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BIMM118 

“One of the features which is thought to 

distinguish man from other animals is his 

desire to take medicines” 

(Sir William Osler, 1849-1919)

BIMM118 

Definitions 

• Pharmacology is the science of the interaction of chemicals with living 

systems at all levels 

• Pharmacokinetics investigates the effects of the biological system on drugs 

(absorption, distribution, elimination…) 

• Pharmacodynamics describes the fundamental action of a drug on a 

physiological, biochemical or molecular level 

• Pharmacogenetics examines the effects of genetic factors to variations in the 

drug response 

• Toxicology studies the undesirable effects of chemicals on living systems 

(includes poisons, antidotes and unwanted side effects of drugs) 

• Pharmacy is the art of preparing, compounding and dispensing chemicals for 

medicinal use

BIMM118 

Definitions 

• Prophylactic refers to a drug or procedure aimed to prevent disease 

• Palliative refers to a drug or procedure aimed to relieve symptoms 

• Therapeutic refers to a drug or procedure aimed to cure disease 

• Tolerance is the increased resistance to the usual effects of an established 

dose of a particular drug 

• Effective dose (ED50) is the concentration at which 50% of the subject show 

a predefined response 

• Efficacy refers to the inherent capability of a drug to produce a desired effect 

• Potency compares the relative effectiveness of drugs to produce a desired effect 

e.g. Drug A requires fewer milligrams than Drug B to achieve the same pharmacological response 

--> Drug A has the higher potency, yet, both drugs have the same efficacy.

BIMM118 

History of Pharmacology 

• Initially most medicines were of 

botanical or zoological origin 

• Since 1950’s, large increase in 

synthetic organic chemicals 

• Recent introduction of recombinant 

DNA technology has extended 

synthesis to molecules of human origin

BIMM118 


• Early agents were naturally occurring inorganic salts and plant 

alkaloids 

– Opium 

– Foxglove 

– Mercury, arsenic or lead compounds 

• Most ineffective or actually dangerous 

• Standardization of dose very difficult 

– Narrow therapeutic index with foxglove

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Homeopathy 

• 1790-96: Dr. Samuel Hahnemann: 

To discover the true mode of action by which cinchona bark cured 

malaria, he ingested cinchona juice twice daily for a few days. To his 

great astonishment, he very soon developed symptoms very similar 

to malarial fever. 

– Postulated a new principle of treatment: “Likes cure likes” 

– Drug is called the remedy, obtained through serial dilutions of the 

chemical 

The remedy is mainly extracted from the plants, animals and minerals. The medicinal extract is diluted and 

potentiated to such an extent that not even an atom of the mother material can be detected in the remedy by the 

time it reaches the 12th potency. Dilutions are done in steps. For example: In the centi scale, one drop of mother 

tincture is mixed with 99 drops of alcohol and shaken rigorously using pre-determined strokes. This is termed as 

1c. From this, one drop is mixed with 99 drops of alcohol and is termed as 2c and so on. The higher the dilution, 

the more powerful the remedy. It was proposed recently that the magnetic aura of the remedy increases with 

potency (supposedly, this had been proven with Kirlian photography). 

Since the remedies are used after diluting several times, it cannot have chemical effects on the body to create a 

long standing side effect.

BIMM118 


• Major advance in safe use of naturally derived agents 

was the isolation, purification and chemical 

characterization of the active compound: 

– Allowed administration of a controlled dose 

– Allowed administration of the active component of herbal 

mixtures to be given alone 

– Identification and characterization of active component 

allowed definition of mechanism of action, leading to 

synthesis of improved agents with greater selectivity, 

potency, altered duration of action, etc.

BIMM118 

• Aspirin® - first synthetic drug 


– Hippocrates: pain relief treatments with powder made from the bark and leaves of 

the willow tree (Salix sp.) 

– Johann Buchner (1829): isolated Salicin as the 

active ingredient in Meadowsweet (Spiraea ulmaria) 

(hydrolyzed into glucose and Salicyl-aldehyde -> 

oxidyzed to Salicylic Acid) 

Salicylic Acid is very tough on the stomach-> 

– Felix Hoffman (1898-9): Chemist at Bayer 

synthezised Acetyl-Salicylic Acid, 

(process discovered originally by Charles Gerhardt in 1853) 

and tested it on his arthritis-suffering father! 

– March 6, 1899: Bayer receives patent for Aspirin® 

– Sales today exceed 50 billion pills per year

BIMM118 


• 20 th Century: Dramatic change in antimicrobial therapy 

– Survival of patients with severe infections with historically high 

mortality 

– Introduction of sulfonamides (Gelmo 1908: Sulfanilamide) and 

arsenic compounds (Ehrlich 1908/10: arsephenamine= Salvarsan) 

and subsequently penicillins (Fleming 1928/29)

BIMM118 

New Drug Discovery 

• Analogues to existing drugs 

– Usually shows only minor changes in potency, absorption, 

duration of action 

• New applications for existing drugs 

– Occasionally unexpected additional properties may become 

evident when the compounds are tested in humans 

• Sulfanilamide --> thiazide diuretics 

• Sulfanilamide --> sulfonylurea hypoglycemics 

• Aspirin® --> Anti-aggregatory --> Cardioprotective

BIMM118 


• Synthesis and screening of new chemical entities 

• Subject new chemicals to a battery of tests designed to detect 

a particular type of biological activity (“Drug screening”) 

• Chemicals produced by direct synthesis, or isolation from 

biological sources (or combination of both: semi-synthetic) 

• Apparently not an efficient method since huge numbers of 

chemicals may need to be screened, however, new robotic 

instruments are now screening millions of compounds against 

defined receptors or enzymes

BIMM118 


• Design of compounds for a specific biological function 

(“Rational drug design”) 

– Synthesis of naturally occurring compounds or structural analogues 

• Examples: 

– Levodopa, H2 receptor antagonists, omeprazole 

– Use of structural information (receptor, enzyme) to develop 

interacting compounds 

• Examples: 

– STI571 (Glevec®): Bcr-Abl specific inhibitor, but high pK => 

2 nd generation Bcr-Abl inhibitors are being designed based on the 

structure of the Bcr-Abl/STI571 complex 

– Cloning of genes to produce large biologically active peptides 

• Examples: 

– Rec. hormones, cytokines; soluble receptor; antibodies

BIMM118 


• Extremely high cost of new drug development in general restricts 

it to the province of large pharmaceutical companies 

• Cost of new drug development is in the $100 to $500 million 

range 

• Cost of initial marketing is also very high 

• Incentives are very high with important new drugs having greater 

than $1 Billion in yearly sales

BIMM118 

Patent Protection of new Drugs 

• Patent life in the US is 20 years 

• Drug is frequently patented five years or more before 

marketing begins 

• After patents expire, other manufacturers may 

produce and sell bioequivalent “generic” products 

(usually much cheaper, as these companies had very little “development” cost)

BIMM118 

Orphan Drugs 

• Drugs for conditions affecting less than 200,000 

individuals in the US 

• Orphan Drug Act of 1983 provides incentives for the 

development of drugs for this small market segment 

(tax breaks, exclusive marketing rights, grant funding) 

• 890 Orphan drugs in the US for the treatment of 6.5 

million people

BIMM118 

• Brand Name 

Drug Nomenclature 

– Prevacid®, Zoton® (New Zealand), Keval® (Mexico), Lanzor® (France), etc. 

• Generic Name 

– Lansoprazole 

• Chemical Name 

– 2-[[[3-methyl-4-(2,2,2-trifluroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole

BIMM118 

Drug Approval 

Historically, manufacturers or sellers had no responsibility 

--> Regulatory systems have arisen to protect patients from toxicity and 

more recently to ensure benefit (efficacy) 

1938 - Federal Food, Drug and Cosmetic Act

BIMM118 

• Safety 

Drug Approval 

– Introduction of new drugs has sometimes been bought at the price of 

significant toxicity 

• 1937: >100 deaths due to diethylene glycol in Sulfanilamide elixir 

• 1960’s: Thalidomide (Contergan®) disaster: 

– developed by the company Grünenthal as a sleep-inducing drug and to 

combat symptoms associated with morning sickness of pregnant women

BIMM118 

• Safety 

Drug Approval 

– Bacterial, isolated cellular, and intact animal toxicity testing 

– Testing for toxicities including 

• Teratogenicity 

• Mutagenicity 

• Reproductive toxicity

BIMM118 

• Regulatory bodies (FDA) 

Drug Quality 

– ensure quality of prescribed drugs 

• Defined criteria for: 

– Purity 

– Stability and sterility 

– Limits of potentially toxic impurities 

– Defined, approved amount of drug, released at a specified rate (United 

States Pharmacopoeia, British Pharmacopoeia, European Pharmacopoeia)

BIMM118 

Drug Efficacy 

• Efficacy must be established in patients for whom the 

medicine is intended 

• All medicines, except dietary supplements, must 

have evidence of efficacy for their licensed 

indications.

BIMM118 

Drug Efficacy - Dietary Supplements? 

• Leptoprin® (30 pills = $153): 

– Calcium (amino acid chelate) 264mg 

– Vitamin B6 25mg 

– Acetylsalicylic acid 324mg 

– Caffeine 200mg 

– Green Tea Extract (no amount listed) 

– L-Tyrosine (no amount listed) 

– Kelp 100mg 

– Ephedrine 20mg 

– Cayenne (no amount listed) 

The FDA had previously issued a policy that ephedrine products must be 

labeled with possible adverse effects, contain no more than 8 milligrams of 

ephedrine per serving, and be used for no longer than seven days, because of 

the significant dangers associated with ephedra or ephedrine use. 

Since April 2004, ephedrine has been banned in dietary supplements! 

Conclusion: The only ingredient in Leptoprin that might assist in weight loss 

is calcium. If you do not get enough calcium in your diet, you can buy cheap 

supplements at any drugstore.

BIMM118 

Drug Efficacy - Dietary Supplements? 

• CortiSlim® (30 pills = $78): 

– “Dr”. Greg Cynaumon? 

Ph.D. from “Sierra University” in Psychology - School was shut down by 

the State of California! 

– September 2004 : Greg Cynaumon forced to admit that he is not a 

psychologist or a marriage and family therapist.The California Board of 

Psychology issues a citation and fines Greg Cynaumon $1,500 for 

continuing to impersonate a psychologist. 

