Color Atlas Of Pharmacology.pdf - Bio-Nica.info
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VPrefaceThe present second edition of the <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> goes to print six yearsafter the first edition. Numerous revisions were needed, highlighting the dramaticcontinuing progress in the drug sciences. In particular, it appeared necessary to includenovel therapeutic principles, such as the inhibitors of platelet aggregationfrom the group of integrin GPIIB/IIIA antagonists, the inhibitors of viral protease, orthe non-nucleoside inhibitors of reverse transcriptase. Moreover, the re-evaluationand expanded use of conventional drugs, e.g., in congestive heart failure, bronchialasthma, or rheumatoid arthritis, had to be addressed. In each instance, the primaryemphasis was placed on essential sites of action and basic pharmacological principles.Details and individual drug properties were deliberately omitted in the interestof making drug action more transparent and affording an overview of the pharmacologicalbasis of drug therapy.The authors wish to reiterate that the <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> cannot replace atextbook of pharmacology, nor does it aim to do so. Rather, this little book is designedto arouse the curiosity of the pharmacological novice; to help students of medicineand pharmacy gain an overview of the discipline and to review certain bits of<strong>info</strong>rmation in a concise format; and, finally, to enable the experienced therapist torecall certain factual data, with perhaps some occasional amusement.Our cordial thanks go to the many readers of the multilingual editions of the <strong>Color</strong><strong>Atlas</strong> for their suggestions. We are indebted to Prof. Ulrike Holzgrabe, Würzburg,Doc. Achim Meißner, Kiel, Prof. Gert-Hinrich Reil, Oldenburg, Prof. Reza Tabrizchi, St.John’s, Mr Christian Klein, Bonn, and Mr Christian Riedel, Kiel, for providing stimulatingand helpful discussions and technical support, as well as to Dr. Liane Platt-Rohloff, Stuttgart, and Dr. David Frost, New York, for their editorial and stylistic guidance.Heinz LüllmannKlaus MohrAlbrecht ZieglerDetlef BiegerJürgen WirthFall 1999Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
VIContentsGeneral <strong>Pharmacology</strong> . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1History of <strong>Pharmacology</strong> . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Drug SourcesDrug and Active Principle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Drug Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Drug AdministrationDosage Forms for Oral, and Nasal Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Dosage Forms for Parenteral Pulmonary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Rectal or Vaginal, and Cutaneous Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Drug Administration by Inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Dermatalogic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16From Application to Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Cellular Sites of ActionPotential Targets of Drug Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Distribution in the BodyExternal Barriers of the Body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22Blood-Tissue Barriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Membrane Permeation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Possible Modes of Drug Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28Binding to Plasma Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30Drug EliminationThe Liver as an Excretory Organ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32<strong>Bio</strong>transformation of Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34Enterohepatic Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38The Kidney as Excretory Organ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40Elimination of Lipophilic and Hydrophilic Substances . . . . . . . . . . . . . . . . . . . . . 42PharmacokineticsDrug Concentration in the Body as a Function of Time.First-Order (Exponential) Rate Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44Time Course of Drug Concentration in Plasma . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46Time Course of Drug Plasma Levels During RepeatedDosing and During Irregular Intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48Accumulation: Dose, Dose Interval, and Plasma Level Fluctuation . . . . . . . . . . 50Change in Elimination Characteristics During Drug Therapy . . . . . . . . . . . . . . . 50Quantification of Drug ActionDose-Response Relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52Concentration-Effect Relationship – Effect Curves . . . . . . . . . . . . . . . . . . . . . . . . 54Concentration-Binding Curves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56Drug-Receptor InteractionTypes of Binding Forces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58Agonists-Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60Enantioselectivity of Drug Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62Receptor Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64Mode of Operation of G-Protein-Coupled Receptors . . . . . . . . . . . . . . . . . . . . . . 66Time Course of Plasma Concentration and Effect . . . . . . . . . . . . . . . . . . . . . . . . . 68Adverse Drug Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
ContentsVIIDrug Allergy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72Drug Toxicity in Pregnancy and Lactation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74Drug-independent EffectsPlacebo – Homeopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76Systems <strong>Pharmacology</strong> . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79Drug Acting on the Sympathetic Nervous SystemSympathetic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80Structure of the Sympathetic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82Adrenoceptor Subtypes and Catecholamine Actions . . . . . . . . . . . . . . . . . . . . . . 84Structure – Activity Relationship of Sympathomimetics . . . . . . . . . . . . . . . . . . . 86Indirect Sympathomimetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88α-Sympathomimetics, α-Sympatholytics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90β-Sympatholytics (β-Blockers) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92Types of β-Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94Antiadrenergics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96Drugs Acting on the Parasympathetic Nervous SystemParasympathetic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98Cholinergic Synapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100Parasympathomimetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102Parasympatholytics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104NicotineGanglionic Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108Effects of Nicotine on Body Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110Consequences of Tobacco Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112<strong>Bio</strong>genic Amines<strong>Bio</strong>genic Amines – Actions andPharmacological Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114Serotonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116VasodilatorsVasodilators – Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118Organic Nitrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120Calcium Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122Inhibitors of the RAA System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124Drugs Acting on Smooth Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Drugs Used to Influence Smooth Muscle Organs . . . . . . . . . . . . . . . . . . . . . . . . . . 126Cardiac DrugsOverview of Modes of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128Cardiac Glycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130Antiarrhythmic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134Electrophysiological Actions of Antiarrhythmics ofthe Na + -Channel Blocking Type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136AntianemicsDrugs for the Treatment of Anemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138Iron Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140AntithromboticsProphylaxis and Therapy of Thromboses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142Coumarin Derivatives – Heparin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144Fibrinolytic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146Intra-arterial Thrombus Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148Formation, Activation, and Aggregation of Platelets . . . . . . . . . . . . . . . . . . . . . . . 148Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
VIIIContentsInhibitors of Platelet Aggregation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150Presystemic Effect of Acetylsalicylic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150Adverse Effects of Antiplatelet Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150Plasma Volume Expanders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152Drugs used in HyperlipoproteinemiasLipid-Lowering Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154DiureticsDiuretics – An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158NaCI Reabsorption in the Kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160Osmotic Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160Diuretics of the Sulfonamide Type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162Potassium-Sparing Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164Antidiuretic Hormone (/ADH) and Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . 164Drugs for the Treatment of Peptic UlcersDrugs for Gastric and Duodenal Ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166Laxatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170AntidiarrhealsAntidiarrheal Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178Other Gastrointestinal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180Drugs Acting on Motor SystemsDrugs Affecting Motor Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182Muscle Relaxants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184Depolarizing Muscle Relaxants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186Antiparkinsonian Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188Antiepileptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190Drugs for the Suppression of Pain, Analgesics,Pain Mechanisms and Pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194Antipyretic AnalgesicsEicosanoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196Antipyretic Analgesics and Antiinflammatory DrugsAntipyretic Analgesics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198Antipyretic AnalgesicsNonsteroidal Antiinflammatory(Antirheumatic) Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200Thermoregulation and Antipyretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202Local Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204OpioidsOpioid Analgesics – Morphine Type . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210General Anesthetic DrugsGeneral Anesthesia and General Anesthetic Drugs . . . . . . . . . . . . . . . . . . . . . . . . 216Inhalational Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218Injectable Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220HypnoticsSoporifics, Hypnotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222Sleep-Wake Cycle and Hypnotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224PsychopharmacologicalsBenzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226Pharmacokinetics of Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228Therapy of Manic-Depressive Illnes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230Therapy of Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236Psychotomimetics (Psychedelics, Hallucinogens) . . . . . . . . . . . . . . . . . . . . . . . . . 240Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
ContentsIXHormonesHypothalamic and Hypophyseal Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242Thyroid Hormone Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244Hyperthyroidism and Antithyroid Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246Glucocorticoid Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248Androgens, Anabolic Steroids, Antiandrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252Follicular Growth and Ovulation, Estrogen andProgestin Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254Oral Contraceptives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256Insulin Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258Treatment of Insulin-DependentDiabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260Treatment of Maturity-Onset (Type II)Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262Drugs for Maintaining Calcium Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264Antibacterial DrugsDrugs for Treating Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266Inhibitors of Cell Wall Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268Inhibitors of Tetrahydrofolate Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272Inhibitors of DNA Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274Inhibitors of Protein Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276Drugs for Treating Mycobacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280Antifungal DrugsDrugs Used in the Treatment of Fungal Infection . . . . . . . . . . . . . . . . . . . . . . . . . 282Antiviral DrugsChemotherapy of Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284Drugs for Treatment of AIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288DisinfectantsDisinfectants and Antiseptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290Antiparasitic AgentsDrugs for Treating Endo- and Ectoparasitic Infestations . . . . . . . . . . . . . . . . . . . 292Antimalarials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294Anticancer DrugsChemotherapy of Malignant Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296Immune ModulatorsInhibition of Immune Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300AntidotesAntidotes and treatment of poisonings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302Therapy of Selected DiseasesAngina Pectoris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306Antianginal Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308Acute Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312Hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314Gout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320Migraine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322Common Cold . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324Allergic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326Bronchial Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328Emesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. 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XContentsFurther Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332Drug Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
General <strong>Pharmacology</strong>Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
2 History of <strong>Pharmacology</strong>History of <strong>Pharmacology</strong>Since time immemorial, medicamentshave been used for treating disease inhumans and animals. The herbals of antiquitydescribe the therapeutic powersof certain plants and minerals. Belief inthe curative powers of plants and certainsubstances rested exclusively upontraditional knowledge, that is, empirical<strong>info</strong>rmation not subjected to critical examination.The IdeaThe ImpetusTheophrastus von Hohenheim (1493–1541 A.D.), called Paracelsus, began toquesiton doctrines handed down fromantiquity, demanding knowledge of theactive ingredient(s) in prescribed remedies,while rejecting the irrational concoctionsand mixtures of medieval medicine.He prescribed chemically definedsubstances with such success that professionalenemies had him prosecutedas 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 isn‘t a poison? All thingsare poison, nothing is without poison; thedose alone causes a thing not to be poison.”Early BeginningsClaudius Galen (129–200 A.D.) first attemptedto consider the theoreticalbackground of pharmacology. Both theoryand practical experience were tocontribute equally to the rational use ofmedicines through interpretation of observedand experienced results.“The empiricists say that all is found byexperience. We, however, maintain that itis found in part by experience, in part bytheory. Neither experience nor theoryalone is apt to discover all.”Johann Jakob Wepfer (1620–1695)was the first to verify by animal experimentationassertions about pharmacologicalor toxicological actions.“I pondered at length. Finally I resolved toclarify the matter by experiments.”Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
History of <strong>Pharmacology</strong> 3FoundationRudolf Buchheim (1820–1879) foundedthe first institute of pharmacology atthe University of Dorpat (Tartu, Estonia)in 1847, ushering in pharmacology as anindependent scientific discipline. In additionto a description of effects, hestrove to explain the chemical propertiesof drugs.“The science of medicines is a theoretical,i.e., explanatory, one. It is to provide uswith knowledge by which our judgementabout the utility of medicines can be validatedat the bedside.”Consolidation – General Recognitionreputation of pharmacology. Fundamentalconcepts such as structure-activityrelationship, drug receptor, andselective toxicity emerged from thework of, respectively, T. Frazer (1841–1921) in Scotland, J. Langley (1852–1925) in England, and P. Ehrlich(1854–1915) in Germany. Alexander J.Clark (1885–1941) in England first formalizedreceptor theory in the early1920s by applying the Law of Mass Actionto drug-receptor interactions. Togetherwith the internist, BernhardNaunyn (1839–1925), Schmiedebergfounded the first journal of pharmacology,which has since been publishedwithout interruption. The “Father ofAmerican <strong>Pharmacology</strong>”, John J. Abel(1857–1938) was among the firstAmericans to train in Schmiedeberg‘slaboratory and was founder of the Journalof <strong>Pharmacology</strong> and ExperimentalTherapeutics (published from 1909 untilthe present).Status QuoAfter 1920, pharmacological laboratoriessprang up in the pharmaceutical industry,outside established universityinstitutes. After 1960, departments ofclinical pharmacology were set up atmany universities and in industry.Oswald Schmiedeberg (1838–1921),together with his many disciples (12 ofwhom were appointed to chairs of pharmacology),helped to establish the highLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
4 Drug SourcesDrug and Active PrincipleUntil the end of the 19 th century, medicineswere natural organic or inorganicproducts, mostly dried, but also fresh,plants or plant parts. These might containsubstances possessing healing(therapeutic) properties or substancesexerting a toxic effect.In order to secure a supply of medicallyuseful products not merely at thetime of harvest but year-round, plantswere preserved by drying or soakingthem in vegetable oils or alcohol. Dryingthe plant or a vegetable or animal productyielded a drug (from French“drogue” – dried herb). Colloquially, thisterm nowadays often refers to chemicalsubstances with high potential for physicaldependence and abuse. Used scientifically,this term implies nothing aboutthe quality of action, if any. In its original,wider sense, drug could refer equallywell to the dried leaves of peppermint,dried lime blossoms, dried flowersand leaves of the female cannabis plant(hashish, marijuana), or the dried milkyexudate obtained by slashing the unripeseed capsules of Papaver somniferum(raw opium). Nowadays, the term is appliedquite generally to a chemical substancethat is used for pharmacotherapy.Soaking plants parts in alcohol(ethanol) creates a tincture. In this process,pharmacologically active constituentsof the plant are extracted by the alcohol.Tinctures do not contain the completespectrum of substances that existin the plant or crude drug, only thosethat are soluble in alcohol. In the case ofopium tincture, these ingredients arealkaloids (i.e., basic substances of plantorigin) including: morphine, codeine,narcotine = noscapine, papaverine, narceine,and others.Using a natural product or extractto treat a disease thus usually entails theadministration of a number of substancespossibly possessing very different activities.Moreover, the dose of an individualconstituent contained within agiven amount of the natural product issubject to large variations, dependingupon the product‘s geographical origin(biotope), time of harvesting, or conditionsand length of storage. For the samereasons, the relative proportion of individualconstituents may vary considerably.Starting with the extraction ofmorphine from opium in 1804 by F. W.Sertürner (1783–1841), the active principlesof many other natural productswere subsequently isolated in chemicallypure form by pharmaceutical laboratories.The aims of isolating active principlesare:1. Identification of the active ingredient(s).2. Analysis of the biological effects(pharmacodynamics) of individual ingredientsand of their fate in the body(pharmacokinetics).3. Ensuring a precise and constant dosagein the therapeutic use of chemicallypure constituents.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 effortto optimize pharmacological properties.Thus, derivatives of the original constituentwith improved therapeutic usefulnessmay be developed.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Sources 5Raw opiumPreparationofopium tinctureOpium tincture (laudanum)MorphineCodeineNarcotinePapaverineetc.A. From poppy to morphineLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
6 Drug DevelopmentDrug DevelopmentThis process starts with the synthesis ofnovel chemical compounds. Substanceswith complex structures may be obtainedfrom various sources, e.g., plants(cardiac glycosides), animal tissues(heparin), microbial cultures (penicillinG), or human cells (urokinase), or bymeans of gene technology (human insulin).As more insight is gained into structure-activityrelationships, the searchfor new agents becomes more clearlyfocused.Preclinical testing yields <strong>info</strong>rmationon the biological effects of new substances.Initial screening may employbiochemical-pharmacological investigations(e.g., receptor-binding assaysp. 56) or experiments on cell cultures,isolated cells, and isolated organs. Sincethese models invariably fall short ofreplicating complex biological processesin the intact organism, any potentialdrug must be tested in the whole animal.Only animal experiments can revealwhether the desired effects will actuallyoccur at dosages that produce littleor no toxicity. Toxicological investigationsserve to evaluate the potential for:(1) toxicity associated with acute orchronic administration; (2) geneticdamage (genotoxicity, mutagenicity);(3) production of tumors (onco- or carcinogenicity);and (4) causation of birthdefects (teratogenicity). In animals,compounds under investigation alsohave to be studied with respect to theirabsorption, distribution, metabolism,and elimination (pharmacokinetics).Even at the level of preclinical testing,only a very small fraction of new compoundswill prove potentially fit for usein humans.Pharmaceutical technology providesthe methods for drug formulation.Clinical testing starts with Phase Istudies on healthy subjects and seeks todetermine whether effects observed inanimal experiments also occur in humans.Dose-response relationships aredetermined. In Phase II, potential drugsare first tested on selected patients fortherapeutic efficacy in those diseasestates for which they are intended.Should a beneficial action be evidentand the incidence of adverse effects beacceptably small, Phase III is entered,involving a larger group of patients inwhom the new drug will be comparedwith standard treatments in terms oftherapeutic outcome. As a form of humanexperimentation, these clinicaltrials are subject to review and approvalby institutional ethics committees accordingto international codes of conduct(Declarations of Helsinki, Tokyo,and Venice). During clinical testing,many drugs are revealed to be unusable.Ultimately, only one new drug remainsfrom approximately 10,000 newly synthesizedsubstances.The decision to approve a newdrug is made by a national regulatorybody (Food & Drug Administration inthe U.S.A., the Health Protection BranchDrugs Directorate in Canada, UK, Europe,Australia) to which manufacturersare required to submit their applications.Applicants must document bymeans of appropriate test data (frompreclinical and clinical trials) that thecriteria of efficacy and safety have beenmet and that product forms (tablet, capsule,etc.) satisfy general standards ofquality control.Following approval, the new drugmay be marketed under a trade name(p. 333) and thus become available forprescription by physicians and dispensingby pharmacists. As the drug gainsmore widespread use, regulatory surveillancecontinues in the form of postlicensingstudies (Phase IV of clinicaltrials). Only on the basis of long-termexperience will the risk: benefit ratio beproperly assessed and, thus, the therapeuticvalue of the new drug be determined.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Development 7ClinicaltrialPhase 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, toxicity10,000SubstancesTissuehomogenateA. From drug synthesis to approvalLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
8 Drug AdministrationDosage Forms for Oral, Ocular, andNasal ApplicationsA medicinal agent becomes a medicationonly after formulation suitable fortherapeutic use (i.e., in an appropriatedosage form). The dosage form takesinto account the intended mode of useand also ensures ease of handling (e.g.,stability, precision of dosing) by patientsand physicians. Pharmaceuticaltechnology is concerned with the designof suitable product formulations andquality control.Liquid preparations (A) may takethe form of solutions, suspensions (asol or mixture consisting of small water-insolublesolid drug particles dispersedin water), or emulsions (dispersionof minute droplets of a liquid agentor a drug solution in another fluid, e.g.,oil in water). Since storage will causesedimentation of suspensions and separationof emulsions, solutions are generallypreferred. In the case of poorlywatersoluble substances, solution is oftenaccomplished by adding ethanol (orother solvents); thus, there are bothaqueous and alcoholic solutions. Thesesolutions are made available to patientsin specially designed drop bottles, enablingsingle doses to be measured exactlyin terms of a defined number ofdrops, the size of which depends on thearea of the drip opening at the bottlemouth and on the viscosity and surfacetension of the solution. The advantageof a drop solution is that the dose, thatis, the number of drops, can be preciselyadjusted to the patient‘s need. Its disadvantagelies in the difficulty thatsome patients, disabled by disease orage, will experience in measuring a prescribednumber of drops.When the drugs are dissolved in alarger volume — as in the case of syrupsor mixtures — the single dose is measuredwith a measuring spoon. Dosingmay also be done with the aid of atablespoon or teaspoon (approx. 15 and5 ml, respectively). However, due to thewide variation in the size of commerciallyavailable spoons, dosing will notbe very precise. (Standardized medicinalteaspoons and tablespoons areavailable.)Eye drops and nose drops (A) aredesigned for application to the mucosalsurfaces of the eye (conjunctival sac)and nasal cavity, respectively. In orderto prolong contact time, nasal drops areformulated as solutions of increasedviscosity.Solid dosage forms include tablets,coated tablets, and capsules (B).Tablets have a disk-like shape, producedby mechanical compression ofactive substance, filler (e.g., lactose, calciumsulfate), binder, and auxiliary material(excipients). The filler providesbulk enough to make the tablet easy tohandle and swallow. It is important toconsider that the individual dose ofmany drugs lies in the range of a fewmilligrams or less. In order to conveythe idea of a 10-mg weight, two squaresare marked below, the paper mass ofeach weighing 10 mg. Disintegration ofthe tablet can be hastened by the use ofdried starch, which swells on contactwith water, or of NaHCO 3, which releasesCO 2 gas on contact with gastric acid.Auxiliary materials are important withregard to tablet production, shelf life,palatability, and identifiability (color).Effervescent tablets (compressedeffervescent powders) do not representa solid dosage form, because they aredissolved in water immediately prior toingestion and are, thus, actually, liquidpreparations.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Administration 9Dosage:in drops5 - 50 ml5 - 50 mlAqueoussolution20 drops = 1gAlcoholicsolution40 drops = 1gEyedropsSterileisotonicpH-neutralViscoussolution100 - 500 mlNosedropsDosage:in spoonSolutionMixtureA. Liquid preparationsDrug~0.5 – 500 mgMixing andforming bycompressionEffervescenttabletFiller30 – 250 mgDisintegratingagentOtherexcipients20 – 200 mg30 – 15 mgmin 100 – 1000 mg maxpossible tablet sizeB. Solid preparations for oral applicationTabletCoated tabletCapsuleCapsuleTimeCoatedtabletCapsulewith coateddrug pelletsDrug releaseMatrixtabletC. Dosage forms controlling rate of drug dissolutionLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
10 Drug AdministrationThe coated tablet contains a drug withina core that is covered by a shell, e.g., awax coating, that serves to: (1) protectperishable drugs from decomposing; (2)mask a disagreeable taste or odor; (3)facilitate passage on swallowing; or (4)permit color coding.Capsules usually consist of an oblongcasing — generally made of gelatin— that contains the drug in powder orgranulated form (See. p. 9, C).In the case of the matrix-type tablet,the drug is embedded in an inertmeshwork from which it is released bydiffusion upon being moistened. In contrastto solutions, which permit directabsorption of drug (A, track 3), the useof solid dosage forms initially requirestablets to break up and capsules to open(disintegration) before the drug can bedissolved (dissolution) and passthrough the gastrointestinal mucosallining (absorption). Because disintegrationof the tablet and dissolution of thedrug take time, absorption will occurmainly in the intestine (A, track 2). Inthe case of a solution, absorption startsin the stomach (A, track 3).For acid-labile drugs, a coating ofwax or of a cellulose acetate polymer isused to prevent disintegration of soliddosage forms in the stomach. Accordingly,disintegration and dissolutionwill take place in the duodenum at normalspeed (A, track 1) and drug liberationper se is not retarded.The liberation of drug, hence thesite and time-course of absorption, aresubject to modification by appropriateproduction methods for matrix-typetablets, coated tablets, and capsules. Inthe case of the matrix tablet, the drug isincorporated into a lattice from which itcan be slowly leached out by gastrointestinalfluids. As the matrix tabletundergoes enteral transit, drug liberationand absorption proceed en route (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, track 5) bowel. Thus, by matchingdissolution time with small-bowel transittime, drug release can be timed to occurin the colon.Drug liberation and, hence, absorptioncan also be spread out when thedrug is presented in the form of a granulateconsisting of pellets coated with awaxy film of graded thickness. Dependingon film thickness, gradual dissolutionoccurs during enteral transit, releasingdrug at variable rates for absorption.The principle illustrated for a capsulecan also be applied to tablets. In thiscase, either drug pellets coated withfilms of various thicknesses are compressedinto a tablet or the drug is incorporatedinto a matrix-type tablet. Contraryto timed-release capsules (Spansules® ), slow-release tablets have the advantageof being dividable ad libitum;thus, fractions of the dose containedwithin the entire tablet may be administered.This kind of retarded drug releaseis employed when a rapid rise in bloodlevel of drug is undesirable, or when absorptionis being slowed in order to prolongthe action of drugs that have ashort sojourn in the body.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Administration 11Administration in form ofEntericcoatedtabletTablet,capsuleDrops,mixture,effervescentsolutionMatrixtabletCoatedtablet withdelayedrelease1 2 3 4 5A. Oral administration: drug release and absorptionLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
12 Drug AdministrationDosage Forms for Parenteral (1),Pulmonary (2), Rectal or Vaginal (3),and Cutaneous ApplicationDrugs need not always be administeredorally (i.e., by swallowing), but may alsobe given parenterally. This route usuallyrefers to an injection, although enteralabsorption is also bypassed whendrugs are inhaled or applied to the skin.For intravenous, intramuscular, orsubcutaneous injections, drugs are oftengiven as solutions and, less frequently,in crystalline suspension forintramuscular, subcutaneous, or intraarticularinjection. An injectable solutionmust be free of infectious agents,pyrogens, or suspended matter. Itshould have the same osmotic pressureand pH as body fluids in order to avoidtissue damage at the site of injection.Solutions for injection are preserved inairtight glass or plastic sealed containers.From ampules for multiple or singleuse, the solution is aspirated via aneedle into a syringe. The cartridge ampuleis fitted into a special injector thatenables its contents to be emptied via aneedle. An infusion refers to a solutionbeing administered over an extendedperiod of time. Solutions for infusionmust meet the same standards as solutionsfor injection.Drugs can be sprayed in aerosolform onto mucosal surfaces of body cavitiesaccessible from the outside (e.g.,the respiratory tract [p. 14]). An aerosolis a dispersion of liquid or solid particlesin a gas, such as air. An aerosol resultswhen a drug solution or micronizedpowder is reduced to a spray on beingdriven through the nozzle of a pressurizedcontainer.Mucosal application of drug via therectal or vaginal route is achieved bymeans of suppositories and vaginaltablets, respectively. On rectal application,absorption into the systemic circulationmay be intended. With vaginaltablets, the effect is generally confinedto the site of application. Usually thedrug is incorporated into a fat that solidifiesat room temperature, but melts inthe rectum or vagina. The resulting oilyfilm spreads over the mucosa and enablesthe drug to pass into the mucosa.Powders, ointments, and pastes(p. 16) are applied to the skin surface. Inmany cases, these do not contain drugsbut are used for skin protection or care.However, drugs may be added if a topicalaction on the outer skin or, morerarely, a systemic effect is intended.Transdermal drug deliverysystems are pasted to the epidermis.They contain a reservoir from whichdrugs may diffuse and be absorbedthrough the skin. They offer the advantagethat a drug depot is attached noninvasivelyto the body, enabling thedrug to be administered in a mannersimilar to an infusion. Drugs amenableto this type of delivery must: (1) be capableof penetrating the cutaneous barrier;(2) be effective in very small doses(restricted capacity of reservoir); and(3) possess a wide therapeutic margin(dosage not adjustable).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Administration 13Sterile, iso-osmolarAmpule1 – 20 mlCartridgeampule 2 mlPropellant gasDrug solutionWith and withoutfracture ring<strong>Of</strong>ten withpreservativeJet nebulizer235 ºCVaginaltabletSuppositoryMultiple-dosevial 50 – 100 ml,always withpreservativeInfusionsolution500 – 1000 ml1 35 ºC Melting point 3Backing layerDrug reservoirAdhesive coatPasteOintmentTransdermal delivery system (TDS)Drug releasePowderOintmentTDSTime 12 24 h4A. Preparations for parenteral (1), inhalational (2), rectal or vaginal (3),and percutaneous (4) applicationLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
14 Drug AdministrationDrug Administration by InhalationInhalation in the form of an aerosol(p. 12), a gas, or a mist permits drugs tobe applied to the bronchial mucosa and,to a lesser extent, to the alveolar membranes.This route is chosen for drugs intendedto affect bronchial smooth muscleor the consistency of bronchial mucus.Furthermore, gaseous or volatileagents can be administered by inhalationwith the goal of alveolar absorptionand systemic effects (e.g., inhalationalanesthetics, p. 218). Aerosols areformed when a drug solution or micronizedpowder is converted into a mist ordust, respectively.In conventional sprays (e.g., nebulizer),the air blast required for aerosolformation is generated by the stroke of apump. Alternatively, the drug is deliveredfrom a solution or powder packagedin a pressurized canister equippedwith a valve through which a metereddose is discharged. During use, the inhaler(spray dispenser) is held directlyin front of the mouth and actuated atthe start of inspiration. The effectivenessof delivery depends on the positionof the device in front of the mouth, thesize of aerosol particles, and the coordinationbetween opening of the sprayvalve and inspiration. The size of aerosolparticles determines the speed at whichthey are swept along by inhaled air,hence the depth of penetration intothe respiratory tract. Particles >100 µm in diameter are trapped in theoropharyngeal cavity; those having diametersbetween 10 and 60µm will bedeposited on the epithelium of thebronchial tract. Particles < 2 µm in diametercan reach the alveoli, but theywill be largely exhaled because of theirlow tendency to impact on the alveolarepithelium.Drug deposited on the mucous liningof the bronchial epithelium is partlyabsorbed and partly transported withbronchial mucus towards the larynx.Bronchial mucus travels upwards due tothe orally directed undulatory beat ofthe epithelial cilia. Physiologically, thismucociliary transport functions to removeinspired dust particles. Thus, onlya portion of the drug aerosol (~ 10 %)gains access to the respiratory tract andjust a fraction of this amount penetratesthe mucosa, whereas the remainder ofthe aerosol undergoes mucociliarytransport to the laryngopharynx and isswallowed. The advantage of inhalation(i.e., localized application) is fully exploitedby using drugs that are poorlyabsorbed from the intestine (isoproterenol,ipratropium, cromolyn) or are subjectto first-pass elimination (p. 42; beclomethasonedipropionate, budesonide,flunisolide, fluticasone dipropionate).Even when the swallowed portionof an inhaled drug is absorbed in unchangedform, administration by thisroute has the advantage that drug concentrationsat the bronchi will be higherthan in other organs.The efficiency of mucociliary transportdepends on the force of kinociliarymotion and the viscosity of bronchialmucus. Both factors can be alteredpathologically (e.g., in smoker’s cough,bronchitis) or can be adversely affectedby drugs (atropine, antihistamines).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Administration 15Depth ofpenetrationof inhaledaerosolizeddrug solution10%90%100 µmNasopharynxDrug swept upis swallowedLarynx10 µmTrachea-bronchi1 µmBronchioli, alveoliMucociliary transport1 cm/minAs completepresystemiceliminationas possibleAs littleenteralabsorptionas possibleLow systemic burdenCiliated epitheliumA. Application by inhalationLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
16 Drug AdministrationDermatologic AgentsPharmaceutical preparations applied tothe outer skin are intended either toprovide skin care and protection fromnoxious influences (A), or to serve as avehicle for drugs that are to be absorbedinto the skin or, if appropriate, into thegeneral circulation (B).Skin Protection (A)Protective agents are of several kinds tomeet different requirements accordingto skin condition (dry, low in oil,chapped vs moist, oily, elastic), and thetype of noxious stimuli (prolonged exposureto water, regular use of alcoholcontainingdisinfectants [p. 290], intensesolar irradiation).Distinctions among protectiveagents are based upon consistency, physicochemicalproperties (lipophilic, hydrophilic),and the presence of additives.Dusting Powders are sprinkled ontothe intact skin and consist of talc,magnesium stearate, silicon dioxide(silica), or starch. They adhere to theskin, forming a low-friction film that attenuatesmechanical irritation. Powdersexert a drying (evaporative) effect.Lipophilic ointment (oil ointment)consists of a lipophilic base (paraffin oil,petroleum jelly, wool fat [lanolin]) andmay contain up to 10 % powder materials,such as zinc oxide, titanium oxide,starch, or a mixture of these. Emulsifyingointments are made of paraffins andan emulsifying wax, and are misciblewith water.Paste (oil paste) is an ointmentcontaining more than 10 % pulverizedconstituents.Lipophilic (oily) cream is an emulsionof water in oil, easier to spread thanoil paste or oil ointments.Hydrogel and water-soluble ointmentachieve their consistency bymeans of different gel-forming agents(gelatin, methylcellulose, polyethyleneglycol). Lotions are aqueous suspensionsof water-insoluble and solid constituents.Hydrophilic (aqueous) cream is anemulsion of an oil in water formed withthe aid of an emulsifier; it may also beconsidered an oil-in-water emulsion ofan emulsifying ointment.All dermatologic agents having alipophilic base adhere to the skin as awater-repellent coating. They do notwash off and they also prevent (occlude)outward passage of water fromthe skin. The skin is protected from drying,and its hydration and elasticity increase.Diminished evaporation of waterresults in warming of the occluded skinarea. Hydrophilic agents wash off easilyand do not impede transcutaneous outputof water. Evaporation of water is feltas a cooling effect.Dermatologic Agents as Vehicles (B)In order to reach its site of action, a drug(D) must leave its pharmaceutical preparationand enter the skin, if a local effectis desired (e.g., glucocorticoid ointment),or be able to penetrate it, if asystemic action is intended (transdermaldelivery system, e.g., nitroglycerinpatch, p. 120). The tendency for the drugto leave the drug vehicle (V) is higherthe more the drug and vehicle differ inlipophilicity (high tendency: hydrophilicD and lipophilic V, and vice versa). Becausethe skin represents a closed lipophilicbarrier (p. 22), only lipophilicdrugs are absorbed. Hydrophilic drugsfail even to penetrate the outer skinwhen applied in a lipophilic vehicle.This formulation can be meaningfulwhen high drug concentrations are requiredat the skin surface (e.g., neomycinointment for bacterial skin infections).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Administration 17PowderSolidLiquidSolutionPasteDermatologicalsAqueoussolutionAlcoholictinctureOily pasteSemi-solidHydrogelLipophilicointmentOintmentHydrophilicointmentLipophiliccreamCreamHydrophiliccreamSuspensionLotionEmulsionFat, oilWater in oilOil in waterGel, waterOcclusivePermeable,coolantPerspirationimpossible possibleDry, non-oily skinOily, moist skinA. Dermatologicals as skin protectantsLipophilic drugin lipophilicbaseLipophilic drugin hydrophilicbaseHydrophilic drugin lipophilicbaseHydrophilic drugin hydrophilicbaseEpitheliumStratumcorneumSubcutaneous fat tissueB. Dermatologicals as drug vehiclesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
18 Drug AdministrationFrom Application to Distributionin the BodyAs a rule, drugs reach their target organsvia the blood. Therefore, they must firstenter the blood, usually the venous limbof the circulation. There are several possiblesites of entry.The drug may be injected or infusedintravenously, in which case the drug isintroduced directly into the bloodstream.In subcutaneous or intramuscularinjection, the drug has to diffusefrom its site of application into theblood. Because these procedures entailinjury to the outer skin, strict requirementsmust be met concerning technique.For that reason, the oral route(i.e., simple application by mouth) involvingsubsequent uptake of drugacross the gastrointestinal mucosa intothe blood is chosen much more frequently.The disadvantage of this routeis that the drug must pass through theliver on its way into the general circulation.This fact assumes practical significancewith any drug that may be rapidlytransformed or possibly inactivated inthe liver (first-pass hepatic elimination;p. 42). Even with rectal administration,at least a fraction of the drug enters thegeneral circulation via the portal vein,because only veins draining the shortterminal segment of the rectum communicatedirectly with the inferior venacava. Hepatic passage is circumventedwhen absorption occurs buccally orsublingually, because venous bloodfrom the oral cavity drains directly intothe superior vena cava. The same wouldapply to administration by inhalation(p. 14). However, with this route, a localeffect is usually intended; a systemic actionis intended only in exceptional cases.Under certain conditions, drug canalso be applied percutaneously in theform of a transdermal delivery system(p. 12). In this case, drug is slowly releasedfrom the reservoir, and then penetratesthe epidermis and subepidermalconnective tissue where it enters bloodcapillaries. Only a very few drugs can beapplied transdermally. The feasibility ofthis route is determined by both thephysicochemical properties of the drugand the therapeutic requirements(acute vs. long-term effect).Speed of absorption is determinedby the route and method of application.It is fastest with intravenous injection,less fast which intramuscular injection,and slowest with subcutaneous injection.When the drug is applied to theoral mucosa (buccal, sublingual route),plasma levels rise faster than with conventionaloral administration becausethe drug preparation is deposited at itsactual site of absorption and very highconcentrations in saliva occur upon thedissolution of a single dose. Thus, uptakeacross the oral epithelium is accelerated.The same does not hold true forpoorly water-soluble or poorly absorbabledrugs. Such agents should be givenorally, because both the volume of fluidfor dissolution and the absorbing surfaceare much larger in the small intestinethan in the oral cavity.<strong>Bio</strong>availability is defined as thefraction of a given drug dose that reachesthe circulation in unchanged formand becomes available for systemic distribution.The larger the presystemicelimination, the smaller is the bioavailabilityof an orally administered drug.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Administration 19SublingualbuccalInhalationalIntravenousTransdermalOralAortaSubcutaneousDistribution in bodyIntramuscularA. From application to distributionRectalLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
20 Cellular Sites of ActionPotential Targets of Drug ActionDrugs are designed to exert a selectiveinfluence on vital processes in order toalleviate or eliminate symptoms of disease.The smallest basic unit of an organismis the cell. The outer cell membrane,or plasmalemma, effectively demarcatesthe cell from its surroundings,thus permitting a large degree of internalautonomy. Embedded in the plasmalemmaare transport proteins thatserve to mediate controlled metabolicexchange with the cellular environment.These include energy-consumingpumps (e.g., Na, K-ATPase, p. 130), carriers(e.g., for Na/glucose-cotransport, p.178), and ion channels e.g., for sodium(p. 136) or calcium (p. 122) (1).Functional coordination betweensingle cells is a prerequisite for viabilityof the organism, hence also for the survivalof individual cells. Cell functionsare regulated by means of messengersubstances for the transfer of <strong>info</strong>rmation.Included among these are “transmitters”released from nerves, whichthe cell is able to recognize with thehelp of specialized membrane bindingsites or receptors. Hormones secretedby endocrine glands into the blood, theninto the extracellular fluid, representanother class of chemical signals. Finally,signalling substances can originatefrom neighboring cells, e.g., prostaglandins(p. 196) and cytokines.The effect of a drug frequently resultsfrom interference with cellularfunction. Receptors for the recognitionof endogenous transmitters are obvioussites of drug action (receptor agonistsand antagonists, p. 60). Altered activityof transport systems affects cell function(e.g., cardiac glycosides, p. 130;loop diuretics, p. 162; calcium-antagonists,p. 122). Drugs may also directlyinterfere with intracellular metabolicprocesses, for instance by inhibiting(phosphodiesterase inhibitors, p. 132)or activating (organic nitrates, p. 120)an enzyme (2).In contrast to drugs acting from theoutside on cell membrane constituents,agents acting in the cell’s interior needto penetrate the cell membrane.The cell membrane basically consistsof a phospholipid bilayer (80Å =8 nm in thickness) in which are embeddedproteins (integral membrane proteins,such as receptors and transportmolecules). Phospholipid moleculescontain two long-chain fatty acids in esterlinkage with two of the three hydroxylgroups of glycerol. Bound to thethird hydroxyl group is phosphoric acid,which, in turn, carries a further residue,e.g., choline, (phosphatidylcholine = lecithin),the amino acid serine (phosphatidylserine)or the cyclic polyhydric alcoholinositol (phosphatidylinositol). Interms of solubility, phospholipids areamphiphilic: the tail region containingthe apolar fatty acid chains is lipophilic,the remainder – the polar head – is hydrophilic.By virtue of these properties,phospholipids aggregate spontaneouslyinto a bilayer in an aqueous medium,their polar heads directed outwards intothe aqueous medium, the fatty acidchains facing each other and projectinginto the inside of the membrane (3).The hydrophobic interior of thephospholipid membrane constitutes adiffusion barrier virtually impermeablefor charged particles. Apolar particles,however, penetrate the membraneeasily. This is of major importance withrespect to the absorption, distribution,and elimination of drugs.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Cellular Sites of Action 211NeuralcontrolDNerveTransmitterReceptorIon channelHormonalcontrolHormonesDHormonereceptorsCellulartransportsystems forcontrolledtransfer ofsubstratesDD= DrugEnzymeDDirect actionon metabolismTransportmolecule2 3CholineDPhospholipidmatrixDPhosphoricacidGlycerolProteinFatty acidEffectIntracellularsite of actionA. Sites at which drugs act to modify cell functionLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
22 Distribution in the BodyExternal Barriers of the BodyPrior to its uptake into the blood (i.e.,during absorption), a drug has to overcomebarriers that demarcate the bodyfrom its surroundings, i.e., separate theinternal milieu from the external milieu.These boundaries are formed bythe skin and mucous membranes.When absorption takes place in thegut (enteral absorption), the intestinalepithelium is the barrier. This singlelayeredepithelium is made up of enterocytesand mucus-producing gobletcells. On their luminal side, these cellsare joined together by zonulae occludentes(indicated by black dots in the inset,bottom left). A zonula occludens ortight junction is a region in which thephospholipid membranes of two cellsestablish close contact and becomejoined via integral membrane proteins(semicircular inset, left center). The regionof fusion surrounds each cell like aring, so that neighboring cells are weldedtogether in a continuous belt. In thismanner, an unbroken phospholipidlayer is formed (yellow area in the schematicdrawing, bottom left) and acts asa continuous barrier between the twospaces separated by the cell layer – inthe case of the gut, the intestinal lumen(dark blue) and the interstitial space(light blue). The efficiency with whichsuch a barrier restricts exchange of substancescan be increased by arrangingthese occluding junctions in multiplearrays, as for instance in the endotheliumof cerebral blood vessels. The connectingproteins (connexins) furthermoreserve to restrict mixing of otherfunctional membrane proteins (ionpumps, ion channels) that occupy specificareas of the cell membrane.This phospholipid bilayer representsthe intestinal mucosa-blood barrierthat a drug must cross during its enteralabsorption. Eligible drugs are thosewhose physicochemical properties allowpermeation through the lipophilicmembrane interior (yellow) or that aresubject to a special carrier transportmechanism. Absorption of such drugsproceeds rapidly, because the absorbingsurface is greatly enlarged due to theformation of the epithelial brush border(submicroscopic foldings of the plasmalemma).The absorbability of a drug ischaracterized by the absorption quotient,that is, the amount absorbed dividedby the amount in the gut availablefor absorption.In the respiratory tract, cilia-bearingepithelial cells are also joined on theluminal side by zonulae occludentes, sothat the bronchial space and the interstitiumare separated by a continuousphospholipid barrier.With sublingual or buccal application,a drug encounters the non-keratinized,multilayered squamous epitheliumof the oral mucosa. Here, the cellsestablish punctate contacts with eachother in the form of desmosomes (notshown); however, these do not seal theintercellular clefts. Instead, the cellshave the property of sequestering phospholipid-containingmembrane fragmentsthat assemble into layers withinthe extracellular space (semicircular inset,center right). In this manner, a continuousphospholipid barrier arises alsoinside squamous epithelia, although atan extracellular location, unlike that ofintestinal epithelia. A similar barrierprinciple operates in the multilayeredkeratinized squamous epithelium of theouter skin. The presence of a continuousphospholipid layer means thatsquamous epithelia will permit passageof lipophilic drugs only, i.e., agents capableof diffusing through phospholipidmembranes, with the epithelial thicknessdetermining the extent and speedof absorption. In addition, cutaneous absorptionis impeded by the keratinlayer, the stratum corneum, which isvery unevenly developed in various areasof the skin.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Distribution in the Body 23Ciliated epitheliumNonkeratinizedsquamous epitheliumEpithelium withbrush borderKeratinized squamousepitheliumA. External barriers of the bodyLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
24 Distribution in the BodyBlood-Tissue BarriersDrugs are transported in the blood todifferent tissues of the body. In order toreach their sites of action, they mustleave the bloodstream. Drug permeationoccurs largely in the capillary bed,where both surface area and time availablefor exchange are maximal (extensivevascular branching, low velocity offlow). The capillary wall forms theblood-tissue barrier. Basically, thisconsists of an endothelial cell layer anda basement membrane enveloping thelatter (solid black line in the schematicdrawings). The endothelial cells are“riveted” to each other by tight junctionsor occluding zonulae (labelled Z inthe electron micrograph, top left) suchthat no clefts, gaps, or pores remain thatwould permit drugs to pass unimpededfrom the blood into the interstitial fluid.The blood-tissue barrier is developeddifferently in the various capillarybeds. Permeability to drugs of the capillarywall is determined by the structuraland functional characteristics of the endothelialcells. In many capillary beds,e.g., those of cardiac muscle, endothelialcells are characterized by pronouncedendo- and transcytotic activity,as evidenced by numerous invaginationsand vesicles (arrows in the EM micrograph,top right). Transcytotic activityentails transport of fluid or macromoleculesfrom the blood into the interstitiumand vice versa. Any solutestrapped in the fluid, including drugs,may traverse the blood-tissue barrier. Inthis form of transport, the physicochemicalproperties of drugs are of littleimportance.In some capillary beds (e.g., in thepancreas), endothelial cells exhibit fenestrations.Although the cells are tightlyconnected by continuous junctions,they possess pores (arrows in EM micrograph,bottom right) that are closedonly by diaphragms. Both the diaphragmand basement membrane canbe readily penetrated by substances oflow molecular weight — the majority ofdrugs — but less so by macromolecules,e.g., proteins such as insulin (G: insulinstorage granules. Penetrability of macromoleculesis determined by molecularsize and electrical charge. Fenestratedendothelia are found in the capillariesof the gut and endocrine glands.In the central nervous system(brain and spinal cord), capillary endothelialack pores and there is little transcytoticactivity. In order to cross theblood-brain barrier, drugs must diffusetranscellularly, i.e., penetrate the luminaland basal membrane of endothelialcells. Drug movement along this pathrequires specific physicochemical properties(p. 26) or the presence of a transportmechanism (e.g., L-dopa, p. 188).Thus, the blood-brain barrier is permeableonly to certain types of drugs.Drugs exchange freely betweenblood and interstitium in the liver,where endothelial cells exhibit largefenestrations (100 nm in diameter) facingDisse’s spaces (D) and where neitherdiaphragms nor basement membranesimpede drug movement. Diffusion barriersare also present beyond the capillarywall: e.g., placental barrier of fusedsyncytiotrophoblast cells; blood: testiclebarrier — junctions interconnectingSertoli cells; brain choroid plexus: bloodbarrier — occluding junctions betweenependymal cells.(Vertical bars in the EM micrographsrepresent 1 µm; E: cross-sectionederythrocyte; AM: actomyosin; G:insulin-containing granules.)Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Distribution in the Body 25CNSHeart muscleEAMZDGLiverPancreasA. Blood-tissue barriersLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
26 Distribution in the BodyMembrane PermeationAn ability to penetrate lipid bilayers is aprerequisite for the absorption of drugs,their entry into cells or cellular organelles,and passage across the bloodbrainbarrier. Due to their amphiphilicnature, phospholipids form bilayerspossessing a hydrophilic surface and ahydrophobic interior (p. 20). Substancesmay traverse this membrane in threedifferent ways.Diffusion (A). Lipophilic substances(red dots) may enter the membranefrom the extracellular space (areashown in ochre), accumulate in themembrane, and exit into the cytosol(blue area). Direction and speed of permeationdepend on the relative concentrationsin the fluid phases and themembrane. The steeper the gradient(concentration difference), the moredrug will be diffusing per unit of time(Fick’s Law). The lipid membrane representsan almost insurmountable obstaclefor hydrophilic substances (blue triangles).Transport (B). Some drugs maypenetrate membrane barriers with thehelp of transport systems (carriers), irrespectiveof their physicochemicalproperties, especially lipophilicity. As aprerequisite, the drug must have affinityfor the carrier (blue triangle matchingrecess on “transport system”) and,when bound to the latter, be capable ofbeing ferried across the membrane.Membrane passage via transport mechanismsis subject to competitive inhibitionby another substance possessingsimilar affinity for the carrier. Substanceslacking in affinity (blue circles) arenot transported. Drugs utilize carriersfor physiological substances, e.g., L-dopauptake by L-amino acid carrier acrossthe blood-intestine and blood-brainbarriers (p. 188), and uptake of aminoglycosidesby the carrier transportingbasic polypeptides through the luminalmembrane of kidney tubular cells (p.278). Only drugs bearing sufficient resemblanceto the physiological substrateof a carrier will exhibit affinity forit.Finally, membrane penetrationmay occur in the form of small membrane-coveredvesicles. Two differentsystems are considered.Transcytosis (vesicular transport,C). When new vesicles are pinched off,substances dissolved in the extracellularfluid are engulfed, and then ferriedthrough the cytoplasm, vesicles (phagosomes)undergo fusion with lysosomesto form phagolysosomes, and the transportedsubstance is metabolized. Alternatively,the vesicle may fuse with theopposite cell membrane (cytopempsis).Receptor-mediated endocytosis(C). The drug first binds to membranesurface receptors (1, 2) whose cytosolicdomains contact special proteins (adaptins,3). Drug-receptor complexes migratelaterally in the membrane and aggregatewith other complexes by aclathrin-dependent process (4). The affectedmembrane region invaginatesand eventually pinches off to form a detachedvesicle (5). The clathrin coat isshed immediately (6), followed by theadaptins (7). The remaining vesicle thenfuses with an “early” endosome (8),whereupon proton concentration risesinside the vesicle. The drug-receptorcomplex dissociates and the receptorreturns into the cell membrane. The“early” endosome delivers its contentsto predetermined destinations, e.g., theGolgi complex, the cell nucleus, lysosomes,or the opposite cell membrane(transcytosis). Unlike simple endocytosis,receptor-mediated endocytosis iscontingent on affinity for specific receptorsand operates independently of concentrationgradients.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Distribution in the Body 27A. Membrane permeation: diffusion B. Membrane permeation: transport123489756Vesicular transportLysosomePhagolysosomeExtracellularIntracellularExtracellularC. Membrane permeation: receptor-mediated endocytosis, vesicular uptake, andtransportLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
28 Distribution in the BodyPossible Modes of Drug DistributionFollowing its uptake into the body, thedrug is distributed in the blood (1) andthrough it to the various tissues of thebody. Distribution may be restricted tothe extracellular space (plasma volumeplus interstitial space) (2) or may alsoextend into the intracellular space (3).Certain drugs may bind strongly to tissuestructures, so that plasma concentrationsfall significantly even beforeelimination has begun (4).After being distributed in blood,macromolecular substances remainlargely confined to the vascular space,because their permeation through theblood-tissue barrier, or endothelium, isimpeded, even where capillaries arefenestrated. This property is exploitedtherapeutically when loss of blood necessitatesrefilling of the vascular bed,e.g., by infusion of dextran solutions (p.152). The vascular space is, moreover,predominantly occupied by substancesbound with high affinity to plasma proteins(p. 30; determination of the plasmavolume with protein-bound dyes).Unbound, free drug may leave thebloodstream, albeit with varying ease,because the blood-tissue barrier (p. 24)is differently developed in different segmentsof the vascular tree. These regionaldifferences are not illustrated inthe accompanying figures.Distribution in the body is determinedby the ability to penetrate membranousbarriers (p. 20). Hydrophilicsubstances (e.g., inulin) are neither takenup into cells nor bound to cell surfacestructures and can, thus, be used to determinethe extracellular fluid volume(2). Some lipophilic substances diffusethrough the cell membrane and, as a result,achieve a uniform distribution (3).Body weight may be broken downas follows:Solid substance and andstructurally bound waterboundwater40%40%intracellularwater20%extra-cellularextracellularwaterwaterPotential aqueous solventspaces for drugsPotential aqueous solventspaces for drugsFurther subdivisions are shown inthe table.The volume ratio interstitial: intracellularwater varies with age and bodyweight. On a percentage basis, interstitialfluid volume is large in premature ornormal neonates (up to 50 % of bodywater), and smaller in the obese and theaged.The concentration (c) of a solutioncorresponds to the amount (D) of substancedissolved in a volume (V); thus, c= D/V. If the dose of drug (D) and itsplasma concentration (c) are known, avolume of distribution (V) can be calculatedfrom V = D/c. However, this representsan apparent volume of distribution(V app), because an even distributionin the body is assumed in its calculation.Homogeneous distribution will not occurif drugs are bound to cell membranes(5) or to membranes of intracellularorganelles (6) or are stored withinthe latter (7). In these cases, V app can exceedthe actual size of the available fluidvolume. The significance of V app as apharmacokinetic parameter is discussedon p. 44.L llmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> ' 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Distribution in the Body 291 2 34Distribution in tissuePlasma6%4%Interstitium25%65%ErythrocytesIntracellular spaceAqueous spaces of the organismA. Compartments for drug distributionLysosomesMitochondriaNucleusCell5 6membrane7Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
30 Distribution in the BodyBinding to Plasma ProteinsHaving entered the blood, drugs maybind to the protein molecules that arepresent in abundance, resulting in theformation of drug-protein complexes.Protein binding involves primarily albuminand, to a lesser extent, β-globulinsand acidic glycoproteins. Otherplasma proteins (e.g., transcortin, transferrin,thyroxin-binding globulin) servespecialized functions in connectionwith specific substances. The degree ofbinding is governed by the concentrationof the reactants and the affinity of adrug for a given protein. Albumin concentrationin plasma amounts to4.6 g/100 mL or O.6 mM, and thus providesa very high binding capacity (twosites per molecule). As a rule, drugs exhibitmuch lower affinity (K D approx.10 –5 –10 –3 M) for plasma proteins thanfor their specific binding sites (receptors).In the range of therapeutically relevantconcentrations, protein binding ofmost drugs increases linearly with concentration(exceptions: salicylate andcertain sulfonamides).The albumin molecule has differentbinding sites for anionic and cationic ligands,but van der Waals’ forces alsocontribute (p. 58). The extent of bindingcorrelates with drug hydrophobicity(repulsion of drug by water).Binding to plasma proteins is instantaneousand reversible, i.e., anychange in the concentration of unbounddrug is immediately followed by a correspondingchange in the concentrationof bound drug. Protein binding is ofgreat importance, because it is the concentrationof free drug that determinesthe intensity of the effect. At an identicaltotal plasma concentration (say, 100ng/mL) the effective concentration willbe 90 ng/mL for a drug 10 % bound toprotein, but 1 ng/mL for a drug 99 %bound to protein. The reduction in concentrationof free drug resulting fromprotein binding affects not only the intensityof the effect but also biotransformation(e.g., in the liver) and eliminationin the kidney, because only freedrug will enter hepatic sites of metabolismor undergo glomerular filtration.When concentrations of free drug fall,drug is resupplied from binding sites onplasma proteins. Binding to plasma proteinis equivalent to a depot in prolongingthe duration of the effect by retardingelimination, whereas the intensityof the effect is reduced. If two substanceshave affinity for the same binding siteon the albumin molecule, they maycompete for that site. One drug may displaceanother from its binding site andthereby elevate the free (effective) concentrationof the displaced drug (a formof drug interaction). Elevation of thefree concentration of the displaced drugmeans increased effectiveness and acceleratedelimination.A decrease in the concentration ofalbumin (liver disease, nephrotic syndrome,poor general condition) leads toaltered pharmacokinetics of drugs thatare highly bound to albumin.Plasma protein-bound drugs thatare substrates for transport carriers canbe cleared from blood at great velocity,e.g., p-aminohippurate by the renal tubuleand sulfobromophthalein by theliver. Clearance rates of these substancescan be used to determine renal or hepaticblood flow.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Distribution in the Body 31Drug isnot boundto plasmaproteinsDrug isstronglybound toplasmaproteinsEffector cellEffectEffector cellEffect<strong>Bio</strong>transformation<strong>Bio</strong>transformationRenal eliminationRenal eliminationPlasma concentrationPlasma concentrationFree drugBound drugFree drugTimeTimeA. Importance of protein binding for intensity and duration of drug effectLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
32 Drug EliminationThe Liver as an Excretory OrganAs the chief organ of drug biotransformation,the liver is richly supplied withblood, of which 1100 mL is receivedeach minute from the intestinesthrough the portal vein and 350 mLthrough the hepatic artery, comprisingnearly 1 / 3 of cardiac output. The bloodcontent of hepatic vessels and sinusoidsamounts to 500 mL. Due to the wideningof the portal lumen, intrahepaticblood flow decelerates (A). Moreover,the endothelial lining of hepatic sinusoids(p. 24) contains pores largeenough to permit rapid exit of plasmaproteins. Thus, blood and hepatic parenchymaare able to maintain intimatecontact and intensive exchange of substances,which is further facilitated bymicrovilli covering the hepatocyte surfacesabutting Disse’s spaces.The hepatocyte secretes biliaryfluid into the bile canaliculi (darkgreen), tubular intercellular clefts thatare sealed off from the blood spaces bytight junctions. Secretory activity in thehepatocytes results in movement offluid towards the canalicular space (A).The hepatocyte has an abundance of enzymescarrying out metabolic functions.These are localized in part in mitochondria,in part on the membranes of therough (rER) or smooth (sER) endoplasmicreticulum.Enzymes of the sER play a most importantrole in drug biotransformation.At this site, molecular oxygen is used inoxidative reactions. Because these enzymescan catalyze either hydroxylationor oxidative cleavage of -N-C- or -O-Cbonds,they are referred to as “mixedfunction”oxidases or hydroxylases. Theessential component of this enzymesystem is cytochrome P450, which in itsoxidized state binds drug substrates (R-H). The Fe III -P450-RH binary complex isfirst reduced by NADPH, then forms theternary complex, O 2-Fe II -P450-RH,which accepts a second electron and finallydisintegrates into Fe III -P450, oneequivalent of H 2O, and hydroxylateddrug (R-OH).Compared with hydrophilic drugsnot undergoing transport, lipophilicdrugs are more rapidly taken up fromthe blood into hepatocytes and morereadily gain access to mixed-functionoxidases embedded in sER membranes.For instance, a drug having lipophilicityby virtue of an aromatic substituent(phenyl ring) (B) can be hydroxylatedand, thus, become more hydrophilic(Phase I reaction, p. 34). Besides oxidases,sER also contains reductases andglucuronyl transferases. The latter conjugateglucuronic acid with hydroxyl,carboxyl, amine, and amide groups (p.38); hence, also phenolic products ofphase I metabolism (Phase II conjugation).Phase I and Phase II metabolitescan be transported back into the blood— probably via a gradient-dependentcarrier — or actively secreted into bile.Prolonged exposure to certain substrates,such as phenobarbital, carbamazepine,rifampicin results in a proliferationof sER membranes (cf. C and D).This enzyme induction, a load-dependenthypertrophy, affects equally all enzymeslocalized on sER membranes. Enzymeinduction leads to acceleratedbiotransformation, not only of the inducingagent but also of other drugs (aform of drug interaction). With continuedexposure, induction develops in afew days, resulting in an increase in reactionvelocity, maximally 2–3fold, thatdisappears after removal of the inducingagent.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Elimination 33HepatocyteBiliary capillaryDisse´s spacePortal veinIntestineGall-bladderA. Flow patterns in portal vein, Disse’s space, and hepatocytePhase I-metaboliteBiliarycapillaryrERsERC. Normal hepatocyteCarrierGlucuronidePhase IImetaboliterERsERB. Fate of drugs undergoingB. hepatic hydroxylationD. Hepatocyte afterD. phenobarbital administrationLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
34 Drug Elimination<strong>Bio</strong>transformation of DrugsMany drugs undergo chemical modificationin the body (biotransformation).Most frequently, this process entails aloss of biological activity and an increasein hydrophilicity (water solubility),thereby promoting elimination viathe renal route (p. 40). Since rapid drugelimination improves accuracy in titratingthe therapeutic concentration, drugsare often designed with built-in weaklinks. Ester bonds are such links, beingsubject to hydrolysis by the ubiquitousesterases. Hydrolytic cleavages, alongwith oxidations, reductions, alkylations,and dealkylations, constitute Phase I reactionsof drug metabolism. These reactionssubsume all metabolic processesapt to alter drug molecules chemicallyand take place chiefly in the liver. InPhase II (synthetic) reactions, conjugationproducts of either the drug itselfor its Phase I metabolites are formed, forinstance, with glucuronic or sulfuric acid(p. 38).The special case of the endogenoustransmitter acetylcholine illustrateswell the high velocity of ester hydrolysis.Acetylcholine is broken down at itssites of release and action by acetylcholinesterase(pp. 100, 102) so rapidly as tonegate its therapeutic use. Hydrolysis ofother esters catalyzed by various esterasesis slower, though relatively fast incomparison with other biotransformations.The local anesthetic, procaine, is acase in point; it exerts its action at thesite of application while being largelydevoid of undesirable effects at other locationsbecause it is inactivated by hydrolysisduring absorption from its siteof application.Ester hydrolysis does not invariablylead to inactive metabolites, as exemplifiedby acetylsalicylic acid. The cleavageproduct, salicylic acid, retains pharmacologicalactivity. In certain cases,drugs are administered in the form ofesters in order to facilitate absorption(enalapril enalaprilate; testosteroneundecanoate testosterone) or to reduceirritation of the gastrointestinalmucosa (erythromycin succinate erythromycin). In these cases, the esteritself is not active, but the cleavageproduct is. Thus, an inactive precursoror prodrug is applied, formation of theactive molecule occurring only after hydrolysisin the blood.Some drugs possessing amidebonds, such as prilocaine, and of course,peptides, can be hydrolyzed by peptidasesand inactivated in this manner.Peptidases are also of pharmacologicalinterest because they are responsiblefor the formation of highly reactivecleavage products (fibrin, p. 146) andpotent mediators (angiotensin II, p. 124;bradykinin, enkephalin, p. 210) frombiologically inactive peptides.Peptidases exhibit some substrateselectivity and can be selectively inhibited,as exemplified by the formation ofangiotensin II, whose actions inter aliainclude vasoconstriction. Angiotensin IIis formed from angiotensin I by cleavageof the C-terminal dipeptide histidylleucine.Hydrolysis is catalyzed by “angiotensin-convertingenzyme” (ACE). Peptideanalogues such as captopril (p. 124)block this enzyme. Angiotensin II is degradedby angiotensinase A, which clipsoff the N-terminal asparagine residue.The product, angiotensin III, lacks vasoconstrictoractivity.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Elimination 35Esterases Ester Peptidases Amides AnilidesAcetylcholineConvertingenzymeAcetic acidProcaineCholineAngiotensin IAngiotensin IIAngiotensin IIIAngiotensinasep-Aminobenzoic acidDiethylaminoethanolAcetylsalicylic acidPrilocaineAcetic acidSalicylic acidN-PropylalanineToluidineA. Examples of chemical reactions in drug biotransformation (hydrolysis)Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
36 Drug EliminationOxidation reactions can be dividedinto two kinds: those in which oxygen isincorporated into the drug molecule,and those in which primary oxidationcauses part of the molecule to be lost.The former include hydroxylations,epoxidations, and sulfoxidations. Hydroxylationsmay involve alkyl substituents(e.g., pentobarbital) or aromaticring systems (e.g., propranolol). In bothcases, products are formed that are conjugatedto an organic acid residue, e.g.,glucuronic acid, in a subsequent Phase IIreaction.Hydroxylation may also take placeat nitrogen atoms, resulting in hydroxylamines(e.g., acetaminophen). Benzene,polycyclic aromatic compounds (e.g.,benzopyrene), and unsaturated cycliccarbohydrates can be converted bymono-oxygenases to epoxides, highlyreactive electrophiles that are hepatotoxicand possibly carcinogenic.The second type of oxidative biotransformationcomprises dealkylations.In the case of primary or secondaryamines, dealkylation of an alkylgroup starts at the carbon adjacent tothe nitrogen; in the case of tertiaryamines, with hydroxylation of the nitrogen(e.g., lidocaine). The intermediaryproducts are labile and break up into thedealkylated amine and aldehyde of thealkyl group removed. O-dealkylationR 2R 1NCH3DesalkylierungR 1R 2N OHCH 3R 1O 2+NR 2 Hand S-dearylation proceed via an analogousmechanism (e.g., phenacetin andazathioprine, respectively).Oxidative deamination basicallyresembles the dealkylation of tertiaryamines, beginning with the formation ofa hydroxylamine that then decomposesinto ammonia and the correspondingaldehyde. The latter is partly reduced toan alcohol and partly oxidized to a carboxylicacid.Reduction reactions may occur atoxygen or nitrogen atoms. Keto-oxygensare converted into a hydroxylgroup, as in the reduction of the prodrugscortisone and prednisone to theactive glucocorticoids cortisol and prednisolone,respectively. N-reductions occurin azo- or nitro-compounds (e.g., nitrazepam).Nitro groups can be reducedto amine groups via nitroso and hydroxylaminointermediates. Likewise, dehalogenationis a reductive process involvinga carbon atom (e.g., halothane, p.218).Methylations are catalyzed by afamily of relatively specific methyltransferasesinvolving the transfer ofmethyl groups to hydroxyl groups (Omethylationas in norepinephrine [noradrenaline])or to amino groups (Nmethylationof norepinephrine, histamine,or serotonin).In thio compounds, desulfurationresults from substitution of sulfur byoxygen (e.g., parathion). This exampleagain illustrates that biotransformationis not always to be equated with bioinactivation.Thus, paraoxon (E600)formed in the organism from parathion(E605) is the actual active agent (p. 102).HCOCH 3L llmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> ' 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Elimination 37PropranololPentobarbitalHydroxylationLidocainePhenacetinParathionN-DealkylationO-DealkylationDesulfurationDealkylationNorepinephrineS-DealkylationAzathioprineO-MethylationMethylationNitrazepamBenzpyreneChlorpromazineSulfoxidationAcetaminophenEpoxidationReductionOxidationHydroxylamineA. Examples of chemical reactions in drug biotransformationLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
38 Drug EliminationEnterohepatic Cycle (A)After an orally ingested drug has beenabsorbed from the gut, it is transportedvia the portal blood to the liver, where itcan be conjugated to glucuronic or sulfuricacid (shown in B for salicylic acidand deacetylated bisacodyl, respectively)or to other organic acids. At the pH ofbody fluids, these acids are predominantlyionized; the negative charge confershigh polarity upon the conjugateddrug molecule and, hence, low membranepenetrability. The conjugatedproducts may pass from hepatocyte intobiliary fluid and from there back intothe intestine. O-glucuronides can becleaved by bacterial β-glucuronidases inthe colon, enabling the liberated drugmolecule to be reabsorbed. The enterohepaticcycle acts to trap drugs in thebody. However, conjugated productsenter not only the bile but also theblood. Glucuronides with a molecularweight (MW) > 300 preferentially passinto the blood, while those with MW >300 enter the bile to a larger extent.Glucuronides circulating in the bloodundergo glomerular filtration in the kidneyand are excreted in urine becausetheir decreased lipophilicity preventstubular reabsorption.Drugs that are subject to enterohepaticcycling are, therefore, excretedslowly. Pertinent examples include digitoxinand acidic nonsteroidal anti-inflammatoryagents (p. 200).Amines may form N-glucuronides that,unlike O-glucuronides, are resistant tobacterial β-glucuronidases.Soluble cytoplasmic sulfotransferasesconjugate activated sulfate (3’-phosphoadenine-5’-phosphosulfate)with alcohols and phenols. The conjugatesare acids, as in the case of glucuronides.In this respect, they differ fromconjugates formed by acetyltransferasesfrom activated acetate (acetylcoenzymeA) and an alcohol or a phenol.Acyltransferases are involved in theconjugation of the amino acids glycineor glutamine with carboxylic acids. Inthese cases, an amide bond is formedbetween the carboxyl groups of the acceptorand the amino group of the donormolecule (e.g., formation of salicyluricacid from salicylic acid and glycine).The acidic group of glycine or glutamineremains free.Conjugations (B)The most important of phase II conjugationreactions is glucuronidation. Thisreaction does not proceed spontaneously,but requires the activated form ofglucuronic acid, namely glucuronic aciduridine diphosphate. Microsomal glucuronyltransferases link the activatedglucuronic acid with an acceptor molecule.When the latter is a phenol or alcohol,an ether glucuronide will beformed. In the case of carboxyl-bearingmolecules, an ester glucuronide is theresult. All of these are O-glucuronides.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Elimination 391HepatocyteSinusoidBiliary capillary734Conjugation withglucuronic acid5Biliaryelimination2Portal veinE n t e r oh e p a t i cc ir c u l a ti o n6Deconjugationby microbialβ-glucuronidase8RenaleliminationLipophilicdrugHydrophilicconjugation productEnteralabsorptionA. Enterohepatic cycleUDP-α-Glucuronic acid3'-Phosphoadenine-5'-phosphosulfateGlucuronyltransferaseSulfotransferaseSalicylic acidActive moiety of bisacodylB. Conjugation reactionsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
40 Drug EliminationThe Kidney as Excretory OrganMost drugs are eliminated in urine eitherchemically unchanged or as metabolites.The kidney permits eliminationbecause the vascular wall structure inthe region of the glomerular capillaries(B) allows unimpeded passage of bloodsolutes having molecular weights (MW)< 5000. Filtration diminishes progressivelyas MW increases from 5000 to70000 and ceases at MW > 70000. Withfew exceptions, therapeutically useddrugs and their metabolites have muchsmaller molecular weights and can,therefore, undergo glomerular filtration,i.e., pass from blood into primaryurine. Separating the capillary endotheliumfrom the tubular epithelium, thebasal membrane consists of chargedglycoproteins and acts as a filtrationbarrier for high-molecular-weight substances.The relative density of this barrierdepends on the electrical charge ofmolecules that attempt to permeate it.Apart from glomerular filtration(B), drugs present in blood may passinto urine by active secretion. Certaincations and anions are secreted by theepithelium of the proximal tubules intothe tubular fluid via special, energyconsumingtransport systems. Thesetransport systems have a limited capacity.When several substrates are presentsimultaneously, competition for thecarrier may occur (see p. 268).During passage down the renal tubule,urinary volume shrinks more than100-fold; accordingly, there is a correspondingconcentration of filtered drugor drug metabolites (A). The resultingconcentration gradient between urineand interstitial fluid is preserved in thecase of drugs incapable of permeatingthe tubular epithelium. However, withlipophilic drugs the concentration gradientwill favor reabsorption of the filteredmolecules. In this case, reabsorptionis not based on an active processbut results instead from passive diffusion.Accordingly, for protonated substances,the extent of reabsorption isdependent upon urinary pH or the degreeof dissociation. The degree of dissociationvaries as a function of the urinarypH and the pK a, which representsthe pH value at which half of the substanceexists in protonated (or unprotonated)form. This relationship is graphicallyillustrated (D) with the example ofa protonated amine having a pK a of 7.0.In this case, at urinary pH 7.0, 50 % of theamine will be present in the protonated,hydrophilic, membrane-impermeantform (blue dots), whereas the other half,representing the uncharged amine(orange dots), can leave the tubular lumenin accordance with the resultingconcentration gradient. If the pK a of anamine is higher (pK a = 7.5) or lower (pK a= 6.5), a correspondingly smaller orlarger proportion of the amine will bepresent in the uncharged, reabsorbableform. Lowering or raising urinary pH byhalf a pH unit would result in analogouschanges for an amine having a pK a of7.0.The same considerations hold foracidic molecules, with the importantdifference that alkalinization of theurine (increased pH) will promote thedeprotonization of -COOH groups andthus impede reabsorption. Intentionalalteration in urinary pH can be used inintoxications with proton-acceptor substancesin order to hasten elimination ofthe toxin (alkalinization phenobarbital;acidification amphetamine).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Elimination 41180 LPrimaryurineGlomerularfiltrationof drugBloodPlasmaproteinEndotheliumBasalmembraneDrugEpitheliumPrimary urineB. Glomerular filtrationpH = 7.0pK a of substancepK a = 7.0100+501.2 LFinalurineConcentrationof drugin tubule%1006 6.5 7 7.5 8pK a = 7.5A. Filtration and concentration50+++++ ++ + ++++++++ ++ +++ +%1006 6.5 7 7.5 8pK a = 6.5Tubulartransportsystem for+ Cations– Anions----- -- - ------ ----- -- -pH = 7.050%6 6.5 7 7.5 8pH of urineC. Active secretionD. Tubular reabsorptionLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
42 Drug EliminationElimination of Lipophilic andHydrophilic SubstancesThe terms lipophilic and hydrophilic(or hydro- and lipophobic) refer to thesolubility of substances in media of lowand high polarity, respectively. Bloodplasma, interstitial fluid, and cytosol arehighly polar aqueous media, whereaslipids — at least in the interior of the lipidbilayer membrane — and fat constituteapolar media. Most polar substancesare readily dissolved in aqueous media(i.e., are hydrophilic) and lipophilicones in apolar media. A hydrophilicdrug, on reaching the bloodstream,probably after a partial, slow absorption(not illustrated), passes through the liverunchanged, because it either cannot,or will only slowly, permeate the lipidbarrier of the hepatocyte membraneand thus will fail to gain access to hepaticbiotransforming enzymes. The unchangeddrug reaches the arterial bloodand the kidneys, where it is filtered.With hydrophilic drugs, there is littlebinding to plasma proteins (proteinbinding increases as a function of lipophilicity),hence the entire amountpresent in plasma is available for glomerularfiltration. A hydrophilic drug isnot subject to tubular reabsorption andappears in the urine. Hydrophilic drugsundergo rapid elimination.If a lipophilic drug, because of itschemical nature, cannot be convertedinto a polar product, despite having accessto all cells, including metabolicallyactive liver cells, it is likely to be retainedin the organism. The portion filteredduring glomerular passage will bereabsorbed from the tubules. Reabsorptionwill be nearly complete, becausethe free concentration of a lipophilicdrug in plasma is low (lipophilic substancesare usually largely proteinbound).The situation portrayed for alipophilic non-metabolizable drugwould seem undesirable because pharmacotherapeuticmeasures once initiatedwould be virtually irreversible (poorcontrol over blood concentration).Lipophilic drugs that are convertedin the liver to hydrophilic metabolitespermit better control, because thelipophilic agent can be eliminated inthis manner. The speed of formation ofhydrophilic metabolite determines thedrug’s length of stay in the body.If hepatic conversion to a polar metaboliteis rapid, only a portion of theabsorbed drug enters the systemic circulationin unchanged form, the remainderhaving undergone presystemic(first-pass) elimination. When biotransformationis rapid, oral administrationof the drug is impossible (e.g.,glyceryl trinitate, p. 120). Parenteral or,alternatively, sublingual, intranasal, ortransdermal administration is then requiredin order to bypass the liver. Irrespectiveof the route of administration,a portion of administered drug may betaken up into and transiently stored inlung tissue before entering the generalcirculation. This also constitutes presystemicelimination.Presystemic elimination refers tothe fraction of drug absorbed that isexcluded from the general circulationby biotransformation or by first-passbinding.Presystemic elimination diminishesthe bioavailability of a drug after itsoral administration. Absolute bioavailability= systemically available amount/dose administered; relative bioavailability= availability of a drug containedin a test preparation with reference to astandard preparation.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Elimination 43Hydrophilic drugLipophilic drugno metabolismRenalexcretionExcretionimpossibleLipophilic drugLipophilic drugSlow conversionin liver tohydrophilic metaboliteRapid and completeconversion in liver tohydrophilic metaboliteRenal excretionof metaboliteRenal excretionof metaboliteA. Elimination of hydrophilic and hydrophobic drugsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
44 PharmacokineticsDrug Concentration in the Bodyas a Function of Time. First-Order(Exponential) Rate ProcessesProcesses such as drug absorption andelimination display exponential characteristics.As regards the former, this followsfrom the simple fact that theamount of drug being moved per unit oftime depends on the concentration difference(gradient) between two bodycompartments (Fick’s Law). In drug absorptionfrom the alimentary tract, theintestinal contents and blood wouldrepresent the compartments containingan initially high and low concentration,respectively. In drug elimination via thekidney, excretion often depends on glomerularfiltration, i.e., the filteredamount of drug present in primaryurine. As the blood concentration falls,the amount of drug filtered per unit oftime diminishes. The resulting exponentialdecline is illustrated in (A). Theexponential time course implies constancyof the interval during which theconcentration decreases by one-half.This interval represents the half-life(t 1/2) and is related to the eliminationrate constant k by the equation t 1/2 = ln2/k. The two parameters, together withthe initial concentration c o, describe afirst-order (exponential) rate process.The constancy of the process permitscalculation of the plasma volumethat would be cleared of drug, if the remainingdrug were not to assume a homogeneousdistribution in the total volume(a condition not met in reality).This notional plasma volume freed ofdrug per unit of time is termed theclearance. Depending on whether plasmaconcentration falls as a result of urinaryexcretion or metabolic alteration,clearance is considered to be renal orhepatic. Renal and hepatic clearancesadd up to total clearance (Cl tot) in thecase of drugs that are eliminated unchangedvia the kidney and biotransformedin the liver. Cl tot represents thesum of all processes contributing toelimination; it is related to the half-life(t 1/2) and the apparent volume of distributionV app (p. 28) by the equation:V appt 1/2 = In 2 x ––––Cl totThe smaller the volume of distributionor the larger the total clearance, theshorter is the half-life.In the case of drugs renally eliminatedin unchanged form, the half-life ofelimination can be calculated from thecumulative excretion in urine; the finaltotal amount eliminated corresponds tothe amount absorbed.Hepatic elimination obeys exponentialkinetics because metabolizingenzymes operate in the quasilinear regionof their concentration-activitycurve; hence the amount of drug metabolizedper unit of time diminisheswith decreasing blood concentration.The best-known exception to exponentialkinetics is the elimination of alcohol(ethanol), which obeys a lineartime course (zero-order kinetics), atleast at blood concentrations > 0.02 %. Itdoes so because the rate-limiting enzyme,alcohol dehydrogenase, achieveshalf-saturation at very low substrateconcentrations, i.e., at about 80 mg/L(0.008 %). Thus, reaction velocity reachesa plateau at blood ethanol concentrationsof about 0.02 %, and the amount ofdrug eliminated per unit of time remainsconstant at concentrations abovethis level.L llmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> ' 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Pharmacokinetics 45Concentration (c) of drug in plasma [amount/vol]CoPlasma half life t 1 21c t 12 = — c2 oln 2t 1 = 2—–kc t = c o · e -ktc 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) = DoseTimeA. Exponential elimination of drugLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
46 PharmacokineticsTime Course of Drug Concentration inPlasmaA. Drugs are taken up into and eliminatedfrom the body by various routes. Thebody thus represents an open systemwherein the actual drug concentrationreflects the interplay of intake (ingestion)and egress (elimination). When anorally administered drug is absorbedfrom the stomach and intestine, speedof uptake depends on many factors, includingthe speed of drug dissolution (inthe case of solid dosage forms) and ofgastrointestinal transit; the membranepenetrability of the drug; its concentrationgradient across the mucosa-bloodbarrier; and mucosal blood flow. Absorptionfrom the intestine causes thedrug concentration in blood to increase.Transport in blood conveys the drug todifferent organs (distribution), intowhich it is taken up to a degree compatiblewith its chemical properties andrate of blood flow through the organ.For instance, well-perfused organs suchas the brain receive a greater proportionthan do less well-perfused ones. Uptakeinto tissue causes the blood concentrationto fall. Absorption from the gut diminishesas the mucosa-blood gradientdecreases. Plasma concentration reachesa peak when the drug amount leavingthe blood per unit of time equals thatbeing absorbed.Drug entry into hepatic and renaltissue constitutes movement into theorgans of elimination. The characteristicphasic time course of drug concentrationin plasma represents the sum ofthe constituent processes of absorption,distribution, and elimination,which overlap in time. When distributiontakes place significantly faster thanelimination, there is an initial rapid andthen a greatly retarded fall in the plasmalevel, the former being designatedthe α-phase (distribution phase), thelatter the β-phase (elimination phase).When the drug is distributed faster thanit is absorbed, the time course of theplasma level can be described in mathematicallysimplified form by the Batemanfunction (k 1 and k 2 represent therate constants for absorption and elimination,respectively).B. The velocity of absorption dependson the route of administration.The more rapid the administration, theshorter will be the time (t max) requiredto reach the peak plasma level (c max),the higher will be the c max, and the earlierthe plasma level will begin to fallagain.The area under the plasma level timecurve (AUC) is independent of the routeof administration, provided the dosesand bioavailability are the same (Dost’slaw of corresponding areas). The AUCcan thus be used to determine the bioavailabilityF of a drug. The ratio of AUCvalues determined after oral or intravenousadministration of a given dose of aparticular drug corresponds to the proportionof drug entering the systemiccirculation after oral administration.The determination of plasma levels affordsa comparison of different proprietarypreparations containing the samedrug in the same dosage. Identical plasmalevel time-curves of differentmanufacturers’ products with referenceto a standard preparation indicate bioequivalenceof the preparation underinvestigation with the standard.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Pharmacokinetics 47AbsorptionUptake fromstomach andintestinesinto bloodDistributioninto bodytissues:α-phaseEliminationfrom body bybiotransformation(chemical alteration),excretion via kidney:ß-phaseDrug concentration in blood (c)Bateman-functionDose kc = x 1 x (e -k 1t -e-k 2 t )˜ V app k 2 - k 1Time (t)A. Time course of drug concentrationDrug concentration in blood (c)IntravenousIntramuscularSubcutaneousOralTime (t)B. Mode of application and time course of drug concentrationLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
48 PharmacokineticsTime Course of Drug Plasma LevelsDuring Repeated Dosing (A)When a drug is administered at regularintervals over a prolonged period, therise and fall of drug concentration inblood will be determined by the relationshipbetween the half-life of eliminationand the time interval betweendoses. If the drug amount administeredin each dose has been eliminated beforethe next dose is applied, repeated intakeat constant intervals will result in similarplasma levels. If intake occurs beforethe preceding dose has been eliminatedcompletely, the next dose will add on tothe residual amount still present in thebody, i.e., the drug accumulates. Theshorter the dosing interval relative tothe elimination half-life, the larger willbe the residual amount of drug to whichthe next dose is added and the more extensivelywill the drug accumulate inthe body. However, at a given dosingfrequency, the drug does not accumulateinfinitely and a steady state (C ss) oraccumulation equilibrium is eventuallyreached. This is so because the activityof elimination processes is concentration-dependent.The higher the drugconcentration rises, the greater is theamount eliminated per unit of time. Afterseveral doses, the concentration willhave climbed to a level at which theamounts eliminated and taken in perunit of time become equal, i.e., a steadystate is reached. Within this concentrationrange, the plasma level will continueto rise (peak) and fall (trough) as dosingis continued at a regular interval.The height of the steady state (C ss) dependsupon the amount (D) administeredper dosing interval (τ) and theclearance (Cl tot):Time Course of Drug Plasma LevelsDuring Irregular Intake (B)In practice, it proves difficult to achievea plasma level that undulates evenlyaround the desired effective concentration.For instance, if two successive dosesare omitted, the plasma level willdrop below the therapeutic range and alonger period will be required to regainthe desired plasma level. In everydaylife, patients will be apt to neglect drugintake at the scheduled time. Patientcompliance means strict adherence tothe prescribed regimen. Apart frompoor compliance, the same problemmay occur when the total daily dose isdivided into three individual doses (tid)and the first dose is taken at breakfast,the second at lunch, and the third atsupper. Under this condition, the nocturnaldosing interval will be twice thediurnal one. Consequently, plasma levelsduring the early morning hours mayhave fallen far below the desired or,possibly, urgently needed range.DC ss = –––––––––(τ · Cl tot)The speed at which the steady stateis reached corresponds to the speed ofelimination of the drug. The time neededto reach 90 % of the concentrationplateau is about 3 times the t 1/2 of elimination.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Pharmacokinetics 49Dosing intervalDrug concentrationDosing intervalTimeTimeAccumulation:administered drug isnot completely eliminatedduring intervalSteady state:drug intake equalselimination duringdosing intervalDrug concentrationTimeA. Time course of drug concentration in blood during regular intakeDrug concentrationDesiredtherapeuticlevel? ? ?TimeB. Time course of drug concentration with irregular intakeLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
50 PharmacokineticsAccumulation: Dose, Dose Interval, andPlasma Level FluctuationSuccessful drug therapy in many illnessesis accomplished only if drug concentrationis maintained at a steady highlevel. This requirement necessitatesregular drug intake and a dosage schedulethat ensures that the plasma concentrationneither falls below the therapeuticallyeffective range nor exceedsthe minimal toxic concentration. A constantplasma level would, however, beundesirable if it accelerated a loss of effectiveness(development of tolerance),or if the drug were required to bepresent at specified times only.A steady plasma level can beachieved by giving the drug in a constantintravenous infusion, the steadystateplasma level being determined bythe infusion rate, dose D per unit of timeτ, and the clearance, according to theequation:DC ss = –––––––––(τ · Cl tot)This procedure is routinely used inintensive care hospital settings, but isotherwise impracticable. With oral administration,dividing the total dailydose into several individual ones, e.g.,four, three, or two, offers a practicalcompromise.When the daily dose is given in severaldivided doses, the mean plasmalevel shows little fluctuation. In practice,it is found that a regimen of frequentregular drug ingestion is not welladhered to by patients. The degree offluctuation in plasma level over a givendosing interval can be reduced by use ofa dosage form permitting slow (sustained)release (p. 10).The time required to reach steadystateaccumulation during multipleconstant dosing depends on the rate ofelimination. As a rule of thumb, a plateauis reached after approximatelythree elimination half-lives (t 1/2).For slowly eliminated drugs, whichtend to accumulate extensively (phenprocoumon,digitoxin, methadone), theoptimal plasma level is attained only aftera long period. Here, increasing theinitial doses (loading dose) will speedup the attainment of equilibrium, whichis subsequently maintained with a lowerdose (maintenance dose).Change in Elimination CharacteristicsDuring Drug Therapy (B)With any drug taken regularly and accumulatingto the desired plasma level, itis important to consider that conditionsfor biotransformation and excretion donot necessarily remain constant. Eliminationmay be hastened due to enzymeinduction (p. 32) or to a change in urinarypH (p. 40). Consequently, thesteady-state plasma level declines to anew value corresponding to the newrate of elimination. The drug effect maydiminish or disappear. Conversely,when elimination is impaired (e.g., inprogressive renal insufficiency), themean plasma level of renally eliminateddrugs rises and may enter a toxic concentrationrange.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Pharmacokinetics 51Drug concentration in blood4 x daily 50 mg2 x daily 100 mg1 x daily 200 mgSingle 50 mgDesired plasma level612 18 24 6 12 18 24 6 12 18 24 6 12A. Accumulation: dose, dose interval, and fluctuation of plasma levelInhibition of eliminationDrug concentration in bloodAccelerationof eliminationDesired plasma level6 12 18 24 6 12 18 24 6 12 18 24 6 12 18B. Changes in elimination kinetics in the course of drug therapyLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
52 Quantification of Drug ActionDose–Response RelationshipThe effect of a substance depends on theamount administered, i.e., the dose. Ifthe dose chosen is below the criticalthreshold (subliminal dosing), an effectwill be absent. Depending on the natureof the effect to be measured, ascendingdoses may cause the effect to increase inintensity. Thus, the effect of an antipyreticor hypotensive drug can be quantifiedin a graded fashion, in that the extentof fall in body temperature or bloodpressure is being measured. A dose-effectrelationship is then encountered, asdiscussed on p. 54.The dose-effect relationship mayvary depending on the sensitivity of theindividual person receiving the drug,i.e., for the same effect, different dosesmay be required in different individuals.Interindividual variation in sensitivity isespecially obvious with effects of the“all-or-none” kind.To illustrate this point, we consideran experiment in which the subjects individuallyrespond in all-or-none fashion,as in the Straub tail phenomenon(A). Mice react to morphine with excitation,evident in the form of an abnormalposture of the tail and limbs. The dosedependence of this phenomenon is observedin groups of animals (e.g., 10mice per group) injected with increasingdoses of morphine. At the low dose,only the most sensitive, at increasingdoses a growing proportion, at the highestdose all of the animals are affected(B). There is a relationship between thefrequency of responding animals andthe dose given. At 2 mg/kg, one out of 10animals reacts; at 10 mg/kg, 5 out of 10respond. The dose-frequency relationshipresults from the different sensitivityof individuals, which as a rule exhibitsa log-normal distribution (C, graph atright, linear scale). If the cumulative frequency(total number of animals respondingat a given dose) is plottedagainst the logarithm of the dose (abscissa),a sigmoidal curve results (C,graph at left, semilogarithmic scale).The inflection point of the curve lies atthe dose at which one-half of the grouphas responded. The dose range encompassingthe dose-frequency relationshipreflects the variation in individual sensitivityto the drug. Although similar inshape, a dose-frequency relationshiphas, thus, a different meaning than doesa dose-effect relationship. The latter canbe evaluated in one individual and resultsfrom an intraindividual dependencyof the effect on drug concentration.The evaluation of a dose-effect relationshipwithin a group of human subjectsis compounded by interindividualdifferences in sensitivity. To account forthe biological variation, measurementshave to be carried out on a representativesample and the results averaged.Thus, recommended therapeutic doseswill be appropriate for the majority ofpatients, but not necessarily for each individual.The variation in sensitivity may bebased on pharmacokinetic differences(same dose different plasma levels)or on differences in target organ sensitivity(same plasma level different effects).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Quantification of Drug Action 53A. Abnormal posture in mouse given morphineDose = 0 = 2 mg/kg = 10 mg/kg= 20 mg/kg = 100 mg/kg= 140 mg/kgB. Incidence of effect as a function of dose% Cumulative frequency100Frequency of dose needed806040204321mg/kg 2 10 20 100 1402 10 20100 140 mg/kgC. Dose-frequency relationshipLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
54 Quantification of Drug ActionConcentration-Effect Relationship (A)The relationship between the concentrationof a drug and its effect is determinedin order to define the range of activedrug concentrations (potency) andthe maximum possible effect (efficacy).On the basis of these parameters, differencesbetween drugs can be quantified.As a rule, the therapeutic effect or toxicaction depends critically on the responseof a single organ or a limitednumber of organs, e.g., blood flow is affectedby a change in vascular luminalwidth. By isolating critical organs or tissuesfrom a larger functional system,these actions can be studied with moreaccuracy; for instance, vasoconstrictoragents can be examined in isolatedpreparations from different regions ofthe vascular tree, e.g., the portal orsaphenous vein, or the mesenteric, coronary,or basilar artery. In many cases,isolated organs or organ parts can bekept viable for hours in an appropriatenutrient medium sufficiently suppliedwith oxygen and held at a suitable temperature.Responses of the preparation to aphysiological or pharmacological stimuluscan be determined by a suitable recordingapparatus. Thus, narrowing of ablood vessel is recorded with the help oftwo clamps by which the vessel is suspendedunder tension.Experimentation on isolated organsoffers several advantages:1. The drug concentration in the tissueis usually known.2. Reduced complexity and ease of relatingstimulus and effect.3. It is possible to circumvent compensatoryresponses that may partiallycancel the primary effect in the intactorganism — e.g., the heart rate increasingaction of norepinephrinecannot be demonstrated in the intactorganism, because a simultaneousrise in blood pressure elicits a counter-regulatoryreflex that slows cardiacrate.4. The ability to examine a drug effectover its full rage of intensities — e.g.,it would be impossible in the intactorganism to follow negative chronotropiceffects to the point of cardiacarrest.Disadvantages are:1. Unavoidable tissue injury during dissection.2. Loss of physiological regulation offunction in the isolated tissue.3. The artificial milieu imposed on thetissue.Concentration-Effect Curves (B)As the concentration is raised by a constantfactor, the increment in effect diminishessteadily and tends asymptoticallytowards zero the closer one comesto the maximally effective concentration.Theconcentration at which a maximaleffect occurs cannot be measuredaccurately; however, that eliciting ahalf-maximal effect (EC 50) is readily determined.It typically corresponds to theinflection point of the concentration–responsecurve in a semilogarithmicplot (log concentration on abscissa).Full characterization of a concentration–effectrelationship requires determinationof the EC 50, the maximallypossible effect (E max), and the slope atthe point of inflection.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Quantification of Drug Action 55Portal veinMesenteric arteryCoronaryarteryBasilararterySaphenousveinVasoconstrictionActive tension1 min1251020Drug concentration304050100A. Measurement of effect as a function of concentration50Effect(in mm of registration unit,e.g., tension developed)%100Effect(% of maximum effect)408030602040102010 20 30 40 50Concentration (linear)1 10 100Concentration (logarithmic)B. Concentration-effect relationshipLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
56 Quantification of Drug ActionConcentration-Binding CurvesIn order to elicit their effect, drug moleculesmust be bound to the cells of theeffector organ. Binding commonly occursat specific cell structures, namely,the receptors. The analysis of drug bindingto receptors aims to determine theaffinity of ligands, the kinetics of interaction,and the characteristics of thebinding site itself.In studying the affinity and numberof such binding sites, use is made ofmembrane suspensions of different tissues.This approach is based on the expectationthat binding sites will retaintheir characteristic properties duringcell homogenization. Provided thatbinding sites are freely accessible in themedium in which membrane fragmentsare suspended, drug concentration atthe “site of action” would equal that inthe medium. The drug under study is radiolabeled(enabling low concentrationsto be measured quantitatively),added to the membrane suspension,and allowed to bind to receptors. Membranefragments and medium are thenseparated, e.g., by filtration, and theamount of bound drug is measured.Binding increases in proportion to concentrationas long as there is a negligiblereduction in the number of free bindingsites (c = 1 and B ≈ 10% of maximumbinding; c = 2 and B ≈ 20 %). As bindingapproaches saturation, the number offree sites decreases and the incrementin binding is no longer proportional tothe increase in concentration (in the exampleillustrated, an increase in concentrationby 1 is needed to increasebinding from 10 to 20 %; however, an increaseby 20 is needed to raise it from 70to 80 %).The law of mass action describesthe hyperbolic relationship betweenbinding (B) and ligand concentration (c).This relationship is characterized by thedrug’s affinity (1/K D) and the maximumbinding (B max), i.e., the total number ofbinding sites per unit of weight of membranehomogenate.cB = B max · –––––––c + K DK D is the equilibrium dissociation constantand corresponds to that ligandconcentration at which 50 % of bindingsites are occupied. The values given in(A) and used for plotting the concentration-bindinggraph (B) result when K D =10.The differing affinity of different ligandsfor a binding site can be demonstratedelegantly by binding assays. Althoughsimple to perform, these bindingassays pose the difficulty of correlatingunequivocally the binding sites concernedwith the pharmacological effect;this is particularly difficult when morethan one population of binding sites ispresent. Therefore, receptor bindingmust not be implied until it can beshown thatbinding is saturable (saturability);• the only substances bound are thosepossessing the same pharmacologicalmechanism of action (specificity);• binding affinity of different substancesis correlated with their pharmacologicalpotency.Binding assays provide <strong>info</strong>rmationabout the affinity of ligands, but they donot give any clue as to whether a ligandis an agonist or antagonist (p. 60). Use ofradiolabeled drugs bound to their receptorsmay be of help in purifying andanalyzing further the receptor protein.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Quantification of Drug Action 57OrgansAddition ofradiolabeleddrug indifferentconcentrationsHomogenizationMembranesuspensionMixing and incubationCentrifugationDeterminationof radioactivityc = 1 c = 2 c = 5B = 10% B = 20% B = 30%c = 10 c = 20 c = 40B = 50% B = 70% B = 80%A. Measurement of binding (B) as a function of concentration (c)% Binding (B)% Binding (B)100100806040208060402010 20 30 40 50Concentration (linear)B. Concentration-binding relationship110Concentration (logarithmic)100Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
58 Drug-Receptor InteractionTypes of Binding ForcesUnless a drug comes into contact withintrinsic structures of the body, it cannotaffect body function.Covalent bond. Two atoms enter acovalent bond if each donates an electronto a shared electron pair (cloud).This state is depicted in structural formulasby a dash. The covalent bond is“firm”, that is, not reversible or onlypoorly so. Few drugs are covalentlybound to biological structures. Thebond, and possibly the effect, persist fora long time after intake of a drug hasbeen discontinued, making therapy difficultto control. Examples include alkylatingcytostatics (p. 298) or organophosphates(p. 102). Conjugation reactionsoccurring in biotransformation alsorepresent a covalent linkage (e.g., toglucuronic acid, p. 38).Noncovalent bond. There is no formationof a shared electron pair. Thebond is reversible and typical of mostdrug-receptor interactions. Since a drugusually attaches to its site of action bymultiple contacts, several of the types ofbonds described below may participate.Electrostatic attraction (A). A positiveand negative charge attract eachother.Ionic interaction: An ion is a particlecharged either positively (cation) ornegatively (anion), i.e., the atom lacks orhas surplus electrons, respectively. Attractionbetween ions of oppositecharge is inversely proportional to thesquare of the distance between them; itis the initial force drawing a chargeddrug to its binding site. Ionic bonds havea relatively high stability.Dipole-ion interaction: When bondelectrons are asymmetrically distributedover both atomic nuclei, one atomwill bear a negative (δ – ), and its partnera positive (δ + ) partial charge. The moleculethus presents a positive and a negativepole, i.e., has polarity or a dipole. Apartial charge can interact electrostaticallywith an ion of opposite charge.Dipole-dipole interaction is the electrostaticattraction between oppositepartial charges. When a hydrogen atombearing a partial positive charge bridgestwo atoms bearing a partial negativecharge, a hydrogen bond is created.A van der Waals’ bond (B) isformed between apolar moleculargroups that have come into close proximity.Spontaneous transient distortionof electron clouds (momentary faint dipole,δδ) may induce an opposite dipolein the neighboring molecule. The vander Waals’ bond, therefore, is a form ofelectrostatic attraction, albeit of verylow strength (inversely proportional tothe seventh power of the distance).Hydrophobic interaction (C). Theattraction between the dipoles of wateris strong enough to hinder intercalationof any apolar (uncharged) molecules. Bytending towards each other, H 2O moleculessqueeze apolar particles fromtheir midst. Accordingly, in the organism,apolar particles have an increasedprobability of staying in nonaqueous,apolar surroundings, such as fatty acidchains of cell membranes or apolar regionsof a receptor.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug-Receptor Interaction 59Drug + Binding site Complex+δ –δδ –δ − apolarparticle in polar solvent (H 2 O)D+50nm–D–δ + δ ––1.5nmDD–IonIonIonic bondδ + δ – δ – δ + D0.5nmDδ – δ –Dipole (permanent) Ionδ +δ +D = DrugDipoleDipoleHydrogen bondA. Electrostatic attractionδδ +δδ + δδ –δδ – δδ +DD δδ – δδ +Inducedtransientfluctuating dipolesB. van der Waals’ bondδ +"Repulsion" of apolarpolarPhospholipid membraneApolaracyl chainInsertion in apolar membrane interiorAdsorption toapolar surfaceC. Hydrophobic interactionLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
60 Drug-Receptor InteractionAgonists – AntagonistsAn agonist has affinity (binding avidity)for its receptor and alters the receptorprotein in such a manner as to generatea stimulus that elicits a change in cellfunction: “intrinsic activity“. The biologicaleffect of the agonist, i.e., thechange in cell function, depends on theefficiency of signal transduction steps(p. 64, 66) initiated by the activated receptor.Some agonists attain a maximaleffect even when they occupy only asmall fraction of receptors (B, agonistA). Other ligands (agonist B), possessingequal affinity for the receptor but loweractivating capacity (lower intrinsic activity),are unable to produce a full maximalresponse even when all receptorsare occupied: lower efficacy. Ligand B isa partial agonist. The potency of an agonistcan be expressed in terms of theconcentration (EC 50) at which the effectreaches one-half of its respective maximum.Antagonists (A) attenuate the effectof agonists, that is, their action is“anti-agonistic”.Competitive antagonists possessaffinity for receptors, but binding to thereceptor does not lead to a change incell function (zero intrinsic activity).When an agonist and a competitiveantagonist are present simultaneously,affinity and concentration of the two rivalswill determine the relative amountof each that is bound. Thus, although theantagonist is present, increasing theconcentration of the agonist can restorethe full effect (C). However, in the presenceof the antagonist, the concentration-responsecurve of the agonist isshifted to higher concentrations (“rightwardshift”).Molecular Models of Agonist/AntagonistAction (A)Agonist induces active conformation.The agonist binds to the inactive receptorand thereby causes a change fromthe resting conformation to the activestate. The antagonist binds to the inac-Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.tive receptor without causing a conformationalchange.Agonist stabilizes spontaneouslyoccurring active conformation. Thereceptor can spontaneously “flip” intothe active conformation. However, thestatistical probability of this event isusually so small that the cells do not revealsigns of spontaneous receptor activation.Selective binding of the agonistrequires the receptor to be in the activeconformation, thus promoting its existence.The “antagonist” displays affinityonly for the inactive state and stabilizesthe latter. When the system shows minimalspontaneous activity, applicationof an antagonist will not produce a measurableeffect. When the system hashigh spontaneous activity, the antagonistmay cause an effect that is the oppositeof that of the agonist: inverse agonist.A “true” antagonist lacking intrinsicactivity (“neutral antagonist”) displaysequal affinity for both the active and inactivestates of the receptor and doesnot alter basal activity of the cell.According to this model, a partial agonistshows lower selectivity for the activestate and, to some extent, also bindsto the receptor in its inactive state.Other Forms of AntagonismAllosteric antagonism. The antagonistis bound outside the receptor agonistbinding site proper and induces a decreasein affinity of the agonist. It is alsopossible that the allosteric deformationof the receptor increases affinity for anagonist, resulting in an allosteric synergism.Functional antagonism. Two agonistsaffect the same parameter (e.g.,bronchial diameter) via different receptorsin the opposite direction (epinephrine dilation; histamine constriction).
