutenizing hormone, 248, 250Lyell syndrome, 74Lymphokines, 72Lysergic acid derivatives, 130Lysergic acid diethylamide (LSD), 130, 236bad trip, 236Lysine salts, 334MMacrocortin, 244Macrolides, 278Macromolecules, plasma protein replacement,156Maintenance dose, 50Major histocompatibility complex, 304Malignant neuroleptic syndrome, 232Malignant tumours, 298Mania, 230Manic depressive illness, 226Mannitoldiuretics, 164laxatives, 174

394 Subject IndexMaprotiline, 228Mast cell stabilizers, 118, 338bronchial asthma, 340Matrix-type tablets, 12Mebendazole, 292Mechlorethamine, 300Meclizine, 342Medicinal charcoal, 180Medroxyprogesterone acetate, 250Megaloblastic anemia, 192Meloxicam, 200Melphalan, 300Meperidine, 130, 212Mepivacaine, 2066-Mercatopurine, 300Merozoites, 294Mesalazine, 274Mescaline, 120, 236Mesterolone, 248Mestranol, 252Metabolic syndrome, 262Metamizole, 198Metenolone, 248Metformin, 264Methadone, 50L-Methadone, 208Methamphetamine, 328Methemoglobin, 310Methohexital, 218Methotrexate, 140, 300, 304, 332Methoxyverapamil, 126Methylations, 36N-Methyl D-aspartame, 2181-α Methyldihydrotestosterone, 248Methyldopa, 100Methylenedioxyamphetamine derivatives, 236Methylergometrine, 130Methylprednisolone, 34217-α Methyltestosterone, 248Methylxathines, 338Methysergide, 334Metoclopramide, 334, 342'Me-too' drugs, 10Metoprolol, 98, 314, 334Metronidazole, 276Mevalonic acid, 158Mezclocillin, 272Micromonospora bacteria, 278Micturition, 102Midazolam, 218Mifepristone, 196, 254Miglitol, 264Migraine, 334attack treatment, 334Mineralocorticoid, 324Minimal alveolar concentration, 216Minipill, 252Minocycline, 280Minoxidil, 122Miosis, opioids, 210Mirtazapine, 228Misoprostol, 172Mites, 292Mitotic spindle damage, 298Mivacurium, 184Mixed function oxidases, 32Mizolastine, 118Moclobemide, 92, 228Molgramostim, 300Molsidomine, 124, 318Monoamine oxidase, 86degradation, 90dopamine, 116Monoamine oxidase inhibitors, 92, 228cheese and, 228Chianti and, 228MAOI-B, 188Monoanesthesia, 214Monoglutamine-FA, 140Mood change, opioids, 208Morning-after pill, 252Morphine, 4, 5, 52, 70, 208myocardial infarction, 320Morpholine, 284Motion sickness, 342α-Motoneurons, 182Motor end plate, nicotine, 112Motor function, 182Motor system, drugs used for, 182Mouth dryness, parasympatholytics, 110Mucolytics, 336Multidrug resistance associated protein 2(MRP2), 32Multiple sclerosis, 304Murein lattice, 270Muromonab CD3, 304Muscarinic (M-) ACh receptors, 104phenothiazines, 232Muscinol, 236Muscle relaxants, 184, 186clinical uses, 186Musculature, 84Myasthenia gravis, 106Mycobacterial infections, 282Mycobacterium leprae, 276, 282Mycobacterium tuberculosis, 268, 276, 282Mycophenolate mofetil, 304Mycoses, 284Mycotoxin amanitin, 160Mydriatics, 108Myocardial hypoxia, 316Myocardial infarction, 194, 320Myometrial relaxants, 130Myometrial stimulants, 130