– The California Board of Behavioral Sciences issued a citation and fined 

Greg Cynaumon $1,000 for continuing to impersonate a 

marriage/family therapist. 

– “FTC Targets Products Claiming to Affect the Stress Hormone Cortisol” 

Agency Alleges That Marketers of CortiSlim and CortiStress Made 

False or Unsubstantiated Claims

BIMM118 

Establishing Safety and Efficacy 

• Preclinical studies 

• Phase I clinical studies 

• Phase II clinical studies 

• Phase III clinical studies 

• Phase IV post-marketing 

surveillance

BIMM118 

Preclinical Studies 

• Pharmacological effects or pharmacological profile 

– In-vitro effects using isolated cells/organs 

– Receptor-binding characteristics 

– in-vivo effects in animals/animal models of human disease 

• Drugs are lacking where a good animal model of a human 

disease does not exist 

– Prediction of potential therapeutic use

BIMM118 

• Pharmacokinetics 


– Identification of metabolites (since these may be the active 

form of the compound) 

– Evidence of bioavailability (to assist in design of clinical trials 

and assess toxicity) 

– Establishment of principal route of administration and rate of 

elimination

BIMM118 

• Toxicological effects 


– In vitro and in vivo batteries of tests to identify toxic 

compounds and metabolites prior to extensive exposure of 

animals and subsequently humans 

– Toxicity testing has two primary goals: 

• Recognition of hazards 

• Prediction of that hazard occurring in humans at therapeutic 

doses 

– A wide range of doses is tested 

» High doses to detect toxicity 

» Low doses to predict risk at therapeutic doses

BIMM118 

Toxicity Testing 

• Mutagenicity 

• A variety of in vitro tests using bacteria and mammalian cell 

lines are employed at an early stage to define any potential 

effect on DNA that may be linked to carcinogenicity or 

teratogenicity 

• Carcinogenicity 

• Repeated doses given throughout lifetime of an animal (usually 

two year rodent assay) 

• Especially important in drugs intended for chronic 

administration (greater than one year) 

• Reproductive toxicity 

• Repeated doses given prior to mating and throughout gestation 

• Assesses effect on fertility, implantation, fetal growth, 

production of fetal abnormalities and neonatal growth

BIMM118 

• Acute Toxicity 


• Animal model - single dose given by proposed route for 

humans 

• Defines dose range associated with toxicity 

• Defines dose range for initial human trials 

• Subacute Toxicity 

• Repeated doses given for 14 or 28 days 

• Reveals target for toxic effects 

• Comparison with single-dose studies indicate potential for 

accumulation 

• Chronic Toxicity 

• Repeated doses given up to six months 

• Reveals target(s) for toxicity (except cancer) 

• Aim is to define doses associated with adverse effects and “no 

observed adverse effect level” associated with “safe” dose

BIMM118 

• Animal Studies: 


– Remain an important part of toxicological testing 

– Essential to investigate both interference with integrative 

function and complex homeostatic mechanisms 

– Necessary to prevent extensive toxicity in subsequent 

human trials 

– Extensive research underway to reduce the need for animal 

studies by using in vitro methodology

BIMM118 

• Animal Studies: 


– Methodology is not perfect, but animal studies do provide an 

effective predictive screen 

– Not all hazards detected at very high doses in experimental 

animals are relevant to human health 

– FDA has to judge if there is clinical relevance of data in 

animals at doses that may be two orders of magnitude 

above those intended for human use

BIMM118 

Premarketing Clinical Studies: Phase I-III Trials 

• Notice of Claimed Investigational New Drug (IND) is 

filed with the FDA 

– Information on composition and source of drug 

– Manufacturing information 

– Data from animal studies 

– Clinical plans and protocols 

– Names and credentials of physicians conducting the trials

BIMM118 

Phase I Studies 

• Studies carried out in healthy volunteers 

• Carried out by pharmaceutical companies or major hospitals 

• In some cases patients with the disease in question may be 

enrolled (cancer chemotherapy) 

• Initially small doses (as little as one fiftieth of intended dose) 

• Toxicity evaluated with routine hematology and biochemical 

monitoring of liver and renal function 

• Dose is escalated until pharmacologic effect is observed or 

toxicity occurs

BIMM118 

Phase I Studies 

• Used to study the disposition, metabolism and main pathways of 

elimination of the new drug in humans 

• Identify the most suitable dose and route of administration for 

further clinical studies 

• Use of isotope-labeled (usually beta-emitting) compounds to 

investigate pharmacokinetics and metabolism

BIMM118 

Phase II Studies 

• Pharmacology of the new drug is determined in patients with the 

intended clinical condition 

• Principal aim is to define relationship between dose and 

pharmacological and/or therapeutic response in humans 

• During phase II some evidence of beneficial effect may emerge 

• Adress subjective element in human illness (placebo effect) 

• Additional studies: 

• Special populations (elderly, etc.) 

• Tests for potential interactions with other drugs 

• Optimum dosage established for use in phase III trials

BIMM118 

• Main clinical trial 

Phase III Studies 

– Drug is compared to placebo, or if this would be unethical (effective 

treatment for the disease in question already exists), an established 

drug in use for this disease 

– Comparison to other established treatments 

– Addition to established treatment with placebo control

BIMM118 


• Random placebo-controlled studies 

– Randomization of patient population 

– Sometimes there is double-blinding of the study 

– Between patient population studies 

• Separate patient population arms 

• With or without crossover 

• Require greater number of patients 

– Within patient population studies (crossover) 

• Alternate treatment with new drug and standard therapy or 

placebo 

• Takes longer

BIMM118 


• Measurements of adverse effects and possible 

benefit made at regular intervals 

• Attention to detecting likely occuring side effects 

(type A reactions), and unpredictable, rarer 

complications (type B reactions) 

– Majority of type B reactions may not be seen until post 

marketing because during the Phase III trial usually only 2- 

3000 people will take the drug, usually for short periods 

– Type B reactions typically occur in one in 1000 to 10,000 

patients

BIMM118 

Phase IV studies: 

• Postmarketing Surveillance 

– Ongoing monitoring of drug safety under actual conditions of use in 

large numbers of patients. (Pharmacovigilance) 

– Physician and pharmacist reporting of adverse drug events 

– No fixed duration 

– Picks up adverse events occurring in less than one in 1000 

subjects

BIMM118 

Adverse Reactions to Drugs 

• Severe adverse effects: 

– Uncommon, but explainable extensions of known 

pharmacologic effects 

– Unexpected, may not be recognized until a drug has been 

marketed for years, sometimes unexplainable (Thalidomide) 

• Often represent immunological reactions 

– Urticaria, angioedema, 

– Lupus-like, serum sickness, cell mediated allergies 

– Severest form --> Anaphylactic shock!

BIMM118 

The Four Cornerstones of Pharmacokinetics 

• Absorption 

• Distribution 

• Metabolism 

• Elimination 

Absorption and distribution are influenced by the formulation: 

Medicinal Agent --> Formulation --> Medication 

Galenic = Science of pharmaceutical formulation 

(Galenos of Pergamon, 129-199 AD)

BIMM118 

Drug Administration and Absorption 

Routes of Drug Administration: 

• Oral 

• Topical (Percutaneous) 

• Rectal or Vaginal 

• Pulmonal 

• Parenteral

BIMM118 

Oral Drug Administration 

• Pills 

– Antiquated single-dose unit; round, produced by mixing 

drug powder with syrup and rolling into shape 

• Tablets 

– Oblong or disk-like shape, produced through mechanical 

pressure; filler 

material provides mass; starch or carbonates facilitate 

disintegration

BIMM118 


• Coated Tablets 

– Tablet covered by a “shell” (wax, highly specialized polymers = 

Eudragit®) to facilitate swallowing, cover bad taste or protect 

active ingredient from stomach acid

BIMM118 


• Matrix Tablets 

– Drug is embedded in inert “carrier” meshwork --> 

extended or targeted (intestinal) release 

• Capsules 

– Oblong casing (Gelatin); contains drug in liquid, 

powder or granulated form 

• Troches or Lozenges; Sublingual Tablets 

– Intended to be held in the mouth until dissolved

BIMM118 

Oral Drug Administration

BIMM118 


• Aequous Solutions (with Sugar=Syrup) 

– Mostly for pediatric use 

– 20 drops=1g 

• Alcoholic Solutions (=Tinctures) 

– Often plant extracts 

– 40 drops=1g 

• Suspensions 

– Insoluble drug particles in aequous or lipophilic media

BIMM118 

Percutaneous Drug Administration 

Specific formulation determined by physician/dermatologist: 

• based on skin type: 

– Dry vs. Oily 

– Young vs. Old 

– Intact vs. Injured 

• based on drug properties: 

– Hydrophilic vs. Lipophilic 

– Soluble vs. Insoluble

BIMM118 

Percutaneous Drug Administration

BIMM118 


• Ointment and Lipophilic Cream 

– Either pure lipophilic base (lanolin=wool fat; paraffin oil; petrolium jelly) or 

“water-in-oil” emulsions 

• Paste 

– Ointment with >10% pulverized solids (e.g. Zinc- or Titanium-Oxide) 

• Lotion and Hydrophilic Cream 

– “oil-in-water” emulsions 

• Gels 

– Either alcohol or aequous solution based (Ethanol gels --> Cooling effect) 

– Increased consistency due to gel-forming agents

BIMM118 


•Transdermal Drug Delivery Systems =“Patches” (Nicotin, Isosorbid-Nitrate) 

– Single Layer 

• Inclusion of the drug directly within the skincontacting 

adhesive. In this transdermal 

system design, the adhesive not only serves 

to affix the system to the skin, but also 

serves as the formulation foundation 

– Multi-Layer 

• Similar to Single-layer, however, the multilayer 

encompasses either the addition of a 

membrane between two distinct drug-inadhesive 

layers or the addition of multiple 

drug-in-adhesive layers under a single 

backing film 

– Reservoir 

• Inclusion of a liquid compartment containing 

a drug solution or suspension separated from 

the release liner by a semi-permeable 

membrane and adhesive.