Drug-Receptor Interaction 61AgonistAntagonistReceptorAntagonistRarespontaneoustransitionAgonistactiveEC 50inactiveEC 50Agonistinduces activeconformation ofreceptor proteinAntagonistoccupies receptorwithout conformationalchangeAntagonistselects inactivereceptorconformationAgonistselects activereceptorconformationA. Molecular mechanisms of drug-receptor interactionAgonist AReceptors Increase in tensionReceptor occupationEfficacyConcentration (log) of agonistsmoothmuscle cellAgonist BPotencyB. Potency and Efficacy of agonistsAgonist effect0 1 10 100 100010000ConcentrationofantagonistC. Competitive antagonismAgonist concentration (log)Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
62 Drug-Receptor InteractionEnantioselectivity of Drug ActionMany drugs are racemates, including β-blockers, nonsteroidal anti-inflammatoryagents, and anticholinergics (e.g.,benzetimide A). A racemate consists ofa molecule and its corresponding mirrorimage which, like the left and righthand, cannot be superimposed. Suchchiral (“handed”) pairs of molecules arereferred to as enantiomers. Usually,chirality is due to a carbon atom (C)linked to four different substituents(“asymmetric center”). Enantiomerism isa special case of stereoisomerism. Nonchiralstereoisomers are called diastereomers(e.g., quinidine/quinine).Bond lengths in enantiomers, butnot in diastereomers, are the same.Therefore, enantiomers possess similarphysicochemical properties (e.g., solubility,melting point) and both forms areusually obtained in equal amounts bychemical synthesis. As a result of enzymaticactivity, however, only one of theenantiomers is usually found in nature.In solution, enantiomers rotate thewave plane of linearly polarized lightin opposite directions; hence they arerefered to as “dextro”- or “levo-rotatory”,designated by the prefixes d or (+) and lor (-), respectively. The direction of rotationgives no clue concerning the spatialstructure of enantiomers. The absoluteconfiguration, as determined bycertain rules, is described by the prefixesS and R. In some compounds, designationas the D- and L-form is possibleby reference to the structure of D- andL-glyceraldehyde.For drugs to exert biological actions,contact with reaction partners inthe body is required. When the reactionfavors one of the enantiomers, enantioselectivityis observed.Enantioselectivity of affinity. If areceptor has sites for three of the substituents(symbolized in B by a cone, asphere, and a cube) on the asymmetriccarbon to attach to, only one of theenantiomers will have optimal fit. Its affinitywill then be higher. Thus, dexetimidedisplays an affinity at the muscarinicACh receptors almost 10000 times(p. 98) that of levetimide; and at β-adrenoceptors, S(-)-propranolol has anaffinity 100 times that of the R(+)-form.Enantioselectivity of intrinsic activity.The mode of attachment at thereceptor also determines whether an effectis elicited and whether or not a substancehas intrinsic activity, i.e., acts asan agonist or antagonist. For instance,(-) dobutamine is an agonist at α-adrenoceptorswhereas the (+)-enantiomer isan antagonist.Inverse enantioselectivity at anotherreceptor. An enantiomer maypossess an unfavorable configuration atone receptor that may, however, be optimalfor interaction with another receptor.In the case of dobutamine, the(+)-enantiomer has affinity at β-adrenoceptors10 times higher than that of the(-)-enantiomer, both having agonist activity.However, the α-adrenoceptorstimulant action is due to the (-)-form(see above).As described for receptor interactions,enantioselectivity may also bemanifested in drug interactions withenzymes and transport proteins. Enantiomersmay display different affinitiesand reaction velocities.Conclusion: The enantiomers of aracemate can differ sufficiently in theirpharmacodynamic and pharmacokineticproperties to constitute two distinctdrugs.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug-Receptor Interaction 63RACEMATEBenzetimideENANTIOMERDexetimideRatio1 : 1ENANTIOMERLevetimidePhysicochemical propertiesequal+ 125°(Dextrorotatory)Deflection of polarized light[α] 20D- 125°(LevorotatoryS = sinisterAbsolute configurationR = rectusca. 10 000Potency1(rel. affinity at m-ACh-receptorsA. Example of an enantiomeric pair with different affinity forA. a stereoselective receptorCCTransport proteinAffinityTransport proteinPharmacodynamicpropertiesIntrinsicactivityTurnoverratePharmacokineticpropertiesB. Reasons for different pharmacological properties of enantiomersLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
64 Drug-Receptor InteractionReceptor TypesReceptors are macromolecules that bindmediator substances and transduce thisbinding into an effect, i.e., a change incell function. Receptors differ in termsof their structure and the manner inwhich they translate occupancy by a ligandinto a cellular response (signaltransduction).G-protein-coupled receptors (A)consist of an amino acid chain thatweaves in and out of the membrane inserpentine fashion. The extramembranalloop regions of the molecule maypossess sugar residues at different N-glycosylation sites. The seven α-helicalmembrane-spanning domains probablyform a circle around a central pocketthat carries the attachment sites for themediator substance. Binding of the mediatormolecule or of a structurally relatedagonist molecule induces a changein the conformation of the receptor protein,enabling the latter to interact witha G-protein (= guanyl nucleotide-bindingprotein). G-proteins lie at the innerleaf of the plasmalemma and consist ofthree 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, leading in turn to activationof another protein (enzyme, ion channel).A large number of mediator substancesact via G-protein-coupled receptors(see p. 66 for more details).An example of a ligand-gated ionchannel (B) is the nicotinic cholinoceptorof the motor endplate. The receptorcomplex consists of five subunits, eachof which contains four transmembranedomains. Simultaneous binding of twoacetylcholine (ACh) molecules to thetwo α-subunits results in opening of theion channel, with entry of Na + (and exitof some K + ), membrane depolarization,and triggering of an action potential (p.82). The ganglionic N-cholinoceptorsapparently consist only of α and β subunits(α 2β 2). Some of the receptors forthe transmitter γ-aminobutyric acid(GABA) belong to this receptor family:the GABA A subtype is linked to a chloridechannel (and also to a benzodiazepine-bindingsite, see p. 227). Glutamateand glycine both act via ligandgatedion channels.The insulin receptor protein representsa ligand-operated enzyme (C), acatalytic receptor. When insulin bindsto the extracellular attachment site, atyrosine kinase activity is “switched on”at the intracellular portion. Proteinphosphorylation leads to altered cellfunction via the assembly of other signalproteins. Receptors for growth hormonesalso belong to the catalytic receptorclass.Protein synthesis-regulating receptors(D) for steroids, thyroid hormone,and retinoic acid are found in thecytosol and in the cell nucleus, respectively.Binding of hormone exposes a normallyhidden domain of the receptorprotein, thereby permitting the latter tobind to a particular nucleotide sequenceon a gene and to regulate its transcription.Transcription is usually initiated orenhanced, rarely blocked.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug-Receptor Interaction 65Amino acids-NH 2AgonistH 2 N3 4 5 6 7COOHα-HelicesTransmembrane domains34576COOHG-ProteinEffector proteinEffectA. G-Protein-coupled receptorAChNa +γ δα αβK +Na + K +AChNicotinicacetylcholinereceptorSubunitconsisting offour transmembranedomainsInsulinSSS S S SPhosphorylation oftyrosine-residues in proteinsTyrosine kinaseB. Ligand-gated ion channel C. Ligand-regulated enzymeCytosolNucleusSteroidHormoneTranscriptionTranslationProteinDNAmRNAReceptorD. Protein synthesis-regulating receptorLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
66 Drug-Receptor InteractionMode of Operation of G-Protein-Coupled ReceptorsSignal transduction at G-protein-coupledreceptors uses essentially the samebasic mechanisms (A). Agonist bindingto the receptor leads to a change in receptorprotein conformation. Thischange propagates to the G-protein: theα-subunit exchanges GDP for GTP, thendissociates from the two other subunits,associates with an effector protein, andalters its functional state. The α-subunitslowly hydrolyzes bound GTP to GDP.G α-GDP has no affinity for the effectorprotein and reassociates with the β andγ subunits (A). G-proteins can undergolateral diffusion in the membrane; theyare not assigned to individual receptorproteins. However, a relation existsbetween receptor types and G-proteintypes (B). Furthermore, the α-subunitsof individual G-proteins are distinct interms of their affinity for different effectorproteins, as well as the kind of influenceexerted on the effector protein. G α-GTP of the G S-protein stimulates adenylatecyclase, whereas G α-GTP of the G i-protein is inhibitory. The G-proteincoupledreceptor family includes muscariniccholinoceptors, adrenoceptorsfor norepinephrine and epinephrine, receptorsfor dopamine, histamine, serotonin,glutamate, GABA, morphine, prostaglandins,leukotrienes, and many othermediators and hormones.Major effector proteins for G-protein-coupledreceptors include adenylatecyclase (ATP intracellular messengercAMP), phospholipase C (phosphatidylinositol intracellular messengersinositol trisphosphate and diacylglycerol),as well as ion channelproteins. Numerous cell functions areregulated by cellular cAMP concentration,because cAMP enhances activity ofprotein kinase A, which catalyzes thetransfer of phosphate groups onto functionalproteins. Elevation of cAMP levelsinter alia leads to relaxation of smoothmuscle tonus and enhanced contractilityof cardiac muscle, as well as increasedglycogenolysis and lipolysis (p.84). Phosphorylation of cardiac calcium-channelproteins increases theprobability of channel opening duringmembrane depolarization. It should benoted that cAMP is inactivated by phosphodiesterase.Inhibitors of this enzymeelevate intracellular cAMP concentrationand elicit effects resembling thoseof epinephrine.The receptor protein itself mayundergo phosphorylation, with a resultantloss of its ability to activate the associatedG-protein. This is one of themechanisms that contributes to a decreasein sensitivity of a cell during prolongedreceptor stimulation by an agonist(desensitization).Activation of phospholipase C leadsto cleavage of the membrane phospholipidphosphatidylinositol-4,5 bisphosphateinto inositol trisphosphate (IP 3)and diacylglycerol (DAG). IP 3 promotesrelease of Ca 2+ from storage organelles,whereby contraction of smooth musclecells, breakdown of glycogen, or exocytosismay be initiated. Diacylglycerolstimulates protein kinase C, whichphosphorylates certain serine- or threonine-containingenzymes.The α-subunit of some G-proteinsmay induce opening of a channel protein.In this manner, K + channels can beactivated (e.g., ACh effect on sinus node,p. 100; opioid action on neural impulsetransmission, p. 210).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug-Receptor Interaction 67Receptor G-Protein EffectorproteinAgonistβγ αβγβγαGDPGTPαβγαA. G-Protein-mediated effect of an agonistG s + - G iATPAdenylate cyclasecAMPProtein kinase APhosphorylation offunctional proteinse. g., GlycogenolysislipolysisCa-channelactivationCa 2+Phospholipase CIP 3PPDAGPProteinkinase CActivationPhosphorylationof enzymese. g., Contractionof smooth muscle,glandularsecretionFacilitationof ionchannelopeningTransmembraneion movementsEffect on:e. g., Membraneaction potential,homeostasis ofcellular ionsB. G-Proteins, cellular messenger substances, and effectsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
68 Drug-Receptor InteractionTime Course of Plasma Concentrationand EffectAfter the administration of a drug, itsconcentration in plasma rises, reaches apeak, and then declines gradually to thestarting level, due to the processes ofdistribution and elimination (p. 46).Plasma concentration at a given point intime depends on the dose administered.Many drugs exhibit a linear relationshipbetween plasma concentration anddose within the therapeutic range(dose-linear kinetics; (A); note differentscales on ordinate). However, thesame does not apply to drugs whoseelimination processes are already sufficientlyactivated at therapeutic plasmalevels so as to preclude further proportionalincreases in the rate of eliminationwhen the concentration is increasedfurther. Under these conditions,a smaller proportion of the dose administeredis eliminated per unit of time.The time course of the effect and ofthe concentration in plasma are notidentical, because the concentrationeffectrelationships obeys a hyperbolicfunction (B; cf. also p. 54). This meansthat the time course of the effect exhibitsdose dependence also in the presenceof dose-linear kinetics (C).In the lower dose range (example1), the plasma level passes through aconcentration range (0 0.9) in whichthe concentration effect relationship isquasi-linear. The respective time coursesof plasma concentration and effect (Aand C, left graphs) are very similar.However, if a high dose (100) is applied,there is an extended period of time duringwhich the plasma level will remainin a concentration range (between 90and 20) in which a change in concentrationdoes not cause a change in the sizeof the effect. Thus, at high doses (100),the time-effect curve exhibits a kind ofplateau. The effect declines only whenthe plasma level has returned (below20) into the range where a change inplasma level causes a change in the intensityof the effect.The dose dependence of the timecourse of the drug effect is exploitedwhen the duration of the effect is to beprolonged by administration of a dosein excess of that required for the effect.This is done in the case of penicillin G(p. 268), when a dosing interval of 8 h isbeing recommended, although the drugis eliminated with a half-life of 30 min.This procedure is, of course, feasible onlyif supramaximal dosing is not associatedwith toxic effects.Futhermore it follows that a nearlyconstant effect can be achieved, althoughthe plasma level may fluctuategreatly during the interval betweendoses.The hyperbolic relationship between plasma concentration and effectexplains why the time course of the effect,unlike that of the plasma concentration,cannot be described in terms ofa simple exponential function. A halflifecan be given for the processes ofdrug absorption and elimination, hencefor the change in plasma levels, but generallynot for the onset or decline ofthe effect.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug-Receptor Interaction 691,0Concentration10Concentration100Concentration0,5t 1 25t 1 250t 1 20,1110Dose = 1TimeDose = 10TimeDose = 100TimeA. Dose-linear kinetics100Effect500Concentration110 20 30 40 50 60 70 80 90 100B. Concentration-effect relationship100Effect100Effect100Effect505050101010Dose = 1TimeDose = 10TimeDose = 100TimeC. Dose dependence of the time course of effectLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
70 Adverse Drug EffectsAdverse Drug EffectsThe desired (or intended) principal effectof any drug is to modify body functionin such a manner as to alleviatesymptoms caused by the patient’s illness.In addition, a drug may also causeunwanted effects that can be groupedinto minor or “side” effects and major oradverse effects. These, in turn, may giverise to complaints or illness, or mayeven cause death.Causes of adverse effects: overdosage(A). The drug is administered ina higher dose than is required for theprincipal effect; this directly or indirectlyaffects other body functions. For instances,morphine (p. 210), given in theappropriate dose, affords excellent painrelief by influencing nociceptive pathwaysin the CNS. In excessive doses, itinhibits the respiratory center andmakes apnea imminent. The dose dependenceof both effects can be graphedin the form of dose-response curves(DRC). The distance between both DRCsindicates the difference between thetherapeutic and toxic doses. This marginof safety indicates the risk of toxicitywhen standard doses are exceeded.“The dose alone makes the poison”(Paracelsus). This holds true for bothmedicines and environmental poisons.No substance as such is toxic! In order toassess the risk of toxicity, knowledge isrequired of: 1) the effective dose duringexposure; 2) the dose level at whichdamage is likely to occur; 3) the durationof exposure.Increased Sensitivity (B). If certainbody functions develop hyperreactivity,unwanted effects can occur even at normaldose levels. Increased sensitivity ofthe respiratory center to morphine isfound in patients with chronic lung disease,in neonates, or during concurrentexposure to other respiratory depressantagents. The DRC is shifted to the leftand a smaller dose of morphine is sufficientto paralyze respiration. Geneticanomalies of metabolism may also leadto hypersensitivity. Thus, several drugs(aspirin, antimalarials, etc.) can provokepremature breakdown of red blood cells(hemolysis) in subjects with a glucose-6-phosphate dehydrogenase deficiency.The discipline of pharmacogenetics dealswith the importance of the genotype forreactions to drugs.The above forms of hypersensitivitymust be distinguished from allergies involvingthe immune system (p. 72).Lack of selectivity (C). Despite appropriatedosing and normal sensitivity,undesired effects can occur because thedrug does not specifically act on the targeted(diseased) tissue or organ. For instance,the anticholinergic, atropine, isbound only to acetylcholine receptors ofthe muscarinic type; however, these arepresent in many different organs.Moreover, the neuroleptic, chlorpromazine,formerly used as a neuroleptic,is able to interact with severaldifferent receptor types. Thus, its actionis neither organ-specific nor receptorspecific.The consequences of lack of selectivitycan often be avoided if the drugdoes not require the blood route toreach the target organ, but is, instead,applied locally, as in the administrationof parasympatholytics in the form of eyedrops or in an aerosol for inhalation.With every drug use, unwanted effectsmust be taken into account. Beforeprescribing a drug, the physician shouldtherefore assess the risk: benefit ratio.In this, knowledge of principal and adverseeffects is a prerequisite.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Adverse Drug Effects 71Decrease inpain perception(nociception)MorphineRespiratory depressionMorphineoverdoseDoseA. Adverse drug effect: overdosingIncreasedsensitivity ofrespiratorycenterEffectSafetymarginNormaldoseDoseB. Adverse drug effect: increased sensitivityAtropinee. g., ChlorpromazinemAChreceptorReceptorspecificitybut lacking organselectivityEffectDecrease inNociception RespiratoryactivitySafetymarginmAChreceptorα-adrenoceptorAtropineDopaminereceptorHistaminereceptorLackingreceptorspecificityC. Adverse drug effect: lacking selectivityLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
72 Adverse Drug EffectsDrug AllergyThe immune system normally functionsto rid the organism of invading foreignparticles, such as bacteria. Immune responsescan occur without appropriatecause or with exaggerated intensity andmay harm the organism, for instance,when allergic reactions are caused bydrugs (active ingredient or pharmaceuticalexcipients). Only a few drugs, e.g.(heterologous) proteins, have a molecularmass (> 10,000) large enough to actas effective antigens or immunogens,capable by themselves of initiating animmune response. Most drugs or theirmetabolites (so-called haptens) mustfirst be converted to an antigen by linkageto a body protein. In the case of penicillinG, a cleavage product (penicilloylresidue) probably undergoes covalentbinding to protein. During initial contactwith the drug, the immune systemis sensitized: antigen-specific lymphocytesof the T-type and B-type (antibodyformation) proliferate in lymphatic tissueand some of them remain as socalledmemory cells. Usually, these processesremain clinically silent. Duringthe second contact, antibodies are alreadypresent and memory cells proliferaterapidly. A detectable immune response,the allergic reaction, occurs.This can be of severe intensity, even at alow dose of the antigen. Four types ofreactions can be distinguished:Type 1, anaphylactic reaction.Drug-specific antibodies of the IgE typecombine via their F c moiety with receptorson the surface of mast cells. Bindingof the drug provides the stimulus for therelease of histamine and other mediators.In the most severe form, a lifethreateninganaphylactic shock develops,accompanied by hypotension,bronchospasm (asthma attack), laryngealedema, urticaria, stimulation of gutmusculature, and spontaneous bowelmovements (p. 326).Type 2, cytotoxic reaction. Drugantibody(IgG) complexes adhere to thesurface of blood cells, where either circulatingdrug molecules or complexes alreadyformed in blood accumulate.These complexes mediate the activationof complement, a family of proteins thatcirculate in the blood in an inactiveform, but can be activated in a cascadelikesuccession by an appropriate stimulus.“Activated complement” normallydirected against microorganisms, candestroy the cell membranes and therebycause cell death; it also promotes phagocytosis,attracts neutrophil granulocytes(chemotaxis), and stimulates otherinflammatory responses. Activationof complement on blood cells results intheir destruction, evidenced by hemolyticanemia, agranulocytosis, andthrombocytopenia.Type 3, immune complex vasculitis(serum sickness, Arthus reaction).Drug-antibody complexes precipitate onvascular walls, complement is activated,and an inflammatory reaction is triggered.Attracted neutrophils, in a futileattempt to phagocytose the complexes,liberate lysosomal enzymes that damagethe vascular walls (inflammation,vasculitis). Symptoms may include fever,exanthema, swelling of lymphnodes, arthritis, nephritis, and neuropathy.Type 4, contact dermatitis. A cutaneouslyapplied drug is bound to thesurface of T-lymphocytes directed specificallyagainst it. The lymphocytes releasesignal molecules (lymphokines)into their vicinity that activate macrophagesand provoke an inflammatoryreaction.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Adverse Drug Effects 73Reaction of immune system to first drug exposureProteinDrug(= hapten)Immune system(^ = lymphatictissue)recognizes:"Non-self"Production ofantibodies(Immunoglobulins)e.g. IgEIgG etc.Proliferation ofantigen-specificlymphocytesMacromoleculeMW > 10 000AntigenDistributionin 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 reactionMembraneinjuryDeposition onvessel wallType 3 reaction:Immune complexFormation ofimmune complexesActivationof:complementandneutrophilsInflammatoryreactionContactdermatitisInflammatoryreactionLymphokinesCelldestructionAntigenspecificT-lymphocyteType 4 reaction:lymphocytic delayed reactionA. Adverse drug effect: allergic reactionLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
74 Adverse Drug EffectsDrug Toxicity in Pregnancy andLactationDrugs taken by the mother can bepassed on transplacentally or via breastmilk and adversely affect the unborn orthe neonate.Pregnancy (A)Limb malformations induced by thehypnotic, thalidomide, first focused attentionon the potential of drugs tocause malformations (teratogenicity).Drug effects on the unborn fall into twobasic categories:1. Predictable effects that derive fromthe known pharmacological drugproperties. Examples are: masculinizationof the female fetus by androgenichormones; brain hemorrhagedue to oral anticoagulants; bradycardiadue to β-blockers.2. Effects that specifically affect the developingorganism and that cannotbe predicted on the basis of theknown pharmacological activity profile.In assessing the risks attendingdrug use during pregnancy, the followingpoints have to be considered:a) Time of drug use. The possible sequelaeof exposure to a drug depend onthe stage of fetal development, asshown in A. Thus, the hazard posedby a drug with a specific action is limitedin time, as illustrated by the tetracyclines,which produce effects onteeth and bones only after the thirdmonth of gestation, when mineralizationbegins.b) Transplacental passage. Most drugscan pass in the placenta from the maternalinto the fetal circulation. Thefused cells of the syncytiotrophoblastform the major diffusion barrier.They possess a higher permeability todrugs than is suggested by the term“placental barrier”.c) Teratogenicity. Statistical risk estimatesare available for familiar, frequentlyused drugs. For many drugs,teratogenic potency cannot be demonstrated;however, in the case ofnovel drugs it is usually not yet possibleto define their teratogenic hazard.Drugs with established human teratogenicityinclude derivatives of vitaminA (etretinate, isotretinoin [usedinternally in skin diseases]), and oralanticoagulants. A peculiar type of damageresults from the synthetic estrogenicagent, diethylstilbestrol, following itsuse during pregnancy; daughters oftreated mothers have an increased incidenceof cervical and vaginal carcinomaat the age of approx. 20.In assessing the risk: benefit ratio, it isalso necessary to consider the benefitfor the child resulting from adequatetherapeutic treatment of its mother. Forinstance, therapy with antiepilepticdrugs is indispensable, because untreatedepilepsy endangers the infant at leastas much as does administration of anticonvulsants.Lactation (B)Drugs present in the maternal organismcan be secreted in breast milk and thusbe ingested by the infant. Evaluation ofrisk should be based on factors listed inB. In case of doubt, potential danger tothe infant can be averted only by weaning.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Adverse Drug Effects 75Ovum1 daySperm cells ~3 daysEndometriumBlastocystAge of fetus(weeks)Developmentstage1 2 1 212NidationEmbryo: organdevelopmentFetus: growthandmaturation38Fetal deathMalformationFunctional disturbancesArteryUterus wallVeinSequelaeofdamageby drugTransferofmetabolitesCapillarySyncytiotrophoblastPlacentalbarrierFetus MotherPlacental transfer of metabolitesTo umbilical cordA. Pregnancy: fetal damage due to drugsDrugTherapeuticeffect inmother?Unwantedeffectin childExtent oftransfer ofdrug intomilkInfant doseDrug concentrationin infant´s bloodSensitivity ofsite of actionDistributionof drugin infantRate ofeliminationof drugfrom infantEffectB. Lactation: maternal intake of drugLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
76 Drug-independent EffectsPlacebo (A)A placebo is a dosage form devoid of anactive ingredient, a dummy medication.Administration of a placebo may elicitthe desired effect (relief of symptoms)or undesired effects that reflect achange in the patient’s psychologicalsituation brought about by the therapeuticsetting.Physicians may consciously or unconsciouslycommunicate to the patientwhether or not they are concernedabout the patient’s problem, or certainabout the diagnosis and about the valueof prescribed therapeutic measures. Inthe care of a physician who projectspersonal warmth, competence, and confidence,the patient in turn feels comfortableand less anxious and optimisticallyanticipates recovery.The physical condition determinesthe psychic disposition and vice versa.Consider gravely wounded combatantsin war, oblivious to their injuries whilefighting to survive, only to experiencesevere pain in the safety of the field hospital,or the patient with a peptic ulcercaused by emotional stress.Clinical trials. In the individualcase, it may be impossible to decidewhether therapeutic success is attributableto the drug or to the therapeuticsituation. What is therefore required is acomparison of the effects of a drug andof a placebo in matched groups of patientsby means of statistical procedures,i.e., a placebo-controlled trial. Aprospective trial is planned in advance, aretrospective (case-control) study followspatients backwards in time. Patientsare randomly allotted to twogroups, namely, the placebo and the activeor test drug group. In a double-blindtrial, neither the patients nor the treatingphysicians know which patient isgiven drug and which placebo. Finally, aswitch from drug to placebo and viceversa can be made in a successive phaseof treatment, the cross-over trial. In thisfashion, drug vs. placebo comparisonscan be made not only between two patientgroups, but also within eithergroup itself.Homeopathy (B) is an alternativemethod of therapy, developed in the1800s by Samuel Hahnemann. His ideawas this: when given in normal (allopathic)dosage, a drug (in the sense ofmedicament) will produce a constellationof symptoms; however, in a patientwhose disease symptoms resemble justthis mosaic of symptoms, the same drug(simile principle) would effect a curewhen given in a very low dosage (“potentiation”).The body’s self-healingpowers were to be properly activatedonly by minimal doses of the medicinalsubstance.The homeopath’s task is not to diagnosethe causes of morbidity, but tofind the drug with a “symptom profile”most closely resembling that of thepatient’s illness. This drug is then appliedin very high dilution.A direct action or effect on bodyfunctions cannot be demonstrated forhomeopathic medicines. Therapeuticsuccess is due to the suggestive powersof the homeopath and the expectancy ofthe patient. When an illness is stronglyinfluenced by emotional (psychic) factorsand cannot be treated well by allopathicmeans, a case can be made in favorof exploiting suggestion as a therapeutictool. Homeopathy is one of severalpossible methods of doing so.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug-independent Effects 77Consciousandunconscioussignals:language,facial expression,gesturesConsciousandunconsciousexpectationsWell-beingcomplaintsMindPlaceboEffect:- wanted- unwantedBodyPhysicianPatientA. Therapeutic effects resulting from physician´s power of suggestion“Similia similibus curentur”“Drug”Normal, allopathic dosesymptom profileDilution“effect reversal”Very low homeopathic doseelimination of diseasesymptoms correspondingto allopathic symptom“profile”“Potentiation”increase in efficacywith progressive dilutionHomeopathPatientProfile of disease symptomsSymptom“profile”“Drug diagnosis”StocksolutionHomeopathicremedy (“Simile”)Dilution1 1 1 1 1 1 1 1 1 10 10 10 10 10 10 10 10 10D91 1000 000 000B. Homeopathy: concepts and procedureLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Systems <strong>Pharmacology</strong>Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
80 Drugs Acting on the Sympathetic Nervous SystemSympathetic Nervous SystemIn the course of phylogeny an efficientcontrol system evolved that enabled thefunctions of individual organs to be orchestratedin increasingly complex lifeforms and permitted rapid adaptationto changing environmental conditions.This regulatory system consists of theCNS (brain plus spinal cord) and twoseparate pathways for two-way communicationwith peripheral organs, viz.,the somatic and the autonomic nervoussystems. The somatic nervous systemcomprising extero- and interoceptiveafferents, special sense organs, and motorefferents, serves to perceive externalstates and to target appropriate bodymovement (sensory perception: threat response: flight or attack). The autonomic(vegetative) nervous system(ANS), together with the endocrinesystem, controls the milieu interieur. Itadjusts internal organ functions to thechanging needs of the organism. Neuralcontrol permits very quick adaptation,whereas the endocrine system providesfor a long-term regulation of functionalstates. The ANS operates largely beyondvoluntary control; it functions autonomously.Its central components residein the hypothalamus, brain stem, andspinal cord. The ANS also participates inthe regulation of endocrine functions.The ANS has sympathetic andparasympathetic branches. Both aremade up of centrifugal (efferent) andcentripetal (afferent) nerves. In manyorgans innervated by both branches, respectiveactivation of the sympatheticand parasympathetic input evokes opposingresponses.In various disease states (organmalfunctions), drugs are employed withthe intention of normalizing susceptibleorgan functions. To understand the biologicaleffects of substances capable ofinhibiting or exciting sympathetic orparasympathetic nerves, one must firstenvisage the functions subserved by thesympathetic and parasympathetic divisions(A, Responses to sympathetic activation).In simplistic terms, activationof the sympathetic division can be considereda means by which the bodyachieves a state of maximal work capacityas required in fight or flight situations.In both cases, there is a need forvigorous activity of skeletal musculature.To ensure adequate supply of oxygenand nutrients, blood flow in skeletalmuscle is increased; cardiac rate andcontractility are enhanced, resulting in alarger blood volume being pumped intothe circulation. Narrowing of splanchnicblood vessels diverts blood into vascularbeds in muscle.Because digestion of food in the intestinaltract is dispensable and onlycounterproductive, the propulsion of intestinalcontents is slowed to the extentthat peristalsis diminishes and sphincterictonus increases. However, in orderto increase nutrient supply to heart andmusculature, glucose from the liver andfree fatty acid from adipose tissue mustbe released into the blood. The bronchiare dilated, enabling tidal volume andalveolar oxygen uptake to be increased.Sweat glands are also innervated bysympathetic fibers (wet palms due toexcitement); however, these are exceptionalas regards their neurotransmitter(ACh, p. 106).Although the life styles of modernhumans are different from those ofhominid ancestors, biological functionshave remained the same.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on the Sympathetic Nervous System 81CNS:drivealertnessEyes:pupillary dilationSaliva:little, viscousBronchi:dilationSkin:perspiration(cholinergic)Heart:rateforceblood pressureFat tissue:lipolysisfatty acidliberationLiver:glycogenolysisglucose releaseBladder:Sphinctertonedetrusor muscleGI-tract:peristalsissphincter toneblood flowSkeletal muscle:blood flowglycogenolysisA. Responses to sympathetic activationLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
82 Drugs Acting on the Sympathetic Nervous SystemStructure of the Sympathetic NervousSystemThe sympathetic preganglionic neurons(first neurons) project from the intermediolateralcolumn of the spinal graymatter to the paired paravertebral ganglionicchain lying alongside the vertebralcolumn and to unpaired prevertebralganglia. These ganglia representsites of synaptic contact between preganglionicaxons (1 st neurons) andnerve cells (2 nd neurons or sympathocytes)that emit postganglionic axonsterminating on cells in various end organs.In addition, there are preganglionicneurons that project either to peripheralganglia in end organs or to the adrenalmedulla.Sympathetic Transmitter SubstancesWhereas acetylcholine (see p. 98)serves as the chemical transmitter atganglionic synapses between first andsecond neurons, norepinephrine(= noradrenaline) is the mediator atsynapses of the second neuron (B). Thissecond neuron does not synapse withonly a single cell in the effector organ;rather, it branches out, each branchmaking en passant contacts with severalcells. At these junctions the nerve axonsform enlargements (varicosities) resemblingbeads on a string. Thus, excitationof the neuron leads to activation ofa larger aggregate of effector cells, althoughthe action of released norepinephrinemay be confined to the regionof each junction. Excitation of preganglionicneurons innervating the adrenalmedulla causes a liberation of acetylcholine.This, in turn, elicits a secretionof epinephrine (= adrenaline) into theblood, by which it is distributed to bodytissues as a hormone (A).converted via two intermediate steps todopamine, which is taken up into thevesicles and there converted to norepinephrineby dopamine-β-hydroxylase.When stimulated electrically, the sympatheticnerve discharges the contentsof part of its vesicles, including norepinephrine,into the extracellular space.Liberated norepinephrine reacts withadrenoceptors located postjunctionallyon the membrane of effector cells orprejunctionally on the membrane ofvaricosities. Activation of presynapticα 2-receptors inhibits norepinephrinerelease. By this negative feedback, releasecan be regulated.The effect of released norepinephrinewanes quickly, because approx.90 % is actively transported back intothe axoplasm, then into storage vesicles(neuronal re-uptake). Small portions ofnorepinephrine are inactivated by theenzyme catechol-O-methyltransferase(COMT, present in the cytoplasm ofpostjunctional cells, to yield normetanephrine),and monoamine oxidase(MAO, present in mitochondria of nervecells and postjunctional cells, to yield3,4-dihydroxymandelic acid).The liver is richly endowed withCOMT and MAO; it therefore contributessignificantly to the degradation ofcirculating norepinephrine and epinephrine.The end product of the combinedactions of MAO and COMT is vanillylmandelicacid.Adrenergic SynapseWithin the varicosities, norepinephrineis stored in small membrane-enclosedvesicles (granules, 0.05 to 0.2 µm in diameter).In the axoplasm, L-tyrosine isLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on the Sympathetic Nervous System 83Psychicstressor physicalstressFirst neuronFirst neuronAdrenalmedullaSecondneuronEpinephrineNorepinephrineA. Epinephrine as hormone, norepinephrine as transmitterReceptorsPresynapticα 2 -receptors3.4-DihydroxymandelicacidMAOReceptorsβ 2β 1αNorepinephrineCOMTNormetanephrineB. Second neuron of sympathetic system, varicosity, norepinephrine releaseLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
84 Drugs Acting on the Sympathetic Nervous SystemAdrenoceptor Subtypes andCatecholamine ActionsAdrenoceptors fall into three majorgroups, designated α 1, α 2, and β, withineach of which further subtypes can bedistinguished pharmacologically. Thedifferent adrenoceptors are differentiallydistributed according to region andtissue. Agonists at adrenoceptors (directsympathomimetics) mimic the actionsof the naturally occurring catecholamines,norepinephrine and epinephrine,and are used for various therapeuticeffects.Smooth muscle effects. The opposingeffects on smooth muscle (A) ofα-and β-adrenoceptor activation aredue to differences in signal transduction(p. 66). This is exemplified by vascularsmooth muscle (A). α 1-Receptor stimulationleads to intracellular release ofCa 2+ via activation of the inositol trisphosphate(IP 3) pathway. In concertwith the protein calmodulin, Ca 2+ canactivate myosin kinase, leading to a risein tonus via phosphorylation of the contractileprotein myosin. cAMP inhibitsactivation of myosin kinase. Via the formereffector pathway, stimulation of α-receptors results in vasoconstriction;via the latter, β 2-receptors mediate vasodilation,particularly in skeletal muscle— an effect that has little therapeuticuse.Vasoconstriction. Local application ofα-sympathomimetics can be employedin infiltration anesthesia (p. 204) or fornasal decongestion (naphazoline, tetrahydrozoline,xylometazoline; pp. 90,324). Systemically administered epinephrineis important in the treatmentof anaphylactic shock for combating hypotension.Bronchodilation. β 2-Adrenoceptor-mediatedbronchodilation (e.g., withterbutaline, fenoterol, or salbutamol)plays an essential part in the treatmentof bronchial asthma (p. 328).Tocolysis. The uterine relaxant effectof β 2-adrenoceptor agonists, such asterbutaline or fenoterol, can be used toprevent premature labor. Vasodilationwith a resultant drop in systemic bloodpressure results in reflex tachycardia,which is also due in part to the β 1-stimulantaction of these drugs.Cardiostimulation. By stimulatingβ 1-receptors, hence activation of adenylatcyclase(Ad-cyclase) and cAMPproduction, catecholamines augment allheart functions, including systolic force(positive inotropism), velocity of shortening(p. clinotropism), sinoatrial rate(p. chronotropism), conduction velocity(p. dromotropism), and excitability (p.bathmotropism). In pacemaker fibers,diastolic depolarization is hastened, sothat the firing threshold for the actionpotential is reached sooner (positivechronotropic effect, B). The cardiostimulanteffect of β-sympathomimeticssuch as epinephrine is exploited in thetreatment of cardiac arrest. Use of β-sympathomimetics in heart failure carriesthe risk of cardiac arrhythmias.Metabolic effects. β-Receptors mediateincreased conversion of glycogen toglucose (glycogenolysis) in both liverand skeletal muscle. From the liver, glucoseis released into the blood, In adiposetissue, triglycerides are hydrolyzedto fatty acids (lipolysis, mediated by β 3-receptors), which then enter the blood(C). The metabolic effects of catecholaminesare not amenable to therapeuticuse.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on the Sympathetic Nervous System 85α 1G iPhospholipase CIP 3β 2CalmodulinG sCa 2+Ad-cyclaseα 2G icAMP+ -Ad-cyclaseMyosinkinaseMyosinMyosin-PA. Vasomotor effects of catecholaminesβ 1G sAd-cyclaseβG sAd-cyclasecAMP+cAMP+Force (mN)TimeMembrane potential (mV)GlycogenolysisGlucoseGlycogenolysisLipolysisFatty acidsGlucoseTimeB. Cardiac effects of catecholaminesC. Metabolic effects of catecholaminesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
86 Drugs Acting on the Sympathetic Nervous SystemStructure – Activity Relationships ofSympathomimeticsDue to its equally high affinity for all α-and β-receptors, epinephrine does notpermit selective activation of a particularreceptor subtype. Like most catecholamines,it is also unsuitable for oraladministration (catechol is a trivialname for o-hydroxyphenol). Norepinephrinediffers from epinephrine by itshigh affinity for α-receptors and low affinityfor β 2-receptors. In contrast, isoproterenolhas high affinity for β-receptors,but virtually none for α-receptors(A).norepinephrine α, β 1epinephrine α, β 1, β 2isoproterenol β 1, β 2Knowledge of structure–activityrelationships has permitted the synthesisof sympathomimetics that displaya high degree of selectivity atadrenoceptor subtypes.Direct-acting sympathomimetics(i.e., adrenoceptor agonists) typicallyshare a phenylethylamine structure. Theside chain β-hydroxyl group confers affinityfor α- and β-receptors. Substitutionon the amino group reduces affinityfor α-receptors, but increases it for β-receptors(exception: α-agonist phenylephrine),with optimal affinity beingseen after the introduction of only oneisopropyl group. Increasing the bulk ofthe amino substituent favors affinity forβ 2-receptors (e.g., fenoterol, salbutamol).Both hydroxyl groups on the aromaticnucleus contribute to affinity;high activity at α-receptors is associatedwith hydroxyl groups at the 3 and 4 positions.Affinity for β-receptors is preservedin congeners bearing hydroxylgroups at positions 3 and 5 (orciprenaline,terbutaline, fenoterol).The hydroxyl groups of catecholaminesare responsible for the very lowlipophilicity of these substances. Polarityis increased at physiological pH dueto protonation of the amino group. Deletionof one or all hydroxyl groups improvesmembrane penetrability at theintestinal mucosa-blood and the bloodbrainbarriers. Accordingly, these noncatecholaminecongeners can be givenorally and can exert CNS actions; however,this structural change entails a lossin affinity.Absence of one or both aromatichydroxyl groups is associated with anincrease in indirect sympathomimeticactivity, denoting the ability of a substanceto release norepinephrine fromits neuronal stores without exerting anagonist action at the adrenoceptor (p.88).An altered position of aromatic hydroxylgroups (e.g., in orciprenaline, fenoterol,or terbutaline) or their substitution(e.g., salbutamol) protectsagainst inactivation by COMT (p. 82). Indroductionof a small alkyl residue atthe carbon atom adjacent to the aminogroup (ephedrine, methamphetamine)confers resistance to degradation byMAO (p. 80), as does replacement on theamino groups of the methyl residuewith larger substituents (e.g., ethyl inetilefrine). Accordingly, the congenersare less subject to presystemic inactivation.Since structural requirements forhigh affinity, on the one hand, and oralapplicability, on the other, do notmatch, choosing a sympathomimetic isa matter of compromise. If the high affinityof epinephrine is to be exploited,absorbability from the intestine must beforegone (epinephrine, isoprenaline). Ifgood bioavailability with oral administrationis desired, losses in receptor affinitymust be accepted (etilefrine).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on the Sympathetic Nervous System 87NorepinephrineEpinephrineIsoproterenolA. Chemical structure of catecholamines and affinity for α- and β-receptorsReceptor affinityCatecholamine-O-methyltransferasePenetrabilitythroughmembranebarriers(Enteral absorbabilityCNS permeability)MetabolicstabilityMonoamine oxidaseEpinephrine Orciprenaline FenoterolEtilefrine Ephedrine MethamphetamineAffinity for α-receptorsAffinity for β-receptorsIndirectactionResistance to degradationAbsorbabilityB. Structure-activity relationship of epinephrine derivativesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
88 Drugs Acting on the Sympathetic Nervous SystemIndirect SympathomimeticsApart from receptors, adrenergic neurotransmissioninvolves mechanismsfor the active re-uptake and re-storageof released amine, as well as enzymaticbreakdown by monoamine oxidase(MAO). Norepinephrine (NE) displaysaffinity for receptors, transport systems,and degradative enzymes. Chemical alterationsof the catecholamine differentiallyaffect these properties and resultin substances with selective actions.Inhibitors of MAO (A). The enzymeis located predominantly on mitochondria,and serves to scavenge axoplasmicfree NE. Inhibition of the enzyme causesfree NE concentrations to rise. Likewise,dopamine catabolism is impaired, makingmore of it available for NE synthesis.Consequently, the amount of NE storedin granular vesicles will increase, andwith it the amount of amine releasedper nerve impulse.In the CNS, inhibition of MAO affectsneuronal storage not only of NEbut also of dopamine and serotonin.These mediators probably play significantroles in CNS functions consistentwith the stimulant effects of MAO inhibitorson mood and psychomotor driveand their use as antidepressants in thetreatment of depression (A). Tranylcypromineis used to treat particular formsof depressive illness; as a covalentlybound suicide substrate, it causes longlastinginhibition of both MAO isozymes,(MAO A, MAO B). Moclobemide reversiblyinhibits MAO A and is also usedas an antidepressant. The MAO B inhibitorselegiline (deprenyl) retards the catobolismof dopamine, an effect used inthe treatment of parkinsonism (p. 188).Indirect sympathomimetics (B)are agents that elevate the concentrationof NE at neuroeffector junctions,because they either inhibit re-uptake(cocaine), facilitate release, or slowbreakdown by MAO, or exert all three ofthese effects (amphetamine, methamphetamine).The effectiveness of suchindirect sympathomimetics diminishesor disappears (tachyphylaxis) when vesicularstores of NE close to the axolemmaare depleted.Indirect sympathomimetics canpenetrate the blood-brain barrier andevoke such CNS effects as a feeling ofwell-being, enhanced physical activityand mood (euphoria), and decreasedsense of hunger or fatigue. Subsequently,the user may feel tired and depressed.These after effects are partlyresponsible for the urge to re-administerthe drug (high abuse potential). Toprevent their misuse, these substancesare subject to governmental regulations(e.g., Food and Drugs Act: Canada; ControlledDrugs Act: USA) restricting theirprescription and distribution.When amphetamine-like substancesare misused to enhance athletic performance(doping), there is a risk of dangerousphysical overexertion. Becauseof the absence of a sense of fatigue, adrugged athlete may be able to mobilizeultimate energy reserves. In extremesituations, cardiovascular failure mayresult (B).Closely related chemically to amphetamineare the so-called appetitesuppressants or anorexiants, such asfenfluramine, mazindole, and sibutramine.These may also cause dependenceand their therapeutic value and safetyare questionable.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
MAOMAODrugs Acting on the Sympathetic Nervous System 89Inhibitor: Moclobemide MAO-ASelegiline MAO-BNorepinephrineMAOMAONorepinephrinetransport systemEffector organA. Monoamine oxidase inhibitor§§Pain stimulusLocalanestheticeffectAmphetamineControlledSubstancesAct regulatesuse ofcocaine andamphetamineCocaine"Doping"Runner-upB. Indirect sympathomimetics with central stimulant activity and abuse potentialLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
90 Drugs Acting on the Sympathetic Nervous Systemα-Sympathomimetics,α-Sympatholyticsα-Sympathomimetics can be usedsystemically in certain types of hypotension(p. 314) and locally for nasal or conjunctivaldecongestion (pp. 324, 326) oras adjuncts in infiltration anesthesia (p.206) for the purpose of delaying the removalof local anesthetic. With localuse, underperfusion of the vasoconstrictedarea results in a lack of oxygen(A). In the extreme case, local hypoxiacan lead to tissue necrosis. The appendages(e.g., digits, toes, ears) are particularlyvulnerable in this regard, thus precludingvasoconstrictor adjuncts in infiltrationanesthesia at these sites.Vasoconstriction induced by an α-sympathomimetic is followed by aphase of enhanced blood flow (reactivehyperemia, A). This reaction can be observedafter the application of α-sympathomimetics(naphazoline, tetrahydrozoline,xylometazoline) to the nasal mucosa.Initially, vasoconstriction reducesmucosal blood flow and, hence, capillarypressure. Fluid exuded into theinterstitial space is drained through theveins, thus shrinking the nasal mucosa.Due to the reduced supply of fluid, secretionof nasal mucus decreases. In coryza,nasal patency is restored. However,after vasoconstriction subsides, reactivehyperemia causes renewed exudationof plasma fluid into the interstitialspace, the nose is “stuffy” again, and thepatient feels a need to reapply decongestant.In this way, a vicious cyclethreatens. Besides rebound congestion,persistent use of a decongestant entailsthe risk of atrophic damage caused byprolonged hypoxia of the nasal mucosa.α-Sympatholytics (B). The interactionof norepinephrine with α-adrenoceptorscan be inhibited by α-sympatholytics( α-adrenoceptor antagonists, α-blockers). This inhibition can be put totherapeutic use in antihypertensivetreatment (vasodilation peripheralresistance ↓, blood pressure ↓, p. 118).The first α-sympatholytics blocked theaction of norepinephrine at both postandprejunctional α-adrenoceptors(non-selective α-blockers, e.g., phenoxybenzamine,phentolamine).Presynaptic α 2-adrenoceptors functionlike sensors that enable norepinephrineconcentration outside theaxolemma to be monitored, thus regulatingits release via a local feedbackmechanism. When presynaptic α 2-receptorsare stimulated, further releaseof norepinephrine is inhibited. Conversely,their blockade leads to uncontrolledrelease of norepinephrine withan overt enhancement of sympatheticeffects at β 1-adrenoceptor-mediatedmyocardial neuroeffector junctions, resultingin tachycardia and tachyarrhythmia.Selective α-Sympatholyticsα-Blockers, such as prazosin, or thelonger-acting terazosin and doxazosin,lack affinity for prejunctional α 2-adrenoceptors.They suppress activation ofα 1-receptors without a concomitant enhancementof norepinephrine release.α 1-Blockers may be used in hypertension(p. 312). Because they preventreflex vasoconstriction, they are likelyto cause postural hypotension withpooling of blood in lower limb capacitanceveins during change from the supineto the erect position (orthostaticcollapse: ↓ venous return, ↓ cardiac output,fall in systemic pressure, ↓ bloodsupply to CNS, syncope, p. 314).In benign hyperplasia of the prostate,α-blockers (terazosin, alfuzosin)may serve to lower tonus of smoothmusculature in the prostatic region andthereby facilitate micturition (p. 252).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on the Sympathetic Nervous System 91Beforeα-AgonistAfterO 2 supply = O 2 demandO 2 supply < O 2 demandO 2 supply = O 2 demandA. Reactive hyperemia due to α-sympathomimetics, e.g., following decongestionof nasal mucosaα 2 α 2 α 2NEnonselectiveα-blockerα 1 -blockerα 1 β 1 α 1 β 1 α 1β 1B. Autoinhibition of norepinephrine release and α-sympatholyticsHigh blood pressureα 1 -blockere.g., terazosinBenignprostatic hyperplasiaONH 3 CONNOH 3 CONH 2NResistancearteriesInhibition ofα 1 -adrenergicstimulation ofsmooth muscleNeck of bladder,prostateC. Indications for α 1 -sympatholyticsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
92 Drugs Acting on the Sympathetic Nervous Systemβ-Sympatholytics (β-Blockers)β-Sympatholytics are antagonists ofnorepiphephrine and epinephrine at β-adrenoceptors; they lack affinity for α-receptors.Therapeutic effects. β-Blockersprotect the heart from the oxygenwastingeffect of sympathetic inotropism(p. 306) by blocking cardiac β-receptors;thus, cardiac work can no longerbe augmented above basal levels (theheart is “coasting”). This effect is utilizedprophylactically in angina pectoristo prevent myocardial stress that couldtrigger an ischemic attack (p. 308, 310).β-Blockers also serve to lower cardiacrate (sinus tachycardia, p. 134) and elevatedblood pressure due to high cardiacoutput (p. 312). The mechanism underlyingtheir antihypertensive action viareduction of peripheral resistance is unclear.Applied topically to the eye, β-blockers are used in the management ofglaucoma; they lower production ofaqueous humor without affecting itsdrainage.Undesired effects. The hazards oftreatment with β-blockers become apparentparticularly when continuousactivation of β-receptors is needed inorder to maintain the function of an organ.Congestive heart failure: In myocardialinsufficiency, the heart depends ona tonic sympathetic drive to maintainadequate cardiac output. Sympatheticactivation gives rise to an increase inheart rate and systolic muscle tension,enabling cardiac output to be restoredto a level comparable to that in ahealthy subject. When sympatheticdrive is eliminated during β-receptorblockade, stroke volume and cardiacrate decline, a latent myocardial insufficiencyis unmasked, and overt insufficiencyis exacerbated (A).On the other hand, clinical evidencesuggests that β-blockers produce favorableeffects in certain forms of congestiveheart failure (idiopathic dilated cardiomyopathy).Bradycardia, A-V block: Eliminationof sympathetic drive can lead to amarked fall in cardiac rate as well as todisorders of impulse conduction fromthe atria to the ventricles.Bronchial asthma: Increased sympatheticactivity prevents bronchospasmin patients disposed to paroxysmalconstriction of the bronchial tree(bronchial asthma, bronchitis in smokers).In this condition, β 2-receptorblockade will precipitate acute respiratorydistress (B).Hypoglycemia in diabetes mellitus:When treatment with insulin or oral hypoglycemicsin the diabetic patient lowersblood glucose below a critical level,epinephrine is released, which thenstimulates hepatic glucose release viaactivation of β 2-receptors. β-Blockerssuppress this counter-regulation; in addition,they mask other epinephrinemediatedwarning signs of imminenthypoglycemia, such as tachycardia andanxiety, thereby enhancing the risk ofhypoglycemic shock.Altered vascular responses: Whenβ 2-receptors are blocked, the vasodilatingeffect of epinephrine is abolished,leaving the α-receptor-mediated vasoconstrictionunaffected: peripheralblood flow ↓ – “cold hands and feet”.β-Blockers exert an “anxiolytic“action that may be due to the suppressionof somatic responses (palpitations,trembling) to epinephrine release thatis induced by emotional stress; in turn,these would exacerbate “anxiety” or“stage fright”. Because alertness is notimpaired by β-blockers, these agents areoccasionally taken by orators and musiciansbefore a major performance (C).Stage fright, however, is not a diseaserequiring drug therapy.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on the Sympathetic Nervous System 93β-Blockerblocksreceptorβ-Receptor100 mlStrokevolume1 secβ 1 -Blockade1 secβ 1 -StimulationHeart failure HealthyA. β-Sympatholytics: effect on cardiac functionAsthmaticHealthyαα β 2 α β 2β 2 -Blockadeβ 2 -Stimulationβ 2 -Blockadeβ 2 -StimulationB. β-Sympatholytics: effect on bronchial and vascular toneC. “Anxiolytic” effect of β-sympatholyticsβ-BlockadeLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
94 Drugs Acting on the Sympathetic Nervous SystemTypes of β-BlockersThe basic structure shared by most β-sympatholytics is the side chain of β-sympathomimetics (cf. isoproterenolwith the β-blockers propranolol, pindolol,atenolol). As a rule, this basic structureis linked to an aromatic nucleus bya methylene and oxygen bridge. Theside chain C-atom bearing the hydroxylgroup forms the chiral center. Withsome exceptions (e.g., timolol, penbutolol),all β-sympatholytics are brought asracemates into the market (p. 62).Compared with the dextrorotatoryform, the levorotatory enantiomer possessesa greater than 100-fold higher affinityfor the β-receptor and is, therefore,practically alone in contributing tothe β-blocking effect of the racemate.The side chain and substituents on theamino group critically affect affinity forβ-receptors, whereas the aromatic nucleusdetermines whether the compoundpossess intrinsic sympathomimeticactivity (ISA), that is, acts as apartial agonist (p. 60) or partial antagonist.In the presence of a partial agonist(e.g., pindolol), the ability of a full agonist(e.g., isoprenaline) to elicit a maximaleffect would be attenuated, becausebinding of the full agonist is impeded.However, the β-receptor at which suchpartial agonism can be shown appearsto be atypical (β 3 or β 4 subtype). WhetherISA confers a therapeutic advantageon a β-blocker remains an open question.As cationic amphiphilic drugs, β-blockers can exert a membrane-stabilizingeffect, as evidenced by the abilityof the more lipophilic congeners to inhibitNa + -channel function and impulseconduction in cardiac tissues. At theusual therapeutic dosage, the high concentrationrequired for these effects willnot be reached.Some β-sympatholytics possesshigher affinity for cardiac β 1-receptorsthan for β 2-receptors and thus displaycardioselectivity (e.g., metoprolol, acebutolol,bisoprolol). None of theseblockers is sufficiently selective to permitits use in patients with bronchialasthma or diabetes mellitus (p. 92).The chemical structure of β-blockersalso determines their pharmacokineticproperties. Except for hydrophilicrepresentatives (atenolol), β-sympatholyticsare completely absorbed from theintestines and subsequently undergopresystemic elimination to a major extent(A).All the above differences are oflittle clinical importance. The abundanceof commercially available congenerswould thus appear all the more curious(B). Propranolol was the first β-blockerto be introduced into therapy in 1965.Thirty-five years later, about 20 differentcongeners are being marketed in differentcountries. This questionable developmentunfortunately is typical of anydrug group that has major therapeuticrelevance, in addition to a relativelyfixed active structure. Variation of themolecule will create a new patentablechemical, not necessarily a drug with anovel action. Moreover, a drug no longerprotected by patent is offered as a genericby different manufacturers under dozensof different proprietary names.Propranolol alone has been marketed by13 manufacturers under 11 differentnames.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on the Sympathetic Nervous System 95Isoproterenol Pindolol Propranolol AtenololAgonistβ-Receptor β-Receptor β-ReceptorEffectpartialAgonistAntagonistNo effectAntagonistββ 1β 1β 1β 1β 1 2βCardio-2β 2 β 2 β 2 selectivityPresystemic100%50%A. Types of β-sympatholytics1965 1970AlprenololPropranololOxprenololPindololBupranololTimololSotalolTalinololYear introducedCarteololMepindololPenbutololCarazololNadololAcebutololBunitrololAtenololMetipranolMetoprololB. Avalanche-like increase in commercially available β-sympatholyticseliminationTertatololCarvedilolEsmololBopindololBisoprololCeliprololBetaxololBefunolol1975 1980 1985 1990Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
96 Drugs Acting on the Sympathetic Nervous SystemAntiadrenergicsAntiadrenergics are drugs capable oflowering transmitter output from sympatheticneurons, i.e., “sympathetictone”. Their action is hypotensive (indication:hypertension, p. 312); however,being poorly tolerated, they enjoy onlylimited therapeutic use.Clonidine is an α 2-agonist whosehigh lipophilicity (dichlorophenyl ring)permits rapid penetration through theblood-brain barrier. The activation ofpostsynaptic α 2-receptors dampens theactivity of vasomotor neurons in themedulla oblongata, resulting in a resettingof systemic arterial pressure at alower level. In addition, activation ofpresynaptic α 2-receptors in the periphery(pp. 82, 90) leads to a decreased releaseof both norepinephrine (NE) andacetylcholine.Side effects. Lassitude, dry mouth;rebound hypertension after abrupt cessationof clonidine therapy.Methyldopa (dopa = dihydroxyphenylalanine),as an amino acid, istransported across the blood-brain barrier,decarboxylated in the brain to α-methyldopamine, and then hydroxylatedto α-methyl-NE. The decarboxylationof methyldopa competes for a portion ofthe available enzymatic activity, so thatthe rate of conversion of L-dopa to NE(via dopamine) is decreased. The falsetransmitter α-methyl-NE can be stored;however, unlike the endogenous mediator,it has a higher affinity for α 2- thanfor α 1-receptors and therefore produceseffects similar to those of clonidine. Thesame events take place in peripheral adrenergicneurons.Adverse effects. Fatigue, orthostatichypotension, extrapyramidal Parkinson-likesymptoms (p. 88), cutaneousreactions, hepatic damage, immune-hemolyticanemia.Reserpine, an alkaloid from theRauwolfia plant, abolishes the vesicularstorage of biogenic amines (NE, dopamine= DA, serotonin = 5-HT) by inhibitingan ATPase required for the vesicularamine pump. The amount of NE releasedper nerve impulse is decreased.To a lesser degree, release of epinephrinefrom the adrenal medulla is alsoimpaired. At higher doses, there is irreversibledamage to storage vesicles(“pharmacological sympathectomy”),days to weeks being required for theirresynthesis. Reserpine readily entersthe brain, where it also impairs vesicularstorage of biogenic amines.Adverse effects. Disorders of extrapyramidalmotor function with developmentof pseudo-Parkinsonism (p. 88),sedation, depression, stuffy nose, impairedlibido, and impotence; increasedappetite. These adverse effects haverendered the drug practically obsolete.Guanethidine possesses high affinityfor the axolemmal and vesicularamine transporters. It is stored insteadof NE, but is unable to mimic the functionsof the latter. In addition, it stabilizesthe axonal membrane, thereby impedingthe propagation of impulses intothe sympathetic nerve terminals. Storageand release of epinephrine from theadrenal medulla are not affected, owingto the absence of a re-uptake process.The drug does not cross the blood-brainbarrier.Adverse effects. Cardiovascular crisesare a possible risk: emotional stressof the patient may cause sympathoadrenalactivation with epinephrine release.The resulting rise in blood pressurecan be all the more marked becausepersistent depression of sympatheticnerve activity induces supersensitivityof effector organs to circulatingcatecholamines.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on the Sympathetic Nervous System 97Stimulation of central α 2 -receptorsSuppression ofsympatheticimpulses invasomotorcenterTyrosineDopaDopamineNEFalse transmitterα-Methyl-NEin brainInhibition ofDopa-decarboxylaseα-Methyl-NEClonidineα-MethyldopaNEDA5HTCNSInhibition ofbiogenic aminestoragePeripheralsympathetic activityReserpineNo epinephrine from adrenal medulladue to central sedative effectVaricosityInhibition ofperipheralsympathetic activityGuanethidineActive uptake andstorage instead ofnorepinephrine;not a transmitterRelease from adrenal medullaunaffectedVaricosityA. Inhibitors of sympathetic toneLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
98 Drugs Acting on the Parasympathetic Nervous SystemParasympathetic Nervous SystemResponses to activation of the parasympatheticsystem. Parasympatheticnerves regulate processes connectedwith energy assimilation (food intake,digestion, absorption) and storage.These processes operate when the bodyis at rest, allowing a decreased tidal volume(increased bronchomotor tone)and decreased cardiac activity. Secretionof saliva and intestinal fluids promotesthe digestion of foodstuffs; transportof intestinal contents is speeded upbecause of enhanced peristaltic activityand lowered tone of sphincteric muscles.To empty the urinary bladder (micturition),wall tension is increased bydetrusor activation with a concurrentrelaxation of sphincter tonus.Activation of ocular parasympatheticfibers (see below) results in narrowingof the pupil and increased curvatureof the lens, enabling near objects tobe brought into focus (accommodation).Anatomy of the parasympatheticsystem. The cell bodies of parasympatheticpreganglionic neurons are locatedin the brainstem and the sacral spinalcord. Parasympathetic outflow is channelledfrom the brainstem (1) throughthe third cranial nerve (oculomotor n.)via the ciliary ganglion to the eye; (2)through the seventh cranial nerve (facialn.) via the pterygopalatine and submaxillaryganglia to lacrimal glands andsalivary glands (sublingual, submandibular),respectively; (3) through theninth cranial nerve (glossopharyngealn.) via the otic ganglion to the parotidgland; and (4) via the tenth cranialnerve (vagus n.) to thoracic and abdominalviscera. Approximately 75 % of allparasympathetic fibers are containedwithin the vagus nerve. The neurons ofthe sacral division innervate the distalcolon, rectum, bladder, the distal ureters,and the external genitalia.Acetylcholine (ACh) as a transmitter.ACh serves as mediator at terminalsof all postganglionic parasympatheticfibers, in addition to fulfilling its transmitterrole at ganglionic synapses withinboth the sympathetic and parasympatheticdivisions and the motor endplateson striated muscle. However, differenttypes of receptors are present atthese synaptic junctions:Localization Agonist Antagonist Receptor TypeTarget tissues of 2 nd ACh Atropine Muscarinic (M)parasympathetic Muscarine cholinoceptor;neuronsG-protein-coupledreceptorprotein with7 transmembranedomainsSympathetic & ACh Trimethaphan Ganglionic typeparasympathetic Nicotine (α3 β4)gangliaNicotinic (N)cholinoceptor ligandgatedcation channelformed by five transmembranesubunitsMotor endplate ACh d-Tubocurarine muscular typeNicotine(α1 2β1γδ)The existence of distinct cholinoceptorsat different cholinergic synapsesallows selective pharmacologicalinterventions.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on the Parasympathetic Nervous System 99Eyes:Accommodationfor near vision,miosisSaliva:copious, liquidBronchi:constrictionsecretionHeart:rateblood pressureGI tract:secretionperistalsissphincter toneBladder:sphincter tonedetrusorA. Responses to parasympathetic activationLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
100 Drugs Acting on the Parasympathetic Nervous SystemCholinergic SynapseAcetylcholine (ACh) is the transmitterat postganglionic synapses of parasympatheticnerve endings. It is highly concentratedin synaptic storage vesiclesdensely present in the axoplasm of theterminal. ACh is formed from cholineand activated acetate (acetylcoenzymeA), a reaction catalyzed by the enzymecholine acetyltransferase. The highlypolar choline is actively transported intothe axoplasm. The specific choline transporteris localized exclusively to membranesof cholinergic axons and terminals.The mechanism of transmitter releaseis not known in full detail. The vesiclesare anchored via the protein synapsinto the cytoskeletal network. This arrangementpermits clustering of vesiclesnear the presynaptic membrane, whilepreventing fusion with it. During activationof the nerve membrane, Ca 2+ isthought to enter the axoplasm throughvoltage-gated channels and to activateprotein kinases that phosphorylate synapsin.As a result, vesicles close to themembrane are detached from their anchoringand allowed to fuse with thepresynaptic membrane. During fusion,vesicles discharge their contents into thesynaptic gap. ACh quickly diffusesthrough the synaptic gap (the acetylcholinemolecule is a little longer than0.5 nm; the synaptic gap is as narrow as30–40 nm). At the postsynaptic effectorcell membrane, ACh reacts with its receptors.Because these receptors can alsobe activated by the alkaloid muscarine,they are referred to as muscarinic(M-)cholinoceptors. In contrast, at ganglionic(p. 108) and motor endplate (p.184) cholinoceptors, the action of ACh ismimicked by nicotine and they are,therefore, said to be nicotinic cholinoceptors.Released ACh is rapidly hydrolyzedand inactivated by a specific acetylcholinesterase,present on pre- and postjunctionalmembranes, or by a less specificserum cholinesterase (butyryl cholinesterase),a soluble enzyme present inserum and interstitial fluid.M-cholinoceptors can be classifiedinto subtypes according to their molecularstructure, signal transduction, andligand affinity. Here, the M 1, M 2, and M 3subtypes are considered. M 1 receptorsare present on nerve cells, e.g., in ganglia,where they mediate a facilitation ofimpulse transmission from preganglionicaxon terminals to ganglion cells.M 2 receptors mediate acetylcholine effectson the heart: opening of K + channelsleads to slowing of diastolic depolarizationin sinoatrial pacemaker cellsand a decrease in heart rate. M 3 receptorsplay a role in the regulation ofsmooth muscle tone, e.g., in the gut andbronchi, where their activation causesstimulation of phospholipase C, membranedepolarization, and increase inmuscle tone. M 3 receptors are alsofound in glandular epithelia, which similarlyrespond with activation of phospholipaseC and increased secretory activity.In the CNS, where all subtypes arepresent, cholinoceptors serve diversefunctions, including regulation of corticalexcitability, memory, learning, painprocessing, and brain stem motor control.The assignment of specific receptorsubtypes to these functions has yet to beachieved.In blood vessels, the relaxant actionof ACh on muscle tone is indirect, becauseit involves stimulation of M 3-cholinoceptorson endothelial cells that respondby liberating NO (= endotheliumderivedrelaxing factor). The latter diffusesinto the subjacent smooth musculature,where it causes a relaxation ofactive tonus (p. 121).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on the Parasympathetic Nervous System 101Acetyl coenzyme A + cholineCholine acetyltransferaseAction potentialCa 2+ influxAcetylcholineStorage ofacetylcholinein vesiclesactivereuptake ofcholineCa 2+ProteinkinaseVesiclereleaseExocytosisestericcleavageReceptoroccupationSerumcholinesteraseAcetylcholineesterase: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-90TimeA. Acetylcholine: release, effects, and degradationLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
102 Drugs Acting on the Parasympathetic Nervous SystemParasympathomimeticsAcetylcholine (ACh) is too rapidly hydrolyzedand inactivated by acetylcholinesterase(AChE) to be of any therapeuticuse; however, its action can be mimickedby other substances, namely director indirect parasympathomimetics.Direct Parasympathomimetics.The choline ester, carbachol, activatesM-cholinoceptors, but is not hydrolyzedby AChE. Carbachol can thus be effectivelyemployed for local application tothe eye (glaucoma) and systemic administration(bowel atonia, bladder atonia).The alkaloids, pilocarpine (from Pilocarpusjaborandi) and arecoline (fromAreca catechu; betel nut) also act as directparasympathomimetics. As tertiaryamines, they moreover exert central effects.The central effect of muscarinelikesubstances consists of an enlivening,mild stimulation that is probablythe effect desired in betel chewing, awidespread habit in South Asia. <strong>Of</strong> thisgroup, only pilocarpine enjoys therapeuticuse, which is limited to local applicationto the eye in glaucoma.Indirect Parasympathomimetics.AChE can be inhibited selectively, withthe result that ACh released by nerveimpulses will accumulate at cholinergicsynapses and cause prolonged stimulationof cholinoceptors. Inhibitors ofAChE are, therefore, indirect parasympathomimetics.Their action is evidentat all cholinergic synapses. Chemically,these agents include esters of carbamicacid (carbamates such as physostigmine,neostigmine) and of phosphoricacid (organophosphates such as paraoxon= E600 and nitrostigmine = parathion= E605, its prodrug).Members of both groups react likeACh with AChE and can be consideredfalse substrates. The esters are hydrolyzedupon formation of a complex withthe enzyme. The rate-limiting step inACh hydrolysis is deacetylation of theenzyme, which takes only milliseconds,thus permitting a high turnover rateand activity of AChE. Decarbaminoylationfollowing hydrolysis of a carbamatetakes hours to days, the enzymeremaining inhibited as long as it is carbaminoylated.Cleavage of the phosphateresidue, i.e. dephosphorylation,is practically impossible; enzyme inhibitionis irreversible.Uses. The quaternary carbamateneostigmine is employed as an indirectparasympathomimetic in postoperativeatonia of the bowel or bladder. Furthermore,it is needed to overcome the relativeACh-deficiency at the motor endplatein myasthenia gravis or to reversethe neuromuscular blockade (p. 184)caused by nondepolarizing muscle relaxants(decurarization before discontinuationof anesthesia). The tertiarycarbamate physostigmine can be usedas an antidote in poisoning with parasympatholyticdrugs, because it has accessto AChE in the brain. Carbamates(neostigmine, pyridostigmine, physostigmine)and organophosphates (paraoxon,ecothiopate) can also be appliedlocally to the eye in the treatment ofglaucoma; however, their long-term useleads to cataract formation. Agents fromboth classes also serve as insecticides.Although they possess high acute toxicityin humans, they are more rapidly degradedthan is DDT following theiremission into the environment.Tacrine is not an ester and interferesonly with the choline-binding site ofAChE. It is effective in alleviating symptomsof dementia in some subtypes ofAlzheimer’s disease.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on the Parasympathetic Nervous System 103CarbacholAcetylcholineDirect parasympathomimeticsAChEArecolineArecoline =ingredient ofbetel nut:betelchewingAChEffector organAChEPhysostigmineInhibitors ofacetylcholinesterase(AChE)IndirectNeostigmine parasympathomimeticsParaoxon (E 600)Acetylcholine+AChECholineAcetylmsDeacetylationNitrostigmine =Parathion =E 605Neostigmine+AChEParaoxon+AChECarbaminoylPhosphorylHours to daysDecarbaminoylationA. Direct and indirect parasympathomimeticsDephosphorylation impossibleLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
104 Drugs Acting on the Parasympathetic Nervous SystemParasympatholyticsExcitation of the parasympathetic divisionof the autonomic nervous systemcauses release of acetylcholine at neuroeffectorjunctions in different target organs.The major effects are summarizedin A (blue arrows). Some of these effectshave therapeutic applications, as indicatedby the clinical uses of parasympathomimetics(p. 102).Substances acting antagonisticallyat the M-cholinoceptor are designatedparasympatholytics (prototype: the alkaloidatropine; actions shown in red inthe panels). Therapeutic use of theseagents is complicated by their low organselectivity. Possibilities for a targetedaction include:local application• selection of drugs with either good orpoor membrane penetrability as thesituation demands• administration of drugs possessingreceptor subtype selectivity.Parasympatholytics are employedfor the following purposes:1. Inhibition of exocrine glandsBronchial secretion. Premedicationwith atropine before inhalation anesthesiaprevents a possible hypersecretionof bronchial mucus, which cannotbe expectorated by coughing during intubation(anesthesia).Gastric secretion. Stimulation ofgastric acid production by vagal impulsesinvolves an M-cholinoceptor subtype(M 1-receptor), probably associated withenterochromaffin cells. Pirenzepine (p.106) displays a preferential affinity forthis receptor subtype. Remarkably, theHCl-secreting parietal cells possess onlyM 3-receptors. M 1-receptors have alsobeen demonstrated in the brain; however,these cannot be reached by pirenzepinebecause its lipophilicity is toolow to permit penetration of the bloodbrainbarrier. Pirenzepine was formerlyused in the treatment of gastric and duodenalulcers (p. 166).2. Relaxation of smooth musculatureBronchodilation can be achieved by theuse of ipratropium in conditions of increasedairway resistance (chronic obstructivebronchitis, bronchial asthma).When administered by inhalation,this quaternary compound has little effecton other organs because of its lowrate of systemic absorption.Spasmolysis by N-butylscopolaminein biliary or renal colic (p. 126). Becauseof its quaternary nitrogen, thisdrug does not enter the brain and requiresparenteral administration. Itsspasmolytic action is especially markedbecause of additional ganglionic blockingand direct muscle-relaxant actions.Lowering of pupillary sphincter tonusand pupillary dilation by local administrationof homatropine or tropicamide(mydriatics) allows observationof the ocular fundus. For diagnostic uses,only short-term pupillary dilation isneeded. The effect of both agents subsidesquickly in comparison with that ofatropine (duration of several days).3. CardioaccelerationIpratropium is used in bradycardia andAV-block, respectively, to raise heartrate and to facilitate cardiac impulseconduction. As a quaternary substance,it does not penetrate into the brain,which greatly reduces the risk of CNSdisturbances (see below). Relativelyhigh oral doses are required because ofan inefficient intestinal absorption.Atropine may be given to preventcardiac arrest resulting from vagal reflexactivation, incident to anesthetic induction,gastric lavage, or endoscopicprocedures.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on the Parasympathetic Nervous System 105N. oculomotoriusN. facialisN. glossopharyngeusN. vagusDeadly nightshadeAtropabelladonnaNn. sacralesAtropineAcetylcholineMuscarinic acetylcholine receptorSchlemm’scanal wide+Ciliary musclecontracted+Pupil narrowPupil widePhotophobiaNear vision impossibleDrainage of aqueoushumor impairedRateAV conductionRateAV conduction-++Salivary secretion+Gastric acidproduction+Pancreatic juiceproduction+Bowel peristalsis+Bladder toneRestlessnessIrritabilityHallucinationsAntiparkinsonianeffectAntiemetic effectSweat productionEvaporative heatlossIncreased blood flowfor increasingheat dissipation"Flusheddry skin"+Bronchial secretionBronchoconstrictionBronchial secretiondecreasedBronchodilationSympatheticnervesDry mouthAcid productiondecreasedPancreaticsecretory activitydecreasedBowel peristalsisdecreasedBladder tonedecreasedA. Effects of parasympathetic stimulation and blockadeLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
106 Drugs Acting on the Parasympathetic Nervous System4. CNS-dampening effectsScopolamine is effective in the prophylaxisof kinetosis (motion sickness, seasickness, see p. 330); it is well absorbedtranscutaneously. Scopolamine (pK a =7.2) penetrates the blood-brain barrierfaster than does atropine (pK a = 9), becauseat physiologic pH a larger proportionis present in the neutral, membrane-permeantform.In psychotic excitement (agitation),sedation can be achieved withscopolamine. Unlike atropine, scopolamineexerts a calming and amnesiogenicaction that can be used to advantagein anesthetic premedication.Symptomatic treatment in parkinsonismfor the purpose of restoring adopaminergic-cholinergic balance inthe corpus striatum. Antiparkinsonianagents, such as benzatropine (p. 188),readily penetrate the blood-brain barrier.At centrally equi-effective dosage,their peripheral effects are less markedthan are those of atropine.Contraindications forparasympatholyticsGlaucoma: Since drainage of aqueoushumor is impeded during relaxation ofthe pupillary sphincter, intraocularpressure rises.Prostatic hypertrophy with impairedmicturition: loss of parasympatheticcontrol of the detrusor muscle exacerbatesdifficulties in voiding urine.exchange through increased cutaneousblood flow. Decreased peristaltic activityof the intestines leads to constipation.Central: Motor restlessness, progressingto maniacal agitation, psychicdisturbances, disorientation, and hallucinations.Elderly subjects are moresensitive to such central effects. In thiscontext, the diversity of drugs producingatropine-like side effects should beborne in mind: e.g., tricyclic antidepressants,neuroleptics, antihistamines,antiarrhythmics, antiparkinsonianagents.Apart from symptomatic, generalmeasures (gastric lavage, cooling withice water), therapy of severe atropineintoxication includes the administrationof the indirect parasympathomimeticphysostigmine (p. 102). The mostcommon instances of “atropine” intoxicationare observed after ingestion ofthe berry-like fruits of belladonna (children)or intentional overdosage withtricyclic antidepressants in attemptedsuicide.Atropine poisoningParasympatholytics have a wide therapeuticmargin. Rarely life-threatening,poisoning with atropine is characterizedby the following peripheral andcentral effects:Peripheral: tachycardia; drymouth; hyperthermia secondary to theinhibition of sweating. Although sweatglands are innervated by sympatheticfibers, these are cholinergic in nature.When sweat secretion is inhibited, thebody loses the ability to dissipate metabolicheat by evaporation of sweat (p.202). There is a compensatory vasodilationin the skin allowing increased heatLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on the Parasympathetic Nervous System 107Homatropine0.2 mgMM 1 1M 1M 1M 3M 3M3M 3Benzatropine1 – 2 mgM 2Pirenzepine50 mgM 1M 1 MM 11M 1M 1N-Butylscopolamine10–20 mgAtropine(0.2 – 2 mg)Ipratropium10 mg+ ganglioplegic+ direct muscle relaxantA. ParasympatholyticsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
108 NicotineGanglionic TransmissionWhether sympathetic or parasympathetic,all efferent visceromotor nervesare made up of two serially connectedneurons. The point of contact (synapse)between the first and second neuronsoccurs mainly in ganglia; therefore, thefirst neuron is referred to as preganglionicand efferents of the second aspostganglionic.Electrical excitation (action potential)of the first neuron causes the releaseof acetylcholine (ACh) within theganglia. ACh stimulates receptors locatedon the subsynaptic membrane of thesecond neuron. Activation of these receptorscauses the nonspecific cationchannel to open. The resulting influx ofNa + leads to a membrane depolarization.If a sufficient number of receptorsis activated simultaneously, a thresholdpotential is reached at which the membraneundergoes rapid depolarization inthe form of a propagated action potential.Normally, not all preganglionic impulseselicit a propagated response inthe second neuron. The ganglionic synapseacts like a frequency filter (A). Theeffect of ACh elicited at receptors on theganglionic neuronal membrane can beimitated by nicotine; i.e., it involves nicotiniccholinoceptors.Ganglionic action of nicotine. If asmall dose of nicotine is given, the ganglioniccholinoceptors are activated. Themembrane depolarizes partially, butfails to reach the firing threshold. However,at this point an amount of releasedACh smaller than that normallyrequired will be sufficient to elicit apropagated action potential. At a lowconcentration, nicotine acts as a ganglionicstimulant; it alters the filterfunction of the ganglionic synapse, allowingaction potential frequency in thesecond neuron to approach that of thefirst (B). At higher concentrations, nicotineacts to block ganglionic transmission.Simultaneous activation of manynicotinic cholinoceptors depolarizes theganglionic cell membrane to such an extentthat generation of action potentialsis no longer possible, even in the face ofan intensive and synchronized releaseof ACh (C).Although nicotine mimics the actionof ACh at the receptors, it cannotduplicate the time course of intrasynapticagonist concentration required forappropriate high-frequency ganglionicactivation. The concentration of nicotinein the synaptic cleft can neitherbuild up as rapidly as that of ACh releasedfrom nerve terminals nor cannicotine be eliminated from the synapticcleft as quickly as ACh.The ganglionic effects of ACh can beblocked by tetraethylammonium, hexamethonium,and other substances (ganglionicblockers). None of these has intrinsicactivity, that is, they fail to stimulateganglia even at low concentration;some of them (e.g., hexamethonium)actually block the cholinoceptor-linkedion channel, but others (mecamylamine,trimethaphan) are typical receptorantagonists.Certain sympathetic preganglionicneurons project without interruption tothe chromaffin cells of the adrenal medulla.The latter are embryologic homologuesof ganglionic sympathocytes. Excitationof preganglionic fibers leads torelease of ACh in the adrenal medulla,whose chromaffin cells then respondwith a release of epinephrine into theblood (D). Small doses of nicotine, by inducinga partial depolarization of adrenomedullarycells, are effective in liberatingepinephrine (pp. 110, 112).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Nicotine 109First neuron Preganglionic Second neuron postganglionic-70 mVAcetylcholineImpulse frequencyA. Ganglionic transmission: normal stateLow concentrationNicotine-55 mVPersistentdepolarizationGanglionic activationB. Ganglionic transmission: excitation by nicotineHigh concentrationNicotine-30 mVDepolarizationGanglionic blockadeC. Ganglionic transmission: blockade by nicotineAdrenal medullaNicotineExcitationEpinephrineD. Adrenal medulla: epinephrine release by nicotineLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
110 NicotineEffects of Nicotine on Body FunctionsAt a low concentration, the tobacco alkaloidnicotine acts as a ganglionic stimulantby causing a partial depolarizationvia activation of ganglionic cholinoceptors(p. 108). A similar action is evidentat diverse other neural sites, consideredbelow in more detail.Autonomic ganglia. Ganglionicstimulation occurs in both the sympatheticand parasympathetic divisions ofthe autonomic nervous system. Parasympatheticactivation results in increasedproduction of gastric juice(smoking ban in peptic ulcer) and enhancedbowel motility (“laxative” effectof the first morning cigarette: defecation;diarrhea in the novice).Although stimulation of parasympatheticcardioinhibitory neuronswould tend to lower heart rate, this responseis overridden by the simultaneousstimulation of sympathetic cardioaccelerantneurons and the adrenal medulla.Stimulation of sympatheticnerves resulting in release of norepinephrinegives rise to vasoconstriction;peripheral resistance rises.Adrenal medulla. On the one hand,release of epinephrine elicits cardiovasculareffects, such as increases in heartrate und peripheral vascular resistance.On the other, it evokes metabolic responses,such as glycogenolysis and lipolysis,that generate energy-rich substrates.The sensation of hunger is suppressed.The metabolic state correspondsto that associated with physicalexercise – “silent stress”.Baroreceptors. Partial depolarizationof baroreceptors enables activationof the reflex to occur at a relativelysmaller rise in blood pressure, leadingto decreased sympathetic vasoconstrictoractivity.Neurohypophysis. Release of vasopressin(antidiuretic hormone) resultsin lowered urinary output (p. 164).Levels of vasopressin necessary for vasoconstrictionwill rarely be producedby nicotine.Carotid body. Sensitivity to arterialpCO 2 increases; increased afferent inputaugments respiratory rate and depth.Receptors for pressure, temperature,and pain. Sensitivity to the correspondingstimuli is enhanced.Area postrema. Sensitization ofchemoceptors leads to excitation of themedullary emetic center.At low concentration, nicotine is alsoable to augment the excitability ofthe motor endplate. This effect can bemanifested in heavy smokers in theform of muscle cramps (calf musculature)and soreness.The central nervous actions of nicotineare thought to be mediated largelyby presynaptic receptors that facilitatetransmitter release from excitatoryaminoacidergic (glutamatergic) nerveterminals in the cerebral cortex. Nicotineincreases vigilance and the abilityto concentrate. The effect reflects an enhancedreadiness to perceive externalstimuli (attentiveness) and to respondto them.The multiplicity of its effects makesnicotine ill-suited for therapeutic use.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Nicotine 111VigilanceAntidiureticeffectRespiratory rateSensitivityRelease ofvasopressinPartialdepolarization incarotid body andother gangliaPartial depolarizationof sensory nerveendings of mechanoandnociceptorsPartialdepolarizationof baroreceptorsNicotinePartialdepolarization ofchemoreceptorsin area postremaEpinephrinereleaseEmetic centerPartial depolarizationof autonomic gangliaEmesisSympatheticactivityParasympatheticactivityVasoconstrictionVasoconstrictionHerzfrequenzBowel Darmtätigkeit motilityBlood pressureDefecation,diarrheaGlycogenolysis,lipolysis,“silent stress”Blood glucoseandfree fatty acidsA.Effects of nicotine in the bodyLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