Subject Index 395Myosin, 88Myosin kinase, 88Myristoyl, 290NNa 2 Ca-EDTA, 308Na 2 Ca-pentetrate, 308Nabilone, 342Nadolol, 334Naftidine, 284Nalbuphine, 210Nalidixic acid, 276Naloxone, 210Naltrexone, 210Nandrolone, 248Naphazoline, 88, 338reactive hyperemia, 94Naproxene, 200Naratriptan, 334Narrow-spectrum antibiotics, 268Nasal decongestants, 94Nedocromil, 338Nefazodone, 228Nelfinavir, 290Neomycin, 280Nephron, 164Nephrotoxicity, 280Nerve cells, 86Netilmicin, 280Neuraminidase inhibitors, 288Neurodermatitis, 338Neurohypophyseal hormone, 238Neuroleptanalgesia, 214Neuroleptics, 116, 232, 342atypical see Atypical neurolepticsNeuromuscular blocking agents, 214Neurotransmitters, 20Neutral antagonist, 60Neutral protamine Hagedorn (NPH), 258Nevirapine, 290Nicotiana tabacum, 114Nicotine, 112body function, 112motor end plate, 112Nicotinic ACh receptors, 104, 112Nicotinic acid, 160Nicotinic cholinoreceptorsmotor function, 182muscle relaxants, 186Nifedipine, 130, 318Nimodipine, 126Nisoldipine, 126Nitrates, 132angina pectoris, 316Nitrazepam, drug metabolism, 78Nitrendipine, 126Nitric oxide, 124thrombus formation, 152Nitrogen mustard, 300Nitroglycerin, 22, 124, 318, 320Nitroimidazle derivatives, 276Nitrous oxide, 216Nizatidine,118,172NMDA (N-methyl D-aspartate), 218receptor, 190NMDA receptor antagonist, 344Nodes of Ranvier, local anesthetics, 202Nondepolarizing muscle relaxants, 184Non-insulin-dependent diabetes, 262Nonselective COX inhibitors, 332Non-steroidal anti-inflammatory drugs (NSAIDs),172, 198, 326Nonucleoside inhibitors, 290Noradrenaline see NorepinephrineNordiazepam, 224Norepinephrine (noradrenaline), 86, 92, 100transporter, 86, 92Norfloxacin, 276Normal metabolizers, 78Noscapine, 210, 336NuclearfactorofactivatedTcells,306Nucleobase synthesis inhibition, 300Nucleoside agents, 290Nucleosides, 286Nystatin, 284OObesity, 328diabetes mellitus, 262secondary disorders, 328Obidoxime, 310Octreotide, 238Ofloxacin, 276Olanzapine, 234Omeprazole, 172Onchocerciasis, 296Ondansetron, 120, 342Open-angle glaucoma, 346Opiates, 208abuse, 210Opioid analgesics-morphine type, 208Opioids, 208addictive potential, 208antidiarrheals, 180antitussive effect, 210bladder emptying, 210endogenous, 208miosis, 210mood change, 208psychological dependence, 208receptors, 208

396 Subject IndexOpium tincture, 180Oral administration routes, 12Oral anticoagulants, 146International Normalized Ratio, 146Oral antidiabetics, 264Oral contraceptives, 252Oral rehydration solution, 180Organic nitrates, 124, 318mechanism of action, 124unwanted reactions, 124Organophosphates, 106, 310Orlistat, 328Ornipressin, 168Orthostasis, acute hypotension, 324Osmotically active laxatives, 174, 308Osmotic diuretics, 164Osteoclasts, 266Osteomalacia, 192, 266Osteopenia, 330Osteoporosis, 330idiopathic, 330Ototoxicity, 280Overdose, adverse drug effects, 70Ovulation, 250inhibitors, 252Oxacillin, 272Oxazepam, 224Oxazolidinones, 280Oxiconazole, 284Oxidation reactions, 36Oxycarbazepine, 192Oxycodone, 212Oxygen demand, determining factors, 316Oxygen supply, determining factors, 316Oxymetazoline, 338Oxypurinol, 326Oxytocin, 130PPaclitaxel, 298Paget disease, 266PainAδ fibers, 194Cfibers,194inflammation, 194laminae, 194mechanisms and pathways, 194modification, 194Pancreatic lipase inhibitor, 328Pancreozymin, 178Pancuronium, 184Pantoprazole, 172Papaverine, 208Papaver somniferum, 4Paracelsus, 2Paracetamol, 198Parasympathetic nervous system, 84, 102activation responses, 102anatomy, 102Parasympatholytics, 108, 324, 342bronchial secretion inhibition, 108cardioacceleration, 108CNS damping