BIMM118 

•Eye Drops 

•Sterile; Isotonic; pH-neutral 

•Nose Drops/Nasal Sprays 

•Viscous Solutions 

Other Topical Drug Administration 

•Pulmonary Formulations 

•Inhalation anesthetics (Hospital use only) 

•Nebulizers (mostly propellant operated) 

•dispense defined amount of Aerosol 

(= dispersion of liquid or or solid particles in a gas) 

•Size of aerosol particles determines depth of penetration into the 

respiratory tract: 

>100 µm: Nasopharynx 

10-100 µm: Trachea, bronchii 

BIMM118 

Other Topical Drug Administration 

•Suppositories 

•Drug incorporated into a fat with a melting point ~35ºC 

•Rectal: Absorption mostly intended into systemic circulation (e.g. analgesics) 

•Vaginal: Effects intended to be confined to site of application (e.g. candidiasis)

BIMM118 

Parenteral Drug Administration 

Sterile; iso-osmolar; pyrogen-free; pH=7.4 

• Ampules 

– Single use (mostly with fracture ring) 

• Single and Multi-dose Vials 

– 10-100 ml; contain preservatives 

• Cartridge ampules 

• Infusions 

– Solution administered over an extended period of time

BIMM118 

• Advantages: 

– 100% “Absorption” 

Parenteral Drug Administration 

– Drug enters general circulation without hepatic passage --> 

No first-pass hepatic elimination 

– Better bioavailability of hydrophilic drugs 

• Bioavailability/Speed of Absorption 

– Intravenous (i.v.): Fastest (infusions; cardio-vascular drugs) 

– Intramuscular (i.m.): Medium (anti-inflammatory; antibiotics) 

– Subcutaneous (s.c.): Slowest (vaccines; insulin; depot contraceptives)

BIMM118 

Drug Distribution

BIMM118 

Drug Distribution 

• To be absorbed and distributed, drugs must cross barriers (membranes) to 

enter and leave the blood stream. 

• Body contains two type of barriers which are made up of epithelial or 

endothelial cells: 

– External (Absorption Barriers): Keratinized epithelium (skin), ciliated epithelium 

(lung), epithelium with microvilli (intestine), etc. 

These epithelial cells are connected via zonulae occludens (tight junctions) to create 

an unbroken phospholipid bilayer. Therefore, drugs MUST cross the lipophilic 

membrane to enter the body (except parenteral).

BIMM118 


– Internal (Blood-Tissue Barriers): Drug permeation occurs mostly in the capillary bed, 

which is made up of endothelial cells joined via zonulae occludens. 

Blood-Tissue Barrier is developed differently in various capillary beds: 

• Cardiac muscle: high endo- and transcytotic activity-> drug transport via vesicles 

• Endocrine glands, gut: Fenestrations of endothelial cells (= pores closed by diaphragms) 

allow for the passage of small molecules. 

• Liver: Large fenestration (100 nm) without diaphragms-> drugs exchange freely between 

blood and interstitium 

• CNS, placenta: Endothelia lack pores and possess only little trans-cytotic activity-> drugs 

must diffuse transcellularly, which requires specific physicochemical properties -> Barriers 

are very restrictive, permeable only to certain types of drugs.

BIMM118 

• Membrane Permeation: 

– Passive Diffusion: 


• Requires some degree of lipid solubility, which is in part determined by the charge of the 

molecule 

• For weak acids or bases (which account for the vast majority of drugs), the charge of the 

molecule in dependence of the pH of the medium is determined by the 

Henderson-Hasselbalch Equation: 

Log ([H + Drug] / [Drug]) = pK a - pH 

– Active Transport: Drugs “highjack” cellular transporter (e.g. L-DOPA uptake via L-amino acid 

carrier) 

– Receptor-mediated Endocytosis: Clathrin-coated pits form endosomal vesicles; receptor gets 

“recycled” to the cell surface

BIMM118 


Drug concentration is a 

function of absorbtion 

AND elimination: 

Typical plasma drug 

concentration as function 

of time after a single oral 

dose 

AUC = Area Under Curve

BIMM118 


Bioavailability (F): 

the AUC of the (orally) 

administered drug divided 

by the AUC of the 

intravenously 

administered drug

BIMM118 

Bioavailability: 


• Intravenous 100% by definition 

• Intramuscular 75 to

BIMM118 


Volume of Distribution (V d ) [ml or l]: 

= Amount of drug in the body [mg] / drug concentration plasma [mg/ml] 

• V d is an apparent volume (volume that the drug must be distributed 

in to produce measured plasma concentration 

• Drug with near complete restriction to plasma compartment would 

have V d = plasma volume (.04 L/kg) = 2.8 L/70 kg patient 

• But: Many drugs are highly tissue bound => large V d 

e.g. Chloroquine: V d = 13,000 L

BIMM118 


Rate of Elimination: 

Drug elimination via kidney occurs by filtration => with falling blood 

concentration the amount of drug filtered per time unit diminishes 

Drug elimination via liver occurs by metabolism, where most enzymes 

operate in the quasi-linear range of their concentration-activity curve => 

with falling blood concentration the amount of drug metabolized per time 

unit diminishes 

==>Vast majority of drugs follows first-order kinetics (= rate is proportional to drug 

concentration) 

Only three drugs follow linear, zero-order (=concentration-independent) 

elimination characteristic: Ethanol, Aspirin and Phenytoin

BIMM118 

Clearance (CL) [ml/min]: 


= Rate of Elimination [mg/min] / Drug concentration plasma (C P ) [mg/ml] where 

Rate of Elimination [mg/min] = k [1/min] x C P [mg/ml] x V d [ml] and 

Elimination rate constant (k) [1/min] = ln 2 / t 1/2 (=half-life) 

(ln 2 = 0.693) 

=> CL [ml/min] = Elimination rate constant (k) [1/min] x V d [ml] = ln 2 x V d / t 1/2 

• It is the sum of all separate organ clearances: 

CL = CL renal + CL liver + CL other 

• Clearance is the volume of plasma cleared of all drug per unit of time (a 

constant for any given drug [ml/min]) 

• The actual quantity of drug [mg] removed per time unit [min] depends on both 

the clearance [ml/min] and the concentration [mg/ml].

BIMM118 

Half-life (t 1/2 ) [min]: 


= ln 2 x V d [ml] / CL [ml/min] (ln 2 = 0.693) 

or 

= ln 2 / Elimination rate constant (k) [1/min] 

• Half-life is the time required for the concentration of a drug to 

fall by 50% 

• The half-life is constant and related to (k) for drugs that 

follow first-order kinetics

BIMM118 


Dosage Regimens: 

With multiple dosing or continuous infusion, a drug will accumulate until 

the amount administered per time unit equals the amount eliminated per 

time unit. The plasma concentration at this point is called the steady-state 

concentration (C SS ) [mg/ml]: 

C SS = Infusion rate [mg/min] / 

Clearance [ml/min] 

Typically, 90% of the C SS is 

reached after 3.3 half-lifes; 

~100% after 5 half-lifes

BIMM118 

Loading Dose: 


For drugs with long t 1/2 , 3-5 half-lifes is to long to wait for C SS 

=> loading dose is used. 

Loading dose must ‘fill’ the V d to achieve the target C P : 

Maintenance Dose: 

Loading dose [mg] = V d [ml] x C P [mg/ml] 

Must replace the drug that is being eliminated over time: 

C SS [mg/ml] = Infusion rate [mg/min] / Clearance [ml/min] => 

Infusion rate [mg/min] = Clearance [ml/min] x C SS [mg/ml] => 

Infusion rate [mg/min] = ln 2 x V d [ml] / t 1/2 [min] x C SS [mg/ml]

BIMM118 


• Drug Binding to Plasma Proteins: 

• Primarily albumin (4.6g/100ml), also β-globulins and acidic glycoproteins 

• Other specialized plasma proteins (transcortin; thyroxin-binding globulin; etc.) 

Binding to plasma proteins is instantaneous and reversible. 

• Of great importance, as the free (=effective) drug concentration determines 

intensity of response 

Drug-protein binding also influences biotransformation and elimination => 

Binding to plasma proteins is equivalent to depot formulations 

– Possible site for drug interactions: 

If two drugs bind to the same site on e.g. the albumin molecule, then drug B has 

the potential of displacing drug A from its binding site --> effective concentration 

of drug A is increased --> Toxic concentration or increased elimination 

– Impaired liver function: 

can lead to altered pharmacokinetics of drugs that bind to albumin at high rates 

due to decreased albumin concentrations in the blood

BIMM118 

BLOOD LEVEL 

TOXIC 

LEVELS 

Margin of safety 


THERAPEUTIC 

RANGE 

Therapeutic Range 

TIME 

In this example the 

treatment would not be 

effective as a therapeutic 

concentration in the blood 

is not maintained

BIMM118 

BLOOD LEVEL 

TOXIC 

LEVELS 



THERAPEUTIC 

RANGE 


TIME 

In this example severe 

toxicity would occur as the 

therapeutic concentration 

in the blood is exceeded 

due to accumulation of the 

drug

BIMM118 

BLOOD LEVEL 

TOXIC 

LEVELS 



THERAPEUTIC 

RANGE 


TIME 

In this example the 

treatment would be 

effective as the therapeutic 

concentration in the blood 

is maintained without 

approaching toxic levels

BIMM118 

• Therapeutic Index: 


= Maximum non-toxic dose / Minimum effective dose 

Problem: 

Does not take into account variability between individuals 

=> “Improved formula”: 

= LD 50 / ED 50 

Problems: 

• LD 50 reflects only death, but no other toxic side effects (e.g. Ototoxicity of aminoglycosides) 

• ED 50 depends on condition treated (e.g. Aspirin: Headache vs. rheumatism) 

• LD 50 depends on patients overall condition (e.g. Aspirin: dangerous to asthmatic patients) 

==> 

Therapeutic Index is not particularly useful to describe the clinical usefulness of a drug!

BIMM118 

Drug Metabolism and Elimination 

• Elimination of drugs occurs primarily through renal mechanism 

– Secretion into bile also possible, but allows for re-absorption in the intestine 

• Secretion into the urine requires ionized or hydrophilic molecules, but: 

– Most drugs are not small molecules that are highly ionized at body pH 

– Most drugs are poorly ionized and lipophilic 

=> This decreases renal excretion and facilitates renal tubular reabsorption 

– Many drugs are highly protein bound, and therefore not efficiently filtered in the kidney 

– Most drugs would have a long duration of action if termination of their effects 

depended only on renal excretion 

Solution: Drug Metabolism

BIMM118 

Drug Metabolism 

• Most metabolic products are less pharmacologically active 

Important exceptions: 

• Where the metabolite is more active 

(Prodrugs, e.g. Erythromycin-succinate (less irritation of GI) --> Erythromycin) 

• Where the metabolite is toxic (acetaminophen) 

• Where the metabolite is carcinogenic 

• Close relationship between the biotransformation of drugs and normal biochemical 

processes occurring in the body: 

– Metabolism of drugs involves many pathways associated with the synthesis of endogenous 

substrates such as steroid hormones, cholesterol and bile acids 

– Many of the enzymes involved in drug metabolism are principally designed for the metabolism 

of endogenous compounds 

– These enzymes metabolize drugs only because the drugs resemble the natural compound

BIMM118 

• Phase I Reactions 

Phases of Drug Metabolism 

– Convert parent compound into a more polar (=hydrophilic) metabolite by adding or 

unmasking functional groups (-OH, -SH, -NH2, -COOH, etc.) 