112 NicotineConsequences of Tobacco SmokingThe dried and cured leaves of the nightshadeplant Nicotiana tabacum areknown as tobacco. Tobacco is mostlysmoked, less frequently chewed or takenas dry snuff. Combustion of tobaccogenerates approx. 4000 chemical compoundsin detectable quantities. Thexenobiotic burden on the smoker dependson a range of parameters, includingtobacco quality, presence of a filter,rate and temperature of combustion,depth of inhalation, and duration ofbreath holding.Tobacco contains 0.2–5 % nicotine.In tobacco smoke, nicotine is present asa constituent of small tar particles. It israpidly absorbed through bronchi andlung alveoli, and is detectable in thebrain only 8 s after the first inhalation.Smoking of a single cigarette yields peakplasma levels in the range of 25–50ng/mL. The effects described on p. 110become evident. When intake stops,nicotine concentration in plasma showsan initial rapid fall, reflecting distributioninto tissues, and a terminal eliminationphase with a half-life of 2 h. Nicotineis degraded by oxidation.The enhanced risk of vascular disease(coronary stenosis, myocardial infarction,and central and peripheral ischemicdisorders, such as stroke andintermittent claudication) is likely to bea consequence of chronic exposure tonicotine. Endothelial impairment andhence dysfunction has been proven toresult from smoking, and nicotine isunder discussion as a factor favoringthe progression of arteriosclerosis. Byreleasing epinephrine, it elevates plasmalevels of glucose and free fatty acidsin the absence of an immediate physiologicalneed for these energy-rich metabolites.Furthermore, it promotesplatelet aggregability, lowers fibrinolyticactivity of blood, and enhances coagulability.The health risks of tobacco smokingare, however, attributable not only tonicotine, but also to various other ingredientsof tobacco smoke, some of whichpossess demonstrable carcinogenicproperties.Dust particles inhaled in tobaccosmoke, together with bronchial mucus,must be removed from the airways bythe ciliated epithelium. Ciliary activity,however, is depressed by tobaccosmoke; mucociliary transport is impaired.This depression favors bacterial infectionand contributes to the chronicbronchitis associated with regularsmoking. Chronic injury to the bronchialmucosa could be an important causativefactor in increasing the risk insmokers of death from bronchial carcinoma.Statistical surveys provide an impressivecorrelation between the numberof cigarettes smoked a day and therisk of death from coronary disease orlung cancer. Statistics also show that, oncessation of smoking, the increased riskof death from coronary infarction orother cardiovascular disease declinesover 5–10 years almost to the level ofnon-smokers. Similarly, the risk of developingbronchial carcinoma is reduced.Abrupt cessation of regular smokingis not associated with severe physicalwithdrawal symptoms. In general,subjects complain of increased nervousness,lack of concentration, and weightgain.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Nicotine 113NicotineNicotianatabacum"Tar"Nitrosamines,acrolein,polycyclichydrocarbonse. g.,benzopyreneheavy metalsSum of noxiousstimuliPlateletaggregationFibrinolyticactivityDamage tovascularendotheliumEpinephrineDamage tobronchialepitheliumYearsDuration ofexposureInhibition ofmucociliarytransportMonthsFreefatty acidsChronicbronchitisBronchitisCoronary diseaseAnnual deaths/1000 peopleBronchial carcinomaAnnual cases/1000 people5432Ex-smoker0 –10 –20 –40 >40 0 1–14 15-40 >40Number of cigarettes per dayA. Sequelae of tobacco smokingLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
114 <strong>Bio</strong>genic Amines<strong>Bio</strong>genic Amines — Actions andPharmacological ImplicationsDopamine A. As the precursor of norepinephrineand epinephrine (p. 184),dopamine is found in sympathetic (adrenergic)neurons and adrenomedullarycells. In the CNS, dopamine itself servesas a neuromediator and is implicated inneostriatal motor programming (p. 188),the elicitation of emesis at the level ofthe area postrema (p. 330), and inhibitionof prolactin release from the anteriorpituitary (p. 242).Dopamine receptors are coupled to G-proteins and exist as different subtypes.D 1-receptors (comprising subtypes D 1and D 5) and D 2-receptors (comprisingsubtypes D 2, D 3, and D 4). The aforementionedactions are mediated mainly byD 2 receptors. When given by infusion,dopamine causes dilation of renal andsplanchnic arteries. This effect is mediatedby D 1 receptors and is utilized in thetreatment of cardiovascular shock andhypertensive emergencies by infusion ofdopamine and fenoldopam, respectively.At higher doses, β 1-adrenoceptorsand, finally, α-receptors are activated, asevidenced by cardiac stimulation andvasoconstriction, respectively.Dopamine is not to be confused with dobutaminewhich stimulates α- and β-adrenoceptorsbut not dopamine receptors(p. 62).Dopamine-mimetics. Administrationof the precursor L-dopa promotesendogenous synthesis of dopamine (indication:parkinsonian syndrome,p. 188). The ergolides, bromocriptine,pergolide, and lisuride, are ligands at D-receptors whose therapeutic effects areprobably due to stimulation of D 2 receptors(indications: parkinsonism, suppressionof lactation, infertility, acromegaly,p. 242). Typical adverse effects ofthese substances are nausea and vomiting.As indirect dopamine-mimetics, (+)-amphetamine and ritaline augment dopaminerelease.Inhibition of the enzymes involvedin dopamine degradation, catecholamine-oxygen-methyl-transferase(COMT) and monoamineoxidase (MAO),is another means to increase actualavailable dopamine concentration(COMT-inhibitors, p. 188), MAO B-inhibitors,p. 88, 188).Dopamine antagonist activity is thehallmark of classical neuroleptics. Theantihypertensive agents, reserpine (obsolete)and α-methyldopa, deplete neuronalstores of the amine. A common adverseeffect of dopamine antagonists ordepletors is parkinsonism.Histamine (B). Histamine is storedin basophils and tissue mast cells. Itplays a role in inflammatory and allergicreactions (p. 72, 326) and producesbronchoconstriction, increased intestinalperistalsis, and dilation and increasedpermeability of small blood vessels.In the gastric mucosa, it is releasedfrom enterochromaffin-like cells andstimulates acid secretion by the parietalcells. In the CNS, it acts as a neuromodulator.Two receptor subtypes (G-protein-coupled),H 1 and H 2, are of therapeuticimportance; both mediate vascularresponses. Prejunctional H 3 receptorsexist in brain and the periphery.Antagonists. Most of the so-calledH 1-antihistamines also block other receptors,including M-cholinoceptors andD-receptors. H 1-antihistamines are usedfor the symptomatic relief of allergies(e.g., bamipine, chlorpheniramine, clemastine,dimethindene, mebhydrolinepheniramine); as antiemetics (meclizine,dimenhydrinate, p. 330), as overthe-counterhypnotics (e.g., diphenhydramine,p. 222). Promethazine representsthe transition to the neurolepticphenothiazines (p. 236). Unwanted effectsof most H 1-antihistamines are lassitude(impaired driving skills) and atropine-likereactions (e.g., dry mouth, constipation).At the usual therapeutic doses,astemizole, cetrizine, fexofenadine,and loratidine are practically devoid ofsedative and anticholinergic effects. H 2-antihistamines (cimetidine, ranitidine,famotidine, nizatidine) inhibit gastricacid secretion, and thus are useful in thetreatment of peptic ulcers.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
<strong>Bio</strong>genic Amines 115Dopaminergic neuronIncrease in dopamine synthesisL-DopaInhibition of synthesis and formationof false transmitter: MethyldopaDestruction of storage vesicles: ReserpineDopaminD 2 -Agonistse.g., bromocriptineD 1 /D 2 -AntagonistsNeurolepticsD 2 -Antagonistse.g., metoclopramideD 1D 2ReceptorsStriatum (extrapyramidal motor function)Area postrema (emesis)Adenohypophysis (prolactin secretion )DopamineD 1 -Agonistse.g., fenoldopamBloodflowA. Dopamine actions as influenced by drugsH 1 -Antagonistse.g., fexofenadineH 1 -ReceptorsHistamineH 2 -Antagonistse.g., ranitidineH 2 -ReceptorsBronchoconstrictionBowel peristalsisVasodilationpermeabilityHCl“H 1 -Antihistamines”DiphenhydramineChlorpromazineParietal cellAcetylcholinemACh-ReceptorSedation,hypnotic,antiemeticactionDopamineDopamine receptorsB. Histamine actions as influenced by drugsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
116 <strong>Bio</strong>genic AminesInhibitors of histamine release: Oneof the effects of the so-called mast cellstabilizers cromoglycate (cromolyn)and nedocromil is to decrease the releaseof histamine from mast cells (p.72, 326). Both agents are applied topically.Release of mast cell mediators canalso be inhibited by some H 1 antihistamines,e.g., oxatomide and ketotifen,which are used systemically.SerotoninOccurrence. Serotonin (5-hydroxytryptamine,5-HT) is synthesized from L-tryptophan in enterochromaffin cells ofthe intestinal mucosa. 5-HT-synthesizingneurons occur in the enteric nerveplexus and the CNS, where the aminefulfills a neuromediator function. Bloodplatelets are unable to synthesize 5HT,but are capable of taking up, storing,and releasing it.Serotonin receptors. Based on biochemicaland pharmacological criteria,seven receptor classes can be distinguished.<strong>Of</strong> major pharmacotherapeuticimportance are those designated 5-HT 1,5-HT 2, 5-HT 4, and 5-HT 7, all of which areG-protein-coupled, whereas the 5-HT 3subtype represents a ligand-gated nonselectivecation channel.Serotonin actions. The cardiovasculareffects of 5-HT are complex, becausemultiple, in part opposing, effects areexerted via the different receptor subtypes.Thus, 5-HT 2A and 5-HT 7 receptorson vascular smooth muscle cells mediatedirect vasoconstriction and vasodilation,respectively. Vasodilation andlowering of blood pressure can also occurby several indirect mechanisms: 5-HT 1A receptors mediate sympathoinhibition( decrease in neurogenic vasoconstrictortonus) both centrally andperipherally; 5-HT 2B receptors on vascularendothelium promote release ofvasorelaxant mediators (NO, p. 120;prostacyclin, p. 196) 5-HT released fromplatelets plays a role in thrombogenesis,hemostasis, and the pathogenesis ofpreeclamptic hypertension.Ketanserin is an antagonist at 5-HT 2A receptors and produces antihypertensiveeffects, as well as inhibition ofthrombocyte aggregation. Whether 5-HT antagonism accounts for its antihypertensiveeffect remains questionable,because ketanserin also blocks α-adrenoceptors.Sumatriptan and other triptans areantimigraine drugs that possess agonistactivity at 5-HT 1 receptors of the B, Dand F subtypes and may thereby alleviatethis type of headache (p. 322).Gastrointestinal tract. Serotoninreleased from myenteric neurons or enterochromaffincells acts on 5-HT 3 and5-HT 4 receptors to enhance bowel motilityand enteral fluid secretion. Cisaprideis a prokinetic agent that promotespropulsive motor activity in thestomach and in small and large intestines.It is used in motility disorders. Itsmechanism of action is unclear, butstimulation of 5HT 4 receptors may beimportant.Central Nervous System. Serotoninergicneurons play a part in variousbrain functions, as evidenced by the effectsof drugs likely to interfere with serotonin.Fluoxetine is an antidepressantthat, by blocking re-uptake, inhibits inactivationof released serotonin. Its activityspectrum includes significant psychomotorstimulation, depression of appetite,and anxiolysis. Buspirone also hasanxiolytic properties thought to be mediatedby central presynaptic 5-HT 1A receptors.Ondansetron, an antagonist atthe 5-HT 3 receptor, possesses strikingeffectiveness against cytotoxic drug-inducedemesis, evident both at the startof and during cytostatic therapy. Tropisetronand granisetron produce analogouseffects.Psychedelics (LSD) and other psychotomimeticssuch as mescaline andpsilocybin can induce states of alteredawareness, or induce hallucinations andanxiety, probably mediated by 5-HT 2Areceptors. Overactivity of these receptorsmay also play a role in the genesisof negative symptoms in schizophrenia(p. 238) and sleep disturbances.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
<strong>Bio</strong>genic Amines 117Serotoninergic neuronLSDLysergic acid diethylamidePsychedelic5-HT 1ABuspironeAnxiolyticHallucination5-HT 2AOndansetronAntiemeticFluoxetine5-HT- reuptakeinhibitor5-HT 3Antidepressant5-HT 1DEmesisSumatriptanAntimigraine5-Hydroxy-tryptamineCisaprideSerotoninProkineticBlood vesselIntestineEndotheliummediatedDilation5-HT 2B5-HT 4PlateletsConstrictionPropulsivemotility5-HT 2EnterochromaffincellA. Serotonin receptors and actionsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
118 VasodilatorsVasodilators–OverviewThe distribution of blood within the circulationis a function of vascular caliber.Venous tone regulates the volume ofblood returned to the heart, hence,stroke volume and cardiac output. Theluminal diameter of the arterial vasculaturedetermines peripheral resistance.Cardiac output and peripheral resistanceare prime determinants of arterialblood pressure (p. 314).In A, the clinically most importantvasodilators are presented in the orderof approximate frequency of therapeuticuse. Some of these agents possessdifferent efficacy in affecting the venousand arterial limbs of the circulation(width of beam).Possible uses. Arteriolar vasodilatorsare given to lower blood pressure inhypertension (p. 312), to reduce cardiacwork in angina pectoris (p. 308), and toreduce ventricular afterload (pressureload) in cardiac failure (p. 132). Venousvasodilators are used to reduce venousfilling pressure (preload) in angina pectoris(p. 308) or cardiac failure (p. 132).Practical uses are indicated for eachdrug group.Counter-regulation in acute hypotensiondue to vasodilators (B). Increasedsympathetic drive raises heartrate (reflex tachycardia) and cardiacoutput and thus helps to elevate bloodpressure. Patients experience palpitations.Activation of the renin-angiotensin-aldosterone(RAA) system serves toincrease blood volume, hence cardiacoutput. Fluid retention leads to an increasein body weight and, possibly,edemas. These counter-regulatory processesare susceptible to pharmacologicalinhibition (β-blockers, ACE inhibitors,AT1-antagonists, diuretics).Mechanisms of action. The tonusof vascular smooth muscle can be decreasedby various means. ACE inhibitors,antagonists at AT1-receptors andantagonists at α-adrenoceptors protectagainst the effects of excitatory mediatorssuch as angiotensin II and norepinephrine,respectively. Prostacyclin analoguessuch as iloprost, or prostaglandinE 1 analogues such as alprostanil,mimic the actions of relaxant mediators.Ca 2+ antagonists reduce depolarizing inwardCa 2+ currents, while K + -channel activatorspromote outward (hyperpolarizing)K + currents. Organic nitrovasodilatorsgive rise to NO, an endogenousactivator of guanylate cyclase.Individual vasodilators. Nitrates(p. 120) Ca 2+ -antagonists (p. 122). α 1-antagonists (p. 90), ACE-inhibitors, AT1-antagonists (p. 124); and sodium nitroprusside(p. 120) are discussed elsewhere.Dihydralazine and minoxidil (viaits sulfate-conjugated metabolite) dilatearterioles and are used in antihypertensivetherapy. They are, however, unsuitablefor monotherapy because of compensatorycirculatory reflexes. Themechanism of action of dihydralazine isunclear. Minoxidil probably activates K +channels, leading to hyperpolarizationof smooth muscle cells. Particular adversereactions are lupus erythematosuswith dihydralazine and hirsutismwith minoxidil—used topically for thetreatment of baldness (alopecia androgenetica).Diazoxide given i.v. causes prominentarteriolar dilation; it can be employedin hypertensive crises. After itsoral administration, insulin secretion isinhibited. Accordingly, diazoxide can beused in the management of insulin-secretingpancreatic tumors. Both effectsare probably due to opening of (ATPgated)K + channels.The methylxanthine theophylline(p. 326), the phosphodiesterase inhibitoramrinone (p. 132), prostacyclins (p.197), and nicotinic acid derivatives (p.156) also possess vasodilating activity.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Vasodilators 119Venous bed Vasodilation Arterial bedNitratesCa-antagonistsACE-inhibitorsDihydralazineMinoxidilα 1 -AntagonistsNitroprusside sodiumA. VasodilatorsSympathetic nervesVasoconstrictionVasodilationBloodpressureVasomotorcenterHeart rateBlood volumeβ-BlockerCardiacoutputBloodpressureAngiotensinconvertingenzyme(ACE)ACE-inhibitorsReninAngiotensinogen AldosteroneAngiotensin IAngiotensin II VasoconstrictionRenin-angiotensin-aldosterone-systemB. Counter-regulatory responses in hypotension due to vasodilatorsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
120 VasodilatorsOrganic NitratesVarious esters of nitric acid (HNO 3) andpolyvalent alcohols relax vascularsmooth muscle, e.g., nitroglycerin (glyceryltrinitrate)and isosorbide dinitrate.The effect is more pronounced in venousthan in arterial beds.These vasodilator effects producehemodynamic consequences that canbe put to therapeutic use. Due to a decreasein both venous return (preload)and arterial afterload, cardiac work isdecreased (p. 308). As a result, the cardiacoxygen balance improves. Spasmodicconstriction of larger coronaryvessels (coronary spasm) is prevented.Uses. Organic nitrates are usedchiefly in angina pectoris (p. 308, 310),less frequently in severe forms of chronicand acute congestive heart failure.Continuous intake of higher doses withmaintenance of steady plasma levelsleads to loss of efficacy, inasmuch as theorganism becomes refractory (tachyphylactic).This “nitrate tolerance” canbe avoided if a daily “nitrate-free interval”is maintained, e.g., overnight.At the start of therapy, unwantedreactions occur frequently in the formof a throbbing headache, probablycaused by dilation of cephalic vessels.This effect also exhibits tolerance, evenwhen daily “nitrate pauses” are kept.Excessive dosages give rise to hypotension,reflex tachycardia, and circulatorycollapse.Mechanism of action. The reductionin vascular smooth muscle tone ispresumably due to activation of guanylatecyclase and elevation of cyclic GMPlevels. The causative agent is most likelynitric oxide (NO) generated from the organicnitrate. NO is a physiological messengermolecule that endothelial cellsrelease onto subjacent smooth musclecells (“endothelium-derived relaxingfactor,” EDRF). Organic nitrates wouldthus utilize a pre-existing pathway,hence their high efficacy. The generationof NO within the smooth musclecell depends on a supply of free sulfhydryl(-SH) groups; “nitrate-tolerance”has been attributed to a cellular exhaustionof SH-donors but this may be notthe only reason.Nitroglycerin (NTG) is distinguishedby high membrane penetrabilityand very low stability. It is the drugof choice in the treatment of angina pectorisattacks. For this purpose, it is administeredas a spray, or in sublingual orbuccal tablets for transmucosal delivery.The onset of action is between 1 and3 min. Due to a nearly complete presystemicelimination, it is poorly suitedfor oral administration. Transdermal delivery(nitroglycerin patch) also avoidspresystemic elimination. Isosorbidedinitrate (ISDN) penetrates wellthrough membranes, is more stablethan NTG, and is partly degraded intothe weaker, but much longer acting, 5-isosorbide mononitrate (ISMN). ISDNcan also be applied sublingually; however,it is mainly administered orally inorder to achieve a prolonged effect.ISMN is not suitable for sublingual usebecause of its higher polarity and slowerrate of absorption. Taken orally, it is absorbedand is not subject to first-passelimination.Molsidomine itself is inactive. Afteroral intake, it is slowly convertedinto an active metabolite. Apparently,there is little likelihood of "nitrate tolerance”.Sodium nitroprusside contains anitroso (-NO) group, but is not an ester.It dilates venous and arterial bedsequally. It is administered by infusion toachieve controlled hypotension undercontinuous close monitoring. Cyanideions liberated from nitroprusside can beinactivated with sodium thiosulfate(Na 2S 2O 3) (p. 304).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Vasodilators 121PreloadO 2 -supplyAfterloadO 2 -demandBlood pressureVenous blood returnto heartPrevention ofcoronary arteryspasmPeripheralresistanceVenous bed“Nitratetolerance”Arterial bedRoute:e.g., sublingual,transdermalVasodilationRoute:e.g., sublingual,oral, transdermalGlyceryl trinitrateNitroglycerin“Nitrates”Isosorbide dinitrateNOt 12 ~ 2 mint 12 ~ 30 minNOInactivation5-Isosorbide mononitrate,an active metabolitet 1 2~ 240 minR – O – NO 2SH-donorse.g., glutathioneRelease ofNOConsumptionActivation ofguanylate cyclaseActivemetaboliteGTPSmooth muscle cellcGMPRelaxationMolsidomine(precursor)A. Vasodilators: NitratesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
122 VasodilatorsCalcium AntagonistsDuring electrical excitation of the cellmembrane of heart or smooth muscle,different ionic currents are activated,including an inward Ca 2+ current. Theterm Ca 2+ antagonist is applied to drugsthat inhibit the influx of Ca 2+ ions withoutaffecting inward Na + or outward K +currents to a significant degree. Otherlabels are Ca-entry blocker or Ca-channelblocker. Therapeutically used Ca 2+ antagonistscan be divided into threegroups according to their effects onheart and vasculature.I. Dihydropyridine derivatives.The dihydropyridines, e.g., nifedipine,are uncharged hydrophobic substances.They induce a relaxation of vascularsmooth muscle in arterial beds. An effecton cardiac function is practically absentat therapeutic dosage. (However, inpharmacological experiments on isolatedcardiac muscle preparations a clearnegative inotropic effect is demonstrable.)They are thus regarded as vasoselectiveCa 2+ antagonists. Because ofthe dilatation of resistance vessels,blood pressure falls. Cardiac afterload isdiminished (p. 306) and, therefore, alsooxygen demand. Spasms of coronary arteriesare prevented.Indications for nifedipine includeangina pectoris (p. 308) and, — when appliedas a sustained release preparation,— hypertension (p. 312). In angina pectoris,it is effective when given eitherprophylactically or during acute attacks.Adverse effects are palpitation (reflextachycardia due to hypotension), headache,and pretibial edema.Nitrendipine and felodipine are usedin the treatment of hypertension. Nimodipineis given prophylactically aftersubarachnoidal hemorrhage to preventvasospasms due to depolarization byexcess K + liberated from disintegratingerythrocytes or blockade of NO by freehemoglobin.II. Verapamil and other catamphiphilicCa 2+ antagonists. Verapamil containsa nitrogen atom bearing a positivecharge at physiological pH and thus representsa cationic amphiphilic molecule.It exerts inhibitory effects not only onarterial smooth muscle, but also on heartmuscle. In the heart, Ca 2+ inward currentsare important in generating depolarizationof sinoatrial node cells (impulsegeneration), in impulse propagationthrough the AV- junction (atrioventricularconduction), and in electromechanicalcoupling in the ventricular cardiomyocytes.Verapamil thus producesnegative chrono-, dromo-, and inotropiceffects.Indications. Verapamil is used asan antiarrhythmic drug in supraventriculartachyarrhythmias. In atrial flutteror fibrillation, it is effective in reducingventricular rate by virtue of inhibitingAV-conduction. Verapamil is also employedin the prophylaxis of angina pectorisattacks (p. 308) and the treatmentof hypertension (p. 312). Adverse effects:Because of verapamil’s effects onthe sinus node, a drop in blood pressurefails to evoke a reflex tachycardia. Heartrate hardly changes; bradycardia mayeven develop. AV-block and myocardialinsufficiency can occur. Patients frequentlycomplain of constipation.Gallopamil (= methoxyverapamil) isclosely related to verapamil in bothstructure and biological activity.Diltiazem is a catamphiphilic benzothiazepinederivative with an activityprofile resembling that of verapamil.III. T-channel selective blockers.Ca 2+ -channel blockers, such as verapamiland mibefradil, may block both L-and T-type Ca 2+ channels. Mibefradilshows relative selectivity for the latterand is devoid of a negative inotropic effect;its therapeutic usefulness is compromisedby numerous interactionswith other drugs due to inhibition of cytochromeP 450-dependent enzymes(CYP 1A2, 2D6 and, especially, 3A4).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Vasodilators 123Smooth muscle cellAfterloadO 2 -demandContractionCa 2+Inhibition ofcoronary spasmArterialblood vesselBlood pressurePeripheralresistanceVasodilation in arterial bedNa + Ca 2+10 -3 MNifedipine(dihydropyridine derivative)Membrane depolarizationCa 2+10 -7 MSelectiveinhibition ofcalcium influxK +Verapamil(cationic amphiphilic)Inhibition of cardiac functionsCa 2+Sinus nodeImpulsegenerationHeart rateReflex tachycardiawith nifedipineAV-nodeImpulseconductionAVconductionVentricularmuscleElectromechanicalcouplingContractilityHeart muscle cellA.Vasodilators: calcium antagonistsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
124 Inhibitors of the RAA SystemInhibitors of the RAA SystemAngiotensin-converting enzyme (ACE)is a component of the antihypotensiverenin-angiotensin-aldosterone (RAA)system. Renin is produced by specializedcells in the wall of the afferent arterioleof the renal glomerulus. Thesecells belong to the juxtaglomerular apparatusof the nephron, the site of contactbetween afferent arteriole and distaltubule, and play an important part incontrolling nephron function. Stimulieliciting release of renin are: a drop inrenal perfusion pressure, decreased rateof delivery of Na + or Cl – to the distal tubules,as well as β-adrenoceptor-mediatedsympathoactivation. The glycoproteinrenin enzymatically cleaves thedecapeptide angiotensin I from its circulatingprecursor substrate angiotensinogen.ACE, in turn, produces biologicallyactive angiotensin II (ANG II) fromangiotensin I (ANG I).ACE is a rather nonspecific peptidasethat can cleave C-terminal dipeptidesfrom various peptides (dipeptidylcarboxypeptidase). As “kininase II,” itcontributes to the inactivation of kinins,such as bradykinin. ACE is also present inblood plasma; however, enzyme localizedin the luminal side of vascular endotheliumis primarily responsible for theformation of angiotensin II. The lung isrich in ACE, but kidneys, heart, and otherorgans also contain the enzyme.Angiotensin II can raise blood pressurein different ways, including (1)vasoconstriction in both the arterial andvenous limbs of the circulation; (2)stimulation of aldosterone secretion,leading to increased renal reabsorptionof NaCl and water, hence an increasedblood volume; (3) a central increase insympathotonus and, peripherally, enhancementof the release and effects ofnorepinephrine.ACE inhibitors, such as captopriland enalaprilat, the active metabolite ofenalapril, occupy the enzyme as falsesubstrates. Affinity significantly influencesefficacy and rate of elimination.Enalaprilat has a stronger and longerlastingeffect than does captopril. Indicationsare hypertension and cardiacfailure.Lowering of an elevated blood pressureis predominantly brought about bydiminished production of angiotensin II.Impaired degradation of kinins that exertvasodilating actions may contributeto the effect.In heart failure, cardiac output risesagain because ventricular afterload diminishesdue to a fall in peripheral resistance.Venous congestion abates as aresult of (1) increased cardiac outputand (2) reduction in venous return (decreasedaldosterone secretion, decreasedtonus of venous capacitancevessels).Undesired effects. The magnitudeof the antihypertensive effect of ACE inhibitorsdepends on the functional stateof the RAA system. When the latter hasbeen activated by loss of electrolytesand water (resulting from treatmentwith diuretic drugs), cardiac failure, orrenal arterial stenosis, administration ofACE inhibitors may initially cause an excessivefall in blood pressure. In renalarterial stenosis, the RAA system may beneeded for maintaining renal functionand ACE inhibitors may precipitate renalfailure. Dry cough is a fairly frequentside effect, possibly caused by reducedinactivation of kinins in the bronchialmucosa. Rarely, disturbances of tastesensation, exanthema, neutropenia,proteinuria, and angioneurotic edemamay occur. In most cases, ACE inhibitorsare well tolerated and effective. Neweranalogues include lisinopril, perindopril,ramipril, quinapril, fosinopril, benazepril,cilazapril, and trandolapril.Antagonists at angiotensin II receptors.Two receptor subtypes can bedistinguished: AT1, which mediates theabove actions of AT II; and AT2, whosephysiological role is still unclear. Thesartans (candesartan, eprosartan, irbesartan,losartan, and valsartan) are AT1antagonists that reliably lower highblood pressure. They do not inhibitdegradation of kinins and cough is not afrequent side-effect.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Inhibitors of the RAA System 125KidneyRRHOOCACE inhibitorsONCH 3SHCaptoprilHOOCONReninCH 3O O CH 3Enalaprilat EnalaprilAngiotensinogen(α 2 -globulin)COOHAngiotensin I (Ang I)Ang IACEAngiotensin I-convertingenzymeKininaseIIDipeptidyl-CarboxypeptidaseKininsACEVascularendotheliumAngiotensin IIH 2 NReceptorsAng IIClNH 3 CCH 2 OHNNNDegradationproductsHNNAT 1 -receptor antagonistsLosartanVenoussupplyCardiacoutputArterialbloodpressurevenouscapacitancevesselsVasoconstrictionResistance vesselsPeripheralresistanceNaClH 2 OAldosteronesecretionSympathoactivationK +A. Renin-angiotensin-aldosterone system and inhibitorsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
126 Drugs Acting on Smooth MuscleDrugs Used to Influence Smooth MuscleOrgansBronchodilators. Narrowing of bronchiolesraises airway resistance, e.g., inbronchial or bronchitic asthma. Severalsubstances that are employed as bronchodilatorsare described elsewhere inmore detail: β 2-sympathomimetics (p.84, given by pulmonary, parenteral, ororal route), the methylxanthine theophylline(p. 326, given parenterally ororally), as well as the parasympatholyticipratropium (pp. 104, 107, given by inhalation).Spasmolytics. N-Butylscopolamine(p. 104) is used for the relief of painfulspasms of the biliary or ureteral ducts.Its poor absorption (N.B. quaternary N;absorption rate
Drugs Acting on Smooth Muscle 127Bronchial asthmaBiliary / renal colicO 2Spasm ofsmooth muscleBronchodilationTheophyllineSpasmolysisN-ButylscopolamineScopolamineInhibition of laborβ 2 -SympathomimeticsInduction of laborOxytocinβ 2 -Sympathomimeticse.g., fenoterolIpratropiumNitratese.g., nitroglycerinProstaglandinsF 2α , E 2Secale cornutum(ergot)Tonic contraction of uteruse.g., ergometrineO 2Contraindication:before deliveryFungus:Claviceps purpureaSecale alkaloidsIndication:postpartumuterine atoniaEffect onvasomotor tonee.g., ergotamineA. Drugs used to alter smooth muscle functionFixation of lumen at intemediate caliberLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
128 Cardiac DrugsOverview of Modes of Action (A)1. The pumping capacity of the heart isregulated by sympathetic and parasympatheticnerves (pp. 84, 105). Drugs capableof interfering with autonomicnervous function therefore provide ameans of influencing cardiac performance.Thus, anxiolytics of the benzodiazepinetype (p. 226), such as diazepam,can be employed in myocardial infarctionto suppress sympathoactivationdue to life-threatening distress.Under the influence of antiadrenergicagents (p. 96), used to lower an elevatedblood pressure, cardiac work is decreased.Ganglionic blockers (p. 108)are used in managing hypertensiveemergencies. Parasympatholytics (p.104) and β-blockers (p. 92) prevent thetransmission of autonomic nerve impulsesto heart muscle cells by blockingthe respective receptors.2. An isolated mammalian heartwhose extrinsic nervous connectionshave been severed will beat spontaneouslyfor hours if it is supplied with anutrient medium via the aortic trunkand coronary arteries (Langendorffpreparation). In such a preparation, onlythose drugs that act directly on cardiomyocyteswill alter contractile force andbeating rate.Parasympathomimetics and sympathomimeticsact at membrane receptorsfor visceromotor neurotransmitters.The plasmalemma also harborsthe sites of action of cardiac glycosides(the Na/K-ATPases, p. 130), of Ca 2+ antagonists(Ca 2+ channels, p. 122), and ofagents that block Na + channels (localanesthetics; p. 134, p. 204). An intracellularsite is the target for phosphodiesteraseinhibitors (e.g., amrinone, p. 132).3. Mention should also be made ofthe possibility of affecting cardiac functionin angina pectoris (p. 306) or congestiveheart failure (p. 132) by reducingvenous return, peripheral resistance,or both, with the aid of vasodilators;and by reducing sympathetic driveapplying β-blockers.Events Underlying Contraction andRelaxation (B)The signal triggering contraction is apropagated action potential (AP) generatedin the sinoatrial node. Depolarizationof the plasmalemma leads to a rapidrise in cytosolic Ca 2+ levels, whichcauses the contractile filaments toshorten (electromechanical coupling).The level of Ca 2+ concentration attaineddetermines the degree of shortening,i.e., the force of contraction. Sources ofCa 2+ are: a) extracellular Ca 2+ enteringthe cell through voltage-gated Ca 2+channels; b) Ca 2+ stored in membranoussacs of the sarcoplasmic reticulum (SR);c) Ca 2+ bound to the inside of the plasmalemma.The plasmalemma of cardiomyocytesextends into the cell interiorin the form of tubular invaginations(transverse tubuli).The trigger signal for relaxation isthe return of the membrane potential toits resting level. During repolarization,Ca 2+ levels fall below the threshold foractivation of the myofilaments (310 –7M), as the plasmalemmal binding sitesregain their binding capacity; the SRpumps Ca 2+ into its interior; and Ca 2+that entered the cytosol during systoleis again extruded by plasmalemmalCa 2+ -ATPases with expenditure of energy.In addition, a carrier (antiporter),utilizing the transmembrane Na + gradientas energy source, transports Ca 2+ outof the cell in exchange for Na + movingdown its transmembrane gradient(Na + /Ca 2+ exchange).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Cardiac Drugs 129Drugs withindirect actionPsychotropicdrugsSympatholyticsGanglionicblockersSympatheticEpinephrineCardiacglycosidesForceDrugs with direct actionNutrient solutionForceRateβ-SympathomimeticsPhosphodiesterase inhibitorsRateParasympathomimeticsCatamphiphilicCa-antagonistsLocal anestheticsA. Possible mechanisms for influencing heart functionContractionelectricalexcitationCa 2 +10 -3 M0Membrane potential[mV]Ca-channelSarcoplasmicreticulumHeart muscle cellTransversetubuleCa 2+10 -5 M-80Action potentialtRelaxationCa 2 +10 -3 MNa +ForceParasympatheticNa/CaexchangePlasmalemmalbinding sitesNa +Ca 2+Ca 2+10 -7 MCa-ATPaseCa 2+ Ca 2+Na +B. Processes in myocardial contraction and relaxationContraction300 mstLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
130 Cardiac DrugsCardiac GlycosidesDiverse plants (A) are sources of sugarcontainingcompounds (glycosides) thatalso contain a steroid ring (structuralformulas, p. 133) and augment the contractileforce of heart muscle (B): cardiotonicglycosides. cardiosteroids, or “digitalis.”If the inotropic, “therapeutic” doseis exceeded by a small increment, signsof poisoning appear: arrhythmia andcontracture (B). The narrow therapeuticmargin can be explained by the mechanismof action.Cardiac glycosides (CG) bind to theextracellular side of Na + /K + -ATPases ofcardiomyocytes and inhibit enzyme activity.The Na + /K + -ATPases operate topump out Na + leaked into the cell and toretrieve K + leaked from the cell. In thismanner, they maintain the transmembranegradients for K + and Na + , the negativeresting membrane potential, andthe normal electrical excitability of thecell membrane. When part of the enzymeis occupied and inhibited by CG,the unoccupied remainder can increaseits level of activity and maintain Na + andK + transport. The effective stimulus is asmall elevation of intracellular Na + concentration(normally approx. 7 mM).Concomitantly, the amount of Ca 2+ mobilizedduring systole and, thus, contractileforce, increases. It is generallythought that the underlying cause is thedecrease in the Na + transmembranegradient, i.e., the driving force for theNa + /Ca 2+ exchange (p. 128), allowing theintracellular Ca 2+ level to rise. When toomany ATPases are blocked, K + and Na +homeostasis is deranged; the membranepotential falls, arrhythmias occur.Flooding with Ca 2+ prevents relaxationduring diastole, resulting in contracture.The CNS effects of CG (C) are alsodue to binding to Na + /K + -ATPases. Enhancedvagal nerve activity causes a decreasein sinoatrial beating rate and velocityof atrioventricular conduction. Inpatients with heart failure, improvedcirculation also contributes to the reductionin heart rate. Stimulation of thearea postrema leads to nausea and vomiting.Disturbances in color vision areevident.Indications for CG are: (1) chroniccongestive heart failure; and (2) atrialfibrillation or flutter, where inhibition ofAV conduction protects the ventriclesfrom excessive atrial impulse activityand thereby improves cardiac performance(D). Occasionally, sinus rhythmis restored.Signs of intoxication are: (1) cardiacarrhythmias, which under certaincircumstances are life-threatening, e.g.,sinus bradycardia, AV-block, ventricularextrasystoles, ventricular fibrillation(ECG); (2) CNS disturbances — alteredcolor vision (xanthopsia), agitation,confusion, nightmares, hallucinations;(3) gastrointestinal — anorexia, nausea,vomiting, diarrhea; (4) renal — loss ofelectrolytes and water, which must bedifferentiated from mobilization of accumulatededema fluid that occurs withtherapeutic dosage.Therapy of intoxication: administrationof K + , which inter alia reducesbinding of CG, but may impair AV-conduction;administration of antiarrhythmics,such as phenytoin or lidocaine (p.136); oral administration of colestyramine(p. 154, 156) for binding and preventingabsorption of digitoxin presentin the intestines (enterohepatic cycle);injection of antibody (Fab) fragmentsthat bind and inactivate digitoxin anddigoxin. Compared with full antibodies,fragments have superior tissue penetrability,more rapid renal elimination,and lower antigenicity.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Cardiac Drugs 131Helleborus nigerChristmas roseDigitalis purpureaRed foxgloveConvallariamajalisLily of the valleyA. Plants containing cardiac glycosidesContractionArrhythmiaContractureTime ´therapeutic´ ´toxic´ Dose of cardiac glycoside (CG)Na/K-ATPaseCGCGNa + Na +CouplingCa 2+Ca 2+K +K +Na +K + Ca 2+CGK + Na + Disturbance ofHeart muscle cellCGCGB. Therapeutic and toxic effects of cardiac glycosides (CG)color vision"Re-entrant"excitation inatrialfibrillationExcitation ofN. vagus:Heart rateCardiacglycosideDecrease inventricularrateArea postrema:nausea, vomitingC. Cardiac glycoside effects on the CNSD. Cardiac glycoside effects inatrial fibrillationLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
132 Cardiac DrugsSubstance Fraction Plasma concentr. Digitalizing Elimination Maintenanceabsorbed free total dose dose% (ng/mL) (mg) %/d (mg)Digitoxin 100 1 20 1 10 0.1Digoxin 50–90 1 1.5 1 30 0.3Ouabain
Cardiac Drugs 133OuabainPlasmaDigoxin95%Digitoxin0%35%AlbuminLivercellDigitoxinDigoxinCleavageof sugarConjugationIntestinal epitheliumRenal tubularepitheliumDeconjugationPlasma t 129 h 2 – 3 days 5 – 7 daysA. Pharmacokinetics of cardiac glycosidesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
134 Cardiac DrugsAntiarrhythmic DrugsThe electrical impulse for contraction(propagated action potential; p. 136)originates in pacemaker cells of the sinoatrialnode and spreads through theatria, atrioventricular (AV) node, andadjoining parts of the His-Purkinje fibersystem to the ventricles (A). Irregularitiesof heart rhythm can interfere dangerouslywith cardiac pumping function.I. Drugs for selective control of sinoatrialand AV nodes. In some formsof arrhythmia, certain drugs can be usedthat are capable of selectively facilitatingand inhibiting (green and red arrows,respectively) the pacemaker functionof sinoatrial or atrioventricularcells.Sinus bradycardia. An abnormallylow sinoatrial impulse rate (100 beats/min). β-Blockers eliminatesympathoexcitation and decrease cardiacrate.Atrial flutter or fibrillation. An excessiveventricular rate can be decreasedby verapamil (p. 122) or cardiacglycosides (p. 130). These drugs inhibitimpulse propagation through the AVnode, so that fewer impulses reach theventricles.II. Nonspecific drug actions onimpulse generation and propagation.Impulses originating at loci outside thesinus node are seen in supraventricularor ventricular extrasystoles, tachycardia,atrial or ventricular flutter, and fibrillation.In these forms of rhythm disorders,antiarrhythmics of the local anesthetic,Na + -channel blocking type (B) areused for both prophylaxis and therapy.Local anesthetics inhibit electrical excitationof nociceptive nerve fibers (p.204); concomitant cardiac inhibition(cardiodepression) is an unwanted effect.However, in certain types of arrhythmias(see above), this effect is useful.Local anesthetics are readily cleaved(arrows) and unsuitable for oral administration(procaine, lidocaine). Given judiciously,intravenous lidocaine is an effectiveantiarrhythmic. Procainamideand mexiletine, congeners endowedwith greater metabolic stability, are examplesof orally effective antiarrhythmics.The desired and undesired effectsare inseparable. Thus, these antiarrhythmicsnot only depress electricalexcitability of cardiomyocytes (negativebathmotropism, membrane stabilization),but also lower sinoatrial rate (neg.chronotropism), AV conduction (neg.dromotropism), and force of contraction(neg. inotropism). Interference with normalelectrical activity can, not too paradoxically,also induce cardiac arrhythmias–arrhythmogenicaction.Inhibition of CNS neurons is theunderlying cause of neurological effectssuch as vertigo, confusion, sensory disturbances,and motor disturbances(tremor, giddiness, ataxia, convulsions).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Cardiac Drugs 135Sinus nodeAtriumAV-nodeParasympatholyticsβ-SympathomimeticsBundle of HisTawara´snodePurkinjefibersVentricleβ-BlockerVerapamilCardiacglycoside(Vagalstimulation)A. Cardiac impulse generation and conductionMain effectAntiarrhythmiceffectAntiarrhythmics of the local anesthetic(Na+-channel blocking) type:Inhibition of impulse generation and conductionEsterasesProcaineAdverse effectsProcainamideLidocaineCNS-disturbancesMexiletineArrhythmiaCardiodepressionB. Antiarrhythmics of the Na+-channel blocking typeLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
136 Cardiac DrugsElectrophysiological Actions ofAntiarrhythmics of the Na + -ChannelBlocking TypeAction potential and ionic currents.The transmembrane electrical potentialof cardiomyocytes can be recordedthrough an intracellular microelectrode.Upon electrical excitation, a characteristicchange occurs in membrane potential—theaction potential (AP). Its underlyingcause is a sequence of transientionic currents. During rapid depolarization(Phase 0), there is a short-lived influxof Na + through the membrane. Asubsequent transient influx of Ca 2+ (aswell as of Na + ) maintains the depolarization(Phase 2, plateau of AP). A delayedefflux of K + returns the membranepotential (Phase 3, repolarization) to itsresting value (Phase 4). The velocity ofdepolarization determines the speed atwhich the AP propagates through themyocardial syncytium.Transmembrane ionic currents involveproteinaceous membrane pores:Na + , Ca 2+ , and K + channels. In A, thephasic change in the functional state ofNa + channels during an action potentialis illustrated.Effects of antiarrhythmics. Antiarrhythmicsof the Na + -channel blockingtype reduce the probability that Na +channels will open upon membrane depolarization(“membrane stabilization”).The potential consequences are(A, bottom): 1) a reduction in the velocityof depolarization and a decrease inthe speed of impulse propagation; aberrantimpulse propagation is impeded. 2)Depolarization is entirely absent; pathologicalimpulse generation, e.g., in themarginal zone of an infarction, is suppressed.3) The time required until anew depolarization can be elicited, i.e.,the refractory period, is increased; prolongationof the AP (see below) contributesto the increase in refractory period.Consequently, premature excitationwith risk of fibrillation is prevented.Mechanism of action. Na + -channelblocking antiarrhythmics resemblemost local anesthetics in being cationicamphiphilic molecules (p. 208, exception:phenytoin, p. 190). Possible molecularmechanisms of their inhibitory effectsare outlined on p. 204 in more detail.Their low structural specificity isreflected by a low selectivity towardsdifferent cation channels. Besides theNa + channel, Ca 2+ and K + channels are alsolikely to be blocked. Accordingly, cationicamphiphilic antiarrhythmics affectboth the depolarization and repolarizationphases. Depending on the substance,AP duration can be increased(Class IA), decreased (Class IB), or remainthe same (Class IC).Antiarrhythmics representativeof these categories include: Class IA—quinidine, procainamide, ajmaline, disopyramide,propafenone; Class IB—lidocaine,mexiletine, tocainide, as well asphenytoin; Class IC—flecainide.Note: With respect to classification,β-blockers have been assigned to ClassII, and the Ca 2+ -channel blockers verapamiland diltiazem to Class IV.Commonly listed under a separaterubric (Class III) are amiodarone and theβ-blocking agent sotalol, which both inhibitK + -channels and which both causemarked prolongation of the AP with alesser effect on Phase 0 rate of rise.Therapeutic uses. Because of theirnarrow therapeutic margin, these antiarrhythmicsare only employed whenrhythm disturbances are of such severityas to impair the pumping action ofthe heart, or when there is a threat ofother complications. The choice of drugis empirical. If the desired effect is notachieved, another drug is tried. Combinationsof antiarrhythmics are not customary.Amiodarone is reserved for specialcases.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Cardiac Drugs 137[mV]1Membrane potential200Rate ofdepolarizationSpeed of APpropagation3Actionpotential(AP)-800Refractory period4250 Time [ms]Heart muscle cellNa + Ca 2+ (+Na + )K +Phase 0 Phases 1,2Phase 3 Phase 4FastNa + -entry”Slow Ca 2+ -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 inexcitabilityA. Effects of antiarrhythmics of the Na+-channel blocking typeLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
138 AntianemicsDrugs for the Treatment of AnemiasAnemia denotes a reduction in redblood cell count, hemoglobin content,or both. Oxygen (O 2) transport capacityis decreased.Erythropoiesis (A). Blood corpusclesdevelop from stem cells throughseveral cell divisions. Hemoglobin isthen synthesized and the cell nucleus isextruded. Erythropoiesis is stimulatedby the hormone erythropoietin (a glycoprotein),which is released from thekidneys when renal O 2 tension declines.Given an adequate production oferythropoietin, a disturbance of erythropoiesisis due to two principal causes:1. Cell multiplication is inhibited becauseDNA synthesis is insufficient. Thisoccurs in deficiencies of vitamin B 12 orfolic acid (macrocytic hyperchromicanemia). 2. Hemoglobin synthesis isimpaired. This situation arises in irondeficiency, since Fe 2+ is a constituent ofhemoglobin (microcytic hypochromicanemia).Vitamin B 12 (B)Vitamin B 12 (cyanocobalamin) is producedby bacteria; B 12 generated in thecolon, however, is unavailable for absorption(see below). Liver, meat, fish,and milk products are rich sources ofthe vitamin. The minimal requirementis about 1 µg/d. Enteral absorption of vitaminB 12 requires so-called “intrinsicfactor” from parietal cells of the stomach.The complex formed with this glycoproteinundergoes endocytosis in theileum. Bound to its transport protein,transcobalamin, vitamin B 12 is destinedfor storage in the liver or uptake into tissues.A frequent cause of vitamin B 12 deficiencyis atrophic gastritis leading to alack of intrinsic factor. Besides megaloblasticanemia, damage to mucosal liningsand degeneration of myelinsheaths with neurological sequelae willoccur (pernicious anemia).Optimal therapy consists in parenteraladministration of cyanocobalaminor hydroxycobalamin (VitaminB 12a; exchange of -CN for -OH group).Adverse effects, in the form of hypersensitivityreactions, are very rare.Folic Acid (B). Leafy vegetables andliver are rich in folic acid (FA). The minimalrequirement is approx. 50 µg/d.Polyglutamine-FA in food is hydrolyzedto monoglutamine-FA prior to being absorbed.FA is heat labile. Causes of deficiencyinclude: insufficient intake, malabsorptionin gastrointestinal diseases,increased requirements during pregnancy.Antiepileptic drugs (phenytoin,primidone, phenobarbital) may decreaseFA absorption, presumably by inhibitingthe formation of monoglutamine-FA.Inhibition of dihydro-FA reductase(e.g., by methotrexate, p. 298)depresses the formation of the activespecies, tetrahydro-FA. Symptoms of deficiencyare megaloblastic anemia andmucosal damage. Therapy consists inoral administration of FA or in folinicacid (p. 298) when deficiency is causedby inhibitors of dihydro—FA—reductase.Administration of FA can mask avitamin B 12 deficiency. Vitamin B 12 is requiredfor the conversion of methyltetrahydro-FAto tetrahydro-FA, which isimportant for DNA synthesis (B). Inhibitionof this reaction due to B 12 deficiencycan be compensated by increased FAintake. The anemia is readily corrected;however, nerve degeneration progressesunchecked and its cause is mademore difficult to diagnose by the absenceof hematological changes. Indiscriminateuse of FA-containing multivitaminpreparations can, therefore, beharmful.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antianemics 139Inhibition of DNAsynthesis(cell multiplication)Vit. B 12 deficiencyInhibition ofhemoglobin synthesisIron deficiencyFolate deficiencyA very few largehemoglobin-richerythrocytesA few smallhemoglobin-poorerythrocytesA. Erythropoiesis in bone marrowFolic acid H 4DNAsynthesisH 3 C- Folic acid H 4Vit. B 12Folic acidH 3 C- Vit. B 12H 3 C-Vit. B 12Storagesupply for3 yearsVit. B 12TranscobalaminIIIntrinsicfactorHClParietal celli.m.StreptomycesgriseusB. Vitamin B 12 and folate metabolismLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
140 AntianemicsIron CompoundsNot all iron ingested in food is equallyabsorbable. Trivalent Fe 3+ is virtuallynot taken up from the neutral milieu ofthe small bowel, where the divalent Fe 2+is markedly better absorbed. Uptake isparticularly efficient in the form ofheme (present in hemo- and myoglobin).Within the mucosal cells of the gut,iron is oxidized and either deposited asferritin (see below) or passed on to thetransport protein, transferrin, a β 1-glycoprotein.The amount absorbed doesnot exceed that needed to balance lossesdue to epithelial shedding from skinand mucosae or hemorrhage (so-called“mucosal block”). In men, this amountis approx. 1 mg/d; in women, it is approx.2 mg/d (menstrual blood loss),corresponding to about 10% of the dietaryintake. The transferrin-iron complexundergoes endocytotic uptakemainly into erythroblasts to be utilizedfor hemoglobin synthesis.About 70% of the total body store ofiron (~5 g) is contained within erythrocytes.When these are degraded by macrophagesof the reticuloendothelial(mononuclear phagocyte) system, ironis liberated from hemoglobin. Fe 3+ canbe stored as ferritin (= protein apoferritin+ Fe 3+ ) or returned to erythropoiesissites via transferrin.A frequent cause of iron deficiencyis chronic blood loss due to gastric/intestinalulcers or tumors. One liter ofblood contains 500 mg of iron. Despite asignificant increase in absorption rate(up to 50%), absorption is unable to keepup with losses and the body store of ironfalls. Iron deficiency results in impairedsynthesis of hemoglobin and anemia (p.138).The treatment of choice (after thecause of bleeding has been found andeliminated) consists of the oral administrationof Fe 2+ compounds, e.g., ferroussulfate (daily dose 100 mg of ironequivalent to 300 mg of FeSO 4, dividedinto multiple doses). Replenishing ofiron stores may take several months.Oral administration, however, is advantageousin that it is impossible to overloadthe body with iron through an intactmucosa because of its demand-regulatedabsorption (mucosal block).Adverse effects. The frequent gastrointestinalcomplaints (epigastricpain, diarrhea, constipation) necessitateintake of iron preparations with or aftermeals, although absorption is higherfrom the empty stomach.Interactions. Antacids inhibit ironabsorption. Combination with ascorbicacid (Vitamin C), for protecting Fe 2+from oxidation to Fe 3+ , is theoreticallysound, but practically is not needed.Parenteral administration of Fe 3+salts is indicated only when adequateoral replacement is not possible. Thereis a risk of overdosage with iron depositionin tissues (hemosiderosis). Thebinding capacity of transferrin is limitedand free Fe 3+ is toxic. Therefore, Fe 3+complexes are employed that can donateFe 3+ directly to transferrin or canbe phagocytosed by macrophages, enablingiron to be incorporated into ferritinstores. Possible adverse effects are,with i.m. injection: persistent pain atthe injection site and skin discoloration;with i.v. injection: flushing, hypotension,anaphylactic shock.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antianemics 141Fe III-SaltsOralintakeFe II-SaltsHeme-FeFe IIIFe IIIAbsorptionDuodenumupper jejunumFe IIIFerritinTransportplasmaFe IIITransferrinFe IIIParenteraladministrationi.v.i.m.Uptake intoerythroblastbone marrowHemoglobinFe III-complexesFe IIIErythrocytebloodLoss throughbleedingFerritinHemosiderin= aggregatedferritinUptake into macrophagesspleen, liver, bone marrowA. Iron: possible routes of administration and fate in the organismLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
142 AntithromboticsProphylaxis and Therapy of ThrombosesUpon vascular injury, the coagulationsystem is activated: thrombocytes andfibrin molecules coalesce into a “plug”(p. 148) that seals the defect and haltsbleeding (hemostasis). Unnecessaryformation of an intravascular clot – athrombosis – can be life-threatening. Ifthe clot forms on an atheromatousplaque in a coronary artery, myocardialinfarction is imminent; a thrombus in adeep leg vein can be dislodged, carriedinto a lung artery, and cause completeor partial interruption of pulmonaryblood flow (pulmonary embolism).Drugs that decrease the coagulabilityof blood, such as coumarins and heparin(A), are employed for the prophylaxisof thromboses. In addition, attemptsare directed at inhibiting the aggregationof blood platelets, which areprominently involved in intra-arterialthrombogenesis (p. 148). For the therapyof thrombosis, drugs are used thatdissolve the fibrin meshwork→fibrinolytics(p. 146).An overview of the coagulationcascade and sites of action for coumarinsand heparin is shown in A. There aretwo ways to initiate the cascade (B): 1)conversion of factor XII into its activeform (XII a, intrinsic system) at intravascularsites denuded of endothelium; 2)conversion of factor VII into VII a (extrinsicsystem) under the influence of a tissue-derivedlipoprotein (tissue thromboplastin).Both mechanisms convergevia factor X into a common final pathway.The clotting factors are proteinmolecules. “Activation” mostly meansproteolysis (cleavage of protein fragments)and, with the exception of fibrin,conversion into protein-hydrolyzingenzymes (proteases). Some activatedfactors require the presence of phospholipids(PL) and Ca 2+ for their proteolyticactivity. Conceivably, Ca 2+ ionscause the adhesion of factor to a phospholipidsurface, as depicted in C. Phospholipidsare contained in platelet factor3 (PF3), which is released from aggregatedplatelets, and in tissue thromboplastin(B). The sequential activationof several enzymes allows the aforementionedreactions to “snowball”, culminatingin massive production of fibrin(p. 148).Progression of the coagulation cascadecan be inhibited as follows:1) coumarin derivatives decreasethe blood concentrations of inactive factorsII, VII, IX, and X, by inhibiting theirsynthesis; 2) the complex consisting ofheparin and antithrombin III neutralizesthe protease activity of activated factors;3) Ca 2+ chelators prevent the enzymaticactivity of Ca 2+ -dependent factors;they contain COO-groups that bindCa 2+ ions (C): citrate and EDTA (ethylenediaminetetraaceticacid) form solublecomplexes with Ca 2+ ; oxalate precipitatesCa 2+ as insoluble calcium oxalate.Chelation of Ca 2+ cannot be usedfor therapeutic purposes because Ca 2+concentrations would have to be loweredto a level incompatible with life(hypocalcemic tetany). These compounds(sodium salts) are, therefore,used only for rendering blood incoagulableoutside the body.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antithrombotics 143XIIXIIXXIIaVIII + Ca 2+ + PlXIaIXaSynthesis susceptible toinhibition by coumarinsReaction susceptible toinhibition by heparinantithrombincomplexVIIaVIICa 2+ + Pl (Phospholipids)XXaV + Ca 2+ + PlProthrombin IIIIa ThrombinFibrinogen IIa FibrinA. Inhibition of clotting cascade in vivoPlateletsEndothelialdefectXIICOO –+TissuethrombokinaseXIIaPF 3 VIIa VIIFibrinVesselruptureClotting factorCOO -Ca 2+ -chelationCitrateEDTAOxalateCOO –Ca+ –– – – – –Phospholipidse.g., PF 3B. Activation of clottingC. Inhibition of clotting by removal of Ca 2+Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
144 AntithromboticsCoumarin Derivatives (A)Vitamin K promotes the hepatic γ-carboxylationof glutamate residues on theprecursors of factors II, VII, IX, and X, aswell as that of other proteins, e.g., proteinC, protein S, or osteocalcin. Carboxylgroups are required for Ca 2+ -mediatedbinding to phospholipid surfaces (p.142). There are several vitamin K derivativesof different origins: K 1 (phytomenadione)from chlorophyllousplants; K 2 from gut bacteria; and K 3(menadione) synthesized chemically.All are hydrophobic and require bile acidsfor absorption.Oral anticoagulants. Structurallyrelated to vitamin K, 4-hydroxycoumarinsact as “false” vitamin K and preventregeneration of reduced (active) vitaminK from vitamin K epoxide, hencethe synthesis of vitamin K-dependentclotting factors.Coumarins are well absorbed afteroral administration. Their duration ofaction varies considerably. Synthesis ofclotting factors depends on the intrahepatocyticconcentration ratio of coumarinsto vitamin K. The dose requiredfor an adequate anticoagulant effectmust be determined individually foreach patient (one-stage prothrombintime). Subsequently, the patient mustavoid changing dietary consumption ofgreen vegetables (alteration in vitaminK levels), refrain from taking additionaldrugs likely to affect absorption or eliminationof coumarins (alteration in coumarinlevels), and not risk inhibitingplatelet function by ingesting acetylsalicylicacid.The most important adverse effectis bleeding. With coumarins, thiscan be counteracted by giving vitaminK 1. Coagulability of blood returns tonormal only after hours or days, whenthe liver has resumed synthesis and restoredsufficient blood levels of clottingfactors. In urgent cases, deficient factorsmust be replenished directly (e.g., bytransfusion of whole blood or of prothrombinconcentrate).Heparin (B)A clotting factor is activated when thefactor that precedes it in the clottingcascade splits off a protein fragment andthereby exposes an enzymatic center.The latter can again be inactivated physiologicallyby complexing with antithrombinIII (AT III), a circulating glycoprotein.Heparin acts to inhibit clottingby accelerating formation of thiscomplex more than 1000-fold. Heparinis present (together with histamine) inthe vesicles of mast cells; its physiologicalrole is unclear. Therapeutically usedheparin is obtained from porcine gut orbovine lung. Heparin molecules arechains of amino sugars bearing -COO –and -SO 4 groups; they contain approx.10 to 20 of the units depicted in (B);mean molecular weight, 20,000. Anticoagulantefficacy varies with chainlength. The potency of a preparation isstandardized in international units ofactivity (IU) by bioassay and comparisonwith a reference preparation.The numerous negative charges aresignificant in several respects: (1) theycontribute to the poor membrane penetrability—heparinis ineffective whenapplied by the oral route or topically ontothe skin and must be injected; (2) attractionto positively charged lysine residuesis involved in complex formationwith ATIII; (3) they permit binding ofheparin to its antidote, protamine(polycationic protein from salmonsperm).If protamine is given in heparin-inducedbleeding, the effect of heparin isimmediately reversed.For effective thromboprophylaxis, alow dose of 5000 IU is injected s.c. twoto three times daily. With low dosage ofheparin, the risk of bleeding is sufficientlysmall to allow the first injectionto be given as early as 2 h prior to surgery.Higher daily i.v. doses are requiredto prevent growth of clots. Besidesbleeding, other potential adverse effectsare: allergic reactions (e.g., thrombocytopenia)and with chronic administration,reversible hair loss and osteoporosis.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antithrombotics 145Duration of action/daysVit. K 1PhytomenadionePhenprocoumonVit. K 2WarfarinVit. K 3MenadioneAcenocoumarolCarboxylation of glutamine residuesII, VII, IX, XVit. K derivatives4-Hydroxy-Coumarin derivativesA. Vitamin K-antagonists of the coumarin type and vitamin KActivatedclotting factorIIa,IXa, Xa, XIa, XIIa, XIIIaInactivationInactivationMast cell+AT III+ + + +- - - -AT III+ + + +- - - -- - - -Heparin 3 x 5000 IU s.c.30 000 IU i.v.+ + + + + + ++ ++ProtamineB. Heparin: origin, structure, and mechanism of actionLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
146 AntithromboticsLow-molecular-weight heparin (averageMW ~5000) has a longer durationof action and needs to be given onlyonce daily (e.g., certoparin, dalteparin,enoxaparin, reviparin, tinzaparin).Frequent control of coagulability isnot necessary with low molecularweight heparin and incidence of side effects(bleeding, heparin-induced thrombocytopenia)is less frequent than withunfractionated heparin.Fibrinolytic Therapy (A)Fibrin is formed from fibrinogenthrough thrombin (factor IIa)-catalyzedproteolytic removal of two oligopeptidefragments. Individual fibrin moleculespolymerize into a fibrin mesh that canbe split into fragments and dissolved byplasmin. Plasmin derives by proteolysisfrom an inactive precursor, plasminogen.Plasminogen activators can be infusedfor the purpose of dissolving clots(e.g., in myocardial infarction). Thrombolysisis not likely to be successful unlessthe activators can be given very soonafter thrombus formation. Urokinaseis an endogenous plasminogen activatorobtained from cultured human kidneycells. Urokinase is better tolerated thanis streptokinase. By itself, the latter isenzymatically inactive; only after bindingto a plasminogen molecule doesthe complex become effective in convertingplasminogen to plasmin. Streptokinaseis produced by streptococcalbacteria, which probably accounts forthe frequent adverse reactions. Streptokinaseantibodies may be present as aresult of prior streptococcal infections.Binding to such antibodies would neutralizestreptokinase molecules.With alteplase, another endogenousplasminogen activator (tissueplasminogen activator, tPA) is available.With physiological concentrations thisactivator preferentially acts on plasminogenbound to fibrin. In concentrationsneeded for therapeutic fibrinolysis thispreference is lost and the risk of bleedingdoes not differ with alteplase andstreptokinase. Alteplase is rather shortlived(inactivation by complexing withplasminogen activator inhibitor, PAI)and has to be applied by infusion. Reteplase,however, containing only theproteolytic active part of the alteplasemolecule, allows more stabile plasmalevels and can be applied in form of twoinjections at an interval of 30 min.Inactivation of the fibrinolyticsystem can be achieved by “plasmin inhibitors,”such as ε-aminocaproic acid,p-aminomethylbenzoic acid (PAMBA),tranexamic acid, and aprotinin, whichalso inhibits other proteases.Lowering of blood fibrinogenconcentration. Ancrod is a constituentof the venom from a Malaysian pit viper.It enzymatically cleaves a fragmentfrom fibrinogen, resulting in the formationof a degradation product that cannotundergo polymerization. Reductionin blood fibrinogen level decreases thecoagulability of the blood. Since fibrinogen(MW ~340 000) contributes to theviscosity of blood, an improved “fluidity”of the blood would be expected.Both effects are felt to be of benefit inthe treatment of certain disorders ofblood flow.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antithrombotics 147FibrinogenThrombinAncrodFibrinPlasmin-inhibitorsPlasminAntibody fromprior infectione.g., Tranexamic acidFever,chills,and inactivationUrokinaseStreptokinaseHuman kidney cell culturePlasminogenStreptococciA. Activators and inhibitors of fibrinolysis; ancrodLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
148 AntithromboticsIntra-arterial Thrombus Formation (A)Activation of platelets, e.g., upon contactwith collagen of the extracellularmatrix after injury to the vascular wall,constitutes the immediate and decisivestep in initiating the process of primaryhemostasis, i.e., cessation of bleeding.However, in the absence of vascular injury,platelets can be activated as a resultof damage to the endothelial celllining of blood vessels. Among the multiplefunctions of the endothelium, theproduction of NO˙ and prostacyclin playsan important role. Both substances inhibitthe tendency of platelets to adhereto the endothelial surface (platelet adhesiveness).Impairment of endothelialfunction, e.g., due to chronic hypertension,cigarette smoking, chronic elevationof plasma LDL levels or of bloodglucose, increases the probability ofcontact between platelets and endothelium.The adhesion process involvesGP IB/IX, a glycoprotein present in theplatelet cell membrane and von Willebrandt’sfactor, an endothelial membraneprotein. Upon endothelial contact,the platelet is activated with a resultantchange in shape and affinity tofibrinogen. Platelets are linked to eachother via fibrinogen bridges: theyundergo aggregation.Platelet aggregation increases likean avalanche because, once activated,platelets can activate other platelets. Onthe injured endothelial cell, a plateletthrombus is formed, which obstructsblood flow. Ultimately, the vascular lumenis occluded by the thrombus as thelatter is solidified by a vasoconstrictionproduced by the release of serotoninand thromboxane A 2 from the aggregatedplatelets. When these events occur ina larger coronary artery, the consequenceis a myocardial infarction; involvementof a cerebral artery leads tostroke.The von Willebrandt’s factor plays akey role in thrombogenesis. Lack of thisfactor causes thrombasthenia, a pathologicallydecreased platelet aggregation.Relative deficiency of the von Willebrandt’sfactor can be temporarily overcomeby the vasopressin anlogue desmopressin(p. 164), which increases therelease of available factor from storagesites.Formation, Activation, and Aggregationof Platelets (B)Platelets originate by budding off frommultinucleate precursor cells, the megakaryocytes.As the smallest formedelement of blood (dia. 1–4 µm), they canbe activated by various stimuli. Activationentails an alteration in shape andsecretion of a series of highly active substances,including serotonin, platelet activatingfactor (PAF), ADP, and thromboxaneA 2. In turn, all of these can activateother platelets, which explains theexplosive nature of the process.The primary consequence of activationis a conformational change of an integrinpresent in the platelet membrane,namely, GPIIB/IIIA. In its activeconformation, GPIIB/IIIA shows high affinityfor fibrinogen; each platelet containsup to 50,000 copies. The high plasmaconcentration of fibrinogen and thehigh density of integrins in the plateletmembrane permit rapid cross-linking ofplatelets and formation of a plateletplug.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antithrombotics 149AggregationAdhesiondysfunctional endothelial cellPlateletActivatedplateletvon Willebrandt’sfactorFibrinogenA. ThrombogenesisMegakaryocyteActivationContact withcollagenADPThrombinThromboxane A2SerotoninPlateletActivatedplateletFibrinogenGlycoproteinIIB/IIIAFibrinogenbinding:impossiblepossibleB. Aggregation of platelets by the integrin GPIIB/IIIALüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
150 AntithromboticsInhibitors of Platelet Aggregation (A)Platelets can be activated by mechanicaland diverse chemical stimuli, some ofwhich, e.g., thromboxane A 2, thrombin,serotonin, and PAF, act via receptors onthe platelet membrane. These receptorsare coupled to G q proteins that mediateactivation of phospholipase C and hencea rise in cytosolic Ca 2+ concentration.Among other responses, this rise in Ca 2+triggers a conformational change inGPIIB/IIIA, which is thereby convertedto its fbrinogen-binding form. In contrast,ADP activates platelets by inhibitingadenylyl cyclase, thus causing internalcAMP levels to decrease. High cAMPlevels would stabilize the platelet in itsinactive state. Formally, the two messengersubstances, Ca 2+ and cAMP, canbe considered functional antagonists.Platelet aggregation can be inhibitedby acetylsalicylic acid (ASA), whichblocks thromboxane synthase, or by recombinanthirudin (originally harvestedfrom leech salivary gland), whichbinds and inactivates thrombin. As yet,no drugs are available for blocking aggregationinduced by serotonin or PAF.ADP-induced aggregation can be preventedby ticlopidine and clopidogrel;these agents are not classic receptor antagonists.ADP-induced aggregation isinhibited only in vivo but not in vitro instored blood; moreover, once induced,inhibition is irreversible. A possible explanationis that both agents alreadyinterfere with elements of ADP receptorsignal transduction at the megakaryocyticstage. The ensuing functional defectwould then be transmitted to newlyformed platelets, which would be incapableof reversing it.The intra-platelet levels of cAMPcan be stabilized by prostacyclin or itsanalogues (e.g., iloprost) or by dipyridamole.The former activates adenyl cyclasevia a G-protein-coupled receptor;the latter inhibits a phosphodiesterasethat breaks down cAMP.The integrin (GPIIB/IIIA)-antagonistsprevent cross-linking of platelets.Their action is independent of the aggregation-inducingstimulus. Abciximabis a chimeric human-murine monoclonalantibody directed against GPIIb/IIIathat blocks the fibrinogen-binding siteand thus prevents attachment of fibrinogen.The peptide derivatives, eptifibatideand tirofiban block GPIIB/IIIAcompetitively, more selectively and havea shorter effect than does abciximab.Presystemic Effect of Acetylsalicylic Acid(B)Inhibition of platelet aggregation byASA is due to a selective blockade ofplatelet cyclooxygenase (B). Selectivityof this action results from acetylation ofthis enzyme during the initial passage ofthe platelets through splanchnic bloodvessels. Acetylation of the enzyme is irreversible.ASA present in the systemiccirculation does not play a role in plateletinhibition. Since ASA undergoes extensivepresystemic elimination, cyclooxygenasesoutside platelets, e.g., in endothelialcells, remain largely unaffected.With regular intake, selectivity is enhancedfurther because the anuclearplatelets are unable to resynthesize newenzyme and the inhibitory effects ofconsecutive doses are added to eachother. However, in the endothelial cells,de novo synthesis of the enzyme permitsrestoration of prostacyclin production.Adverse Effects of Antiplatelet DrugsAll antiplatelet drugs increase the risk ofbleeding. Even at the low ASA dosesused to inhibit platelet function (100mg/d), ulcerogenic and bronchoconstrictor(aspirin asthma) effects may occur.Ticlopidine frequently causes diarrheaand, more rarely, leukopenia, necessitatingcessation of treatment. Clopidogrelreportedly does not cause hematologicalproblems.As peptides, hirudin and abciximabneed to be injected; therefore their useis restricted to intensive-care settings.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antithrombotics 151ArachidonicacidThrombinHirudinArgatrobanSerotoninPAFASAThromboxaneA 2AbciximabTirofibanEptifibatideGPIIB/IIIA[withoutaffinity forfibrinogen]PhosphodiesteraseATPAdenylatecyclaseGPIIB/IIIA[Affinity forfibrinogenhigh]DipyridamoleADPInactiveTiclopidine, ClopidogrelActiveA. Inhibitors of platelet aggregationPlatelet withacetylated andblockedcyclooxygenasePlateletLow dose ofacetylsalicylicacidCOOHO CCH 3OB. Presystemic inactivation of platelet cyclooxygenase by acetylsalicylic acidLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
152 Plasma Volume ExpandersPlasma Volume ExpandersMajor blood loss entails the danger oflife-threatening circulatory failure, i.e.,hypovolemic shock. The immediatethreat results not so much from the lossof erythrocytes, i.e., oxygen carriers, asfrom the reduction in volume of circulatingblood.To eliminate the threat of shock, replenishmentof the circulation is essential.With moderate loss of blood, administrationof a plasma volume expandermay be sufficient. Blood plasmaconsists basically of water, electrolytes,and plasma proteins. However, a plasmasubstitute need not contain plasmaproteins. These can be suitably replacedwith macromolecules (“colloids”)that, like plasma proteins, (1) donot readily leave the circulation and arepoorly filtrable in the renal glomerulus;and (2) bind water along with its solutesdue to their colloid osmotic properties. Inthis manner, they will maintain circulatoryfilling pressure for many hours. Onthe other hand, volume substitution isonly transiently needed and thereforecomplete elimination of these colloidsfrom the body is clearly desirable.Compared with whole blood orplasma, plasma substitutes offer severaladvantages: they can be produced moreeasily and at lower cost, have a longershelf life, and are free of pathogens suchas hepatitis B or C or AIDS viruses.Three colloids are currently employedas plasma volume expanders—the two polysaccharides, dextran andhydroxyethyl starch, as well as the polypeptide,gelatin.Dextran is a glucose polymerformed by bacteria and linked by a 1→6instead of the typical 1→4 bond. Commercialsolutions contain dextran of amean molecular weight of 70 kDa (dextran70) or 40 kDa (lower-molecularweightdextran, dextran 40). The chainlength of single molecules, however,varies widely. Smaller dextran moleculescan be filtered at the glomerulusand slowly excreted in urine; the largerones are eventually taken up and degradedby cells of the reticuloendothelialsystem. Apart from restoring bloodvolume, dextran solutions are used forhemodilution in the management ofblood flow disorders.As for microcirculatory improvement,it is occasionally emphasized thatlow-molecular-weight dextran, unlikedextran 70, may directly reduce the aggregabilityof erythrocytes by alteringtheir surface properties. With prolongeduse, larger molecules will accumulatedue to the more rapid renal excretionof the smaller ones. Consequently,the molecular weight of dextran circulatingin blood will tend towards ahigher mean molecular weight with thepassage of time.The most important adverse effectresults from the antigenicity of dextrans,which may lead to an anaphylacticreaction.Hydroxyethyl starch (hetastarch) isproduced from starch. By virtue of itshydroxyethyl groups, it is metabolizedmore slowly and retained significantlylonger in blood than would be the casewith infused starch. Hydroxyethylstarch resembles dextrans in terms ofits pharmacological properties andtherapeutic applications.Gelatin colloids consist of crosslinkedpeptide chains obtained fromcollagen. They are employed for bloodreplacement, but not for hemodilution,in circulatory disturbances.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Plasma Volume Expanders 153CirculationGelatin colloids= cross-linked peptide chainsMW 35, 000Peptides MW ~ 15, 000Gelatin MW ~ 100, 000Collagen MW ~ 300, 000Blood lossdanger of shockDextranMW 70, 000MW 40, 000HydroxyethylationPlasmasubstitutewith colloidsErythrocytesHydroxyethyl starchMW 450, 000SucroseFructoseBacteriumLeuconostocmesenteroidesPlasmaPlasmaproteinsStarchA. Plasma substitutesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
154 li Drugs KT used in HyperlipoproteinemiasLipid-Lowering AgentsTriglycerides and cholesterol are essentialconstituents of the organism.Among other things, triglycerides representa form of energy store and cholesterolis a basic building block of biologicalmembranes. Both lipids are waterinsoluble and require appropriate transportvehicles in the aqueous media oflymph and blood. To this end, smallamounts of lipid are coated with a layerof phospholipids, embedded in whichare additional proteins—the apolipoproteins(A). According to the amount andthe composition of stored lipids, as wellas the type of apolipoprotein, one distinguishes4 transport forms:Origin Density Mean sojourn Diameterin blood (nm)plasma (h)Chylomicron Gut epithelium
Drugs used in Hyperlipoproteinemias 155Dietary fatsCell metabolismCholesterolChylomicronFat tissueLDLHDLHeartSkeletal muscleVLDLHDLLDLChylomicronremnantLipoproteinsynthesisCholesterolTriglyceridesCholesterolFatty acidsLipoproteinLipaseLiver cellCholesterolesterTriglyceridesApolipoproteinOHOHOHCholesterolA. Lipoprotein metabolismColestyramineGut::binding andexcretion ofbile acids (BA)Liver:BA synthesisCholesterolconsumptionBile acidsCholesterolstoreLipoproteinsLiver cellβ-SitosterolGut:CholesterolabsorptionSynthesisLDLHMG-CoA-Reductase inhibitorsB. Cholesterol metabolism in liver cell and cholesterol-lowering drugsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
156 Drugs used in Hyperlipoproteinemiasliver meets its increased cholesterol demandby enhancing the expression ofHMG CoA reductase and LDL receptors(negative feedback).At the required dosage, the resinscause diverse gastrointestinal disturbances.In addition, they interfere withthe absorption of fats and fat-soluble vitamins(A, D, E, K). They also adsorb anddecrease the absorption of such drugs asdigitoxin, vitamin K antagonists, anddiuretics. Their gritty texture and bulkmake ingestion an unpleasant experience.The statins, lovastatin (L), simvastatin(S), pravastatin (P), fluvastatin (F),cerivastatin, and atorvastatin, inhibitHMG CoA reductase. The active group ofL, S, P, and F (or their metabolites) resemblesthat of the physiological substrateof the enzyme (A). L and S are lactonesthat are rapidly absorbed by theenteral route, subjected to extensivefirst-pass extraction in the liver, andthere hydrolyzed into active metabolites.P and F represent the active formand, as acids, are actively transported bya specific anion carrier that moves bileacids from blood into liver and also mediatesthe selective hepatic uptake ofthe mycotoxin, amanitin (A). Atorvastatinhas the longest duration of action.Normally viewed as presystemic elimination,efficient hepatic extractionserves to confine the action of the statinsto the liver. Despite the inhibition ofHMG CoA reductase, hepatic cholesterolcontent does not fall, because hepatocytescompensate any drop in cholesterollevels by increasing the synthesis ofLDL receptor protein (along with the reductase).Because the newly formed reductaseis inhibited, too, the hepatocytemust meet its cholesterol demand byuptake of LDL from the blood (B). Accordingly,the concentration of circulatingLDL decreases, while its hepaticclearance from plasma increases. Thereis also a decreased likelihood of LDL beingoxidized into its proatherosleroticdegradation product. The combinationof a statin with an ion-exchange resinintensifies the decrease in LDL levels. Arare, but dangerous, side effect of thestatins is damage to skeletal musculature.This risk is increased by combineduse of fibric acid agents (see below).Nicotinic acid and its derivatives(pyridylcarbinol, xanthinol nicotinate,acipimox) activate endothelial lipoproteinlipase and thereby lower triglyceridelevels. At the start of therapy, aprostaglandin-mediated vasodilationoccurs (flushing and hypotension) thatcan be prevented by low doses of acetylsalicylicacid.Clofibrate and derivatives (bezafibrate,etofibrate, gemfibrozil) lower plasmalipids by an unknown mechanism.They may damage the liver and skeletalmuscle (myalgia, myopathy, rhabdomyolysis).Probucol lowers HDL more thanLDL; nonetheless, it appears effective inreducing atherogenesis, possibly by reducingLDL oxidation. 3-Polyunsaturated fatty acids (eicosapentaenoate,docosahexaenoate)are abundant in fish oils. Dietary supplementationresults in lowered levelsof triglycerides, decreased synthesis ofVLDL and apolipoprotein B, and improvedclearance of remnant particles,although total and LDL cholesterol arenot decreased or are even increased.High dietary intake may correlate with areduced incidence of coronary heartdisease.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs used in Hyperlipoproteinemias 157Low systemic availability3-Hydroxy-3-methylglutaryl-CoAMevalonateHMG-CoAReductaseCholesterol<strong>Bio</strong>activationActive formHOOH 3 C OH 3 COOExtractionof lipophiliclactoneCH 3OraladministrationActiveuptake ofanionFHOCOOHOHCH 3N CH 3H 3 CLovastatin FluvastatinA. Accumulation and effect of HMG-CoA reductase inhibitors in liverInhibition ofHMG-CoA reductaseLDL-ReceptorHMG-CoAreductaseExpressionExpressionCholesterolLDLin bloodIncreased receptormediateduptake of LDLB. Regulation by cellular cholesterol concentration of HMG-CoA reductaseand LDL-receptorsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
158 DiureticsDiuretics – An OverviewDiuretics (saluretics) elicit increasedproduction of urine (diuresis). In thestrict sense, the term is applied to drugswith a direct renal action. The predominantaction of such agents is to augmenturine excretion by inhibiting the reabsorptionof NaCl and water.The most important indications fordiuretics are:Mobilization of edemas (A): In edemathere is swelling of tissues due to accumulationof fluid, chiefly in the extracellular(interstitial) space. When a diureticis given, increased renal excretionof Na + and H 2O causes a reduction inplasma volume with hemoconcentration.As a result, plasma protein concentrationrises along with oncotic pressure.As the latter operates to attractwater, fluid will shift from interstitiuminto the capillary bed. The fluid contentof tissues thus falls and the edemas recede.The decrease in plasma volumeand interstitial volume means a diminutionof the extracellular fluid volume(EFV). Depending on the condition, useis made of: thiazides, loop diuretics, aldosteroneantagonists, and osmotic diuretics.Antihypertensive therapy. Diureticshave long been used as drugs of firstchoice for lowering elevated blood pressure(p. 312). Even at low dosage, theydecrease peripheral resistance (withoutsignificantly reducing EFV) and therebynormalize blood pressure.Therapy of congestive heart failure.By lowering peripheral resistance, diureticsaid the heart in ejecting blood (reductionin afterload, pp. 132, 306); cardiacoutput and exercise tolerance areincreased. Due to the increased excretionof fluid, EFV and venous return decrease(reduction in preload, p. 306).Symptoms of venous congestion, suchas ankle edema and hepatic enlargement,subside. The drugs principallyused are thiazides (possibly combinedwith K + -sparing diuretics) and loop diuretics.Prophylaxis of renal failure. In circulatoryfailure (shock), e.g., secondary tomassive hemorrhage, renal productionof urine may cease (anuria). By means ofdiuretics an attempt is made to maintainurinary flow. Use of either osmoticor loop diuretics is indicated.Massive use of diuretics entails ahazard of adverse effects (A): (1) thedecrease in blood volume can lead tohypotension and collapse; (2) blood viscosityrises due to the increase in erythro-and thrombocyte concentration,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 initiatecounter-regulatory responses (B),namely, activation of the renin-angiotensin-aldosteronesystem (p. 124). Becauseof the diminished blood volume,renal blood flow is jeopardized. Thisleads to release from the kidneys of thehormone, renin, which enzymaticallycatalyzes the formation of angiotensin I.Angiotensin I is converted to angiotensinII by the action of angiotensin-convertingenzyme (ACE). Angiotensin IIstimulates release of aldosterone. Themineralocorticoid promotes renal reabsorptionof NaCl and water and thuscounteracts the effect of diuretics. ACEinhibitors (p. 124) augment the effectivenessof diuretics by preventing thiscounter-regulatory response.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Diuretics 159Protein moleculesEdemaHemoconcentrationColloidosmoticpressureMobilization ofedema fluidCollapse,danger ofthrombosisDiureticA. Mechanism of edema fluid mobilization by diureticsSalt andfluid retentionDiureticDiureticEFV:Na + , Cl - ,H 2 OAngiotensinogenReninAngiotensin IACEAngiotensin IIAldosteroneB. Possible counter-regulatory responses during long-term diuretic therapyLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
160 DiureticsNaCl Reabsorption in the Kidney (A)The smallest functional unit of the kidneyis the nephron. In the glomerularcapillary loops, ultrafiltration of plasmafluid into Bowman’s capsule (BC) yieldsprimary urine. In the proximal tubules(pT), approx. 70% of the ultrafiltrate isretrieved by isoosmotic reabsorption ofNaCl and water. In the thick portion ofthe ascending limb of Henle’s loop (HL),NaCl is absorbed unaccompanied bywater. This is the prerequisite for thehairpin countercurrent mechanism thatallows build-up of a very high NaCl concentrationin the renal medulla. In thedistal tubules (dT), NaCl and water areagain jointly reabsorbed. At the end ofthe nephron, this process involves an aldosterone-controlledexchange of Na +against K + or H + . In the collecting tubule(C), vasopressin (antidiuretic hormone,ADH) increases the epithelial permeabilityfor water, which is drawn intothe hyperosmolar milieu of the renalmedulla and thus retained in the body.As a result, a concentrated urine entersthe renal pelvis.Na + transport through the tubularcells basically occurs in similar fashionin all segments of the nephron. Theintracellular concentration of Na + is significantlybelow that in primary urine.This concentration gradient is the drivingforce for entry of Na + into the cytosolof tubular cells. A carrier mechanismmoves Na + across the membrane. Energyliberated during this influx can beutilized for the coupled outward transportof another particle against a gradient.From the cell interior, Na + is movedwith expenditure of energy (ATP hydrolysis)by Na + /K + -ATPase into the extracellularspace. The enzyme moleculesare confined to the basolateral parts ofthe cell membrane, facing the interstitium;Na + can, therefore, not escape backinto tubular fluid.All diuretics inhibit Na + reabsorption.Basically, either the inward or theoutward transport of Na + can be affected.Osmotic Diuretics (B)Agents: mannitol, sorbitol. Site of action:mainly the proximal tubules. Mode ofaction: Since NaCl and H 2O are reabsorbedtogether in the proximal tubules,Na + concentration in the tubular fluiddoes not change despite the extensivereabsorption of Na + and H 2O. Body cellslack transport mechanisms for polyhydricalcohols such as mannitol (structureon p. 171) and sorbitol, which arethus prevented from penetrating cellmembranes. Therefore, they need to begiven by intravenous infusion. They alsocannot be reabsorbed from the tubularfluid after glomerular filtration. Theseagents bind water osmotically and retainit in the tubular lumen. When Naions are taken up into the tubule cell,water cannot follow in the usualamount. The fall in urine Na + concentrationreduces Na + reabsorption, in partbecause the reduced concentration gradienttowards the interior of tubule cellsmeans a reduced driving force for Na +influx. The result of osmotic diuresis is alarge volume of dilute urine.Indications: prophylaxis of renalhypovolemic failure, mobilization ofbrain edema, and acute glaucoma.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Diuretics 161AldosteroneNa + , Cl -dTK +Na + , Cl - + H 2 OH 2 OBCCLumenInterstitiumpTNa +"carrier"Na +Thickportionof HLCortexMedullaNa +Na/K-ATPaseDiureticsADHHLA. Kidney: NaCl reabsorption in nephron and tubular cellMannitol[Na + ] inside = [Na + ] outside[Na + ] inside < [Na + ] outsideB. NaCl reabsorption in proximal tubule and effect of mannitolLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