effects, 110common cold, 336contraindications, 110disorientation, 110gastric secretion inhibition, 108glandular secretion inhibition, 108hyperthermia, 110mouth dryness, 110parkinsonism, 110smooth muscle relaxation, 108tachycardia, 110Parasympathomimetics, 106direct, 106indirect, 106decarbaminoylation, 106uses, 106Parathormone, 266, 330Parecoxib, 200Parental administration, iron salts, 142Parkinsonian syndrome, 234Parkinsonism, parasympatholytics, 110Parkinson's disease, 188pharmacotherapeutic measures, 188treatment for advanced, 188Paromomycin, 280Paroxetine, 228Patient compliance, 48, 50Pegvisomant, 238Pemphigus-like reactions, 74D-Penicillamine, 308Penicillin(s), 270anaphylactic reaction, 74resistance, 272D-Penicillinase, 74Penicillinase-resistance, 272Penicillin G, 270Penicillin notatum, 270Penicillin V, 272Pentazocine, 210, 212Peptic ulcers, drugs used, 170Peptidases, 34Peptide synthesis, 278Peptidoglycan lattice, 270Peptidyltransferase, 278Perchlorate, 242Perineurium, local anesthetic, 204Permethrin, 292Pernicious anemia, 140Peroglide, 188

Subject Index 397Peroxisome proliferator-activated receptor,160, 264Perphenazine, 342PGE 2 ,196PGF 2a ,196PGI 2 ,196P-glycoprotein, 42, 180Phagosomes, 26Pharmacodynamics, genetic variants, 78Pharmacogenetics, 52, 78Pharmacokinetics, 44–50genetic variations, 78Phase I clinical testing, 8Phase II clinical testing, 8Phase III clinical testing, 8Phase IV clinical testing, 8Phenazone, 198Phencylidine, 236Phenobarbital, 190, 192Phenolphthalein, 178Phenothiazine derivatives, 232Phenothiazines, 232, 342M-ACh receptors, 232Phenoxymethylpenicillin, 272Phenprocoumon, 50Phenytoin, 190, 192Philadelphia chromosome, 302Phosphatase calcineurin, 306Phosphodiesterase inhibitors, 122, 322Phospholamban, 88Phospholipase C, 66adrenoreceptors, 88muscarinic (M-) ACh receptors, 104Phospholipids, 20Phosphorylated acetylcholinesterase reactivators,310Photoallergenic reactions, 74Photosensitivity, 74, 280Phototoxic reactions, 74Pilocarpine, 106Pilocarpus jaborandi, 106Pindolol, 98Pioglitazone, 264Piperacillin, 272Pirenzepine, cholinoreceptors, 170Piretanide, 166Pizotifen, 334Pizotyline, 334Placebo, 80Placebo-controlled trials, 80Plantago species, 174Plasmalemma damage, 268Plasma proteindrug binding, 30replacement, macromolecules, 156Plasma volume expanders, 156Plasmin inhibitors, 150Plasminogen activators, 150Plasmodia, 294Plasmodium falciparum, 294Plasmodium ovale, 294Plasmodium vivax, 294Platelet-activating factor (PAF), 152Platelet activation, 152Platelet-aggregation, inhibitors, 154, 320Platelet formation, 152Platelet glycoprotein, 152Poisonings, 308symptomatic measures, 308Polidocanol, 206Polyarthritis, chronic, 332Polyene antibiotics, 284Polyhydric alcohols, 174Polymorphisms, 78Polymyxins, 268Porcine insulin, 258Postganglionic synapses, 86Postmenopausal osteoporosis, 330Potassium-sparing diuretics, 168Potency, 60Pralidoxime, 310Pramipexole, 188Pravastatin, 160Prazepam, 224Praziquantel, 292Prazosin, 94Prednisolone, 244Preganglionic axons, 86Pregnancydrug toxicity, 76vomiting, 342Presystemic elimination, 42Prilocaine, 34, 206Primaquine, 294Primary adrenocortical insuf ciency, 244Primidone, 192Probenecid, 326Procaine, 34, 206Prodrugs, 34Progabide, 190Progesterone, 250Progestin, 248, 250production, 250receptor antagonist, 254Proguanil, 294Prolactin inhibitors, 116Prolactin release-inhibiting hormone, 238Propofol, 218Propranolol, 98Prostacyclin, 196Prostaglandins, 130peptic ulcers, 172PGE 2 ,196PGF 2a ,196