– Often these metabolites are inactive 

– May be sufficiently polar to be excreted readily 

• Phase II Reactions 

– Conjugation with endogenous substrate to further increase aqueous solubility 

– Conjugation with glucoronide, sulfate, acetate, amino acid 

– Phase I usually precede phase II reactions 

Liver is principal site of drug metabolism: 

– Other sites include the gut, lungs, skin and kidneys 

– For orally administered compounds, there is the 

“First Pass Effect” 

• Intestinal metabolism 

• Liver metabolism 

• Enterohepatic recycling 

• Gut microorganisms - glucuronidases

BIMM118 

Drug Metabolism

BIMM118 

Drug Metabolism - Phase I 

• Phase I Reactions 

– Oxidation 

– Reduction 

– Hydrolytic cleavage 

– Alkylation (Methylation) 

– Dealkylation 

– Ring cyclization 

– N-carboxylation 

– Dimerization 

– Transamidation 

– Isomerization 

– Decarboxylation

BIMM118 

Drug Metabolism - Oxidation 

Two types of oxidation reactions: 

– Oxygen is incorporated into the drug molecule (e.g. hydroxylation) 

– Oxidation causes the loss of part of the drug molecule 

(e.g. oxidative deimination, dealkylation) 

Microsomal Mixed Function Oxidases (MFOs) 

• “Microsomes” 

form in vitro after cell homogenization and fractionation of ER 

– Rough microsomes are primarily associated with protein synthesis 

– Smooth microsomes contain a class of oxidative enzymes called 

• “Mixed Function Oxidases” or “Monooxygenases” 

– These enzymes require a reducing agent (NADPH) and molecular oxygen 

(one oxygen atom appearing in the product and the other in the form of water)

BIMM118 


• MFO consists of two enzymes: 

– Flavoprotein, NADPH-cytochrome c reductase 

• One mole of this enzyme contains one mole each of flavin 

mononucleotide (FMN) and flavin adenine dinucleotide (FAD) 

• Enzyme is also called NADPH-cytochrome P450 reductase 

– Cytochrome P450 

• named based on its light absorption at 450 nm when complexed 

with carbon monoxide 

• is a hemoprotein containing an iron atom which can alternate 

between the ferrous (Fe ++ ) and ferric (Fe +++ ) states 

• Electron acceptor 

• Serves as terminal oxidase 

• its relative abundance compared to NADPH-cytochrome P450 

reductase makes it the rate-limiting step in the oxidation reactions

BIMM118 


• Humans have 18 families of cytochrome P450 genes and 43 subfamilies: 

– CYP1 drug metabolism (3 subfamilies, 3 genes, 1 pseudogene) 

– CYP2 drug and steroid metabolism (13 subfamilies, 16 genes, 16 pseudogenes) 

– CYP3 drug metabolism (1 subfamily, 4 genes, 2 pseudogenes) 

– CYP4 arachidonic acid or fatty acid metabolism (5 subfamilies, 11 genes, 10 pseudogenes) 

– CYP5 Thromboxane A2 synthase (1 subfamily, 1 gene) 

– CYP7A bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus (1 subfamily member) 

– CYP7B brain specific form of 7-alpha hydroxylase (1 subfamily member) 

– CYP8A prostacyclin synthase (1 subfamily member) 

– CYP8B bile acid biosynthesis (1 subfamily member) 

– CYP11 steroid biosynthesis (2 subfamilies, 3 genes) 

– CYP17 steroid biosynthesis (1 subfamily, 1 gene) 17-alpha hydroxylase 

– CYP19 steroid biosynthesis (1 subfamily, 1 gene) aromatase forms estrogen 

– CYP20 Unknown function (1 subfamily, 1 gene) 

– CYP21 steroid biosynthesis (1 subfamily, 1 gene, 1 pseudogene) 

– CYP24 vitamin D degradation (1 subfamily, 1 gene) 

– CYP26A retinoic acid hydroxylase important in development (1 subfamily member) 

– CYP26B probable retinoic acid hydroxylase (1 subfamily member) 

– CYP26C probabvle retinoic acid hydroxylase (1 subfamily member) 

– CYP27A bile acid biosynthesis (1 subfamily member) 

– CYP27B Vitamin D3 1-alpha hydroxylase activates vitamin D3 (1 subfamily member) 

– CYP27C Unknown function (1 subfamily member) 

– CYP39 7 alpha hydroxylation of 24 hydroxy cholesterol (1 subfamily member) 

– CYP46 cholesterol 24-hydroxylase (1 subfamily member) 

– CYP51 cholesterol biosynthesis (1 subfamily, 1 gene, 3 pseudogenes) lanosterol 14-alpha demethylase

BIMM118 


• Induction of P450 enzymes: 

– PPAR (peroxisome proliferator activated receptor) ligands 

(e.g.clofibrate) 

– CYP1 family are induced by aromatic hydrocarbons 

(cigarette smoke; charred food) 

– CYP2E enzymes induced by ethanol 

– CYP2B enzymes induced 40-50 fold by barbiturates 

• Polymorphisms cause differences in drug metabolism: 

– CYP2C19 has a polymorphism that changes the enzyme's ability to metabolize mephenytoin (a 

marker drug). In Caucasians, the polymorphism for the poor metabolizer phenotype is only seen 

in 3% of the population. However, it is seen in 20% of the asian population. 

=> It is important to be aware of a person's race when drugs are given that are 

metabolized differently by different populations 

• P450s and drug interactions: 

– Barbiturates induce CYP2B => increased metabolism of other drugs 

– Antifungals (e.g. ketoconazole) inhibit fungal CYP51 and unintentionally also human CYP3A4 

=> reduced metabolism of other drugs 

– Grapefruit juice contains a CYP3A4 inhibitor =>12 fold increase in some drug concentrations 

CYP3A4 Substrates: • Acetominophen (Tylenol) • Codeine (narcotic) • Cyclosporin A (immunosuppressant), 

• Diazepam (Valium) • Erythromycin (Antibiotic) • Lidocaine (local anaesthetic), • Lovastatin (HMGCoA 

reductase inhibitor), • Taxol (cancer drug), • Warfarin (anticoagulant).

BIMM118 

• Drug oxidation requires: 

– Cytochrome P450 

– Cytochrome P450 reductase 

– NADPH 

– Molecular oxygen 

• The cycle involves four steps: 


1. Oxidized (Fe3+) cytochrome P-450 combines with a drug substrate to form a binary complex. 

2. NADPH donates an electron to the cytochrome P-450 reductase, which in turn reduces the 

oxidized cytochrome P-450-drug complex. 

3. A second electron is introduced from NADPH via the same cytochrome P-450 reductase, which 

serves to reduce molecular oxygen and form an "activated oxygen"-cytochrome P-450-substrate 

complex. 

4. This complex in turn transfers "activated" oxygen to the drug substrate to form the oxidized 

product. The potent oxidizing properties of this activated oxygen permit oxidation of a large number 

of substrates.

BIMM118 

Aromatic hydroxylation: 

Aliphatic hydroxylation: 

Drug Metabolism - Oxidation

BIMM118 

Epoxidation: 

Dealkylation: 

Drug Metabolism - Oxidation

BIMM118 


O-demethylation: S-demethylation: 

N-oxidation: N-hydroxylation:

BIMM118 


Oxidation reactions NOT catalyzed by Cytochrome P450: 

Flavin containing monoxygenase system 

– Present mainly in liver but some is expressed in gut and lung 

– Located in smooth endoplasmic reticulum 

– Oxidizes compounds containing sulfur and nitrogen 

– Uses NADH and NADPH as cofactors 

• Alcohol dehydrogenase (cytosol) 

• Aldehyde oxidation (cytosol) 

• Xanthine oxidase 

• Amine oxidases 

– Monoamine oxidase (nerve terminals, mitochondria) 

– Diamine oxidase found in liver microsomes 

• Primarily endogenous metabolism

BIMM118 

Monoamine Oxidases (MAO): 


• Catalyze oxidative deamination of endogenous catecholamines (epinephrine) 

• Located in nerve terminals and peripheral tissues 

• Substrates for catecholamine metabolism found in foods (tyramine) can 

cause a drug/food interaction 

• Inhibited by class of antidepressants called MAO inhibitors 

(Inhibition of MAO isoforms in the CNS also effects levels of serotonin - Tranylcypromine) 

These drugs can cause severe or fatal drug/drug interactions with drugs that 

increase release of catecholamines or inhibit their reuptake in nerve terminals 

(Meperidine, pentazocine, dextromethorphan, SSRI antidepressants)

BIMM118 

Azo-reduction: 

Nitro-reduction: 

Dehalogenation: 

Drug Metabolism - Reduction

BIMM118 

Hydrolysis reactions 

Ester hydrolysis: 

Drug Metabolism - Reduction 

Amide hydrolysis:

BIMM118 

Drug Metabolism - Phase I 

• Almost any drug can undergo modifications by drug-metabolizing 

enzyme systems 

• Drugs can be subject to several Phase I pathways 

• These reactions create functional groups that place the drugs in a 

correct chemical state to be acted upon by Phase II conjugative 

mechanisms 

• Main function of phase I reactions is to prepare chemicals for phase II 

metabolism and subsequent excretion 

• Phase II is the true “detoxification” step in the metabolism process.