162 DiureticsDiuretics of the Sulfonamide TypeThese drugs contain the sulfonamidegroup -SO 2NH 2. They are suitable fororal administration. In addition to beingfiltered at the glomerulus, they are subjectto tubular secretion. Their concentrationin urine is higher than in blood.They act on the luminal membrane ofthe tubule cells. Loop diuretics have thehighest efficacy. Thiazides are most frequentlyused. Their forerunners, thecarbonic anhydrase inhibitors, are nowrestricted to special indications.Carbonic anhydrase (CAH) inhibitors,such as acetazolamide and sulthiame,act predominantly in the proximaltubules. CAH catalyzes CO 2 hydration/dehydrationreactions:H + + HCO – 3 ↔ H 2CO 3 ↔ H 20 + CO 2.The enzyme is used in tubule cellsto generate H + , which is secreted intothe tubular fluid in exchange for Na + .There, H + captures HCO – 3 , leading to formationof CO 2 via the unstable carbonicacid. Membrane-permeable CO 2 is takenup into the tubule cell and used to regenerateH + and HCO – 3 . When the enzymeis inhibited, these reactions areslowed, so that less Na + , HCO – 3 and waterare reabsorbed from the fast-flowingtubular fluid. Loss of HCO – 3 leads to acidosis.The diuretic effectiveness of CAHinhibitors decreases with prolongeduse. CAH is also involved in the productionof ocular aqueous humor. Presentindications for drugs in this class include:acute glaucoma, acute mountainsickness, and epilepsy. Dorzolamide canbe applied topically to the eye to lowerintraocular pressure in glaucoma.Loop diuretics include furosemide(frusemide), piretanide, and bumetanide.With oral administration, a strongdiuresis occurs within 1 h but persistsfor only about 4 h. The effect is rapid, intense,and brief (high-ceiling diuresis).The site of action of these agents is thethick portion of the ascending limb ofHenle’s loop, where they inhibitNa + /K + /2Cl – cotransport. As a result,these electrolytes, together with water,are excreted in larger amounts. Excretionof Ca 2+ and Mg 2+ also increases.Special toxic effects include: (reversible)hearing loss, enhanced sensitivity torenotoxic agents. Indications: pulmonaryedema (added advantage of i.v. injectionin left ventricular failure: immediatedilation of venous capacitancevessels preload reduction); refractorinessto thiazide diuretics, e.g., in renalhypovolemic failure with creatinineclearance reduction (
Diuretics 163SulfonamidediureticsNormalstateAnionsecretorysystemHypokalemiaUric acidLoss ofNa + , K +H 2 OThiazidesGoutNa +Cl -e.g., hydrochlorothiazideCarbonic anhydrase inhibitorsLoop diureticsNa +H +HCO - 3H 2 OCO 2H + HCO3-CAHCO 2 H 2 ONa +HCO - 3Na +K +2 Cl -e.g., acetazolamidee.g., furosemideA. Diuretics of the sulfonamide typeLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
164 DiureticsPotassium-Sparing Diuretics (A)These agents act in the distal portion ofthe distal tubule and the proximal partof the collecting ducts where Na + is reabsorbedin exchange for K + or H + . Theirdiuretic effectiveness is relatively minor.In contrast to sulfonamide diuretics(p. 162), there is no increase in K + secretion;rather, there is a risk of hyperkalemia.These drugs are suitable for oraladministration.a) Triamterene and amiloride, in additionto glomerular filtration, undergosecretion in the proximal tubule. Theyact on the luminal membrane of tubulecells. Both inhibit the entry of Na + ,hence its exchange for K + and H + . Theyare mostly used in combination withthiazide diuretics, e.g., hydrochlorothiazide,because the opposing effects on K +excretion cancel each other, while theeffects on secretion of NaCl complementeach other.b) Aldosterone antagonists. Themineralocorticoid aldosterone promotesthe reabsorption of Na + (Cl – andH 2O follow) in exchange for K + . Its hormonaleffect on protein synthesis leadsto augmentation of the reabsorptive capacityof tubule cells. Spironolactone, aswell as its metabolite canrenone, are antagonistsat the aldosterone receptorand attenuate the effect of the hormone.The diuretic effect of spironolactone developsfully only with continuous administrationfor several days. Two possibleexplanations are: (1) the conversionof spironolactone into and accumulationof the more slowly eliminatedmetabolite canrenone; (2) an inhibitionof aldosterone-stimulated protein synthesiswould become noticeable only ifexisting proteins had become nonfunctionaland needed to be replaced by denovo synthesis. A particular adverse effectresults from interference with gonadalhormones, as evidenced by the developmentof gynecomastia (enlargementof male breast). Clinical uses includeconditions of increased aldosteronesecretion, e.g., liver cirrhosis withascites.Antidiuretic Hormone (ADH) andDerivatives (B)ADH, a nonapeptide, released from theposterior pituitary gland promotes reabsorptionof water in the kidney. Thisresponse is mediated by vasopressin receptorsof the V 2 subtype. ADH enhancesthe permeability of collecting ductepithelium for water (but not for electrolytes).As a result, water is drawnfrom urine into the hyperosmolar interstitiumof the medulla. Nicotine augments(p. 110) and ethanol decreasesADH release. At concentrations abovethose required for antidiuresis, ADHstimulates smooth musculature, includingthat of blood vessels (“vasopressin”).The latter response is mediated byreceptors of the V 1 subtype. Blood pressurerises; coronary vasoconstrictioncan precipitate angina pectoris. Lypressin(8-L-lysine vasopressin) acts likeADH. Other derivatives may display onlyone of the two actions.Desmopressin is used for the therapyof diabetes insipidus (ADH deficiency),nocturnal enuresis, thrombasthemia(p. 148), and chronic hypotension(p. 314); it is given by injection or viathe nasal mucosa (as “snuff”).Felypressin and ornipressin serve asadjunctive vasoconstrictors in infiltrationlocal anesthesia (p. 206).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Diuretics 165Na +K +TriamtereneAldosteroneNa +K +orH +Protein synthesisTransport capacityAldosteroneantagonistsCanrenoneAmilorideSpironolactoneA. Potassium-sparing diureticsNicotineNeurohypophysisEthanolVasoconstrictionH 2 Opermeabilityof collectingductV 2 Adiuretin = VasopressinV 1DesmopressinOrnipressinFelypressinB. Antidiuretic hormone (ADH) and derivativesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
166 Drugs for the Treatment of Peptic UlcersDrugs for Gastric and Duodenal UlcersIn the area of a gastric or duodenal pepticulcer, the mucosa has been attackedby digestive juices to such an extent asto expose the subjacent connective tissuelayer (submucosa). This self-digestionoccurs when the equilibriumbetween the corrosive hydrochloric acidand acid-neutralizing mucus, whichforms a protective cover on the mucosalsurface, is shifted in favor of hydrochloricacid. Mucosal damage can bepromoted by Helicobacter pylori bacteriathat colonize the gastric mucus.Drugs are employed with the followingtherapeutic aims: (1) to relievepain; (2) to accelerate healing; and (3)to prevent ulcer recurrence. Therapeuticapproaches are threefold: (a) to reduceaggressive forces by lowering H +output; (b) to increase protective forcesby means of mucoprotectants; and (c) toeradicate Helicobacter pylori.I. Drugs for Lowering AcidConcentrationIa. Acid neutralization. H + -bindinggroups such as CO 2– 3 , HCO – 3 or OH – , togetherwith their counter ions, are containedin antacid drugs. Neutralizationreactions occurring after intake ofCaCO 3 and NaHCO 3, respectively, areshown in (A) at left. With nonabsorbableantacids, the counter ion is dissolvedin the acidic gastric juice in theprocess of neutralization. Upon mixturewith the alkaline pancreatic secretion inthe duodenum, it is largely precipitatedagain by basic groups, e.g., as CaCO 3 orAlPO 4, and excreted in feces. Therefore,systemic absorption of counter ions orbasic residues is minor. In the presenceof renal insufficiency, however, absorptionof even small amounts may causean increase in plasma levels of counterions (e.g., magnesium intoxication withparalysis and cardiac disturbances). Precipitationin the gut lumen is responsiblefor other side effects, such as reducedabsorption of other drugs due totheir adsorption to the surface of precipitatedantacid or, phosphate depletionof the body with excessive intake ofAl(OH) 3.Na + ions remain in solution even inthe presence of HCO – 3 -rich pancreaticsecretions and are subject to absorption,like HCO – 3 . Because of the uptake of Na + ,use of NaHCO 3 must be avoided in conditionsrequiring restriction of NaCl intake,such as hypertension, cardiac failure,and edema.Since food has a buffering effect,antacids are taken between meals (e.g.,1 and 3 h after meals and at bedtime).Nonabsorbable antacids are preferred.Because Mg(OH) 2 produces a laxativeeffect (cause: osmotic action, p. 170, releaseof cholecystokinin by Mg 2+ , orboth) and Al(OH) 3 produces constipation(cause: astringent action of Al 3+ , p.178), these two antacids are frequentlyused in combination.Ib. Inhibitors of acid production.Acting on their respective receptors, thetransmitter acetylcholine, the hormonegastrin, and histamine released intramucosallystimulate the parietal cells ofthe gastric mucosa to increase output ofHCl. Histamine comes from enterochromaffin-like(ECL) cells; its release isstimulated by the vagus nerve (via M 1receptors) and hormonally by gastrin.The effects of acetylcholine and histaminecan be abolished by orally appliedantagonists that reach parietal cells viathe blood.The cholinoceptor antagonist pirenzepine,unlike atropine, prefers cholinoceptorsof the M 1 type, does notpenetrate into the CNS, and thus producesfewer atropine-like side effects(p. 104). The cholinoceptors on parietalcells probably belong to the M 3 subtype.Hence, pirenzepine may act by blockingM 1 receptors on ECL cells or submucosalneurons.Histamine receptors on parietalcells belong to the H 2 type (p. 114) andare blocked by H 2-antihistamines. Becausehistamine plays a pivotal role inthe activation of parietal cells, H 2-antihistaminesalso diminish responsivityto other stimulants, e.g., gastrin (in gas-Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs for the Treatment of Peptic Ulcers 167CaCO 3Acid neutralizationCaCO 3H+H 2 CO 3 H+H 2 O CO 2Ca2+Ca2+Pancreas2-CO 3Antacidsabsorbablenot absorbableCaCO 3NaHCO 3Mg(OH) 2Al(OH) 3H 2 O+CO 2Na + HCO- 3H +Na +PancreasH+K+Inhibition of acid productionParietal cellCimetidineN. vagusM 3ATPaseAChH 2HistamineH 3 COOmeprazoleH 3 CNH 3 CProton pumpinhibitorsHNNH 3 CGastrinS ONOCH 3CH 3H 2 -AntihistaminesCH 2HNNCH 3CH 2O CH 2PirenzepineAChM 1ECLcellS(CH 2 ) 2NHC NHCH 3N C NS(CH 2 ) 2NHCaCO 3AbsorptionC NHCH 3HCO 3-Na + HCO 3-RanitidineCH NO 2A. Drugs used to lower gastric acid concentration or productionLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
168 Drugs for the Treatment of Peptic Ulcerstrin-producing pancreatic tumors, Zollinger-Ellisonsyndrome). Cimetidine,the first H 2-antihistamine used therapeutically,only rarely produces side effects(CNS disturbances such as confusion;endocrine effects in the male, suchas gynecomastia, decreased libido, impotence).Unlike cimetidine, its newerand more potent congeners, ranitidine,nizatidine, and famotidine, do not interferewith the hepatic biotransformationof other drugs.Omeprazole (p. 167) can cause maximalinhibition of HCl secretion. Givenorally in gastric juice-resistant capsules,it reaches parietal cells via the blood. Inthe acidic milieu of the mucosa, an activemetabolite is formed and binds covalentlyto the ATP-driven proton pump(H + /K + ATPase) that transports H + in exchangefor K + into the gastric juice. Lansoprazoleand pantoprazole produceanalogous effects. The proton pump inhibitorsare first-line drugs for the treatmentof gastroesophageal reflux disease.II. Protective Drugsgravid uterus) significantly restrict itstherapeutic utility.Carbenoxolone (B) is a derivativeof glycyrrhetinic acid, which occurs inthe sap of licorice root (succus liquiritiae).Carbenoxolone stimulates mucusproduction. At the same time, it has amineralocorticoid-like action (due to inhibitionof 11-β-hydroxysteroid dehydrogenase)that promotes renal reabsorptionof NaCl and water. It may,therefore, exacerbate hypertension,congestive heart failure, or edemas. It isobsolete.III. Eradication of Helicobacter pyloriC. This microorganism plays an importantrole in the pathogenesis ofchronic gastritis and peptic ulcer disease.The combination of antibacterialdrugs and omeprazole has proven effective.In case of intolerance to amoxicillin(p. 270) or clarithromycin (p. 276), metronidazole(p. 274) can be used as a substitute.Colloidal bismuth compoundsare also effective; however, the problemof heavy-metal exposure compromisestheir long-term use.Sucralfate (A) contains numerous aluminumhydroxide residues. However, itis not an antacid because it fails to lowerthe overall acidity of gastric juice. Afteroral intake, sucralfate molecules undergocross-linking in gastric juice, forminga paste that adheres to mucosal defectsand exposed deeper layers. Here sucralfateintercepts H + . Protected from acid,and also from pepsin, trypsin, and bileacids, the mucosal defect can heal morerapidly. Sucralfate is taken on an emptystomach (1 h before meals and at bedtime).It is well tolerated; however, releasedAl 3+ ions can cause constipation.Misoprostol (B) is a semisyntheticprostaglandin derivative with greaterstability than natural prostaglandin,permitting absorption after oral administration.Like locally released prostaglandins,it promotes mucus productionand inhibits acid secretion. Additionalsystemic effects (frequent diarrhea; riskof precipitating contractions of theLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs for the Treatment of Peptic Ulcers 169R– SO 3-R RRRRR RR = – SO 3 [Al 2 (OH) 5 ]H + R = – SO 3 [Al 2 (OH) 4 ] +SucralfateConversionin acidic environmentpH < 4Cross-linkingand formationof pasteCoating ofmucosaldefectsA. Chemical structure and protective effect of sucralfateMucusHClH+ K+ATPaseProstaglandinreceptorParietal cellMisoprostolB. Chemical structure and protective effect of misoprostolInductionof laborHelicobacterpyloriEradicatione.g., short-term triple therapyGastritisPeptic ulcerAmoxicillinClarithromycinOmeprazole(2 x 1000 mg)(2 x 500 mg)(2 x 20 mg)7 days7 days7 daysC. Helicobacter eradicationLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
170 LaxativesLaxativesLaxatives promote and facilitate bowelevacuation by acting locally to stimulateintestinal peristalsis, to soften bowelcontents, or both.1. Bulk laxatives. Distention of theintestinal wall by bowel contents stimulatespropulsive movements of the gutmusculature (peristalsis). Activation ofintramural mechanoreceptors induces aneurally mediated ascending reflex contraction(red in A) and descending relaxation(blue) whereby the intraluminalbolus is moved in the anal direction.Hydrophilic colloids or bulk gels(B) comprise insoluble and nonabsorbablecarbohydrate substances that expandon taking up water in the bowel.Vegetable fibers in the diet act in thismanner. They consist of the indigestibleplant cell walls containing homoglycansthat are resistant to digestive enzymes,e.g., cellulose (14β-linked glucose moleculesvs. 14α glucoside bond instarch, p. 153).Bran, a grain milling waste product,and linseed (flaxseed) are both rich incellulose. Other hydrophilic colloids derivefrom the seeds of Plantago speciesor karaya gum. Ingestion of hydrophilicgels for the prophylaxis of constipationusually entails a low risk of side effects.However, with low fluid intake in combinationwith a pathological bowelstenosis, mucilaginous viscous materialcould cause bowel occlusion (ileus).Osmotically active laxatives (C)are soluble but nonabsorbable particlesthat retain water in the bowel by virtueof their osmotic action. The osmoticpressure (particle concentration) ofbowel contents always corresponds tothat of the extracellular space. The intestinalmucosa is unable to maintain ahigher or lower osmotic pressure of theluminal contents. Therefore, absorptionof molecules (e.g., glucose, NaCl) occursisoosmotically, i.e., solute molecules arefollowed by a corresponding amount ofwater. Conversely, water remains in thebowel when molecules cannot be absorbed.With Epsom and Glauber’s salts(MgSO 4 and Na 2SO 4, respectively), theSO 2– 4 anion is nonabsorbable and retainscations to maintain electroneutrality.Mg 2+ ions are also believed topromote release from the duodenal mucosaof cholecystokinin/pancreozymin,a polypeptide that also stimulates peristalsis.These so-called saline catharticselicit a watery bowel discharge 1–3 h afteradministration (preferably in isotonicsolution). They are used to purge thebowel (e.g., before bowel surgery) or tohasten the elimination of ingested poisons.Glauber’s salt (high Na + content) iscontraindicated in hypertension, congestiveheart failure, and edema. Epsomsalt is contraindicated in renal failure(risk of Mg 2+ intoxication).Osmotic laxative effects are alsoproduced by the polyhydric alcohols,mannitol and sorbitol, which unlike glucosecannot be transported through theintestinal mucosa, as well as by the nonhydrolyzabledisaccharide, lactulose.Fermentation of lactulose by colon bacteriaresults in acidification of bowelcontents and microfloral damage. Lactuloseis used in hepatic failure in orderto prevent bacterial production of ammoniaand its subsequent absorption(absorbable NH 3 nonabsorbableNH + 4 ), so as to forestall hepatic coma.2. Irritant laxatives—purgativescathartics. Laxatives in this group exertan irritant action on the enteric mucosa(A). Consequently, less fluid is absorbedthan is secreted. The increased filling ofthe bowel promotes peristalsis; excitationof sensory nerve endings elicits enteralhypermotility. According to thesite of irritation, one distinguishes thesmall bowel irritant castor oil from thelarge bowel irritants anthraquinone anddiphenolmethane derivatives (for detailssee p. 174).Misuse of laxatives. It is a widelyheld belief that at least one bowelmovement per day is essential forhealth; yet three bowel evacuations perweek are quite normal. The desire forfrequent bowel emptying probablystems from the time-honored, albeitLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Laxatives 171Stretch receptorsContractionRelaxationA. Stimulation of peristalsis by an intraluminal bolusH 2 OH 2 OCellulose, agar-agar, bran, linseedB. Bulk 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 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 OH 2 ONa + , Cl -H 2 OIsoosmoticabsorptionGH 2 OGH 2 OGGH 2 OG = GlucoseG H 2 OGH 2 OH 2 OH 2 O2 Na + 2-SO 4 H2 O H 2 OH 2 OMannitolH 2 OC. Osmotically active laxativesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
172 Laxativesmistaken, notion that absorption of coloncontents is harmful. Thus, purginghas long been part of standard therapeuticpractice. Nowadays, it is knownthat intoxication from intestinal substancesis impossible as long as the liverfunctions normally. Nonetheless, purgativescontinue to be sold as remedies to“cleanse the blood” or to rid the body of“corrupt humors.”There can be no objection to the ingestionof bulk substances for the purposeof supplementing low-residue“modern diets.” However, use of irritantpurgatives or cathartics is not withouthazards. Specifically, there is a risk oflaxative dependence, i.e., the inability todo without them. Chronic intake of irritantpurgatives disrupts the water andelectrolyte balance of the body and canthus cause symptoms of illness (e.g.,cardiac arrhythmias secondary to hypokalemia).Causes of purgative dependence(B). The defecation reflex is triggeredwhen the sigmoid colon and rectum arefilled. A natural defecation empties thelarge bowel up to and including the descendingcolon. The interval betweennatural stool evacuations depends onthe speed with which these colon segmentsare refilled. A large bowel irritantpurgative clears out the entire colon.Accordingly, a longer period is neededuntil the next natural defecation can occur.Fearing constipation, the user becomesimpatient and again resorts tothe laxative, which then produces thedesired effect as a result of emptyingout the upper colonic segments. Therefore,a “compensatory pause” followingcessation of laxative use must not givecause for concern (1).In the colon, semifluid material enteringfrom the small bowel is thickenedby absorption of water and salts(from about 1000 to 150 mL/d). If, dueto the action of an irritant purgative, thecolon empties prematurely, an enteralloss of NaCl, KCl and water will be incurred.To forestall depletion of NaCland water, the body responds with anincreased release of aldosterone (p.124), which stimulates their reabsorptionin the kidney. The action of aldosteroneis, however, associated with increasedrenal excretion of KCl. The enteraland renal K + loss add up to a K + depletionof the body, evidenced by a fallin serum K + concentration (hypokalemia).This condition is accompanied bya reduction in intestinal peristalsis(bowel atonia). The affected individualinfers “constipation,” again partakes ofthe purgative, and the vicious circle isclosed (2).Chologenic diarrhea results whenbile acids fail to be absorbed in the ileum(e.g., after ileal resection) and enterthe colon, where they cause enhancedsecretion of electrolytes and water,leading to the discharge of fluid stools.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Laxatives 173ReflexIrritationof mucosaFillingPeristalsisAbsorption Secretionof fluidA. Stimulation of peristalsis by mucosal irritationIntervalneeded torefill colonNormal fillingdefecation reflexAfter normalevacuation of colon1LaxativeLonger interval neededto refill rectum“Constipation”Renal retentionof Na + , H 2 OLaxativeBowel inertiaAldosteroneHypokalemiaEnteralloss of K +Renallossof K +2Na + , H 2 OB. Causes of laxative habituationLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
174 Laxatives and Purgatives2.a Small Bowel Irritant Purgative,Ricinoleic AcidCastor oil comes from Ricinus communis(castor plants; Fig: sprig, panicle,seed); it is obtained from the first coldpressingof the seed (shown in naturalsize). Oral administration of 10–30 mLof castor oil is followed within 0.5 to 3 hby discharge of a watery stool. Ricinoleicacid, but not the oil itself, is active. Itarises as a result of the regular processesinvolved in fat digestion: the duodenalmucosa releases the enterohormonecholecystokinin/pancreozymin into theblood. The hormone elicits contractionof the gallbladder and discharge of bileacids via the bile duct, as well as releaseof lipase from the pancreas (intestinalperistalsis is also stimulated). Becauseof its massive effect, castor oil is hardlysuitable for the treatment of ordinaryconstipation. It can be employed afteroral ingestion of a toxin in order to hastenelimination and to reduce absorptionof toxin from the gut. Castor oil isnot indicated after the ingestion of lipophilictoxins likely to depend on bile acidsfor their absorption.2.b Large Bowel Irritant Purgatives(p. 177 ff)Anthraquinone derivatives (p. 176) areof plant origin. They occur in the leaves(folia sennae) or fruits (fructus sennae)of the senna plant, the bark of Rhamnusfrangulae and Rh. purshiana, (cortexfrangulae, cascara sagrada), the roots ofrhubarb (rhizoma rhei), or the leaf extractfrom Aloe species (p. 176). Thestructural features of anthraquinone derivativesare illustrated by the prototypestructure depicted on p. 177.Among other substituents, the anthraquinonenucleus contains hydroxylgroups, one of which is bound to a sugar(glucose, rhamnose). Following ingestionof galenical preparations or of theanthraquinone glycosides, discharge ofsoft stool occurs after a latency of 6 to 8h. The anthraquinone glycosides themselvesare inactive but are converted bycolon bacteria to the active free aglycones.Diphenolmethane derivatives (p. 177)were developed from phenolphthalein,an accidentally discovered laxative, useof which had been noted to result inrare but severe allergic reactions. Bisacodyland sodium picosulfate are convertedby gut bacteria into the active colonirritantprinciple. Given by the enteralroute, bisacodyl is subject to hydrolysisof acetyl residues, absorption, conjugationin liver to glucuronic acid (or also tosulfate, p. 38), and biliary secretion intothe duodenum. Oral administration isfollowed after approx. 6 to 8 h by dischargeof soft formed stool. When givenby suppository, bisacodyl produces itseffect within 1 h.Indications for colon-irritant purgativesare the prevention of straining atstool following surgery, myocardial infarction,or stroke; and provision of reliefin painful diseases of the anus, e.g.,fissure, hemorrhoids.Purgatives must not be given in abdominalcomplaints of unclear origin.3. Lubricant laxatives. Liquid paraffin(paraffinum subliquidum) is almost nonabsorbableand makes feces softer andmore easily passed. It interferes withthe absorption of fat-soluble vitaminsby trapping them. The few absorbedparaffin particles may induce formationof foreign-body granulomas in entericlymph nodes (paraffinomas). Aspirationinto the bronchial tract can result in lipoidpneumonia. Because of these adverseeffects, its use is not advisable.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Laxatives and Purgatives 175RicinuscommunisGallbladderCK/PZRicinoleic acid – O – CH 2Castor oilRicinoleic acid – O – CHRicinoleic acid – O – CH 2PeristalsisBileacidsLipaseGlycerol +3 Ricinoleic acidsPancreasDuodenumCK/PZ =Cholecystokinin/pancreozyminA. Small-bowel irritant laxative: ricinoleic acidLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
176 Laxatives and PurgativesSennaFrangulaRhubarbAloeA. Plants containing anthraquinone glycosidesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Laxatives and Purgatives 177sugare.g., 1,8-Dihydroxyanthraquinoneglycoside1,8-Dihydroxyanthrone-AnthranolReductionSugar cleavageBacteriaAnthraquinoneglycosideA. Large-bowel irritant laxatives: anthraquinone derivativesGlucuronidationBisacodylSodiumpicosulfateDiphenolEsteraseDiphenolSulfateGlucuronideGlucuronateBacteriaB. Large-bowel irritant laxatives: diphenylmethane derivativesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
178 AntidiarrhealsAntidiarrheal AgentsCauses of diarrhea (in red): Many bacteria(e.g., Vibrio cholerae) secrete toxinsthat inhibit the ability of mucosal enterocytesto absorb NaCl and water and, atthe same time, stimulate mucosal secretoryactivity. Bacteria or viruses that invadethe gut wall cause inflammationcharacterized by increased fluid secretioninto the lumen. The enteric musculaturereacts with increased peristalsis.The aims of antidiarrheal therapyare to prevent: (1) dehydration andelectrolyte depletion; and (2) excessivelyhigh stool frequency. Different therapeuticapproaches (in green) listedare variously suited for these purposes.Adsorbent powders are nonabsorbablematerials with a large surfacearea. These bind diverse substances, includingtoxins, permitting them to beinactivated and eliminated. Medicinalcharcoal possesses a particularly largesurface because of the preserved cellstructures. The recommended effectiveantidiarrheal dose is in the range of4–8 g. Other adsorbents are kaolin (hydratedaluminum silicate) and chalk.Oral rehydration solution (g/L ofboiled water: NaCl 3.5, glucose 20,NaHCO 3 2.5, KCl 1.5). Oral administrationof glucose-containing salt solutionsenables fluids to be absorbed becausetoxins do not impair the cotransport ofNa + and glucose (as well as of H 2O)through the mucosal epithelium. In thismanner, although frequent discharge ofstool is not prevented, dehydration issuccessfully corrected.Opioids. Activation of opioid receptorsin the enteric nerve plexus resultsin inhibition of propulsive motor activityand enhancement of segmentationactivity. This antidiarrheal effect wasformerly induced by application of opiumtincture (paregoric) containing morphine.Because of the CNS effects (sedation,respiratory depression, physicaldependence), derivatives with peripheralactions have been developed.Whereas diphenoxylate can still produceclear CNS effects, loperamide does notaffect brain functions at normal dosage.Loperamide is, therefore, the opioidantidiarrheal of first choice. The prolongedcontact time of intestinal contentsand mucosa may also improve absorptionof fluid. With overdosage,there is a hazard of ileus. It is contraindicatedin infants below age 2 y.Antibacterial drugs. Use of theseagents (e.g., cotrimoxazole, p. 272) isonly rational when bacteria are thecause of diarrhea. This is rarely the case.It should be kept in mind that antibioticsalso damage the intestinal florawhich, in turn, can give rise to diarrhea.Astringents such as tannic acid(home remedy: black tea) or metal saltsprecipitate surface proteins and arethought to help seal the mucosal epithelium.Protein denaturation must not includecellular proteins, for this wouldmean cell death. Although astringentsinduce constipation (cf. Al 3+ salts,p. 166), a therapeutic effect in diarrheais doubtful.Demulcents, e.g., pectin (homeremedy: grated apples) are carbohydratesthat expand on absorbing water.They improve the consistency of bowelcontents; beyond that they are devoidof any favorable effect.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antidiarrheals 179ToxinsNa +Adsorptione.g., tomedicinalcharcoalToxinsCl -Fluid secretionNa +GlucoseOralrehydrationsolution:salts andglucoseAntibacterialdrugs:e.g., co-trimoxazoleResidentmicrofloraPathogenicbacteriaMucosal injuryVirusesOpium tincturewith morphineDiphenoxylateLoperamideCNSEnhanced peristalsisOpioidreceptorsProteincontainingmucusAstringents:e.g., tannic acidInhibition ofpropulsiveperistalsisPrecipitation ofsurface proteins,sealing ofmucosaFluid lossDiarrheaA. Antidiarrheals and their sites of actionLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
180 Other Gastrointestinal DrugsDrugs for Dissolving Gallstones (A)Following its secretion from liver intobile, water-insoluble cholesterol is heldin solution in the form of micellar complexeswith bile acids and phospholipids.When more cholesterol is secretedthan can be emulsified, it precipitatesand forms gallstones (cholelithiasis).Precipitated cholesterol can be reincorporatedinto micelles, provided the cholesterolconcentration in bile is belowsaturation. Thus, cholesterol-containingstones can be dissolved slowly. Thiseffect can be achieved by long-term oraladministration of chenodeoxycholicacid (CDCA) or ursodeoxycholic acid(UDCA). Both are physiologically occurring,stereoisomeric bile acids (positionof the 7-hydroxy group being β in UCDAand α in CDCA). Normally, they representa small proportion of the totalamount of bile acid present in the body(circle diagram in A); however, this increasesconsiderably with chronic administrationbecause of enterohepaticcycling, p. 38). Bile acids undergo almostcomplete reabsorption in the ileum.Small losses via the feces are made upby de novo synthesis in the liver, keepingthe total amount of bile acids constant(3–5 g). Exogenous supply removesthe need for de novo synthesis ofbile acids. The particular acid being suppliedgains an increasingly larger shareof the total store.The altered composition of bile increasesthe capacity for cholesterol uptake.Thus, gallstones can be dissolvedin the course of a 1- to 2 y treatment,provided that cholesterol stones arepure and not too large (
Other Gastrointestinal Drugs 181CA : Cholic acidDCA : Desoxy-CAUDCA : Ursodesoxy-CACDCA : Chenodesoxy-CAUDCASynthesis of bileacids to maintainstoreGall-stoneformed bycholesterolDAACDCACAUDCADCACDCA CAUDCAIleumExcretionin fecesA. Gallstone dissolution“Pancreatin” of slaughter animals:Protease, Amylase,LipaseStomachDuodenumCK/PZFatcontainingchymusPancreaticenzymeCirculationAdditionofdimethicone“Defoaming”B. Release of pancreatic enzymes andtheir replacementC. Carminative effect ofdimethiconeLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
182 Drugs Acting on Motor SystemsDrugs Affecting Motor FunctionThe smallest structural unit of skeletalmusculature is the striated muscle fiber.It contracts in response to an impulse ofits motor nerve. In executing motor programs,the brain sends impulses to thespinal cord. These converge on α-motoneuronsin the anterior horn of the spinalmedulla. Efferent axons course, bundledin motor nerves, to skeletal muscles.Simple reflex contractions to sensorystimuli, conveyed via the dorsalroots to the motoneurons, occur withoutparticipation of the brain. Neuralcircuits that propagate afferent impulsesinto the spinal cord contain inhibitoryinterneurons. These serve to preventa possible overexcitation of motoneurons(or excessive muscle contractions)due to the constant barrage ofsensory stimuli.Neuromuscular transmission (B) ofmotor nerve impulses to the striatedmuscle fiber takes place at the motorendplate. The nerve impulse liberatesacetylcholine (ACh) from the axon terminal.ACh binds to nicotinic cholinoceptorsat the motor endplate. Activation ofthese receptors causes depolarization ofthe endplate, from which a propagatedaction potential (AP) is elicited in thesurrounding sarcolemma. The AP triggersa release of Ca 2+ from its storage organelles,the sarcoplasmic reticulum(SR), within the muscle fiber; the rise inCa 2+ concentration induces a contractionof the myofilaments (electromechanicalcoupling). Meanwhile, ACh ishydrolyzed by acetylcholinesterase(p. 100); excitation of the endplate subsides.If no AP follows, Ca 2+ is taken upagain by the SR and the myofilamentsrelax.Clinically important drugs (withthe exception of dantrolene) all interferewith neural control of the musclecell (A, B, p. 183ff.)Centrally acting muscle relaxants(A) lower muscle tone by augmentingthe activity of intraspinal inhibitoryinterneurons. They are used in the treatmentof painful muscle spasms, e.g., inspinal disorders. Benzodiazepines enhancethe effectiveness of the inhibitorytransmitter GABA (p. 226) at GABA A receptors.Baclofen stimulates GABA B receptors.α 2-Adrenoceptor agonists suchas clonidine and tizanidine probably actpresynaptically to inhibit release of excitatoryamino acid transmitters.The convulsant toxins, tetanus toxin(cause of wound tetanus) and strychninediminish the efficacy of interneuronalsynaptic inhibition mediated bythe amino acid glycine (A). As a consequenceof an unrestrained spread ofnerve impulses in the spinal cord, motorconvulsions develop. The involvementof respiratory muscle groups endangerslife.Botulinum toxin from Clostridiumbotulinum is the most potent poisonknown. The lethal dose in an adult is approx.3 10 –6 mg. The toxin blocks exocytosisof ACh in motor (and also parasympathetic)nerve endings. Death iscaused by paralysis of respiratory muscles.Injected intramuscularly at minusculedosage, botulinum toxin type A isused to treat blepharospasm, strabismus,achalasia of the lower esophagealsphincter, and spastic aphonia.A pathological rise in serum Mg 2+levels also causes inhibition of ACh release,hence inhibition of neuromusculartransmission.Dantrolene interferes with electromechanicalcoupling in the muscle cellby inhibiting Ca 2+ release from the SR. Itis used to treat painful muscle spasmsattending spinal diseases and skeletalmuscle disorders involving excessiverelease of Ca 2+ (malignant hyperthermia).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on Motor Systems 183AntiepilepticsAntiparkinsonian drugsMyotonolytics DantroleneMuscle relaxantsMyotonolyticsConvulsantsIncreasedinhibitionAttenuatedinhibitionInhibitoryneuronInhibitoryinterneuronBenzodiazepinese.g., diazepamGABAAgonistBaclofenGlycineStrychnineReceptorantagonistTetanusToxinInhibitionof release(GABA =γ-aminobutyric acid)A. Mechanisms for influencing skeletal muscle toneMotorneuronMg 2+Botulinum toxininhibitACh-releaseMuscle relaxantsinhibit generationof actionpotentialAction potentialSarcoplasmicreticulumt-TubuleMotorendplateAChDepolarizationMembrane potentialDantroleneinhibitsCa 2+ releaseMyofilamentsACh receptor(nicotinic)Muscle tonems 10 20Ca 2+ContractionB. Inhibition of neuromuscular transmission and electromechanical couplingLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
184 Drugs Acting on Motor SystemsMuscle RelaxantsMuscle relaxants cause a flaccid paralysisof skeletal musculature by binding tomotor endplate cholinoceptors, thusblocking neuromuscular transmission (p.182). According to whether receptor occupancyleads to a blockade or an excitationof the endplate, one distinguishesnondepolarizing from depolarizingmuscle relaxants (p. 186). As adjuncts togeneral anesthetics, muscle relaxantshelp to ensure that surgical proceduresare not disturbed by muscle contractionsof the patient (p. 216).Nondepolarizing muscle relaxantsCurare is the term for plant-derived arrowpoisons of South American natives.When struck by a curare-tipped arrow,an animal suffers paralysis of skeletalmusculature within a short time afterthe poison spreads through the body;death follows because respiratory musclesfail (respiratory paralysis). Killedgame can be eaten without risk becauseabsorption of the poison from the gastrointestinaltract is virtually nil. The curareingredient of greatest medicinalimportance is d-tubocurarine. Thiscompound contains a quaternary nitrogenatom (N) and, at the opposite end ofthe molecule, a tertiary N that is protonatedat physiological pH. These twopositively charged N atoms are commonto all other muscle relaxants. The fixedpositive charge of the quaternary N accountsfor the poor enteral absorbability.d-Tubocurarine is given by i.v. injection(average dose approx. 10 mg). Itbinds to the endplate nicotinic cholinoceptorswithout exciting them, acting asa competitive antagonist towards ACh.By preventing the binding of releasedACh, it blocks neuromuscular transmission.Muscular paralysis develops withinabout 4 min. d-Tubocurarine does notpenetrate into the CNS. The patientwould thus experience motor paralysisand inability to breathe, while remainingfully conscious but incapable of expressinganything. For this reason, caremust be taken to eliminate consciousnessby administration of an appropriatedrug (general anesthesia) before usinga muscle relaxant. The effect of a singledose lasts about 30 min.The duration of the effect of d-tubocurarinecan be shortened by administeringan acetylcholinesterase inhibitor,such as neostigmine (p. 102). Inhibitionof ACh breakdown causes the concentrationof ACh released at the endplateto rise. Competitive “displacement” byACh of d-tubocurarine from the receptorallows transmission to be restored.Unwanted effects produced by d-tubocurarineresult from a nonimmunemediatedrelease of histamine frommast cells, leading to bronchospasm, urticaria,and hypotension. More commonly,a fall in blood pressure can be attributedto ganglionic blockade by d-tubocurarine.Pancuronium is a synthetic compoundnow frequently used and notlikely to cause histamine release or ganglionicblockade. It is approx. 5-foldmore potent than d-tubocurarine, witha somewhat longer duration of action.Increased heart rate and blood pressureare attributed to blockade of cardiac M 2-cholinoceptors, an effect not shared bynewer pancuronium congeners such asvecuronium and pipecuronium.Other nondepolarizing muscle relaxantsinclude: alcuronium, derivedfrom the alkaloid toxiferin; rocuronium,gallamine, mivacurium, and atracurium.The latter undergoes spontaneouscleavage and does not depend onhepatic or renal elimination.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on Motor Systems 185Arrow poison of indigenous South Americansd-Tubocurarine(no enteral absorption)PancuroniumAChBlockade of ACh receptorsNo depolarization ofendplateRelaxation of skeletal muscles(Respiratory paralysis)A. Non-depolarizing muscle relaxantsArtificialventilationnecessary(plus generalanesthesia!)Antidote:cholinesteraseinhibitorse.g., neostigmineLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
186 Drugs Acting on Motor SystemsDepolarizing Muscle RelaxantsIn this drug class, only succinylcholine(succinyldicholine, suxamethonium, A)is of clinical importance. Structurally, itcan be described as a double ACh molecule.Like ACh, succinylcholine acts asagonist at endplate nicotinic cholinoceptors,yet it produces muscle relaxation.Unlike ACh, it is not hydrolyzed byacetylcholinesterase. However, it is asubstrate of nonspecific plasma cholinesterase(serum cholinesterase, p. 100).Succinylcholine is degraded more slowlythan is ACh and therefore remains inthe synaptic cleft for several minutes,causing an endplate depolarization ofcorresponding duration. This depolarizationinitially triggers a propagatedaction potential (AP) in the surroundingmuscle cell membrane, leading to contractionof the muscle fiber. After its i.v.injection, fine muscle twitches (fasciculations)can be observed. A new AP canbe elicited near the endplate only if themembrane has been allowed to repolarize.The AP is due to opening of voltagegatedNa-channel proteins, allowingNa + ions to flow through the sarcolemmaand to cause depolarization. After afew milliseconds, the Na channels closeautomatically (“inactivation”), themembrane potential returns to restinglevels, and the AP is terminated. As longas the membrane potential remains incompletelyrepolarized, renewed openingof Na channels, hence a new AP, isimpossible. In the case of released ACh,rapid breakdown by ACh esterase allowsrepolarization of the endplate andhence a return of Na channel excitabilityin the adjacent sarcolemma. Withsuccinylcholine, however, there is a persistentdepolarization of the endplateand adjoining membrane regions. Becausethe Na channels remain inactivated,an AP cannot be triggered in the adjacentmembrane.Because most skeletal muscle fibersare innervated only by a single endplate,activation of such fibers, with lengthsup to 30 cm, entails propagation of theAP through the entire cell. If the AP fails,the muscle fiber remains in a relaxedstate.The effect of a standard dose of succinylcholinelasts only about 10 min. Itis often given at the start of anesthesiato facilitate intubation of the patient. Asexpected, cholinesterase inhibitors areunable to counteract the effect of succinylcholine.In the few patients with agenetic deficiency in pseudocholinesterase(= nonspecific cholinesterase), thesuccinylcholine effect is significantlyprolonged.Since persistent depolarization ofendplates is associated with an efflux ofK + ions, hyperkalemia can result (risk ofcardiac arrhythmias).Only in a few muscle types (e.g.,extraocular muscle) are muscle fiberssupplied with multiple endplates. Heresuccinylcholine causes depolarizationdistributed over the entire fiber, whichresponds with a contracture. Intraocularpressure rises, which must be taken intoaccount during eye surgery.In skeletal muscle fibers whose motornerve has been severed, ACh receptorsspread in a few days over the entirecell membrane. In this case, succinylcholinewould evoke a persistent depolarizationwith contracture and hyperkalemia.These effects are likely to occurin polytraumatized patients undergoingfollow-up surgery.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on Motor Systems 187AcetylcholineSuccinylcholineAChDepolarizationPropagation ofaction potential (AP)SuccinylcholineDepolarizationContractionSkeletalmusclecellContraction1Rapid ACh cleavage byacetylcholine esterasesSuccinylcholine not degradedby acetylcholine esterases2Repolarization of end platePersistent depolarization of end plateAChNew AP and contractioncan be elicitedNew AP and contractioncannot be elicited3Membrane potentialNa + -channelMembrane potentialOpenClosed(opening not possible)RepolarizationClosed(opening possible)Membrane potentialPersistent depolarizationNo repolarization,renewed opening ofNa+-channelimpossibleA. Action of the depolarizing muscle relaxant succinylcholineLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
188 Drugs Acting on Motor SystemsAntiparkinsonian DrugsParkinson’s disease (shaking palsy) andits syndromal forms are caused by a degenerationof nigrostriatal dopamineneurons. The resulting striatal dopaminedeficiency leads to overactivity ofcholinergic interneurons and imbalanceof striopallidal output pathways, manifestedby poverty of movement (akinesia),muscle stiffness (rigidity), tremorat rest, postural instability, and gait disturbance.Pharmacotherapeutic measures areaimed at restoring dopaminergic functionor suppressing cholinergic hyperactivity.L-Dopa. Dopamine itself cannotpenetrate the blood-brain barrier; however,its natural precursor, L-dihydroxyphenylalanine(levodopa), is effective inreplenishing striatal dopamine levels,because it is transported across theblood-brain barrier via an amino acidcarrier and is subsequently decarboxylatedby DOPA-decarboxylase, presentin striatal tissue. Decarboxylation alsotakes place in peripheral organs wheredopamine is not needed, likely causingundesirable effects (tachycardia, arrhythmiasresulting from activation ofβ 1-adrenoceptors [p. 114], hypotension,and vomiting). Extracerebral productionof dopamine can be prevented byinhibitors of DOPA-decarboxylase (carbidopa,benserazide) that do not penetratethe blood-brain barrier, leavingintracerebral decarboxylation unaffected.Excessive elevation of brain dopaminelevels may lead to undesirable reactions,such as involuntary movements(dyskinesias) and mental disturbances.Dopamine receptor agonists. Deficientdopaminergic transmission in thestriatum can be compensated by ergotderivatives (bromocriptine [p. 114], lisuride,cabergoline, and pergolide) andnonergot compounds (ropinirole, pramipexole).These agonists stimulate dopaminereceptors (D 2, D 3, and D 1 subtypes),have lower clinical efficacy thanlevodopa, and share its main adverse effects.Inhibitors of monoamine oxidase-B(MAO B). This isoenzyme breaksdown dopamine in the corpus striatumand can be selectively inhibited by selegiline.Inactivation of norepinephrine,epinephrine, and 5-HT via MAO A is unaffected.The antiparkinsonian effects ofselegiline may result from decreaseddopamine inactivation (enhanced levodoparesponse) or from neuroprotectivemechanisms (decreased oxyradical formationor blocked bioactivation of anunknown neurotoxin).Inhibitors of catechol-O-methyltransferase(COMT). L-Dopa and dopaminebecome inactivated by methylation.The responsible enzyme can beblocked by entacapone, allowing higherlevels of L-dopa and dopamine to beachieved in corpus striatum.Anticholinergics. Antagonists atmuscarinic cholinoceptors, such asbenzatropine and biperiden (p. 106),suppress striatal cholinergic overactivityand thereby relieve rigidity andtremor; however, akinesia is not reversedor is even exacerbated. Atropinelikeperipheral side effects and impairmentof cognitive function limit the tolerabledosage.Amantadine. Early or mild parkinsonianmanifestations may be temporarilyrelieved by amantadine. Theunderlying mechanism of action mayinvolve, inter alia, blockade of ligandgatedion channels of the glutamate/NMDA subtype, ultimately leading to adiminished release of acetylcholine.Administration of levodopa pluscarbidopa (or benserazide) remains themost effective treatment, but does notprovide benefit beyond 3–5 y and is followedby gradual loss of symptom control,on-off fluctuations, and developmentof orobuccofacial and limb dyskinesias.These long-term drawbacks oflevodopa therapy may be delayed byearly monotherapy with dopamine receptoragonists. Treatment of advanceddisease requires the combined administrationof antiparkinsonian agents.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on Motor Systems 189Normal stateSelegilineDopamineAcetylcholineAmantadineHNHNInhibition ofdopamine degradationby MAO-B in CNSCHCH 3CH 3HDopaminedeficiencyPredominanceof acetylcholineParkinson´s diseaseNMDAreceptor:Blockadeof ionophore:attenuationof cholinergicneuronsBlood-brain barrierDopadecarboxylaseCarbidopaDopamineEntacaponeOH 3 C NHN 2 HOCN 2 H 5CStimulation of2 H 5CNHOCOOH peripheral dopaminereceptorsNO 2Inhibition of dopadecarboxylaseInhibition ofcatechol-Adverse effectsO-methyltransferaseDopamine substitution2000 mg 200 mgCOMTBromocriptineL-DopaH 3 CNBenzatropineHCH H3 C 3OHOONNNHONOCH 3H 3 C CH 3HOHOHNHCOOHOHHNBrDopamine-receptoragonistDopamine precursorAcetylcholine antagonistA. Antiparkinsonian drugsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
190 Drugs Acting on Motor SystemsAntiepilepticsEpilepsy is a chronic brain disease of diverseetiology; it is characterized by recurrentparoxysmal episodes of uncontrolledexcitation of brain neurons. Involvinglarger or smaller parts of thebrain, the electrical discharge is evidentin the electroencephalogram (EEG) assynchronized rhythmic activity andmanifests itself in motor, sensory, psychic,and vegetative (visceral) phenomena.Because both the affected brain regionand the cause of abnormal excitabilitymay differ, epileptic seizures cantake many forms. From a pharmacotherapeuticviewpoint, these may beclassified as:– general vs. focal seizures;– seizures with or without loss of consciousness;– seizures with or without specificmodes of precipitation.The brief duration of a single epilepticfit makes acute drug treatmentunfeasible. Instead, antiepileptics areused to prevent seizures and thereforeneed to be given chronically. Only in thecase of status epilepticus (a succession ofseveral tonic-clonic seizures) is acuteanticonvulsant therapy indicated —usually with benzodiazepines given i.v.or, if needed, rectally.The initiation of an epileptic attackinvolves “pacemaker” cells; these differfrom other nerve cells in their unstableresting membrane potential, i.e., a depolarizingmembrane current persistsafter the action potential terminates.Therapeutic interventions aim tostabilize neuronal resting potential and,hence, to lower excitability. In specificforms of epilepsy, initially a single drugis tried to achieve control of seizures,valproate usually being the drug of firstchoice in generalized seizures, and carbamazepinebeing preferred for partial(focal), especially partial complex, seizures.Dosage is increased until seizuresare no longer present or adverse effectsbecome unacceptable. Only whenmonotherapy with different agentsproves inadequate can changeover to asecond-line drug or combined use (“addon”) be recommended (B), providedthat the possible risk of pharmacokineticinteractions is taken into account (seebelow). The precise mode of action ofantiepileptic drugs remains unknown.Some agents appear to lower neuronalexcitability by several mechanisms ofaction. In principle, responsivity can bedecreased by inhibiting excitatory or activatinginhibitory neurons. Most excitatorynerve cells utilize glutamate andmost inhibitory neurons utilize γ-aminobutyricacid (GABA) as their transmitter(p. 193A). Various drugs can lowerseizure threshold, notably certain neuroleptics,the tuberculostatic isoniazid,and β-lactam antibiotics in high doses;they are, therefore, contraindicated inseizure disorders.Glutamate receptors comprisethree subtypes, of which the NMDAsubtype has the greatest therapeuticimportance. (N-methyl-D-aspartate is asynthetic selective agonist.) This receptoris a ligand-gated ion channel that,upon stimulation with glutamate, permitsentry of both Na + and Ca 2+ ions intothe cell. The antiepileptics lamotrigine,phenytoin, and phenobarbital inhibit,among other things, the release of glutamate.Felbamate is a glutamate antagonist.Benzodiazepines and phenobarbitalaugment activation of the GABA A receptorby physiologically released amountsof GABA (B) (see p. 226). Chloride influxis increased, counteracting depolarization.Progabide is a direct GABA-mimetic.Tiagabin blocks removal of GABAfrom the synaptic cleft by decreasing itsre-uptake. Vigabatrin inhibits GABA catabolism.Gabapentin may augment theavailability of glutamate as a precursorin GABA synthesis (B) and can also act asa K + -channel opener.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on Motor Systems 191Drugs used in the treatment of status epilepticus:Benzodiazepines, e.g., diazepamWaking stateµV1501005001 secEEGEpileptic attackµV1501005001 secDrugs used in the prophylaxis of epileptic seizuresNC ONH 2CarbamazepineHN ONHOPhenytoinHON C 2 H 5ONHOPhenobarbitalH 3 C OH 5 C 2N HOEthosuximideClClNNH 2 N N NH 2LamotrigineCH 3H 3 COH COOH3 CO OH 2 NCOOHH 3 CCH 2 OCNHH 22 CCHOCH 2 OCNH 2 OH 2 NCOOHOOH 3 C OSO 2 NH CH32Valproic acid Vigabatrin Gabapentin Felbamate TopiramateA. Epileptic attack, EEG, and antiepilepticsFocalseizuresGeneralizedattacksSimple seizuresComplexor secondarilygeneralizedTonic-clonicattack (grand mal)Tonic attackClonic attackMyoclonic attackAbsenceseizureCarbamazepine+I. II. III. ChoiceValproic acid+Valproic acid,Phenytoin,ClobazamCarbamazepine,PhenytoinEthosuximidePrimidone,PhenobarbitalLamotrigine or Vigabatrin or GabapentinLamotrigine,Primidone,PhenobarbitalLamotrigine or Vigabatrin or Gabapentinalternativeaddition+ Lamotrigine or ClonazepamB. Indications for antiepilepticsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
192 Drugs Acting on Motor SystemsCarbamazepine, valproate, andphenytoin enhance inactivation of voltage-gatedsodium and calcium channelsand limit the spread of electrical excitationby inhibiting sustained high-frequencyfiring of neurons.Ethosuximide blocks a neuronal T-type Ca 2+ channel (A) and represents aspecial class because it is effective onlyin absence seizures.All antiepileptics are likely, albeit todifferent degrees, to produce adverseeffects. Sedation, difficulty in concentrating,and slowing of psychomotor driveencumber practically all antiepileptictherapy. Moreover, cutaneous, hematological,and hepatic changes may necessitatea change in medication. Phenobarbital,primidone, and phenytoin maylead to osteomalacia (vitamin D prophylaxis)or megaloblastic anemia (folateprophylaxis). During treatment withphenytoin, gingival hyperplasia may developin ca. 20% of patients.Valproic acid (VPA) is gaining increasingacceptance as a first-line drug;it is less sedating than other anticonvulsants.Tremor, gastrointestinal upset,and weight gain are frequently observed;reversible hair loss is a rarer occurrence.Hepatotoxicity may be due toa toxic catabolite (4-en VPA).Adverse reactions to carbamazepineinclude: nystagmus, ataxia, diplopia,particularly if the dosage is raisedtoo fast. Gastrointestinal problems andskin rashes are frequent. It exerts anantidiuretic effect (sensitization of collectingducts to vasopressin water intoxication).Carbamazepine is also used to treattrigeminal neuralgia and neuropathicpain.Valproate, carbamazepine, and otheranticonvulsants pose teratogenicrisks. Despite this, treatment shouldcontinue during pregnancy, as the potentialthreat to the fetus by a seizure isgreater. However, it is mandatory to administerthe lowest dose affording safeand effective prophylaxis. Concurrenthigh-dose administration of folate mayprevent neural tube developmental defects.Carbamazepine, phenytoin, phenobarbital,and other anticonvulsants (exceptfor gabapentin) induce hepatic enzymesresponsible for drug biotransformation.Combinations between anticonvulsantsor with other drugs may resultin clinically important interactions(plasma level monitoring!).For the often intractable childhoodepilepsies, various other agents areused, including ACTH and the glucocorticoid,dexamethasone. Multiple(mixed) seizures associated with theslow spike-wave (Lennox–Gastaut) syndromemay respond to valproate, lamotrigine,and felbamate, the latter beingrestricted to drug-resistant seizuresowing to its potentially fatal liver andbone marrow toxicity.Benzodiazepines are the drugs ofchoice for status epilepticus (seeabove); however, development of tolerancerenders them less suitable forlong-term therapy. Clonazepam is usedfor myoclonic and atonic seizures.Clobazam, a 1,5-benzodiazepine exhibitingan increased anticonvulsant/sedativeactivity ratio, has a similar range ofclinical uses. Personality changes andparadoxical excitement are potentialside effects.Clomethiazole can also be effectivefor controlling status epilepticus, but isused mainly to treat agitated states, especiallyalcoholic delirium tremens andassociated seizures.Topiramate, derived from D-fructose,has complex, long-lasting anticonvulsantactions that cooperate to limitthe spread of seizure activity; it is effectivein partial seizures and as an add-onin Lennox–Gastaut syndrome.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs Acting on Motor Systems 193Na + Ca ++Ca 2+ -channelGABAtransaminaseNMDAreceptorNMDA-receptorantagonistfelbamate,valproic acidExcitatory neuronGlutamateInhibition ofglutamaterelease:phenytoin,lamotriginephenobarbitalT-Typecalciumchannel blockerethosuximide,(valproic acid)VoltagedependentNa + -channelEnhancedinactivation:GABA A -receptorCI –InhibitoryneuronGABAGabamimetics:benzodiazepinebarbituratesvigabatrintiagabinegabapentincarbamazepinevalproic acidphenytoinA. Neuronal sites of action of antiepilepticsBenzodiazepineAllostericenhancementofGABAactionαγβαβGABA A -receptorβα αγ βChloridechannelTiagabineInhibition ofGABAreuptakeBarbituratesEnding ofinhibitoryneuronGABAGlutamic aciddecarboxylaseGlutamicacidProgabideGABAmimeticSuccinicsemialdehydeSuccinic acidGabapentinImproved utilizationof GABA precursor:glutamateVigabatrinInhibitor ofGABAtransaminaseB. Sites of action of antiepileptics in GABAergic synapseLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
194 Drugs for the Suppression of Pain (Analgesics)Pain Mechanisms and PathwaysPain is a designation for a spectrum ofsensations of highly divergent characterand intensity ranging from unpleasantto intolerable. Pain stimuli are detectedby physiological receptors (sensors,nociceptors) least differentiated morphologically,viz., free nerve endings.The body of the bipolar afferent first-orderneuron lies in a dorsal root ganglion.Nociceptive impulses are conducted viaunmyelinated (C-fibers, conduction velocity0.2–2.0 m/s) and myelinated axons(Aδ-fibers, 5–30 m/s). The free endingsof Aδ fibers respond to intensepressure or heat, those of C-fibers respondto chemical stimuli (H + , K + , histamine,bradykinin, etc.) arising from tissuetrauma. Irrespective of whetherchemical, mechanical, or thermal stimuliare involved, they become significantlymore effective in the presence ofprostaglandins (p. 196).Chemical stimuli also underlie painsecondary to inflammation or ischemia(angina pectoris, myocardial infarction),or the intense pain that occurs duringoverdistention or spasmodic contractionof smooth muscle abdominal organs,and that may be maintained by localanoxemia developing in the area ofspasm (visceral pain).Aδ and C-fibers enter the spinalcord via the dorsal root, ascend in thedorsolateral funiculus, and then synapseon second-order neurons in thedorsal horn. The axons of the second-orderneurons cross the midline and ascendto the brain as the anterolateralpathway or spinothalamic tract. Basedon phylogenetic age, neo- and paleospinothalamictracts are distinguished.Thalamic nuclei receiving neospinothalamicinput project to circumscribed areasof the postcentral gyrus. Stimuliconveyed via this path are experiencedas sharp, clearly localizable pain. Thenuclear regions receiving paleospinothalamicinput project to the postcentralgyrus as well as the frontal, limbiccortex and most likely represent thepathway subserving pain of a dull, aching,or burning character, i.e., pain thatcan be localized only poorly.Impulse traffic in the neo- and paleospinothalamicpathways is subject tomodulation by descending projectionsthat originate from the reticular formationand terminate at second-order neurons,at their synapses with first-orderneurons, or at spinal segmental interneurons(descending antinociceptivesystem). This system can inhibit impulsetransmission from first- to second-orderneurons via release of opiopeptides(enkephalins) or monoamines(norepinephrine, serotonin).Pain sensation can be influencedor modified as follows: elimination of the cause of pain lowering of the sensitivity of nociceptors(antipyretic analgesics, localanesthetics) interrupting nociceptive conductionin sensory nerves (local anesthetics) suppression of transmission of nociceptiveimpulses in the spinal medulla(opioids) inhibition of pain perception (opioids,general anesthetics) altering emotional responses topain, i.e., pain behavior (antidepressantsas “co-analgesics,” p. 230).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drugs for the Suppression of Pain (Analgesics) 195Gyrus postcentralisPerception:sharpquicklocalizablePerception:dulldelayeddiffuseAnestheticsThalamusAntidepressantsLocal anestheticsOpioidsNeospinothalamictractPaleospinothalamictractReticularformationDescendingantinociceptivepathwayOpioidsNociceptorsCyclooxygenaseinhibitorsProstaglandinsInflammationCause of painA. Pain mechanisms and pathwaysLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
196 Antipyretic AnalgesicsEicosanoidsOrigin and metabolism. The eicosanoids,prostaglandins, thromboxane,prostacyclin, and leukotrienes, areformed in the organism from arachidonicacid, a C20 fatty acid with fourdouble bonds (eicosatetraenoic acid).Arachidonic acid is a regular constituentof cell membrane phospholipids; it isreleased by phospholipase A 2 and formsthe substrate of cyclooxygenases andlipoxygenases.Synthesis of prostaglandins (PG),prostacyclin, and thromboxane proceedsvia intermediary cyclic endoperoxides.In the case of PG, a cyclopentanering forms in the acyl chain. The lettersfollowing PG (D, E, F, G, H, or I) indicatedifferences in substitution with hydroxylor keto groups; the number subscriptsrefer to the number of doublebonds, and the Greek letter designatesthe position of the hydroxyl group at C9(the substance shown is PGF 2α). PG areprimarily inactivated by the enzyme 15-hydroxyprostaglandindehydrogenase.Inactivation in plasma is very rapid;during one passage through the lung,90% of PG circulating in plasma are degraded.PG are local mediators that attainbiologically effective concentrationsonly at their site of formation.<strong>Bio</strong>logical effects. The individualPG (PGE, PGF, PGI = prostacyclin) possessdifferent biological effects.Nociceptors. PG increase sensitivityof sensory nerve fibers towards ordinarypain stimuli (p. 194), i.e., at a givenstimulus strength there is an increasedrate of evoked action potentials.Thermoregulation. PG raise the setpoint of hypothalamic (preoptic) thermoregulatoryneurons; body temperatureincreases (fever).Vascular smooth muscle. PGE 2and PGI 2 produce arteriolar vasodilation;PGF 2α, venoconstriction.Gastric secretion. PG promote theproduction of gastric mucus and reducethe formation of gastric acid (p. 160).Menstruation. PGF 2α is believed tobe responsible for the ischemic necrosisof the endometrium preceding menstruation.The relative proportions of individualPG are said to be altered in dysmenorrheaand excessive menstrualbleeding.Uterine muscle. PG stimulate laborcontractions.Bronchial muscle. PGE 2 and PGI 2induce bronchodilation; PGF 2α causesconstriction.Renal blood flow. When renalblood flow is lowered, vasodilating PGare released that act to restore bloodflow.Thromboxane A 2 and prostacyclinplay a role in regulating the aggregabilityof platelets and vascular diameter (p.150).Leukotrienes increase capillarypermeability and serve as chemotacticfactors for neutrophil granulocytes. As“slow-reacting substances of anaphylaxis,”they are involved in allergic reactions(p. 326); together with PG, theyevoke the spectrum of characteristic inflammatorysymptoms: redness, heat,swelling, and pain.Therapeutic applications. PG derivativesare used to induce labor or tointerrupt gestation (p. 126); in the therapyof peptic ulcer (p. 168), and in peripheralarterial disease.PG are poorly tolerated if givensystemically; in that case their effectscannot be confined to the intended siteof action.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antipyretic Analgesics 197Phospholipase A 2LipoxygenaseThromboxaneProstacyclinCyclooxygenaseArachidonic acidProstaglandinse.g., PGF 2αLeukotrienese.g.,leukotriene A 4involved inallergic reactions[ H + ]MucusproductionFeverKidneyfunctionVasodilationLaborImpulsefrequency insensory fiberCapillary permeabilityNociceptorsensibilityPain stimulusA. Origin and effects of prostaglandinsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
198 Antipyretic Analgesics and Antiinflammatory DrugsAntipyretic AnalgesicsAcetaminophen, the amphiphilic acidsacetylsalicylic acid (ASA), ibuprofen,and others, as well as some pyrazolonederivatives, such as aminopyrine anddipyrone, are grouped under the labelantipyretic analgesics to distinguishthem from opioid analgesics, becausethey share the ability to reduce fever.Acetaminophen (paracetamol) hasgood analgesic efficacy in toothachesand headaches, but is of little use in inflammatoryand visceral pain. Its mechanismof action remains unclear. It canbe administered orally or in the form ofrectal suppositories (single dose,0.5–1.0 g). The effect develops afterabout 30 min and lasts for approx. 3 h.Acetaminophen undergoes conjugationto glucuronic acid or sulfate at the phenolichydroxyl group, with subsequentrenal elimination of the conjugate. Attherapeutic dosage, a small fraction isoxidized to the highly reactive N-acetylp-benzoquinonimine,which is detoxifiedby coupling to glutathione. After ingestionof high doses (approx. 10 g), theglutathione reserves of the liver are depletedand the quinonimine reacts withconstituents of liver cells. As a result,the cells are destroyed: liver necrosis.Liver damage can be avoided if the thiolgroup donor, N-acetylcysteine, is givenintravenously within 6–8 h after ingestionof an excessive dose of acetaminophen.Whether chronic regular intake ofacetaminophen leads to impaired renalfunction remains a matter of debate.Acetylsalicylic acid (ASA) exerts anantiinflammatory effect, in addition toits analgesic and antipyretic actions.These can be attributed to inhibition ofcyclooxygenase (p. 196). ASA can be givenin tablet form, as effervescent powder,or injected systemically as lysinate(analgesic or antipyretic single dose,O.5–1.0 g). ASA undergoes rapid esterhydrolysis, first in the gut and subsequentlyin the blood. The effect outlaststhe presence of ASA in plasma (t 1/2 ~20 min), because cyclooxygenases areirreversibly inhibited due to covalentbinding of the acetyl residue. Hence, theduration of the effect depends on therate of enzyme resynthesis. Furthermore,salicylate may contribute to theeffect. ASA irritates the gastric mucosa(direct acid effect and inhibition of cytoprotectivePG synthesis, p. 200) andcan precipitate bronchoconstriction(“aspirin asthma,” pseudoallergy) dueto inhibition of PGE 2 synthesis and overproductionof leukotrienes. Because ASAinhibits platelet aggregation and prolongsbleeding time (p. 150), it shouldnot be used in patients with impairedblood coagulability. Caution is alsoneeded in children and juveniles becauseof Reye’s syndrome. The latter hasbeen observed in association with febrileviral infections and ingestion ofASA; its prognosis is poor (liver andbrain damage). Administration of ASA atthe end of pregnancy may result in prolongedlabor, bleeding tendency inmother and infant, and premature closureof the ductus arteriosus. Acidicnonsteroidal antiinflammatory drugs(NSAIDS; p. 200) are derived from ASA.Among antipyretic analgesics, dipyrone(metamizole) displays the highestefficacy. It is also effective in visceralpain. Its mode of action is unclear, butprobably differs from that of acetaminophenand ASA. It is rapidly absorbedwhen given via the oral or rectal route.Because of its water solubility, it is alsoavailable for injection. Its active metabolite,4-aminophenazone, is eliminatedfrom plasma with a t 1/2 of approx. 5 h.Dipyrone is associated with a low incidenceof fatal agranulocytosis. In sensitizedsubjects, cardiovascular collapsecan occur, especially after intravenousinjection. Therefore, the drug should berestricted to the management of painrefractory to other analgesics. Propyphenazonepresumably acts like metamizoleboth pharmacologically and toxicologically.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antipyretic Analgesics and Antiinflammatory Drugs 199ToothacheHeadacheFeverInflammatorypainPain of colicAcetaminophen Acetylsalicylic acid DipyroneAcutemassiveoverdoseChronicabuse>10g?AgranulocytosisBronchoconstrictionImpairedhemostasis withrisk of bleedingIrritationofgastrointestinalmucosaHepatotoxicityNephrotoxicityRisk ofanaphylactoidshockA. Antipyretic analgesicsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
200 Antipyretic AnalgesicsNonsteroidal Antiinflammatory(Antirheumatic) AgentsAt relatively high dosage (> 4 g/d), ASA(p. 198) may exert antiinflammatory effectsin rheumatic diseases (e.g., rheumatoidarthritis). In this dose range,central nervous signs of overdosagemay occur, such as tinnitus, vertigo,drowsiness, etc. The search for bettertolerated drugs led to the family of nonsteroidalantiinflammatory drugs(NSAIDs). Today, more than 30 substancesare available, all of them sharingthe organic acid nature of ASA. Structurally,they can be grouped into carbonicacids (e.g., diclofenac, ibuprofen, naproxene,indomethacin [p. 320]) orenolic acids (e.g., azapropazone, piroxicam,as well as the long-known butpoorly tolerated phenylbutazone). LikeASA, these substances have analgesic,antipyretic, and antiinflammatory activity.In contrast to ASA, they inhibit cyclooxygenasein a reversible manner.Moreover, they are not suitable as inhibitorsof platelet aggregation. Sincetheir desired effects are similar, thechoice between NSAIDs is dictated bytheir pharmacokinetic behavior andtheir adverse effects.Salicylates additionally inhibit thetranscription factor NF KB, hence the expressionof proinflammatory proteins.This effect is shared with glucocorticoids(p. 248) and ibuprofen, but notwith some other NSAIDs.Pharmacokinetics. NSAIDs arewell absorbed enterally. They are highlybound to plasma proteins (A). They areeliminated at different speeds: diclofenac(t 1/2 = 1–2 h) and piroxicam (t 1/2 ~ 50h); thus, dosing intervals and risk of accumulationwill vary. The elimination ofsalicylate, the rapidly formed metaboliteof ASA, is notable for its dose dependence.Salicylate is effectively reabsorbedin the kidney, except at high urinarypH. A prerequisite for rapid renalelimination is a hepatic conjugation reaction(p. 38), mainly with glycine (→salicyluric acid) and glucuronic acid. Athigh dosage, the conjugation may becomerate limiting. Elimination now increasinglydepends on unchanged salicylate,which is excreted only slowly.Group-specific adverse effects canbe attributed to inhibition of cyclooxygenase(B). The most frequent problem,gastric mucosal injury with risk of pepticulceration, results from reduced synthesisof protective prostaglandins (PG),apart from a direct irritant effect. Gastropathymay be prevented by co-administrationof the PG derivative, misoprostol(p. 168). In the intestinal tract,inhibition of PG synthesis would similarlybe expected to lead to damage ofthe blood mucosa barrier and enteropathy.In predisposed patients, asthma attacksmay occur, probably because of alack of bronchodilating PG and increasedproduction of leukotrienes. Becausethis response is not immune mediated,such “pseudoallergic” reactionsare a potential hazard with all NSAIDs.PG also regulate renal blood flow asfunctional antagonists of angiotensin IIand norepinephrine. If release of the lattertwo is increased (e.g., in hypovolemia),inhibition of PG production mayresult in reduced renal blood flow and renalimpairment. Other unwanted effectsare edema and a rise in blood pressure.Moreover, drug-specific side effectsdeserve attention. These concern theCNS (e.g., indomethacin: drowsiness,headache, disorientation), the skin (piroxicam:photosensitization), or theblood (phenylbutazone: agranulocytosis).Outlook: Cyclooxygenase (COX)has two isozymes: COX-1, a constitutiveform present in stomach and kidney;and COX-2, which is induced in inflammatorycells in response to appropriatestimuli. Presently available NSAIDs inhibitboth isozymes. The search forCOX-2-selective agents (Celecoxib, Rofecoxib)is intensifying because, in theory,these ought to be tolerated better.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antipyretic Analgesics 201High doset 1/2 =13-30hLow doset 1/2~3h50%Salicylic acidt 1/2 =1-2h90% Acetylsalicylicacid95%t 1/2 =15minDiclofenac99%99%AzapropazoneIbuprofent 1/2 ~2ht 1/2 =9-12ht 1/2~50hPiroxicam99%Naproxen99%t 1/2~14hPlasma protein bindingA. Nonsteroidal antiinflammatory drugs (NSAIDs)NSAID-inducednephrotoxicityArachidonic acidLeukotrienesRenal bloodflowProstaglandinsAirway resistanceNSAID-inducedgastropathyMucus productionAcid secretionMucosal blood flowNSAID-inducedasthmaB. NSAIDs: group-specific adverse effectsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
202 Antipyretic AnalgesicsThermoregulation and AntipyreticsBody core temperature in the human isabout 37 °C and fluctuates within ± 1 °Cduring the 24 h cycle. In the restingstate, the metabolic activity of vital organscontributes 60% (liver 25%, brain20%, heart 8%, kidneys 7%) to total heatproduction. The absolute contributionto heat production from these organschanges little during physical activity,whereas muscle work, which contributesapprox. 25% at rest, can generateup to 90% of heat production duringstrenuous exercise. The set point of thebody temperature is programmed in thehypothalamic thermoregulatory center.The actual value is adjusted to the setpoint by means of various thermoregulatorymechanisms. Blood vessels supplyingthe skin penetrate the heat-insulatinglayer of subcutaneous adipose tissueand therefore permit controlledheat exchange with the environment asa function of vascular caliber and rate ofblood flow. Cutaneous blood flow canrange from ~ 0 to 30% of cardiac output,depending on requirements. Heat conductionvia the blood from interior sitesof production to the body surface providesa controllable mechanism for heatloss.Heat dissipation can also beachieved by increased production ofsweat, because evaporation of sweat onthe skin surface consumes heat (evaporativeheat loss). Shivering is a mechanismto generate heat. Autonomic neuralregulation of cutaneous blood flowand sweat production permit homeostaticcontrol of body temperature (A).The sympathetic system can either reduceheat loss via vasoconstriction orpromote it by enhancing sweat production.When sweating is inhibited due topoisoning with anticholinergics (e.g.,atropine), cutaneous blood flow increases.If insufficient heat is dissipatedthrough this route, overheating occurs(hyperthermia).Thyroid hyperfunction poses aparticular challenge to the thermoregulatorysystem, because the excessive secretionof thyroid hormones causesmetabolic heat production to increase.In order to maintain body temperatureat its physiological level, excess heatmust be dissipated—the patients have ahot skin and are sweating.The hypothalamic temperaturecontroller (B1) can be inactivated byneuroleptics (p. 236), without impairmentof other centers. Thus, it is possibleto lower a patient’s body temperaturewithout activating counter-regulatorymechanisms (thermogenic shivering).This can be exploited in the treatmentof severe febrile states (hyperpyrexia)or in open-chest surgery withcardiac by-pass, during which bloodtemperature is lowered to 10 °C bymeans of a heart-lung machine.In higher doses, ethanol and barbituratesalso depress the thermoregulatorycenter (B1), thereby permittingcooling of the body to the point of death,given a sufficiently low ambient temperature(freezing to death in drunkenness).Pyrogens (e.g., bacterial matter) elevate—probablythrough mediation byprostaglandins (p. 196) and interleukin-1—the set point of the hypothalamictemperature controller (B2). The bodyresponds by restricting heat loss (cutaneousvasoconstriction → chills) and byelevating heat production (shivering), inorder to adjust to the new set point (fever).Antipyretics such as acetaminophenand ASA (p. 198) return the setpoint to its normal level (B2) and thusbring about a defervescence.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antipyretic Analgesics 203Thermoregulatorycenter(set point)α-AdrenoceptorsSympathetic systemAcetylcholinereceptorsHyperthyroidismIncreasedheatproduction35º36º37º38º39ºCutaneousblood flowSweatproductionHeat productionHeat conductionHeat radiationEvaporation of sweatRespirationParasympatholytics(Atropine)MetabolicactivityHeatproductionHeatlossInhibitionof sweatproductionHyperthermia35º36º37º38º39ºBody temperatureA. ThermoregulationNeurolepticsPreferentialinhibitionHeatcenterEthanolBarbituratese.g.,paralysisPyrogen35º36º37º38º39ºAntipyreticsControlledhypothermiaUncontrolledheat lossSet pointelevation“Artificialhibernation”Hypothermia,freezingto deathTemperaturerise35ºFever37º37º1 236º38º39ºB. Disturbances of thermoregulation35º36º38º39ºLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
204 Local AnestheticsLocal AnestheticsLocal anesthetics reversibly inhibit impulsegeneration and propagation innerves. In sensory nerves, such an effectis desired when painful proceduresmust be performed, e.g., surgical or dentaloperations.Mechanism of action. Nerve impulseconduction occurs in the form ofan action potential, a sudden reversal inresting transmembrane potential lastingless than 1 ms. The change in potentialis triggered by an appropriate stimulusand involves a rapid influx of Na +into the interior of the nerve axon (A).This inward flow proceeds through achannel, a membrane pore protein, that,upon being opened (activated), permitsrapid movement of Na + down a chemicalgradient ([Na + ] ext ~ 150 mM, [Na + ] int~ 7 mM). Local anesthetics are capableof inhibiting this rapid inward flux ofNa + ; initiation and propagation of excitationare therefore blocked (A).Most local anesthetics exist in partin the cationic amphiphilic form (cf. p.208). This physicochemical property favorsincorporation into membraneinterphases, boundary regions betweenpolar and apolar domains. These arefound in phospholipid membranes andalso in ion-channel proteins. Some evidencesuggests that Na + -channel blockaderesults from binding of local anestheticsto the channel protein. It appearscertain that the site of action is reachedfrom the cytosol, implying that the drugmust first penetrate the cell membrane(p. 206).Local anesthetic activity is alsoshown by uncharged substances, suggestinga binding site in apolar regionsof the channel protein or the surroundinglipid membrane.Mechanism-specific adverse effects.Since local anesthetics block Na +influx not only in sensory nerves but alsoin other excitable tissues, they areapplied locally and measures are taken(p. 206) to impede their distributioninto the body. Too rapid entry into thecirculation would lead to unwantedsystemic reactions such as: blockade of inhibitory CNS neurons,manifested by restlessness and seizures(countermeasure: injection of abenzodiazepine, p. 226); general paralysiswith respiratory arrest afterhigher concentrations. blockade of cardiac impulse conduction,as evidenced by impaired AVconduction or cardiac arrest (countermeasure:injection of epinephrine).Depression of excitatory processesin the heart, while undesiredduring local anesthesia, can be put totherapeutic use in cardiac arrhythmias(p. 134).Forms of local anesthesia. Localanesthetics are applied via differentroutes, including infiltration of the tissue(infiltration anesthesia) or injectionnext to the nerve branch carryingfibers from the region to be anesthetized(conduction anesthesia of thenerve, spinal anesthesia of segmentaldorsal roots), or by application to thesurface of the skin or mucosa (surfaceanesthesia). In each case, the local anestheticdrug is required to diffuse tothe nerves concerned from a depotplaced in the tissue or on the skin.High sensitivity of sensory nerves,low sensitivity of motor nerves. Impulseconduction in sensory nerves isinhibited at a concentration lower thanthat needed for motor fibers. This differencemay be due to the higher impulsefrequency and longer action potentialduration in nociceptive, as opposed tomotor, fibers.Alternatively, it may be related tothe thickness of sensory and motornerves, as well as to the distancebetween nodes of Ranvier. In saltatoryimpulse conduction, only the nodalmembrane is depolarized. Because depolarizationcan still occur after blockadeof three or four nodal rings, the areaexposed to a drug concentration sufficientto cause blockade must be largerfor motor fibers (p. 205B).This relationship explains why sensorystimuli that are conducted viaLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Local Anesthetics 205Local anestheticNa + -entryPropagatedimpulseActivatedNa+-channelNa +Peripheral nerveCNSBlockedNa+-channelNa +ConductionblockRestlessness,convulsions,respiratoryparalysisBlockedNa+-channelNa +HeartLocalapplicationA. Effects of local anestheticsImpulseconductioncardiac arrestLocal anestheticpolar+apolarCationicamphiphiliclocalanestheticUnchargedlocalanestheticAα motor0.8 – 1.4 mmAδ sensory0.3 – 0.7 mmC sensory andpostganglionicB. Inhibition of impulse conduction in different types of nerve fibersLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
206 Local Anestheticsmyelinated Aδ-fibers are affected laterand to a lesser degree than are stimuliconducted via unmyelinated C-fibers.Since autonomic postganglionic fiberslack a myelin sheath, they are particularlysusceptible to blockade by localanesthetics. As a result, vasodilation ensuesin the anesthetized region, becausesympathetically driven vasomotor tonedecreases. This local vasodilation is undesirable(see below).Diffusion and EffectDuring diffusion from the injection site(i.e., the interstitial space of connectivetissue) to the axon of a sensory nerve,the local anesthetic must traverse theperineurium. The multilayered perineuriumis formed by connective tissuecells linked by zonulae occludentes(p. 22) and therefore constitutes aclosed lipophilic barrier.Local anesthetics in clinical use areusually tertiary amines; at the pH ofinterstitial fluid, these exist partly as theneutral lipophilic base (symbolized byparticles marked with two red dots) andpartly as the protonated form, i.e., amphiphiliccation (symbolized by particlesmarked with one blue and one reddot). The uncharged form can penetratethe perineurium and enters the endoneuralspace, where a fraction of thedrug molecules regains a positivecharge in keeping with the local pH. Thesame process is repeated when the drugpenetrates the axonal membrane (axolemma)into the axoplasm, from whichit exerts its action on the sodium channel,and again when it diffuses out of theendoneural space through the unfenestratedendothelium of capillaries intothe blood.The concentration of local anestheticat the site of action is, therefore,determined by the speed of penetrationinto the endoneurium and the speed ofdiffusion into the capillary blood. In orderto ensure a sufficiently fast build-upof drug concentration at the site of action,there must be a correspondinglylarge concentration gradient betweendrug depot in the connective tissue andthe endoneural space. Injection of solutionsof low concentration will fail toproduce an effect; however, too highconcentrations must also be avoided becauseof the danger of intoxication resultingfrom too rapid systemic absorptioninto the blood.To ensure a reasonably long-lastinglocal effect with minimal systemic action,a vasoconstrictor (epinephrine,less frequently norepinephrine (p. 84)or a vasopressin derivative; p. 164) is oftenco-administered in an attempt toconfine the drug to its site of action. Asblood flow is diminished, diffusion fromthe endoneural space into the capillaryblood decreases because the criticalconcentration gradient between endoneuralspace and blood quickly becomessmall when inflow of drug-free blood isreduced. Addition of a vasoconstrictor,moreover, helps to create a relativeischemia in the surgical field. Potentialdisadvantages of catecholamine-typevasoconstrictors include reactive hyperemiafollowing washout of the constrictoragent (p. 90) and cardiostimulationwhen epinephrine enters the systemiccirculation. In lieu of epinephrine,the vasopressin analogue felypressin(p. 164, 165) can be used as an adjunctivevasoconstrictor (less pronouncedreactive hyperemia, no arrhythmogenicaction, but danger of coronary constriction).Vasoconstrictors must not be appliedin local anesthesia involving theappendages (e.g., fingers, toes).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Local Anesthetics 207Interstitium0.1 mmCross section through peripheralnerve (light microscope)AxonInterstitiumPerineuriumEndoneuralspaceCapillarywallAxolemmaAxoplasmVasoconstrictione.g., with epinephrineAxolemmalipophilic AxoplasmamphiphilicA. Disposition of local anesthetics in peripheral nerve tissueLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
208 Local AnestheticsCharacteristics of chemical structure.Local anesthetics possess a uniformstructure. Generally they are secondaryor tertiary amines. The nitrogenis linked through an intermediary chainto a lipophilic moiety—most often anaromatic ring system.The amine function means that localanesthetics exist either as the neutralamine or positively charged ammoniumcation, depending upon their dissociationconstant (pK a value) and theactual pH value. The pK a of typical localanesthetics lies between 7.5 and 9.0.The pk a indicates the pH value at which50% of molecules carry a proton. In itsprotonated form, the molecule possessesboth a polar hydrophilic moiety (protonatednitrogen) and an apolar lipophilicmoiety (ring system)—it is amphiphilic.Graphic images of the procainemolecule reveal that the positive chargedoes not have a punctate localization atthe N atom; rather it is distributed, asshown by the potential on the van derWaals’ surface. The non-protonatedform (right) possesses a negative partialcharge in the region of the ester bondand at the amino group at the aromaticring and is neutral to slightly positivelycharged (blue) elsewhere. In the protonatedform (left), the positive charge isprominent and concentrated at the aminogroup of the side chain (dark blue).Depending on the pK a, 50 to 5% ofthe drug may be present at physiologicalpH in the uncharged lipophilic form.This fraction is important because itrepresents the lipid membrane-permeableform of the local anesthetic (p. 26),which must take on its cationic amphiphilicform in order to exert its action(p. 204).Clinically used local anesthetics areeither esters or amides. This structuralelement is unimportant for efficacy;even drugs containing a methylenebridge, such as chlorpromazine (p. 236)or imipramine (p. 230), would exert alocal anesthetic effect with appropriateapplication. Ester-type local anestheticsare subject to inactivation by tissue esterases.This is advantageous because ofthe diminished danger of systemic intoxication.On the other hand, the highrate of bioinactivation and, therefore,shortened duration of action is a disadvantage.Procaine cannot be used as a surfaceanesthetic because it is inactivated fasterthan it can penetrate the dermis ormucosa.The amide type local anestheticlidocaine is broken down primarily inthe liver by oxidative N-dealkylation.This step can occur only to a restrictedextent in prilocaine and articaine becauseboth carry a substituent on the C-atom adjacent to the nitrogen group. Articainepossesses a carboxymethylgroup on its thiophen ring. At this position,ester cleavage can occur, resultingin the formation of a polar -COO – group,loss of the amphiphilic character, andconversion to an inactive metabolite.Benzocaine (ethoform) is a memberof the group of local anesthetics lackinga nitrogen that can be protonated atphysiological pH. It is used exclusivelyas a surface anesthetic.Other agents employed for surfaceanesthesia include the uncharged polidocanoland the catamphiphilic cocaine,tetracaine, and lidocaine.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Local Anesthetics 209Procaine Lidocaine PrilocaineArticaine Mepivacaine Benzocaine100[H + ] Proton concentration0802060404060208001006 7 8 9 10pH valueActive formcationicamphiphilicMembranepermeableformPoorAbility to penetratelipophilicbarriers andcell membranesGoodA. Local anesthetics and pH valueLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