398 Subject IndexProstaglandin synthase inhibitors, 332Prostatic hyperplasia, 110Protamine, 148Protamine zinc, 258Protease, thromboses, 144Protease inhibitors, 290Protein synthesis inhibitors, 278Protein synthesis regulating receptors, 64Prothrombin concentrate, 146Proton pump inhibitors, 170Pseudocholinesterase, 186Psilocin, 236Psilocybin, 120, 236Psychedelics, 236Psychological dependence, opioids, 208Psychomotor drive, antiepileptics, 192Psychotomimetics, 236Pulmonary hypertension, vasodilators, 122Pupillary sphincter tonus, lowering, 108Purgativescolon-irritant, 178dependence, 176small-bowel irritant, 178Pyrazinamide, 282Pyridoxine, 282Pyridylcarbinol, 160Pyrimethamine, 294Pyrophosphate, 330QQuantification of drug action, 54Quinagolide, 116Quinine, 2944-Quinolone-3-carboxylic acid, 276RRabeprazole, 172Racemate, 62Radioiodine, 242Raloxifene, 254, 330Ranitidine,118,172Rapamycin, 306Rapid acting insulin analogues, 258Rapid eye moment, 220Rasburicase, 326Reactive hyperemia, 94Receptorsdrug targets, 20types, 64Recombinant human parathormone, 330Recombinant insulin, 258Recombinant tissue plasminogenactivators, 3205α-Reductase, 248Reduction reactions, 36Regional anesthesia, 214Rehydration solution, oral, 180Renal colic, 108Renal electrolyte loss, 134Renal failure, prophylaxis, 162Renal hypervolemic failure, 164Renal insuf ciency, 50Renal tubule, 40Renal water loss, 134Renin-angiotensin-aldosterone systemangiotensin-converting enzyme, 128diuretics, 162inhibitors, 126vasodilators, 122Renin-angiotensin-II system, 322Repaglinide, 264Repeated dosing, 48Reserpine, 100Respiratory tract, 22Reteplase, 150Reverse transcriptase inhibitors, 290Rhabdomyolysis, 160Rhamnus frangulae, 178Rhamnus purshiana, 178Rheumatoid arthritis, 308, 332Rhinitis, 336Rhizoma rhei, 178Rhodanese, 310Ricinoleic acid, 178Rickets, 266Rifabutin, 276, 282Rifampicin, 38, 276Rifampin,276,282Right atrial pressure, 316Risedronate, 330Risperidone, 234, 236Ritonavir, 290Rivastigmine, 106River blindness, 296Rizatriptan, 334RNA synthesis, 300Rocuronium, 184Rolitetracycline, 280Ropinirole, 188Rosiglitazone, 264Rough endoplasmic reticulum (rER), 32Roxithromycin, 278Ryanodine receptors, 88SSalbutamol, 340Salix alba, 6, 7Salix viminalis, 6

Subject Index 399Salmeterol, 338Salmonella species, 268Saquinavir, 290Sarcolemma, 186Sarcoplasmic reticulum, 132, 182Saturated NaCl solution, 308Schistosoma mansoni, 296Schistosomiasis, 296Schizogony, 294Schizonts, 294Schizophrenia, 232Schmiedeberg, Oswald, 3Scopolamine, 22, 236, 342Sedationantiepileptics, 192scopolamine, 110Sedatives, 220anxiolytic effect, 220Selective estrogen receptor modulators, 254Selective serotonin reuptakeinhibitors, 226, 228Selective α 1 -sympatholytics, 94Selegiline, 92Senna, 178Sensitization, immune system, 72Serotonin, 116, 120, 228gastrointestinal tract, 1205-HT 2 receptors, 3345-HT 3 receptor antagonists, 342receptors, 120Sertaline, 