BIMM118 

Drug Metabolism - Phase II 

• Conjugation reactions 

– Glucuronidation by UDP-Glucuronosyltransferase: 

(on -OH, -COOH, -NH2, -SH groups) 

– Sulfation by Sulfotransferase: 

(on -NH2, -SO2NH2, -OH groups) 

– Acetylation by acetyltransferase: 

(on -NH2, -SO2NH2, -OH groups) 

– Amino acid conjugation 

(on -COOH groups) 

– Glutathione conjugation by Glutathione-S-transferase: 

(to epoxides or organic halides) 

– Fatty acid conjugation 

(on -OH groups) 

– Condensation reactions

BIMM118 

Drug Metabolism - Glucuronidation 

• Glucuronidation ( = conjugation to α-d-glucuronic acid) 

– Quantitatively the most important phase II pathway for drugs and endogenous 

compounds 

– Products are often excreted in the bile. 

– Enterohepatic recycling may occur due to gut glucuronidases 

– Requires enzyme UDP-glucuronosyltransferase (UGT): 

• Genetic family of enzymes 

– Metabolizes a broad range of structurally diverse endogenous and exogenous compounds 

– Structurally related family with approximately 16 isoforms in man

BIMM118 


• Glucuronidation – requires creation of high energy intermediate: 

UDP-Glucuronic Acid:

BIMM118 


• Glucuronidation Pathway and Enterohepatic Recirculation

BIMM118 


• N-glucuronidation: 

– Occurs with amines (mainly aromatic ) 

– Occurs with amides and sulfonamides

BIMM118 


• O-glucuronidation: 

– Occurs by ester linkages with carboxylic acids 

– Occurs by ether linkages with phenols and alcohols

BIMM118 

Sulfation: 

Drug Metabolism - Sulfation 

• Major pathway for phenols but also occurs for alcohols, amines and thiols 

• Energy rich donor required: 

PAPS (3’-Phosphoadenosine-5’-phosphosulfate) 

• Sulfation and glucuronidation are competing pathways: 

– Sulfation predominates at low substrate concentrations 

– Glucuronidation predominates at higher concentrations 

– There is relatively less PAPS in cell cytosol compared to UDPGA 

• Sulfotransferases (=SULTs) catalyze transfer of sulfate to substrates: 

– Phenol, alcohol and arylamine sulfotransferases are fairly non-specific 

– Steroid sulfotransferases are very specific

BIMM118 

Acetylation: 

Drug Metabolism - Acylation 

• Common reaction for aromatic amines and sulfonamides 

• Requires co-factor acetyl-CoA 

• Responsible enzyme is N-acetyltransferase 

• Takes place mainly in the liver 

• Important in sulfonamide metabolism because acetyl-sulfonamides are less 

soluble than the parent compound and may cause renal toxicity due to 

precipitation in the kidney 

Fatty Acid Conjugation: 

• Stearic and palmitic acids are conjugated to drug by esterification reaction 

• Occurs in liver microsomal fraction 

(Cannabiols are excreted in this fashion => long half-life)

BIMM118 

Drug Metabolism - Other conjugations 

Amino Acid Conjugation: 

• ATP-dependent acid:CoA ligase forms active CoA-amino acid conjugates which then 

react with drugs by N-Acetylation: 

– Usual amino acids involved are: 

• Glycine. Glutamine, Ornithine, Arginine 

Glutathione Conjugation: 

• Tripeptide Gly-Cys-Glu; conjugated by glutathione-S-transferase (GST) 

• Glutathione is a protective factor for removal of potentially toxic compounds 

• Conjugated compounds can subsequently be attacked by 

γ-glutamyltranspeptidase and a peptidase to yield the cysteine conjugate => 

product can be further acetylated to N-acetylcysteine conjugate

BIMM118 

Drug Metabolism - Phase I & II 

Phase I and II - Summary: 

• Products are generally more water soluble 

• These reactions products are ready for (renal) excretion 

• There are many complementary, sequential and competing 

pathways 

• Phase I and Phase II metabolism are a coupled interactive 

system interfacing with endogenous metabolic pathways

BIMM118 

Drug Action: Receptor Theory 

Many drugs act by binding to receptors (see Lecture 4) where they either provoke 

or inhibit a biological response. 

Agonists: 

• Can be drugs or endogenous ligands for the receptor 

• Increasing concentrations of the agonist will produce an increase in the 

biological response: 

– Full Agonist: Evokes 100% of the maximum possible effect 

– Partial Agonist: Produces the same type of biological response, but cannot 

achieve 100% even at very high doses

BIMM118 

Antagonists: 

Drug Action: Receptor Theory 

• Block or reverse the effects of agonists. They have no effects on their own 

– Competitive Antagonists: Compete with agonist for receptor binding => Agonist 

appears less potent, but can still achieve 100% effect (but at higher 

concentrations) 

– Non-competitive Antagonists: Bind to receptor at different site and either prevent 

agonist binding or the agonist effect => maximal achievable response reduced 

– Inverse Agonists: Not the same as antagonists! Inverse agonists trigger a 

negative response (= reduce baseline) (e.g. diazepam = full agonist = 

anticonvulsant BUT inverse agonists of benzodiazepin receptor are convulsants)

BIMM118 

Four major drug targets: 

Drug Targets 

Exceptions: Colchicin (acts on tubulin), Cyclosporin (acts via immunophillins), etc.

BIMM118 

Drug Targets

BIMM118 

Drug Targets

BIMM118 

Drug Targets: Receptors 

Responses to the extracellular environment involve cell membrane or 

intracellular receptors whose engagement modulates cellular components 

that generate, amplify, coordinate and terminate postreceptor signaling via 

(cytoplasmic) second messengers. 

Transmembrane signaling is accomplished by only a few mechanisms: 

– Transmembrane ion channels: open or close upon binding of a ligand or upon 

membrane depolarization 

– G-protein-coupled receptors: Transmembrane receptor protein that stimulates 

a GTP-binding signal transducer protein (G-protein) which in turn generates an 

intracellular second messenger 

– Nuclear receptors: Lipid soluble ligand that crosses the cell membrane and acts 

on an intracellular receptor 

– Kinase-linked receptors: Transmembrane receptor proteins with intrinsic or 

associated kinase activity which is allosterically regulated by a ligand that binds to 

the receptor’s extracellular domain

BIMM118 

Drug Targets: Receptors

BIMM118 

Receptors 

• Rapidly acting (milliseconds) transmembrane ion channels: Multi-unit complexes 

with central aqueous channel. Upon binding of a ligand, channel opening allows a 

specific ion travel down its concentration gradient ==> 

Transient cell membrane depolarization (post synaptic potential) 

• Example: Nicotinic acetylcholine receptor: Pentameric structure (two alpha chains, one each 

beta, gamma, and delta chain). Activation occurs by binding of two molecules ACh to the alpha 

subunits, triggering the opening of the channel for Na + and K + ions. 

Myasthenia gravis: Autoimmune disease caused by inactivating antibodies against NAchR

BIMM118 

Receptors 

Many other types of transmembrane ion channels ==> 

Ion channels are common drug targets! 

• Voltage-gated channels: 

• Gating: controlled by membrane polarization/depolarization 

• Selectivity: Na + , K + or Ca + ions 

• Intracellular ligand-gated channels: 

• Ca + controlled K + channel 

• ATP-sensitive K + channel 

• IP 3 -operated Ca + channel (in the ER membrane)

BIMM118 

Calcium as Second Messenger 

Ca ++ ==> very important in regulating cellular and physiological responses 

– Extracellular concentrations are 2 mM (EM, blood), and levels in cytoplasmic vesicles and the 

ER can reach up to 10mM. 

– Baseline cytosolic Ca 2+ concentration is around 100 nM in resting cells. 

Conc in mM ECF ICF 

K+ 4.5 160 

Na+ 144 7 

Cl- 114 7 

Ca++ 2.2 0.0001 

– High gradient makes this a very fast and sensitive signaling system: only slight changes in 

membrane permeability will result in dramatic changes in the concentration of [Ca 2+ ] i . 

– Low level of [Ca 2+ ] i is also necessary to facilitate a phosphate oriented cellular metabolism 

(high calcium and high phosphate concentrations are incompatible!!) 

==> Evolutionary challenge: Maintain calcium gradient !!! 

– Evolvement of proteins that bind Ca 2+ with high affinity, but reject magnesium! 

– Two classes of Ca-binding proteins: 

• membrane-integrated (unlimited capacity --> transporter systems: Ca-channels, calcium pumps) 

• non-membranous (limited capacity --> not only buffering, but processing of signal through 

conformational changes that enable interaction with target proteins: Calmodulin, Troponin C ...)

BIMM118 

Sources of Ca ++ : 


• Extracellular compartment: (predominantly in nerve, cardiac and smooth muscle cells) 

Three types of plasma-membrane localized calcium channels: 

– Voltage operated calcium channels: 

Action potental depolarizes plasma membrane, which results in the opening of “voltage” 

dependent calcium channels (channels can be opened by increase in extracellular K + ). 

Each channel protein has four homologous domains, each containing six membrane spanning 

α-helices (the fourth one functions as the “voltage” sensor.

BIMM118 

Three types: 

Type 

L 

N 

T 


Properties 

High activation threshold; 

slow inactivation 

Low activation threshold; 

slow inactivation 

Low activation threshold; 

fast inactivation 

– Ligand gated calcium channels: 

Calcium channels opened after ligand binding to the receptor (e.g. glutamate/NMDA receptor; 

ATP receptor; nicotinic ACh receptors ( muscarinic ACh receptors signal through G-Proteins 

--> slower), prostaglandin receptors 

– Store operated calcium channels: 

Location/Function 

Plasma membrane of many cells; 

main Ca ++ source for contraction in 

smooth and cardiac muscle 

Main Ca ++ source for transmitter 

release by nerve terminals 

Widely distributed; important in 

cardiac pacemaker and Purkinje 

cells 

Activated by emptying of intracellular stores, exact mechanism unknown 

Blockers 

Dihydropyridines; 

verapamil; diltiazem 

ω-Conotoxin 

(snail venom) 

Mibefradil; (verapamil; 

diltiazem)

BIMM118 


Intracellular compartment: (predominantly in muscle cells) 

– Calcium stored in mM concentrations in endo/sarcoplasmatic reticulum bound to Calsequestrin . 