210 OpioidsOpioid Analgesics—Morphine TypeSource of opioids. Morphine is an opiumalkaloid (p. 4). Besides morphine,opium contains alkaloids devoid of analgesicactivity, e.g., the spasmolytic papaverine,that are also classified as opiumalkaloids. All semisynthetic derivatives(hydromorphone) and fully syntheticderivatives (pentazocine, pethidine= meperidine, l-methadone, andfentanyl) are collectively referred to asopioids. The high analgesic effectivenessof xenobiotic opioids derives from theiraffinity for receptors normally actedupon by endogenous opioids (enkephalins,β-endorphin, dynorphins; A). Opioidreceptors occur in nerve cells. Theyare found in various brain regions andthe spinal medulla, as well as in intramuralnerve plexuses that regulate themotility of the alimentary and urogenitaltracts. There are several types of opioidreceptors, designated µ, δ, κ, thatmediate the various opioid effects; allbelong to the superfamily of G-proteincoupledreceptors (p. 66).Endogenous opioids are peptidesthat are cleaved from the precursorsproenkephalin, pro-opiomelanocortin,and prodynorphin. All contain the aminoacid sequence of the pentapeptides[Met]- or [Leu]-enkephalin (A). The effectsof the opioids can be abolished byantagonists (e.g., naloxone; A), with theexception of buprenorphine.Mode of action of opioids. Mostneurons react to opioids with hyperpolarization,reflecting an increase in K +conductance. Ca 2+ influx into nerve terminalsduring excitation is decreased,leading to a decreased release of excitatorytransmitters and decreased synapticactivity (A). Depending on the cellpopulation affected, this synaptic inhibitiontranslates into a depressant or excitanteffect (B).Effects of opioids (B). The analgesiceffect results from actions at the levelof the spinal cord (inhibition of nociceptiveimpulse transmission) and thebrain (attenuation of impulse spread,inhibition of pain perception). Attentionand ability to concentrate are impaired.There is a mood change, the directionof which depends on the initial condition.Aside from the relief associatedwith the abatement of strong pain,there is a feeling of detachment (floatingsensation) and sense of well-being(euphoria), particularly after intravenousinjection and, hence, rapid buildupof drug levels in the brain. The desireto re-experience this state by renewedadministration of drug may becomeoverpowering: development of psychologicaldependence. The atttempt to quitrepeated use of the drug results in withdrawalsigns of both a physical (cardiovasculardisturbances) and psychological(restlessness, anxiety, depression)nature. Opioids meet the criteria of “addictive”agents, namely, psychologicaland physiological dependence as well asa compulsion to increase the dose. Forthese reasons, prescription of opioids issubject to special rules (Controlled SubstancesAct, USA; Narcotic Control Act,Canada; etc). Regulations specify,among other things, maximum dosage(permissible single dose, daily maximaldose, maximal amount per single prescription).Prescriptions need to be issuedon special forms the completion ofwhich is rigorously monitored. Certainopioid analgesics, such as codeine andtramadol, may be prescribed in the usualmanner, because of their lesser potentialfor abuse and development ofdependence.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Opioids 211ProopiomelanocortinProenkephalinMorphineCH 3Nβ-LipotropinHOO6OHβ-EndorphinEnkephalinOpioid receptorsHOCH 2NCHCH 2K+-permeabilityExcitabilityCa2+-influxRelease oftransmittersHOOO NaloxoneA. Action of endogenous and exogenous opioids at opioid receptorsStimulant effectsVagal centers,Chemoreceptorsof area postremaOculomotorcenter(Edinger's nucleus)AntinociceptivesystemAnalgesicSmooth musculaturestomachbowelspasticconstipationAntidiarrhealUreterbladderbladder sphincterMediated byopioid receptorsDampening effectsPain sensationAnalgesicMoodalertnessRespiratory centerCough centerAntitussiveEmetic centerB. Effects of opioidsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
212 OpioidsDifferences between opioids regardingefficacy and potential for dependenceprobably reflect differing affinityand intrinsic activity profiles forthe individual receptor subtypes. A givensustance does not necessarily behaveas an agonist or antagonist at all receptorsubtypes, but may act as an agonistat one subtype and as a partial agonist/antagonistor as a pure antagonist(p. 214) at another. The abuse potentialis also determined by kinetic properties,because development of dependence isfavored by rapid build-up of brain concentrations.With any of the high-efficacyopioid analgesics, overdosage is likelyto result in respiratory paralysis (impairedsensitivity of medullary chemoreceptorsto CO 2). The maximally possibleextent of respiratory depression isthought to be less in partial agonist/antagonists at opioid receptors (pentazocine,nalbuphine).The cough-suppressant (antitussive)effect produced by inhibition of thecough reflex is independent of the effectson nociception or respiration(antitussives: codeine. noscapine).Stimulation of chemoreceptors inthe area postrema (p. 330) results invomiting, particularly after first-time administrationor in the ambulant patient.The emetic effect disappears with repeateduse because a direct inhibition ofthe emetic center then predominates,which overrides the stimulation of areapostrema chemoreceptors.Opioids elicit pupillary narrowing(miosis) by stimulating the parasympatheticportion (Edinger-Westphal nucleus)of the oculomotor nucleus.Peripheral effects concern the motilityand tonus of gastrointestinalsmooth muscle; segmentation is enhanced,but propulsive peristalsis is inhibited.The tonus of sphincter musclesis raised markedly. In this fashion, morphineelicits the picture of spastic constipation.The antidiarrheic effect isused therapeutically (loperamide, p.178). Gastric emptying is delayed (pyloricspasm) and drainage of bile andpancreatic juice is impeded, because thesphincter of Oddi contracts. Likewise,bladder function is affected; specificallybladder emptying is impaired due to increasedtone of the vesicular sphincter.Uses: The endogenous opioids(metenkephalin, leuenkephalin, β-endorphin)cannot be used therapeuticallybecause, due to their peptide nature,they are either rapidly degraded or excludedfrom passage through the bloodbrainbarrier, thus preventing access totheir sites of action even after parenteraladministration (A).Morphine can be given orally orparenterally, as well as epidurally orintrathecally in the spinal cord. The opioidsheroin and fentanyl are highly lipophilic,allowing rapid entry into theCNS. Because of its high potency, fentanylis suitable for transdermal delivery(A).In opiate abuse, “smack” (“junk,”“jazz,” “stuff,” “China white;” mostlyheroin) is self administered by injection(“mainlining”) so as to avoid first-passmetabolism and to achieve a faster risein brain concentration. Evidently, psychiceffects (“kick,” “buzz,” “rush”) areespecially intense with this route of administration.The user may also resort toother more unusual routes: opium canbe smoked, and heroin can be taken assnuff (B).Metabolism (C). Like other opioidsbearing a hydroxyl group, morphine isconjugated to glucuronic acid and eliminatedrenally. Glucuronidation of theOH-group at position 6, unlike that atposition 3, does not affect affinity. Theextent to which the 6-glucuronide contributesto the analgesic action remainsuncertain at present. At any rate, the activityof this polar metabolite needs tobe taken into account in renal insufficiency(lower dosage or longer dosinginterval).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Opioids 213Met-Enkephalin Morphine FentanylCH 3Tyr Gly Gly Phe Met NHOOOHNCONCH 2CH 2 CH 2CH 3CH 3NH 3 C C O O O C CH 3OOHeroinA. <strong>Bio</strong>availability of opioids with different routes of administrationNasalmucosa,e.g.,heroinsniffingOpioidOralapplicationMorphineIntravenousapplication"Mainlining"Morphine-6-glucuronideMorphine-3-glucuronideBronchialmucosae.g., opiumsmokingB. Application and rate of dispositionC. Metabolism of morphineLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
214 OpioidsTolerance. With repeated administrationof opioids, their CNS effects canlose intensity (increased tolerance). Inthe course of therapy, progressivelylarger doses are needed to achieve thesame degree of pain relief. Developmentof tolerance does not involve the peripheraleffects, so that persistent constipationduring prolonged use mayforce a discontinuation of analgesictherapy however urgently needed.Therefore, dietetic and pharmacologicalmeasures should be taken prophylacticallyto prevent constipation, wheneverprolonged administration of opioiddrugs is indicated.Morphine antagonists and partialagonists. The effects of opioids can beabolished by the antagonists naloxoneor naltrexone (A), irrespective of the receptortype involved. Given by itself,neither has any effect in normal subjects;however, in opioid-dependentsubjects, both precipitate acute withdrawalsigns. Because of its rapid presystemicelimination, naloxone is onlysuitable for parenteral use. Naltrexoneis metabolically more stable and is givenorally. Naloxone is effective as antidotein the treatment of opioid-inducedrespiratory paralysis. Since it is morerapidly eliminated than most opioids,repeated doses may be needed. Naltrexonemay be used as an adjunct in withdrawaltherapy.Buprenorphine behaves like a partialagonist/antagonist at µ-receptors.Pentazocine is an antagonist at µ-receptorsand an agonist at κ-receptors (A).Both are classified as “low-ceiling” opioids(B), because neither is capable ofeliciting the maximal analgesic effectobtained with morphine or meperidine.The antagonist action of partial agonistsmay result in an initial decrease in effectof a full agonist during changeover tothe latter. Intoxication with buprenorphinecannot be reversed with antagonists,because the drug dissociates onlyvery slowly from the opioid receptorsand competitive occupancy of the receptorscannot be achieved as fast as theclinical situation demands.Opioids in chronic pain: In themanagement of chronic pain, opioidplasma concentration must be kept continuouslyin the effective range, becausea fall below the critical level wouldcause the patient to experience pain.Fear of this situation would prompt intakeof higher doses than necessary.Strictly speaking, the aim is a prophylacticanalgesia.Like other opioids (hydromorphone,meperidine, pentazocine, codeine),morphine is rapidly eliminated,limiting its duration of action to approx.4 h. To maintain a steady analgesic effect,these drugs need to be given every4 h. Frequent dosing, including at nighttime,is a major inconvenience forchronic pain patients. Raising the individualdose would permit the dosinginterval to be lengthened; however, itwould also lead to transient peaksabove the therapeutically required plasmalevel with the attending risk of unwantedtoxic effects and tolerance development.Preferred alternatives includethe use of controlled-releasepreparations of morphine, a fentanyladhesive patch, or a longer-acting opioidsuch as l-methadone. The kineticproperties of the latter, however, necessitateadjustment of dosage in thecourse of treatment, because low dosageduring the first days of treatmentfails to provide pain relief, whereas highdosage of the drug, if continued, willlead to accumulation into a toxic concentrationrange (C).When the oral route is unavailableopioids may be administered by continuousinfusion (pump) and when appropriateunder control by the patient – advantage:constant therapeutic plasmalevel; disadvantage: indwelling catheter.When constipation becomes intolerablemorphin can be applied near thespinal cord permitting strong analgesiceffect at much lower total dosage.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Opioids 215HOHONCOONCH 2HOOCH 2CH 3NNCH 3OHCH 2CH 2OHµκMorphineµκMeperidineµκFentanylµκPentazocineµκNalbuphineµκNaloxoneHOHOH 3 CH 3 CCOCH 2 CHOOCH 3NCH 3CH 2OCHCH 2NCH 3CH 3CHCH 2NOA. Opioids: µ- and κ-receptor ligands B. Opioids: dose-response relationshipAnalgesic effectFentanyl0,1 1 10 100Dose (mg)BuprenorphineMorphineMeperidinePentazocineDrug concentration in plasmaIntoxicationAnalgesiaHigh doseMorphinet 1/2 = 2 hat low doseevery 4 hDisadvantage:frequent dosingfor sustainedanalgesiaMorphine in"high dose"every 12 hDisadvantages:transient hazardof intoxication,transient lossof analgesiaLow Dose1 2 3 41 2 3 4 DaysC. Morphine and methadone dosage regimensMethadonet 1/2 = 55 hDisadvantage:dose difficultto titrateLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
216 General Anesthetic DrugsGeneral Anesthesia and GeneralAnesthetic DrugsGeneral anesthesia is a state of drug-inducedreversible inhibition of centralnervous function, during which surgicalprocedures can be carried out in the absenceof consciousness, responsivenessto pain, defensive or involuntary movements,and significant autonomic reflexresponses (A).The required level of anesthesia dependson the intensity of the pain-producingstimuli, i.e., the degree of nociceptivestimulation. The skilful anesthetist,therefore, dynamically adapts theplane of anesthesia to the demands ofthe surgical situation. Originally, anesthetizationwas achieved with a singleanesthetic agent (e.g., diethylether—first successfully demonstrated in 1846by W. T. G. Morton, Boston). To suppressdefensive reflexes, such a “mono-anesthesia”necessitates a dosage in excessof that needed to cause unconsciousness,thereby increasing the risk of paralyzingvital functions, such as cardiovascularhomeostasis (B). Modern anesthesiaemploys a combination of differentdrugs to achieve the goals of surgicalanesthesia (balanced anesthesia). Thisapproach reduces the hazards of anesthesia.In C are listed examples of drugsthat are used concurrently or sequentiallyas anesthesia adjuncts. In the caseof the inhalational anesthetics, thechoice of adjuncts relates to the specificproperty to be exploited (see below).Muscle relaxants, opioid analgesics suchas fentanyl, and the parasympatholyticatropine are discussed elsewhere inmore detail.Neuroleptanalgesia can be considereda special form of combination anesthesia,in which the short-acting opioidanalgesics fentanyl, alfentanil, remifentanilis combined with the stronglysedating and affect-blunting neurolepticdroperidol. This procedure is used inhigh-risk patients (e.g., advanced age,liver damage).Neuroleptanesthesia refers to thecombined use of a short-acting analgesic,an injectable anesthetic, a short-actingmuscle relaxant, and a low dose of aneuroleptic.In regional anesthesia (spinal anesthesia)with a local anesthetic (p.204), nociception is eliminated, whileconsciousness is preserved. This procedure,therefore, does not fall under thedefinition of general anesthesia.According to their mode of application,general anesthetics in the restrictedsense are divided into inhalational(gaseous, volatile) and injectable agents.Inhalational anesthetics are administeredin and, for the most part, eliminatedvia respired air. They serve tomaintain anesthesia. Pertinent substancesare considered on p. 218.Injectable anesthetics (p. 220) arefrequently employed for induction.Intravenous injection and rapid onset ofaction are clearly more agreeable to thepatient than is breathing a stupefyinggas. The effect of most injectable anestheticsis limited to a few minutes. Thisallows brief procedures to be carried outor to prepare the patient for inhalationalanesthesia (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 madeof injectable, instead of inhalational, anestheticsduring prolonged combinedanesthesia (total intravenous anesthesia—TIVA).“TIVA” has become feasible thanksto the introduction of agents with a suitablyshort duration of action, includingthe injectable anesthetics propofol andetomidate, the analgesics alfentanil undremifentanil, and the muscle relaxantmivacurium. These drugs are eliminatedwithin minutes after being adminstered,irrespective of the duration ofanesthesia.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
General Anesthetic Drugs 217Muscle relaxation Loss of consciousness Autonomic stabilizationMotorreflexesPain andsufferingAutonomicreflexesNociceptionAnalgesiaA. Goals of surgical anesthesiaPain stimulusMono-anesthesiae.g., diethyletherReduced painsensitivityLoss of consciousnessMuscle relaxationParalysis ofvital centersFormusclerelaxatione.g., pancuroniumForunconsciousness:e.g., halothaneor propofolForanalgesiae.g., N 2 Oor fentanylForautonomicstabilizatione.g.,atropineB. Traditional monoanesthesia vs. modern balanced anesthesiaPremedicationInduction Maintenance RecoveryAtropineautonomic stabilizationMidazolam unconsciousnessmuscle relaxation; intubationNeostigmine reversal ofneuromuscular blockSuccinycholinePancuroniumN2OHalothanePentazocine analgesiaPentazocine analgesiaDiazepam anxiolysisMuscle relaxationAnalgesiaUnconsciousnessC. Regimen for balanced anesthesiaLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
218 General Anesthetic DrugsInhalational AnestheticsThe mechanism of action of inhalationalanesthetics is unknown. The diversityof chemical structures (inert gasxenon; hydrocarbons; halogenated hydrocarbons)possessing anesthetic activityappears to rule out involvement ofspecific receptors. According to one hypothesis,uptake into the hydrophobicinterior of the plasmalemma of neuronsresults in inhibition of electrical excitabilityand impulse propagation in thebrain. This concept would explain thecorrelation between anesthetic potencyand lipophilicity of anesthetic drugs (A).However, an interaction with lipophilicdomains of membrane proteins is alsoconceivable. Anesthetic potency can beexpressed in terms of the minimal alveolarconcentration (MAC) at which50% of patients remain immobile followinga defined painful stimulus (skinincision). Whereas the poorly lipophilicN 2O must be inhaled in high concentrations(>70% of inspired air has to be replaced),much smaller concentrations(
General Anesthetic Drugs 219Low potencyhigh partial pressure neededrelatively little binding to tissueAnesthetic potencyNitrous oxideN 2 OXenonHalothaneEnfluraneDiethyletherCyclopropaneChloroformLipophilicityN 2 OPartial pressure of anestheticTissue Blood Alveolar airBindingHalothanePartial pressure in tissueTermination of intakeHigh potencylow partial pressure sufficientrelatively high binding in tissueTimeA. Lipophilicity, potency and elimination of N 2 O and halothaneMetabolitesMetabolitesN 2 O Nitrous oxideH 5 C 2 OC 2 H 5 EtherHalothaneMethoxyfluraneB. Elimination routes of different volatile anestheticsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
220 General Anesthetic DrugsInjectable AnestheticsSubstances from different chemicalclasses suspend consciousness whengiven intravenously and can be used asinjectable anesthetics (B). Unlike inhalationalagents, most of these drugs affectconsciousness only and are devoidof analgesic activity (exception: ketamine).The effect cannot be ascribed tononselective binding to neuronal cellmembranes, although this may hold forpropofol.Most injectable anesthetics arecharacterized by a short duration of action.The rapid cessation of action islargely due to redistribution: afterintravenous injection, brain concentrationclimbs rapidly to anesthetic levelsbecause of the high cerebral blood flow;the drug then distributes evenly in thebody, i.e., concentration rises in 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 ofthe same dose, given immediately afterrecovery from the preceding dose, cantherefore produce a more intense andlonger effect. Usually, a single injectionis administered. However, etomidateand propofol may be given by infusionover a longer time period to maintainunconsciousness.Thiopental and methohexital belongto the barbiturates which, depending ondose, produce sedation, sleepiness, oranesthesia. Barbiturates lower the painthreshold and thereby facilitate defensivereflex movements; they also depressthe respiratory center. Barbituratesare frequently used for inductionof anesthesia.Ketamine has analgesic activity thatpersists beyond the period of unconsciousnessup to 1 h after injection. Onregaining consciousness, the patientmay experience a disconnectionbetween outside reality and inner mentalstate (dissociative anesthesia). Frequentlythere is memory loss for the durationof the recovery period; however,adults in particular complain about distressingdream-like experiences. Thesecan 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 theNMDA subtype, at which ketamine actsas a channel blocker. The non-naturalexcitatory amino acid N-methyl-Daspartateis a selective agonist at this receptor.Release of catecholamines witha resultant increase in heart rate andblood pressure is another unrelated actionof ketamine.Propofol has a remarkably simplestructure. Its effect has a rapid onset anddecays quickly, being experienced bythe patient as fairly pleasant. The intensityof the effect can be well controlledduring prolonged administration.Etomidate hardly affects the autonomicnervous system. Since it inhibitscortisol synthesis, it can be used in thetreatment of adrenocortical overactivity(Cushing’s disease).Midazolam is a rapidly metabolizedbenzodiazepine (p. 228) that is used forinduction of anesthesia. The longer-actinglorazepam is preferred as adjunctanesthetic in prolonged cardiac surgerywith cardiopulmonary bypass; its amnesiogeniceffect is pronounced.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
General Anesthetic Drugs 221CNS:relativelyhighblood flowHigh concentrationin tissueRelatively largeamount of drugi.v. injectionPeriphery:relativelylow bloodflowml bloodmin x g tissueRelatively smallamount of drugmg drugmin x g tissueInitial situationLow concentrationin tissuePreferential accumulationof drug in brainDecreasein tissueconcentrationFurtherincreasein tissueconcentrationRedistributionA. Termination of drug effect by redistributionSteady-state of distributionSodium thiopental Ketamine EtomidateB. Intravenous anestheticsSodiummethohexital Propofol MidazolamLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
222 HypnoticsSoporifics, HypnoticsDuring sleep, the brain generates a patternedrhythmic activity that can bemonitored by means of the electroencephalogram(EEG). Internal sleep cyclesrecur 4 to 5 times per night, eachcycle being interrupted by a Rapid EyeMovement (REM) sleep phase (A). TheREM stage is characterized by EEG activitysimilar to that seen in the wakingstate, rapid eye movements, vividdreams, and occasional twitches of individualmuscle groups against a backgroundof generalized atonia of skeletalmusculature. Normally, the REM stage isentered only after a preceding non-REMcycle. Frequent interruption of sleepwill, therefore, decrease the REM portion.Shortening of REM sleep (normallyapprox. 25% of total sleep duration) resultsin increased irritability and restlessnessduring the daytime. With undisturbednight rest, REM deficits arecompensated by increased REM sleepon subsequent nights (B).Hypnotics fall into different categories,including the benzodiazepines(e.g., triazolam, temazepam, clotiazepam,nitrazepam), barbiturates (e.g.,hexobarbital, pentobarbital), chloral hydrate,and H 1-antihistamines with sedativeactivity (p. 114). Benzodiazepinesact at specific receptors (p. 226). Thesite and mechanism of action of barbiturates,antihistamines, and chloral hydrateare incompletely understood.All hypnotics shorten the timespent in the REM stages (B). With repeatedingestion of a hypnotic on severalsuccessive days, the proportion oftime spent in REM vs. non-REM sleepreturns to normal despite continueddrug intake. Withdrawal of the hypnoticdrug results in REM rebound, which tapersoff only over many days (B). SinceREM stages are associated with vividdreaming, sleep with excessively longREM episodes is experienced as unrefreshing.Thus, the attempt to discontinueuse of hypnotics may result in theimpression that refreshing sleep callsfor a hypnotic, probably promotinghypnotic drug dependence.Depending on their blood levels,both benzodiazepines and barbituratesproduce calming and sedative effects,the former group also being anxiolytic.At higher dosage, both groups promotethe onset of sleep or induce it (C).Unlike barbiturates, benzodiazepinederivatives administered orallylack a general anesthetic action; cerebralactivity is not globally inhibited(respiratory paralysis is virtually impossible)and autonomic functions, such asblood pressure, heart rate, or body temperature,are unimpaired. Thus, benzodiazepinespossess a therapeutic marginconsiderably wider than that of barbiturates.Zolpidem (an imidazopyridine)and zopiclone (a cyclopyrrolone) arehypnotics that, despite their differentchemical structure, possess agonist activityat the benzodiazepine receptor (p.226).Due to their narrower margin ofsafety (risk of misuse for suicide) andtheir potential to produce physical dependence,barbiturates are no longer oronly rarely used as hypnotics. Dependenceon them has all the characteristicsof an addiction (p. 210).Because of rapidly developing tolerance,choral hydrate is suitable onlyfor short-term use.Antihistamines are popular asnonprescription (over-the-counter)sleep remedies (e.g., diphenhydramine,doxylamine, p. 114), in which case theirsedative side effect is used as the principaleffect.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Hypnotics 223WakingstateSleepstageISleepstageIISleepstageIIISleepstageIVREM-sleep= Rapid Eye Movement sleepREMNREM = No Rapid Eye Movement sleepA. Succession of different sleep phases during night restRatioREMNREMNightswithouthypnotic5 10 15 20 25 30Nights Nights afterwith withdrawalhypnotic of hypnoticB. Effect of hypnotics on proportion of REM/NREMBarbiturates:EffectParalyzingPentobarbitalBenzodiazepines:PentobarbitalAnesthetizingHypnogenicHypnagogicCalming, anxiolyticTriazolamTriazolamConcentration in bloodC. Concentration dependence of barbiturate and benzodiazepine effectsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
224 HypnoticsSleep–Wake Cycle and HypnoticsThe physiological mechanisms regulatingthe sleep-wake rhythm are not completelyknown. There is evidence thathistaminergic, cholinergic, glutamatergic,and adrenergic neurons are moreactive during waking than during theNREM sleep stage. Via their ascendingthalamopetal projections, these neuronsexcite thalamocortical pathwaysand inhibit GABA-ergic neurons. Duringsleep, input from the brain stem decreases,giving rise to diminished thalamocorticalactivity and disinhibitionof the GABA neurons (A). The shift inbalance between excitatory (red) andinhibitory (green) neuron groupsunderlies a circadian change in sleeppropensity, causing it to remain low inthe morning, to increase towards earlyafternoon (midday siesta), then to declineagain, and finally to reach its peakbefore midnight (B1).Treatment of sleep disturbances.Pharmacotherapeutic measures are indicatedonly when causal therapy hasfailed. Causes of insomnia include emotionalproblems (grief, anxiety, “stress”),physical complaints (cough, pain), orthe ingestion of stimulant substances(caffeine-containing beverages, sympathomimetics,theophylline, or certainantidepressants). As illustrated for emotionalstress (B2), these factors cause animbalance in favor of excitatory influences.As a result, the interval betweengoing to bed and falling asleep becomeslonger, total sleep duration decreases,and sleep may be interrupted by severalwaking periods.Depending on the type of insomnia,benzodiazepines (p. 226) with short orintermediate duration of action are indicated,e.g., triazolam and brotizolam(t 1/2 ~ 4–6 h); lormetazepam or temazepam(t 1/2 ~ 10–15 h). These drugs shortenthe latency of falling asleep, lengthentotal sleep duration, and reduce the frequencyof nocturnal awakenings. Theyact by augmenting inhibitory activity.Even with the longer-acting benzodiazepines,the patient awakes after about6–8 h of sleep, because in the morningexcitatory activity exceeds the sum ofphysiological and pharmacological inhibition(B3). The drug effect may, however,become unmasked at daytime whenother sedating substances (e.g., ethanol)are ingested and the patient shows anunusually pronounced response due toa synergistic interaction (impaired abilityto concentrate or react).As the margin between excitatoryand inhibitory activity decreases withage, there is an increasing tendency towardsshortened daytime sleep periodsand more frequent interruption of nocturnalsleep (C).Use of a hypnotic drug should notbe extended beyond 4 wk, because tolerancemay develop. The risk of a rebounddecrease in sleep propensity afterdrug withdrawal may be avoided bytapering off the dose over 2 to 3 wk.With any hypnotic, the risk of suicidaloverdosage cannot be ignored.Since benzodiazepine intoxication maybecome life-threatening only whenother central nervous depressants (ethanol)are taken simultaneously and can,moreover, be treated with specific benzodiazepineantagonists, the benzodiazepinesshould be given preferenceas sleep remedies over the all but obsoletebarbiturates.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Hypnotics 225Neurons withtransmitters:HistamineAcetylcholineGlutamateNorepinephrineGABAWaking stateNREM-sleepA. Transmitters: waking state and sleep1Emotional stress2Hypnotic3B. Wake-sleep pattern, stress, and hypnotic drug action1HypnoticC. Changes of the arousal reaction in the elderly2Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
226 PsychopharmacologicalsBenzodiazepinesBenzodiazepines modify affective responsesto sensory perceptions; specifically,they render a subject indifferenttowards anxiogenic stimuli, i.e., anxiolyticaction. Furthermore, benzodiazepinesexert sedating, anticonvulsant,and muscle-relaxant (myotonolytic, p.182) effects. All these actions resultfrom augmenting the activity of inhibitoryneurons and are mediated by specificbenzodiazepine receptors thatform an integral part of the GABA A receptor-chloridechannel complex. Theinhibitory transmitter GABA acts toopen the membrane chloride channels.Increased chloride conductance of theneuronal membrane effectively shortcircuitsresponses to depolarizing inputs.Benzodiazepine receptor agonistsincrease the affinity of GABA to its receptor.At a given concentration ofGABA, binding to the receptors will,therefore, be increased, resulting in anaugmented response. Excitability of theneurons is diminished.Therapeutic indications for benzodiazepinesinclude anxiety states associatedwith neurotic, phobic, and depressivedisorders, or myocardial infarction(decrease in cardiac stimulationdue to anxiety); insomnia; preanesthetic(preoperative) medication;epileptic seizures; and hypertonia ofskeletal musculature (spasticity, rigidity).Since GABA-ergic synapses are confinedto neural tissues, specific inhibitionof central nervous functions can beachieved; for instance, there is littlechange in blood pressure, heart rate,and body temperature. The therapeuticindex of benzodiazepines, calculatedwith reference to the toxic dose producingrespiratory depression, is greaterthan 100 and thus exceeds that of barbituratesand other sedative-hypnoticsby more than tenfold. Benzodiazepineintoxication can be treated with a specificantidote (see below).Since benzodiazepines depress responsivityto external stimuli, automotivedriving skills and other tasks requiringprecise sensorimotor coordinationwill be impaired.Triazolam (t 1/2 of elimination~1.5–5.5 h) is especially likely to impairmemory (anterograde amnesia) and tocause rebound anxiety or insomnia anddaytime confusion. The severity of theseand other adverse reactions (e.g., rage,violent hostility, hallucinations), andtheir increased frequency in the elderly,has led to curtailed or suspended use oftriazolam in some countries (UK).Although benzodiazepines are welltolerated, the possibility of personalitychanges (nonchalance, paradoxical excitement)and the risk of physical dependencewith chronic use must not beoverlooked. Conceivably, benzodiazepinedependence results from a kind ofhabituation, the functional counterpartsof which become manifest during abstinenceas restlessness and anxiety; evenseizures may occur. These symptomsre<strong>info</strong>rce chronic ingestion of benzodiazepines.Benzodiazepine antagonists, suchas flumazenil, possess affinity for benzodiazepinereceptors, but they lack intrinsicactivity. Flumazenil is an effectiveantidote in the treatment of benzodiazepineoverdosage or can be usedpostoperatively to arouse patients sedatedwith a benzodiazepine.Whereas benzodiazepines possessingagonist activity indirectly augmentchloride permeability, inverse agonistsexert an opposite action. These substancesgive rise to pronounced restlessness,excitement, anxiety, and convulsiveseizures. There is, as yet, notherapeutic indication for their use.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Psychopharmacologicals 227R 2NR 1 epineNBenzo R 3R 1 = Cl R 4R 2 = CH 3R 3 = R 4 = HDiazepamdiazOAnxiolysisInhibition ofexcitationHyper-Benzodiazepinepolari-zationreceptorGABA=γ-aminobutrycacidCl -ChlorideionophoreGABAplus anticonvulsant effect,sedation, muscle relaxationGABA-gated Cl - -channelGABA-receptorBenzodiazepinesGABA-ergic neuronUnopposed excitationA. Action of benzodiazepinesNormalGABA-ergic inhibitionEnhancedGABA-ergic inhibitionLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
228 PsychopharmacologicalsPharmacokinetics of BenzodiazepinesAll benzodiazepines exert their actionsat specific receptors (p. 226). The choicebetween different agents is dictated bytheir speed, intensity, and duration ofaction. These, in turn, reflect physicochemicaland pharmacokinetic properties.Individual benzodiazepines remainin the body for very different lengths oftime and are chiefly eliminated throughbiotransformation. Inactivation may entaila single chemical reaction or severalsteps (e.g., diazepam) before an inactivemetabolite suitable for renal eliminationis formed. Since the intermediaryproducts may, in part, be pharmacologicallyactive and, in part, be excretedmore slowly than the parent substance,metabolites will accumulate with continuedregular dosing and contributesignificantly to the final effect.<strong>Bio</strong>transformation begins either atsubstituents on the diazepine ring (diazepam:N-dealkylation at position 1;midazolam: hydroxylation of the methylgroup on the imidazole ring) or at thediazepine ring itself. Hydroxylated midazolamis quickly eliminated followingglucuronidation (t 1/2 ~ 2 h). N-demethyldiazepam(nordazepam) is biologicallyactive and undergoes hydroxylationat position 3 on the diazepinering. The hydroxylated product (oxazepam)again is pharmacologically active.By virtue of their long half-lives, diazepam(t 1/2 ~ 32 h) and, still more so, itsmetabolite, nordazepam (t 1/2 50–90 h),are eliminated slowly and accumulateduring repeated intake. Oxazepamundergoes conjugation to glucuronic acidvia its hydroxyl group (t 1/2 = 8 h) andrenal excretion (A).The range of elimination half-livesfor different benzodiazepines or theiractive metabolites is represented by theshaded areas (B). Substances with ashort half-life that are not converted toactive metabolites can be used for inductionor maintenance of sleep (lightblue area in B). Substances with a longhalf-life are preferable for long-termanxiolytic treatment (light green area)because they permit maintenance ofsteady plasma levels with single dailydosing. Midazolam enjoys use by the i.v.route in preanesthetic medication andanesthetic combination regimens.Benzodiazepine DependenceProlonged regular use of benzodiazepinescan lead to physical dependence.With the long-acting substances marketedinitially, this problem was less obviousin comparison with other dependence-producingdrugs because of thedelayed appearance of withdrawalsymptoms. The severity of the abstinencesyndrome is inversely related tothe elimination t 1/2, ranging from mildto moderate (restlessness, irritability,sensitivity to sound and light, insomnia,and tremulousness) to dramatic (depression,panic, delirium, grand mal seizures).Some of these symptoms posediagnostic difficulties, being indistinguishablefrom the ones originally treated.Administration of a benzodiazepineantagonist would abruptly provoke abstinencesigns. There are indicationsthat substances with intermediate eliminationhalf-lives are most frequentlyabused (violet area in B).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Psychopharmacologicals 229MidazolamDiazepamas glucuronideInactiveNordazepamOxazepamActive metabolitesA. <strong>Bio</strong>transformation of benzodiazepinesHypnagogiceffectAbuseliabilityTriazolamBrotizolamOxazepamLormetazepamBromazepamFlunitrazepamLorazepamCamazepamNitrazepamClonazepamDiazepamTemazepamAnxiolytic effectPrazepam0 10 20 30 40 50 60 >60 hPlasma elimination half-lifeApplied drugActive metaboliteB. Rate of elimination of benzodiazepinesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
230 PsychopharmacologicalsTherapy of Manic-Depressive IllnessManic-depressive illness connotes apsychotic disorder of affect that occursepisodically without external cause. Inendogenous depression (melancholia),mood is persistently low. Mania refersto the opposite condition (p. 234). Patientsmay oscillate between these twoextremes with interludes of normalmood. Depending on the type of disorder,mood swings may alternatebetween the two directions (bipolar depression,cyclothymia) or occur in onlyone direction (unipolar depression).I. Endogenous DepressionIn this condition, the patient experiencesprofound misery (beyond theobserver’s empathy) and feelings of severeguilt because of imaginary misconduct.The drive to act or move is inhibited.In addition, there are disturbancesmostly of a somatic nature (insomnia,loss of appetite, constipation, palpitations,loss of libido, impotence, etc.). Althoughthe patient may have suicidalthoughts, psychomotor retardation preventssuicidal impulses from being carriedout. In A, endogenous depression isillustrated by the layers of somber colors;psychomotor drive, symbolized bya sine oscillation, is strongly reduced.Therapeutic agents fall into twogroups: Thymoleptics, possessing a pronouncedability to re-elevate depressedmood e.g., the tricyclic antidepressants; Thymeretics, having a predominantactivating effect on psychomotordrive, e g., monoamine oxidase inhibitors.It would be wrong to administerdrive-enhancing drugs, such as amphetamines,to a patient with endogenousdepression. Because this therapy fails toelevate mood but removes psychomotorinhibition (A), the danger of suicideincreases.Tricyclic antidepressants (TCA;prototype: imipramine) have had thelongest and most extensive therapeuticuse; however, in the past decade, theyhave been increasingly superseded bythe serotonin-selective reuptake inhibitors(SSRI; prototype: fluoxetine).The central seven-membered ringof the TCAs imposes a 120° anglebetween the two flanking aromaticrings, in contradistinction to the flatring system present in phenothiazinetype neuroleptics (p. 237). The sidechain nitrogen is predominantly protonatedat physiological pH.The TCAs have affinity for both receptorsand transporters of monoaminetransmitters and behave as antagonistsin both respects. Thus, the neuronal reuptakeof norepinephrine (p. 82) and serotonin(p. 116) is inhibited, with a resultantincrease in activity. Muscarinicacetylcholine receptors, α-adrenoceptors,and certain 5-HT and histamine(H1) receptors are blocked. Interferencewith the dopamine system isrelatively minor.How interference with these transmitter/modulatorsubstances translatesinto an antidepressant effect is still hypothetical.The clinical effect emergesonly after prolonged intake, i.e., 2–3 wk,as evidenced by an elevation of moodand drive. However, the alteration inmonoamine metabolism occurs as soonas therapy is started. Conceivably, adaptiveprocesses (such as downregulationof cortical serotonin and β-adrenoceptors)are ultimately responsible. Inhealthy subjects, the TCAs do not improvemood (no euphoria).Apart from the antidepressant effect,acute effects occur that are evidentalso in healthy individuals. These varyin degree among individual substancesand thus provide a rationale for differentiatedclinical use (p. 233), basedupon the divergent patterns of interferencewith amine transmitters/modulators.Amitriptyline exerts anxiolytic,sedative and psychomotor dampeningeffects. These are useful in depressivepatients who are anxious and agitated.In contrast, desipramine producespsychomotor activation. ImipramineLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Psychopharmacologicals 231EndogenousdepressionDeficient driveWeek 9 Week 7 Week 5 Week 35HT orNAInhibition ofre-uptakeImipramineAchNAM, H 1 , α 1Blockade ofreceptorsEffects on synaptic transmissionby inhibition of amine re-uptakeand by receptor antagonismAmphetamineImmediateNormalmoodNormal driveA. Effect of antidepressantsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
232 Psychopharmacologicalsoccupies an intermediate position. Itshould be noted that, in the organism,biotransformation of imipramine leadsto desipramine (N-desmethylimipramine).Likewise, the desmethyl derivativeof amitriptyline (nortriptyline) isless dampening.In nondepressive patients whosecomplaints are of predominantly psychogenicorigin, the anxiolytic-sedativeeffect may be useful in efforts to bringabout a temporary “psychosomatic uncoupling.”In this connection, clinicaluse as “co-analgesics” (p. 194) may benoted.The side effects of tricyclic antidepressantsare largely attributable to theability of these compounds to bind toand block receptors for endogenoustransmitter substances. These effectsdevelop acutely. Antagonism at muscariniccholinoceptors leads to atropinelikeeffects such as tachycardia, inhibitionof exocrine glands, constipation,impaired micturition, and blurred vision.Changes in adrenergic function arecomplex. Inhibition of neuronal catecholaminereuptake gives rise to superimposedindirect sympathomimeticstimulation. Patients are supersensitiveto catecholamines (e.g., epinephrine inlocal anesthetic injections must beavoided). On the other hand, blockadeof α 1-receptors may lead to orthostatichypotension.Due to their cationic amphiphilicnature, the TCA exert membrane-stabilizingeffects that can lead to disturbancesof cardiac impulse conductionwith arrhythmias as well as decreases inmyocardial contractility. All TCA lowerthe seizure threshold. Weight gain mayresult from a stimulant effect on appetite.Maprotiline, a tetracyclic compound,largely resembles tricyclicagents in terms of its pharmacologicaland clinical actions. Mianserine alsopossesses a tetracyclic structure, butdiffers insofar as it increases intrasynapticconcentrations of norepinephrineby blocking presynaptic α 2-receptors,rather than reuptake. Moreover, it hasless pronounced atropine-like activity.Fluoxetine, along with sertraline,fluvoxamine, and paroxetine, belongs tothe more recently developed group ofSSRI. The clinical efficacy of SSRI is consideredcomparable to that of establishedantidepressants. Added advantagesinclude: absence of cardiotoxicity,fewer autonomic nervous side effects,and relative safety with overdosage.Fluoxetine causes loss of appetite andweight reduction. Its main adverse effectsinclude: overarousal, insomnia,tremor, akathisia, anxiety, and disturbancesof sexual function.Moclobemide is a new representativeof the group of MAO inhibitors. Inhibitionof intraneuronal degradation ofserotonin and norepinephrine causes anincrease in extracellular amine levels. Apsychomotor stimulant thymeretic actionis the predominant feature of MAOinhibitors. An older member of thisgroup, tranylcypromine, causes irreversibleinhibition of the two isozymesMAO A and MAO B. Therefore, presystemicelimination in the liver of biogenicamines, such as tyramine, which are ingestedin food (e.g., aged cheese andChianti), will be impaired. To avoid thedanger of a hypertensive crisis, therapywith tranylcypromine or other nonselectiveMAO inhibitors calls for stringentdietary rules. With moclobemide,this hazard is much reduced because itinactivates only MAO A and does so in areversible manner.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Psychopharmacologicals 233Serotonin5-HT-ReceptorDopamine D-Receptorα-AdrenoceptorNorepinephrineAcetylcholineM-CholinoceptorAnxiolysisDrive, energyα 1 -BlockadeParasympatholyticactivityIndicationAmitriptylinePatient:50-150 mg/dt 1/2 = 30-40hDepressive,anxious,agitatedImipraminePatient:50-200 mg/dt 1/2 = 9-20hDepressive,normaldriveDesipraminePatient:75-200 mg/dt 1/2 = 15-60hDepressive,lack ofdriveandenergyFluoxetinePatient:20-40 mg/dt 1/2 = 48-96hDepressive,lack ofdriveandenergyMoclobemidePatient:300 mg/dt 1/2 = 1-2hDepressive,lack ofdriveandenergyA. Antidepressants: activity profilesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
234 PsychopharmacologicalsII. ManiaThe manic phase is characterized by exaggeratedelation, flight of ideas, and apathologically increased psychomotordrive. This is symbolically illustrated inA by a disjointed structure and aggressivecolor tones. The patients are overconfident,continuously active, showprogressive incoherence of thought andloosening of associations, and act irresponsibly(financially, sexually etc.).Lithium ions. Lithium salts (e.g.,acetate, carbonate) are effective in controllingthe manic phase. The effect becomesevident approx. 10 d after thestart of therapy. The small therapeuticindex necessitates frequent monitoringof Li + serum levels. Therapeutic levelsshould be kept between 0.8–1.0 mM infasting morning blood samples. At highervalues there is a risk of adverse effects.CNS symptoms include fine tremor,ataxia or seizures. Inhibition of the renalactions of vasopressin (p. 164) leads topolyuria and thirst. Thyroid function isimpaired (p. 244), with compensatorydevelopment of (euthyroid) goiter.The mechanism of action of Li ionsremains to be fully elucidated. Chemically,lithium is the lightest of the alkalimetals, which include such biologicallyimportant elements as sodium and potassium.Apart from interference withtransmembrane cation fluxes (via ionchannels and pumps), a lithium effect ofmajor significance appears to be membranedepletion of phosphatidylinositolbisphosphates, the principal lipid substrateused by various receptors intransmembrane signalling (p. 66).Blockade of this important signal transductionpathway leads to impaired abilityof neurons to respond to activationof membrane receptors for transmittersor other chemical signals. Another siteof action of lithium may be GTP-bindingproteins responsible for signal transductioninitiated by formation of the agonist-receptorcomplex.Rapid control of an acute attack ofmania may require the use of a neuroleptic(see below).Alternate treatments. Mood-stabilizationand control of manic or hypomanicepisodes in some subtypes ofbipolar illness may also be achievedwith the anticonvulsants valproate andcarbamazepine, as well as with calciumchannel blockers (e.g., verapamil, nifedipine,nimodipine). Effects are delayedand apparently unrelated to the mechanismsresponsible for anticonvulsantand cardiovascular actions, respectively.III. ProphylaxisWith continued treatment for 6 to 12months, lithium salts prevent the recurrenceof either manic or depressivestates, effectively stabilizing mood at anormal level.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Psychopharmacologicals 235ManiaHDay 8 Day 6 Day 4 Day 2Li+LithiumNaKRbCsDepression ManiaBeMgCaSrBaNormalstateDay 10Normal stateA. Effect of lithium salts in maniaLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
236 PsychopharmacologicalsTherapy of SchizophreniaSchizophrenia is an endogenous psychosisof episodic character. Its chiefsymptoms reflect a thought disorder(i.e., distracted, incoherent, illogicalthinking; impoverished intellectualcontent; blockage of ideation; abruptbreaking of a train of thought: claims ofbeing subject to outside agencies thatcontrol the patient’s thoughts), and adisturbance of affect (mood inappropriateto the situation) and of psychomotordrive. In addition, patients exhibit delusionalparanoia (persecution mania) orhallucinations (fearfulness hearing ofvoices). Contrasting these “positive”symptoms, the so-called “negative”symptoms, viz., poverty of thought, socialwithdrawal, and anhedonia, assumeadded importance in determining theseverity of the disease. The disruptionand incoherence of ideation is symbolicallyrepresented at the top left (A) andthe normal psychic state is illustrated ason p. 237 (bottom left).NeurolepticsAfter administration of a neuroleptic,there is at first only psychomotor dampening.Tormenting paranoid ideas andhallucinations lose their subjective importance(A, dimming of flashy colors);however, the psychotic processes stillpersist. In the course of weeks, psychicprocesses gradually normalize (A); thepsychotic episode wanes, althoughcomplete normalization often cannot beachieved because of the persistence ofnegative symptoms. Nonetheless, thesechanges are significant because the patientexperiences relief from the tormentof psychotic personality changes;care of the patient is made easier andreturn to a familiar community environmentis accelerated.The conventional (or classical) neurolepticscomprise two classes of compoundswith distinctive chemical structures:1. the phenothiazines derivedfrom the antihistamine promethazine(prototype: chlorpromazine), includingtheir analogues (e.g., thioxanthenes);and 2. the butyrophenones (prototype:haloperidol). According to the chemicalstructure of the side chain, phenothiazinesand thioxanthenes can be subdividedinto aliphatic (chlorpromazine,triflupromazine, p. 239 and piperazinecongeners (trifluperazine, fluphenazine,flupentixol, p. 239).The antipsychotic effect is probablydue to an antagonistic action at dopaminereceptors. Aside from their mainantipsychotic action, neuroleptics displayadditional actions owing to theirantagonism at– muscarinic acetylcholine receptors atropine-like effects;– α-adrenoceptors for norepinephrine disturbances of blood pressureregulation;– dopamine receptors in the nigrostriatalsystem extrapyramidal motordisturbances; in the area postrema antiemetic action (p. 330), and in thepituitary gland increased secretionof prolactin (p. 242);– histamine receptors in the cerebralcortex possible cause of sedation.These ancillary effects are also elicitedin healthy subjects and vary in intensityamong individual substances.Other indications. Acutely, there issedation with anxiolysis after neuroleptizationhas been started. This effect canbe utilized for: “psychosomatic uncoupling”in disorders with a prominentpsychogenic component; neuroleptanalgesia(p. 216) by means of the butyrophenonedroperidol in combinationwith an opioid; tranquilization of overexcited,agitated patients; treatment ofdelirium tremens with haloperidol; aswell as the control of mania (see p. 234).It should be pointed out that neurolepticsdo not exert an anticonvulsantaction, on the contrary, they may lowerseizure thershold.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Psychopharmacologicals 237NeurolepticsWeek 3after start of therapyPhenothiazine type:ChlorpromazineButyrophenone type:HaloperidolWeek 9 Week 7 Week 5SedationAutonomic disturbancedue to atropine-likeactionMovement disordersdue to dopamineantagonismAntiemetic effectA. Effects of neuroleptics in schizophreniaLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
238 PsychopharmacologicalsBecause they inhibit the thermoregulatorycenter, neuroleptics can be employedfor controlled hypothermia(p. 202).Adverse Effects. Clinically mostimportant and therapy-limiting are extrapyramidaldisturbances; these resultfrom dopamine receptor blockade.Acute dystonias occur immediately afterneuroleptization and are manifestedby motor impairments, particularly inthe head, neck, and shoulder region. Afterseveral days to months, a parkinsoniansyndrome (pseudoparkinsonism)or akathisia (motor restlessness) maydevelop. All these disturbances can betreated by administration of antiparkinsondrugs of the anticholinergic type,such as biperiden (i.e., in acute dystonia).As a rule, these disturbances disappearafter withdrawal of neurolepticmedication. Tardive dyskinesia may becomeevident after chronic neuroleptizationfor several years, particularlywhen the drug is discontinued. It is dueto hypersensitivity of the dopamine receptorsystem and can be exacerbatedby administration of anticholinergics.Chronic use of neuroleptics can, onoccasion, give rise to hepatic damage associatedwith cholestasis. A very rare,but dramatic, adverse effect is the malignantneuroleptic syndrome (skeletalmuscle rigidity, hyperthermia, stupor)that can end fatally in the absence of intensivecountermeasures (includingtreatment with dantrolene, p. 182).Neuroleptic activity profiles. Themarked differences in action spectra ofthe phenothiazines, their derivativesand analogues, which may partially resemblethose of butyrophenones, areimportant in determining therapeuticuses of neuroleptics. Relevant parametersinclude: antipsychotic efficacy(symbolized by the arrow); the extentof sedation; and the ability to induce extrapyramidaladverse effects. The latterdepends on relative differences in antagonismtowards dopamine and acetylcholine,respectively (p. 188). Thus,the butyrophenones carry an increasedrisk of adverse motor reactions becausethey lack anticholinergic activity and,hence, are prone to upset the balancebetween striatal cholinergic and dopaminergicactivity.Derivatives bearing a piperazinemoiety (e.g., trifluperazine, fluphenazine)have greater antipsychotic potencythan do drugs containing an aliphaticside chain (e.g., chlorpromazine, triflupromazine).However, their antipsychoticeffects are qualitatively indistinguishable.As structural analogues of thephenothiazines, thioxanthenes (e.g.,chlorprothixene, flupentixol) possess acentral nucleus in which the N atom isreplaced by a carbon linked via a doublebond to the side chain. Unlike the phenothiazines,they display an added thymolepticactivity.Clozapine is the prototype of theso-called atypical neuroleptics, a groupthat combines a relative lack of extrapyramidaladverse effects with superiorefficacy in alleviating negative symptoms.Newer members of this class includerisperidone, olanzapine, and sertindole.Two distinguishing features ofthese atypical agents are a higher affinityfor 5-HT 2 (or 5-HT 6) receptors thanfor dopamine D 2 receptors and relativeselectivity for mesolimbic, as opposedto nigrostriatal, dopamine neurons.Clozapine also exhibits high affinity fordopamine receptors of the D 4 subtype,in addition to H 1 histamine and muscarinicacetylcholine receptors. Clozapinemay cause dose–dependent seizuresand agranulocytosis, necessitating closehematological monitoring. It is stronglysedating.When esterified with a fatty acid,both fluphenazine and haloperidol canbe applied intramuscularly as depotpreparations.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Psychopharmacologicals 2391Triflupromazine30 – 150 mg/dClozapine25 – 200 mg/d10Trifluoperazine15 – 20 mg/dFlupentixol2 – 10 mg/d5040%40%R20%Relative potencyRR=H Fluphenazine2.5 – 10 mg/dR=H Haloperidol2 – 6 mg/dLong-actingor“depot”R =OC C 9 H 19-decanoateR =OC C 9 H 19-decanoateneuroleptics i.m. 50–150 mg every 2 weeks i.m. 50–150 mg every 4 weekslessDopamine- ≈ ACh effectsedatingstronglyDopamineAChDopamine- < ACh effectextrapyramidal disturbancesA. Neuroleptics: Antipsychotic potency, sedative, and extrapyramidal motor effectsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
240 PsychopharmacologicalsPsychotomimetics(Psychedelics, Hallucinogens)Psychotomimetics are able to elicit psychicchanges like those manifested inthe course of a psychosis, such as illusionarydistortion of perception andhallucinations. This experience may beof dreamlike character; its emotional orintellectual transposition appears inadequateto the outsider.A psychotomimetic effect is pictoriallyrecorded in the series of portraitsdrawn by an artist under the influenceof lysergic acid diethylamide (LSD). Asthe intoxicated state waxes and waneslike waves, he reports seeing the face ofthe portrayed subject turn into a grimace,phosphoresce bluish-purple, andfluctuate in size as if viewed through amoving zoom lens, creating the illusionof abstruse changes in proportion andgrotesque motion sequences. The diaboliccaricature is perceived as threatening.Illusions also affect the senses ofhearing and smell; sounds (tones) are“experienced” as floating beams andvisual impressions as odors (“synesthesia”).Intoxicated individuals see themselvestemporarily from the outside andpass judgement on themselves andtheir condition. The boundary betweenself and the environment becomesblurred. An elating sense of being onewith the other and the cosmos sets in.The sense of time is suspended; there isneither present nor past. Objects areseen that do not exist, and experiencesfelt that transcend explanation, hencethe term “psychedelic” (Greek delosis =revelation) implying expansion of consciousness.The contents of such illusions andhallucinations can occasionally becomeextremely threatening (“bad” or “bumtrip”); the individual may feel provokedto turn violent or to commit suicide. Intoxicationis followed by a phase of intensefatigue, feelings of shame, and humiliatingemptiness.The mechanism of the psychotogeniceffect remains unclear. Some hallucinogenssuch as LSD, psilocin, psilocybin(from fungi), bufotenin (the cutaneousgland secretion of a toad), mescaline(from the Mexican cactuses Lophophorawilliamsii and L. diffusa; peyote) bear astructural resemblance to 5-HT (p. 116),and chemically synthesized amphetamine-derivedhallucinogens (4-methyl-2,5-dimethoxyamphetamine; 3,4-dimethoxyamphetamine;2,5-dimethoxy-4-ethyl amphetamine) are thought tointeract with the agonist recognitionsite of the 5-HT 2A receptor. Conversely,most of the psychotomimetic effects areannulled by neuroleptics having 5-HT 2Aantagonist activity (e.g. clozapine, risperidone).The structures of otheragents such as tetrahydrocannabinol(from the hemp plant, Cannabis sativa—hashish, marihuana), muscimol (fromthe fly agaric, Amanita muscaria), orphencyclidine (formerly used as an injectablegeneral anesthetic) do not reveala similar connection. Hallucinationsmay also occur as adverse effectsafter intake of other substances, e.g.,scopolamine and other centrally activeparasympatholytics.The popular psychostimulant, methylenedioxy-methamphetamine(MD-MA, “ecstasy”) acutely increases neuronaldopamine and norepinephrine releaseand causes a delayed and selectivedegeneration of forebrain 5-HT nerveterminals.Although development of psychologicaldependence and permanent psychicdamage cannot be considered establishedsequelae of chronic use of psychotomimetics,the manufacture andcommercial distribution of these drugsare prohibited (Schedule I, ControlledDrugs).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Psychopharmacologicals 241OCC 2 H 5NC 2 H 5NCH3Lysergic aciddiethylamide0.0001 g/70 kgHNA. Psychotomimetic effect of LSD in a portrait artistLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
242 HormonesHypothalamic and HypophysealHormonesThe endocrine system is controlled bythe brain. Nerve cells of the hypothalamussynthesize and release messengersubstances that regulate adenohypophyseal(AH) hormone release or arethemselves secreted into the body ashormones. The latter comprise the socalledneurohypophyseal (NH) hormones.The axonal processes of hypothalamicneurons project to the neurohypophysis,where they store the nonapeptidesvasopressin (= antidiuretic hormone,ADH) and oxytocin and releasethem on demand into the blood. Therapeutically(ADH, p. 64, oxytocin, p. 126),these peptide hormones are given parenterallyor via the nasal mucosa.The hypothalamic releasing hormonesare peptides. They reach theirtarget cells in the AH lobe by way of aportal vascular route consisting of twoserially connected capillary beds. Thefirst of these lies in the hypophysealstalk, the second corresponds to thecapillary bed of the AH lobe. Here, thehypothalamic hormones diffuse fromthe blood to their target cells, whose activitythey control. Hormones releasedfrom the AH cells enter the blood, inwhich they are distributed to peripheralorgans (1).Nomenclature of releasing hormones:RH–releasing hormone; RIH—releaseinhibiting hormone.GnRH: gonadotropin-RH = gonadorelinstimulates the release of FSH(follicle-stimulating hormone) and LH(luteinizing hormone).TRH: thyrotropin-RH (protirelin)stimulates the release of TSH (thyroidstimulating hormone = thyrotropin).CRH: corticotropin-RH stimulatesthe release of ACTH (adrenocorticotropichormone = corticotropin).GRH: growth hormone-RH (somatocrinin)stimulates the release of GH(growth hormone = STH, somatotropichormone). GRIH somatostatin inhibitsrelease of STH (and also other peptidehormones including insulin, glucagon,and gastrin).PRH: prolactin-RH remains to becharacterized or established. Both TRHand vasoactive intestinal peptide (VIP)are implicated.PRIH inhibits the release of prolactinand could be identical with dopamine.Hypothalamic releasing hormonesare mostly administered (parenterally)for diagnostic reasons to test AH function.Therapeutic control of AH cells.GnRH is used in hypothalamic infertilityin women to stimulate FSH and LH secretionand to induce ovulation. For thispurpose, it is necessary to mimic thephysiologic intermittent “pulsatile” release(approx. every 90 min) by meansof a programmed infusion pump.Gonadorelin superagonists areGnRH analogues that bind with veryhigh avidity to GnRH receptors of AHcells. As a result of the nonphysiologicuninterrupted receptor stimulation, initialaugmentation of FSH and LH outputis followed by a prolonged decrease. Buserelin,leuprorelin, goserelin, and triptorelinare used in patients with prostaticcarcinoma to reduce production oftestosterone, which promotes tumorgrowth. Testosterone levels fall as muchas after extirpation of the testes (2).The dopamine D 2 agonists bromocriptineand cabergoline (pp. 114, 188)inhibit prolactin-releasing AH cells (indications:suppression of lactation, prolactin-producingtumors). Excessive,but not normal, growth hormone releasecan also be inhibited (indication:acromegaly) (3).Octreotide is a somatostatin analogue;it is used in the treatment ofsomatostatin-secreting pituitary tumors.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Hormones 243Hypothalamicreleasing hormonesSynthesisRelease intobloodHypothalamusADHOxytocinSynthesisRelease intobloodGnRHSynthesis andTRH CRH GRHGRIHrelease ofAH hormonesPRHPRIHApplicationparenteralNeurohypophysisAdenohypophysis (AH)AH-cellsnasalFSH, LHTSHACTHSTH(GH)ProlactinADHOxytocinOvum maturation;Estradiol,ProgesteroneSomatomedinsH 2 O1Spermatogenesis;TestosteroneThyroxineCortisolGrowthLactationLaborMilk ejectionGnRHBuserelinReleased amount90 minPulsatile releaseLeuprorelinDopamine agonistBromocriptineRhythmic stimulationAHcellPersistent stimulationCessation of hormone secretion, Inhibition ofFSH LH"chemical castration"prolactin2 3.A. Hypothalamic and hypophyseal hormonesD 2 -Receptorssecretion ofSTHLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
244 HormonesThyroid Hormone TherapyThyroid hormones accelerate metabolism.Their release (A) is regulated bythe hypophyseal glycoprotein TSH,whose release, in turn, is controlled bythe hypothalamic tripeptide TRH. Secretionof TSH declines as the blood level ofthyroid hormones rises; by means ofthis negative feedback mechanism, hormoneproduction is “automatically” adjustedto demand.The thyroid releases predominantlythyroxine (T 4). However, the active formappears to be triiodothyronine (T 3); T 4 isconverted in part to T 3, receptor affinityin target organs being 10-fold higher forT 3. The effect of T 3 develops more rapidlyand has a shorter duration than doesthat of T 4. Plasma elimination t 1/2 for T 4is about 7 d; that for T 3, however, is only1.5 d. Conversion of T 4 to T 3 releases iodide;150 µg T 4 contains 100 µg of iodine.For therapeutic purposes, T 4 is chosen,although T 3 is the active form andbetter absorbed from the gut. However,with T 4 administration, more constantblood levels can be achieved becausedegradation of T 4 is so slow. Since absorptionof T 4 is maximal from an emptystomach, T 4 is taken about 1 / 2 h beforebreakfast.Replacement therapy of hypothyroidism.Whether primary, i.e., causedby thyroid disease, or secondary, i.e., resultingfrom TSH deficiency, hypothyroidismis treated by oral administrationof T 4. Since too rapid activation ofmetabolism entails the hazard of cardiacoverload (angina pectoris, myocardialinfarction), therapy is usually startedwith low doses and gradually increased.The final maintenance dose requiredto restore a euthyroid state dependson individual needs (approx.150 µg/d).Thyroid suppression therapy ofeuthyroid goiter (B). The cause of goiter(struma) is usually a dietary deficiencyof iodine. Due to an increasedTSH action, the thyroid is activated toraise utilization of the little iodine availableto a level at which hypothyroidismis averted. Therefore, the thyroid increasesin size. In addition, intrathyroiddepletion of iodine stimulates growth.Because of the negative feedbackregulation of thyroid function, thyroidactivation can be inhibited by administrationof T 4 doses equivalent to the endogenousdaily output (approx.150 µg/d). Deprived of stimulation, theinactive thyroid regresses in size.If a euthyroid goiter has not persistedfor too long, increasing iodine supply(potassium iodide tablets) can also beeffective in reversing overgrowth of thegland.In older patients with goiter due toiodine deficiency there is a risk of provokinghyperthyroidism by increasingiodine intake (p. 247): During chronicmaximal stimulation, thyroid folliclescan become independent of TSH stimulation(“autonomic tissue”). If the iodinesupply is increased, thyroid hormoneproduction increases while TSH secretiondecreases due to feedback inhibition.The activity of autonomic tissue,however, persists at a high level; thyroxineis released in excess, resulting iniodine-induced hyperthyroidism.Iodized salt prophylaxis. Goiter isendemic in regions where soils are deficientin iodine. Use of iodized table saltallows iodine requirements (150–300 µg/d) to be met and effectively preventsgoiter.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Hormones 245HypothalamusTRHHypophysisDecrease insensivityto TRHL-Thyroxine, Levothyroxine,3,5,3´,5´-Tetraiodothyronine, T 4TSHThyroidLiothyronine3,5,3´-Triiodothyronine, T 3~ 90 µg/Day ~ 9 µg/DayThyroxineTriiodothyronineEffector cell:receptor affinityT 3 10=T 4 1Deiodinase~ 25 µg/DayDuration2. 9.DayI - I - DeiodinationcouplingI - I -"reverse T 3 "3,3´,5´-Triiodothyronine Urine FecesA. Thyroid hormones - release, effects, degradationT 3 T 410 20 30 40 DaysHypophysisTSHTSHInhibitionNormalstateI - T 4 , T 3 T 4 , T 3Therap.administrationT 4B. Endemic goiter and its treatment with thyroxineLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
246 HormonesHyperthyroidism and Antithyroid DrugsThyroid overactivity in Graves’ disease(A) results from formation of IgG antibodiesthat bind to and activate TSH receptors.Consequently, there is overproductionof hormone with cessation ofTSH secretion. Graves’ disease can abatespontaneously after 1–2 y. Therefore,initial therapy consists of reversiblesuppression of thyroid activity bymeans of antithyroid drugs. In otherforms of hyperthyroidism, such as hormone-producing(morphologically benign)thyroid adenoma, the preferredtherapeutic method is removal of tissue,either by surgery or administration of131 iodine in sufficient dosage. Radioiodineis taken up into thyroid cells anddestroys tissue within a sphere of a fewmillimeters by emitting β-(electron)particles during its radioactive decay.Concerning iodine-induced hyperthyroidism,see p. 244 (B).Antithyroid drugs inhibit thyroidfunction. Release of thyroid hormone(C) is preceded by a chain of events. Amembrane transporter actively accumulatesiodide in thyroid cells; this isfollowed by oxidation to iodine, iodinationof tyrosine residues in thyroglobulin,conjugation of two diiodotyrosinegroups, and formation of T 4 and T 3moieties. These reactions are catalyzedby thyroid peroxidase, which is localizedin the apical border of the follicularcell membrane. T 4-containing thyroglobulinis stored inside the thyroid folliclesin the form of thyrocolloid. Uponendocytotic uptake, colloid undergoeslysosomal enzymatic hydrolysis, enablingthyroid hormone to be released asrequired. A “thyrostatic” effect can resultfrom inhibition of synthesis or release.When synthesis is arrested, theantithyroid effect develops after a delay,as stored colloid continues to be utilized.Antithyroid drugs for long-termtherapy (C). Thiourea derivatives(thioureylenes, thioamides) inhibitperoxidase and, hence, hormone synthesis.In order to restore a euthyroidstate, two therapeutic principles can beapplied in Graves’ disease: a) monotherapywith a thioamide with gradual dosereduction as the disease abates; b) administrationof high doses of a thioamidewith concurrent administrationof thyroxine to offset diminished hormonesynthesis. Adverse effects of thioamidesare rare; however, the possibilityof agranulocytosis has to be kept inmind.Perchlorate, given orally as the sodiumsalt, inhibits the iodide pump. Adversereactions include aplastic anemia.Compared with thioamides, its therapeuticimportance is low but it is usedas an adjunct in scintigraphic imaging ofbone by means of technetate whenaccumulation in the thyroid gland hasto be blocked.Short-term thyroid suppression(C). Iodine in high dosage (>6000 µg/d)exerts a transient “thyrostatic” effect inhyperthyroid, but usually not in euthyroid,individuals. Since release is alsoblocked, the effect develops more rapidlythan does that of thioamides.Clinical applications include: preoperativesuppression of thyroid secretionaccording to Plummer with Lugol’s solution(5% iodine + 10% potassium iodide,50–100 mg iodine/d for a maximum of10 d). In thyrotoxic crisis, Lugol’s solutionis given together with thioamidesand β-blockers. Adverse effects: allergies;contraindications: iodine-inducedthyrotoxicosis.Lithium ions inhibit thyroxine release.Lithium salts can be used insteadof iodine for rapid thyroid suppressionin iodine-induced thyrotoxicosis. Regardingadministration of lithium inmanic-depressive illness, see p. 234.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Hormones 247HypophysisTSHAutonomoustissueI -TSHlikeantibodiesT 4 , T 3T 4 , T 3A. Graves’ disease B. Iodine hyperthyroidosis in endemic goiterI -T 4 , T 3ThioamidesConversionduringabsorptionPropylthiouracilThiamazoleMethimazoleCarbimazolePeroxidaseClO 4-PerchlorateI - IeI - TyrosineI TG T 4 -TyrosineIT 4 -SynthesisIodine inhigh doseReleaseT 4 -Storagein colloidT 4LysosomeLithiumionsC. Antithyroid drugs and their modes of actionLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
248 HormonesGlucocorticoid TherapyI. Replacement therapy. The adrenalcortex (AC) produces the glucocorticoidcortisol (hydrocortisone) and the mineralocorticoidaldosterone. Both steroidhormones are vitally important in adaptationresponses to stress situations,such as disease, trauma, or surgery. Cortisolsecretion is stimulated by hypophysealACTH, aldosterone secretion byangiotensin II in particular (p. 124). InAC failure (primary AC insuffiency:Addison’s disease), both cortisol and aldosteronemust be replaced; when ACTHproduction is deficient (secondary AC insufficiency),cortisol alone needs to be replaced.Cortisol is effective when givenorally (30 mg/d, 2/3 a.m., 1/3 p.m.). Instress situations, the dose is raised by5- to 10-fold. Aldosterone is poorlyeffective via the oral route; instead,the mineralocorticoid fludrocortisone(0.1 mg/d) is given.II. Pharmacodynamic therapywith glucocorticoids (A). In unphysiologicallyhigh concentrations, cortisol orother glucocorticoids suppress all phases(exudation, proliferation, scar formation)of the inflammatory reaction, i.e.,the organism’s defensive measuresagainst foreign or noxious matter. Thiseffect is mediated by multiple components,all of which involve alterations ingene transcription (p. 64). Glucocorticoidsinhibit the expression of genes encodingfor proinflammatory proteins(phospholipase-A2, cyclooxygenase 2,IL-2-receptor). The expression of thesegenes is stimulated by the transcriptionfactor NF ΚB. Binding to the glucocorticoidreceptor complex prevents translocationaf NF ΚB to the nucleus. Conversely,glucocorticoids augment the expressionof some anti-inflammatory proteins,e.g., lipocortin, which in turn inhibitsphospholipase A2. Consequently,release of arachidonic acid is diminished,as is the formation of inflammatorymediators of the prostaglandin andleukotriene series (p. 196). At very highdosage, nongenomic effects may alsocontribute.Desired effects. As anti-allergics,immunosuppressants, or anti-inflammatorydrugs, glucocorticoids display excellentefficacy against “undesired” inflammatoryreactions.Unwanted effects. With short-termuse, glucocorticoids are practically freeof adverse effects, even at the highestdosage. Long-term use is likely to causechanges mimicking the signs ofCushing’s syndrome (endogenousoverproduction of cortisol). Sequelae ofthe anti-inflammatory action: loweredresistance to infection, delayed woundhealing, impaired healing of peptic ulcers.Sequelae of exaggerated glucocorticoidaction: a) increased gluconeogenesisand release of glucose; insulin-dependentconversion of glucose to triglycerides(adiposity mainly noticeable inthe face, neck, and trunk); “steroid-diabetes”if insulin release is insufficient;b) increased protein catabolism withatrophy of skeletal musculature (thinextremities), osteoporosis, growth retardationin infants, skin atrophy. Sequelaeof the intrinsically weak, butnow manifest, mineralocorticoid actionof cortisol: salt and fluid retention, hypertension,edema; KCl loss with dangerof hypokalemia.Measures for Attenuating or PreventingDrug-Induced Cushing’s Syndromea) Use of cortisol derivatives with less(e.g., prednisolone) or negligible mineralocorticoidactivity (e.g., triamcinolone,dexamethasone). Glucocorticoid activityof these congeners is more pronounced.Glucorticoid, anti-inflammatoryand feedback inhibitory (p. 250) actionson the hypophysis are correlated.An exclusively anti-inflammatory congenerdoes not exist. The “glucocorticoid”related Cushingoid symptomscannot be avoided. The table lists relativeactivity (potency) with reference tocortisol, whose mineralo- and glucocorticoidactivities are assigned a value of1.0. All listed glucocorticoids are effectiveorally.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Hormones 249Inflammationredness,swelling heat,pain;scarHypertensionNa +H 2 OMineralocorticoidactionK +UnwantedWantedunphysiologicallyhigh concentrationCortisole.g., allergyautoimmune disease,transplant rejectionHealing oftissue injurydue to bacteria,viruses, fungi, traumaGlucocorticoidactionDiabetesmellitusGlucoseGluconeogenesisAmino acidsProtein catabolismPotency10,8003000CortisolPrednisoloneTriamcinoloneDexamethasone147,5300,3MuscleweaknessOsteoporosisGrowth inhibitionTissue atrophySkinatrophyPrednisoloneTriamcinoloneDexamethasoneAldosteroneA. Glucocorticoids: principal and adverse effectsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
250 Hormonesb) Local application. Typical adverseeffects, however, also occur locally, e.g.,skin atrophy or mucosal colonizationwith candidal fungi. To minimizesystemic absorption after inhalation,derivatives should be used that have ahigh rate of presystemic elimination,such as beclomethasone dipropionate,flunisolide, budesonide, or fluticasonepropionate (p. 14).b) Lowest dosage possible. For longtermmedication, a just sufficient doseshould be given. However, in attemptingto lower the dose to the minimal effectivelevel, it is necessary to take intoaccount that administration of exogenousglucocorticoids will suppress productionof endogenous cortisol due toactivation of an inhibitory feedbackmechanism. In this manner, a very lowdose could be “buffered,” so that unphysiologicallyhigh glucocorticoid activityand the anti-inflammatory effectare both prevented.Effect of glucocorticoid administrationon adrenocortical cortisol production(A). Release of cortisol dependson stimulation by hypophyseal ACTH,which in turn is controlled by hypothalamiccorticotropin-releasing hormone(CRH). In both the hypophysis and hypothalamusthere are cortisol receptorsthrough which cortisol can exert a feedbackinhibition of ACTH or CRH release.By means of these cortisol “sensors,” theregulatory centers can monitor whetherthe actual blood level of the hormonecorresponds to the “set-point.” If theblood level exceeds the set-point, ACTHoutput is decreased and, thus, also thecortisol production. In this way cortisollevel is maintained within the requiredrange. The regulatory centers respondto synthetic glucocorticoids as they doto cortisol. Administration of exogenouscortisol or any other glucocorticoid reducesthe amount of endogenous cortisolneeded to maintain homeostasis. Releaseof CRH and ACTH declines ("inhibitionof higher centers by exogenousglucocorticoid”) and, thus, cortisol secretion(“adrenocortical suppression”).After weeks of exposure to unphysiologicallyhigh glucocorticoid doses, thecortisol-producing portions of the adrenalcortex shrink (“adrenocorticalatrophy”). Aldosterone-synthesizing capacity,however, remains unaffected.When glucocorticoid medication is suddenlywithheld, the atrophic cortex isunable to produce sufficient cortisol anda potentially life-threatening cortisoldeficiency may develop. Therefore, glucocorticoidtherapy should always betapered off by gradual reduction of thedosage.Regimens for prevention ofadrenocortical atrophy. Cortisol secretionis high in the early morning andlow in the late evening (circadianrhythm). This fact implies that the regulatorycenters continue to release CRHor ACTH in the face of high morningblood levels of cortisol; accordingly,sensitivity to feedback inhibition mustbe low in the morning, whereas the oppositeholds true in the late evening.a) Circadian administration: Thedaily dose of glucocorticoid is given inthe morning. Endogenous cortisol productionwill have already begun, theregulatory centers being relatively insensitiveto inhibition. In the earlymorning hours of the next day, CRF/-ACTH release and adrenocortical stimulationwill resume.b) Alternate-day therapy: Twice thedaily dose is given on alternate mornings.On the “off” day, endogenous cortisolproduction is allowed to occur.The disadvantage of either regimenis a recrudescence of disease symptomsduring the glucocorticoid-free interval.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Hormones 251HypothalamusCRHACTHAdrenalcortexHypophysisAdrenocorticalatrophyCortisol30 mg/dayCortisolproduction undernormalconditionsExogenousadministrationDecrease 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 8hA. Cortisol release and its modification by glucocorticoidsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
252 HormonesAndrogens, Anabolic Steroids,AntiandrogensAndrogens are masculinizing substances.The endogenous male gonadal hormoneis the steroid testosterone fromthe interstitial Leydig cells of the testis.Testosterone secretion is stimulated byhypophyseal luteinizing hormone (LH),whose release is controlled by hypothalamicGnRH (gonadorelin, p. 242). Releaseof both hormones is subject tofeedback inhibition by circulating testosterone.Reduction of testosterone todihydrotestosterone occurs in most targetorgans; the latter possesses higheraffinity for androgen receptors. Rapidintrahepatic degradation (plasma t 1/2 ~15 min) yields androsterone amongother metabolites (17-ketosteroids)that are eliminated as conjugates in theurine. Because of rapid hepatic metabolism,testosterone is unsuitable for oraluse. Although it is well absorbed, itundergoes virtually complete presystemicelimination.Testosterone (T.) derivatives forclinical use. T. esters for i.m. depot injectionare T. propionate and T. heptanoate(or enanthate). These are given in oilysolution by deep intramuscular injection.Upon diffusion of the ester fromthe depot, esterases quickly split off theacyl residue, to yield free T. With increasinglipophilicity, esters will tend toremain in the depot, and the duration ofaction therefore lengthens. A T. ester fororal use is the undecanoate. Owing to thefatty acid nature of undecanoic acid, thisester is absorbed into the lymph, enablingit to bypass the liver and enter, viathe thoracic duct, the general circulation.17-a Methyltestosterone is effectiveby the oral route due to its increasedmetabolic stability, but because of thehepatotoxicity of C17-alkylated androgens(cholestasis, tumors) its use shouldbe avoided. Orally active mesterolone is1α-methyl-dihydrotestosterone. Transdermaldelivery systems for T. are alsoavailable.Indications. For hormone replacementin deficiency of endogenous T.production and palliative treatment ofbreast cancer, T. esters for depot injectionare optimally suited. Secondary sexcharacteristics and libido are maintained;however, fertility is not promoted.On the contrary, spermatogenesismay be suppressed because of feedbackinhibition of hypothalamohypophysealgonadotropin secretion.Stimulation of spermatogenesisin gonadotropin (FSH, LH) deficiencycan be achieved by injection of HMGand HCG. HMG or human menopausalgonadotropin is obtained from the urineof postmenopausal women and is richin FSH activity. HCG, human chorionicgonadotropin, from the urine of pregnantwomen, acts like LH.Anabolics are testosterone derivatives(e.g., clostebol, metenolone, nandrolone,stanozolol) that are used in debilitatedpatients, and misused by athletes,because of their protein anaboliceffect. They act via stimulation of androgenreceptors and, thus, also display androgenicactions (e.g., virilization in females,suppression of spermatogenesis).The antiandrogen cyproteroneacts as a competitive antagonist of T. Inaddition, it has progestin activitywhereby it inhibits gonadotropin secretion(p. 254). Indications: in men, inhibitionof sex drive in hypersexuality;prostatic cancer. In women: treatmentof virilization, with potential utilizationof the gestagenic contraceptive effect.Flutamide, an androgen receptorantagonist possessing a different chemicalstructure, lacks progestin activity.Finasteride inhibits 5α-reductase,the enzyme converting T. into dihydrotestosterone(DHT). Thus, the androgenicstimulus is reduced in those tissues inwhich DHT is the active species (e.g.,prostate). T.-dependent tissues or functionsare not or hardly affected (e.g.,skeletal muscle, negative feedback inhibitionof gonadotropin secretion, and libido).Finasteride can be used in benignprostate hyperplasia to shrink the glandand, possibly, to improve micturition.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Hormones 253HypothalamusGnRHHypophysisTestesInhibitionRSkeletal muscleTestosterone esterin oily solutioni. m. DepotinjectionLH R =Estercleavage-propionate C – C 1 2-heptanoateC – C – C – C – C – CDuration of effect 2 weeksTestosteroneTarget cellDihydrotestosteroneEster cleavageDuctusthoracicusAntagonistCyproteroneOral intakeAndrosteroneInactivationConjugationwith sulfate, glucuronateTestosteroneMethyltestosterone17-KetosteroidA. Testosterone and derivativesTestosteroneundecanoateLymph vesselsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
254 HormonesFollicular Growth and Ovulation,Estrogen and Progestin ProductionFollicular maturation and ovulation, aswell as the associated production of femalegonadal hormones, are controlledby the hypophyseal gonadotropins FSH(follicle-stimulating hormone) and LH(luteinizing hormone). In the first half ofthe menstrual cycle, FSH promotesgrowth and maturation of ovarian folliclesthat respond with accelerating synthesisof estradiol. Estradiol stimulatesendometrial growth and increases thepermeability of cervical mucus forsperm cells. When the estradiol bloodlevel approaches a predetermined setpoint,FSH release is inhibited due tofeedback action on the anterior hypophysis.Since follicle growth and estrogenproduction are correlated, hypophysisand hypothalamus can “monitor” thefollicular phase of the ovarian cyclethrough their estrogen receptors. Withinhours after ovulation, the tertiary follicledevelops into the corpus luteum,which then also releases progesteronein response to LH. The former initiatesthe secretory phase of the endometrialcycle and lowers the permeability ofcervical mucus. Nonruptured folliclescontinue to release estradiol under theinfluence of FSH. After 2 wk, productionof progesterone and estradiol subsides,causing the secretory endometrial layerto be shed (menstruation).The natural hormones are unsuitablefor oral application because theyare subject to presystemic hepatic elimination.Estradiol is converted via estroneto estriol; by conjugation, all threecan be rendered water soluble andamenable to renal excretion. The majormetabolite of progesterone is pregnandiol,which is also conjugated and eliminatedrenally.Estrogen preparations. Depotpreparations for i.m. injection are oilysolutions of esters of estradiol (3- or 17-OH group). The hydrophobicity of theacyl moiety determines the rate of absorption,hence the duration of effect(p. 252). Released ester is hydrolyzed toyield free estradiol.Orally used preparations. Ethinylestradiol(EE) is more stable metabolically,passes largely unchanged throughthe liver after oral intake and mimics estradiolat estrogen receptors. Mestranolitself is inactive; however, cleavage ofthe C-3 methoxy group again yields EE.In oral contraceptives, one of the twoagents forms the estrogen component(p. 256). (Sulfate-)conjugated estrogenscan be extracted from equine urine andare used for the prevention of postmenopausalosteoporosis and in thetherapy of climacteric complaints. Becauseof their high polarity (sulfate, glucuronide),they would hardly appearsuitable for this route of administration.For transdermal delivery, an adhesivepatch is available that releases estradioltranscutaneously into the body.Progestin preparations. Depotformulations for i.m. injection are 17-α-hydroxyprogesterone caproate andmedroxyprogesterone acetate. Preparationsfor oral use are derivatives of 17αethinyltestosterone= ethisterone (e.g.,norethisterone, dimethisterone, lynestrenol,desogestrel, gestoden), or of17α-hydroxyprogesterone acetate (e.g.,chlormadinone acetate or cyproteroneacetate). These agents are mainly usedas the progestin component in oral contraceptives.Indications for estrogens and progestinsinclude: hormonal contraception(p. 256), hormone replacement, asin postmenopausal women for prophylaxisof osteoporosis; bleeding anomalies,menstrual complaints. Concerningadverse effects, see p. 256.Estrogens with partial agonist activity(raloxifene, tamoxifene) are beinginvestigated as agents used to replaceestrogen in postmenopausal osteoporosistreatment, to lower plasmalipids, and as estrogen antagonists inthe prevention of breast cancer. Raloxifen—incontrast to tamoxifen—is an antagonistat uterine estrogen receptors.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Hormones 255Estradiol-valerateHypothalamusGnRHHydroxyprogesteronecaproate3 weeks-benzoate1 2weekDuration of effectHypophysisFSH LHOvaryMedroxyprogesteroneacetate1 week8 - 12 weeksDuration of effectEstradiolProgesteroneEstriol Estrone EstradiolPregnanediolConjugationwith sulfate, glucuronateInactivationInactivationConjugationEstradiolProgesteroneEthinylestradiol(EE)Ethinyltestosterone,a gestagenConjugatedestrogensMestranol =3-Methylether of EEA. Estradiol, progesterone, and derivativesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