228Sertürner, F.W, 4Serum Mg 2+ rise, 182Sevoflurane, 216Sexual dysfunction, lithium, 230Sibutramine, 92, 120Simvastatin, 160Sinus bradycardia, 136Sinus tachycardia, 96, 136Sirolimus, 306Sisomycin, 280β-Sitosterin, 160Slow metabolizers, 78Smack, opiate abuse, 210Small-bowel irritant purgative, 178Smoking see Tobacco smokingSmoking cessation aids, 112Smooth endoplasmic reticulum (sER), 32Smooth muscleadrenoreceptors effects, 88drugs acting on, 130Sodium, transport, tubular cells, 164Sodium chloride reabsorption, kidney, 164Sodium nitroprusside, 124Sodium picosulfate, 178Sodium thiosulfate, 310Somatic nervous system, 84Somatorelin, 238Somatostatin, 238Sorbitoldiuretics, 164laxatives, 174Spasmolytics, 130Specific immune therapy, 338Sphincter of Oddi, 210Spinal anesthesia, 202, 214Spironolactone, 168Sporozoite, 294Stanozolol, 248St Anthony's fire, 130Starling's law of the heart, 132Statins, 160Status epilepticus, 190Stavudine, 290Steady state concentration (C ss ), 48Steven-Johnson syndrome, 74Stibogluconate, 296St John's Wort, 38, 226Straub tail phenomenon, 52Streptokinase, 150, 320Streptomyces, 278Streptomyces hydroscopicus, 306Streptomyces pilosus, 308Streptomyces tsukubaensis, 306Streptomycin, 278, 282Stroke, 136Stuff, opiate abuse, 210Subcutaneous injection, 18Subliminal dosing, 52Substance P, 194Substantia nigra, 188Subthalamic nucleus, 188Succinylcholine, 186Sucralfate, 172Sudek syndrome, 266Sulbactam, 272Sulfadoxine, 294Sulfasalazine, 274, 332Sulfobromophthalein, 30Sulfomethoxazole, 274Sulfonamides, 274drug metabolism, 78Sulfonylurea, 264Sulfoxidations, 36Sulfur transferase, 310Sulpiride, 342Sulprostone, 130Sumatriptan, 120, 334Surface anesthesia, 202agents, 336Sustained release formulation, 50Sympathetic autonomic nervous system, 84structure, 86transmitters, 86

400 Subject Indexα 1 -Sympatholytics, selective, 94α-Sympatholytics, 94β-Sympatholytics, 96Sympathomimetics, 324direct acting, 90doping, 92indirect, 92structure-activity relationship, 90α-Sympathomimetics, 94, 336, 338β 2 -Sympathomimetics, 130, 338bronchial asthma, 340TTachycardia, parasympatholytics, 110Tachyphylaxis, indirectsympathomimetics, 92Tacrolimus, 306Tamoxifen, 254, 256Tardive dyskinesia, 234Taxus brevifolia, 298Tazobactam, 272Tecans, 300Telithromycin, 278Template damage, 300Tenecteplase, 150Tenoposide, 300Teratogenicity, 76cytostatics, 298Terbutaline, 338Teriparatide, 266, 330Terminal ileitis, 274Testosterone, 248heptanoate, 248propionate, 248Tetracaine, 206, 336Tetracyclines, 278, 280Tetrahydrofolate synthesis inhibitors, 274Tetrahydrofolic acid, 274, 300Tetrahydrozoline, 88, 338reactive hyperemia, 94Thalidomide, 76adverse drug effects, 70Thallium salts, 310Theophylline, 130, 338bronchial asthma, 340Therapeutic index, 70Thiazide diuretics, 166, 314Thioamides, 242Thiocyanate, 310Thiopental, 218Thiopurine methyltransferase, 78Thio-TEPA, 300Thioureylenes, 242Thrombin, 152platelet aggregation, 154Thromboembolism, 252Thrombosesprophylaxis and therapy, 144proteases, 144Thromboxane A 2 ,196platelet aggregation, 154Thrombus formation, fibrinogen bridges, 152Thymeretics, 228Thymidine, 286Thymine, 286Thymoleptics, 226Thyroid hormone therapy, 240Thyroid peroxidase, 242Thyroid