(Previously mitochondria were thought to play an important role as Ca ++ -stores, but the uptake rate 

is 10x lower than that of the ER/SR -> not useful) 

Calcium release from the ER/SR is regulated by two receptors in the ER/SR membrane: 

– Ryanodine receptors (RyR): 

• Named after sensitivity to Ryanodine: plant alkaloid, irreversible inhibitor 

• Very important in skeletal muscle: direct coupling of RyRs with the dihydropyridine receptors of the T-tubules 

(dihydropyridine receptors are closely related to the L-type Ca ++ channels) (see Ca ++ effects) 

• Activity of RyRs in non-muscle cell lacking T-tubules regulated by cyclic ADP ribose 

• Caffeine: reversible activator of RYRs 

– IP 3 - Receptors (IP 3 R): 

• Inositol-1,4,5-triphosphate is produced through the 

activity of receptor activated phospholipases C --> 

diffuses through cytoplasm and binds IP 3 R

BIMM118 

Removal of Ca ++ : 

• Ca ++ - pumps: 


Activity of these pumps is induced by increases in cytosolic calcium. 

– Plasma membrane Na + /Ca 2+ exchanger (mainly in excitable cells, e.g. cardiac cells) 

three Na + - ions are exchanged for one Ca ++ -ion 

Digitalis alkaloids: Na + / K + -ATPase inhibitors => intracellular Na + raises => Na + /Ca 2+ exchange less efficient => 

Ca 2+ intracellular increases => stronger contractions 

– Plasma membrane Ca 2+ -ATPase (PMCA) 

two Ca ++ - ions are transported per ATP molecule hydrolyzed; regulated by CaM, PKA or PKC 

– SR/ER Ca ++ -ATPase (SERCA): 

80% (!) of integral membrane protein of SR 

target of thapsigargin ( => Ca ++ -release from intracellular stores) 

• Ca ++ - buffers: 

Low affinity (!) but high capacity (50-100 Ca ++ -ions/molecule) 

– Calsequestrin (very acidic, 37% of amino acids are aspartic and glutamic acid), 

– Calreticulin, Parvalbumin

BIMM118 

Ca ++ Sensors: 

• Annexins: 


Family of proteins w/ common feature that they interact w/ membranes in a Ca ++ - dependent manner. 

Low affinity for Ca ++ -ions restricts action to membrane proximity (high local Ca ++ conc.!); 

implicated in the regulation of PLA2, cytoskeletal (re)organization and vesicle movement 

• EF-hand proteins: 

named after the shape created by the E and F α-helices of the Ca ++ -binding domain; high affinity

BIMM118 


– Calmodulin: 

ubiquitous expression; binds 4 Ca ++ -ions; acts through stimulation of either protein kinases 

(CaMKs) 

or protein phosphatases (Calcineurin); also activates cAMP phosphodiesterase 

– Troponin C: 

restricted expression, regulates contraction of skeletal and heart muscle

BIMM118 

Calcium as Second Messenger

BIMM118 


Function of cytoplasmic free Ca ++ : 

• Muscle contraction: 

– Skeletal and cardiac muscle: 

• Contraction (=actin-myosin interaction) controlled by proteins on actin filaments (tropomyosin w/ troponin) 

• Troponin I inhibits formation of cross-bridges between actin and myosin => muscle relaxed. 

• Troponin C combines with Ca 2+ -ions and blocks the action of Troponin I => muscle contracted

BIMM118 

– Smooth muscle: 


Contraction controlled by proteins acting either on actin.... 

• NO Troponin=>regulation occurs through the CaM binding Caldesmon : 

Low [Ca ++ ]: Caldesmon forms complex with actin and tropomyosin => access of myosin to actin restricted 

=>muscle relaxed. 

… or on myosin 

• Myosin light chains inhibit actin-myosin interaction: 

phosphorylation of myosin light chain (MLC) by MLC kinase (MLCK) relieves this inhibition => 

phosphorylated myosin is able to interact w/ actin => contraction

BIMM118 


• Neuronal excitibility and secretion: 

– Increase of [Ca ++ ] induces fusion of the synaptic vesicles with the plasma mambrane => 

this causes exocytosis of neuro-transmitters into the synaptic cleft.

BIMM118 

• Immune response: 


– TCR stimulation => [Ca ++ ] increases => activates Calcineurin => dephosphorylates NFATc on 

ser/thr => NFATc translocates to nucleus where it combines with NFATn and induces transcription 

of IL-2 gene => T cell proliferation 

Calcineurin: target of immunesuppressive drugs FK506 and ciclosporin, which form a complex with 

immunophillins and compete with Ca ++ /CaM for binding to calcineurin => no NFATc activation

BIMM118 

G-Protein-coupled Receptors 

GPCR: Large family of receptors with a probable common evolutionary precursor. Transmembrane protein 

that is serpentine in shape, crossing the lipid bilayer seven times. 

G-Proteins: 

– Guanine nucleotide binding proteins: 

participate in reversible, GTP-mediated interactions. 

– Common features: 

• bind GDP and GTP with high affinity, but adopt different structure depending on the bound nucleotide. 

• GTP-bound complex has high affinity for other proteins (“acceptor’), affecting their enzymatic activity 

• possess intrinsic GTPase activity that is usually activated by interaction with regulatory proteins (e.g. GAPs) 

• covalent attachment of various lipids (myristoylation, palmitoylation,...) is responsible for membrane targeting 

– Additional control exerted through: 

• GTPase Activating Proteins (GAPs): function on small GTP binding proteins 

• Guanine-nucleotide Exchange Factors (GEFs): promote GDP release 

• Regulators of G-protein Signaling (RGSs): similar to GAPs, but act on heterotrimeric G-Proteins

BIMM118 

G-Proteins: 

Two major groups: 


• “Small GTP binding proteins” (act downstream of receptor: ras, rac etc.) => see growth factor 

receptor signaling 

• “Heterotrimeric G-proteins” (directly coupled to receptor and enzyme): 

• Coupled to 7 transmembrane spanning receptors: (β-adrenergic R, PG-R) 

• All members are heterotrimeric, consisting of α, β and γ subunits

BIMM118 


α, β and γ subunits: 

α-subunit (23 isoforms): contains the GTP/GDP binding site, is responsible for identity 

β (5 isoforms) and γ (12 isoforms) subunits: are identical or very similar; interchangeable in vitro; 

most of them are ubiquitiously expressed; membrane anchored through prenylation of G β 

– G q and 

– G olf (expressed only in olfactory cells) are coupled to PLCβ 

– G T (=Transducin) is coupled to a cGMP phosphodiesterase and is expressed only in the rod cells of the 

retina (these cells are INactivated by light!). Photons hit Rhodopsin => activated opsin is generated => 

facilitates GTP loading of G T => activates cGMP phosphodiesterase => cGMP (keeps Na + and Ca 2+ 

channels open to cause membrane depolarization => neuro-transmitter release) converted to 5’GMP 

(inactive => channels closed) => membrane polarization => NO neurotransmitter release)

BIMM118 

Main targets: 

Phospholipase Cβ: 


see Lipid and Inositol Signaling 

Adenylate cyclase: 

• Two repeats of six transmembrane α-helices and two catalytic domains that convert ATP into cAMP 

• Activated or inhibited by G-proteins (a brain specific isoform is also activated through activated CaM): 

GTP-bound G αs activates AC, GTP-bound G αi inhibits activity (Forskolin: direct activator of AC => cAMP⇑)

BIMM118 


Cholera-toxin: causes ADP-ribosylation of G sα => release of GTP inhibited => G sα trapped in active form. cAMP 

regulates secretion of fluid into the intestinum => enormous loss of liquid and electrolytes => death! 

Pertussis-toxin: causes ADP-ribosylation of G iα , release of GDP inhibited => G iα locked in its INactive form => can not 

inhibit AC!

BIMM118 

Targets of cAMP: 

Protein Kinase A (PKA): 

– Consists of four subunits: two regulatory 

and two catalytic subunits => after cAMP 

binding to the regulatory subunits the 

catalytic subunits dissociate and 

translocate to the target substrates. 

Cyclic Nucleotides 

– First identified process regulated by PKA 

was glycogenolysis (PKA phosphorylates 

glycogen phosphorylase kinase which in 

turn activates glycogen phosphorylase. 

PKA also phosphorylates and inactivates 

glycogen synthase => release of glucose)

BIMM118 


– PKA also phosphorylates transcription factors: CREB 

• CRE (cAMP response element) in the promoter of cAMP responsive genes 

• CREB becomes phosphorylated by PKA that translocated to the nucleus

BIMM118 


• Guanylate Cyclase: 

– Yields cyclic GMP 

– Second messenger in only a few cell types (intestinal mucosa, vascular smooth 

muscle) 

– cGMP stimulates cGMP-dependent protein kinases 

– Action terminated by hydrolysis of cGMP and dephosphorylation of protein kinase 

substrates 

– Nitric Oxide activates cytoplasmic guanylyl cyclase:

BIMM118 

Phosphodiesterases: 


• Attenuate G-protein/AC coupled-receptor derived signals by converting cAMP to 5’AMP, 

or cGMP to 5’GMP 

• several families; activation creates feed-back loops 

• Phosphodiesterase inhibitors: 

Methylxanthines: 

Caffeine, theophylline => 

enhance and prolong the signals 

originating from adrenergic receptors 

Sildenafil (Viagra®): 

Specific PDE V inhibitor

BIMM118 

Regulation of Receptors 

• Receptors not only initiate regulation of physiological and 

biochemical function but are themselves subject to many regulatory 

and homeostatic controls. 

• Controls include regulation of synthesis and degradation of the 

receptor by multiple mechanisms; covalent modification, 

association with other regulatory proteins, and/or relocalization 

within the cell. 

• Modulating inputs may come from other receptors, directly or 

indirectly. 

• Receptors are always subject to feedback regulation by their own 

signaling outputs.

BIMM118 

Regulation of Receptors 

• Heterologous desensitization: 

– Four residues in the cytosolic domain of the β-adrenergic receptor 

can be phosphorylated by PKA 

– Activity of all Gs protein – coupled receptors, not just the βadrenergic 

receptor, is reduced 

• Homologous desensitization: 

– Other residues in the cytosolic domain of the β-adrenergic 

receptor are phosphorylated by the receptor-specific β-adrenergic 

receptor kinase (BARK) 

– BARK only phosphorylates the β-adrenergic receptor which 

facilitates β-arrestin binding to the phosphorylated receptor

BIMM118 

Receptor Desensitization

BIMM118 

Receptor Down-Regulation 

• Slower onset (hours to days), more prolonged effect 

• Decreased synthesis of receptor proteins 

• Increase in receptor internalization and degradation 

• Internalization involves endocytosis of receptor: the endocytic vesicle 

may ultimately return the receptor to the cell surface, or alternatively 

may deliver the receptor to a lysosome for destruction. 