256 HormonesOral ContraceptivesInhibitors of ovulation. Negative feedbackcontrol of gonadotropin releasecan be utilized to inhibit the ovarian cycle.Administration of exogenous estrogens(ethinylestradiol or mestranol)during the first half of the cycle permitsFSH production to be suppressed (as itis by administration of progestinsalone). Due to the reduced FSH stimulationof tertiary follicles, maturation offollicles and, hence, ovulation are prevented.In effect, the regulatory braincenters are deceived, as it were, by theelevated estrogen blood level, whichsignals normal follicular growth and adecreased requirement for FSH stimulation.If estrogens alone are given duringthe first half of the cycle, endometrialand cervical responses, as well as otherfunctional changes, would occur in thenormal fashion. By adding a progestin(p. 254) during the second half of the cycle,the secretory phase of the endometriumand associated effects can be elicited.Discontinuance of hormone administrationwould be followed bymenstruation.The physiological time course of estrogen-progesteronerelease is simulatedin the so-called biphasic (sequential)preparations (A). In monophasicpreparations, estrogen and progestinare taken concurrently. Early administrationof progestin re<strong>info</strong>rces the inhibitionof CNS regulatory mechanisms,prevents both normal endometrialgrowth and conditions for ovum implantation,and decreases penetrabilityof cervical mucus for sperm cells. Thetwo latter effects also act to preventconception. According to the staging ofprogestin administration, one distinguishes(A): one-, two-, and three-stagepreparations. In all cases, “withdrawalbleeding”occurs when hormone intakeis discontinued (if necessary, by substitutingdummy tablets).Unwanted effects: An increased incidenceof thrombosis and embolism isattributed to the estrogen component inparticular. Hypertension, fluid retention,cholestasis, benign liver tumors,nausea, chest pain, etc. may occur. Apparentlythere is no increased overallrisk of malignant tumors.Minipill. Continuous low-dose administrationof progestin alone can preventconception. Ovulations are notsuppressed regularly; the effect is thendue to progestin-induced alterations incervical and endometrial function. Becauseof the need for constant intake atthe same time of day, a lower successrate, and relatively frequent bleedinganomalies, these preparations are nowrarely employed.“Morning-after” pill. This refers toadministration of a high dose of estrogenand progestin, preferably within 12to 24 h, but no later than 72 h after coitus.Menstrual bleeding ensues, whichprevents implantation of the fertilizedovum (normally on the 7th day after fertilization,p. 74). Similarly, implantationcan be inhibited by mifepristone, whichis an antagonist at both progesteroneand glucocorticoid receptors and whichalso offers a noninvasive means of inducingtherapeutic abortion in earlypregnancy.Stimulation of ovulation. Gonadotropinsecretion can be increased bypulsatile delivery of GnRH (p. 242). Theestrogen antagonists clomiphene and cyclofenilblock receptors mediating feedbackinhibition of central neuroendocrinecircuits and thereby disinhibitgonadotropin release. Gonadotropinscan be given in the form of HMG andHCG (p. 252).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Hormones 257HypophysisHypophysisFSHLH1.7. 14. 21. 28.InhibitionMinipillOvulationOvaryOvulationOvaryEstradiolEstradiolProgesteroneIntake ofestradiolderivativeIntake ofprogestinProgesteronePenetrabilityby sperm cells1.7. 14. 21. 28.Day of cycleReadinessfornidationNo ovulationBiphasic preparationDays of cycle7. 14. 21. 28.Monophasic preparationsOne-stage regimenTwo-stage regimenThree-stage regimenA. Oral contraceptivesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
258 HormonesInsulin TherapyInsulin is synthesized in the B- (or β-)cells of the pancreatic islets of Langerhans.It is a protein (MW 5800) consistingof two peptide chains linked by twodisulfide bridges; the A chain has 21 andthe B chain 30 amino acids. Insulin is the“blood-sugar lowering” hormone. Uponingestion of dietary carbohydrates, it isreleased into the blood and acts to preventa significant rise in blood glucoseconcentration by promoting uptake ofglucose in specific organs, viz., theheart, adipose tissue, and skeletal muscle,or its conversion to glycogen in theliver. It also increases lipogenesis andprotein synthesis, while inhibiting lipolysisand release of free fatty acids.Insulin is used in the replacementtherapy of diabetes mellitus to supplementa deficient secretion of endogenoushormone.Sources of therapeutic insulinpreparations (A). Insulin can be obtainedfrom pancreatic tissue of slaughteredanimals. Porcine insulin differsfrom human insulin merely by one Bchain amino acid, bovine insulin by twoamino acids in the A chain and one inthe B chain. With these slight differences,animal and human hormone displaysimilar biological activity. Comparedwith human hormone, porcine insulin isbarely antigenic and bovine insulin hasa little higher antigenicity. Human insulinis produced by two methods: biosynthetically,by substituting threonine forthe C-terminal alanine in the B chain ofporcine insulin; or by gene technologyinvolving insertion of the appropriatehuman DNA into E. coli bacteria.Types of preparations (B). As apeptide, insulin is unsuitable for oraladministration (destruction by gastrointestinalproteases) and thus needsto be given parenterally. Usually, insulinpreparations are injected subcutaneously.The duration of action dependson the rate of absorption from the injectionsite.Short-acting insulin is dispensedas a clear neutral solution known asregular insulin. In emergencies, such ashyperglycemic coma, it can be givenintravenously (mostly by infusion becausei.v. injections have too brief an action;plasma t 1/2 ~ 9 min). With the usualsubcutaneous application, the effectis evident within 15 to 20 min, reaches apeak after approx. 3 h, and lasts for approx.6 h. Lispro insulin has a faster onsetand slightly shorter duration of action.Insulin suspensions. When thehormone is injected as a suspension ofinsulin-containing particles, its dissolutionand release in subcutaneous tissueare retarded (rapid, intermediate, andslow insulins). Suitable particles can beobtained by precipitation of apolar,poorly water-soluble complexes consistingof anionic insulin and cationicpartners, e.g., the polycationic proteinprotamine or the compound aminoquinuride(Surfen). In the presence of zincand acetate ions, insulin crystallizes;crystal size determines the rate of dissolution.Intermediate insulin preparations(NPH or isophane, lente or zinc insulin)act for 18 to 26 h, slow preparations(protamine zinc insulin, ultralenteor extended zinc insulin) for up to 36 h.Combination preparations containinsulin mixtures in solution and insuspension (e.g., ultralente); the plasmaconcentration-time curve representsthe sum of the two components.Unwanted effects. Hypoglycemiaresults from absolute or relative overdosage(see p. 260). Allergic reactions arerare—locally: redness at injection site,atrophy of adipose tissue (lipodystrophy);systemically: urticaria, skin rash,anaphylaxis. Insulin resistance can resultfrom binding to inactivating antibodies.A possible local lipohypertrophycan be avoided by alternating injectionsites.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Hormones 259Porcine insulinAlaInsulin30ThrHuman insulinB-chainS - SS - SA-chainProduction: DNAE. coliA. Insulin productionHours after injection6 12 18 24Insulin suspension = protamine zinc insulin Insulin solution = regular insulinInsulinmixturesInsulin concentration in bloodRapidIntermediateSlowB. Insulin: preparations and blood level-time curvesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
260 HormonesTreatment of Insulin-DependentDiabetes Mellitus“Juvenile onset” (type I) diabetes mellitusis caused by the destruction of insulin-producingB cells in the pancreas,necessitating replacement of insulin(daily dose approx. 40 U, equivalent toapprox. 1.6 mg).Therapeutic objectives are: (1)prevention of life-threatening hyperglycemic(diabetic) coma; (2) prevention ofdiabetic sequelae (angiopathy withblindness, myocardial infarction, renalfailure), with precise “titration” of thepatient being essential to avoid evenshort-term spells of pathological hyperglycemia;(3) prevention of insulinoverdosage leading to life-threateninghypoglycemic shock (CNS disturbancedue to lack of glucose).Therapeutic principles. In healthysubjects, the amount of insulin is “automatically”matched to carbohydrate intake,hence to blood glucose concentration.The critical secretory stimulus isthe rise in plasma glucose level. Food intakeand physical activity (increasedglucose uptake into musculature, decreasedinsulin demand) are accompaniedby corresponding changes in insulinsecretion (A, left track).In the diabetic, insulin could be administeredas it is normally secreted;that is, injection of short-acting insulinbefore each main meal plus bedtime administrationof a Lente preparation toavoid a nocturnal shortfall of insulin.This regimen requires a well-educated,cooperative, and competent patient. Inother cases, a fixed-dosage schedulewill be needed, e.g., morning and eveninginjections of a combination insulinin constant respective dosage (A). Toavoid hypo- or hyperglycemias withthis regimen, dietary carbohydrate (CH)intake must be synchronized with thetime course of insulin absorption fromthe s.c. depot. Caloric intake is to be distributed(50% CH, 30% fat, 20% protein)in small meals over the day so as toachieve a steady CH supply—snacks, latenight meal. Rapidly absorbable CH(sweets, cakes) must be avoided (hyperglycemic—peaks)and replaced withslowly digestible ones.Acarbose (an α-glucosidase inhibitor)delays intestinal formation of glucosefrom disaccharides.Any change in eating and livinghabits can upset control of blood sugar:skipping a meal or unusual physicalstress leads to hypoglycemia; increasedCH intake provokes hyperglycemia.Hypoglycemia is heralded bywarning signs: tachycardia, unrest,tremor, pallor, profuse sweating. Someof these are due to the release of glucose-mobilizingepinephrine. Countermeasures:glucose administration, rapidlyabsorbed CH orally or 10–20 g glucosei.v. in case of unconsciousness; ifnecessary, injection of glucagon, thepancreatic hyperglycemic hormone.Even with optimal control of bloodsugar, s.c. administration of insulin cannotfully replicate the physiological situation.In healthy subjects, absorbedglucose and insulin released from thepancreas simultaneously reach the liverin high concentration, whereby effectivepresystemic elimination of bothsubstances is achieved. In the diabetic,s.c. injected insulin is uniformly distributedin the body. Since insulin concentrationin blood supplying the liver cannotrise, less glucose is extracted fromportal blood. A significant amount ofglucose enters extrahepatic tissues,where it has to be utilized.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Hormones 261BTimeL10HealthysubjectB = BreakfastS = SnackL = LunchD = DinnerN = SupperLBDCarbohydrateabsorptionBlood sugarInsulin releasefrom pancreas12141618202224246810Carbohydrate absorptionBlood sugarInsulin releasefrom depotNDBSLSFeast12B16182224GlucoseSLSnolunchB246FeastL810D121416SLBDiabetic202224A. Control of blood sugar in healthy and diabetic subjectsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
262 HormonesTreatment of Maturity-Onset (Type II)Diabetes MellitusIn overweight adults, a diabetic metaboliccondition may develop (type II ornon-insulin-dependent diabetes) whenthere is a relative insulin deficiency—enhanced demand cannot be met by adiminishing insulin secretion. Thecause of increased insulin requirementis a loss of insulin receptors or animpairment of the signal cascade activatedby the insulin receptor. Accordingly,insulin sensitivity of cells declines.This can be illustrated by comparingconcentration-binding curves incells from normal and obese individuals(A). In the obese, the maximum bindingpossible (plateau of curve) is displaceddownward, indicative of the reductionin receptor numbers. Also, at low insulinconcentrations, there is less binding ofinsulin, compared with the control condition.For a given metabolic effect acertain number of receptors must be occupied.As shown by the binding curves(dashed lines), this can still be achievedwith a reduced receptor number, althoughonly at a higher concentration ofinsulin.Development of adult diabetes(B). Compared with a normal subject,the obese subject requires a continuallyelevated output of insulin (orangecurves) to avoid an excessive rise ofblood glucose levels (green curves) duringa glucose load. When the secretorycapacity of the pancreas decreases, thisis first noted as a rise in blood glucoseduring glucose loading (latent diabetes).Subsequently, not even the fastingblood level can be maintained (manifest,overt diabetes). A diabetic conditionhas developed, although insulin releaseis not lower than that in a healthyperson (relative insulin deficiency).Treatment. Caloric restriction torestore body weight to normal is associatedwith an increase in insulin receptornumber or cellular responsiveness.The releasable amount of insulin isagain adequate to maintain a normalmetabolic rate.Therapy of first choice is weightreduction, not administration ofdrugs! Should the diabetic condition failto resolve, consideration should first begiven to insulin replacement (p. 260).Oral antidiabetics of the sulfonylureatype increase the sensitivity of B-cellstowards glucose, enabling them to increaserelease of insulin. These drugsprobably promote depolarization of theβ-cell membrane by closing off ATP-gatedK + channels. Normally, these channelsare closed when intracellular levelsof glucose, hence of ATP, increase. Thisdrug class includes tolbutamide (500–2000 mg/d) and glyburide (glibenclamide)(1.75–10.5 mg/d). In some patients,it is not possible to stimulate insulinsecretion from the outset; in others,therapy fails later on. Matching dosageof the oral antidiabetic and caloricintake follows the same principles asapply to insulin. Hypoglycemia is themost important unwanted effect. Enhancementof the hypoglycemic effectcan result from drug interactions: displacementof antidiabetic drug fromplasma protein-binding sites by sulfonamidesor acetylsalicylic acid.Metformin, a biguanide derivative,can lower excessive blood glucoselevels, provided that insulin is present.Metformin does not stimulate insulin release.Glucose release from the liver isdecreased, while peripheral uptake isenhanced. The danger of hypoglycemiaapparently is not increased. Frequentadverse effects include: anorexia, nausea,and diarrhea. Overproduction of lacticacid (lactate acidosis, lethality 50%) isa rare, potentially fatal reaction. Metforminis used in combination with sulfonylureasor by itself. It is contraindicated inrenal insufficiency and should thereforebe avoided in elderly patients.Thiazolidinediones (Glitazones: rosiglitazone,pioglitazone) are insulinsensitizingagents that augment tissueresponsiveness by promoting the synthesisor the availability of plasmalemmalglucose transporters via activationof a transcription factor (peroxisomeproliferator-activated receptor-γ).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Hormones 263Insulin bindingNormal receptor numberInsulin receptorbindingneededfor euglycemiaDecreasedreceptor numberNormaldietInsulin concentrationObesityA. Insulin concentration and binding in normal and overweight subjectsOralantidiabeticGlucose in blood Insulin releaseTimeTherapy of 1st choiceDiagnosis:latent overtDiabetes mellitusTherapy of 2nd choiceB. Development of maturity-onset diabetesMembranedepolarizationK +BlockadeSulfonylurea derivativesInsulinATPB cellC. Action of oral antidiabetic drugsGlucoseTolbutamideLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
264 HormonesDrugs for Maintaining CalciumHomeostasisAt rest, the intracellular concentrationof free calcium ions (Ca 2+ ) is kept at0.1 µM (see p. 128 for mechanisms involved).During excitation, a transientrise of up to 10 µM elicits contraction inmuscle cells (electromechanical coupling)and secretion in glandular cells(electrosecretory coupling). The cellularcontent of Ca 2+ is in equilibrium withthe extracellular Ca 2+ concentration(approx. 1000 µM), as is the plasma protein-boundfraction of calcium in blood.Ca 2+ may crystallize with phosphate toform hydroxyapatite, the mineral ofbone. Osteoclasts are phagocytes thatmobilize Ca 2+ by resorption of bone.Slight changes in extracellular Ca 2+ concentrationcan alter organ function:thus, excitability of skeletal muscle increasesmarkedly as Ca 2+ is lowered(e.g., in hyperventilation tetany). Threehormones are available to the body formaintaining a constant extracellularCa 2+ concentration.Vitamin D hormone is derivedfrom vitamin D (cholecalciferol). VitaminD can also be produced in the body; it isformed in the skin from dehydrocholesterolduring irradiation with UV light.When there is lack of solar radiation,dietary intake becomes essential, codliver oil being a rich source. Metabolicallyactive vitamin D hormone resultsfrom two successive hydroxylations: inthe liver at position 25 ( calcifediol)and in the kidney at position 1 ( calcitriol= vit. D hormone). 1-Hydroxylationdepends on the level of calcium homeostasisand is stimulated by parathormoneand a fall in plasma levels of Ca 2+or phosphate. Vit. D hormone promotesenteral absorption and renal reabsorptionof Ca 2+ and phosphate. As a result ofthe increased Ca 2+ and phosphate concentrationin blood, there is an increasedtendency for these ions to bedeposited in bone in the form of hydroxyapatitecrystals. In vit. D deficiency,bone mineralization is inadequate(rickets, osteomalacia). Therapeuticuse aims at replacement. Mostly, vit. D isgiven; in liver disease calcifediol may beindicated, in renal disease calcitriol. Effectiveness,as well as rate of onset andcessation of action, increase in the ordervit. D. < 25-OH-vit. D < 1,25-di-OH-vit.D. Overdosage may induce hypercalcemiawith deposits of calcium salts intissues (particularly in kidney and bloodvessels): calcinosis.The polypeptide parathormone isreleased from the parathyroid glandswhen plasma Ca 2+ level falls. It stimulatesosteoclasts to increase bone resorption;in the kidneys, it promotes calciumreabsorption, while phosphate excretionis enhanced. As blood phosphateconcentration diminishes, the tendencyof calcium to precipitate as bone mineraldecreases. By stimulating the formationof vit. D hormone, parathormonehas an indirect effect on the enteral uptakeof Ca 2+ and phosphate. In parathormonedeficiency, vitamin D can be usedas a substitute that, unlike parathormone,is effective orally.The polypeptide calcitonin is secretedby thyroid C-cells during imminenthypercalcemia. It lowers plasmaCa 2+ levels by inhibiting osteoclast activity.Its uses include hypercalcemia andosteoporosis. Remarkably, calcitonin injectionmay produce a sustained analgesiceffect that is not restricted to bonepain.Hypercalcemia can be treated by(1) administering 0.9% NaCl solutionplus furosemide (if necessary) renalexcretion ; (2) the osteoclast inhibitorscalcitonin, plicamycin, or clodronate(a bisphosphonate) bone calciummobilization ; (3) the Ca 2+ chelatorsEDTA sodium or sodium citrate; aswell as (4) glucocorticoids.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Hormones 265ElectricalexcitabilityCa 10 (PO 4 ) 6 (OH) 2Bone trabeculaeHydroxyapatite crystals~1 x 10 -7 MCa 2+ 1 x 10 -3 M Ca 2+ + PO3-4ParafollicularParathyroidcells ofCa 2+ glandsMuscle cell Gland cellOsteoclast~10 -5 MCa 2+Contraction SecretionSkinParathyroid hormone, Ca 2+ , 3-PO 425 25177-Dehydrocholesterol1Cholecalciferol(vitamin D 3 )50-5000µg/day25-Hydroxycholecalciferol(calcifediol)1,25-Dihydroxycholecalciferol(calcitriol)0,5-2µg/dayCod liver oilVit. D-HormonethyroidEffect on cell functionCa Ca~1 x 10 -3 MAlbuminGlobulinCalcitoninParathyroidhormoneCa 2+ + PO 43-A. Calcium homeostasis of the bodyLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
266 Antibacterial DrugsAntibacterial DrugsDrugs for Treating Bacterial InfectionsWhen bacteria overcome the cutaneousor mucosal barriers and penetrate bodytissues, a bacterial infection is present.Frequently the body succeeds in removingthe invaders, without outward signsof disease, by mounting an immune response.If bacteria multiply faster thanthe body’s defenses can destroy them,infectious disease develops with inflammatorysigns, e.g., purulent wound infectionor urinary tract infection. Appropriatetreatment employs substancesthat injure bacteria and thereby preventtheir further multiplication, withoutharming cells of the host organism (1).Apropos nomenclature: antibioticsare produced by microorganisms (fungi,bacteria) and are directed “against life”at any phylogenetic level (prokaryotes,eukaryotes). Chemotherapeutic agentsoriginate from chemical synthesis. Thisdistinction has been lost in current usage.Specific damage to bacteria is particularlypracticable when a substanceinterferes with a metabolic process thatoccurs in bacterial but not in host cells.Clearly this applies to inhibitors of cellwall synthesis, because human and animalcells lack a cell wall. The points ofattack of antibacterial agents are schematicallyillustrated in a grossly simplifiedbacterial cell, as depicted in (2).In the following sections, polymyxinsand tyrothricin are not consideredfurther. These polypeptide antibioticsenhance cell membrane permeability.Due to their poor tolerability, they areprescribed in humans only for topicaluse.The effect of antibacterial drugs canbe observed in vitro (3). Bacteria multiplyin a growth medium under controlconditions. If the medium contains anantibacterial drug, two results can bediscerned: 1. bacteria are killed—bactericidaleffect; 2. bacteria survive, but donot multiply—bacteriostatic effect. Althoughvariations may occur undertherapeutic conditions, different drugscan be classified according to their respectiveprimary mode of action (colortone in 2 and 3).When bacterial growth remains unaffectedby an antibacterial drug, bacterialresistance is present. This may occurbecause of certain metabolic characteristicsthat confer a natural insensitivityto the drug on a particular strain ofbacteria (natural resistance). Dependingon whether a drug affects only a few ornumerous types of bacteria, the termsnarrow-spectrum (e.g., penicillin G) orbroad-spectrum (e.g., tetracyclines)antibiotic are applied. Naturally susceptiblebacterial strains can be transformedunder the influence of antibacterialdrugs into resistant ones (acquiredresistance), when a random genetic alteration(mutation) gives rise to a resistantbacterium. Under the influence ofthe drug, the susceptible bacteria dieoff, whereas the mutant multiplies unimpeded.The more frequently a givendrug is applied, the more probable theemergence of resistant strains (e.g., hospitalstrains with multiple resistance)!Resistance can also be acquiredwhen DNA responsible for nonsusceptibility(so-called resistance plasmid) ispassed on from other resistant bacteriaby conjugation or transduction.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antibacterial Drugs 267Bacterialinvasion:infectionAntibacterialdrugs1.ImmunedefensesSelectiveantibacterialtoxicityBody cellsBacteriaPenicillinsCephalosporinsBacitracinVancomycinPolymyxinsTyrothricinCell wallTetrahydrofolatesynthesisDNARNAProteinCellmembrane2.BacteriumSulfonamidesTrimethoprimRifampin"Gyrase-inhibitors"NitroimidazolesTetracyclinesAminoglycosidesChloramphenicolErythromycinClindamycin1 dayResistanceAntibioticInsensitive strainBactericidal3.BacteriostaticA. Principles of antibacterial therapySensitive strain withresistant mutantSelectionLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
268 Antibacterial DrugsInhibitors of Cell Wall SynthesisIn most bacteria, a cell wall surroundsthe cell like a rigid shell that protectsagainst noxious outside influences andprevents rupture of the plasma membranefrom a high internal osmoticpressure. The structural stability of thecell wall is due mainly to the murein(peptidoglycan) lattice. This consists ofbasic building blocks linked together toform a large macromolecule. Each basicunit contains the two linked aminosugarsN-acetylglucosamine and N-acetylmuramylacid; the latter bears a peptidechain. The building blocks are synthesizedin the bacterium, transported outwardthrough the cell membrane, andassembled as illustrated schematically.The enzyme transpeptidase cross-linksthe peptide chains of adjacent aminosugarchains.Inhibitors of cell wall synthesisare suitable antibacterial agents, becauseanimal and human cells lack a cellwall. They exert a bactericidal action ongrowing or multiplying germs. Membersof this class include β-lactam antibioticssuch as the penicillins and cephalosporins,in addition to bacitracin andvancomycin.Penicillins (A). The parent substanceof this group is penicillin G (benzylpenicillin).It is obtained from culturesof mold fungi, originally from Penicilliumnotatum. Penicillin G containsthe basic structure common to all penicillins,6-amino-penicillanic acid (p.271, 6-APA), comprised of a thiazolidineand a 4-membered β-lactam ring. 6-APA itself lacks antibacterial activity.Penicillins disrupt cell wall synthesis byinhibiting transpeptidase. When bacteriaare in their growth and replicationphase, penicillins are bactericidal; dueto cell wall defects, the bacteria swelland burst.Penicillins are generally well tolerated;with penicillin G, the daily dosecan range from approx. 0.6 g i.m. (= 10 6international units, 1 Mega I.U.) to 60 gby infusion. The most important adverseeffects are due to hypersensitivity(incidence up to 5%), with manifestationsranging from skin eruptions toanaphylactic shock (in less than 0.05% ofpatients). Known penicillin allergy is acontraindication for these drugs. Becauseof an increased risk of sensitization,penicillins must not be used locally.Neurotoxic effects, mostly convulsionsdue to GABA antagonism, may occurif the brain is exposed to extremelyhigh concentrations, e.g., after rapid i.v.injection of a large dose or intrathecalinjection.Penicillin G undergoes rapid renalelimination mainly in unchanged form(plasma t 1/2 ~ 0.5 h). The duration ofthe effect can be prolonged by:1. Use of higher doses, enabling plasmalevels to remain above the minimallyeffective antibacterial concentration;2. Combination with probenecid. Renalelimination of penicillin occurschiefly via the anion (acid)-secretorysystem of the proximal tubule (-COOHof 6-APA). The acid probenecid (p. 316)competes for this route and thus retardspenicillin elimination;3. Intramuscular administration indepot form. In its anionic form (-COO - )penicillin G forms poorly water-solublesalts with substances containing a positivelycharged amino group (procaine,p. 208; clemizole, an antihistamine;benzathine, dicationic). Depending onthe substance, release of penicillin fromthe depot occurs over a variable interval.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antibacterial Drugs 269Cell wallCell membraneBacteriumCross-linkedbytranspeptidasePenicillin GInhibition ofcell wall synthesisAmino acidchainSugarHumanPenicillinallergyCell wallbuilding blockAntibodyFungusPenicillium notatumNeurotoxicityat veryhigh dosagePlasma concentration3 x DoseMinimalbactericidalconcentrationTimeProbenecidAnionsecretorysystemPenicillinDuration of action (d)~1~2~7-28+-ProcainePenicillin+-ClemizolePenicillinBenzathine2 Penicillins+-+Increasing the doseCombination with probenecidDepot preparationsA. Penicillin G: structure and origin; mode of action of penicillins; methodsfor prolonging duration of actionLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
270 Antibacterial DrugsAlthough very well tolerated, penicillinG has disadvantages (A) that limitits therapeutic usefulness: (1) It is inactivatedby gastric acid, which cleavesthe β-lactam ring, necessitating parenteraladministration. (2) The β-lactamring can also be opened by bacterial 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,gram-negative cocci, and spirochetes,many gram-negative pathogensare unaffected.Derivatives with a different substituenton 6-APA possess advantages(B): (1) Acid resistance permits oral administration,provided that enteral absorptionis possible. All derivativesshown in (B) can be given orally. PenicillinV (phenoxymethylpenicillin) exhibitsantibacterial properties similar tothose of penicillin G. (2) Due to theirpenicillinase resistance, isoxazolylpenicillins(oxacillin dicloxacillin, flucloxacillin)are suitable for the (oral) treatmentof infections caused by penicillinaseproducingstaphylococci. (3) Extendedactivity spectrum: The aminopenicillinamoxicillin is active against many gramnegativeorganisms, e.g., coli bacteria orSalmonella typhi. It can be protectedfrom destruction by penicillinase bycombination with inhibitors of penicillinase(clavulanic acid, sulbactam, tazobactam).The structurally close congener ampicillin(no 4-hydroxy group) has a similaractivity spectrum. However, becauseit is poorly absorbed (
Antibacterial Drugs 2716-Aminopenicillanic acidPenicillin GAcid sensitivityPenicillinasesensitivityPenicillinaseStaphylococciSalmonella typhiE. coliNarrow-action spectrumActiveGram-positive Gram-negativeNot activeGonococciPneumococciStreptococciA. Disadvantages of penicillin GAcidPenicillinaseSpectrumConcentration neededto inhibit penicillin G-sensitive bacteriaPenicillin VResistantSensitiveNarrowOxacillinResistantResistantNarrowCefalexinResistantAmoxicillinB. Derivatives of penicillin GResistantBroadH + Cl - ResistantResistant,but sensitivetocephalosporinaseBroadC. CephalosporinLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
272 Antibacterial DrugsInhibitors of Tetrahydrofolate SynthesisTetrahydrofolic acid (THF) is a co-enzymein the synthesis of purine basesand thymidine. These are constituentsof DNA and RNA and required for cellgrowth and replication. Lack of THFleads to inhibition of cell proliferation.Formation of THF from dihydrofolate(DHF) is catalyzed by the enzyme dihydrofolatereductase. DHF is made fromfolic acid, a vitamin that cannot be synthesizedin the body, but must be takenup from exogenous sources. Most bacteriado not have a requirement for folate,because they are capable of synthesizingfolate, more precisely DHF, fromprecursors. Selective interference withbacterial biosynthesis of THF can beachieved with sulfonamides and trimethoprim.Sulfonamides structurally resemblep-aminobenzoic acid (PABA), a precursorin bacterial DHF synthesis. Asfalse substrates, sulfonamides competitivelyinhibit utilization of PABA, henceDHF synthesis. Because most bacteriacannot take up exogenous folate, theyare depleted of DHF. Sulfonamides thuspossess bacteriostatic activity against abroad spectrum of pathogens. Sulfonamidesare produced by chemical synthesis.The basic structure is shown in(A). Residue R determines the pharmacokineticproperties of a given sulfonamide.Most sulfonamides are well absorbedvia the enteral route. They aremetabolized to varying degrees andeliminated through the kidney. Rates ofelimination, hence duration of effect,may vary widely. Some members arepoorly absorbed from the gut and arethus suitable for the treatment of bacterialbowel infections. Adverse effectsmay include, among others, allergic reactions,sometimes with severe skindamage, displacement of other plasmaprotein-bound drugs or bilirubin in neonates(danger of kernicterus, hence contraindicationfor the last weeks of gestationand in the neonate). Because of thefrequent emergence of resistant bacteria,sulfonamides are now rarely used.Introduced in 1935, they were the firstbroad-spectrum chemotherapeutics.Trimethoprim inhibits bacterialDHF reductase, the human enzyme beingsignificantly less sensitive than thebacterial one (rarely bone marrow depression).A 2,4-diaminopyrimidine, trimethoprim,has bacteriostatic activityagainst a broad spectrum of pathogens.It is used mostly as a component of cotrimoxazole.Co-trimoxazole is a combination oftrimethoprim and the sulfonamide sulfamethoxazole.Since THF synthesis isinhibited at two successive steps, theantibacterial effect of co-trimoxazole isbetter than that of the individual components.Resistant pathogens are infrequent;a bactericidal effect may occur.Adverse effects correspond to those ofthe components.Although initially developed as anantirheumatic agent (p. 320), sulfasalazine(salazosulfapyridine) is used mainlyin the treatment of inflammatorybowel disease (ulcerative colitis andterminal ileitis or Crohn’s disease). Gutbacteria split this compound into thesulfonamide sulfapyridine and mesalamine(5-aminosalicylic acid). The latteris probably the anti-inflammatory agent(inhibition of synthesis of chemotacticsignals for granulocytes, and of H 2O 2formation in mucosa), but must bepresent on the gut mucosa in high concentrations.Coupling to the sulfonamideprevents premature absorptionin upper small bowel segments. Thecleaved-off sulfonamide can be absorbedand may produce typical adverseeffects (see above).Dapsone (p. 280) has several therapeuticuses: besides treatment of leprosy,it is used for prevention/prophylaxisof malaria, toxoplasmosis, and actinomycosis.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antibacterial Drugs 273p-Aminobenzoic acidSulfonamidesFolic acidR determinespharmacokinetics(Vitamin)Duration of effectDihydrofolicacid(DHF)Sulfisoxazole6 hoursSulfamethoxazole12 hoursSulfalene7 daysDosing intervalDHF-ReductaseCo-trimoxazole =Tetrahydro- folic acidTrimethoprimCombination ofTrimethoprim andSulfamethoxazoleSulfasalazine(not absorbable)Synthesis ofpurinesThymidineBacteriumCleavage byintestinal bacteriaHuman cellMesalamine Sulfapyridine(absorbable)A. Inhibitors of tetrahydrofolate synthesisLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
274 Antibacterial DrugsInhibitors of DNA FunctionDeoxyribonucleic acid (DNA) serves as atemplate for the synthesis of nucleic acids.Ribonucleic acid (RNA) executesprotein synthesis and thus permits cellgrowth. Synthesis of new DNA is a prerequisitefor cell division. Substancesthat inhibit reading of genetic <strong>info</strong>rmationat the DNA template damage theregulatory center of cell metabolism.The substances listed below are usefulas antibacterial drugs because they donot affect human cells.Gyrase inhibitors. The enzyme gyrase(topoisomerase II) permits the orderlyaccommodation of a ~1000 µmlongbacterial chromosome in a bacterialcell of ~1 µm. Within the chromosomalstrand, double-stranded DNA has adouble helical configuration. The former,in turn, is arranged in loops thatare shortened by supercoiling. The gyrasecatalyzes this operation, as illustrated,by opening, underwinding, andclosing the DNA double strand such thatthe full loop need not be rotated.Derivatives of 4-quinolone-3-carboxylicacid (green portion of ofloxac<strong>info</strong>rmula) are inhibitors of bacterial gyrases.They appear to prevent specificallythe resealing of opened strands andthereby act bactericidally. These agentsare absorbed after oral ingestion. Theolder drug, nalidixic acid, affects exclusivelygram-negative bacteria and attainseffective concentrations only inurine; it is used as a urinary tract antiseptic.Norfloxacin has a broader spectrum.<strong>Of</strong>loxacin, ciprofloxacin, andenoxacin, and others, also yield systemicallyeffective concentrations and areused for infections of internal organs.Besides gastrointestinal problemsand allergy, adverse effects particularlyinvolve the CNS (confusion, hallucinations,seizures). Since they can damageepiphyseal chondrocytes and joint cartilagesin laboratory animals, gyrase inhibitorsshould not be used during pregnancy,lactation, and periods of growth.Azomycin (nitroimidazole) derivatives,such as metronidazole, damageDNA by complex formation or strandbreakage. This occurs in obligate anaerobes,i.e., bacteria growing under O 2exclusion. Under these conditions, conversionto reactive metabolites that attackDNA 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 andurethritis) and Entamoeba histolytica(causative agent of large bowel inflammation,amebic dysentery, and hepaticabscesses). Metronidazole is well absorbedvia the enteral route; it is alsogiven i.v. or topically (vaginal insert).Because metronidazole is consideredpotentially mutagenic, carcinogenic,and teratogenic in the human, it shouldnot be used longer than 10 d, if possible,and be avoided during pregnancy andlactation. Timidazole may be consideredequivalent to metronidazole.Rifampin inhibits the bacterial enzymethat catalyzes DNA template-directedRNA transcription, i.e., DNA-dependentRNA polymerase. Rifampin actsbactericidally against mycobacteria (M.tuberculosis, M. leprae), as well as manygram-positive and gram-negative bacteria.It is well absorbed after oral ingestion.Because resistance may developwith frequent usage, it is restricted tothe treatment of tuberculosis and leprosy(p. 280).Rifampin is contraindicated in thefirst trimester of gestation and duringlactation.Rifabutin resembles rifampin butmay be effective in infections resistantto the latter.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antibacterial Drugs 275123Gyrase inhibitors4-Quinolone-3-carboxylatederivates,e. g.ofloxacin4Twisting byopening, underwinding,and closureof DNA strandGyraseDNA-double helixIndication: TBBacterialchromosomeDNA-dependentRNA polymeraseRifampicinStreptomycesspeciesDamageto DNARNATrichomonas infectionNitroimidazoleAmebic infectionAnaerobicbacteriae. g., metronidazoleA. Antibacterial drugs acting on DNALüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
276 Antibacterial DrugsInhibitors of Protein SynthesisProtein synthesis means translationinto a peptide chain of a genetic messagefirst copied (transcribed) into m-RNA (p. 274). Amino acid (AA) assemblyoccurs at the ribosome. Delivery of aminoacids to m-RNA involves differenttransfer RNA molecules (t-RNA), each ofwhich binds a specific AA. Each t-RNAbears an “anticodon” nucleobase tripletthat is complementary to a particularm-RNA coding unit (codon, consisting of3 nucleobases.Incorporation of an AA normally involvesthe following steps (A):1. The ribosome “focuses” two codonson m-RNA; one (at the left) hasbound its t-RNA-AA complex, the AAhaving already been added to the peptidechain; the other (at the right) isready to receive the next t-RNA-AAcomplex.2. After the latter attaches, the AAsof the two adjacent complexes arelinked by the action of the enzyme peptidesynthetase (peptidyltransferase).Concurrently, AA and t-RNA of the leftcomplex disengage.3. The left t-RNA dissociates fromm-RNA. The ribosome can advancealong the m-RNA strand and focus onthe next codon.4. Consequently, the right t-RNA-AA complex shifts to the left, allowingthe next complex to be bound at theright.These individual steps are susceptibleto inhibition by antibiotics of differentgroups. The examples shown originateprimarily from Streptomyces bacteria,some of the aminoglycosides alsobeing derived from Micromonosporabacteria.1a. Tetracyclines inhibit the bindingof t-RNA-AA complexes. Their actionis bacteriostatic and affects a broadspectrum of pathogens.1b. Aminoglycosides induce thebinding of “wrong” t-RNA-AA complexes,resulting in synthesis of false proteins.Aminoglycosides are bactericidal.Their activity spectrum encompassesmainly gram-negative organisms.Streptomycin and kanamycin are usedpredominantly in the treatment of tuberculosis.Note on spelling: -mycin designatesorigin from Streptomyces species; -micin(e.g., gentamicin) from Micromonosporaspecies.2. Chloramphenicol inhibits peptidesynthetase. It has bacteriostatic activityagainst a broad spectrum ofpathogens. The chemically simple moleculeis now produced synthetically.3. Erythromycin suppresses advancementof the ribosome. Its action ispredominantly bacteriostatic and directedagainst gram-positve organisms.For oral administration, the acid-labilebase (E) is dispensed as a salt (E. stearate)or an ester (e.g., E. succinate).Erythromycin is well tolerated. It is asuitable substitute in penicillin allergyor resistance. Azithromycin, clarithromycin,and roxithromycin are derivativeswith greater acid stability and betterbioavailability. The compounds mentionedare the most important membersof the macrolide antibiotic group, whichincludes josamycin and spiramycin. Anunrelated action of erythromycin is itsmimicry of the gastrointestinal hormonemotiline ( interprandial bowelmotility).Clindamycin has antibacterial activitysimilar to that of erythromycin. Itexerts a bacteriostatic effect mainly ongram-positive aerobic, as well as on anaerobicpathogens. Clindamycin is asemisynthetic chloro analogue of lincomycin,which derives from a Streptomycesspecies. Taken orally, clindamycinis better absorbed than lincomycin,has greater antibacterial efficacy and isthus preferred. Both penetrate well intobone tissue.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antibacterial Drugs 277mRNARibosomePeptide chaintRNATetracyclinesAmino acidInsertion ofincorrectamino acidAminoglycosidesDoxycyclineTobramycinChloramphenicolPeptidesynthetaseChloramphenicolErythromycinErythromycinStreptomyces speciesA. Protein synthesis and modes of action of antibacterial drugsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
278 Antibacterial DrugsTetracyclines are absorbed fromthe gastrointestinal tract to differing degrees,depending on the substance, absorptionbeing nearly complete fordoxycycline and minocycline. Intravenousinjection is rarely needed (rolitetracyclineis available only for i.v. administration).The most common unwantedeffect is gastrointestinal upset(nausea, vomiting, diarrhea, etc.) due to(1) a direct mucosal irritant action ofthese substances and (2) damage to thenatural bacterial gut flora (broad-spectrumantibiotics) allowing colonizationby pathogenic organisms, includingCandida fungi. Concurrent ingestion ofantacids or milk would, however, be inappropriatebecause tetracyclines forminsoluble complexes with plurivalentcations (e.g., Ca 2+ , Mg 2+ , Al 3+ , Fe 2+/3+ ) resultingin their inactivation; that is, absorbability,antibacterial activity, andlocal irritant action are abolished. Theability to chelate Ca 2+ accounts for thepropensity of tetracyclines to accumulatein growing teeth and bones. As a result,there occurs an irreversible yellowbrowndiscoloration of teeth and a reversibleinhibition of bone growth. Becauseof these adverse effects, tetracyclineshould not be given after the secondmonth of pregnancy and not prescribedto children aged 8 y and under. Otheradverse effects are increased photosensitivityof the skin and hepatic damage,mainly after i.v. administration.The broad-spectrum antibioticchloramphenicol is completely absorbedafter oral ingestion. It undergoeseven distribution in the body and readilycrosses diffusion barriers such as theblood-brain barrier. Despite these advantageousproperties, use of chloramphenicolis rarely indicated (e.g., in CNSinfections) because of the danger ofbone marrow damage. Two types of bonemarrow depression can occur: (1) adose-dependent, toxic, reversible formmanifested during therapy and, (2) afrequently fatal form that may occur aftera latency of weeks and is not dosedependent. Due to high tissue penetrability,the danger of bone marrow depressionmust also be taken into accountafter local use (e.g., eye drops).Aminoglycoside antibiotics consistof glycoside-linked amino-sugars(cf. gentamicin C 1α, a constituent of thegentamicin mixture). They contain numeroushydroxyl groups and aminogroups that can bind protons. Hence,these compounds are highly polar,poorly membrane permeable, and notabsorbed enterally. Neomycin and paromomycinare given orally to eradicateintestinal bacteria (prior to bowel surgeryor for reducing NH 3 formation bygut bacteria in hepatic coma). Aminoglycosidesfor the treatment of seriousinfections must be injected (e.g., gentamicin,tobramycin, amikacin, netilmicin,sisomycin). In addition, local inlaysof a gentamicin-releasing carrier can beused in infections of bone or soft tissues.Aminoglycosides gain access to the bacterialinterior by the use of bacterialtransport systems. In the kidney, theyenter the cells of the proximal tubulesvia an uptake system for oligopeptides.Tubular cells are susceptible to damage(nephrotoxicity, mostly reversible). Inthe inner ear, sensory cells of the vestibularapparatus and Corti’s organ may beinjured (ototoxicity, in part irreversible).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antibacterial Drugs 279TetracyclinesChloramphenicolInactivation bychelation ofCa 2+ , Al 3+ etc.Advantage:good penetrationthrough barriersIrritation ofmucousmembranesAbsorptionAntibacterialeffect ongut floraChelationDisadvantage:bone marrowtoxicitye.g.,neomycinGentamicin C 1aCochlear andvestibularHigh hydrophilicityototoxicityno passive diffusionthrough membranes H +H + H +BasicoligopeptidesTransport systemBacteriumNephrotoxicityNo absorption"bowel sterilization"A. Aspects of the therapeutic use of tetracyclines, chloramphenicol, andaminoglycosidesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
280 Antibacterial DrugsDrugs for Treating MycobacterialInfectionsMycobacteria are responsible for twodiseases: tuberculosis, mostly caused byM. tuberculosis, and leprosy due to M. leprae.The therapeutic principle applicableto both is combined treatmentwith two or more drugs. Combinationtherapy prevents the emergence of resistantmycobacteria. Because the antibacterialeffects of the individual substancesare additive, correspondinglysmaller doses are sufficient. Therefore,the risk of individual adverse effects islowered. Most drugs are active againstonly one of the two diseases.Antitubercular Drugs (1)Drugs of choice are: isoniazid, rifampin,ethambutol, along with streptomycinand pyrazinamide. Less well tolerated,second-line agents include: p-aminosalicylicacid, cycloserine, viomycin, kanamycin,amikacin, capreomycin, ethionamide.Isoniazid is bactericidal againstgrowing M. tuberculosis. Its mechanismof action remains unclear. (In the bacteriumit is converted to isonicotinic acid,which is membrane impermeable,hence likely to accumulate intracellularly.)Isoniazid is rapidly absorbed afteroral administration. In the liver, it is inactivatedby acetylation, the rate ofwhich is genetically controlled andshows a characteristic distribution indifferent ethnic groups (fast vs. slowacetylators). Notable adverse effectsare: peripheral neuropathy, optic neuritispreventable by administration ofvitamin B 6 (pyridoxine); hepatitis, jaundice.Rifampin. Source, antibacterial activity,and routes of administration aredescribed on p. 274. Albeit mostly welltolerated, this drug may cause severaladverse effects including hepatic damage,hypersensitivity with flu-likesymptoms, disconcerting but harmlessred/orange discoloration of body fluids,and enzyme induction (failure of oralcontraceptives). Concerning rifabutinsee p. 274.Ethambutol. The cause of its specificantitubercular action is unknown.Ethambutol is given orally. It is generallywell tolerated, but may cause dosedependentdamage to the optic nervewith disturbances of vision (red/greenblindness, visual field defects).Pyrazinamide exerts a bactericidalaction by an unknown mechanism. It isgiven orally. Pyrazinamide may impairliver function; hyperuricemia resultsfrom inhibition of renal urate elimination.Streptomycin must be given i.v. (pp.278ff) like other aminoglycoside antibiotics.It damages the inner ear and thelabyrinth. Its nephrotoxicity is comparativelyminor.Antileprotic Drugs (2)Rifampin is frequently given in combinationwith one or both of the followingagents:Dapsone is a sulfone that, like sulfonamides,inhibits dihydrofolate synthesis(p. 272). It is bactericidal againstsusceptible strains of M. leprae. Dapsoneis given orally. The most frequent adverseeffect is methemoglobinemia withaccelerated erythrocyte degradation(hemolysis).Clofazimine is a dye with bactericidalactivity against M. leprae and antiinflammatoryproperties. It is givenorally, but is incompletely absorbed. Becauseof its high lipophilicity, it accumulatesin adipose and other tissuesand leaves the body only rather slowly(t 1/2 ~ 70 d). Red-brown skin pigmentationis an unwanted effect, particularlyin fair-skinned patients.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antibacterial Drugs 281Reduced risk ofbacterial resistanceCombination therapyReduction of dose and ofrisk of adverse reactionsIsoniazidPyrazinamideCNS damageand peripheralneuropathy(Vit. B 6 -administration)Liver damageEthambutolMycobacteriumtuberculosisIsonicotinic acidLiver damageStreptomycinan aminoglycosideantibioticOptic nerve damageNicotinic acidRifampin12Vestibular andcochlearototoxicityLiver damageand enzyme inductionp-Aminobenzoic acidClofazimineDapsoneFolatesynthesisHemolysisMycobacteriumlepraeSkin discolorationA. Drugs used to treat infections with mycobacteria (1. tuberculosis, 2. leprosy)Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
282 Antifungal DrugsDrugs Used in the Treatment ofFungal InfectionsInfections due to fungi are usually confinedto the skin or mucous membranes:local or superficial mycosis. However, inimmune deficiency states, internal organsmay also be affected: systemic ordeep mycosis.Mycoses are most commonly due todermatophytes, which affect the skin,hair, and nails following external infection.Candida albicans, a yeast organismnormally found on body surfaces, maycause infections of mucous membranes,less frequently of the skin or internal organswhen natural defenses are impaired(immunosuppression, or damageof microflora by broad-spectrum antibiotics).Imidazole derivatives inhibit ergosterolsynthesis. This steroid forms anintegral constituent of cytoplasmicmembranes of fungal cells, analogous tocholesterol in animal plasma membranes.Fungi exposed to imidazole derivativesstop growing (fungistatic effect)or die (fungicidal effect). The spectrumof affected fungi is very broad. Becausethey are poorly absorbed andpoorly tolerated systemically, mostimidazoles are suitable only for topicaluse (clotrimazole, econazole oxiconazole,isoconazole, bifonazole, etc.). Rarely, thisuse may result in contact dermatitis. Miconazoleis given locally, or systemicallyby short-term infusion (despite its poortolerability). Because it is well absorbed,ketoconazole is available for oral administration.Adverse effects are rare; however,the possibility of fatal liver damageshould be noted. Remarkably, ketoconazolemay inhibit steroidogenesis(gonadal and adrenocortical hormones).Fluconazole and itraconazole are newer,orally effective triazole derivatives. Thetopically active allylamine naftidineand the morpholine amorolfine also inhibitergosterol synthesis, albeit at anotherstep.The polyene antibiotics, amphotericinB and nystatin, are of bacterialorigin. They insert themselves into fungalcell membranes (probably next toergosterol molecules) and cause formationof hydrophilic channels. The resultantincrease in membrane permeability,e.g., to K + ions, accounts for the fungicidaleffect. Amphotericin B is activeagainst most organisms responsible forsystemic mycoses. Because of its poorabsorbability, it must be given by infusion,which is, however, poorly tolerated(chills, fever, CNS disturbances, impairedrenal function, phlebitis at theinfusion site). Applied topically to skinor mucous membranes, amphotericin Bis useful in the treatment of candidalmycosis. Because of the low rate of enteralabsorption, oral administration inintestinal candidiasis can be considereda topical treatment. Nystatin is used onlyfor topical therapy.Flucytosine is converted in candidafungi to 5-fluorouracil by the action of aspecific cytosine deaminase. As an antimetabolite,this compound disruptsDNA and RNA synthesis (p. 298), resultingin a fungicidal effect. Given orally,flucytosine is rapidly absorbed. It is welltolerated and often combined with amphotericinB to allow dose reduction ofthe latter.Griseofulvin originates from moldsand has activity only against dermatophytes.Presumably, it acts as a spindlepoison to inhibit fungal mitosis. Althoughtargeted against local mycoses,griseofulvin must be used systemically.It is incorporated into newly formedkeratin. “Impregnated” in this manner,keratin becomes unsuitable as a fungalnutrient. The time required for the eradicationof dermatophytes correspondsto the renewal period of skin, hair, ornails. Griseofulvin may cause uncharacteristicadverse effects. The need forprolonged administration (severalmonths), the incidence of side effects,and the availability of effective and safealternatives have rendered griseofulvintherapeutically obsolete.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antifungal Drugs 283Cell wallCytoplasmic membraneImidazole derivativese.g., clotrimazoleErgosterolSynthesisGriseofulvinMitotic spindleDNA/RNAmetabolismIncorporation intogrowing skin, hair, nails"Impregnation effect"25-50 weeksMold fungi5-FluoruracilUracil2-4 weeksFungal cellCytosineDeaminasePolyene AntibioticsAmphotericin BStreptomyces bacteriaNystatinFlucytosineA. Antifungal drugsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
284 Antiviral DrugsChemotherapy of Viral InfectionsViruses essentially consist of geneticmaterial (nucleic acids, green strands in(A) and a capsular envelope made up ofproteins (blue hexagons), often with acoat (gray ring) of a phospholipid (PL)bilayer with embedded proteins (smallblue bars). They lack a metabolic systembut depend on the infected cell for theirgrowth and replication. Targeted therapeuticsuppression of viral replicationrequires selective inhibition of thosemetabolic processes that specificallyserve viral replication in infected cells.To date, this can be achieved only to alimited extent.Viral replication as exemplifiedby Herpes simplex viruses (A): (1) Theviral particle attaches to the host cellmembrane (adsorption) by linking itscapsular glycoproteins to specific structuresof the cell membrane. (2) The viralcoat fuses with the plasmalemma of thehost cell and the nucleocapsid (nucleicacid plus capsule) enters the cell interior(penetration). (3) The capsule opens(“uncoating”) near the nuclear poresand viral DNA moves into the cell nucleus.The genetic material of the virus cannow direct the cell’s metabolic system.(4a) Nucleic acid synthesis: The geneticmaterial (DNA in this instance) is replicatedand RNA is produced for the purposeof protein synthesis. (4b) The proteinsare used as “viral enzymes” catalyzingviral multiplication (e.g., DNApolymerase and thymidine kinase), ascapsomers, or as coat components, orare incorporated into the host cellmembrane. (5) Individual componentsare assembled into new virus particles(maturation). (6) Release of daughter virusesresults in spread of virus insideand outside the organism. With herpesviruses, replication entails host cell destructionand development of diseasesymptoms.Antiviral mechanisms (A). The organismcan disrupt viral replicationwith the aid of cytotoxic T-lymphocytesthat recognize and destroy virus-producingcells (viral surface proteins) orby means of antibodies that bind to andinactivate extracellular virus particles.Vaccinations are designed to activatespecific immune defenses.Interferons (IFN) are glycoproteinsthat, among other products, are releasedfrom virus-infected cells. Inneighboring cells, interferon stimulatesthe production of “antiviral proteins.”These inhibit the synthesis of viral proteinsby (preferential) destruction of viralDNA or by suppressing its translation.Interferons are not directed againsta specific virus, but have a broad spectrumof antiviral action that is, however,species-specific. Thus, interferon for usein humans must be obtained from cellsof human origin, such as leukocytes(IFN-α), fibroblasts (IFN-β), or lymphocytes(IFN-γ). Interferons are also usedto treat certain malignancies and autoimmunedisorders (e.g., IFN-α for chronichepatitis C and hairy cell leukemia;IFN-β for severe herpes virus infectionsand multiple sclerosis).Virustatic antimetabolites are“false” DNA building blocks (B) or nucleosides.A nucleoside (e.g., thymidine)consists of a nucleobase (e.g., thymine)and the sugar deoxyribose. In antimetabolites,one of the components is defective.In the body, the abnormal nucleosidesundergo bioactivation by attachmentof three phosphate residues(p. 287).Idoxuridine and congeners are incorporatedinto DNA with deleteriousresults. This also applies to the synthesisof human DNA. Therefore, idoxuridineand analogues are suitable only for topicaluse (e.g., in herpes simplex keratitis).Vidarabine inhibits virally inducedDNA polymerase more strongly than itdoes the endogenous enzyme. Its use isnow limited to topical treatment of severeherpes simplex infection. Beforethe introduction of the better toleratedacyclovir, vidarabine played a majorpart in the treatment of herpes simplexencephalitis.Among virustatic antimetabolites,acyclovir (A) has both specificity of thehighest degree and optimal tolerability,Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antiviral Drugs 285Virusinfected1. AdsorptionGlycoproteinInterferonSpecific immunedefensee.g., cytotoxicT-lymphocytesProteins withantigenic propertiesAntiviralproteins2. Penetration3.UncoatingDNACapsuleEnvelope4a. Nucleic acidsynthesisRNA4b. ProteinViral DNApolymeraseDNA5.6. ReleaseA. Virus multiplication and modes of action of antiviral agentsCorrect:ThymidineThymineAntimetabolites = incorrect DNA building blocksIncorrect: R: - I Idoxuridine- CF 3 Trifluridine- C 2 H 2 EdoxudineDesoxyriboseIncorrect:Insertion intoDNA insteadof thymidineVidarabine Acyclovir GanciclovirAdenineGuanineArabinoseInhibition of viral DNA polymeraseB. Chemical structure of virustatic antimetabolitesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
286 Antiviral Drugsbecause it undergoes bioactivation onlyin infected cells, where it preferentiallyinhibits viral DNA synthesis. (1) A virallycoded thymidine kinase (specific to H.simplex and varicella-zoster virus) performsthe initial phosphorylation step;the remaining two phosphate residuesare attached by cellular kinases. (2) Thepolar phosphate residues render acyclovirtriphosphate membrane impermeableand cause it to accumulate in infectedcells. (3) Acyclovir triphosphateis a preferred substrate of viral DNApolymerase; it inhibits enzyme activityand, following its incorporation into viralDNA, induces strand breakage becauseit lacks the 3’-OH group of deoxyribosethat is required for the attachmentof additional nucleotides. The hightherapeutic value of acyclovir is evidentin severe infections with H. simplex viruses(e.g., encephalitis, generalized infection)and varicella-zoster viruses(e.g., severe herpes zoster). In these cases,it can be given by i.v. infusion. Acyclovirmay also be given orally despiteits incomplete (15%–30%) enteral absorption.In addition, it has topical uses.Because host DNA synthesis remainsunaffected, adverse effects do not includebone marrow depression. Acycloviris eliminated unchanged in urine(t 1/2 ~ 2.5 h).Valacyclovir, the L-valyl ester ofacyclovir, is a prodrug that can be administeredorally in herpes zoster infections.Its absorption rate is approx.twice that of acyclovir. During passagethrough the intestinal wall and liver, thevaline residue is cleaved by esterases,generating acyclovir.Famcyclovir is an antiherpetic prodrugwith good bioavailability whengiven orally. It is used in genital herpesand herpes zoster. Cleavage of two acetategroups from the “false sugar” andoxidation of the purine ring to guanineyields penciclovir, the active form. Thelatter differs from acyclovir with respectto its “false sugar” moiety, but mimics itpharmacologically. <strong>Bio</strong>activation ofpenciclovir, like that of acyclovir, involvesformation of the triphosphorylatedantimetabolite via virally inducedthymidine kinase.Ganciclovir (structure on p. 285) isgiven by infusion in the treatment of severeinfections with cytomegaloviruses(also belonging to the herpes group);these do not induce thymidine kinase,phosphorylation being initiated by adifferent viral enzyme. Ganciclovir isless well tolerated and, not infrequently,produces leukopenia and thrombopenia.Foscarnet represents a diphosphateanalogue.As shown in (A), incorporation ofnucleotide into a DNA strand entailscleavage of a diphosphate residue. Foscarnet(B) inhibits DNA polymerase byinteracting with its binding site for thediphosphate group. Indications: systemictherapy of severe cytomegaly infectionin AIDS patients; local therapy ofherpes simplex infections.Amantadine (C) specifically affectsthe replication of influenza A (RNA) viruses,the causative agent of true influenza.These viruses are endocytosedinto the cell. Release of viral DNA requiresprotons from the acidic contentof endosomes to penetrate the virus.Presumably, amantadine blocks a channelprotein in the viral coat that permitsinflux of protons; thus, “uncoating” isprevented. Moreover, amantadine inhibitsviral maturation. The drug is alsoused prophylactically and, if possible,must be taken before the outbreak ofsymptoms. It also is an antiparkinsonian(p. 188).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antiviral Drugs 287AcyclovirInfected cell:herpes simplexor varicella-zosterViralthymidinekinaseCellular kinasesViral DNA templateActive metaboliteBaseBaseBaseDNA-chainterminationDNAsynthesisViralDNA polymeraseInhibitionA. Activation of acyclovir and inhibition of viral DNA synthesisBaseInfluenzaA-virusPOOPOEndosomeOOPOOViralDNA polymeraseViral channelproteinH +OCOInhibition ofuncoatingOPOOFoscarnetAmantadineB. Inhibitor of DNA polymerase:B. FoscarnetC. Prophylaxis for viral fluLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
288 Antiviral DrugsDrugs for the Treatment of AIDSReplication of the human immunodeficiencyvirus (HIV), the causativeagent of AIDS, is susceptible to targetedinterventions, because several virusspecificmetabolic steps occur in infectedcells (A). Viral RNA must first be transcribedinto DNA, a step catalyzed by viral“reverse transcriptase.” DoublestrandedDNA is incorporated into thehost genome with the help of viral integrase.Under control by viral DNA, viralreplication can then be initiated, withsynthesis of viral RNA and proteins (includingenzymes such as reverse transcriptaseand integrase, and structuralproteins such as the matrix protein liningthe inside of the viral envelope).These proteins are assembled not individuallybut in the form of polyproteins.These precursor proteins carry an N-terminalfatty acid (myristoyl) residue thatpromotes their attachment to the interiorface of the plasmalemma. As the virusparticle buds off the host cell, it carrieswith it the affected membrane areaas its envelope. During this process, aprotease contained within the polyproteincleaves the latter into individual,functionally active proteins.I. Inhibitors of Reverse TranscriptaseIA. Nucleoside agentsThese substances are analogues of thymine(azidothymidine, stavudine),adenine (didanosine), cytosine (lamivudine,zalcitabine), and guanine (carbovir,a metabolite of abacavir). Theyhave in common an abnormal sugarmoiety. Like the natural nucleosides,they undergo triphosphorylation, givingrise to nucleotides that both inhibit reversetranscriptase and cause strandbreakage following incorporation intoviral DNA.The nucleoside inhibitors differ interms of l) their ability to decrease circulatingHIV load; 2) their pharmacokineticproperties (half life dosinginterval compliance; organ distribution passage through blood-brainbarrier);3) the type of resistance-inducingmutations of the viral genome and therate at which resistance develops; and4) their adverse effects (bone marrowdepression, neuropathy, pancreatitis).IB. Non-nucleoside inhibitorsThe non-nucleoside inhibitors of reversetranscriptase (nevirapine, delavirdine,efavirenz) are not phosphorylated.They bind to the enzyme withhigh selectivity and thus prevent it fromadopting the active conformation. Inhibitionis noncompetitive.II. HIV protease inhibitorsViral protease cleaves precursor proteinsinto proteins required for viralreplication. The inhibitors of this protease(saquinavir, ritonavir, indinavir,and nelfinavir) represent abnormalproteins that possess high antiviral efficacyand are generally well tolerated inthe short term. However, prolonged administrationis associated with occasionallysevere disturbances of lipid andcarbohydrate metabolism. <strong>Bio</strong>transformationof these drugs involves cytochromeP 450 (CYP 3A4) and is thereforesubject to interaction with various otherdrugs inactivated via this route.For the dual purpose of increasingthe effectiveness of antiviral therapyand preventing the development of atherapy-limiting viral resistance, inhibitorsof reverse transcriptase are combinedwith each other and/or with proteaseinhibitors.Combination regimens are designedin accordance with substancespecificdevelopment of resistance andpharmacokinetic parameters (CNSpenetrability, “neuroprotection,” dosingfrequency).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antiviral Drugs 289EnvelopeMatrix proteinRNAReversetranscriptaseIntegraseViral RNADNAInhibitors ofreversetranscriptaseH 3 CONHN OHOCH 2 O+ -N=N=Ne.g., zidovudineViral RNAPolyproteinsInhibitors ofHIV proteaseONNHH 2NOHNOProteaseHOCleavage ofpolypeptideprecursorNH 3CON HCH 3Mature viruse.g., saquinavirCH 3A. Antiretroviral drugsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
290 DisinfectantsDisinfectants and AntisepticsDisinfection denotes the inactivation orkilling of pathogens (protozoa, bacteria,fungi, viruses) in the human environment.This can be achieved by chemicalor physical means; the latter will not bediscussed here. Sterilization refers tothe killing of all germs, whether pathogenic,dormant, or nonpathogenic. Antisepsisrefers to the reduction by chemicalagents of germ numbers on skin andmucosal surfaces.Agents for chemical disinfectionideally should cause rapid, complete,and persistent inactivation of all germs,but at the same time exhibit low toxicity(systemic toxicity, tissue irritancy,antigenicity) and be non-deleterious toinanimate materials. These requirementscall for chemical properties thatmay exclude each other; therefore,compromises guided by the intendeduse have to be made.Disinfectants come from variouschemical classes, including oxidants,halogens or halogen-releasing agents,alcohols, aldehydes, organic acids, phenols,cationic surfactants (detergents)and formerly also heavy metals. The basicmechanisms of action involve denaturationof proteins, inhibition of enzymes,or a dehydration. Effects are dependenton concentration and contacttime.Activity spectrum. Disinfectantsinactivate bacteria (gram-positive >gram-negative > mycobacteria), less effectivelytheir sporal forms, and a few(e.g., formaldehyde) are virucidal.and mixtures of these. Minimal contacttimes should be at least 15 s on skin areaswith few sebaceous glands and atleast 10 min on sebaceous gland-richones.Mucosal disinfection: Germ countscan be reduced by PVP iodine or chlorhexidine(contact time 2 min), althoughnot as effectively as on skin.Wound disinfection can be achievedwith hydrogen peroxide (0.3%–1% solution;short, foaming action on contactwith blood and thus wound cleansing)or with potassium permanganate(0.0015% solution, slightly astringent),as well as PVP iodine, chlorhexidine,and biguanidines.Hygienic and surgical hand disinfection:The former is required after a suspectedcontamination, the latter beforesurgical procedures. Alcohols, mixturesof alcohols and phenols, cationic surfactants,or acids are available for this purpose.Admixture of other agents prolongsduration of action and reducesflammability.Disinfection of instruments: Instrumentsthat cannot be heat- or steamsterilizedcan be precleaned and thendisinfected with aldehydes and detergents.Surface (floor) disinfection employsaldehydes combined with cationic surfactantsand oxidants or, more rarely,acidic or alkalizing agents.Room disinfection: room air andsurfaces can be disinfected by sprayingor vaporizing of aldehydes, providedthat germs are freely accessible.ApplicationsSkin “disinfection.” Reduction of germcounts prior to punctures or surgicalprocedures is desirable if the risk ofwound infection is to be minimized.Useful agents include: alcohols (1- and2-propanol; ethanol 60–90%; iodine-releasingagents like polyvinylpyrrolidone[povidone, PVP]-iodine as a depot formof the active principle iodine, instead ofiodine tincture), cationic surfactants,Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Disinfectants 291Application sites Examples Active principlesInanimate material: durableagainst chemical + physicalmeasuresDisinfection of floorsor excrementPhenolsNaOClCationicsurfactantsDisinfectionof instruments1. Oxidantse. g., hydrogen peroxide,potassium permanganate,peroxycarbonic acids2. HalogensInanimate matter:sensitive to heat,acids, oxidation etc.SkinMucous membranesSkin disinfectionRegulare.g., handsAcute,e.g., before local proceduresIodinetinctureAlcoholsCationic surfactantsAldehydesPhenolsCationic surfactantsDisinfectionof mucous membranesChlorhexidineChlorhexidineWound disinfectionchlorinesodium hypochloriteiodine tincture3. AlcoholsR-OH (R=C 2 -C 6 )e. g., ethanolisopropanol4. Aldehydese. g., formaldehydeglutaraldehyde5. Organic acidse. g., lactic acid6. PhenolsChlorhexidineH 2 O 2KMnO 4Nonhalogenated:e. g., phenylphenoleugenolthymolhalogenated:chlormethylphenolTissueSTOP7. CationicsurfactantsCationic soapsA. DisinfectantsDisinfectants donot afford selectiveinhibition ofbacteriaviruses, or fungie. g., benzalkoniumchlorhexidine8. Heavy metal saltse. g., phenylmercury borateLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
292 Antiparasitic AgentsDrugs for Treating Endo- andEctoparasitic InfestationsAdverse hygienic conditions favor humaninfestation with multicellular organisms(referred to here as parasites).Skin and hair are colonization sites forarthropod ectoparasites, such as insects(lice, fleas) and arachnids (mites).Against these, insecticidal or arachnicidalagents, respectively, can be used.Endoparasites invade the intestines oreven internal organs, and are mostlymembers of the phyla of flatworms androundworms. They are combated withanthelmintics.Anthelmintics. As shown in the table,the newer agents praziquantel andmebendazole are adequate for the treatmentof diverse worm diseases. Theyare generally well tolerated, as are theother agents listed.Insecticides. Whereas fleas can beeffectively dealt with by disinfection ofclothes and living quarters, lice andmites require the topical application ofinsecticides to the infested subject.Chlorphenothane (DDT) kills insectsafter absorption of a very smallamount, e.g., via foot contact withsprayed surfaces (contact insecticide).The cause of death is nervous systemdamage and seizures. In humans DDTcauses acute neurotoxicity only afterabsorption of very large amounts. DDTis chemically stable and degraded in theenvironment and body at extremelyslow rates. As a highly lipophilic substance,it accumulates in fat tissues.Widespread use of DDT in pest controlhas led to its accumulation in foodchains to alarming levels. For this reasonits use has now been banned inmany countries.Lindane is the active γ-isomer ofhexachlorocyclohexane. It also exerts aneurotoxic action on insects (as well ashumans). Irritation of skin or mucousmembranes may occur after topical use.Lindane is active also against intradermalmites (Sarcoptes scabiei, causativeagent of scabies), besides lice and fleas.It is more readily degraded than DDT.Permethrin, a synthetic pyrethroid,exhibits similar anti-ectoparasiticactivity and may be the drug of choicedue to its slower cutaneous absorption,fast hydrolytic inactivation, and rapidrenal elimination.Worms (helminths)Flatworms (platyhelminths)tape worms (cestodes)flukes (trematodes) e.g., Schistosomaspecies (bilharziasis)Roundworms (nematodes)pinworm (Enterobius vermicularis)whipworm (Trichuris trichiura)Ascaris lumbricoidesTrichinella spiralis**Strongyloides stercoralisHookworm (Necator americanus, andAncylostoma duodenale)Anthelmintic drug of choicepraziquantel*praziquantelmebendazole or pyrantel pamoatemebendazolemebendazole or pyrantel pamoatemebendazole and thiabendazolethiabendazolemebendazole or pyrantel pamoatemebendazole or pyrantel pamoate* not for ocular or spinal cord cysticercosis** [thiabendazole: intestinal phase; mebendazole: tissue phase]Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antiparasitic Agents 293Tapewormse.g., beeftapewormLouseSpasm,injury ofintegumentRoundworms,e.g.,ascarisPraziquantelPinwormDamage to nervous system: convulsions, deathChlorphenothane(DDT)FleaMebendazoleHexachlorocyclohexane(Lindane)TrichinellalarvaeScabies miteA. Endo- and ectoparasites: therapeutic agentsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
294 Antiparasitic DrugsAntimalarialsThe causative agents of malaria are plasmodia,unicellular organisms belongingto the order hemosporidia (class protozoa).The infective form, the sporozoite,is inoculated into skin capillaries wheninfected female Anopheles mosquitoes(A) suck blood from humans. The sporozoitesinvade liver parenchymal cellswhere they develop into primary tissueschizonts. After multiple fission, theseschizonts produce numerous merozoitesthat enter the blood. The preerythrocyticstage is symptom free. Inblood, the parasite enters erythrocytes(erythrocytic stage) where it again multipliesby schizogony, resulting in theformation of more merozoites. Ruptureof the infected erythrocytes releases themerozoites and pyrogens. A fever attackensues and more erythrocytes are infected.The generation period for thenext crop of merozoites determines theinterval between fever attacks. WithPlasmodium vivax and P. ovale, there canbe a parallel multiplication in the liver(paraerythrocytic stage). Moreover,some sporozoites may become dormantin the liver as “hypnozoites” before enteringschizogony. When the sexualforms (gametocytes) are ingested by afeeding mosquito, they can initiate thesexual reproductive stage of the cyclethat results in a new generation oftransmittable sporozoites.Different antimalarials selectivelykill the parasite’s different developmentalforms. The mechanism of action isknown for some of them: pyrimethamineand dapsone inhibit dihydrofolatereductase (p. 273), as does chlorguanide(proguanil) via its active metabolite. Thesulfonamide sulfadoxine inhibits synthesisof dihydrofolic acid (p. 272). Chloroquineand quinine accumulate withinthe acidic vacuoles of blood schizontsand inhibit polymerization of heme, thelatter substance being toxic for theschizonts.Antimalarial drug choice takes intoaccount tolerability and plasmodial resistance.Tolerability. The first availableantimalarial, quinine, has the smallesttherapeutic margin. All newer agentsare rather well tolerated.Plasmodium (P.) falciparum, responsiblefor the most dangerous formof malaria, is particularly prone to developdrug resistance. The incidence ofresistant strains rises with increasingfrequency of drug use. Resistance hasbeen reported for chloroquine and alsofor the combination pyrimethamine/sulfadoxine.Drug choice for antimalarialchemoprophylaxis. In areas with a riskof malaria, continuous intake of antimalarialsaffords the best protectionagainst the disease, although notagainst infection. The drug of choice ischloroquine. Because of its slow excretion(plasma t 1/2 = 3d and longer), a singleweekly dose is sufficient. In areaswith resistant P. falciparum, alternativeregimens are chloroquine plus pyrimethamine/sulfadoxine(or proguanil,or doxycycline), the chloroquine analogueamodiaquine, as well as quinineor the better tolerated derivative mefloquine(blood-schizonticidal). Agents activeagainst blood schizonts do not preventthe (symptom-free) hepatic infection,only the disease-causing infectionof erythrocytes (“suppression therapy”).On return from an endemic malaria region,a 2 wk course of primaquine is adequatefor eradication of the late hepaticstages (P. vivax and P. ovale).Protection from mosquito bites(net, skin-covering clothes, etc.) is avery important prophylactic measure.Antimalarial therapy employs thesame agents and is based on the sameprinciples. The blood-schizonticidalhalofantrine is reserved for therapy only.The pyrimethamine-sulfadoxinecombination may be used for initial selftreatment.Drug resistance is accelerating inmany endemic areas; malaria vaccinesmay hold the greatest hope for controlof infection.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antiparasitic Drugs 295SporozoitesPrimaquineHypnozoitePreerythrocytic cycle1-4 weeksHepatocytePrimary tissue schizontProguanilPl. falcip.PyrimethamineMerozoitesOnlyPl. vivaxPl. ovaleErythrocytic cycleErythrocyteBlood ChloroquineschizontMefloquineHalofantrineQuinineProguanilPyrimethamineSulfadoxineFeverFeverPrimaquinenot P. falcip.2 days :Tertian malariaPl. vivax, Pl. ovale3 days:Quartan malariaPl. malariaeNo feverperiodicity:Pernicious malaria:Pl. falciparumGametocytesChloroquineQuinineFeverA. Malaria: stages of the plasmodial life cycle in the human;h i hLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
296 Anticancer DrugsChemotherapy of Malignant TumorsA tumor (neoplasm) consists of cellsthat proliferate independently of thebody’s inherent “building plan.” A malignanttumor (cancer) is present whenthe tumor tissue destructively invadeshealthy surrounding tissue or when dislodgedtumor cells form secondary tumors(metastases) in other organs. Acure requires the elimination of all malignantcells (curative therapy). Whenthis is not possible, attempts can bemade to slow tumor growth and therebyprolong the patient’s life or improvequality of life (palliative therapy).Chemotherapy is faced with the problemthat the malignant cells are endogenousand are not endowed with specialmetabolic properties.Cytostatics (A) are cytotoxic substancesthat particularly affect proliferatingor dividing cells. Rapidly dividingmalignant cells are preferentially injured.Damage to mitotic processes notonly retards tumor growth but may alsoinitiate apoptosis (programmed celldeath). Tissues with a low mitotic rateare largely unaffected; likewise, mosthealthy tissues. This, however, also appliesto malignant tumors consisting ofslowly dividing differentiated cells. Tissuesthat have a physiologically highmitotic rate are bound to be affected bycytostatic therapy. Thus, typical adverseeffects occur:Loss of hair results from injury tohair follicles; gastrointestinal disturbances,such as diarrhea, from inadequatereplacement of enterocyteswhose life span is limited to a few days;nausea and vomiting from stimulation ofarea postrema chemoreceptors (p. 330);and lowered resistance to infection fromweakening of the immune system (p.300). In addition, cytostatics cause bonemarrow depression. Resupply of bloodcells depends on the mitotic activity ofbone marrow stem and daughter cells.When myeloid proliferation is arrested,the short-lived granulocytes are the firstto be affected (neutropenia), then bloodplatelets (thrombopenia) and, finally,the more long-lived erythrocytes (anemia).Infertility is caused by suppressionof spermatogenesis or follicle maturation.Most cytostatics disrupt DNA metabolism.This entails the risk of a potentialgenomic alteration in healthycells (mutagenic effect). Conceivably,the latter accounts for the occurrence ofleukemias several years after cytostatictherapy (carcinogenic effect). Furthermore,congenital malformations are tobe expected when cytostatics must beused during pregnancy (teratogenic effect).Cytostatics possess different mechanismsof action.Damage to the mitotic spindle (B).The contractile proteins of the spindleapparatus must draw apart the replicatedchromosomes before the cell can divide.This process is prevented by theso-called spindle poisons (see also colchicine,p. 316) that arrest mitosis atmetaphase by disrupting the assemblyof microtubules into spindle threads.The vinca alkaloids, vincristine and vinblastine(from the periwinkle plant, Vincarosea) exert such a cell-cycle-specificeffect. Damage to the nervous system isa predicted adverse effect arising frominjury to microtubule-operated axonaltransport mechanisms.Paclitaxel, from the bark of the pacificyew (Taxus brevifolia), inhibits disassemblyof microtubules and inducesatypical ones. Docetaxel is a semisyntheticderivative.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Anticancer Drugs 297Malignant tissuewith numerous mitosesCytostatics inhibitcell divisionHealthy tissuewith few mitosesWanted effect:inhibition oftumor growthLittle effectHealthy tissue withnumerous mitosesLymph nodeDamage to hair follicleHair lossInhibition ofephithelial renewalUnwantedeffectsInhibition oflymphocytemultiplication:immuneweaknessLowered resistance toinfectionBone marrowInhibition ofgranulo-,thrombocyto-,and erythropoiesisDiarrheaGerminalcell damageA. Chemotherapy of tumors: principal and adverse effectsInhibition offormationVincaalkaloidsMicrotubulesof mitotic spindlePaclitaxelInhibition ofdegradationVinca roseaWestern yew treeB. Cytostatics: inhibition of mitosisLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
298 Anticancer DrugsInhibition of DNA and RNA synthesis(A). Mitosis is preceded by replicationof chromosomes (DNA synthesis)and increased protein synthesis (RNAsynthesis). Existing DNA (gray) serves asa template for the synthesis of new(blue) DNA or RNA. De novo synthesismay be inhibited by:Damage to the template (1). Alkylatingcytostatics are reactive compoundsthat transfer alkyl residues intoa covalent bond with DNA. For instance,mechlorethamine (nitrogen mustard) isable to cross-link double-stranded DNAon giving off its chlorine atoms. Correctreading of genetic <strong>info</strong>rmation is therebyrendered impossible. Other alkylatingagents are chlorambucil, melphalan,thio-TEPA, cyclophosphamide (p. 300,320), ifosfamide, lomustine, and busulfan.Specific adverse reactions includeirreversible pulmonary fibrosis due tobusulfan and hemorrhagic cystitiscaused by the cyclophosphamide metaboliteacrolein (preventable by theuroprotectant mesna). Cisplatin binds to(but does not alkylate) DNA strands.Cystostatic antibiotics insert themselvesinto the DNA double strand; thismay lead to strand breakage (e.g., withbleomycin). The anthracycline antibioticsdaunorubicin and adriamycin (doxorubicin)may induce cardiomyopathy. Bleomycincan also cause pulmonary fibrosis.The epipodophyllotoxins, etoposideand teniposide, interact with topoisomeraseII, which functions to split,transpose, and reseal DNA strands(p. 274); these agents cause strandbreakage by inhibiting resealing.Inhibition of nucleobase synthesis(2). Tetrahydrofolic acid (THF) is requiredfor the synthesis of both purinebases and thymidine. Formation of THFfrom folic acid involves dihydrofolatereductase (p. 272). The folate analoguesaminopterin and methotrexate (amethopterin)inhibit enzyme activity asfalse substrates. As cellular stores of THFare depleted, synthesis of DNA and RNAbuilding blocks ceases. The effect ofthese antimetabolites can be reversedby administration of folinic acid (5-formyl-THF,leucovorin, citrovorum factor).Incorporation of false buildingblocks (3). Unnatural nucleobases (6-mercaptopurine; 5-fluorouracil) or nucleosideswith incorrect sugars (cytarabine)act as antimetabolites. They inhibitDNA/RNA synthesis or lead to synthesisof missense nucleic acids.6-Mercaptopurine results from biotransformationof the inactive precursorazathioprine (p. 37). The uricostatic allopurinolinhibits the degradation of 6-mercaptopurine such that co-administrationof the two drugs permits dosereduction of the latter.Frequently, the combination of cytostaticspermits an improved therapeuticeffect with fewer adverse reactions.Initial success can be followed byloss of effect because of the emergenceof resistant tumor cells. Mechanisms ofresistance are multifactorial:Diminished cellular uptake may resultfrom reduced synthesis of a transportprotein that may be needed formembrane penetration (e.g., methotrexate).Augmented drug extrusion: increasedsynthesis of the P-glycoproteinthat extrudes drugs from the cell (e.g.,anthracyclines, vinca alkaloids, epipodophyllotoxins,and paclitaxel) is reponsiblefor multi-drug resistance(mdr-1 gene amplification).Diminished bioactivation of a prodrug,e.g., cytarabine, which requiresintracellular phosphorylation to becomecytotoxic.Change in site of action: e.g., increasedsynthesis of dihydrofolate reductasemay occur as a compensatoryresponse to methotrexate.Damage repair: DNA repair enzymesmay become more efficient in repairingdefects caused by cisplatin.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Anticancer Drugs 299DNADamageto templateAlkylatione. g., bymechlorethamine1Insertion ofdaunorubicin,doxorubicin,bleomycin,actinomycin D, etc.Streptomyces bacteriaBuilding blocksInhibition of nucleotide synthesisPurinesThymineNucleotideTetrahydrofolateDihydrofolateReductaseFolic acidRNAInhibition byAminopterinMethotrexate2DNADNAInsertion of incorrect building blocksPurine antimetabolite6-Mercaptopurinefrom Azathioprineinstead ofAdeninePyrimidine antimetabolite5-Fluorouracilinstead ofA. Cytostatics: alkylating agents and cytostatic antibiotics (1),inhibitors of tetrahydrofolate synthesis (2), antimetabolites (3)UracilCytarabine Cytosine CytosineArabinose instead of Desoxyribose3Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
300 Immune ModulatorsInhibition of Immune ResponsesBoth the prevention of transplant rejectionand the treatment of autoimmunedisorders call for a suppression of immuneresponses. However, immunesuppression also entails weakened defensesagainst infectious pathogens anda long-term increase in the risk of neoplasms.A specific immune response beginswith the binding of antigen by lymphocytescarrying specific receptorswith the appropriate antigen-bindingsite. B-lymphocytes “recognize” antigensurface structures by means of membranereceptors that resemble the antibodiesformed subsequently. T-lymphocytes(and naive B-cells) require theantigen to be presented on the surfaceof macrophages or other cells in conjunctionwith the major histocompatibilitycomplex (MHC); the latter permitsrecognition of antigenic structuresby means of the T-cell receptor. T-helpercells carry adjacent CD-3 and CD-4complexes, cytotoxic T-cells a CD-8complex. The CD proteins assist in dockingto the MHC. In addition to recognitionof antigen, activation of lymphocytesrequires stimulation by cytokines.Interleukin-1 is formed by macrophages,and various interleukins (IL), includingIL-2, are made by T-helper cells. Asantigen-specific lymphocytes proliferate,immune defenses are set into motion.I. Interference with antigen recognition.Muromonab CD3 is a monoclonalantibody directed against mouseCD-3 that blocks antigen recognition byT-lymphocytes (use in graft rejection).II. Inhibition of cytokine productionor action. Glucocorticoids modulatethe expression of numerousgenes; thus, the production of IL-1 andIL-2 is inhibited, which explains thesuppression of T-cell-dependent immuneresponses. Glucocorticoids areused in organ transplantations, autoimmunediseases, and allergic disorders.Systemic use carries the risk of iatrogenicCushing’s syndrome (p. 248).Cyclosporin A is an antibiotic polypeptidefrom fungi and consists of 11, inpart atypical, amino acids. Given orally,it is absorbed, albeit incompletely. Inlymphocytes, it is bound by cyclophilin,a cytosolic receptor that inhibits thephosphatase calcineurin. The latterplays a key role in T-cell signal transduction.It contributes to the inductionof cytokine production, including that ofIL-2. The breakthroughs of moderntransplantation medicine are largely attributableto the introduction of cyclosporinA. Prominent among its adverseeffects are renal damage, hypertension,and hyperkalemia.Tacrolimus, a macrolide, derivesfrom a streptomyces species; pharmacologicallyit resembles cyclosporin A,but is more potent and efficacious.The monoclonal antibodies daclizumaband basiliximab bind to the α-chain of the II-2 receptor of T-lymphocytesand thus prevent their activation,e.g., during transplant rejection.III. Disruption of cell metabolismwith inhibition of proliferation. Atdosages below those needed to treatmalignancies, some cytostatics are alsoemployed for immunosuppression, e.g.,azathioprine, methotrexate, and cyclophosphamide(p. 298). The antiproliferativeeffect is not specific for lymphocytesand involves both T- and B-cells.Mycophenolate mofetil has a morespecific effect on lymphocytes than onother cells. It inhibits inosine monophosphatedehydrogenase, which catalyzespurine synthesis in lymphocytes.It is used in acute tissue rejection responses.IV. Anti-T-cell immune serum isobtained from animals immunized withhuman T-lymphocytes. The antibodiesbind to and damage T-cells and can thusbe used to attenuate tissue rejection.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Immune Modulators 301AntigenMacrophagePhagocytosisDegradationPresentationVirus-infected cell,transplanted cell.tumor cellSynthesis of"foreign" proteinsPresentationGlucocorticoidsInhibition oftranscriptionof cytokines,e. g.,IL-1 IL-2MHC IIIL-1MHC IT-cellreceptorUptakeDegradationPresentationMHC IICD4T-HelpercellCD3CD8CD3Muromonab-CD3MonoclonalantibodyCyclosporin AB-LymphocyteInterleukinsIL-2IL-2 receptorblockadeDaclizumabBasiliximabT-LymphocyteCyclophilinInhibitionCalcineurin,a phosphataseProliferationTranscription ofcytokines e. g.,IL-2anddifferentiationinto plasma cellsCytotoxic,antiproliferativedrugsCytotoxicT-lymphocytesAzathioprine,Methotrexate,Cyclophosphamide,MycophenolatemofetilCytokines:chemotaxisAntibody-mediatedimmune reactionImmune reaction:delayedhypersensitivityElimination of“foreign” cellsA. Immune reaction and immunosuppressivesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