suppression therapy, euthyroidgoiter, 240Thyrotropin releasing hormone, 238Thyroxine (T 4 ), 240Tiagabine, 190Ticarcillin, 272Ticlopidine, 154Timidazole, 276Timolol, 346Tiotropium, 130, 340Tirazolam, 222Tissue esterases, local anesthetics, 206Tissue plasminogen activator, 150recombinant, 320Tobacco smokingcessation aids, 112consequences, 114vascular disease, 114Tobacco-specific nitrosoketone, 114Tobramycin, 280Tocolysis, 88Tocolytics, 130Tolbutamide, 264Tolonium chloride, 310Toluidine blue, 310Topiramate, 192Topoisomerase II, 276Topotecan, 300Total intravenous anaesthesia, 214, 218Toxic epidermal necrolysis, 74Toxic erythema, 74Toxoplasma gondii, 268Trace state, 236Tramadol, 208, 212Tranexamic acid, 150Transdermal administration routes, 18Transferrin, 142Transpeptidase, 270inhibition, 272Transplacental passage, 76Transplantation medicine, 306Transplant rejection, 306Transport proteins, drug targets, 20Tranylcypromine, 228

Subject Index 401Trastuzumab, 302Trazodone, 228Triamcinolone, 244Triamterene, 168, 314Triazole derivatives, 284Trichlormethiazide, 166Tricyclic antidepressants, 228Triiodothyronine (T 3 ), 240Trimeprazine, 342Trimethoprim, 274Triptorelin, 248Tropisetron, 342Troponin, 88, 320Trypanosoma brucei, 296Trypanosoma cruzi, 296Trypanosomiasis, 296TSH receptors, 242Tubercular disease, 282Tuberculosis, 282D-Tubocurarine, 184Tubular cells, sodium transport, 164Type 2 aquaporins, 168Tyrothricin, 268UUlcerative colitis, 274Ultralente, 258Unipolar depression, 226Unstable angina pectoris, 320Uric acid, 326Uricolytics, 326Uricostatics, 326Uricosurics, 326Urinary excretion, 40Urokinase, 150Urticaria, 74, 338VValaciclovir, 288Valdecoxib, 200Valganciclovir, 288L-Valine, 288Valproate, 190, 192Valproic acid, 192Vancomycin, 270, 272Van der Waals bonds, 58Varicella-zoster virus, 288Vascular disease, tobacco smoking, 114Vascular response, β-blockers, 96Vasoconstrictors, local anesthetics, 204Vasodilators, 122pulmonary hypertension, 122substitution of vasorelaxantmediators, 122Vasopressin, 164, 168, 238local anesthetics, 204Vasopressin derivatives, 168Vecuronium, 184Vegetable fibers, 174Venous vasodilators, 122Verapamil, 126, 136, 318Very low density lipoprotein (VLDL), 158Vesicular ACh transporter, 104Vesicular monoamine transporter, 86Vigabatrin, 190Vinblastine, 298Vincristine, 298Viomycin, 282Viral infectionschemotherapy, 286diarrhea, 180Viral replication, herpes simplex, 286Virustatic antimetabolites, 286Virustatics, 336Vitamin A derivatives, 76Vitamin B 6 , 282Vitamin B 12 ,140,310Vitamin B 12a ,140,310Vitamin D, 330Vitamin D hormone, 266Vitamin K, 146Vitamin K antagonists, 146possibilities for interference, 146Volume of distribution, 28, 44apparent (V app ), 44Vomitingchemotherapy inducing, 342pregnancy, 342von Willebrand factor, 152WWeaning, 116Wepfer, Johann Jakob, 3Wernicke-Korsakow syndrome, 344Wheal flare, 118Wilson disease, 308XXanthine oxidase, 326Xanthinol nicotinate, 160Xanthopsia, 134Ximelagatran, 148Xylometazoline, 88reactive hyperemia, 94

402 Subject IndexZZalcitabine, 290Zaleplone, 220Zanamivir, 288Zidovudine, 290Ziprasidone, 234Zollinger-Ellison syndrome, 172Zolmitriptan, 334Zolpidem, 220Zonulae occludentes, 22, 204Zopiclone, 220