• Endocytic vesicles are associated with phosphatases which can clear 

phosphate from a receptor and ready it for reuse before returning it to 

the plasma membrane.

BIMM118 

Nuclear Receptors 

• Lipid soluble ligands that penetrate cell membrane (corticosteroids, 

mineralocorticoids, sex steroids, Vitamin D, thyroid hormone) 

• Receptors contain DNA-binding domains and act as ligand-regulated 

transcriptional activators or suppressors(=> characteristic lag period of 30 

minutes to several hours): 

Ligand binding of the receptors triggers the formation of a dimeric complex that can interact with 

specific DNA sequences (=“Response Elements”) to induce transcription. The resulting protein 

products possess half-lifes that are significantly longer than those of other signaling 

intermediates => Effects of nuclear receptor agonists can persist for hours or days after plasma 

concentration is zero.

BIMM118 

• Examples: 

Nuclear Receptors 

– Glucocorticoids: Inhibit transcription of COX-2; induce transcription of Lipocortin 

– Mineralcorticoids: Regulate expression of proteins involved in renal function 

– Retinoids (Vit A derivatives): Control embryonic development of limbs and 

organs; affect epidermal differentiation => dermatological use (Acne) 

– PPARs (Peroxisome Proliferation-Activated Receptors): control metabolic 

processes: 

• PPARα: Target of Fibrates (cholesterol lowering drugs: stimulate βoxidation 

of fatty acids) 

• PPARγ: Target of Glitazones (anti-diabetic drugs: induce expression of 

proteins involved in insulin signaling => improved glucose uptake)

BIMM118 

Phospholipids, Phosphoinositols & Eicosanoids

BIMM118 

Phospholipids, Phosphoinositols & Eicosanoids 

Common types of 

Phospholipids:

BIMM118 


Second messenger 

– released through hydrolysis by phospholipases and/or 

– generated through the actions of lipid kinases 

Phospholipases: Phosphatidylinositol-kinases:

BIMM118 


Phospholipases: 

• PLA2: 

– Cytoplasmic form (90 kDa) is regulated through nM Ca ++ (Annexins) and 

phosphorylation; AA specific => signaling function 

– Secreted form (pancreas, 14 kDa) is also Ca ++ dependent (mM range)=> 

digestive function 

• PLC: coupled to a variety of (growth factor) receptors: 

– PLCβ is activated through GPCRs (G qα ) => binding enhances its catalytic 

activity and in return the GTPase activity of G qα (similar to GAP function in ras 

signaling) 

– PLCγ couples with its SH2 domains directly to growth factor receptors (EGFR, 

PDGFR) or the TCR, where it is activated through tyrosine phosphorylation

BIMM118 


Both phospholipases yield finally arachidonic acid (see below), in addition, PLC activity also produces 

DAG and IP 3 : 

• DAG: remains membrane bound; diacylglycerol kinase phosphorylates DAG to generate 

phosphatidic acid which functions as a substrate for PLA 2 . 

Phosphatidyl-serine (PS), Ca ++ and DAG activate PKC on the plasma membrane 

• IP 3 : see Ca ++ signaling!! 

– Glucocorticoids: inhibit PLA2 by transcriptionally inducing Lipocortin, a protein 

which binds to PLA2 and blocks its activity. 

– Phorbol esters: strongest known tumor promotors; mimic DAG => bind PKC and 

activate it. Also potent activator of Ca 2+ influx, MAPK pathway etc.

BIMM118 


Lipid kinases: 

• PI 3 -kinase: 

– binds to and becomes tyrosine phosphorylated in response to activation of 

growth factor receptors or immune receptors 

– 85 kDa regulatory subunit (pY) and a 110 kDa catalytic subunit 

– regulatory subunit contains SH2 and SH3 domains 

– PIP 3 -phosphates can bind to the pleckstrin homology (PH) domain of Akt 

=> Akt activation => phosphorylation of BAD, which dissociates from the 

antiapoptotic protein bcl-2 => inhibition of apoptosis 

• Wortmannin: fungal metabolite, potent, irreversible inhibitor of PI3Kinase 

• Ly290004: synthetic compound, blocks ATP binding site of PI3Kinase

BIMM118 

• Eicosanoids: 

Arachidonic Acid Metabolism 

collective name for derivatives of arachidonic acid (=5,8,11,14 - eicosatetraenic acid) 

– AA is mainly generated through the action of PLA 2 and DAG-lipase. 

– Rapidly metabolized by cyclooxygenase and lipoxygenase into 

prostaglandins and leukotrienes:

BIMM118 

• Prostaglandins: 


– First observed in seminal fluid => name 

– Structure of cyclopentane ring defines letter 

– Double bonds in side chains account for number 

– Greek letter refers to the spatial position of the OH-group at C-9 

Initial step in PG synthesis 

catalyzed by PGH-synthase 

which has dual enzymatic 

activity: 

cyclooxygenase (closes ring 

=>PGG2) 

and 

peroxidase (=> 15-OH)

BIMM118 


Biological functions of PGs: 

• Vascular tone Relaxation: PGs E 1 , E 2 , F 2α and I 2 

Constriction: PGs F 2α , TxA 2 

• Platelet aggregation Increase: PGs E 1 , TxA 2 

Decrease: PGs E 2 , I 2 

• Uterus tone Increase: PGs E 1 , E 2 , F 1α 

• Bronchial muscle Constriction: PGFs 

Relaxation: PGEs 

• Gastric secretion Inhibition: PGs E 1 , E 2 , I 2 

• Temperature and pain Increase: PGEs

BIMM118 

• Leukotrienes: 


– First found in leucocytes; contain 3 conjugated double bonds 

– Lipoxygenase generates Hydroperoxyeicosatetraenoic acid (HPETE) 

– LTC 4 , D 4 and E 4 mediate allergic reaction: Slow Reacting Substance of Anaphylaxis (SRS-A) 

=> mediates anaphylactic shock 10,000 fold more potent than histamine!!! => constricts 

bronchi, dilate blood vessels 

– LTB 4 is a very strong chemoattractant for macrophages

BIMM118 

Growth Factor Receptors 

• Many growth factors (EGF, PDGF, IGF-1, CSF-1, ...) signal through receptors with intrinsic 

tyrosine kinase activity 

• Common features: 

– Large, glycosylated ligand binding domain 

– Single hydrophobic transmembrane domain 

– Activation occurs through ligand mediated oligomerization 

– Undergo ligand induced downregulation by internalization 

– Cytoplasmic tyrosine kinase domain: 

• most highly conserved region 

• GlyXGlyXXGlyX(15-20)Lys 

Lys is critical for ATP binding - mutation renders receptor kinase inactive, which 

abrogates all cellular responses => signaling depends on tyrosine phosphorylation 

of receptor and cytoplasmic substrates 

• Tyrosine kinase receptors also bind and activate cytoplasmic tyrosine kinases 

– Autophosphorylation sites: 

• conserved in the C-term of each receptor class 

• autophosphorylation does not effect K m of receptor kinase activity 

• provide docking sites for SH2 domain containg signaling proteins

BIMM118 


• Three subclasses: 

– Class I: two Cys-rich region in the EC, monomeric ligand 

EGF-R, erbB2, erbB3, erbB4 (heregulin receptors) 

– Class II: heterotetrameric: 2 α and 2 β chains stabilized through S-S bonds: monomeric ligand 

Insulin-R, IGF-1-R 

– Class III: Repeats of mmunoglobulin-like structure, dimeric ligand 

FGF-R, NGF-R, PDGF-R, CSF-1-R, c-kit

BIMM118 

Signaling through Adapter proteins: 


• grb2: adapter with one SH2 domain which binds PY 

residue on RTK, and two SH3 domains which bind to 

• Sos: “Son of Sevenless” (mutation in drosophila 

prevents development of the R7 photoreceptor cell). 

Functions as a GEF to facilitate GTP loading of 

• ras: GTP binding protein, farnesylated; protooncogene, 

provides a docking site on the plasma membrane for raf. 

• ras-GAP: negative regulator of groth factor signaling: 

promotes GTP hydrolysis through the GTPase activity of 

ras.

BIMM118 

Signaling through Adapter proteins: 


• raf: ser/thr kinase of the MAPKKK/MEKK family (MEKK 

does normally NOT phosphorylate MEK, but rather 

MKK4/7 => Stress pathway); requires context of plasma 

membrane for activation (mixing GTP-ras and raf in a 

test tube fails to activate raf) => raf likely to be 

phosphorylated at the plasma membrane. Activated raf 

phosphorylates... 

• MEK: Dual specificity kinase (in case of Stress pathway: 

SEK) phosphorylates ERKs or MAPKs on tyr and thr -> 

• ERKs: migrate to the nucleus where they phosphorylate 

transcription factors such as fos and jun; also feedback 

loop to other signaling molecules

BIMM118 

Growth Factor Receptors

BIMM118 

• “Classical” hormones: 

Cytokine Receptors 

– produced by cells organized into endocrine organs, 

– often referred to as “endocrine signal molecules” 

– target cells usually distant from the site of synthesis 

– hormone carried by blood stream from producing gland to target cells 

– signal through receptors coupled to G-proteins (e.g. epinephrine receptor), ion-channels 

– (e.g. acetylcholine receptor) or receptors with intrinsic enzymatic activity 

• Cytokines: 

– single producing and effector cell 

– only affect target cells in close proximity (autocrine or paracrine) 

– almost exclusively involved in regulating immunological processes 

– sometimes subdivided into different groups based on their origin (lymphokines, monokines, 

interleukines) 

– often carry several (old) names based on their multiple biological functions: e.g. Lymphocyte 

Activating Factor (LAF) = Mitogenic Protein (MP) = T Cell Replacing Factor III (TRF-III) = B 

Cell Activating Factor (BAF) = B cell Differentiation Factor (BDF) = INTERLEUKIN 1

BIMM118 


• Basic characteristics: 

– only one copy of encoding gene per haploid cell (~20 different IFNα’s, but each 

encoded by a distinct gene) 

– genes segmented into 4 or 5 exons (exceptions are IFNα and IFNβ: no introns) 

– mature protein usually between 8 and 25 kDa 

– barely any structural resemblances 

– often N-glycosylated 

– often form oligomers 

– some carry signal sequence in precursor 

– expression is tightly regulated on a transcriptional level 

– generally pleiotropic 

– usually highly species specific (up and down) 

• Multiple (old) classifications: 

– Based on origin (Lymphokines, Monokines..) 