302 AntidotesAntidotes and treatment of poisoningsDrugs used to counteract drug overdosageare considered under the appropriateheadings, e.g., physostigmine withatropine; naloxone with opioids; flumazenilwith benzodiazepines; antibody(Fab fragments) with digitalis; andN-acetyl-cysteine with acetaminophenintoxication.Chelating agents (A) serve as antidotesin poisoning with heavy metals.They act to complex and, thus, “inactivate”heavy metal ions. Chelates (fromGreek: chele = claw [of crayfish]) representcomplexes between a metal ionand molecules that carry several bindingsites for the metal ion. Because oftheir high affinity, chelating agents “attract”metal ions present in the organism.The chelates are non-toxic, are excretedpredominantly via the kidney,maintain a tight organometallic bondalso in the concentrated, usually acidic,milieu of tubular urine and thus promotethe elimination of metal ions.Na 2Ca-EDTA is used to treat leadpoisoning. This antidote cannot penetratecell membranes and must be givenparenterally. Because of its high bindingaffinity, the lead ion displaces Ca 2+ fromits bond. The lead-containing chelate iseliminated renally. Nephrotoxicity predominatesamong the unwanted effects.Na 3Ca-Pentetate is a complex of diethylenetriaminopentaaceticacid (DPTA)and serves as antidote in lead and othermetal intoxications.Dimercaprol (BAL, British Anti-Lewisite)was developed in World War IIas an antidote against vesicant organicarsenicals (B). It is able to chelate variousmetal ions. Dimercaprol forms a liquid,rapidly decomposing substancethat is given intramuscularly in an oilyvehicle. A related compound, both interms of structure and activity, is dimercaptopropanesulfonicacid, whosesodium salt is suitable for oral administration.Shivering, fever, and skin reactionsare potential adverse effects.Deferoxamine derives from thebacterium Streptomyces pilosus. Thesubstance possesses a very high ironbindingcapacity, but does not withdrawiron from hemoglobin or cytochromes.It is poorly absorbed enterally and mustbe given parenterally to cause increasedexcretion of iron. Oral administration isindicated only if enteral absorption ofiron is to be curtailed. Unwanted effectsinclude allergic reactions. It should benoted that blood letting is the most effectivemeans of removing iron from thebody; however, this method is unsuitablefor treating conditions of iron overloadassociated with anemia.D-penicillamine can promote theelimination of copper (e.g., in Wilson’sdisease) and of lead ions. It can be givenorally. Two additional uses are cystinuriaand rheumatoid arthritis. In the former,formation of cystine stones in theurinary tract is prevented because thedrug can form a disulfide with cysteinethat is readily soluble. In the latter, penicillaminecan be used as a basal regimen(p. 320). The therapeutic effectmay result in part from a reaction withaldehydes, whereby polymerization ofcollagen molecules into fibrils is inhibited.Unwanted effects are: cutaneousdamage (diminished resistance to mechanicalstress with a tendency to formblisters), nephrotoxicity, bone marrowdepression, and taste disturbances.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antidotes 303Na 2 Ca-EDTA2Na +Ca2+CH 2N CH 2 CCH 2 CEDTA: Ethylenediaminetetra-acetateOOO -O -N CH 2CO - OCH 2CO - OA. Chelation of lead ions by EDTADimercaprol (i.m.)DeferoxamineD-PenicillamineArsenic, mercury,gold ionsDMPSFe 3 +β,β-Dimethylcysteinechelation withCu 2+ and Pb 2+DimercaptopropanesulfonateDissolution of cystinestones:Cysteine-S-S-CysteineInhibition ofcollagenpolymerizationB. ChelatorsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
304 AntidotesAntidotes for cyanide poisoning(A). Cyanide ions (CN - ) enter the organismin the form of hydrocyanic acid(HCN); the latter can be inhaled, releasedfrom cyanide salts in the acidicstomach juice, or enzymatically liberatedfrom bitter almonds in the gastrointestinaltract. The lethal dose of HCN canbe as low as 50 mg. CN - binds with highaffinity to trivalent iron and thereby arrestsutilization of oxygen via mitochondrialcytochrome oxidases of therespiratory chain. An internal asphyxiation(histotoxic hypoxia) ensues whileerythrocytes remain charged with O 2(venous blood colored bright red).In small amounts, cyanide can beconverted to the relatively nontoxicthiocyanate (SCN - ) by hepatic “rhodanese”or sulfur transferase. As a therapeuticmeasure, thiosulfate can be giveni.v. to promote formation of thiocyanate,which is eliminated in urine. However,this reaction is slow in onset. Amore effective emergency treatment isthe i.v. administration of the methemoglobin-formingagent 4-dimethylaminophenol,which rapidly generatestrivalent from divalent iron in hemoglobin.Competition between methemoglobinand cytochrome oxidase for CN - ionsfavors the formation of cyanmethemoglobin.Hydroxocobalamin is an alternative,very effective antidote because itscentral cobalt atom binds CN - with highaffinity to generate cyanocobalamin.Tolonium chloride (ToluidinBlue). Brown-colored methemoglobin,containing tri- instead of divalent iron,is incapable of carrying O 2. Under normalconditions, methemoglobin is producedcontinuously, but reduced againwith the help of glucose-6-phosphatedehydrogenase. Substances that promoteformation of methemoglobin (B)may cause a lethal deficiency of O 2. Toloniumchloride is a redox dye that canbe given i.v. to reduce methemoglobin.Obidoxime is an antidote used totreat poisoning with insecticides of theorganophosphate type (p. 102). Phosphorylationof acetylcholinesterasecauses an irreversible inhibition of acetylcholinebreakdown and hence floodingof the organism with the transmitter.Possible sequelae are exaggeratedparasympathomimetic activity, blockadeof ganglionic and neuromusculartransmission, and respiratory paralysis.Therapeutic measures include: 1.administration of atropine in high dosageto shield muscarinic acetylcholinereceptors; and 2. reactivation of acetylcholinesteraseby obidoxime, whichsuccessively binds to the enzyme, capturesthe phosphate residue by a nucleophilicattack, and then dissociatesfrom the active center to release the enzymefrom inhibition.Ferric Ferrocyanide (“BerlinBlue,” B) is used to treat poisoning withthallium salts (e.g., in rat poison), theinitial symptoms of which are gastrointestinaldisturbances, followed by nerveand brain damage, as well as hair loss.Thallium ions present in the organismare secreted into the gut but undergoreabsorption. The insoluble, nonabsorbablecolloidal Berlin Blue binds thalliumions. It is given orally to prevent absorptionof acutely ingested thallium or topromote clearance from the organismby intercepting thallium that is secretedinto the intestines.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Antidotes 305PotassiumcyanideKCNSCN -Sulfur donorsNa 2 S 2 O 3RhodaneseH + + CN - Fe III -HbSodium thiosulfateHydrogencyanideHCNK +H +Methemoglob<strong>info</strong>rmationDMAPMitochondrialcytochrome oxidaseFe3+Inhibition ofcellular respirationComplex formationHydroxocobalaminVit.B 12aCyanocobalamin Vit.B 12A. Cyanide poisoning and antidotesSubstances formingmethemoglobine.g., NO- 2 NitriteOrganophosphatese.g., ParaoxonFerric ferrocyanideFe4III [Fe II (CN) 6 ] 3“Prussian Blue”H 2 NO 2 NAnilineNitrobenzeneReactivated=ThalliumionTl + Tl +Fe II -HbAcetylcholineesteraseFe III -HbPhosphorylated,inactivatedTl +2 Cl -2 Cl -Tolonium chloride(toluidin blue)Reactivator:obidoximeTl excretionB. Poisons and antidotesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
306 Therapy of Selected DiseasesAngina PectorisAn anginal pain attack signals a transienthypoxia of the myocardium. As arule, the oxygen deficit results from inadequatemyocardial blood flow due tonarrowing of larger coronary arteries.The underlying causes are: most commonly,an atherosclerotic change of thevascular wall (coronary sclerosis withexertional angina); very infrequently, aspasmodic constriction of a morphologicallyhealthy coronary artery (coronaryspasm with angina at rest; variant angina);or more often, a coronary spasm occurringin an atherosclerotic vascularsegment.The goal of treatment is to preventmyocardial hypoxia either by raisingblood flow (oxygen supply) or by loweringmyocardial blood demand (oxygendemand) (A).Factors determining oxygen supply.The force driving myocardial bloodflow is the pressure difference betweenthe coronary ostia (aortic pressure) andthe opening of the coronary sinus (rightatrial pressure). Blood flow is opposedby coronary flow resistance, which includesthree components. (1) Due totheir large caliber, the proximal coronarysegments do not normally contributesignificantly to flow resistance.However, in coronary sclerosis orspasm, pathological obstruction of flowoccurs here. Whereas the more commoncoronary sclerosis cannot be overcomepharmacologically, the less commoncoronary spasm can be relieved byappropriate vasodilators (nitrates, nifedipine).(2) The caliber of arteriolar resistancevessels controls blood flowthrough the coronary bed. Arteriolarcaliber is determined by myocardial O 2tension and local concentrations ofmetabolic products, and is “automatically”adjusted to the required bloodflow (B, healthy subject). This metabolicautoregulation explains why anginal attacksin coronary sclerosis occur onlyduring exercise (B, patient). At rest, thepathologically elevated flow resistanceis compensated 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 restthey may divert blood from underperfusedinto healthy vascular regions onaccount of redundant arteriolar dilation.The resulting “steal effect” could provokean anginal attack. (3) The intramyocardialpressure, 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 volumeand filling pressure. The organic nitratesreduce preload by decreasing venousreturn to the heart.Factors determining oxygen demand.The heart muscle cell consumesthe most energy to generate contractileforce. O 2 demand rises with an increasein (1) heart rate, (2) contraction velocity,(3) systolic wall tension (“afterload”).The latter depends on ventricular volumeand the systolic pressure needed toempty the ventricle. As peripheral resistanceincreases, aortic pressure rises,hence the resistance against which ventricularblood is ejected. O 2 demand islowered by β-blockers and Ca-antagonists,as well as by nitrates (p. 308).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Therapy of Selected Diseases 307O 2 -supplyduringdiastoleO 2 -demandduringsystoleFlow resistance:Left atrium1. Heart rate1. Coronary arterialcaliberCoronary artery2. Contractionvelocity2. Arteriolarcaliber3. Diastolicwall tension= PreloadRightatriumLeft ventriclep-forceTime3. Systolic walltension= AfterloadPressure pPressure pVenoussupplyAortaVol.Vol.PeripheralresistanceVenousreservoirA. O 2 supply and demand of the myocardiumHealthy subjectPatient with coronary sclerosisNarrowRestWideCompensatorydilation ofarteriolesRateContractionvelocityAfterloadExerciseAdditionaldilationnot possibleWideWideAnginapectorisB. Pathogenesis of exertion angina in coronary sclerosisLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
308 Therapy of Selected DiseasesAntianginal DrugsAntianginal agents derive from threedrug groups, the pharmacological propertiesof which have already been presentedin more detail, viz., the organicnitrates (p. 120), the Ca 2+ antagonists(p. 122), and the β-blockers (pp. 92ff).Organic nitrates (A) increase bloodflow, hence O 2 supply, because diastolicwall tension (preload) declines as venousreturn to the heart is diminished.Thus, the nitrates enable myocardialflow resistance to be reduced even inthe presence of coronary sclerosis withangina pectoris. In angina due to coronaryspasm, arterial dilation overcomesthe vasospasm and restores myocardialperfusion to normal. O 2 demand fallsbecause of the ensuing decrease in thetwo variables that determine systolicwall tension (afterload): ventricular fillingvolume and aortic blood pressure.Calcium antagonists (B) decreaseO 2 demand by lowering aortic pressure,one of the components contributing toafterload. The dihydropyridine nifedipineis devoid of a cardiodepressant effect,but may give rise to reflex tachycardiaand an associated increase in O 2demand. The catamphiphilic drugs verapamiland diltiazem are cardiodepressant.Reduced beat frequency andcontractility contribute to a reduction inO 2 demand; however, AV-block and mechanicalinsufficiency can dangerouslyjeopardize heart function. In coronaryspasm, calcium antagonists can inducespasmolysis and improve blood flow(p. 122).β-Blockers (C) protect the heartagainst the O 2-wasting effect of sympatheticdrive by inhibiting β-receptormediatedincreases in cardiac rate andspeed of contraction.Uses of antianginal drugs (D). Forrelief of the acute anginal attack, rapidlyabsorbed drugs devoid of cardiodepressantactivity are preferred. The drugof choice is nitroglycerin (NTG,0.8–2.4 mg sublingually; onset of actionwithin 1 to 2 min; duration of effect~30 min). Isosorbide dinitrate (ISDN)can also be used (5–10 mg sublingually);compared with NTG, its action issomewhat delayed in onset but of longerduration. Finally, nifedipine may beuseful in chronic stable, or in variant angina(5–20 mg, capsule to be bitten andthe contents swallowed).For sustained daytime angina prophylaxis,nitrates are of limited valuebecause “nitrate pauses” of about 12 hare appropriate if nitrate tolerance is tobe avoided. If attacks occur during theday, ISDN, or its metabolite isosorbidemononitrate, may be given in the morningand at noon (e.g., ISDN 40 mg in extended-releasecapsules). Because ofhepatic presystemic elimination, NTG isnot suitable for oral administration.Continuous delivery via a transdermalpatch would also not seem advisablebecause of the potential development oftolerance. With molsidomine, there isless risk of a nitrate tolerance; however,due to its potential carcinogenicity, itsclinical use is restricted.The choice between calcium antagonistsmust take into account the differentialeffect of nifedipine versus verapamilor diltiazem on cardiac performance(see above). When β-blockers aregiven, the potential consequences of reducingcardiac contractility (withdrawalof sympathetic drive) must be kept inmind. Since vasodilating β 2-receptorsare blocked, an increased risk of vasospasmcannot be ruled out. Therefore,monotherapy with β-blockers is recommendedonly in angina due to coronarysclerosis, but not in variant angina.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Therapy of Selected Diseases 309p Diastole SystolepVolVolVenouscapacitancevesselsPreloadAfterloadResistancevesselsO 2 -supplyNitratetoleranceO 2 -demandVasorelaxationRelaxation ofcoronary spasmNitrates e.g., Nitroglycerin (GTN), Isosorbide dinitrate (ISDN)A. Effects of nitratespAfterloadCaantagonistsRelaxationofresistancevesselsβ-blockerRestSympatheticsystemRateContractionvelocityO 2 -demandRelaxation ofcoronary spasmB. Effects of Ca-antagonistsExerciseC. Effects of β-blockersCoronary sclerosisTherapy of attackAnginal prophylaxisβ-blockerAngina pectorisGTN, ISDNNifedipineLong-acting nitratesCa-antagonistsCoronary spasmD. Clinical uses of antianginal drugsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
310 Therapy of Selected DiseasesAcute Myocardial InfarctionMyocardial infarction is caused byacute thrombotic occlusion of a coronaryartery (A). Therapeutic interventionsaim to restore blood flow in the occludedvessel in order to reduce infarct sizeor to rescue ischemic myocardial tissue.In the area perfused by the affected vessel,inadequate supply of oxygen andglucose impairs the function of heartmuscle: contractile force declines. In thegreat majority of cases, the left ventricle(anterior or posterior wall) is involved.The decreased work capacity of the infarctedmyocardium leads to a reductionin stroke volume (SV) and hencecardiac output (CO). The fall in bloodpressure (RR) triggers reflex activationof the sympathetic system. The resultantstimulation of cardiac β-adrenoceptorselicits an increase in both heartrate and force of systolic contraction,which, in conjunction with an α-adrenoceptor-mediatedincrease in peripheralresistance, leads to a compensatoryrise in blood pressure. In ATP-depletedcells in the infarct border zone, restingmembrane potential declines with aconcomitant increase in excitabilitythat may be further exacerbated by activationof β-adrenoceptors. Together,both processes promote the risk of fatalventricular arrhythmias. As a consequenceof local ischemia, extracellularconcentrations of H + and K + rise in theaffected region, leading to excitation ofnociceptive nerve fibers. The resultantsensation of pain, typically experiencedby the patient as annihilating, re<strong>info</strong>rcessympathetic activation.The success of infarct therapy criticallydepends on the length of timebetween the onset of the attack and thestart of treatment. Whereas some therapeuticmeasures are indicated only afterthe diagnosis is confirmed, others necessitateprior exclusion of contraindicationsor can be instituted only in speciallyequipped facilities. Without exception,however, prompt action is imperative.Thus, a staggered treatmentschedule has proven useful.The antiplatelet agent, ASA, is administeredat the first suspected signs ofinfarction. Pain due to ischemia is treatedpredominantly with antianginaldrugs (e.g., nitrates). In case this treatmentfails (no effect within 30 min, administrationof morphine, if needed incombination with an antiemetic to preventmorphine-induced vomiting, is indicated.If ECG signs of myocardial infarctionare absent, the patient is stabilizedby antianginal therapy (nitrates, β-blockers) and given ASA and heparin.When the diagnosis has been confirmedby electrocardiography, attemptsare started to dissolve thethrombus pharmacologically (thrombolytictherapy: alteplase or streptokinase)or to remove the obstruction bymechanical means (balloon dilation orangioplasty). Heparin is given to preventa possible vascular reocclusion, i.e.,to safeguard the patency of the affectedvessel. Regardless of the outcome ofthrombolytic therapy or balloon dilation,a β-blocker is administered to suppressimminent arrhythmias, unless it iscontraindicated. Treatment of lifethreateningventricular arrhythmiascalls for an antiarrhythmic of the classof Na + -channel blockers, e.g., lidocaine.To improve long-term prognosis, use ismade of a β-blocker ( incidence of reinfarctionand acute cardiac mortality)and an ACE inhibitor (prevention ofventricular enlargement after myocardialinfarction) (A).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Therapy of Selected Diseases 311β-blockerSympatheticnervous systemβββSV x HR = COSV x HR = COIf needed:antiarrhythmic:e.g., lidocaineExcitabilityArrhythmiaSVForceRRAntiplateletdrugs,thrombolyticagent,heparinInfarctαPeripheralresistancePreload reduction:nitrateAnalgesic:opioidsH+ K+PainAfterload reduction:ACE-inhibitorA. Drugs for the treatment of acute myocardial infarctionSuspected myocardialinfarctPersistent pain:opioids and ifneeded: antiemeticsAcetylsalicylicacidGlycerol trinitrateECGIschemic painyes noST-segmentelevationleft bundle blocknoyesThrombolysiscontraindicatednoyesAngioplastycontraindicatedno yesThrombolysissuccessfulyesnoAngioplastyopt. GPIIb/IIIAblockerStandard therapyβ-blocker, ACE-inhibitor, optional heparinA. Algorithm for the treatment of acute myocardial infarctionLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
312 Therapy of Selected DiseasesHypertensionArterial hypertension (high blood pressure)generally does not impair thewell-being of the affected individual;however, in the long term it leads tovascular damage and secondary complications(A). The aim of antihypertensivetherapy is to prevent the latter and,thus, to prolong life expectancy.Hypertension infrequently resultsfrom another disease, such as a catecholamine-secretingtumor (pheochromocytoma);in most cases the causecannot be determined: essential (primary)hypertension. Antihypertensivedrugs are indicated when blood pressurecannot be sufficiently controlled bymeans of weight reduction or a lowsaltdiet. In principle, lowering of eithercardiac output or peripheral resistancemay decrease blood pressure (cf. p. 306,314, blood pressure determinants). Theavailable drugs influence one or both ofthese determinants. The therapeuticutility of antihypertensives is determinedby their efficacy and tolerability.The choice of a specific drug is determinedon the basis of a benefit:risk assessmentof the relevant drugs, in keepingwith the patient’s individual needs.In instituting single-drug therapy(monotherapy), the following considerationsapply: β-blockers (p. 92) are ofvalue in the treatment of juvenile hypertensionwith tachycardia and highcardiac output; however, in patientsdisposed to bronchospasm, even β 1-selectiveblockers are contraindicated.Thiazide diuretics (p. 162) are potentiallywell suited in hypertension associatedwith congestive heart failure; however,they would be unsuitable in hypokalemicstates. When hypertension isaccompanied by angina pectoris, thepreferred choice would be a β-blockeror calcium antagonist (p. 122) ratherthan a diuretic. As for the calcium antagonists,it should be noted that verapamil,unlike nifedipine, possesses cardiodepressantactivity. α-Blockers maybe of particular benefit in patients withbenign prostatic hyperplasia and impairedmicturition. At present, only β-blockers and diuretics have undergonelarge-scale clinical trials, which haveshown that reduction in blood pressureis associated with decreased morbidityand mortality due to stroke and congestiveheart failure.In multidrug therapy, it is necessaryto consider which agents rationallycomplement each other. A β-blocker(bradycardia, cardiodepression due tosympathetic blockade) can be effectivelycombined with nifedipine (reflextachycardia), but obviously not with verapamil(bradycardia, cardiodepression).Monotherapy with ACE inhibitors(p. 124) produces an adequate reductionof blood pressure in 50% of patients;the response rate is increased to90% by combination with a (thiazide)diuretic. When vasodilators such as dihydralazineor minoxidil (p. 118) aregiven, β-blockers would serve to preventreflex tachycardia, and diuretics tocounteract fluid retention.Abrupt termination of continuoustreatment can be followed by reboundhypertension (particularly with shortt 1/2 β-blockers).Drugs for the control of hypertensivecrises include nifedipine (capsule,to be chewed and swallowed), nitroglycerin(sublingually), clonidine (p.o. ori.v., p. 96), dihydralazine (i.v.), diazoxide(i.v.), fenoldopam (by infusion, p. 114)and sodium nitroprusside (p. 120, by infusion).The nonselective α-blockerphentolamine (p. 90) is indicated onlyin pheochromocytoma.Antihypertensives for hypertensionin pregnancy are β 1-selectiveadrenoceptor-blockers, methyldopa(p. 96), and dihydralazine (i.v. infusion)for eclampsia (massive rise in bloodpressure with CNS symptoms).Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Therapy of Selected Diseases 313HypertensionSystolic: blood pressure > 160 mmHgDiastolic: blood pressure > 96 mmHg[mm Hg]Secondary diseases:Heart failureCoronary atherosclerosisangina pectoris, myocardialinfarction, arrhythmiaAtherosclerosis of cerebral vesselscerebral infarction strokeCerebral hemorrhageAtherosclerosis of renal vesselsrenal failureDecreased life expectancyAntihypertensive therapyInitial monotherapywith one of the fivedrug groupsDrug selectionaccording to conditionsand needs of theindividual patientDiureticsβ-blockersIf therapeuticresult inadequateACE inhibitorsAT 1 -antagonistsα 1 -blockersCaantagonistsorchange to drugfrom another groupcombine withdrug from another groupIn severe cases further combination withReserpineα-blockere.g.,prazosineCentralα 2 -agoniste.g., clonidineVasodilatione.g.,dihydralazineminoxidilA. Arterial hypertension and pharmacotherapeutic approachesLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
314 Therapy of Selected DiseasesHypotensionThe venous side of the circulation, excludingthe pulmonary circulation, accommodates~ 60% of the total bloodvolume; because of the low venouspressure (mean ~ 15 mmHg) it is part ofthe low-pressure system. The arterialvascular beds, representing the highpressuresystem (mean pressure,~ 100 mmHg), contain ~ 15%. The arterialpressure generates the driving forcefor perfusion of tissues and organs.Blood draining from the latter collects inthe low-pressure system and is pumpedback by the heart into the high-pressuresystem.The arterial blood pressure (ABP)depends on: (1) the volume of blood perunit of time that is forced by the heartinto the high-pressure system—cardiacoutput corresponding to the product ofstroke volume and heart rate (beats/min), stroke volume being determinedinter alia by venous filling pressure; (2)the counterforce opposing the flow ofblood, i.e., peripheral resistance, whichis a function of arteriolar caliber.Chronic hypotension (systolic BP< 105 mmHg). Primary idiopathic hypotensiongenerally has no clinical importance.If symptoms such as lassitudeand dizziness occur, a program of physicalexercise instead of drugs is advisable.Secondary hypotension is a sign ofan underlying disease that should betreated first. If stroke volume is too low,as in heart failure, a cardiac glycosidecan be given to increase myocardialcontractility and stroke volume. Whenstroke volume is decreased due to insufficientblood volume, plasma substituteswill be helpful in treating bloodloss, whereas aldosterone deficiency requiresadministration of a mineralocorticoid(e.g., fludrocortisone). The latteris the drug of choice for orthostatic hypotensiondue to autonomic failure. Aparasympatholytic (or electrical pacemaker)can restore cardiac rate inbradycardia.Acute hypotension. Failure of orthostaticregulation. A change from therecumbent to the erect position (orthostasis)will cause blood within the lowpressuresystem to sink towards the feetbecause the veins in body parts belowthe heart will be distended, despite a reflexvenoconstriction, by the weight ofthe column of blood in the blood vessels.The fall in stroke volume is partlycompensated by a rise in heart rate. Theremaining reduction of cardiac outputcan be countered by elevating the peripheralresistance, enabling blood pressureand organ perfusion to be maintained.An orthostatic malfunction ispresent when counter-regulation failsand cerebral blood flow falls, with resultantsymptoms, such as dizziness,“black-out,” or even loss of consciousness.In the sympathotonic form, sympatheticallymediated circulatory reflexesare intensified (more pronouncedtachycardia and rise in peripheral resistance,i.e., diastolic pressure); however,there is failure to compensate for the reductionin venous return. Prophylactictreatment with sympathomimeticstherefore would hold little promise. Instead,cardiovascular fitness trainingwould appear more important. An increasein venous return may beachieved in two ways. Increasing NaClintake augments salt and fluid reservesand, hence, blood volume (contraindications:hypertension, heart failure).Constriction of venous capacitance vesselsmight be produced by dihydroergotamine.Whether this effect could alsobe achieved by an α-sympathomimeticremains debatable. In the veryrare asympathotonic form, use of sympathomimeticswould certainly be reasonable.In patients with hypotension due tohigh thoracic spinal cord transections(resulting in an essentially completesympathetic denervation), loss of sympatheticvasomotor control can be compensatedby administration of sympathomimetics.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Therapy of Selected Diseases 315Low-pressuresystemHigh-pressuresystemBrainLungVenousreturnHeartβ-SympathomimeticsCardiacglycosidesStroke vol. x rate= cardiac outputKidneyBlood pressure (BP)IntestinesPeripheral resistanceSkeletal muscleInitial conditionArteriolarcaliberIncrease of blood volume0,9%NaClSaltBPNaCl + H 2 OBPRedistribution of blood volumeBPNaCl+ H 2 OConstriction of venous capacitancevessels, e.g., dihydroergotamine ifappropriate, α-sympathomimeticsα-SympathomimeticsParasympatholyticsMineralocorticoidA. Treatment of hypotensionLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
316 Therapy of Selected DiseasesGoutGout is an inherited metabolic diseasethat results from hyperuricemia, an elevationin the blood of uric acid, theend-product of purine degradation. Thetypical gout attack consists of a highlypainful inflammation of the first metatarsophalangealjoint (“podagra”). Goutattacks are triggered by precipitation ofsodium urate crystals in the synovialfluid of joints.During the early stage of inflammation,urate crystals are phagocytosed bypolymorphonuclear leukocytes (1) thatengulf the crystals by their ameboid cytoplasmicmovements (2). The phagocyticvacuole fuses with a lysosome (3).The lysosomal enzymes are, however,unable to degrade the sodium urate.Further ameboid movement dislodgesthe crystals and causes rupture of thephagolysosome. Lysosomal enzymesare liberated into the granulocyte, resultingin its destruction by self-digestionand damage to the adjacent tissue.Inflammatory mediators, such as prostaglandinsand chemotactic factors, arereleased (4). More granulocytes are attractedand suffer similar destruction;the inflammation intensifies—the goutattack flares up.Treatment of the gout attack aimsto interrupt the inflammatory response.The drug of choice is colchicine, an alkaloidfrom the autumn crocus (Colchicumautumnale). It is known as a “spindlepoison” because it arrests mitosis atmetaphase by inhibiting contractilespindle proteins. Its antigout activity isdue to inhibition of contractile proteinsin the neutrophils, whereby ameboidmobility and phagocytotic activity areprevented. The most common adverseeffects of colchicine are abdominal pain,vomiting, and diarrhea, probably due toinhibition of mitoses in the rapidly dividinggastrointestinal epithelial cells.Colchicine is usually given orally (e.g.,0.5 mg hourly until pain subsides or gastrointestinaldisturbances occur; maximaldaily dose, 10 mg).Nonsteroidal anti-inflammatorydrugs, such as indomethacin and phenylbutazone,are also effective. In severecases, glucocorticoids may be indicated.Effective prophylaxis of gout attacksrequires urate blood levels to belowered to less than 6 mg/100 mL.Diet. Purine (cell nuclei)-rich foodsshould be avoided, e.g., organ meats.Milk, dairy products, and eggs are low inpurines and are recommended. Coffeeand tea are permitted since the methylxanthinecaffeine does not enter purinemetabolism.Uricostatics decrease urate production.Allopurinol, as well as its accumulatingmetabolite alloxanthine (oxypurinol),inhibit xanthine oxidase,which catalyzes urate formation fromhypoxanthine via xanthine. These precursorsare readily eliminated via theurine. Allopurinol is given orally(300–800 mg/d). Except for infrequentallergic reactions, it is well toleratedand is the drug of choice for gout prophylaxis.At the start of therapy, gout attacksmay occur, but they can be preventedby concurrent administration ofcolchicine (0.5–1.5 mg/d). Uricosurics,such as probenecid, benzbromarone(100 mg/d), or sulfinpyrazone, promoterenal excretion of uric acid. Theysaturate the organic acid transportsystem in the proximal renal tubules,making it unavailable for urate reabsorption.When underdosed, they inhibitonly the acid secretory system, whichhas a smaller transport capacity. Urateelimination is then inhibited and a goutattack is possible. In patients with uratestones in the urinary tract, uricosuricsare contraindicated.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Therapy of Selected Diseases 317AllopurinolHypoxanthineAlloxanthineXanthineOxidaseXanthineUricostaticUric acidColchicineNucleusUricosuricProbenecidLysosome12PhagocyteChemotacticfactors3Anion (urate)reabsorption4Anion secretionGout attackA. Gout and its therapyLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
318 Therapy of Selected DiseasesOsteoporosisOsteoporosis is defined as a generalizeddecrease in bone mass (osteopenia) thataffects bone matrix and mineral contentequally, giving rise to fractures of vertebralbodies with bone pain, kyphosis,and shortening of the torso. Fractures ofthe hip and the distal radius are alsocommon. The underlying process is adisequilibrium between bone formationby osteoblasts and bone resorption byosteoclasts.Classification: Idiopathic osteoporosistype I, occurring in postmenopausalfemales; type II, occurring in senescentmales and females (>70 y). Secondaryosteoporosis: associated with primarydisorders such as Cushing’s disease, orinduced by drugs, e.g., chronic therapywith glucocorticoids or heparin. In theseforms, the cause can be eliminated.Postmenopausal osteoporosisrepresents a period of accelerated lossof bone mass. The lower the preexistingbone mass, the earlier the clinical signsbecome manifest.Risk factors are: premature menopause,physical inactivity, cigarettesmoking, alcohol abuse, low bodyweight, and calcium-poor diet.Prophylaxis: Administration of estrogencan protect against postmenopausalloss of bone mass. Frequently,conjugated estrogens are used (p. 254).Because estrogen monotherapy increasesthe risk of uterine cancer, a gestagenneeds to be given concurrently (exceptafter hysterectomy), as e.g., in an oralcontraceptive preparation (p. 256).Under this therapy, menses will continue.The risk of thromboembolic disordersis increased and that of myocardialinfarction probably lowered. Hormonetreatment can be extended for 10 y orlonger. Before menopause, daily calciumintake should be kept at 1 g (containedin 1 L of milk), and 1.5 g thereafter.Therapy. Formation of new bonematrix is induced by fluoride. Administeredas sodium fluoride, it stimulatesosteoblasts. Fluoride is substituted forhydroxyl residues in hydroxyapatite toform fluorapatite, the latter being moreresistant to resorption by osteoclasts. Tosafeguard adequate mineralization ofnew bone, calcium must be supplied insufficient amounts. However, simultaneousadministration would result inprecipitation of nonabsorbable calciumfluoride in the intestines. With sodiummonofluorophosphate this problem iscircumvented. The new bone formedmay have increased resistance to compressive,but not torsional, strain andparadoxically bone fragility may increase.Because the conditions underwhich bone fragility is decreased remainunclear, fluoride therapy is not inroutine use.Calcitonin (p. 264) inhibits osteoclastactivity, hence bone resorption. Asa peptide it needs to be given by injection(or, alternatively, as a nasal spray).Salmonid is more potent than humancalcitonin because of its slower elimination.Bisphosphonates structurallymimic endogenous pyrophosphate,which inhibits precipitation and dissolutionof bone minerals. They retardbone resorption by osteoclasts and, inpart, also decrease bone mineralization.Indications include: tumor osteolysis,hypercalcemia, and Paget’s disease.Clinical trials with etidronate, administeredas an intermittent regimen, haveyielded favorable results in osteoporosis.With the newer drugs clodronate,pamidronate, and alendronate, inhibitionof osteoclasts predominates; a continuousregimen would thus appear tobe feasible.Bisphosphonates irritate esophagealand gastric mucus membranes; tabletsshould be swallowed with a reasonableamount of water (250 mL) and thepatient should keep in an upright positionfor 30 min following drug intake.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Therapy of Selected Diseases 319Normal stateOsteoporosisOrganic bone matrix, OsteoidBone mineral: hydroxyapatiteA. Bone: normal state and osteoporosisIn postmenopauseEstrogen(+ Gestagen)Calcium-salts1 – 1.5g Ca 2+per dayPromotion ofboneformationInhibition ofboneresorptionFluoride ionsNaF:FormationResorptionCalcitoninActivation ofosteoblasts,Formation ofFluorapatiteOsteoblastsOsteoclastsPeptideconsisting of32 aminoacidsPhysiologicalconstituent:BisphosphonatesNH2(CH2)3OH OHHO P O P OHO OPyrophosphoric acidOH OHHO P C P OHO OH Oe. g., alendronic acidB. Osteoporosis: drugs for prophylaxis and treatmentLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
320 Therapy of Selected DiseasesRheumatoid ArthritisRheumatoid arthritis or chronic polyarthritisis a progressive inflammatoryjoint disease that intermittently attacksmore and more joints, predominantlythose of the fingers and toes. The probablecause of rheumatoid arthritis is apathological reaction of the immunesystem. This malfunction can be promotedor triggered by various conditions,including genetic disposition,age–related wear and tear, hypothermia,and infection. An initial noxiousstimulus elicits an inflammation ofsynovial membranes that, in turn,leads to release of antigens throughwhich the inflammatory process ismaintained. Inflammation of the synovialmembrane is associated with liberationof inflammatory mediator substancesthat, among other actions,chemotactically stimulate migration(diapedesis) of phagocytic blood cells(granulocytes, macrophages) into thesynovial tissue. The phagocytes producedestructive enzymes that promote tissuedamage. Due to the production ofprostaglandins and leukotrienes (p.196) and other factors, the inflammationspreads to the entire joint. As a result,joint cartilage is damaged and thejoint is ultimately immobilized or fused.Pharmacotherapy. Acute relief ofinflammatory symptoms can beachieved by prostaglandin synthaseinhibitors; nonsteroidal anti-inflammatorydrugs, or NSAIDs, such as diclofenac,indomethacin, piroxicam, p. 200),and glucocorticoids (p. 248). The inevitablychronic use of NSAIDs is likely tocause adverse effects. Neither NSAIDsnor glucocorticoids can halt the progressivedestruction of joints.The use of disease-modifyingagents may reduce the requirement forNSAIDs. The use of such agents does notmean that intervention in the basic pathogeneticmechanisms (albeit hopedfor) is achievable. Rather, disease-modifyingtherapy permits acutely actingagents to be used as add-ons or as required.The common feature of diseasemodifiersis their delayed effect, whichdevelops only after treatment for severalweeks. Among possible mechanisms ofaction, inhibition of macrophage activityand inhibition of release or activityof lysosomal enzymes are being discussed.Included in this category are:sulfasalazine (an inhibitor of lipoxygenaseand cyclooxygenase, p. 272), chloroquine(lysosomal binding), gold compounds(lysosomal binding; i.m.: aurothioglucose,aurothiomalate; p.o.: auranofin,less effective), as well as D-penicillamine(chelation of metal ions neededfor enzyme activity, p. 302). Frequentadverse reactions are: damage to skinand mucous membranes, renal toxicity,and blood dyscrasias. In addition, use ismade of cytostatics and immune suppressantssuch as methotrexate (lowdose, once weekly) and leflumomid aswell as of cytokin antibodies (infliximab)and soluble cytokin receptors(etanercept). Methotrexate exerts ananti-inflammatory effect, apart from itsanti-autoimmune action and, next tosulfasalazine, is considered to have themost favorable risk:benefit ratio. Inmost severe cases cytostatics such asazathioprin and cyclophosphamide willhave to be used.Surgical removal of the inflamedsynovial membrane (synovectomy) frequentlyprovides long-term relief. If feasible,this approach is preferred becauseall pharmacotherapeutic measures entailsignificant adverse effects.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Therapy of Selected Diseases 321Genetic dispositionEnvironmental factorsAcute triggerInfectiontraumaImmune system: reaction against articular tissueSynovitisPainPermeabilityProstaglandinsInflammationChemotacticfactorsBonedestructionCollagenasesPhospholipasesCartilagedestructionInflammationNon-steroidalanti-inflammatorydrugs(NSAIDs)GlucocorticoidsMethotrexate, p.o. /s.c.weekly dosingSulfasalazine p.o.Gold parenteralPeptidasesIL-1 TNFαSide effects:Pneumonitis, nausea,vomiting, myelosuppressionallergic reaction, nephrotoxicity,gastrointestinal disturbancesLesions of mucous membranes,kidney, skin, blood dyscrasiasRelief of symptoms“Remission”Discontinuation because of:side effectsorinsufficient efficacy1 2 3 4 5 6MonthsYearsA. Rheumatoid arthritis and its treatmentLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
322 Therapy of Selected DiseasesMigraineMigraine is a syndrome characterizedby recurrent attacks of intense headacheand nausea that occur at irregularintervals and last for several hours. Inclassic migraine, the attack is typicallyheralded by an “aura” accompanied byspreading homonymous visual field defectswith colored sharp edges (“fortification”spectra). In addition, the patientcannot focus on certain objects, has aravenous appetite for particular foods,and is hypersensitive to odors (hyperosmia)or light (photophobia). The exactcause of these complaints is unknown;however, a disturbance in cranial bloodflow is the likely underlying pathogeneticmechanism. In addition to an ofteninherited predisposition, precipitatingfactors are required to provoke an attack,e.g., psychic stress, lack of sleep,certain foods. Pharmacotherapy of migrainehas two aims: stopping the acuteattack and preventing subsequent ones.Treatment of the attack. Forsymptomatic relief, headaches aretreated with analgesics (acetaminophen,acetylsalicylic acid), and nausea istreated with metoclopramide (p. 330)or domperidone. Since there is delayedgastric emptying during the attack, drugabsorption can be markedly retarded,hence effective plasma levels are notobtained. Because metoclopramidestimulates gastric emptying, it promotesabsorption of ingested analgesicdrugs and thus facilitates pain relief.If acetylsalicylic acid is administeredi.v. as the lysine salt, its bioavailabilityis complete. Therefore, i.v. injectionmay be advisable in acute attacks.Should analgesics prove insufficientlyeffective, ergotamine or one ofthe 5-HT 1, agonists may help control theacute attack in most cases or prevent animminent attack. The probable commonmechanism of action is a stimulation ofserotonin receptors of the 5-HT 1D (orperhaps also the 1B and 1F) subtype.Moreover, ergotamine has affinity fordopamine receptors ( nausea, emesis),as well as α-adrenoceptors and 5-HT 2 receptors ( vascular tone, platelet aggregation). With frequentuse, the vascular side effects may giverise to severe peripheral ischemia (ergotism).Overuse (>once per week) ofergotamine may provoke “rebound”headaches, thought to result from persistentvasodilation. Though different incharacter (tension-type headache),these prompt further consumption ofergotamine. Thus, a vicious circle developswith chronic abuse of ergotamine orother analgesics that may end with irreversibledisturbances of peripheralblood flow and impairment of renalfunction.Administered orally, ergotamineand sumatriptan, eletriptan, naratriptan,rizatriptan, and zolmitriptan haveonly limited bioavailability. Dihydroergotaminemay be given by i.m. or slowi.v. injection, sumatriptan subcutaneouslyor by nasal spray.Prophylaxis. Taken regularly over alonger period, a heterogeneous group ofdrugs comprising propranolol, nadolol,atenolol, and metoprolol (β-blockers),flunarizine (H 1-histamine, dopamine,and calcium antagonist), pizotifen (pizotyline,5-HT-antagonist), methysergide(partial 5-HT ID-agonist and nonselective5-HT-antagonist, p. 126), NSAIDs(p. 200), and calcitonin (p. 264) may decreasethe frequency, intensity, and durationof migraine attacks. Among the β-blockers (p. 90), only those lacking intrinsicsympathomimetic activity are effective.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Therapy of Selected Diseases 323When therapeutic effect inadequateAcetylsalicylic acid 1000 mgor acetaminophen 1000 mgSumatriptanand other triptansor(Dihydro)-Ergotamine6 mg 100 mg 1 mg 1-2 mgMigraineMetoclopramideMigraine attack:HeadacheHypersensitivityofolfaction, gustation,audition, visionNausea, vomitingNeurogenicinflammation,local edema,vasodilationGastric emptyinginhibited accelerateddelayedDrugabsorptionimproved5-HT 1DRelief ofmigraine5-HT 1DSumatriptanand other triptans5-HT 1AD 2PsychosisNausea,vomiting5-HT 1AD 2Ergotamine5-HT 2Plateletaggregation5-HT 2α 1 + α 2Vasoconstrictionα 1 + α 2A. Migraine and its treatmentLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
324 Therapy of Selected DiseasesCommon ColdThe common cold—colloquially the flu,catarrh, or grippe (strictly speaking, therarer infection with influenza viruses)—is an acute infectious inflammation ofthe upper respiratory tract. Its symptoms,sneezing, running nose (due torhinitis), hoarseness (laryngitis), difficultyin swallowing and sore throat(pharyngitis and tonsillitis), cough associatedwith first serous then mucoussputum (tracheitis, bronchitis), soremuscles, and general malaise can bepresent individually or concurrently invarying combination or sequence. Theterm stems from an old popular beliefthat these complaints are caused by exposureto chilling or dampness. Thecausative pathogens are different viruses(rhino-, adeno-, parainfluenza v.) thatmay be transmitted by aerosol dropletsproduced by coughing and sneezing.Therapeutic measures. First attemptsof a causal treatment consist ofzanamavir, an inhibitor of viral neuraminidase,an enzyme necessary for virusadsorption and infection of cells. However,since symptoms of common coldabate spontaneously, there is no compellingneed to use drugs. Conventionalremedies are intended for symptomaticrelief.Rhinitis. Nasal discharge could beprevented by parasympatholytics; however,other atropine–like effects (pp.104ff) would have to be accepted.Therefore, parasympatholytics arehardly ever used, although a correspondingaction is probably exploited inthe case of H 1 antihistamines, an ingredientof many cold remedies. Locally applied(nasal drops) vasoconstricting α-sympathomimetics (p. 90) decongestthe nasal mucosa and dry up secretions,clearing the nasal passage. Long-termuse may cause damage to nasal mucousmembranes (p. 90).Sore throat, swallowing problems.Demulcent lozenges containingsurface anesthetics such as ethylaminobenzoate(benzocaine) or tetracaine(p. 208) may provide relief; however,the risk of allergic reactions should beborne in mind.Cough. Since coughing serves toexpel excess tracheobronchial secretions,suppression of this physiologicalreflex is justified only when coughing isdangerous (after surgery) or unproductivebecause of absent secretions. Codeineand noscapine (p. 212) suppresscough by a central action.Mucous airway obstruction. Mucolytics,such as acetylcysteine, split disulfidebonds in mucus, hence reduce itsviscosity and promote clearing of bronchialmucus. Other expectorants (e.g.,hot beverages, potassium iodide, andipecac) stimulate production of waterymucus. Acetylcysteine is indicated incystic fibrosis patients and inhaled as anaerosol. Whether mucolytics are indicatedin the common cold and whetherexpectorants like bromohexine or ambroxoleeffectively lower viscosity ofbronchial secretions may be questioned.Fever. Antipyretic analgesics (acetylsalicylicacid, acetaminophen, p. 198)are indicated only when there is high fever.Fever is a natural response and usefulin monitoring the clinical course ofan infection.Muscle aches and pains, headache.Antipyretic analgesics are effectivein relieving these symptoms.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Therapy of Selected Diseases 325Local use ofα-sympathomimetics(nasal drops or spray)AcetylsalicylicacidAcetaminophenSorenessHeadacheFeverH 1 -AntihistaminesCaution: sedationViral infectionDecongestion of mucousmembranesSniffles,runny noseCommon coldFluCausal therapyimpossibleSurface anestheticsCaution:risk of sensitizationAntitussive:DextrometorphanCodeineSore throatCoughMucolyticsAcetylcysteineExpectorants:Stimulation of bronchial secretionGivewarm fluidsPotassiumiodidesolutionBromhexineAirway congestionAccumulation in airwaysof mucus, inadequateexpulsion by coughA. Drugs used in common coldLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
326 Therapy of Selected DiseasesAllergic DisordersIgE-mediated allergic reactions (p. 72)involve mast cell release of histamine(p. 114) and production of other mediators(such as leukotrienes, p. 196). Resultantresponses include: relaxation ofvascular smooth muscle, as evidenced locallyby vasodilation (e.g., conjunctivalcongestion) or systemically by hypotension(as in anaphylactic shock); enhancedcapillary permeability withtransudation of fluid into tissues—swelling of conjunctiva and mucousmembranes of the upper airways (“hayfever”), cutaneous wheal formation;contraction of bronchial smooth muscle—bronchial asthma; stimulation of intestinalsmooth muscle—diarrhea.1. Stabilization of mast cells.Cromolyn prevents IgE-mediated releaseof mediators, although only afterchronic treatment. Moreover, by interferingwith the actions of mediator substanceson inflammatory cells, it causesa more general inhibition of allergic inflammation.It is applied locally to: conjunctiva,nasal mucosa, bronchial tree(inhalation), intestinal mucosa (absorptionalmost nil with oral intake). Indications:prophylaxis of hay fever, allergicasthma, and food allergies.2. Blockade of histamine receptors.Allergic reactions are predominantlymediated by H 1 receptors. H 1antihistamines (p. 114) are mostly usedorally. Their therapeutic effect is oftendisappointing. Indications: allergicrhinitis (hay fever).3. Functional antagonists of mediatorsof allergy. a) α-Sympathomimetics,such as naphazoline, oxymetazoline,and tetrahydrozoline, are appliedtopically to the conjunctival andnasal mucosa to produce local vasoconstriction,and decongestion and to dryup secretions (p. 90), e.g., in hay fever.Since they may cause mucosal damage,their use should be short-term.b) Epinephrine, given i.v., is themost important drug in the managementof anaphylactic shock: it constricts bloodvessels, reduces capillary permeability,and dilates bronchi.c) β 2-Sympathomimetics, such asterbutaline, fenoterol, and albuterol, areemployed in bronchial asthma, mostlyby inhalation, and parenterally in emergencies.Even after inhalation, effectiveamounts can reach the systemic circulationand cause side effects (e.g., palpitations,tremulousness, restlessness, hypokalemia).During chronic administration,the sensitivity of bronchial musculatureis likely to decline.d) Theophylline belongs to themethylxanthines. Whereas caffeine(1,3,7-trimethylxanthine) predominantlystimulates the CNS and constrictscerebral blood vessels, theophylline(1,3-dimethylxanthine) possesses additionalmarked bronchodilator, cardiostimulant,vasorelaxant, and diuretic actions.These effects are attributed toboth inhibition of phosphodiesterase(→ c AMP elevation, p. 66) and antagonismat adenosine receptors. In bronchialasthma, theophylline can be givenorally for prophylaxis or parenterally tocontrol the attack. Manifestations ofoverdosage include tonic-clonic seizuresand cardiac arrhythmias as earlysigns.e) Ipratropium (p. 104) can be inhaledto induce bronchodilation; however,it often lacks sufficient effectivenessin allergic bronchospasm.f) Glucocorticoids (p. 248) havesignificant anti-allergic activity andprobably interfere with different stagesof the allergic response. Indications: hayfever, bronchial asthma (preferably localapplication of analogues with high presystemicelimination, e.g., beclomethasone,budesonide); anaphylactic shock(i.v. in high dosage)—a probably nongenomicaction of immediate onset.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Therapy of Selected Diseases 327Antigen (e.g., pollen, penicillin G)IgE AntibodiesMast cell stabilizationbycromolynOOHO CH2 CH CH2 O OOOC O OCOORelease ofhistamineH 1 -AntihistaminesInhibitors ofleukotriene synthesis:e. g., zileutonClNLeukotrienesSOHCH3CH3COOHLeukotriene receptorantagonist:e. g., zafirlukastGlucocorticoidsHistaminereceptorLeukotrienereceptorReaction of target cellsVascular smooth muscle, permeabilityVasodilation EdemaBronchial musculatureContractionBronchial asthmaα-Sympathomimetics:e. g.,naphazolineNNHMucous membranesof nose and eye:redness swelling,secretionSkin:wheal formationβ2-Sympathomimetics:e. g.,terbutalineHOOHOHHNCH 3CH 3CH 3TheophyllineEpinephrineCirculation:anaphyl. shockH 3 COOHNNCH 3A. Anti-allergic therapyLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
328 Therapy of Selected DiseasesBronchial AsthmaDefinition: a recurrent, episodic shortnessof breath caused by bronchoconstrictionarising from airway inflammationand hyperreactivity.Asthma patients tend to underestimatethe true severity of their disease.Therefore, self-monitoring by the use ofhome peak expiratory flow meters is anessential part of the therapeutic program.With proper education, the patientcan detect early signs of deteriorationand can adjust medication withinthe framework of a physician-directedtherapeutic regimen.Pathophysiology. One of the mainpathogenetic factors is an allergic inflammationof the bronchial mucosa.For instance, leukotrienes that areformed during an IgE-mediated immuneresponse (p. 326) exert a chemotacticeffect on inflammatory cells. Asthe inflammation develops, bronchi becomehypersensitive to spasmogenicstimuli. Thus, stimuli other than theoriginal antigen(s) can act as triggers(A); e.g., breathing of cold air is an importanttrigger in exercise-inducedasthma. Cyclooxygenase inhibitors(p. 196) exemplify drugs acting as asthmatriggers.Management. Avoidance of asthmatriggers is an important prophylacticmeasure, though not always feasible.Drugs that inhibit allergic inflammmatorymechanisms or reduce bronchialhyperreactivity, viz., glucocorticoids,“mast-cell stabilizers,” and leukotrieneantagonists, attack crucial pathogeneticlinks. Bronchodilators, such as β 2-sympathomimetics,theophylline, and ipratropium,provide symptomatic relief.The step scheme (B) illustrates successivelevels of pharmacotherapeuticmanagement at increasing degrees ofdisease severity.First treatment of choice for theacute attack are short-acting, aerosolizedβ 2-sympathomimetics, e.g., salbutamol,albuterol, terbutaline, fenoterol, andothers. Their action occurs within minutesand lasts for 4 to 6 h.If β 2-mimetics have to be usedmore frequently than three times aweek, more severe disease is present. Atthis stage, management includes antiinflammatorydrugs, such as “mast-cellstabilizers” (in children or juvenile patients)or else glucocorticoids. Inhalationaltreatment must be administeredregularly, improvement being evidentonly after several weeks. With properuse of glucocorticoids undergoing highpresystemic elimination, concern aboutsystemic adverse effects is unwarranted.Possible local adverse effects are:oropharyngeal candidiasis and dysphonia.To minimize the risk of candidiasis,drug administration should occur beforemorning or evening meals, or befollowed by rinsing of the oropharynx.Anti-inflammatory therapy is the moresuccessful the less use is made of asneededβ 2-mimetic medication.Severe cases may, however, requirean intensified bronchodilator treatmentwith systemic β 2-mimetics or theophylline(systemic use only; low therapeuticindex; monitoring of plasma levelsneeded). Salmeterol is a long-acting inhalativeβ 2-mimetic (duration: 12 h; onset~20 min) that offers the advantage ofa lower systemic exposure. It is usedprophylactically at bedtime for nocturnalasthma.Zafirlukast is a long-acting, selective,and potent leukotriene receptor(LTD 4, LTE 4) antagonist with anti-inflammatory/antiallergicactivity and efficacyin the maintenance therapy ofchronic asthma. It is given both orallyand by inhalation. The onset of action isslow (3 to 14 d). Protective effectsagainst inhaled LTD 4 last up to 12 to24 h.Ipratropium may be effective insome patients as an adjunct anti-asthmatic,but has greater utility in preventingbronchospastic episodes in chronicbronchitis.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Therapy of Selected Diseases 329AllergensInflammationAntigens,infections,ozone,SO 2 , NO 2Noxious stimuliDust,cold air,drugsBronchial hyperreactivityBronchialspasmAvoidexposureTreatinflammationDilatebronchiA. Bronchial asthma, pathophysiology and therapeutic approachModified afterINTERNATIONALCONSENSUSREPORT 1992Glucocorticoidssystemic< –Maintained bronchodilation3 x /week < – 4 x/day< – 4 x/day< – 4 x/dayTheophylline p.o./ß 2 -mimetics p.o.or long-acting ß 2 -mimetics inhalative"or""or/and"ParasympatholyticsAntiinflammatory treatment, inhalative, chronically“ Mast cellstabilizer”Glucocorticoids Glucocorticoidsorglucocorticoids or leukotriene antagonistsBronchodilation as needed: short-acting inhalative β 2 -mimeticsMild asthmaModerate asthmaSevere asthmaB. Bronchial asthma treatment algorithmLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
330 Therapy of Selected DiseasesEmesisIn emesis the stomach empties in a retrogrademanner. The pyloric sphincteris closed while the cardia and esophagusrelax to allow the gastric contents tobe propelled orad by a forceful, synchronouscontraction of abdominal wallmuscles and diaphragm. Closure of theglottis and elevation of the soft palateprevent entry of vomitus into the tracheaand nasopharynx. As a rule, thereis prodromal salivation or yawning. Coordinationbetween these differentstages depends on the medullary centerfor emesis, which can be activatedby diverse stimuli. These are conveyedvia the vestibular apparatus, visual, olfactory,and gustatory inputs, as wellas viscerosensory afferents from theupper alimentary tract. Furthermore,psychic experiences may also activatethe emetic center. The mechanismsunderlying motion sickness (kinetosis,sea sickness) and vomiting during pregnancyare still unclear.Polar substances cannot reach theemetic center itself because it is protectedby the blood-brain barrier. However,they can indirectly excite the centerby activating chemoreceptors in thearea postrema or receptors on peripheralvagal nerve endings.Antiemetic therapy. Vomiting canbe a useful reaction enabling the body toeliminate an orally ingested poison.Antiemetic drugs are used to prevent kinetosis,pregnancy vomiting, cytotoxicdrug-induced or postoperative vomiting,as well as vomiting due to radiationtherapy.Motion sickness. Effective prophylaxiscan be achieved with the parasympatholyticscopolamine (p. 106) and H 1antihistamines (p. 114) of the diphenylmethanetype (e.g., diphenhydramine,meclizine). Antiemetic activity is not aproperty shared by all parasympatholyticsor antihistamines. The efficacy ofthe drugs mentioned depends on the actualsituation of the individual (gastricfilling, ethanol consumption), environmentalconditions (e.g., the behavior offellow travellers), and the type of motionexperienced. The drugs should betaken 30 min before the start of traveland repeated every 4 to 6 h. Scopolamineapplied transdermally through anadhesive patch can provide effectiveprotection for up to 3 d.Pregnancy vomiting is prone tooccur in the first trimester; thus pharmacotherapywould coincide with theperiod of maximal fetal vulnerability tochemical injury. Accordingly, antiemetics(antihistamines, or neuroleptics ifrequired) should be used only whencontinuous vomiting threatens to disturbelectrolyte and water balance to adegree that places the fetus at risk.Drug-induced vomiting. To preventvomiting during anticancerchemotherapy (especially with cisplatin),effective use can be made of 5-HT 3-receptor antagonists (e.g., ondansetron,granisetron, and tropisetron), alone or incombination with glucocorticoids(methylprednisolone, dexamethasone).Anticipatory nausea and vomiting, resultingfrom inadequately controllednausea and emesis in patients undergoingcytotoxic chemotherapy, can be attenuatedby a benzodiazepine such aslorazepam. Dopamine agonist-inducednausea in parkinsonian patients (p. 188)can be counteracted with D 2-receptorantagonists that penetrate poorly intothe CNS (e.g., domperidone, sulpiride).Metoclopramide is effective in nauseaand vomiting of gastrointestinal origin(5-HT 4-receptor agonism) and at highdosage also in chemotherapy- and radiation-inducedsickness (low potencyantagonism at 5-HT 3- and D 2-receptors).Phenothiazines (e.g., levomepromazine,trimeprazine, perphenazine) maysuppress nausea/emesis that followscertain types of surgery or is due to opioidanalgesics, gastrointestinal irritation,uremia, and diseases accompaniedby elevated intracranial pressure.The synthetic cannabinoids dronabinoland nabilone have antinauseant/antiemeticeffects that may benefitAIDS and cancer patients.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Therapy of Selected Diseases 331PregnancyvomitingKinetosese.g., sea sicknessChemoreceptorsPsychogenicvomitingEmetic centerSightOlfactionVestibularsystemArea postremaTasteIntramucosal sensory nerveendings in mouth, pharynx,and stomachChemoreceptors(drug-inducedvomiting)ParasympatholyticsScopolamineH 1 -AntihistaminesDopamine antagonistsO NHHNONN NClDomperidoneDiphenhydramineMetoclopramideMeclozineOndansetron5-HT 3 -antagonistA. Emetic stimuli and antiemetic drugsLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
332Further ReadingA. Foundations and basic principles ofpharmacologyHardman JG, Limbird LE. Goodman &Gilman’s. The pharmacological basis oftherapeutics. 9 th ed. New York:McGraw-Hill; 1996.Levine RR. <strong>Pharmacology</strong>: drug actionsand reactions. 5 th ed. New York: ParthenonPublishing Group; 1996.Munson PL, Mueller RA, Breese GR. Principlesof pharmacology. London: Chapman& Hall; 1995.Mutschler E, Derendorf H. Drug actions—basicprinciples and therapeuticaspects. Stuttgart: Medpharm ScientificPub.; Boca Raton: CRC Press; 1995.Page CR, Curtis MJ, Sutter MC, WalkerMJA, Hoffman BB. Integrated pharmacology.London: Mosby; 1997.Pratt WB, Taylor P. Principles of drug action—thebasis of pharmacology. 3 rd ed.New York: Churchill Livingstone; 1990.Rang HP, Dale MM, Ritter JM, GardinerP. <strong>Pharmacology</strong>. 4 th ed. New York:Churchill Livingstone; 1999.B. Clinical pharmacologyDipiro JT, Talbert RL, Yee GC, Matzke GR,Wells BG, Posey LM. Pharmacotherapy–apathophysiological approach. 3 rded. Norwalk, Conn: Appleton & Lange;1997.Kuemmerle H, Shibuya T, Tillement JP.Human pharmacology: the basis of clinicalpharmacology. Amsterdam: Elsevier;1991.Laurence DR, Bennett PN. Clinical pharmacology.8 th ed. Edinburgh: ChurchillLivingstone; 1998.Melmon KL, Morelli HF, Hoffman BB,Nierenberg DW. Clinical <strong>Pharmacology</strong>—basicprinciples in therapeutics. 3 rded. New York: McGraw-Hill; 1992.The Medical Letter on Drugs and Therapeutics.New Rochelle NY: The MedicalLetter Inc.; published bi-weekly.Clinical <strong>Pharmacology</strong>—Electronic drugreference. Tampa, Florida: Gold StandardMultimedia Inc.; updated every4 months.C. Drug interactions and adverse effectsD’Arcey PF, Griffin JP. Iatrogenic diseases.Oxford: Oxford University Press;1986.Davies DM. Textbook of adverse drugreactions. 4 th ed. Oxford: Oxford UniversityPress; 1992.Hansten PD, Horn JR. Drug interactions,analysis and management. Vancouver,WA: Applied Therapeutics Inc.; 1999;updated every 4 months.D. Drugs in pregnancy and lactationBriggs GG, Freeman RK, Yaffe SJ. Drugsin pregnancy and lactation: a referenceguide to fetal and neonatal risk. 5 th ed.Baltimore: Williams & Wilkins; 1998.Rubin PC. Prescribing in pregnancy. London:British Medical Journal; 1987E. PharmacokineticsRowland M, Tozer TN. Clinical pharmacokinetics:concepts and applications.3 rd ed. Baltimore: Williams & Wilkins;1995.F. ToxicologyAmdur MO, Doull J, Klaassen CD. Casarettand Doull’s toxicology: the basicscience of poisons. 5 th ed. New York:McGraw-Hill; 1995.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
333Drug IndexesNomenclature. The terms active agentand pharmacon designate substancesthat are capable of modifying life processesirrespective of whether the effectselicited may benefit or harm theorganisms concerned. By this definition,a toxin is also a pharmacon. Taken in anarrower sense, a pharmacon means asubstance that is used for therapeuticpurposes. An unequivocal term for sucha substance is medicinal drug.A drug can be identified by differentdesignations:– the chemical name– the generic (nonproprietary) name– a trade or brand nameThe drug diazepam may serve as anillustrative example. Chemically, thiscompound is called 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one,a term too unwieldy foreveryday use. A simpler name is diazepam.This is not a legally protectedname but a generic (nonproprietary)name. An INN (= international nonproprietaryname) is a generic name thathas been agreed upon by an internationalcommission.Preparations containing diazepamwere first marketed under the tradename Valium by its manufacturer, Hoffmann–LaRoche, Inc. This name is a registeredtrademark. After patent protectionfor the manufacture of diazepamcontainingdrug preparations expired,other companies were free to producepreparations containing this drug. Eachinvented a proprietary name for its“own” preparation. As a result, therenow exists a plethora of proprietary labelsfor diazepam preparations (as of1991, more than 50). Some of these easilyreveal the active ingredient, becausethe company name is simply added tothe generic name, e.g., Diazepam- (company’sname). Other designations arenew creations, as for example, Vivol.Similarly, some other commerciallysuccessful drugs are sold under morethan 20 different brand labels. The numberof proprietary names, therefore,greatly exceeds the number of availabledrugs.For the sake of clarity, only INNs orgeneric (nonproprietary) names areused in this atlas to designate drugs,such as the name “diazepam” in theabove example.Use of IndexesThe indexes are meant to help the reader:1. identify a commercial preparation fora given drug. This <strong>info</strong>rmation is foundin the index “Generic Name → PoprietaryName.”2. obtain <strong>info</strong>rmation about the pharmacologicalproperties of the active ingredientin a commercial preparation. Inorder to find the generic (nonproprietary)name, the second index “ProprietaryName → Generic Name” can beconsulted. Page references pertaining tothe drug can then be looked up in the Index.The list of proprietary names givenbelow will necessarily be incompletedue to their multitude. For drugs thatare marketed under several brandnames, the trade name of the originalmanufacturer will be listed; in the caseof some frequently prescribed generics,some proprietary names of other manufacturerswill also be listed. Brandnames that clearly reveal the drug’sidentity have been omitted. Combinationpreparations have not been included,barring a few exceptions.Many a brand name is not listed inthe index “Proprietary Name → GenericName.” In these cases, it will be useful toconsult the packaging <strong>info</strong>rmation,which should list the generic (nonproprietary)name or INN.Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
334Drug IndexDrug NameTrade NameAAbacavirAbciximabAcarboseAcebutololAcenocoumarin (= Nicoumalone)AcetaminophenAcetazolamideAcetylcysteineAcetyldigoxinAcetylsalicylic acidAciclovirACTHActinomycin DAcyclovirADH (= Vasopressin)AdrenalinAdriamycinAjmalineAlbuterolAlcuroniumAldosteroneAlendronateAlfentanilAlfuzosinAllopurinolAlprazolamAlprenololAlprostadil (= PGE 1)AlteplaseAluminium hydroxideAmantadineAmbroxolAmikacinAmilorideAmiloride + Hydrochlorothiazideε-Aminocaproic acidε-Aminocaproic acid + ThromboplastinAminomethylbenzoic acid5-Aminosalicylic acidAmiodaroneAmitriptylineAmodiaquineAmoxicillin(* denotes investigational drug status in USA)ZiagenReoProPrecoseMonitan, SectralSintromsee ParacetamolDiamox, GlaupaxAirbron, Fabrol, Mucomyst, ParvolexAcylanidAspirin, Arthrisin, Asadrine, Ecotrin,Entrophen, Pyronoval, SupasaZoviraxActhar, CortrophinCosmegenZoviraxPitressin, Presynsee epinephrineSee doxorubicinCardiorhythmino; GilurytmalSee SalbutamolAlloferinAldocortenFosamaxAlfentaAlfoten, XatralAlloprin, Novopurol, Urosin, Zyloprim, ZyloricXanaxAprobal, Aptine, GubernalProstin VR, MinprogActivaseAldrox, Alu-Tab, Amphojel, FluagelSolu-Contenton, Virofral, SymmetrelAmbril, Bronchopront, Mucosolvan, SurfactalAmikin, Briclin, NovaminArumil, Colectril, Midamor, NiluridModuretAmicar, Afibrin, CapramolEpsilon-TachostyptanGumbix, PambaPropasa, RezipasCordarex, CordaroneAmitril, Elavil, Endep, Enovil, Levate, MevarilCamoquin, FlavoquineAmoxil, Clamoxyl, Moxacin, NovamoxinLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Name → Trade Name 335d-AmphetamineAmphotericin BAmpicillinAmrinoneAncrod*Angiotensin IIAprindineArdeparinArticaineAstemizoleAtenololAtorvastatinAtracuriumAtropineAuranofinAurothioglucoseAzapropazoneAzathioprineAzidothymidineAzithromycinAzlocillinAztreonamDexedrine, SynatanAmphozone, Fungilin, Fungizone, MoronalAmcill, Omnipen, Penbritin, Polycillin, Principen, TotacillinInocor, WincoramArvin, Arwin, ViprinexHypertensinAmidonal, Aspenon, FibocilNormifloUltracain, UbistesinHismanalPrenormine, TenorminLipitorTracriumAtropisol, BorotropinRidauraAureotan, Auromyose, SolganalProlixanAzanin, Imuran, ImurekRetrovirZithromaxAzlin, SecuropenAzactamBBacitracinBaclofenBasiliximabBeclomethasoneBenazeprilBenserazideBenzathine-Penicillin GBenztropineBenzbromaroneBenzocaineBetaxololBezafibrateBifonazoleBiperidenBisacodylBismuth subsalicylateBisoprololBitolterolBleomycinBotulinum Toxin Type ABromazepamBromhexineBromocriptineBrotizolamBucindolol*Altracin, Baciguent, TopitracinLioresalSimulectAldecin, Beclovent, Beconase, Becotide, Propaderm,VancerilLotensinMadopar (plus Levodopa)Bicillin, Megacillin, TardocillinCogentinDesuric, Narcaricin, Normurat, UricovacAnaesthesin, Americaine, AnacaineBetoptic, KerloneBefizal, Bezalip, Bezatol, CedurAmycor, Bedriol, Mycospor, MycosporanAkineton, AkinophylBicol, Broxalax, Durolax, Dulcolax, Laxanin, Laxbene,Nigalax, Pyrilax, Telemin, UlcolaxPepto-BismolConcor, Detensiel, Emcor, Isoten, Soprol, ZebetaEffectin, TornalateBlenoxaneOculinumDurazanil, Lectopam, LexotanAuxit, Bisolvon, OphthosolParlodel, Pravidel, Serono-BagrenLendorm (A), LendorminBextraLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
336 Drug Name → Trade NameBudesonideBumetanideBunitrololBupranololBuprenorphineBupropionBuserelinBuspironeBusulfanButizidN-Butyl-scopolaminePulmicort, SpirocortBumex, Burinex, Fontego, FordiuranBetriol, StressonBetadran, Betadrenol, Looser, PanimitBuprene, TemgesicWellbatrin, WellbutrinSprecur, SuprefactBusparMielucin, Mitosan, Myleran, SulfabutinSaltucinBuscopan, Hyoscin-N-ButylbromidCCalcifediolCalcitoninCalcitriolCalcium carbonateCamazepamCanrenoneCandesartanCapreomycinCaptoprilCarazololCarbacholCarbamazepineCarbenicillinCarbenoxoloneCarbidopa + LevodopaCarbimazoleCarboplatinCarteololCarvedilolCefalexinCefazolinCefiximeCefmenoximeCefoperazoneCefotaximeCefoxitinCeftazidimeCeftriaxoneCefuroxime axetilCelluloseCephalexinCerivastatinChenodeoxycholic acidChloralhydrateChlorambucilChloramphenicolChlorhexidineCalderol, Dedrogyl, HidroferolCalcimer, Calsynar, Cibacalcin, KarilRocaltrolCalsan, Caltrate, Nu-CalAlbegoKanrenol, Soldactone, VenactoneAtacandCapastat, CaprolinAcediur, Acepril, Alopresin, Capoten, Cesplon, Hypertil,Lopirin, TensobonConducton, SuacronDoryl, Miostat, LentinEpitol, Mazepine, Sirtal, Tegretol, TimonilAnabactyl (A), Carindapen, Geopen, Pyopen<strong>Bio</strong>gastrone, <strong>Bio</strong>plex, Neogel, SanodinIsicom, Nacom, SinemetNeo-Mercazole, Neo-ThyreostatParaplatinArteoptic, Caltidren, Carteol, Endak, Ocupress, TenalinCoregKeflex, KeftabAncef, KetzolSupraxBestcall, Cefmax, Cemix, TacefCefobid, Cefobis, TomabefClaforanMefoxinFortaz, Fortum, TacicefAcantex, RocephinCeftinAvicelCepexin (A), Ceporex, Keflex, LosporalBaycolChenixLorinal, Noctec, SomnosChloraminophene, LeukeranChloromycetin, Chloroptic, Leukomycin, Paraxin, Sopamycetin,SpersanicolBaxedin, Chlor-hex, Hibidil, Hibitane, Plak-outLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Name → Trade Name 337Chlormadinone acetateChloroquineChlorpromazineChlorpropamideChlorprothixeneChlorthalidoneCholecalciferolClorazepateCilazaprilCimetidineCiprofloxacinCisaprideCisplatinCitalopramClarithromycinClavulanic Acid + AmoxicillinClemastineClindamycinClobazamClodronate*ClofazimineClofibrateClomethiazoleClomipheneClonazepamClonidineClopidogrelClostebolClotiazepamClotrimazoleCloxacillinClozapineCodeineColestipolColestyramineCorticotropinCortisol (Hydrocortisone)CortisoneCotrimoxazoleCromoglycate (Cromolyn)CyanocobalaminCyclofenilCyclopenthiazideCyclophosphamideCyclosporineCyproheptadineCyproterone-acetateCytarabineGestafortinAralen, Avloclor, QuinachlorLargactil, Hibanil, Megaphen, ThorazineDiabineseTaractan, Tarasan, TruxalHygrotonD-Tabs, Vigantol, VigorsanNovoclopate, TranxeneInhibacePeptol, TagametCiprobay, CiproPropulsidPlatinex, PlatinolCelexaBiaxinAugmentinTavistCleocin, Dalacin, SobelinFrisiumClasteon, Ossiten, OstacLamprenAtromid-S, Claripex, SkleromexeDistraneurin, HemineurinClomid, Dyneric, Omifin, Pergotime, SeropheneClonopin, Iktorivil, RivotrilCatapres, DixaritPlavixMacrobin, SteranabolClozan, Rize, Tienor, Trecalmo, VeratranCanesten, Clotrimaderm, Gyne-Lotrimin, Mycelex,TrimystenClovapen, TegopenClozarilCodicept, PaveralCholestabyl, CholestidQuestran, CuemidActhar, Cortigel, CortrophinAlocort, Cortate, Cortef, Cortenema, Hyderm, Hyocort,Rectocort, UnicortCortelan, Cortogen, CortoneBactrim, Novotrimel, Protrin SeptraIntal, Nalcrom, Opticrom, Rynacrom, VistacromAnacobin, Bedoz, Rubion, RubraminFertodur, Ondogyne, Ondonid, Sanocrisin, SexovidNavidrix, SalimidCytoxan, Endoxan, ProcytoxNeoral, Sandimmune, Sang-35Anarexol, Nuran, Periactin, Peritol, VimiconAndrocurUdicil, CytosarLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
338 Drug Name → Trade NameDDaclizumabDactinomycinDalteparinDanaparoidDantroleneDapsoneDaunorubicinDeferoxamineDelavirdineDesipramineDesmopressinDesogestrel + EthinylestradiolDexamethasoneDexetimideDextranDiazepamDiazoxideDiclofenacDicloxacillinDidanosine (ddI)DiethylstilbestrolDigitoxinDigoxin immune FABDihydralazineDihydroergotamineDiltiazemDimenhydrinateDinoprostZenapaxSee Actinomycin DFragminOrgaranDantriumAvlosulfone, Eporal, Diphenasone, UdolacCerubidine, Daunoblastin, OndenaDesferalRescriptorPertofran, NorpraminDDAVP, Minirin, StimateMarvelonDecadron, Deronil, Hexadrol, SpersadexTremblexHyskonApaurin, Atensine, Diastat, Dizac, Eridan, Lembrol,Meval, Noan, Tensium, Valium, Vatran, VivolEudemine, Hyperstat, Mutabase, ProglicemAllvoran, Diclophlogont, Rhumalgan, Voltaren, VoltarolDiclocil, Dynapen, PathocilVidexHonvolCrystodigin, Digicor, Digimerck, Digacin, Lanicor,Lanoxin, Lenoxin, NovodigoxinDigibindDihyzin, Nepresol, PressunicAngionorm, D.E.H.45, Dihydergot, Divegal, EndophlebanCardizemDimetab, Dramamine, Dymenate, MarmineMinprostin F 2α, Prostarmon, Prostin F 2 AlphaDinoprostone Prepidil, Prostin E 2DiphenhydramineAllerdryl, Benadryl, Insommal, NautamineDiphenoxylateDiarsed, Lomotil, RetardinDisopyramideNorpace, RythmodanDobutamineDobutrexDocetaxelTaxotereDolasetronAnzemetDomperidone*Euciton, Evoxin, Motilium, Nauzelin, PeridonDopamineDopastat, IntropinDorzolamideTrusoptDoxacuriumNuromaxDoxazosinCardura, CarduranDoxepinAdapin, Sinequan, TriadapinDoxorubicinAdriblastin, AdriamycinDoxycyclineC-Pak, Doxicin, VibramycinDoxylamineDecaprynDronabinolMarinolDroperidolInapsine, DroleptanLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Name → Trade Name 339EEconazoleEcothiopateEnalaprilEnfluraneEnoxacinEnoxaparinEntacapone*EpinephrineEphedrineEprosartanEptifibatideErgocalciferolErgometrine (= Ergonovine)ErgonovineErgotamineErythomcyinErythromycin-estolateErythromycin-ethylsuccinateErythromycin-propionateErythromycin-stearateErythromycin-succinateErythropoietin (= epoetin alfa)EsmololEstradiolEstradiol-benzoateEstradiol-valerateEstratriol = EstriolEtanerceptEthacrynic acidEthambutolEthinylestradiolEthionamideEthopropazineEthosuximideEtidocaineEtidronateEtilefrineEtodolacEtomidateEtoposideEtretinateEcostatin, Gyno-PevarylPhospholine IodideVasotec, XanefEthraneBactidan, Comprecin, EnoramLovenoxComtanAdrenalin, Bronchaid, Epifin, Epinal, EpiPen, Epitrate,Lyophrin, Simplene, Suprarenin, VaponefrineBofedrol, Efedron, Va-tro-nolTevetenIntegrilineDrisdolErgotrate Maleate, ErmalateErgotrateErgomar, Gynergen, MigrilE-mycin, Eryc, ErythromidDowmycin, Ilosone, NovorythroEES, Erythrocin, WyamycinCimetrinErymycin, ErythrocinMonomycinEpogenBreviblocEstraceProgynon BDelestrogen, Dioval, Femogex, ProgynovaTheelolEnbrelEdecrin, Hydromedin, ReomaxEtibi, MyambutolEstinyl, Feminone, LynoralTrecatorParsitan, ParsitolPetinimid, Suxinutin, ZarontinDuranestCalcimux, Diodronel, DiphosApocretin, Effontil, Effortil, Ethyl Adrianol, Circupon,Kertasin, Pulsamin,LodineAmidateToposar, VePesidTegison, TigasonFFamotidineFelbamateFelodipineFelypressinFenfluraminePepcid, PepdulFelbatolPlendilOctapressinGanal, Ponderal, PondiminLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
340 Drug Name → Trade NameFenofibrateFenoldopamFenoprofenFenoterolFentanylFentanyl + DroperidolFinasterideFlecainideFlucloxacillinFluconazoleFlucytosineFludrocortisoneFlumazenilFlunarizineFlunisolideFlunitrazepam*Fluoxetine5-FluorouracilFlupentixolFluphenazineFlurazepam*FlutamideFluticasoneFluvastatinFluvoxamineFolic acidFoscarnetFosinoprilFurosemideLipidyl, TricorCorlopamNalfon, NalgesicBerotec, PartusistenSublimazeInnovarPropecia, ProscarTambocorFlucloxDiflucanAlcoban, AncotilAlflorone, F-Cortef, FlorinefAnexate, RomaziconDinaplex, Flugeral, SibeliumAerobid, Bronalide, Nasalide, RhinalarHypnosedon, Narcozep, RohypnolProzacAdrucil, Effudex, EffurixDepixol, FluanxolModiten, ProlixinDalmaneDrogenil, EulexinCutivate, Flixonase, Flonase, FloventLescolFloxifral, Faverin, LuvoxFoldine, Folvite, LeucovorinFoscavirMonoprilFusid, Lasix, Seguril, UritolGGabapentinGallamineGallopamilGanciclovirGelatin-colloidsGemfibrozilGentamicinGlibenclamide (= glyburide)GlimepirideGlipizideGlyceryltrinitrate (= nitroglycerin)GlycopyrrolateGonadorelinGoserelinGramicidinGranisetronGriseofulvinGuanabenzGuanethidineGuanfacineNeurontinFlaxedilAlgocor, Corgal, Procorum, WingomCytovene, VitrasertGelafundin, HaemaccelLopidCidomycin, Garamycin, Refobacin, SulmycinDaonil, DiaBeta, Euglucon, Glynase, MicronaseAmarylGlucotrolAng-O-Span, Nitrocap, Nitrogard, Nitroglyn,Nitrolingual, Nitrong, NitrostatRobinulFactrel, Kryptocur, RelefactZoladexGramodermKytrilFulvicin, Grisovin, LikudenWytensinIsmelin, VisutensilTenexLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Name → Trade Name 341HHalofantrineHaloperidolHalothaneHCG (= chorionic gonadotropin)HeparinHeparin, low molecularHetastarch (HES)HexachlorophaneHexobarbitalHydralazineHydrochlorothiazideHydromorphoneHydroxocobalaminHydroxychloroquineHydroxyethyl starchHydroxyprogesterone caproateHyoscyamine sulfateHalfanHaldol, SerenaceFluothane, NarkotanChorex, Choron, Entromone, Follutein, Gonic,Pregnesin, Pregnyl, ProfasiCalciparin, Hepalean, LiqueminFragmin, FraxiparinHespansee LindaneEvipalAlazine, ApresolineAprozide, Diaqua, Diuchlor, Esidrex, Hydromal, Neo-Codema, OreticDilaudid, HymorphanActi-B 12, Alpha-redisol, SytobexPlaquenilHespanDuralutin, Gesterol L.A., Hylutin, Hyroxon, Pro-DepoCystospaz-M, Levbid, LevsinIIbuprofenIdoxuridineIfosfamideIloprostImipramineIndapamideIndinavirIndomethacinInfliximabInsulinActiprophen, Advil, Motrin, Nuprin, TrendarDendrid, Herplex, Kerecid, StoxilIfexLatanaprostDynaprin, Impril, Janimine, Melipramin, Tofranil,TypramineLozide, Lozol, NatrilixCrixivanAmmuno, Indocid, Indocin, Indome, MetacenRemicadeHumalog, Humulin, Iletin, Novolin, VelosulinInterferon-α2 Berofor alpha 2Interferon-α2bIntron AInterferon-α2aRoferon A3Interferon-β Fiblaferon 3Interferon-β-1aAvonexInterferon-β-1bBetaseronInterferon-γActimmuneIpratropiumAtrovent, ItropIrbesartanAvaproIsoconazoleGyno-Travogen, TravogenIsoetharineArm-a-Med, Bisorine, Bronkosol, Dey-LuteIsofluraneForaneIsoniazidArmazid, Isotamine, Lamiazid, Nydrazid, Rimifon, TeebaconinIsoprenaline (= Isoproterenol)Aludrin, Isuprel, Neo Epinin, SaventrineIsosorbide dinitrateCedocard, Coradus, Coronex, Isordil, Sorbitrate5-Isosorbide mononitrateColeb, Elantan, IsmoIsotretinoinAcutane Roche, RoaccutanLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
342 Drug Name → Trade NameIsoxsuprineIsradipineItroconazoleRolisox, Vasodilan, VasoprineDynaCircSporanoxKKanamycinKaolin + Pectin (= attapulgite)KetamineKetoconazolKetorolacKetotifenAnamid, Kantrex, KlebcilKaopectate, Donnagel-MB, PectokayKetalarNizoralAcular, ToradolZaditenLLabetalolLactuloseLamivudine (3TC)LamotrigineLansoprazoleLeflunomideLepirudinLeuprorelideLevodopaLevodopa + BenserazideLevodopa + CarbidopaLevomepromazineLidocaineLincomycinLindaneLiothyronineLisinoprilLispro insulinLisurideLithium carbonateLithium carbonateLomustineLoperamideLoratidineLorazepamLorcainideLormetazepamLosartanLovastatinLypressinNormodyne, TrandateCephulac, Chronulac, DuphalacEpivirLamictalPrevacidAravaRefludanLupronLarodopa, Dopar, DopaidanMadopar, ProlopaSinemetLevoprome, NozinanDalcaine, Lidopen, Nulicaine, Xylocain, XylocardAlbiotic, Cillimycin, LincocinHexit, Kwell, Kildane, ScabeneCytomel, TriostatPrinivil, ZestrilHumalogCuvalit, Dopergin, Eunal, LysenylCarbolite, Duoralith, EskalithLithane, Lithobid, LithotabsCeeNuImodium, Kaopectate IIClaritinAlzapam, Ativan, LorazLopantrol, Lorivox, RemivoxErgocalm, Loramet, NoctamidCozaarMevacor, MevinacorDiapid, Vasopressin SandozMMannitolMaprotilineMazindolMebendazoleMechlorethamineIsotol, OsmitrolLudiomilMazonor, SanorexVermoxMustargenLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Name → Trade Name 343Meclizine (meclozine)Antivert, Antrizine, Bonamine, WhevertMeclofenamateMeclomenMedroxyprogesterone-acetateAmen, Depo-Provera, OragestMefloquineLariamMelphalanAlkeranMenadioneSynkayvitMeperidineDemerolMepindololBetagon, Caridian, CorindolanMepivacaineCarbocaine, Isocaine6-MercaptopurinePurinetholMesalamine (Mesalazine)Asacol, Pentasa, RowasaMesnaMesnex, UromitexanMesteroloneAndroviron, ProvironMestranolMenophase, Norquen, OvastolMetamizol (= Dipyrone)Algocalmin, Bonpyrin, Divarine, Feverall, Metilon, Novalgin,Paralgin, SulpyrinMetaproterenolAlupent, MetaprelMetforminDiabex, GlucophageMethadoneDolophine, Methadose, PhysoseptoneMethamphetamineDesoxyn, MethampexMethimazoleTapazoleMethohexitalBrevitalMethotrexateFolex, MexateMethoxyfluranePenthrane, MethofaneMethyl-DopaAldomet, Amodopa, Dopamet, Novomedopa, Presinol,SembrinaMethylcelluloseCelevac, Cellothyl, Citrucel, Cologel, Lacril, MurocelMethylergometrine (Methylergonovine) Methergine, Metenarin, Methylergobrevin, Ryegonovin,Partergin, Spametrin-MMethylphenidateRitalinMethylprylonNoludarMethyltestosteroneAndroid, Metandren, Testred, VirilonMethysergideSansertMetipranololOptipranololMetoclopramideClopra, Emex, Maxeran, Maxolan, Reclomide, ReglanMetoprololBetaloc, LopressorMetronidazoleClont, Femazole, Flagyl, Metronid, Protostat, SatricMexiletinMexitilMezlocillinMezlinMianserinBolvidon, NorvalMibefradilPosicorMiconazoleMicatin, MonistatMidazolamVersedMifepristone RU 486MilrinonePrimacorMinocyclineMinocin, VectrinMinoxidilLoniten, RogaineMisoprostolCytotecMithramycinMithracinMitoxantroneNovantroneMivacuriumMiracronMoclobemideAurorixMolsidomineCorvaton, Duracoron, MolsidolatLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
344 Drug Name → Trade NameMontelukastMorphine hydrochlorideMorphine sulfateMuromonab-CD3Mycophenolate MofetilSingulairMorphitecAstramorph, Duramorph, Epimorph, Roxanol, StatexOrthoclone OKT3CellCeptNNabiloneNadololNaftifinNalbuphineNalidixic acidNaloxoneNaltrexoneNandroloneNaphazolineNaproxenNarcotine (= Noscapine)Nadroparin*NedocromilNelfinavirNeomycinNeostigmineNetilmicinNevirapine<strong>Nica</strong>rdipineNiclosamideNifedipineNimodipineNisoldipineNitrazepamNitrendipineNitroglycerinNitroprusside sodiumNizatidineNor-DiazepamNoradrenalin (= Norepinephrine)NorethisteroneCesametCorgardNaftinNubainNegram, NogramNarcanNalorex, Revia, TrexanAnabolin, Androlone, Deca-Durabolin, Hybolin Decanoate,KabolinAlbalon, Degest-2, Privine, VasoconAleve, Naprosyn, NaxenCoscopin, CoscotabFraxiparineTiladeViraceptMycifradin, MyciguentProstigminNetromycinViramuneCardeneNiclocide, YomesanAdalat, ProcardiaNimotopSularAtempol, MogadonBayotensin, BaypressSee Glyceryl trinitrateNipride, NitropressAxidTranxilium N, VegesanArterenol, LevophedMicronor= Norethindrone Norlutin, Nor-Q DNorfloxacinNoroxinNoscapine (= Narcotine)Coscopin, CoscotabNortriptylinePamelorNystatinKorostatin, Mycostatin, Mykinac, Nilstat, Nystex, O-VStatinOOctreotide<strong>Of</strong>loxacinOlanzapineOmeprazoleSandostatinTarividZyprexaLosec, PrilosecLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Name → Trade Name 345OndansetronZofranOpium Tincture (laudanum)ParegoricOrciprenaline (= Metaproterenol) AlupentOrnipressin POR 8OxacillinBactocill, ProstaphlinOxatomideTinsetOxazepamOxpam, Serax, ZapexOxiconazoleOxistatOxprenololTrasicorOxymetazolineAfrin, Allerest, Coricidin, Dristan, Neo-Synephrine,SinarestOxytocinPitocin, SyntocinonPPaclitaxelPamidronatePancuroniumPantoprazole*PapaverineParacetamol = acetaminophenParomomycinParoxetinePenbutololPenciclovirD-PenicillaminePenicillin GPencillin VPentazocinePentobarbitalPentoxifyllinePergolidePerindoprilPermethrinPethidine = MeperidinePhencyclidinePheniraminePhenobarbitalPhenolphthaleinPhenoxybenzaminePhenprocoumonPhentolaminePhenylbutazonePhenytoinPhysostigminePhytomenadioneTaxolAminomuxPavulonPantolacCerebid, Cerespan, Delapav, Myobid, Papacon, Pavabid,Pavadur, VasalAcephen, Anacin-3, Bromo-Seltzer, Datril, Tempra,Tylenol, Valadol, ValorinHumatinPaxilLevatolDenavirCuprimine, DepenBicillin, Cryspen, Deltapen, Lanacillin, Megacillin, Parcillin,Pensorb, Pentids, Permapen, PfizerpinBetapen-VK, Bopen-VK, Cocillin-VK, Lanacillin-VK, LedercillinVK, Nadopen-V, Novopen-VK, Penapar VK,Penbec-V, Pen-Vee K, Pfizerpen VK, Robicillin-VK, Uticillin-VK,V-Cillin K, VeetidsFortral, TalwinButylone, Nembutal, Novarectal, PentancaTrentalPermaxCoversumElimite, Nix, PermanoneDemerol, DolantinSernylDaneral, InhistonBarbita, Gardenal, SolfotonAlophen, Correctol, Espotabs, Evac-U-gen, Evac-U-Lax,Ex-Lax, Modane, PruletDibenzylineLiquamar, MarcumarRegitin, RogitinAlgoverine, Azolid, Butagen, Butazolidin, MalgesicDilantinAntiliriumKonakionLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
346 Drug Name → Trade NamePilocarpinePindololPiperacillinPipecuroniumPirenzepinePiroxicamPizotifen = PizotylinePlicamycinPolidocanolPranlukast*PravastatinPrazepamPraziquantelPrazosinPrednisolonePrednisonePrilocainePrimaquinePrimidoneProbenecidProbucolProcaineProcainamideProcarbazineProcyclidineProgabideProgesteronePromethazinePropafenonePropofolPropranololPropylthiouracilPyrantel PamoatePyrazinamidePyridostigminePyridoxinePyrimethaminePyrimethamine + SulfadoxineAkarpine, Almocarpine, I-Pilopine, Miocarpine, Isopto-Carpine, PilokairViskenPipracilArduanGastrozepinFeldenLitec, Mosegor, SandomigranMithracinThesitUltairPravacholCentraxBiltricideMinipressArticulose, Codelsol, Cortalone, Delta-Cortef, Deltastab,Econopred, Hydeltrasol, Inflamase, Key-Pred, Metalone,Metreton, Pediapred, Predate, Predcor, PreloneMeticorten, Orasone, Panasol, WinpredCitanest, XylonestPrimaquineMyidone, Mysoline, SertanBenemid, ProbalanLovelcoNovocaineProcan SR, Promine, Pronestyl, RhythminNatulanKemadrinGabren(e)Femotrone, ProgestasertAnergan, Ganphen, Mallergan, Pentazine, Phenazine,Phenergan, Prometh, Prorex, Provigan, RemsedRhythmolDiprivanDetensol, InderalPropyl-ThyracilAntiminthAldinamide, TebrazidMestinon, RegonolBee-six, Hexa-Betalin, PyroxineDaraprimFansidarQQuazepamQuinacrineQuinaprilQuinidineQuinineDoralAtabrineAccuprilCardioqin, Cin-Quin, Quinalan, Quinidex, QuinoraQuinaminoph, Quinamm, Quine, QuiniteLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Name → Trade Name 347RRaloxifeneRamiprilRanitidineRemifentanilRepaglinideReserpineRibavirinRifabutinRifampinRitodrineRitonavirRocuroniumRolitetracyclinRopinirole*RoxithromycinEvistaAltaceZantacUltivaActulin, NovoNorm, PrandinSandril, Serpalan, Serpasil, ZepineVirazole, RebetolMycobutinRifadin, RimactanYutoparNorvirZemuronReverin, Transcycline, VelacyclineReQuipRulidSSalazosulfapyridine = sulfasalazineSalbutamol (= Albuterol)Salicylic acidSameterolSaquinavirScopolamineSelegelineSennaSertindole*SibutramineSildenafilSimethiconeSimvastatinSitosterolSotalolSpectinomycinSpiramicinSpironolactoneStavudine (d4T)StreptokinaseStreptomycinStreptozocinSuccinylcholineSucralfateSufentanilSulfacetamideSulfacytineSulfadiazineSulfadoxine + PyrimethamineSulfamethoxazoleSulfapyridineSulfisoxazoleAzaline, Azulfidine, S.A.S.-500, SalazopyrinProventil, Novosalmol, VentolinAcnex, Sebcur, Soluver, Trans-Ver-SalSereventFortovase, InviraseTransderm Scop, TriptoneCarbex, Deprenyl, EldeprylBlack Draught, Fletcher’s Castoria, Genna, GentleNature, Nytilax, Senokot, SenolaxSerlectReductilViagraGas.X, Mylicon, Phazyme, SilainZocorSito-LandeSotacorTrobicinRovamycin, SelectomycinAldactoneZeritKabikinase, StreptaseStrepolin, StreptosolZanosarAnectine, Quelicin, SuccostrinCarafate, SulcrateSufentaAK-Sulf Forte, Cetamide, Sulamyd, Sulair, Sulfex, SultenRenoquidMicrosulfonProklarGamazole, Gantanol, MethanoxanolDagenanGantrisin, GulfasinLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
348 Drug Name → Trade NameSulfasalazineSulfinpyrazoneSulprostoneSulthiameSumatriptanAzaline, Azulfidine, SalazopyrinAnturan, AprazoneNaladorOspolotImitrexTt-PA (= alteplase)TacrineTacrolimusTamoxifenTemazepamTeniposideTerazosinTerbutalinTerfenadineTestosterone cypionateTestosterone enantateTestosterone propionateTesterone undecanoateTetracaineTetryzoline (= tetrahydrozoline)ThalidomideTheophyllineThiabendazoleThiamazole (= Methimazole)ThiopentalThio-TEPAThrombinThyroxineTiagabineTicarcillinTiclopidineTimololTinidazolTinzaparin*TirofibanTizanidineTobramycinTocainideTolbutamideTolcaponeTolmetinTolnaftateTolonium chlorideTolterodine tartrateTopiramateTramadolTrandolaprilTranexamic acidTranylcypromineActivaseCognexPrografNolvadex, TamofenEuhypnos, RestorilVumonHytrinBrethine, BricanylSeldaneAndrocyp, Andronate, Duratest, TestojectAndro, Delatestryl, Everone, TestoneTestexAndriolAnethaine, PontocaineCollyrium, Murine, Tyzine, VisineContergan, SynovirAerolate, Bronkodyl, Constant-T, Elixophyllin, Quibron-T, Slo-bid, Somophyllin-T, Sustaire, Theolair, UniphylMintezolTapazole, MercazolPentothal, TrapanalThiotepa LederleThrombinar, ThrombostatCholoxinGabitrilTicarTiclidBlocadren, TimopticFasigyn(CH), Simplotan, SorquetanInnohepAggrastatZanaflexNebcin, TobrexTonocardMobenol, Oramide, OrinaseTasmarTolectinPitrex, TinactinKlot, ToazulDetrolTopamexTramalMavikCyklocapronParnateLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Name → Trade Name 349TrazodoneTriamcinoloneTriamcinolone acetonideTriamtereneTriazolamTrichlormethiazideTrifluoperazineTrifluridineTrihexipheidylTriiodothyronine (= Liothyronine)TrimethaphanTrimethoprimTriptorelinTroglitazoneTropicamideTropisetrond-TubocurarineTyrothricinDesyrel, TrialodineAristocort, Azmacort, Kenacort, Ledercort(CH), VolonAdicort, Azmacort, Kenalog, Kenalone, Triam-ADyreniumHalcionMetahydrin, Naqua, TrichlorexStelazineViropticAparkane, Artane, Tremin, TrihexaneCytomelArfonadProloprim, TrimpexDecapeptylRezulinMydriacyl, MydralNavobanTubarineHydrotricinUUrokinaseUrsodeoxycholic acid = ursodiolAbbokinase, UkidanActigall, Destolit, UrsofalkVValacyclovirValproic AcidValsartanVancomycinVasopressinVecuroniumVenlafaxineVerapamilVidarabineVigabatrin*VinblastineVincamineVincristineViomycineVit. B 12Vit. B 6Vit. DValtrexDepakeneDiovanVancocin, Vancomycin CP LillyPitressinNorcuronEffexorCalan, Isoptin, VerelanVira-ASabrilVelban, VelbeCerebroxineOncovinCeliomycin,Vinactane, Viocin, VionactaneBay-Bee, Berubigen, Betalin 12, Cabadon, Cobex,Cyanoject, Cyomin, Pemavit, Redisol, Rubesol, Sytobex,VibalBee Six, Hexa-Betalin, PyroxineCalciferol, DrisdolWWarfarinCoumadin, Panwarfin, SofarinLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
350 Drug Name → Trade NameDrug Name → Trade Name 350XXanthinol nicotinateXylometazolineComplaminChlorohist, Neosynephrine II, Sinutab, SustaineZZafirlukastZalcitabineZidovudineZileutonZolpidemZopicloneAccolateHividRetrovirZyfloAmbienAmoban, Amovane, Imovane, ZimovaneLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Name → Trade Name 351Drug Name Trade Name Drug Name Trade NameAAbbokinase UrokinaseAcantexCeftriaxoneAccolate ZafirlukastAccupril QuinaprilAcediurCaptoprilAcephen Paracetamol = acetaminophenAceprilCaptoprilAcnexSalicylic acidActharACTHActharCorticotropinActi-B 12 HydroxocobalaminActigall Ursodeoxycholic acid =ursodiolActimmune Interferon-γActiprophen IbuprofenActivase t-PA (= alteplase)ActulinRepaglinideAcularKetorolacAcutane Roche IsotretinoinAcylanid AcetyldigoxinAdalatNifedipineAdapinDoxepinAdicortTriamcinolone acetonideAdrenalin EpinephrineAdriamycin DoxorubicinAdriblastin DoxorubicinAdrucil5-FluorouracilAdvilIbuprofenAerobidFlunisolideAerolate TheophyllineAfibrinε-Aminocaproic acidAfrinOxymetazolineAggrastat TirofibanAirbronAcetylcysteineAkarpine PilocarpineAkineton BiperidenAkinophyl BiperidenAK-Sulf Forte SulfacetamideAlazineHydralazineAlbalonNaphazolineAlbegoCamazepamAlbioticAlcobanAldactoneAldecinAldinamideAldocortenAldometAldroxAlfentaAlfloroneAlfotenAlgocalminAlgocorAlgoverineAlkeranAllerdrylAllerestAlloferinAlloprinAllvoranAlmocarpineAlocortAlophenAlopresinAlpha-redisolAltaceAltracinAlu-TabAludrinAlupentAlzapamAmarylAmbienAmbrilAmcillAmenAmericaineAmicarAmidateAmidonalAmikinAminomuxLincomycinFlucytosineSpironolactoneBeclomethasonePyrazinamideAldosteroneMethyl-DopaAluminium hydroxideAlfentanilFludrocortisoneAlfuzosinMetamizol (= Dipyrone)GallopamilPhenylbutazoneMelphalanDiphenhydramineOxymetazolineAlcuroniumAllopurinolDiclofenacPilocarpineCortisol (Hydrocortisone)PhenolphthaleinCaptoprilHydroxocobalaminRamiprilBacitracinAluminium hydroxideIsoprenaline (= Isoproterenol)MetaproterenolLorazepamGlimepirideZolpidemAmbroxolAmpicillinMedroxyprogesteroneacetateBenzocainee-Aminocaproic acidEtomidateAprindineAmikacinPamidronateLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
352 Drug Name → Trade NameAmitrilAmitriptylineAmmuno IndomethacinAmoban ZopicloneAmodopa Methyl-DopaAmovane ZopicloneAmoxilAmoxicillinAmphojel Aluminium hydroxideAmphozone Amphotericin BAmycorBifonazoleAnabactyl(A) CarbenicillinAnabolin NandroloneAnacaine BenzocaineAnacin-3 Paracetamol = acetaminophenAnacobin CyanocobalaminAnaesthesin BenzocaineAnamidKanamycinAnarexol CyproheptadineAncefCefazolinAncotilFlucytosineAndriolTesterone undecanoateAndroTestosterone enantateAndrocur Cyproterone-acetateAndrocyp Testosterone cypionateAndroid MethyltestosteroneAndrolone NandroloneAndronate Testosterone cypionateAndroviron MesteroloneAnectine SuccinylcholineAnergan PromethazineAnethaine TetracaineAnexate FlumazenilAng-O-Span Glyceryltrinitrate (=nitroglycerin)Angionorm DihydroergotamineAntilirium PhysostigmineAntiminth Pyrantel PamoateAntivert Meclizine (meclozine)Antrizine Meclizine (meclozine)Anturan SulfinpyrazoneAnzemet DolasetronAparkane TrihexiphenidylApaurinDiazepamApocretin EtilefrineAprazone SulfinpyrazoneApresoline HydralazineAprobalAlprenololAprozide HydrochlorothiazideAptineAlprenololAralenChloroquineAravaLeflunomideArduanPipecuroniumArfonadTrimethaphanAristocort TriamcinoloneArm-a-Med IsoetharineArmazid IsoniazidArtaneTrihexiphenidylArteoptic CarteololArterenol Noradrenalin (= Norepinephrine)Arthrisin Acetylsalicylic acidArticulose PrednisoloneArumilAmilorideArvinAncrodArwinAncrodAsacolMesalamineAsadrine Acetylsalicylic acidAspenon AprindineAspirinAcetylsalicylic acidAstramorph Moiphine sulfateAtabrine QuinacrineAtacand CandesartanAtempol NitrazepamAtensine DiazepamAtivanLorazepamAtromid-S ClofibrateAtropisol AtropineAtrovent IpratropiumAugmentin Clavulanic Acid + AmoxicillinAureotan AurothioglucoseAuromyose AurothioglucoseAurorixMoclobemideAuxitBromhexineAvaproIrbesartanAvicelCelluloseAvloclor ChloroquineAvlosulfone DapsoneAxidNizatidineAzactam AztreonamAzaline Salazosulfapyridine =sulfasalazineAzaninAzathioprineAzlinAzlocillinAzmacort TriamcinoloneAzmacort Triamcinolone acetonideAzolidPhenylbutazoneAzulfidine Salazosulfapyridine =sulfasalazineAzulfdine SulfasalazineBBaciguentBactidanBacitracinEnoxacinLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Name → Trade Name 353BactocillBactrimBarbitaBaxedinBay-BeeBaycolBayotensinBaypressBecloventBeconaseBecotideBedozBedriolBee SixBefizalBenadrylBenemidBerofor alpha 2BerotecBerubigenBestcallBetadranBetadrenolBetagonBetalin 12BetalocBetapen-VKBetopticBextraBezalipBezatolBiaxinBicillinBicolBiltricide<strong>Bio</strong>gastrone<strong>Bio</strong>plexBisolvonBisorineBlack DraughtBlenoxaneBlocadrenBofedrolBolvidonBonamineBonpyrinBopen-VKBorotropinBrethineBreviblocBrevitalBricanylBriclinOxacillinCotrimoxazolePhenobarbitalChlorhexidineVit. B12CerivastatinNitrendipineNitrendipineBeclomethasoneBeclomethasoneBeclomethasoneCyanocobalamineBifonazoleVit. B6 PyridoxineBezafbrateDiphenhydramineProbenecidInterferon-a2FenoterolVit. B12CefmenoximeBupranololBupranololMepindololVit. B12MetoprololPencillin VBetaxololBucindolol*BezafibrateBezafibrateClarithromycinBenzathine-Penicillin GBisacodylPraziquantelCarbenoxoloneCarbenoxoloneBromhexineIsoetharineSennaBleomycinTimololEphedrineMianserinMeclizine (meclozine)Metamizol (= Dipyrone)Pencillin VAtropineTerbutalinEsmololMethohexitalTerbutalinAmikacinBromo-SeltzerBronalideBronchaidBronchoprontBronkodylBronkosolBroxalaxBumexBunitrololBupreneBurinexBuscopanBusparButagenButazolidinButyloneCParacetamol = acetaminophenFlunisolideEpinephrineAmbroxolTheophyllineIsoetharineBisacodylBumetanideBumetanideBuprenorphineBumetanideN-Butyl-scopolamineBuspironePhenylbutazonePhenylbutazonePentobarbitalC-PakDoxycyclineCabadon Vit. B12CalanVerapamilCalciferol Vit.DCalcimer CalcitoninCalcimux EtidronateCalderol CalcifediolCalsanCalcium carbonateCalsynar CalcitoninCaltidren CarteololCaltrateCalcium carbonateCamoquin AmodiaquineCanesten ClotrimazoleCapastat CapreomycinCapoten CaptoprilCapramol ε-Aminocaproic acidCaprolin CapreomycinCarafate SucralfateCarbexSelegelineCarbocaine MepivacaineCarbolite Lithium carbonateCardene <strong>Nica</strong>rdipineCardioqin QuinidineCardiorhythmino AjmalineCardizem DiltiazemCarduraDoxazosinCarduran DoxazosinCaridian MepindololCarindapen CarbenicillinCarteolCarteololCatapres ClonidineCedocard Isosorbide dinitrateCedurBezafibrateLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
354 Drug Name → Trade NameCeeNuLomustineCefmaxCefmenoximeCefobisCefmenoximeCefoperazone CefmenoximeCeftinCefuroxime axetilCelevacMethylcelluloseCeliomycin ViomycineCellCept Mycophenolate MofetilCellothyl MethylcelluloseCemixCefmenoximeCentraxPrazepamCepexin(A) CephalexinCephulac LactuloseCeporex CephalexinCerebidPapaverineCerebroxine VincamineCerespan PapaverineCerubidine DaunorubicinCesamet NabiloneCesplonCaptoprilCetamide SulfacetamideChenixChenodeoxycholic acidChlor-hex ChlorhexidineChloraminophene ChlorambucilChlorohist XylometazolineChloromycetin ChloramphenicolChloroptic ChloramphenicolCholestabyl ColestipolCholestid ColestipolCholoxin ThyroxineChorexHCG (= chorionic gonadotropin)ChoronHCG (= chorionic gonadotropin)Chronulac LactuloseCibacalcin CalcitoninCidomycin GentamicinCillimycin LincomycinCimetrin Erythromycin-propionateCin-Quin QuinidineCiproCiprofloxacinCiprobay CiprofloxacinCircupon EtilefrineCitanest PrilocaineCitrucelMethylcelluloseClaforan CefotaximeClamoxyl AmoxicillinClaripex ClofibrateClaritinLoratidineClasteon Clodronate*CleocinClindamycinClobazam ClindamycinClomidClonopinClontClopraClotrimadermCloxacillinClozanClozarilCobexCocillin-VKCodelsolCodiceptCogentinCognexColebColectrilCollyriumCologelComplaminComprecinComtanConcorConductonConstant-TConterganCoradusCordarexCordaroneCoregCorgalCorgardCoricidinCorindblanCorlopamCoronexCorrectolCortaloneCortateCortefCortelanCortenemaCortigelCortogenCortoneCortrophinCorvatonCoscopinClomipheneClonazepamMetronidazoleMetoclopramideClotrimazoleClotrimazoleClotiazepamClozapineVit. B12Pencillin VPrednisoloneCodeineBenztropineTacrine5-Isosorbide mononitrateAmilorideTetryzoline (= tetrahydrozoline)MethylcelluloseXanthinol nicotinateEnoxacinEntacapone*BisoprololCarazololTheophyllineThalidomideIsosorbide dinitrateAmiodaroneAmiodaroneCarvedilolGallopamilNadololOxymetazolineMepindololFenoldopamIsosorbide dinitratePhenolphthaleinPrednisoloneCortisol (Hydrocortisone)Cortisol (Hydrocortisone)CortisoneCortisol (Hydrocortisone)CorticotropinCortisoneCortisoneCorticotropinMolsidomineNoscapine (= Narcotine)Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Name → Trade Name 355Coscotab Narcotine (= Noscapine)Coscotab Noscapine (= Narcotine)Cosmegen Actinomycin DCoumadin WarfarinCoversum PerindoprilCozaarLosartanCrixivan IndinavirCryspen Penicillin GCrystodigin DigitoxinCuemidColestyramineCuprimine D-PenicillamineCutivate FluticasoneCuvalitLisurideCyanoject Vit. B 12Cyklocapron Tranexamic acidCyomin Vit. B 12Cystospaz-M Hyoscyamine sulfateCytomel Triiodothyronine (=Liothyronine)CytosarCytarabineCytotecMisoprostolCytovene GanciclovirCytoxan CyclophosphamideDD-TabsD.E.H.45DDAVPDagenanDalacinDalcaineDalmaneDaneralDantriumDaonilDaraprimDatrilDaunoblastinDeca-DurabolinDecadronDecapeptylDecaprynDedrogylDegest-2DelapavDelatestrylDelestrogenDelta-CortefCholecalciferolDihydroergotamineDesmopressinSulfapyridineClindamycinLidocaineFlurazepamPheniramineDantroleneGlibenclamide (= glyburide)PyrimethamineParacetamol = acetaminophenDaunorubicinNandroloneDexamethasoneTriptorelinDoxylamineCalcifediolNaphazolinePapaverineTestosterone enantateEstradiol-valeratePrednisoloneDeltapen Penicillin GDeltastab PrednisoloneduisolmeDemerol MeperidineDemerol Pethidine = MeperidineDenavirPenciclovirDendrid IdoxuridineDepakene Valproic AcidDepenD-PenicillamineDepixolFlupentixolDepo-Provera MedroxyprogesteroneacetateDeprenyl SelegelineDeronilDexamethasoneDesferal DeferoxamineDesoxyn MethamphetamineDestolit Ursodeoxycholic acid =ursodiolDesuricBenzbromaroneDesyrelTrazodoneDetensiel BisoprololDetensol PropranololDetrolTolteridine tartrateDexedrine d-AmphetamineDey-Lute IsoetharineDiaBetaGlibenclamide (= glyburide)DiabexMetforminDiamoxAcetazolamideDiapidLypressinDiaquaHydrochlorothiazideDiarsedDiphenoxylateDiastatDiazepamDibenzyline PhenoxybenzamineDiclocilDicloxacillinDiclophlogont DiclofenacDiflucan FluconazoleDigacinDigoxinDigibind Digoxin immune FABDigicorDigitoxinDigimerck DigitoxinDigitaline DigitoxinDihydergot DihydroergotamineDihyzinDihydralazineDilantinPhenytoinDilaudid HydromorphoneDimetab DimenhydrinateDinaplex FlunarizineDiodronel EtidronateDiovalEstradiol-valerateDiovanValsartanDiphenasone DapsoneDiphosEtidronateDiprivan PropofolLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
356 Drug Name → Trade NameDistraneurinDiuchlorDivarineDivegalDixaritDizacDobutrexDolantinDolophineDonnagel-MBDopaidanDopametDoparDopastatDoperginDoralDorylDowmycinDoxicinDoxylamineDramamineDrisdolDristanDrogenilDroleptanDulcolaxDuoralithDuphalacDuracoronDuralutinDuramorphDuranestDuratestDurazanilDurolaxDymenateDynaCircDynapenDynaprinDynericDyreniumEEconopredEnbrelE-mycinEcostatinEcotrinEdecrinEfedronClomethiazoleHydrochlorothiazideMetamizol (= Dipyrone)DihydroergotamineClonidineDiazepamDobutaminePethidine = MeperidineMethadoneKaolin + Pectin (= attapulgite)LevodopaMethyl-DopaLevodopaDopamineLisurideQuazepamCarbacholErythromycin-estolateDoxycyclineDoxycyclineDimenhydrinateErgocalciferol Vit. DOxymetazolineFlutamideDroperidolBisacodylLithium carbonateLactuloseMolsidomineHydroxyprogesteronecaproateMorphine sulfateEtidocaineTestosterone cypionateBromazepamBisacodylDimenhydrinateIsradipineDicloxacillinImipramineClomipheneTriamterenePrednisoloneEtanerceptErythomcyinEconazoleAcetylsalicylic acidEthacrynic acidEphedrineEffectinBitolterolEffexorVenlafaxineEffontilEtilefrineEffortilEtilefrineEffudex5-FluorouracilEffurix5-FluorouracilElantan5-Isosorbide mononitrateElavilAmitriptylineEldepryl SelegelineElimitePermethrinElixophyllin TheophyllineEmcorBisoprololEmexMetoclopramideEndakCarteololEndepAmitriptylineEndophleban DihydroergotamineEndoxan CyclophosphamideEnoramEnoxacinEnovilAmitriptylineEntromone HCG (= chorionic gonadotropin)Entrophen Acetylsalicylic acidEpiPenEpinephrineEpifinEpinephrineEpimorph Morphine sulfateEpinalEpinephrineEpitolCarbamazepineEpitrateEpinephrineEpivirLamivudine (3TC)EpogenErythropoietin (= epoetinalfa)EporalDapsoneErgocalm LormetazepamErgomar ErgotamineErgotrate ErgonovineErgotrate Maleate Ergometrine (= Ergonovine)EridanDiazepamErmalate Ergometrine (= Ergonovine)ErycErythromcyinErymycin Erythromycin-stearateErythrocin Erythromycin-estolateErythromid ErythomcyinEsidrexHydrochlorothiazideEskalithLithium carbonateEspotabs PhenolphthaleinEstinylEthinylestradiolEstraceEstradiolEthraneEnfluraneEthyl Adrianol EtilefrineEtibiEthambutolLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Name → Trade Name 357EucitonEudemineEugluconEuhypnosEulexinEunalEvac-U-LaxEvac-U-genEveroneEvipalEvistaEvoxinEx-LaxFDomperidone*DiazoxideGlibenclamide (= glyburide)TemazepamFlutamideLisuridePhenolphthaleinPhenolphthaleinTestosterone enantateHexobarbitalRaloxifeneDomperidone*PhenolphthaleinFontegoForaneFordiuranFortazFortovaseFortralFortumFosamaxFoscavirFragminFraxiparineFrisiumFulvicinFungilinFungizoneFusidBumetanideIsofluraneBumetanideCeftazidimeSaquinavirPentazocineCeftazidimeAlendronateFoscarnetDalteparinNadroparin*ClobazamGriseofulvinAmphotericin BAmphotericin BFurosemideF-Cortef FludrocortisoneFabrolAcetylcysteineFactrelGonadorelinFansidar Pyrimethamine + SulfadoxineFasigyn(CH) TinidazolFaverinFluvoxamineFelbatolFelbamateFeldenPiroxicamFemazole MetronidazoleFeminone EthinylestradiolFemogex Estradiol-valerateFemotrone ProgesteroneFertodur CyclofenilFeverallMetamizol (= Dipyrone)Fiblaferon 3 Interferon-bFibocilAprindineFlagylMetronidazoleFlavoquine AmodiaquineFlaxedilGallamineFletcher’s Castoria SennaFlixonase FluticasoneFlonaseFluticasoneFlorinefFludrocortisoneFloventFluticasoneFloxifral FluvoxamineFluagelAluminium hydroxideFluanxol FlupentixolFlucloxFlucloxacillinFlugeralFlunarizineFluothane HalothaneFoldineFolic acidFolexMethotrexateFollutein HCG (= chorionic gonadotropin)FolviteFolic acidGGabitrilGabren(e)GamazoleGanalGanphenGantanolGantrisinGaramycinGardenalGas. XGastrozepinGelafundinGennaGentle NatureGeopenGestafortinGesterol L.A.GilurytmalGlaupaxGlucophageGlucotrolGonicGramodermGrisovinGubernalGulfasinGumbixGyne-LotriminGynergenGyno-PevarylGyno-TravogenTiagabineProgabideSulfamethoxazoleFenfluraminePromethazineSulfamethoxazoleSulfisoxazoleGentamicinPhenobarbitalSimethiconePirenzepineGelatin-colloidsSennaSennaCarbenicillinChlormadinone acetateHydroxyprogesteronecaproateAjmalineAcetazolamideMetforminGlipizideHCG (= chorionic gonadotropin)GramicidinGriseofulvinAlprenololSulfisoxazoleAminomethylbenzoicacidClotrimazoleErgotamineEconazoleIsoconazoleLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
358 Drug Name → Trade NameHHaemaccel Gelatin-colloidsHalcionTriazolamHaldolHaloperidolHalfanHalofantrineHemineurin ClomethiazoleHepalean HCG (= chorionic gonadotropin)HeparinHCG (= chorionic gonadotropin)HerplexIdoxuridineHespanHetastarch Hydroxyethylstarch (HES)Hexa-Betalin Pyridoxine Vit. B6Hexadrol DexamethasoneHexitChlorhexidineHidroferol CalcifediolHismanal AstemizoleHividZalcitabineHonvolDiethylstilbestrolHumalog InsulinHumatin ParomomycinHumulin InsulinHybolin DecanoateNandroloneHydeltrasol PrednisoloneHyderm Cortisol (Hydrocortisone)Hydromal HydrochlorothiazideHydromedin Ethacrynic acidHydrotricin TyrothricinHygroton ChlorthalidoneHylutinHydroxyprogesteronecaproateHymorphan HydromorphoneHyocortCortisol (Hydrocortisone)Hyoscin-N-ButylbromidN-Butyl-scopolamineHyperstat DiazoxideHypertensin Angiotensin IIHypertil CaptoprilHypnosedon Flunitrazepam*Hyroxon HydroxyprogesteronecaproateHyskonDextranHytrinTerazosinII-PilopineIfexPilocarpineIfosfamideIfosfamideIktorivilIletinIlosoneImitrexImodiumImovaneImprilImuranImurekInapsineInderalIndocidIndocinIndomeInflamaseInhibaceInhistonInnohepInnovarInocorInsommalIntalIntegrilineIntron AIntropinInviraseIsicomIsmelinIsmoIsocaineIsoptinIsopto-CarpineIsordilIsotamineIsotenIsotolIsuprelItropJJanimineKKabikinaseKabolinKanrenolKantrexIdoxuridineClonazepamInsulinErythromycin-estolateSumatriptanLoperamideZopicloneImipramineAzathioprineAzathioprineDroperidolPropranololIndomethacinIndomethacinIndomethacinPrednisolonechnisoloveCilazaprilPheniramineTinzaparin*Fentanyl + DroperidolAmrinoneDiphenhydramineCromoglycateEptifibatideInterferon-a2bDopamineSaquinavirCarbidopa + LevodopaGuanethidine5-Isosorbide mononitrateMepivacaineVerapamilPilocarpineIsosorbide dinitrateIsoniazidBisoprololMannitolIsoprenaline (= Isoproterenol)IpratropiumImipramineStreptokinaseNandroloneCanrenoneKanamycinLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Name → Trade Name 359KaopectateKaopectate IIKarilKeflexKeflexKeftabKemadrinKenacortKenalogKenaloneKerecidKerloneKertasinKetalarKetzolKey-PredKildaneKlebcilKlotKonakionKorostatinKryptocurKwellKytrilLLacrilLamiazidLamictalLamprenLanacillinLanacillin-VKLanicorLanoxinLargactilLariamLarodopaLasixLaxaninLaxbeneLectopamLedercillin VKLedercort(CH)LembrolLendorm(A)LendorminLenoxinLentinKaolin + Pectin (= attapulgite)LoperamideCalcitoninCefalexinCephalexinCefalexinProcyclidineTriamcinoloneTriamcinolone acetonideTriamcinolone acetonideIdoxuridineBetaxololEtilefrineKetamineCefazolinPrednisoloneLindaneKanamycinTolonium chloridePhytomenadioneNystatinGonadorelinLindaneGranisetronMethylcelluloseIsoniazidLamotrigineClofaziminePenicillin GPenicillin VDigoxinDigoxinChlorpromazineMefloquineLevodopaFurosemideBisacodylBisacodylBromazepamPencillin VTriamcinoloneDiazepamBrotizolamBrotizolamDigoxinCarbacholLescolLevopromeLevsinLexotanLidopenLikudenLincocinLindaneLioresalLipitorLiquamarLiqueminLitecLithaneLithobidLithotabsLodineLomotilLonitenLooserLopantrolLopidLopirinLopressorLorametLorazLorinalLorivoxLosecLosporalLotensinLovelcoLovenoxLozideLozolLudiomilLupronLuvoxLynoralLyophrinLysenylMNoradrenalin (= Norepinephrine)LevomepromazineHyoscyamine sulfateBromazepamLidocaineGriseofulvinLincomycinHexachlorophaneBaclofenAtorvastatinPhenprocoumonHCG (= chorionic gonadotropin)Pizotifen = PizotylineLithium carbonateLithium carbonateLithium carbonateEtodolacDiphenoxylateMinoxidilBupranololLorcainideGemfibrozilCaptoprilMetoprololLormetazepamLorazepamChloralhydrateLorcainideOmeprazoleCephalexinBenazeprilProbucolEnoxaparinIndapamideIndapamideMaprotilineLeuprorelideFluvoxamineEthinylestradiolEpinephrineLisurideMacrobin ClostebolMadopar Levodopa + BenserazideMadopar (plus Levodopa)BenserazideMalgesic PhenylbutazoneMallergan PromethazineLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
360 Drug Name → Trade NameMarcumarMarinolMarmineMarvelonMavikMaxeranMaxolanMazepineMazonorMeclomenMefoxinMegacillinMegaphenMelipraminMenophaseMercazolPhenprocoumonDronabinolDimenhydrinateDesogestrel + EthinylestradiolTrandolaprilMetoclopramideMetoclopramideCarbamazepineMazindolMeclofenamateCefoxitinBenzathine-Penicillin GChlorpromazineImipramineMestranolThiamazole (= Methimazole)MesnaPyridostigmineIndomethacinTrichlormethiazidePrednisoloneMethyltestosteroneMetaproterenolMethylcelluloseMethadoneMethamphetamineSulfamethoxazoleMethoxyfluraneMesnexMestinonMetacenMetahydrinMetaloneMetandrenMetaprelMetenarinMethadoseMethampexMethanoxanolMethofaneMethylergobrevin MethylcelluloseMethylergometrineMethylcelluloseMeticortenMetilonMetretonMetronidMevacorMevalMevarilMevinacorMexateMexitilMezlinMicatinMicronaseMicronorMicrosulfonMidamorMielucinMigrilMinipressPrednisoneMetamizol (= Dipyrone)PrednisoloneMetronidazoleLovastatinDiazepamAmitriptylineLovastatinMethotrexateMexiletinMezlocillinMiconazoleGlibenclamide (= glyburide)NorethisteroneSulfadiazineAmilorideBusulfanErgotaminePrazosinMinirinMinocinMinprogMinprostin F2aMintezolMiocarpineMiostatMithracinMitosanMobenolModaneModitenModuretMogadonMolsidolatMonistatMonitanMonomycinMonoprilMoronalMorphitecMosegorMotiliumMotrinMoxacinMucomystMucosolvanMurineMurocelMustargenMutabaseMyambutolMycelexMycifradinMyciguentMycobutinMycosporMycosporanMycostatinMydralMydriacylMyidoneMykinacMyleranMyliconMyobidMysolineDesmopressinMinocyclineAlprostadil (= PGE1)DinoprostThiabendazolePilocarpineCarbacholMithramycin, PlicamycinBusulfanTolbutamidePhenolphthaleinFluphenazineAmiloride + HydrochlorothiazideNitrazepamMolsidomineMiconazoleAcebutololErythromycin-succinateFosinoprilAmphotericin BMorphine hydrochloridePizotifen = PizotylineDomperidone*IbuprofenAmoxicillinAcetylcysteineAmbroxolTetryzoline (= tetrahydrozoline)MethylcelluloseMechlorethamineDiazoxideEthambutolClotrimazoleNeomycinNeomycinRifabutinBifonazoleBifonazoleNystatinTropicamideTropicamidePrimidoneNystatinBusulfanSimethiconePapaverinePrimidoneLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Name → Trade Name 361NNacomCarbidopa + LevodopaNadopen-V Pencillin VNaftinNaftifinNaladorSulprostoneNalcrom CromoglycateNalfonFenoprofenNalgesic FenoprofenNalorexNaltrexoneNaprosyn NaproxenNaquaTrichlormethiazideNarcanNaloxoneNarcaricin BenzbromaroneNarcozep Flunitrazepam*Narkotan HalothaneNasalide FlunisolideNatrilixIndapamideNatulanProcarbazineNautamine DiphenhydramineNauzelin Domperidone*Navidrix CyclopenthiazideNaxenNaproxenNebcinTobramycinNegramNalidixic acidNembutal PentobarbitalNeo Epinin Isoprenaline (= Isoproterenol)Neo-Codema HydrochlorothiazideNeo-Mercazole CarbimazoleNeo-Synephrine OxymetazolineNeo-Thyreostat CarbimazoleNeogelCarbenoxoloneNeoralCyclosporineNeosynephrine II XylometazolineNepresol DihydralazineNetromycin NetilmicinNeurontin GabapentinNiclocide NiclosamideNigalaxBisacodylNilstatNystatinNiluridAmilorideNimotop NimodipineNiprideNitroprusside sodiumNitrocap Glyceryltrinitrate (=nitroglycerin)Nitrogard Glyceryltrinitrate (=nitroglycerin)Nitroglyn Glyceryltrinitrate (=nitroglycerin)Nitrolingual Glyceryltrinitrate (=nitroglycerin)Nitrong Glyceryltrinitrate (=nitroglycerin)Nitropress Nitroprusside sodiumNitrostat Glyceryltrinitrate (=nitroglycerin)NixPermethrinNizoralKetoconazolNoanDiazepamNoctamid LormetazepamNoctecChloralhydrateNogramNalidixic acidNoludar MethylprylonNolvadex TamoxifenNor-Q D NorethindroneNorcuron VecuroniumNorlutin NorethindroneNormiflo ArdeparinNormodyne LabetalolNormurat BenzbromaroneNoroxin NorfloxacinNorpace DisopyramideNorpramin DesipramineNorquen MestranolNorvalMianserinNorvirRitonavirNovalgin Metamizol (= Dipyrone)Novamin AmikacinNovamoxin AmoxicillinNovantrone MitoxantroneNovarectal PentobarbitalNovoNorm RepaglinideNovocaine ProcaineNovoclopate ClorazepateNovodigoxin DigoxinNovolinInsulinNovomedopa Methyl-DopaNovopen-VK Pencillin VNovopurol AllopurinolNovorythro Erythromycin-estolateNovosalmol Salbutamol (= Albuterol)Novotrimel CotrimoxazoleNozinan LevomepromazineNu-CalCalcium carbonateNubainNalbuphineNulicaine LidocaineNuprinIbuprofenNuranCyproheptadineNuromax DoxacuriumNydrazid IsoniazidNystexNystatinNytilaxSennaLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
362 Drug Name → Trade NameOO-V StatinOctapressinOculinumOcupressOmifinOmnipenOncovinOndenaOndogyneOndonidOphthosolOpticromOptipranololOragestOramideOrasoneOreticOrgaranOrinaseOrthoclone OKT3OsmitrolOspolotOssitenOstacOvastolOxistatOxpamPPOR 8PambaPamelorPanasolPanimitPantolacPanwarfinPapaconParalginParaplatinParaxinParcillinParegoricParlodelParnateParomomycinNystatinFelypressinBotulinum Toxin TypeACarteololClomipheneAmphotericin BVincristineDaunorubicinCyclofenilCyclofenilBromhexineCromoglycateMetipranololMedroxyprogesteroneacetateTolbutamidePrednisoneHydrochlorothiazideDanaparoidTolbutamideMuromonab-CD3MannitolSulthiameClodronate*Clodronate*MestranolOxiconazoleOxazepamOrnipressinAminomethylbenzoicacidNortriptylinePrednisoneBupranololPantoprazole*WarfarinPapaverineMetamizol (= Dipyrone)CarboplatinChloramphenicolPenicillin GOpium Tincture (laudanum)BromocriptineTranylcypromineParacetamol = acetaminophenParsitan EthopropazineParsitolEthopropazinePartergin MethylcellulosePartusisten FenoterolParvolex AcetylcysteinePathocilDicloxacillinPavabidPapaverinePavadur PapaverinePaveralCodeinePavulonPancuroniumPaxilParoxetinePectokay Kaolin + Pectin (= attapulgite)Pediapred PrednisolonePemavit Vit. B12Penapar VK Pencillin VPenbec-V Pencillin VPenbritin Amphotericin BPensorbPenicillin GPentanca PentobarbitalPentasaMesalaminePentazine PromethazinePenthrane MethoxyfluranePentidsPenicillin GPentothal ThiopentalPepcidFamotidinePepdulFamotidinePepto-Bismol Bismuth subsalicylatePeptolCimetidinePergotime ClomiphenePeriactin CyproheptadinePeridonDomperidone*PeritolCyproheptadinePermanone PermethrinPermapen Penicillin GPermaxPergolidePertofran DesipraminePetinimid EthosuximidePfizerpin Penicillin GPhazyme SimethiconePhenazine PromethazinePhenergan PromethazinePhospholine IodideEcothiopatePhysoseptone MethadonePilokairPilocarpinePipracilPiperacillinPitocinOxytocinPitressin ADH (= Vasopressin)PitrexTolnaftatePlak-out ChlorhexidinePlaquenil HydroxychloroquinePlatinex CisplatinLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Name → Trade Name 363PlatinolPlavixPlendilPolycillinPonderalPondiminPontocainePosicorPrandinPravacholPravidelPredatePredcorPrecosePregnesinPregnylPrelonePrenorminePrepidilPresinolPressunicPresynPrevacidPrimacorPrimaquinePrincipenPrinivilPrivinePro-DepoProbalanProcan SRProcardiaProcorumProcytoxProfasiProgestasertProglicemPrografProgynon BProgynovaProklarProlixanProlixinProlopaProloprimPromethProminePronestylCisplatinClopidogrelFelodipineAmphotericin BFenfluramineFenfluramineTetracaineMibefradilRepaglinidePravastatinBromocriptinePrednisolonePrednisoloneAcarboseHCG (= chorionic gonadotropin)HCG (= chorionic gonadotropin)PrednisoloneAtenololDinoprostoneMethyl-DopaDihydralazineADH (= Vasopressin)LansoprazoleMilrinonePrimaquineAmphotericin BLisinoprilNaphazolineHydroxyprogesteronecaproateProbenecidProcainamideNifedipineGallopamilCyclophosphamideHCG (= chorionic gonadotropin)ProgesteroneDiazoxideTacrolimusEstradiol-benzoateEstradiol-valerateSulfamethizoleAzapropazoneFluphenazineLevodopa + BenserazideTrimethoprimPromethazineProcainamideProcainamidePropasaPropeciaPropulsidPropyl-ThyracilProrexProscarProstaphlinProstarmonProstigminProstin E2Prostin F2Prostin VRProtostatProtrin SeptraProventilProviganProvironProzacPruletPulmicortPulsaminPurinetholPurodiginPyopenPyrilaxPyronovalPyroxineQQuelicinQuestranQuibron-TQuinachlorQuinalanQuinaminophQuinammQuineQuinidexQuiniteQuinoraRRU 486ReQuipRebetolReclomideRectocortRedisolRefludan5-Aminosalicylic acidFinasterideCisapridePropylthiouracilPromethazineFinasterideOxacillinDinoprostNeostigmineDinoprostoneDinoprostAlprostadil (= PGE1)MetronidazoleCotrimoxazoleSalbutamol (= Albuterol)PromethazineMesteroloneFluoxetinePhenolphthaleinBudesonideEtilefrine6-MercaptopurineDigitoxinCarbenicillinBisacodylAcetylsalicylic acidPyridoxine, Vit. B6SuccinylcholineColestyramineTheophyllineChloroquineQuinidineQuinineQuinineQuinineQuinidineQuinineQuinidineMifepristoneRopinirole*RibavirinMetoclopramideCortisol (Hydrocortisone)Vit. B12LepirudinLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
364 Drug Name → Trade NameRefobacinRegitinReglanRegonolRelefactRemicadeRemivoxRemsedRenoquidReoProReomaxRescriptorRestorilRetardinRetrovirReverinReviaRezipasRezulinRhinalarRhumalganRhythminRhythmolRidauraRifadinRimactanRimifonRitalinRivotrilRizeRoaccutanRobinulRocaltrolRocephinRoferon A3RogaineRogitinRohypnolRolisoxRomaziconRovamycinRowasaRoxanolRubesolRubionRubraminRulidRyegonovinRynacromRythmodanGentamicinPhentolamineMetoclopramidePyridostigmineGonadorelinInfliximabLorcainidePromethazineSulfacytineAbciximabEthacrynic acidDelavirdineTemazepamDiphenoxylateAzidothymidine, ZidovudineRolitetracyclinNaltrexone5-Aminosalicylic acidTroglitazoneFlunisolideDiclofenacProcainamidePropafenoneAuranofinRifampinRifampinIsoniazidMethylphenidateClonazepamClotiazepamIsotretinoinGlycopyrrolateCalcitriolCeftriaxoneInterferon-a2aMinoxidilPhentolamineFlunitrazepam*IsoxsuprineFlumazenilSpiramicinMesalamineMoiphine sulfateVit. B12CyanocobalaminCyanocobalaminRoxithromycinMethylcelluloseCromoglycateDisopyramideSS.A.S.-500 Salazosulfapyridine =sulfasalazineSabrilVigabatrin*Salazopyrin Salazosulfapyridine =sulfasalazineSalimidCyclopenthiazideSaltucinButizidSandimmune CyclosporineSandomigran Pizotifen = PizotylineSandostatin OctreotideSandrilReserpineSang-35 CyclosporineSanocrisin CyclofenilSanodinCarbenoxoloneSanorexMazindolSansertMethysergideSatricMetronidazoleSaventrine Isoprenaline (= Isoproterenol)Scabene LindaneSebcurSalicylic acidSectralAcebutololSecuropen AzlocillinSegurilFurosemideSeldaneTerfenadineSelectomycin SpiramicinSembrina Methyl-DopaSenokotSennaSenolaxSennaSeraxOxazepamSerenace HaloperidolSerevent SameterolSerlectSertindole*SernylPhencyclidineSerono-Bagren BromocriptineSerophene ClomipheneSerpalan ReserpineSerpasilReserpineSertanPrimidoneSexovidCyclofenilSibelium FlunarizineSilainSimethiconeSimplene EpinephrineSimplotan TinidazolSimulect BasiliximabSinarestOxymetazolineSinemet Levodopa + CarbidopaSinequan DoxepinSingulair MontelukastSintromAcenocoumarin (= Nicoumalone)Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Name → Trade Name 365SinutabSirtalSito-LandeSkleromexeSlo-bidSobelinSofarinSoldactoneSolfotonSolganalSolu-ContentonSoluverSomnosSomophyllin-TSopamycetinSoprolSorbitrateSorquetanSotacorSpametrin-MSpersadexSpersanicolSpirocortSporanoxSprecurStatexStelazineSteranabolStimateStoxilStrepolinStreptaseStreptosolStressonSuacronSublimazeSuccostrinSufentaSulairSulamydSularSulcrateSulfabutinSulfexSulmycinSulpyrinSultenSupasaSuprareninSupraxSuprefactSurfactalSustaineXylometazolineCarbamazepineSitosterolClofibrateTheophyllineClindamycinWarfarinCanrenonePhenobarbitalAurothioglucoseAmantadineSalicylic acidChloralhydrateTheophyllineChloramphenicolBisoprololIsosorbide dinitrateTinidazolSotalolMethylcelluloseDexamethasoneChloramphenicolBudesonideItroconazoleBuserelinMorphine sulfateTrifluoperazineClostebolDesmopressinIdoxuridineStreptomycinStreptokinaseStreptomycinBumetanideCarazololFentanylSuccinylcholineSufentanilSulfacetamideSulfacetamideNisoldipineSucralfateBusulfanSulfacetamideGentamicinMetamizol (= Dipyrone)SulfacetamideAcetylsalicylic acidEpinephrineCefiximeBuserelinAmbroxolXylometazolineSustaireSuxinutinSymmetrelSynatanSynkayvitSynovirSyntocinonSytobexSytobexTTacefTacicefTagametTalwinTambocorTamofenTapazoleTapazoleTaractanTarasanTardigalTardocillinTarividTasmarTavistTaxolTaxotereTebrazidTeebaconinTegisonTegopenTegretolTeleminTemgesicTempraTenalinTenexTenorminTensiumTensobonTestexTestojectTestoneTestredTevetenTheelolTheolairThesitTheophyllineEthosuximideAmantadined-AmphetamineMenadioneThalidomideOxytocinHydroxocobalaminVit. B12CefmenoximeCeftazidimeCimetidinePentazocineFlecainideTamoxifenMethimazoleThiamazole (= Methimazole)ChlorprothixeneChlorprothixeneDigitoxinBenzathine-Penicillin G<strong>Of</strong>loxacinTolcaponeClemastinePaclitaxelDocetaxelPyrazinamideIsoniazidEtretinateClotrimazoleCarbamazepineBisacodylBuprenorphineParacetamol = acetaminophenCarteololGuanfacineAtenololDiazepamCaptoprilTestosterone propionateTestosterone cypionateTestosterone enantateMethyltestosteroneEprosartanEstratriol = EstriolTheophyllinePolidocanolLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
366 Drug Name → Trade NameThiotepa Lederle Thio-TEPAThorazine ChlorpromazineThrombinar ThrombinThrombostat ThrombinTicarTicarcillinTiclidTiclopidineTienorClotiazepamTigasonEtretinateTiladeNedocromilTimonilCarbamazepineTimoptic TimololTinactin TolnaftateTinsetOxatomideToazulTolonium chlorideTobrexTobramycinTofranilImipramineTolectinTolmetinTomabef CefmenoximeTonocard TocainideTopamex TopiramateTopitracin BacitracinToposarEtoposideToradolKetorolacTornalate BitolterolTotacillin Amphotericin BTracrium AtracuriumTramalTramadolTrandate LabetalolTrans-Ver-Sal Salicylic acidTranscycline RolitetracyclinTransderm Scop ScopolamineTranxene ClorazepateTranxilium N Nor-DiazepamTrapanal ThiopentalTrasicorOxprenololTravogen IsoconazoleTrecalmo ClotiazepamTrecator EthionamideTremblex DexetimideTreminTrihexiphenidylTrendarIbuprofenTrentalPentoxifyllineTrexanNaltrexoneTriadapin DoxepinTrialodine TrazodoneTriam-A Triamcinolone acetonideTriamterene Triamcinolone acetonideTrichlorex TrichlormethiazideTricorFenofibrate*Trihexane TrihexiphenidylTrimpex TrimethoprimTrimystenTriostatTriptoneTrobicinTrusoptTruxalTubarineTylenolTypramineTyzineUClotrimazoleLiothyronineScopolamineSpectinomycinDorzolamideChlorprothixened-TubocurarineParacetamol = acetaminophenImipramineTetryzoline (= tetrahydrozoline)UdicilCytarabineUdolacDapsoneUkidanUrokinaseUlcolaxBisacodylUltairPranlukast*UltivaRemifentanilUltracain ArticaineUnicortCortisol (Hydrocortisone)UniphylTheophyllineUricovac BenzbromaroneUritolFurosemideUromitexan MesnaUrosinAllopurinolUrsofalk Ursodeoxycholic acid =ursodiolVVa-tro-nolValadolValiumValorinValtrexVancocinVancomycinCP LillyVaponefrineVasalVasoconVasodilanVasopressinSandozVasoprineVasotecVatranEphedrineParacetamol = acetaminophenDiazepamParacetamol = acetaminophenValacyclovirVancomycinVancomycinEpinephrinePapaverineNaphazolineIsoxsuprineLypressinIsoxsuprineEnalaprilDiazepamLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Drug Name → Trade Name 367VePesidVectrinVegesanVelacyclineVelbanVelbeVelosulinVenactoneVentolinVeratranVerelanVermoxVersedViagraVibalVibramycinVidexVigantolVigorsanVimiconVinactaneViocinVionactaneViprinexVira-AViraceptViramuneVirazoleVirilonVirofralViropticVisineViskenVistacromVisutensilVitrasertVivolVolonVoltarenVoltarolVumonWWellbatrinWellbutrinEtoposideMinocyclineNor-DiazepamRolitetracyclinVinblastineVinblastineInsulinCanrenoneSalbutamol (= Albuterol)ClotiazepamVerapamilMebendazoleMidazolamSildenafilVit. B12DoxycyclineDidanosine (ddI)CholecalciferolCholecalciferolCyproheptadineViomycineViomycineViomycineAncrodVidarabineNelfinavirNevirapineRibavirinMethyltestosteroneAmantadineTrifluridineTetryzoline (= tetrahydrozoline)PindololCromoglycateGuanethidineGanciclovirDiazepamTriamcinoloneDiclofenacDiclofenacTeniposideBupropionBupropionWhevertWincoramWingomWinpredWyamycinWytensinXXanaxXanefXatralXylocainXylocardXylonestYYomesanYutoparZZaditenZanaflexZanosarZantacZapexZarontinZebetaZemuronZenapaxZepineZeritZestrilZiagenZimovaneZithromaxZocorZofranZoladexZoviraxZyfloZyloprimZyloricZyprexaMeclizine (meclozine)AmrinoneGallopamilPrednisoneErythromycin-estolateGuanabenzAlprazolamEnalaprilAlfuzosinLidocaineLidocainePrilocaineNiclosamideRitodrineKetotifenTizanidineStreptozocinRanitidineOxazepamEthosuximideBisoprololRocuroniumDaclizumabReserpineStavudine (d4T)LisinoprilAbacavir*ZopicloneAzithromycinSimvastatinOndansetronGoserelinAciclovirZileutonAllopurinolAllopurinolOlanzapineLüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
368IndexAabacavir, 288abciximab, 150Abel, John J., 3abortifacients, 126absorption, 10, 11, 46, 47speed of, 18, 46accommodation, eye, 98accumulation, 48, 49, 50,51accumulation equilibrium,48ACE, see Angiotensin-convertingenzymeACE inhibitors, 118, 124diuretics and, 158heart failure treatment,132hypertension treatment,312, 313myocardial infarctiontherapy, 310acebutolol, 94acetaminophen, 198, 199biotransformation, 36common cold treatment,324, 325intoxication, 302migraine treatment, 322acetazolamide, 162N-acetyl-cysteine, 302acetylcholine (ACh), 82, 98,166, 182binding to nicotinic receptor,64ester hydrolysis, 34, 35muscle relaxant effects,184–187release, 100, 101, 108synthesis, 100see also cholinoceptorsacetylcholinesterase(AChE), 100, 182inhibition, 102acetylcoenzyme A, 100acetylcysteine, 324, 325acetyldigoxin, 132N-acetylglucosamine, 268N-acetylmuramyl acid, 268acetylsalicylic acid (ASA),198, 199, 200biotransformation, 34,35common cold treatment,324, 325migraine treatment, 322myocardial infarctiontherapy, 310platelet aggregation inhibition,150, 151, 310acipimox, 156acrolein, 298acromegaly, 242, 243action potential, 136, 182,186active principle, 4acyclovir, 284, 285, 286,287acylaminopenicillins, 270acyltransferases, 38Addison’s disease, 248adenohypophyseal (AH)hormones, 242, 243adenylate cyclase, 66adrenal cortex (AC), 248insufficiency, 248adrenal medulla, nicotinicstimulation, 108, 109,110adrenaline, see epinephrineadrenergic synapse, 82adrenoceptors, 82, 230agonists, 84, 86, 182subtypes, 84adrenocortical atrophy,250adrenocortical suppression,250adrenocorticotropic hormone(ACTH), 242, 243,248, 250, 251adriamycin, 298adsorbent powders, 178adverse drug effects,70–75aerosols, 12, 14affinity, 56enantioselectivity, 62agitation, 106agonists, 60, 61inverse, 60, 226partial, 60agranulocytosis, 72AIDS treatment, 288–289ajmaline, 136akathisia, 238akinesia, 188albumin, drug binding, 30albuterol, 326, 328alcohol dehydrogenase(ADH), 44alcohol elimination, 44alcuronium, 184aldosterone, 158, 164, 165,248, 249antagonists, 164deficiency, 314purgative use and, 172alendronate, 318alfuzosin, 90alkaloids, 4alkylating cytostatics, 298allergic reactions, 72–73,196, 326–327allopurinol, 298, 316, 317allosteric antagonism, 60allosteric synergism, 60α-blockers, 90alprostanil, 118alteplase, 146, 310Alzheimer’s disease, 102amantadine, 188, 286, 287amikacin, 278, 280amiloride, 164, 1656-amino-penicillanic acid,268γ-aminobutyric acid, seeGABAε-aminocaproic acid, 146aminoglycosides, 267,276–279Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Index 369p-aminomethylbenzoicacid (PAMBA), 146aminopterin, 298aminopyrine, 198aminoquinuride, 2585-aminosalicylic acid, 272p-aminosalicylic acid, 280amiodarone, 136amitriptyline, 230, 232,233amodiaquine, 294amorolfine, 282amoxicillin, 168, 270, 271cAMP, 66, 150amphetamines, 88, 89, 230see also specific drugsamphotericin B, 282, 283ampicillin, 270ampules, 12amrinone, 118, 128, 132anabolic steroids, 252analgesics, 194–203antipyretic, 4, 196–199,202–203, 324see also opioidsanaphylactic reactions, 72,73, 152treatment, 84, 326, 327ancrod, 146, 147Ancylostoma duodenale,292androgens, 252anemia, 138–141, 192megaloblastic, 192pernicious, 138anesthesiabalanced, 216, 217conduction, 204dissociative, 220infiltration, 90, 204premedication, 104, 106,226regional, 216spinal, 204, 216surface, 204total intravenous (TIVA),216see also general anesthetics;local anestheticsangina pectoris, 128,306–308, 311, 312prophylaxis, 308, 311treatment, 92, 118, 120,122, 308, 311angiotensin II, 118, 124,158, 248antagonists, 124biotransformation, 34,35formation, 34angiotensin-convertingenzyme (ACE), 34, 124,158see also ACE inhibitorsangiotensinase, 34Anopheles mosquitoes,294anorexiants, 88antacids, 166–168antagonists, 60, 61anthraquinone derivatives,170, 174, 176, 177antiadrenergics, 95–96,128antianemics, 138–141antiarrhythmics, 134–137electrophysiological actions,136, 137antibacterial drugs,266–282cell wall synthesis inhibitors,268–271DNA function inhibitors,274–275mycobacterial infections,280–281protein synthesis inhibitors,276–279tetrahydrofolate synthesisinhibitors, 272–273antibiotics, 178, 266broad-spectrum, 266cystostatic, 298narrow-spectrum, 266see also antibacterialdrugs; antifungal drugs;antiviral drugsantibodies, 72, 73monoclonal, 300anticancer drugs, 296–299anticholinergics, 188, 202anticoagulants, 144–147anticonvulsants, 190–193,226antidepressants, 88,230–233tricyclic, 230–232antidiabetics, 262, 263antidiarrheals, 178–179antidiuretic hormone(ADH), see vasopressinantidotes, 302–305antiemetics, 114, 310,330–331antiepileptics, 190–193antiflatulents, 180antifungal drugs, 282–283antigens, 72, 73antihelmintics, 292antihistamines, 114–116allergic disorder treatment,326, 327common cold treatment,324, 325motion sickness prophylaxis,330peptic ulcer treatment,166–168sedative activity, 222antimalarials, 294–295antiparasitic drugs,292–295antiparkinsonian drugs,188–190antipyretic analgesics, 4,196–199, 324thermoregulation and,202–203antiseptics, 290, 291antithrombin III, 142, 144antithrombotics, 142–143,148–151antithyroid drugs, 246, 247antiviral drugs, 284–289AIDS treatment,288–289interferons, 284, 285virustatic antimetabolites,284–287anxiety states, 226anxiolytics, 128, 222, 226,228, 236apolipoproteins, 154, 155apoptosis, 296aprotinin, 146appetite suppressants, 88Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
370 Indexarachidonic acid, 196, 201,248area postrema, 110, 130,212, 330area under the curve(AUC), 46arecoline, 102arthritischronic polyarthritis,320rheumatoid, 302,320–321Arthus reaction, 72articaine, 208, 209Ascaris lumbricoides, 292,293aspirin, see acetylsalicylicacidaspirin asthma, 198astemizole, 114–116asthma, 126, 127, 326–329β-blockers and, 92treatment, 84, 104astringents, 178asymmetric center, 62atenolol, 94, 95, 322atherosclerosis, 154, 306atorvastatin, 156atracurium, 184atrial fibrillation, 130, 134atrial flutter, 122, 130, 131,134atropine, 104, 107, 134,166, 216lack of selectivity, 70, 71poisoning, 106, 202, 302auranofin, 320aurothioglucose, 320aurothiomalate, 320autonomic nervoussystem, 80AV block, 92, 104axolemma, 206axoplasm, 206azapropazone, 200azathioprine, 36, 300, 320azidothymidine, 288azithromycin, 276azlocillin, 270azomycin, 274BB lymphocytes, 72, 300bacitracin, 267, 268, 270baclofen, 182bacterial infections, 178,266, 267resistance, 266, 267see also antibacterialdrugsbactericidal effect, 266,267bacteriostatic effect, 266,267balanced anesthesia, 216,217bamipine, 114barbiturates, 202, 203,220, 222dependence, 223baroreceptors, nicotine effects,110barriersblood-tissue, 24–25cell membranes, 26–27external, 22–23basiliximab, 300Bateman function, 46bathmotropism, negative,134beclomethasone, 14, 250,326benazepril, 124benign prostatic hyperplasia,90, 252, 312benserazide, 188benzathiazide, 162benzathine, 268benzatropine, 106, 107,188benzbromarone, 316benzocaine, 208, 209, 324benzodiazepines, 182, 220,226–229antagonists, 226dependence, 223, 226,228epilepsy treatment, 190,192myocardial infarctiontreatment, 128pharmacokinetics, 228,229receptors, 226, 228sleep disturbances and,222, 224benzopyrene, 36benzothiadiazines, see thiazidediureticsbenzylpenicillin, 268Berlin Blue, 304β-blockers, 92–95, 128,136angina treatment, 308,311hypertension treatment,312–313migraine prophylaxis,322myocardial infarctiontreatment, 309, 310sinus tachycardia treatment,134types of, 94, 95bezafibrate, 156bifonazole, 282bile acids, 180bilharziasis, 292binding assays, 56binding curves, 56–57binding forces, 58–59binding sites, 56bioavailability, 18, 42absolute, 42determination of, 46relative, 42bioequivalence, 46biogenic amines, 114–118biotransformation, 34–39benzodiazepines, 228,229in liver, 32, 42biperiden, 188, 238biphosphonates, 318bisacodyl, 174bisoprolol, 94bladder atonia, 100, 102bleomycin, 298blood pressure, 314see also hypertension;hypotensionblood sugar control, 260,261blood-brain barrier, 24blood-tissue barriers,24–25Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Index 371bonds, types of, 58, 59botulinum toxin, 182bowel atonia, 100, 102bradycardia, 92, 104, 134bradykinin, 34brain, blood-brain barrier,24bran, 170bromocriptine, 114, 126,188, 242, 243bronchial asthma, seeasthmabronchial carcinoma, tobaccosmoking and, 112bronchial mucus, 14bronchitis, 324, 328chronic obstructive, 104tobacco smoking and,112bronchoconstriction, 196,198bronchodilation, 84, 104,127, 196, 326bronchodilators, 126, 328brotizolam, 224buccal drug administration,18, 19, 22Buchheim, Rudolf, 3budesonide, 14, 250, 326bufotenin, 240bulk gels, 170, 171bumetanide, 162buprenorphine, 210, 214buserelin, 242, 243buspirone, 116busulfan, 298N-butylscopolamine, 104,126butyrophenones, 236, 238butyryl cholinesterase, 100Ccabergolide, 126, 188, 242caffeine, 326calcifediol, 264calcineurin, 300calcitonin, 264, 265, 318,322calcitriol, 264calcium antagonists,122–123, 128angina treatment, 308,311hypertension treatment,312–313calcium channel blockers,136, 234see also calcium antagonistscalcium chelators, 142calcium homeostasis, 264,265calmodulin, 84cancer, 296–299see also carcinomaCandida albicans, 282canrenone, 164capillary beds, 24capreomycin, 280capsules, 8, 9, 10captopril, 34, 124carbachol, 102, 103carbamates, 102carbamazepine, 190, 191,192, 234carbenicillin, 270carbenoxolone, 168carbidopa, 188carbimazole, 247carbonic acids, 200carbonic anhydrase (CAH),162inhibitors, 162, 163carbovir, 288carboxypenicillins, 270carcinomabronchial, 112prostatic, 242cardiac arrest, 104, 134cardiac drugs, 128–137antiarrhythmics,134–137glycosides, 128, 130,131, 132, 134modes of action, 128,129cardioacceleration, 104cardiodepression, 134cardioselectivity, 94cardiostimulation, 84, 85carminatives, 180, 181carotid body, nicotine effects,110case-control studies, 76castor oil, 170, 174catecholaminesactions of, 84, 85structure-activity relationships,86, 87see also epinephrine;norepinephrinecatecholmin-O-methyltransferase(COMT), 82,86, 114inhibitors of, 188cathartics, 170, 172cefmenoxin, 270cefoperazone, 270cefotaxime, 270ceftazidime, 270ceftriaxone, 270cell membrane, 20membrane stabilization,94, 134, 136permeation, 26–27cells, 20cellulose, 170cephalexin, 270, 271cephalosporinase, 270, 271cephalosporins, 267, 268,270, 271cerivastatin, 156ceruletide, 180cestode parasites, 292cetrizine, 114–116chalk, 178charcoal, medicinal, 178chelating agents, 302, 303chemotherapeutic agents,266chenodeoxycholic acid(CDCA), 180chirality, 62chloral hydrate, 222chlorambucil, 298chloramphenicol, 267,276–279chlorguanide, 294chloride channels, 226chlormadinone acetate,254chloroquine, 294, 295, 320chlorpheniramine, 114chlorphenothane (DDT),292, 293chlorpromazine, 208, 236,238Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
372 Indexlack of selectivity, 70, 71chlorprothixene, 238chlorthalidone, 162cholecalciferol, 264cholecystokinin, 180cholekinetics, 180cholelithiasis, 180choleretics, 180cholestasis, 238cholesterol, 154–157gallstone formation, 180metabolism, 155choline, 100choline acetyltransferase,100cholinergic synapse, 100cholinoceptors, 98, 100,184antacid effects, 166antagonists, 188muscarinic, 100, 188,230nicotinic, 64, 65, 100,108, 182chronic polyarthritis, 320chronotropism, 84negative, 134chylomicrons, 154cilazapril, 124cimetidine, 116, 168ciprofloxacin, 274cisapride, 116cisplatin, 298citrate, 142clarithromycin, 168, 276Clark, Alexander J., 3clavulanic acid, 270clearance, 44clemastine, 114clemizole, 268clindamycin, 267, 276clinical testing, 6clinical trials, 76clobazam, 192clodronate, 264, 318clofazimine, 280, 281clofibrate, 156clomethiazole, 192clomiphene, 256clonazepam, 192clonidine, 96, 182, 312clopidogrel, 150clostebol, 252Clostridium botulinum,182Clostridium difficile, 270clotiazepam, 222clotrimazole, 282clotting factors, 142clozapine, 238, 239, 240co-trimoxazole, 272, 273coagulation cascade, 142,143coated tablets, 8, 9, 10cocaine, 88, 89, 208codeine, 210, 212, 214,324, 325colchicine, 316, 317colds, 324–325colestipol, 154colestyramine, 130, 154colic, 104, 127common cold, 324–325competitive antagonists,60, 61complement activation,72, 73compliance, 48concentration time course,46–47, 68, 69during irregular intake,48, 49during repeated dosing,48, 49concentration-bindingcurves, 56–57concentration-effectcurves, 54, 55concentration-effect relationship,54, 55, 68, 69conformation change, 60congestive heart failure,92, 128, 130, 158, 312conjugation reactions, 38,39, 58conjunctival decongestion,90constipation, 172, 173atropine poisoning and,106see also laxativescontact dermatitis, 72, 73,282controlled trials, 76coronary sclerosis, 306,307corpus luteum, 254corticotropin, 242corticotropin-releasinghormone (CRH), 242,250, 251cortisol, 36, 248, 249, 250,251receptors, 250cortisone, biotransformation,36coryza, 90cotrimoxazole, 178cough, 324, 325coumarins, 142, 144, 145covalent bonds, 58cranial nerves, 98creams, 16, 17cromoglycate, 116cromolyn, 14, 116, 326cross-over trials, 76curare, 184Cushing’s disease, 220,248, 300, 318prevention of, 248cyanide poisoning, 304,305cyanocobalamin, 138, 304,305cyclic endoperoxides, 196cyclofenil, 256cyclooxygenases, 196, 248inhibition, 198, 200, 328cyclophilin, 300cyclophosphamide, 298,300, 320cycloserine, 280cyclosporin A, 300cyclothiazide, 162cyproterone, 252cyproterone acetate, 254cystinuria, 302, 303cystostatic antibiotics, 298cytarabine, 298cytochrome P450, 32cytokines, 300cytomegaloviruses, 286cytostatics, 296, 297, 299,300, 320cytostatics, alkylating, 298cytotoxic reactions, 72, 73Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Index 373Ddaclizumab, 300dantrolene, 182dapsone, 272, 280, 281,294daunorubicin, 298dealkylations, 36deamination, 36decarbaminoylation, 102decongestants, 90deferoxamine, 302, 303dehalogenation, 36delavirdine, 288delirium tremens, 236dementia, 102N-demethyldiazepam, 228demulcents, 178deoxyribonucleic acid(DNA), 274synthesis inhibition, 298,299dependencebenzodiazepines, 223,226, 228hypnotics, 222, 223laxatives, 172, 173opioids, 210–212dephosphorylation, 102depolarizing muscle relaxants,184, 186, 187deprenyl, 88depression, 226, 230endogenous, 230–233manic-depressive illness,230treatment, 88, 230–233dermatologic agents, 16,17as drug vehicles, 16, 17dermatophytes, 282descending antinociceptivesystem, 194desensitization, 66desflurane, 218desipramine, 230, 232, 233desmopressin, 164, 165desogestrel, 254desulfuration, 36, 37dexamethasone, 192, 248,249, 330dexazosin, 90dexetimide, 62, 63dextran, 152diabetes mellitushypoglycemia, 92insulin replacementtherapy, 258insulin-dependent,260–261non-insulin-dependent,262–264diacylglycerol, 66diarrhea, 178antidiarrheals, 178–179chologenic, 172diastereomers, 62diazepam, 128, 228diazoxide, 118, 312dicationic, 268diclofenac, 200, 320dicloxacillin, 270didanosine, 288diethlystilbestrol, 74diethylether, 216diffusionbarrier to, 20membrane permeation,26, 27digitalis, 130, 131, 302digitoxin, 132enterohepatic cycle, 38digoxin, 132dihydralazine, 118, 312dihydroergotamine, 126,322dihydropyridines, 122, 308dihydrotestosterone, 252diltiazem, 122, 136, 308dimenhydrinate, 114dimercaprol, 302, 303dimercaptopropanesulfonicacid, 302, 303dimethicone, 180, 181dimethisterone, 2542,5-dimethoxy-4-ethylamphetamine, 2403,4-dimethoxyamphetamine,240dimetindene, 114dinoprost, 126dinoprostone, 126diphenhydramine, 114,222, 230diphenolmethane derivatives,170, 174, 177diphenoxylate, 178dipole-dipole interaction,58dipole-ion interaction, 58dipyridamole, 150dipyrone, 198, 199disinfectants, 290, 291disintegration, of tabletsand capsules, 10disopyramide, 136disorientation, atropinepoisoning and, 106Disse’s spaces, 24, 32, 33dissolution, of tablets andcapsules, 9, 10distribution, 22–31, 46, 47diuretics, 158–165, 313indications for, 158loop, 162, 163osmotic, 160, 161potassium-sparing, 164,165sulfonamide type, 162,163thiazide, 132, 162, 163,312dobutamine, enantioselectivity,62docetaxel, 296docosahexaenoate, 156domperidone, 322, 330L-dopa, 114, 188DOPA-decarboxylase, 188dopamine, 88, 114, 115,132agonists, 242antagonists, 114in norepinephrine synthesis,82mimetics, 114Parkinson’s disease and,188dopamine receptors, 114,322agonists, 188blockade, 236, 238dopamine-β-hydroxylase,82doping, 88, 89dorzolamide, 162dosage forms, 8dosage schedule, 50, 51dose-linear kinetics, 68, 69Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
374 Indexdose-response relationship,52–53dosingirregular, 48, 49overdosing, 70, 71repeated, 48, 49subliminal, 52double-blind trials, 76doxorubicin, 298doxycycline, 277, 278, 294doxylamine, 22dromotropism, negative,134dronabinol, 330droperidol, 216, 236drops, 8, 9drug interactions, 30, 32anticonvulsants, 192drug-receptor interaction,58–69drugsactive principle, 4administration, 8–19adverse effects, 70–75approval process, 6barriers to, 22–27biotransformation, 32,34–39concentration timecourse, 46–47, 48–49,68, 69development, 6–7distribution in body,22–31, 46, 47liberation of, 10protein binding, 30–31retarded release, 10, 11sites of action, 20–21sources, 4see also elimination ofdrugs; specific typesof drugsduodenal ulcers, 104, 166dusting powders, 16dynorphins, 210dyskinesia, 238dysmenorrhea, 196dystonia, 238EE max, 54E. coli, 270, 271EC 50, 54, 60econazole, 282ecothiopate, 102ecstasy, 240ectoparasites, 292edema, 158, 159EDTA, 142, 264, 302, 303efavirenz, 288effervescent tablets, 8efficacy, 54, 60, 61Ehrlich, P., 3eicosanoids, 196eicosapentaenoate, 156electromechanicalcoupling, 128, 182electrostatic attraction, 58,59elimination of drugs,32–43, 46, 47β-blockers, 94biotransformation,34–39, 42changes during drugtherapy, 50, 51exponential rate processes,44, 45hydrophilic drugs, 42, 43in kidney, 40–41, 44in liver, 18, 32–33, 44lipophilic drugs, 42, 43emesis, 330–331emulsions, 8, 16enalapril, 34enalaprilat, 34, 124enantiomers, 62, 63enantioselectivity, 62endocytosis, 24receptor-mediated, 26,27endoneural space, 206endoparasites, 292β-endorphin, 210, 211, 212endothelium-derived relaxingfactor (EDRF), 100,120enflurane, 218enkephalins, 34, 210, 211enolic acids, 200enoxacin, 274entacapone, 188Entamoeba histolytica, 274Enterobius vermicularis,292enterohepatic cycle, 38, 39enzyme induction, 32ephedrine, 86, 87epilepsy, 190, 191, 226antiepileptics, 190–193childhood, 192treatment, 162epinephrine, 82, 83, 260anaphylactic shock treatment,84, 326, 327β-blockers and, 92cardiac arrest treatment,134local anesthesia and, 206nicotine and, 108, 109,110structure-activity relationships,86, 87epipodophyllotoxins, 298epoxidations, 36epoxides, 36Epsom salts, 170eptifibatide, 150ergocornine, 126ergocristine, 126ergocryptine, 126ergolides, 114ergometrine, 126, 127ergosterol, 282, 283ergot alkaloids, 126ergotamine, 126, 127, 322erythromycin, 34, 267,276, 277erythropoiesis, 138, 139erythropoietin, 138ester hydrolysis, 34estradiol, 254, 255, 257estriol, 254, 255estrogen, 254, 318estrone, 254, 255ethacrynic acid, 162ethambutol, 280, 281ethanol, 202, 203, 224elimination, 44ethinylestradiol (EE), 254,255, 256ethinyltestosterone, 255ethionamide, 280ethisterone, 254ethosuximide, 191, 192ethylaminobenzoate, 324ethylenediaminetetraaceticacid (EDTA), 142Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Index 375etilefrine, 86, 87etofibrate, 156etomidate, 220, 221etoposide, 298etretinate, 74euphoria, 88, 210expectorants, 324, 325exponential rate processes,44, 45extracellular fluid volume(EFV), 158extracellular space, 28extrapyramidal disturbances,238eye drops, 8, 9Ffactor VII, 142factor XII, 142famcyclovir, 286famotidine, 116, 168fatty acids, 20felbamate, 190, 191felodipine, 122felypressin, 164, 206fenestrations, 24fenfluramine, 88fenoldopam, 114, 312fenoterol, 86, 87allergic disorder treatment,326asthma treatment, 328tocolysis, 84, 126fentanyl, 210, 212–216ferric ferrocyanide, 304,305ferritin, 140fever, 202, 203, 324fexofenadine, 114–116fibrillation, 122atrial, 130, 131, 134fibrin, 34, 142, 146fibrinogen, 146, 148, 149fibrinolytic therapy, 146Fick’s Law, 44finasteride, 252first-order rate processes,44–45first-pass hepatic elimination,18, 42fish oil supplementation,156fleas, 292, 293flecainide, 136floxacillin, 270fluconazole, 282flucytosine, 282fludrocortisone, 248, 314flukes, 292flumazenil, 226, 302flunarizine, 322flunisolide, 14, 250fluoride, 3185-fluorouracil, 298fluoxetine, 116, 230, 232,233flupentixol, 236, 238, 239fluphenazine, 236, 238,239flutamide, 252fluticasone dipropionate,14, 250fluvastatin, 156, 157fluvoxamine, 232folic acid, 138, 139, 272,273deficiency, 138follicle-stimulating hormone(FSH), 242, 243,254deficiency, 252suppression, 256follicular maturation, 254foscarnet, 286, 287fosinopril, 124Frazer, T., 3frusemide, 162functional antagonism, 60fungal infections, 282–283fungicidal effect, 282fungistatic effect, 282furosemide, 162, 264GG-protein-coupled receptors,64, 65, 210mode of operation,66–67G-proteins, 64, 66GABA, 190, 224, 226GABA receptors, 64, 226gabapentin, 190, 191, 192Galen, Claudius, 2gallamine, 184gallopamil, 122gallstones, 180dissolving of, 180, 181ganciclovir, 285, 286ganglianicotine action, 108, 110paravertebral, 82prevertebral, 82ganglionic blockers, 108,128gastric secretion, 196gastric ulcers, 104, 166gastrin, 166–168, 242gastritis, atrophic, 138gelatin, 152gels, 16gemfibrozil, 156general anesthetics,216–221inhalational, 216,218–219injectable, 216, 220–221generic drugs, 94gentamicin, 276, 278, 279gestoden, 254gingival hyperplasia, 192Glauber’s salts, 170glaucoma, 106treatment, 92, 102, 162β-globulins, drug binding,30glomerular filtration, 40glucagon, 242glucocorticoids, 200,248–251allergic disorder treatment,326asthma treatment, 328cytokine inhibition, 300gout treatment, 316hypercalcemia treatment,264rheumatoid arthritistreatment, 320glucose metabolism, 260,261see also diabetes mellitusglucose-6-phosphate dehydrogenasedeficiency,70glucuronic acid, 36, 38, 39Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
376 Indexβ-glucuronidases, 38glucuronidation, 38opioids, 212glucuronides, 38glucuronyl transferases,32, 38glutamate, 64, 190receptors, 190glutamine, in conjugationreactions, 38glyburide, 262glyceraldehyde enantiomers,62glycerol, 20glycine, 64, 182, 183in conjugation reactions,38glycogenolysis, 66, 84glycosuria, 162cGMP, 120goiter, 244, 245, 247gold compounds, 320gonadorelin superagonists,242gonadotropin-releasinghormone (GnRH), 242,243,252, 256goserelin, 242gout, 316–317GPIIB/IIIA, 148, 149, 150antagonists, 150granisetron, 116, 330Graves’ disease, 246, 247griseofulvin, 282, 283growth hormone (GH),242, 243growth hormone receptors,64growth hormone releaseinhibiting hormone (-GRIH),242growth hormone-releasinghormone (GRH), 242guanethidine, 96guanylate cyclase, 120gynecomastia, 164, 168gyrase inhibitors, 274, 275HHahnemann, Samuel, 76half-life, 44hallucinations, atropinepoisoning and, 106hallucinogens, 240, 241halofantrine, 294, 295haloperidol, 236, 238, 239halothane, 218, 219haptens, 72, 73hay fever, 326HDL particles, 154heartβ-blockers and, 92cardiac arrest, 104, 134cardiac drugs, 128–137cardioacceleration, 104cardiodepression, 134cardiostimulation, 84, 85see also angina pectoris;myocardial infarction;myocardiumheart failureβ-blockers and, 92congestive, 92, 128, 130,158, 312treatment, 118, 124, 132,158Helicobacter pylori, 166eradication of, 168, 169hemoglobin, 138hemolysis, 70, 72hemosiderosis, 140hemostasis, 142, 148heparin, 142–146, 309,310hepatic elimination, 18,32–33, 44exponential kinetics, 44hepatocytes, 32, 33, 154heroin, 212Herpes simplex viruses,284, 286hexamethonium, 108hexobarbital, 222high blood pressure, seehypertensionhirudin, 150histamine, 72, 114, 115,166, 326antagonists, 114inhibitors of release, 116receptors, 114, 230, 326see also antihistaminesHMG CoA reductase, 154,156, 157Hohenheim, Theophrastusvon, 2homatropine, 107homeopathy, 76, 77hookworm, 292hormone replacementtherapy, 254hormones, 20hypophyseal, 242–243hypothalamic, 242–243see also specific hormoneshuman chorionic gonadotropin(HCG), 252, 256human immunodeficiencyvirus (HIV), 288–289human menopausal gonadotropin(HMG), 252,256hydrochlorothiazide, 162,164hydrocortisone, 248hydrogel, 16, 17hydrolysis, 34, 35hydromorphone, 210, 214hydrophilic colloids, 170,171hydrophilic cream, 16hydrophilic drug elimination,42, 43hydrophobic interactions,58, 59hydroxyapatite, 264, 3184-hydroxycoumarins, 144hydroxyethyl starch, 152hydroxylation reactions,36, 3717-β-hydroxyprogesteronecaproate, 2545-hydroxytryptamine(5HT), see serotoninhypercalcemia, 264hyperglycemia, 162, 258,260hyperkalemia, 186hyperlipoproteinemia,154–157treatment, 154hyperpyrexia, 202hypersensitivity, 70Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Index 377hypertension therapy,312–313α-blockers, 90ACE inhibitors, 124, 312β-blockers, 92, 312calcium antagonists, 122,312diuretics, 158, 312in pregnancy, 312vasodilators, 118, 312hyperthermia, atropinepoisoning and, 106, 202hyperthyroidism, 244,246–247hypertonia, 226hyperuricemia, 162, 316hypnotics, 222–225dependence, 222, 223hypoglycemia, 92, 260hypokalemia, 162, 163,172, 173hypophysis, 242–243, 250hypotension, 118, 119, 314treatment, 90, 314–315hypothalamic releasinghormones, 242, 243hypothalamus, 242, 250,251hypothermia, 238hypothyroidism, 244hypovolemic shock, 152Iibuprofen, 198, 200idiopathic dilated cardiomyopathy,92idoxuridine, 286ifosfamide, 298iloprost, 118imidazole derivatives, 282,283imipramine, 208,230–232, 233immune complex vasculitis,72, 73immune modulators,300–301immune response, 72, 73,300immunogens, 72immunosuppression,300–301, 320indinavir, 288indomethacin, 200, 316,320infertility, 242inflammation, 72, 196, 326asthma, 328, 329glucocorticoid therapy,248, 249rheumatoid arthritis, 320inflammatory bowel disease,272influenza virus, 286, 287,324infusion, 12, 50inhalation, 14, 15, 18, 19injections, 12, 18, 19inosine monophosphatedehydrogenase, 300inositol trisphosphate, 66,84inotropism, 92negative, 134insecticides, 292poisoning, 304, 305insomnia, 224, 226insulin, 242, 258–259diabetes mellitus treatment,260–261, 262preparations, 258, 259regular, 258resistance to, 258insulin receptors, 64insulin-dependent diabetesmellitus, 260–261interferons (IFN), 284, 285interleukins, 300interstitial fluid, 28intestinal epithelium, 22intramuscular injection,18, 19intravenous injection, 18,19intrinsic activity, 60enantioselectivity, 62intrinsic factor, 138intrinsic sympathomimeticactivity (ISA), 94intubation, 216inulin, 28inverse agonists, 60, 226inverse enantioselectivity,62iodine, 246, 247deficiency, 244iodized salt prophylaxis,244ionic currents, 136ionic interaction, 58ipratropium, 14, 107allergic disorder treatment,326bronchodilation, 126,328cardiaoacceleration, 104,134iron compounds, 140iron deficiency, 138, 140iron overload, 302isoconazole, 282isoflurane, 218isoniazid, 190, 280, 281isophane, 258isoprenaline, 94isoproterenol, 14, 94, 95structure-activity relationships,86, 87isosorbide dinitrate (ISDN),120, 308, 3115-isosorbide mononitrate(ISMN), 120isotretinoic acid, 74isoxazolylpenicillins, 270itraconazole, 282Jjosamycin, 276juvenile onset diabetesmellitus, 260KK + channels, see potassiumchannel activationkanamycin, 276, 280kaolin, 178karaya gum, 170ketamine, 220, 221ketanserin, 116ketoconazole, 282ketotifen, 116kidney, 160, 161drug elimination, 40–41,44kinetosis, 106, 330, 331kyphosis, 318Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
378 IndexLβ-lactam ring, 268, 270β-lactamases, 270lactation, drug toxicity, 74,75lactulose, 170lamivudine, 288lamotrigine, 190, 191Langendorff preparation,128Langley, J., 3lansoprazole, 168laryngitis, 324law of mass action, 3, 56laxatives, 170–177bulk, 170, 171dependence, 172, 173irritant, 170, 172–174,175, 177lubricant, 174misuse of, 170–172osmotically active, 170,171LDL particles, 154–157lead poisoning, 302, 303Lennox-Gastaut syndrome,192leprosy, 274, 280leuenkephalin, 212leukotrienes, 196, 320,326, 327, 328NSAIDS and, 200, 201leuprorelin, 242, 243levetimide, 62, 63levodopa, 188levomepromazine, 330lice, 292, 293lidocaine, 134, 136, 208,209biotransformation, 36,37digitoxin intoxicationtreatment, 130myocardial infarctiontreatment, 309, 310ligand-gated ion channel,64, 65ligand-operated enzymes,64, 65lincomycin, 276lindane, 292, 293linseed, 170lipid-lowering agents, 154lipocortin, 248lipolysis, 66, 84lipophilic cream, 16lipophilic drug elimination,42, 43lipophilic ointment, 16lipoprotein metabolism,154, 155lipoxygenases, 196liquid paraffin, 174liquid preparations, 8, 9lisinopril, 124lisuride, 114, 188lithium ions, 234, 235, 246,247liverbiotransformation, 32,42blood supply, 32drug elimination, 18,32–33, 44drug exchange, 24enterohepatic cycle, 38,39lipoprotein metabolism,154–157loading dose, 50local anesthetics, 128, 134,204–209chemical structure,208–209diffusion and effect,206–207mechanism of action,204–206lomustine, 298loop diuretics, 162, 163loperamide, 178, 212loratidine, 116lorazepam, 220, 330lormetazepam, 224lotions, 16, 17lovastatin, 156, 157low blood pressure, seehypotensionLSD, see lysergic acid diethylamideLugol’s solution, 246luteinizing hormone (LH),242, 243, 252, 254deficiency, 252lymphocytes, 72lymphokines, 72lynestrenol, 254lypressin, 164lysergic acid, 126lysergic acid diethylamide(LSD), 126, 240, 241Mmacrophages, 300activation, 72magnesium sulfate, 126maintenance dose, 50major histocompatibilitycomplex (MHC), 300malaria, 294–295malignant neuroleptic syndrome,238mania, 230, 234, 235manic-depressive illness,230mannitol, 160, 161, 170maprotiline, 232margin of safety, 70mass action, law of, 3, 56mast cells, 72inhibitors of histaminerelease, 116stabilization, 326, 328matrix-type tablets, 9, 10maturity-onset diabetesmellitus, 262–264mazindole, 88mebendazole, 292, 293mebhydroline, 114mecamylamine, 108mechlorethamine, 298meclizine, 114, 330medicinal charcoal, 178medroxyprogesterone acetate,254mefloquine, 294, 295megakaryocytes, 148megaloblastic anemia, 192melphalan, 298membrane permeation,26–27membrane stabilization,94, 134, 136memory cells, 72menstrual cycle, 254menstruation, 196Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Index 379meperidine, 126, 210, 214,215mepivacaine, 2096-mercaptopurine, 298mesalamine, 272mescaline, 116, 240mesterolone, 252mestranol, 254, 256metamizole, 198metastases, 296metenkephalin, 212, 213metenolone, 252meteorism, 180metformin, 262l-methadone, 210, 214,215methamphetamine, 86, 87,88methemoglobin, 304, 305methimazole, 247methohexital, 220methotrexate, 298, 300,320methoxyflurane, 218methoxyverapamil, 1224-methyl-2,5-dimethoxyamphetamine,240methylation reactions, 36,37methyldigoxin, 132methyldopa, 96, 114, 312methylenedioxy methamphetamine(MDMA), 240methylergometrine, 126methylprednisolone, 33017-α-methyltestosterone,252methylxanthines, 326methysergide, 322metoclopramide, 322, 330metoprolol, 94, 322metronidazole, 168, 274mexiletine, 134, 136mezclocillin, 270mianserin, 232mibefradil, 122, 308miconazole, 282Micromonospora bacteria,276micturition, 98midazolam, 220, 221, 228mifepristone, 126, 256migraine treatment, 116,126, 322–323milieu interieur, 80milrinone, 132mineralocorticoids, 248,249minimal alveolar concentration(MAC), 218minipill, 256, 257minocycline, 278minoxidil, 118, 312misoprostol, 126, 168, 169,200mites, 292, 293mixed-function oxidases,32mixtures, 8moclobemide, 88, 232, 233molsidomine, 120, 308monoamine oxidase(MAO), 82, 86, 88, 114inhibitors of, 88, 89, 188,230, 232monoclonal antibodies,300mood change, 210morning-after pill, 256morphine, 4, 5, 178,210–215, 310antagonists, 214increased sensitivity, 70metabolism, 212, 213overdosage, 70, 71Straub tail phenomenon,52, 53Morton, W.T.G., 216motiline, 276motion sickness, 106, 330,331motor endplate, 182nicotine and, 110motor systems, drugs actingon, 182–193mountain sickness, 162moxalactam, 270mucociliary transport, 14mucolytics, 324, 325mucosal administration,12, 14, 18, 22mucosal block, 140mucosal disinfection, 290,291murein, 268muromonab CD3, 300muscarinic cholinoceptors,100, 188, 230muscimol, 240muscle relaxants, 182,184–187, 226myasthenia gravis, 102mycobacterial infections,274, 280–281M. leprae, 280M. tuberculosis, 280mycophenolate mofetil,300mycoses, 282–283mydriatics, 104myocardial infarction, 128,148, 226, 309–310myocardial insufficiency,92, 132myocardiumcontraction, 128, 129oxygen demand, 306,307oxygen supply, 306, 307relaxation, 128, 129myometrial relaxants, 126myometrial stimulants,126myosin kinase, 84NNa channel blockers, 128,134–137, 204nabilone, 330NaCl reabsorption, kidney,160, 161nadolol, 322naftidine, 282nalbuphine, 212, 215nalidixic acid, 274naloxone, 210, 211, 214,215, 302naltrexone, 214nandrolone, 252naphazoline, 90, 326naproxene, 200nasal decongestion, 90Naunyn, Bernhard, 3nausea, 330–331see also antiemetics;motion sicknessnazatidine, 116Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
380 Indexnebulizers, 13, 14Necator americanus, 292nedocromil, 116negative bathmotropism,134negative chronotropism,134negative dromotropism,134negative inotropism, 134nelfinavir, 288nematode parasites, 292neomycin, 278, 279neoplasms, see cancer;carcinomaneostigmine, 102, 103, 184nephron, 160, 161netilmicin, 278neurohypophyseal (NH)hormones, 242neurohypophysis, 242, 243nicotine effects, 110neuroleptanalgesia, 216,236neuroleptanesthesia, 216neuroleptics, 114, 216, 240epilepsy and, 190mania treatment, 234schizophrenia treatment,236–238thermoregulation and,202, 203neuromuscular transmission,182, 183blocking, 184neurotic disorders, 226neutral antagonists, 60neutrophils, 72nevirapine, 288nicotine, 108–113effects on body functions,110–111ganglionic action, 108ganglionic transmission,108, 109nicotinic acid, 118, 156nicotinic cholinoceptors,64, 65, 100, 108, 182nifedipine, 122, 123, 126,308hypertension treatment,312mania treatment, 234nimodipine, 122, 234nitrate tolerance, 120nitrates, organic, 120–121nitrazepam, 222nitrendipine, 122nitric acid, 120nitric oxide (NO), 100, 116,120, 148nitroglycerin, 120, 308,311, 312nitroimidazole, 274, 275nitrostigmine, 102nitrous oxide (N 2O), 218,219nizatidine, 168nociceptors, 194, 196non-insulin-dependent diabetesmellitus,262–264noncovalent bonds, 58nondepolarizing musclerelaxants, 184, 185nonsteroidal antiinflammatorydrugs (NSAIDS),38,198, 200–201gout treatment, 316pharmacokinetics, 200rheumatoid arthritistreatment, 320noradrenaline, see norepinephrinenordazepam, 228norepinephrine, 82, 83, 88,118biotransformation, 36,37local anesthesia and, 206neuronal re-uptake, 82,230release of, 90, 91structure-activity relationships,86, 87synthesis, 82, 88norethisterone, 254norfloxacin, 274nortriptyline, 232noscapine, 212, 324nose drops, 8, 9nucleoside inhibitors, 288,289nystatin, 282, 283Oobesity, diabetes mellitusand, 262, 263obidoxime, 304, 305octreotide, 242ofloxacin, 274ointments, 12, 13, 16, 17olanzapine, 238omeprazole, 168ondansetron, 116, 330opioids, 178, 210–215, 302effects, 210–212metabolism, 212, 213mode of action, 210tolerance, 214opium, 4tincture, 4, 5, 178oral administration, 8–11,18, 19, 22dosage schedule, 50oral contraceptives, 254,256–257biphasic preparations,256, 257minipill, 256, 257monophasic preparations,256, 257morning-after pill, 256oral rehydration solution,178orciprenaline, 86, 87organ preparation studies,54organophosphate insecticidepoisoning, 304, 305organophosphates, 102ornipressin, 164, 165osmotic diuretics, 160, 161osteomalacia, 192osteopenia, 318osteoporosis, 264,318–319ouabain, 132overdosage, 70, 71ovulation, 254inhibition, 256stimulation, 256oxacillin, 270, 271oxalate, 142oxatomide, 116oxazepam, 228oxiconazole, 282Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Index 381oxidases, mixed-function,32oxidation reactions, 36, 37oxymetazoline, 326oxytocin, 126, 242, 243Pp-aminobenzoic acid (PA-BA), 272, 273paclitaxel, 296, 297pain, 194, 195see also analgesicspalliative therapy, 296pamidronate, 318pancreatic enzymes, 180,181pancreozymin, 180pancuronium, 184, 185pantoprazole, 168Papaver somniferum, 4papaverine, 210Paracelsus, 2paracetamol, see acetaminophenparaffinomas, 174paraoxon, 36, 102, 103parasitic infections,292–295parasympathetic nervoussystem, 80, 98–107anatomy, 98drugs acting on,102–107responses to activation,98, 99parasympatholytics,104–107, 128, 134, 324contraindications for,106parasympathomimetics,102–103, 128direct, 102, 103indirect, 102, 103parathion, 102biotransformation, 36,37parathormone, 264, 265paravertebral ganglia, 82parenteral administration,12, 13Parkinsonismantiparkinsonian drugs,188–190pseudoparkinsonism,238treatment, 88, 106, 114paromomycin, 278paroxetine, 232partial agonists, 60pastes, 12, 13, 16, 17patient compliance, 48pectin, 178penbutolol, 94penciclovir, 286D-penicillamine, 302, 303,320penicillinase, 270, 271penicillins, 267–270, 271elimination, 268penicillin G, 72, 266,268–270, 271penicillin V, 270, 271Penicillium notatum, 268pentazocine, 210, 212, 214,215pentobarbital, 223biotransformation, 36,37peptic ulcers, 104, 106,166–169peptidases, 34peptide synthetase, 276peptidoglycan, 268perchlorate, 246, 247pergolide, 114, 126, 188perindopril, 124perineurium, 206peristalsis, 170, 171, 173permethrin, 292pernicious anemia, 138perphenazine, 330pethidine, 210pharmacodynamics, 4pharmacogenetics, 70pharmacokinetics, 4, 6,44–51accumulation, 48, 49, 50,51concentration timecourse, 46–49, 68, 69protein binding, 30see also elimination ofdrugspharmacology, history of,2–4pharyngitis, 324α-phase, 46β-phase, 46phase I reactions in drugbiotransformation, 32,34phase II reactions in drugbiotransformation, 32,34phenacetin, 36phencyclidine, 240pheniramine, 114phenobarbital, 138, 190,191, 192, 222enzyme induction, 32, 33phenolphthalein, 174phenothiazines, 236, 238,330phenoxybenzamine, 90phenoxymethylpenicillin,270phentolamine, 90, 312phenylbutazone, 200, 316phenylephrine, 86phenytoin, 130, 136epilepsy treatment, 190,191, 192folic acid absorption and,138phobic disorders, 226phosphodiesterase, 66inhibitors, 128phospholipase A2, 248phospholipase C, 66, 100,150phospholipid bilayer, 20,26as barrier, 22phospholipids, 20, 26phosphoric acid, 20physostigmine, 102, 103,106, 302pilocarpine, 102pindolol, 94, 95pinworm, 292, 293pipecuronium, 184piperacillin, 270piperazine, 236, 238pirenzepine, 104, 107, 166piretanide, 162piroxicam, 200, 320Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
382 Indexpizotifen, 322placebo effect, 76, 77placebo-controlled trials,76placental barrier, 24Plantago, 170plasma volume expanders,152–153plasmalemma, 20plasmin, 146inhibitors, 146plasminogen, 144, 146activators, 146Plasmodium falciparum,294Plasmodium ovale, 294Plasmodium vivax, 294platelet activating factor(PAF), 148, 150platelet cyclooxygenase,150, 151platelet factor 3 (PF3), 142platelets, 148, 149, 196inhibitors of aggregation,150, 151plicamycin, 264poisoningantidotes, 302–305atropine, 106, 202, 302polidocanol, 208polyarthritis, chronic, 320polyene antibiotics, 282,283polymyxins, 266, 267portal vein, 32, 33potassium (K + ) channel activation,66potassium-sparing diuretics,164, 165potency, 54, 60, 61potentiation, 76powders, 12, 13, 16, 17pramipexole, 188pravastatin, 156praziquantel, 292, 293prazosin, 90preclinical testing, 6prednisolone, 36, 248, 249prednisone, biotransformation,36pregnancydrug toxicity, 74, 75hypertension treatment,312vomiting, 330, 331pregnandiol, 254, 255premedication, 104, 106,226prevertebral ganglia, 82prilocaine, 208, 209biotransformation, 34,35primaquine, 294, 295primary biliary cirrhosis,180primidone, 138, 192pro-opiomelanocortin,210, 211probenecid, 268, 269, 316,317probucol, 156procainamide, 134, 136procaine, 134, 208, 209,268biotransformation, 34,35prodrugs, 34prodynorphin, 210proenkephalin, 210, 211progabide, 190progesterone, 254, 255,257progestin preparations,254oral contraceptives, 256proguanil, 294, 295prokinetic agents, 116prolactin, 242, 243prolactin release inhibitinghormone (PRIH), 242prolactin-releasing hormone(PRH), 242promethazine, 114propafenone, 136propofol, 220, 221propranolol, 94, 95, 322biotransformation, 36,37enantioselectivity, 62propylthiouracil, 247propyphenazone, 198prospective trials, 76prostacyclin, 116, 118,148, 150, 196prostaglandin synthase inhibitors,320prostaglandins, 126, 168,196, 197, 320NSAIDS and, 200, 201prostatebenign hyperplasia, 90,252, 312carcinoma, 242hypertrophy, 106protamine, 144protease inhibitors, 288,289protein binding, of drugs,30–31protein kinase A, 66protein synthesis, 276inhibitors, 276–279protein synthesis-regulatingreceptors, 64, 65protirelin, 242pseudocholinesterase deficiency,186pseudoparkinsonism, 238psilocin, 240psilocybin, 116, 240psychedelic drugs,116–118, 240, 241psychological dependence,210–212psychomimetics, 240, 241psychopharmacologicals,226–241psychosomatic uncoupling,232, 236purgatives, 170–177dependence, 172, 173pyrazinamide, 280, 281pyridostigmine, 102pyridylcarbinol, 156pyrimethamine, 294, 295pyrogens, 202, 203Qquinapril, 124quinidine, 136, 295quinine, 2944-quinolone-3-carboxylicacid, 274, 275Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Index 383Rracemates, 62, 63raloxifen, 254ramipril, 124ranitidine, 116, 168rapid eye movement(REM) sleep, 222, 223reactive hyperemia, 90, 91receptor-mediated endocytosis,26, 27receptors, 20drug binding, 56types of, 64–65rectal administration, 12,18, 19reduction reactions, 36, 37renal failure, prophylaxis,158renal tubular secretion, 40renin, 124, 158renin-angiotensin-aldosterone(RAA) system, 118,125, 158inhibitors of, 124–125reserpine, 96, 114resistance, 266, 267respiratory tract, 22inhalation of drugs, 14,15, 18, 19retarded drug release, 10,11reteplase, 146retrospective trials, 76reverse transcriptase, 288inhibitors, 288, 289Reye’s syndrome, 198rheumatoid arthritis, 302,320–321rhinitis, 324ribonucleic acid (RNA),274synthesis inhibition, 298,299ribosomes, 276ricinoleic acid, 174, 175rifabutin, 274rifampin, 267, 274, 280,281risk:benefit ratio, 70risperidone, 238, 240ritodrine, 126ritonavir, 288rocuronium, 184rolitetracycline, 278ropinirole, 188rosiglitazone, 262rough endoplasmic reticulum(rER), 32, 33roundworms, 292, 293Ssalazosulfapyridine, 272salbutamol, 86, 328salicylates, 200salicylic acid, 34see also acetylsalicylicacidsalmeterol, 328Salmonella typhi, 270, 271saluretics, see diureticssaquinavir, 288, 289sarcoplasmic reticulum,182Sarcoptes scabiei, 292sartans, 124Schistosoma, 292schizophrenia, 118, 236,237Schmiedeberg, Oswald, 3scopolamine, 106, 107,240, 330sea sickness, 106, 330, 331sedation, 222, 226scopolamine, 106seizures, 190, 226selectivity, lack of, 70, 71selegiline, 88, 188senna, 174, 176sensitivityincreased, 70, 71variation, 52sensitization, 72serotonin, 88, 116–118actions, 116neuronal reuptake, 230platelet activation, 148,150receptors, 116, 230, 322serotonin-selective reuptakeinhibitors (SSRI),230, 232sertindole, 238sertraline, 232Sertümer, F.W., 4serum sickness, 72sibutramine, 88side effects, 70–75signal transduction, 64, 66lithium ion effects, 234simethicone, 180simile principle, 76simvastatin, 156sinus bradycardia, 134sinus tachycardia, 92, 134sisomycin, 278skinas barrier, 22disinfection, 290, 291protection, 16, 17transdermal drug deliverysystems, 12, 13, 18,19sleep, 222, 223disturbances, 118, 222,224sleep-wake cycle, 224,225slow-release tablets, 10smoking, 112–113see also nicotinesmooth endoplasmic reticulum(sER), 32, 33smooth muscleacetylcholine effects,100, 101adrenoceptor activationeffects, 84drugs acting on,126–127relaxation of, 104, 120,122, 326vascular, 118, 120, 122,196, 326sodium channel blockers,128, 134–137, 204sodium chloride reabsorption,kidney, 160, 161sodium citrate, 264sodium methohexital, 221sodium monofluorophosphate,318sodium nitroprusside, 120,312sodium picosulfate, 174sodium thiopental, 221solutions, 8, 17concentration of, 28Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
384 Indexinjectable, 12somatic nervous system,80somatocrinin, 242somatostatin, 242somatotropic hormone(STH), 242, 243soporifics, 222sorbitol, 160, 170sore throat, 324, 325sotalol, 136spasmolytics, 126, 127spasticity, 226spermatogenesis stimulation,252spiramycin, 276spironolactone, 164, 165stage fright, 92stanozolol, 252Staphylococcus bacteria,270statins, 156status epilepticus, 190, 192stavudine, 288steady state, 48steal effect, 306stereoisomerism, 62sterilization, 290steroid receptors, 64steroids, anabolic, 252Straub tail phenomenon,52, 53streptokinase, 144, 310Streptomyces bacteria,276, 277, 300, 302streptomycin, 276, 280,281stress, sleep disturbancesand, 224, 225stroke, 148Strongyloides stercoralis,292strychnine, 182subcutaneous injection,18, 19subliminal dosing, 52sublingual drug administration,18, 19, 22succinylcholine, 186sucralfate, 168, 169sulbactam, 270sulfadoxine, 294, 295sulfamethoxazole, 272,273sulfapyridine, 272sulfasalazine, 272, 320sulfinpyrazone, 316sulfonamidesantibacterial, 267, 272,273diuretics, 162, 163sulfonylurea, 262sulfotransferases, 38sulfoxidations, 36sulprostone, 126sulthiame, 162sumatriptan, 116, 322suppositories, 12, 13suspensions, 8swallowing problems, 324sweat glandsatropine poisoning and,106sympathetic innervation,80sympathetic nervoussystem, 80–97drugs acting on, 84–97responses to activation,80, 81structure of, 82sympatholyticsα-sympatholytics, 90, 91β-sympatholytics, 92, 93,94, 95non-selective, 90selective, 90sympathomimetics, 90, 91,128, 132, 314allergic disorder treatment,326asthma treatment, 328bronchodilation, 126common cold treatment,324, 325direct, 84, 86indirect, 86, 88, 89intrinsic activity (IS), 94sinus bradycardia and,134structure-activity relationships,86, 87synapseadrenergic, 82cholinergic, 100synapsin, 100synovectomy, 320syrups, 8TT lymphocytes, 72, 300tablets, 8–10vaginal, 12, 13tachycardia, 134atropine poisoning and,106treatment, 92, 122, 134tachyphylaxis, 88tacrine, 102tacrolimus, 300tamoxifen, 254tape worms, 292, 293tardive dyskinesia, 238tazobactam, 270temazepam, 222, 224teniposide, 298teratogenicity, 74terazosin, 90terbutaline, 84, 86, 326,328testingclinical, 6preclinical, 6testosterone, 34, 242, 252,253esters, 252testosterone heptanoate,252testosterone propionate,252testosterone undecanoate,34, 252tetanus toxin, 182, 183tetracaine, 208, 324tetracyclines, 266, 267,276–279tetrahydrocannabinol, 240tetrahydrofolic acid (THF),272, 298, 299tetrahydrozoline, 90, 326thalidomide, 74thallium salt poisoning,304theophylline, 118, 126,127, 326, 328thermoregulation, 196,202–203Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
Index 385thiamazole, 247thiazide diuretics, 132,162, 163, 312thiazolidinediones,262–264thio-TEPA, 298thioamides, 246, 247thiopental, 220thiourea derivatives, 246thioureylenes, 246thioxanthenes, 236, 238thrombasthenia, 148thrombin, 150thrombocytopenia, 72thromboses, 142, 148, 158prophylaxis, 142–143,146, 148–151thromboxane, 148, 150,196thymeretics, 230, 232thymidine kinase, 286thymoleptics, 230, 238thyroid hormone receptors,64thyroid hormone therapy,244–245thyroid hyperfunction, 202thyroid peroxidase, 246thyroid stimulating hormone(TSH), 242, 243,244thyrotropin, 242thyrotropin-releasing hormone(TRH), 242thyroxine, 244, 245, 246tiagabin, 190ticarcillin, 270ticlopidine, 150tight junctions, 22, 24timed-release capsules, 10timidazole, 274timolol, 94tincture, 4tirofiban, 150tissue plasminogen activator(t-PA), 146tizanidine, 182tobacco smoking, 112–113see also nicotinetobramycin, 277, 278tocainide, 136tocolysis, 84, 127tocolytics, 126tolbutamide, 262tolonium chloride, 304,305Toluidine Blue, 304, 305tonsillitis, 324topiramate, 191, 192topoisomerase II, 274total intravenous anesthesia(TIVA), 216toxicological investigations,6tracheitis, 324tramadol, 210trandolapril, 124tranexamic acid, 16transcytosis, 24, 26transdermal drug deliverysystems, 12, 13, 18, 19estrogen preparations,254transferrin, 140transmitter substances, 20cholinergic synapse, 100sympathetic, 82transpeptidase, 268inhibition of, 268, 270transportmembrane permeation,26, 27mucociliary, 14transport proteins, 20tranylcypromine, 88, 232travel sickness, 106trials, clinical, 76triamcinolone, 248, 249triamterene, 164, 165triazolam, 222, 223, 224,226triazole derivatives, 282Trichinella spiralis, 292,293trichlormethiazide, 162Trichomonas vaginalis,274, 275Trichuris trichiura, 292tricyclic antidepressants,230–232trifluperazine, 236, 238,239triflupromazine, 236, 238,239triglycerides, 154–156,248triiodothyronine, 244, 245trimeprazine, 330trimethaphan, 108trimethoprim, 267, 272,273triptorelin, 242troglitazone, 262–264trolnisetron, 330tropisetron, 116tuberculosis, 274, 276, 280d-tubocurarine, 184, 185tumours, see cancer; carcinomatyramine, 232L-tyrosine, 82tyrosine kinase activity, 64tyrothricin, 266, 267Uulcers, peptic, 104, 106,166–169ultralente, 258uricostatics, 316, 317uricosurics, 316, 317urine, drug elimination, 40urokinase, 146ursodeoxycholic acid(UDCA), 180Vvaccinations, 284vaginal tablets, 12, 13vagus nerve, 98valacyclovir, 286valproate, 190, 192, 234valproic acid, 191, 192van der Waals’ bonds, 58,59vancomycin, 267, 268, 270vanillylmandelic acid, 82varicosities, 82vasculitis, 72vasoactive intestinal peptide(VIP), 242vasoconstriction, 84, 90nicotine and, 110serotonin actions, 116vasoconstrictors, local anesthesiaand, 206vasodilation, 84local anesthesia and, 206Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
386 Indexserotonin actions, 116vasodilators, 118–123, 312calcium antagonists,122–123organic nitrates,120–121vasopressin, 148, 160, 164,165, 242nicotine and, 110vecuronium, 184vegetable fibers, 170verapamil, 122, 123, 136angina treatment, 308hypertension and, 312mania treatment, 234ventricular rate modification,134Vibrio cholerae, 178vidarabine, 285, 386vigabatrin, 190, 191vinblastine, 296vincristine, 296viomycin, 280viral infections, 178,284–289AIDS, 288–289common cold, 324–325virustatic antimetabolites,284–287vitamin A derivatives, 74vitamin B 12, 138, 139deficiency, 138vitamin D, 264vitamin D hormone, 264,265vitamin K, 144, 145VLDL particles, 154volume of distribution, 28,44vomitingdrug-induced, 330pregnancy, 330, 331see also antiemetics;motion sicknessVon-Willebrandt factor,148, 149WWepfer, Johann Jakob, 3whipworm, 292Wilson’s disease, 302wound disinfection, 290,291Xxanthine oxidase, 316, 317xanthinol nicotinate, 156xenon, 218xylometazoline, 90Zzafirlukast, 328zalcitabine, 288zero-order kinetics, 44zidovudine, 289zinc insulin, 258Zollinger-Ellison syndrome,168zolpidem, 222zonulae occludentes, 22,24, 206zopiclone, 222Lüllmann, <strong>Color</strong> <strong>Atlas</strong> of <strong>Pharmacology</strong> © 2000 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
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