– Based on action (inhibitory, stimulating, antiviral, chemotactic...) 

– Based on composition of receptor (single-chain vs. multi-chain)

BIMM118 


• Current nomenclature based on structure of receptors: 

– Type I cytokine receptors = hematopoietin receptor family: 

receptors contain W-S-X-W-S motif in the C-terminus 

• IL-2 R, IL-3 R, IL-4 R, IL-5 R, IL-6 R (has also Ig-like domain), IL-7 R, IL-9 R, IL-11 R 

IL-13 R, IL-15 R, GM-CSF R, EPO R, G-CSF R (has also Ig-like domain) 

– Type II cytokine receptors = Interferon receptor family: 

receptors contain IRH1 (200aa extracellular) and IRH2 (50 aa cytoplasmic) domain 

• IFNα/β R, IFNγ R 

– Type III cytokine receptors = TNF receptor family: 

receptors contain 4 Cys rich regions in extracellular domain 

• TNFα R, TNFβ=LT R, NGF R (trk), fas, CD40 

– Type IV cytokine receptors = Immunoglobulin family: 

receptors contain an Ig like repeat in the extracellular domain 

• IL-1 R, M-CSF R (c-fms), SCF R = steel factor R (kit) (tyrosine kinase activity), (IL-6 R) (has 

also W-S-X-W-S motif), (G-CSF R) 

– (Chemokine receptors): 

• C-X-C subgroup (α-family): IL-8, PF4, βTG 

• C-C subgroup (β-family): RANTES, MCAF, MIP-1β

BIMM118 

Signal Transduction: 


Receptors lack intrinsic catalytic activity but associate w/ cytosolic enzymes 

STAT: Signal transducer and activator of transcription 

– contain SH2 domains 

– become tyrosine phosphorylated after stimulation 

– 6 family members 

– homo or heterodimerize 

– translocate to nucleus and bind enhancers 

JAK: Janus kinase 

– large cytoplasmic tyrosine kinases (130-140 kDa) 

– NO SH2 or SH3 domains 

– kinase-like domain

BIMM118 

Ser/Thr-kinase Receptors 

Transforming Growth Factors = TGFs: 

– Murine sarcoma virus infected cells can not bind EGF => cells produce a growth factor that 

competes for EGF binding (=sarcoma growth factor, SGF). 

– SGF promoted anchorage independent growth (reversible) => first evidence that transformed 

cells produce their own growth factor! 

– SGF was found to consist of two subunits: 

TGFα: EGF competitor, binds and signals through the EGF receptor, 

potent mitogen, but does not support anchorage-independent growth 

overexpressed in epithelium of psoriasis patients (=> hyperproliferation of keratinocytes) 

– TGFβ: acts through distinct receptor, it also is a potent mitogen, but it also does not support 

anchorage-independent growth (only combination does!) 

TGFβ- receptors I and II: 

– external ligand binding domain and cytosolic serine/threonine kinase activity. 

– betaglycan: proteoglycan required for TGFβ binding

BIMM118 

Signal Transduction: 

SMADs: 

Ser/Thr-kinase Receptors 

– 8 members - conserved MH1 and MH2 domain 

– rapidly phosphorylated in response to TGFβ (2,3) or 

BMP (1,5,8) 

– Smads function in heteromeric complexes 

– “common” Smad = Smad-4 (Smad-4 required for all 

Smad signaling) 

– translocate to the nucleus 

– phosphorylated by the receptor itself 

– phosphorylation motif: SSXS 

– Smad1 potentially also activated by MAPK 

– Mutations of Smads and /or TGFβR are found in 90% 

of colon cancers

BIMM118 

NFκB 

– originally identified as a transcription factor binding an 

enhancer (κB)in the κ-light chain immunoglobulin gene 

– Activated by a variety of (proinflammatory) signals 

(IL-1, TNF, Phorbol esters...) 

– Homo-or heterodimer composed of p50 and/or p65 

subunits 

– retained in its inactive form in the cytoplasm by the 

inhibitory protein IκB 

– dissociation of NFκB from IκB activates NFκB’s DNA 

binding capabilities 

– NFκB/ IκB association is regulated by serine 

phosphorylation of IκB! 

– Phosphorylated IκB does not dissociate from NFκB, 

rather is marked for degradation (NFκB activation can 

be inhibited by protease inhibitors!) 

– Phosphorylation of IκB through IκB-kinase (complex 

>600 kDa) 

– IKK: two kinase subunits: IKKα and IKKβ, homo- or 

heterodimers IKKγ (NEMO): no kinase activity, 

required for complex assembly = regulatory subunit

BIMM118 

Autonomic Nervous System

BIMM118 


BIMM118 

• Ganglia close to the 

innervated organs 

• Myelinated axons 

• Note: 

Somatic nervous 

system has no 

ganglia! 

Autonomic Nervous System 


spinal column 

• Preganglionic axons 

are myelinated; 

postganglionic axons 

are unmyelinated

BIMM118 

Transmitters: 

• Acetylcholine: 


– ALL preganglionic neurons 

– ALL parasympathetic postganglionic neurons 

• Norepinephrine (= Noradrenalin): 

– MOST sympathetic postganglionic neurons 

– Exceptions: Sweat glands (Acetylcholine); 

Renal arteries (Dopamine) 

• Epinephrine (= Adrenalin): 

– Adrenal medulla upon sympathetic impulses 

(no ganglion!)

BIMM118 

Receptors: 

• Cholinergic Receptors: 


– Muscarinic (M): at the target organ 

named after activation by Muscarine 

(poison of Amanita muscaria) 

– Nicotinic (N): 

ganglia, motor endplate, medulla 

named after activation by Nicotine 

• Adrenergic Receptors: 

– α, β − receptors

BIMM118 

Cholinergic receptors: 

• Muscarinic receptors: 

Hetrotrimeric G protein-coupled 

– CNS, gastric mucosa: M1 

– Cardiac: M2 

– Glandular/Smooth muscle: M3 

• Nicotinic receptors: 

Ion channel-coupled 

– Muscle type (motor endplate) 

– Ganglion type 

– CNS type 

Cholinergic System 

Acetylcholine is rapidly hydrolyzed by a membrane-associated 

Acetylcholinesterase in the synaptic cleft

BIMM118 

Cholinergic System - Agonists 

= Cholinomimetics = Parasympathomimetics 

Two main classes: 

• Direct Parasympathomimetics: 

– Have affinity for M (and/or N receptors) => mimic AcCholine 

– Act mostly on the M type receptors (not subtype selective) 

Exception: Nicotine, (Muscle N type only: Tubocurarine, 

Succinylcholine) 

• Indirect Parasympathomimetics : 

– Inhibit the activity of Acetylcholinesterase => [AcCholine] increased

BIMM118 


Muscarinic Parasympathomimetics 

The extremely short half-life of AcCholine 

makes it therapeutically useless => 

• Carbachol: 

– Not hydrolyzed by AcCholinesterase 

– Also activates N receptors 

• Bethanechol: 

– Not hydrolyzed by AcCholinesterase 

– Does not activate N receptors 

– Lacks cardiovascular effects 

– Treatment of urinary retention 

Bethanechol

BIMM118 


Muscarinic 

Parasympathomimetics 

Pilocarpine: 

– Chief alkaloid in Pilocarpus jaborandi 

– Does not activate N receptors 

– Used to treat glaucoma 

Ciliary muscle contraction=>increased outflow 

of aqueous humor => reduction in intraocular 

pressure 

• Muscarine: 

– Chief alkaloid in Amanita muscaria 

– No therapeutic application

BIMM118 


Acetylcholinesterase Inhibitors 

=> Extend half-life of AcCholine => trigger activation of both M and N receptors

BIMM118 



Reversible Inhibitors: 

Used to treat Glaucoma (topical) and 

Myasthenia Gravis (systemic) 

• Carbamates: 

– Physostigmine (only topical) 

from Physostigma venenosum 

(= Calabar bean; West Africa) 

– Neostigmine 

• Quarternary alcohols: 

– Edrophonium 

Used to diagnose Myasthenia Gravis 

(very short half-life)

BIMM118 



• “Horny goat weed” 

– Epimedium sagittatum 

– Acts as AcCh-esterase inhibitor (active ingredient unknown) 

– Indirect stimulation of vascular M3 receptors triggers NO production => vasodilation 

(action similar to Sildenafil (Viagra®), which potentiates NO effects)

BIMM118 



Irreversible Inhibitors: 

No medical application! 

• Organophosphates: 

– Insecticides 

• Malathion 

• Parathion 

– Nerve gases 

• Sarin 

• Tabun 

• Soman

BIMM118 

Cholinergic System - Antagonists 

= Cholinolytics = Parasympatholytics 

• Muscarinic receptor blockers: 

– Competitive antagonists 

– Widespread medical applications: 

• Inhibition of bronchial and gastric secretion 

• Relaxation of smooth muscles (Bronchii, pupillary sphincter…) 

• Cardioacceleration 

• CNS-altering effects 

• Nicotinic receptor blockers: 

– Ganglion-specific blockers: no clinical applications 

– Neuromuscular blockers: Muscle relaxants

BIMM118 


Muscarinic Parasympatholytics 

Atropine 

Chief alkaloid in Atropa belladonna: CNS-stimulant (leaves were used as “asthma cigarettes”) 

Hyoscine (=Scopolamine) 

Chief alkaloid in Datura stramonium: CNS-depressant => antiemetic (motion sickness)

BIMM118 


Muscarinic Parasympatholytics 

Clinical applications: 

• Atropine: 

– before anesthesia: prevent hypersecretion of bronchial mucus 

– Bradycardy 

– Acetylcholinesterase-inhibitor and mushroom poisoning 

– Ophtalmology (eye exams) 

• Scopolamine: 

– Motion sickness (as patches) 

• Ipratropium: 

– Inhalation for asthma and bronchitis 

• Pirenzepine: 

– Peptic ulcers: selectively inhibits M1 receptors (gastric mucosa) => 

reduced gastric acid production 

• N-Butyl-scopolamine: 

– Spasmolytic (intestinal or menstrual cramps)

BIMM118 


Nicotinic Parasympatholytics 

Two classes (both act as neuromuscular blockers => muscle relaxants): 

• Competitive antagonists = Nondepolarizing blockers 

– Act by competing with AcCh for binding to the N receptors 

– Prevent depolarization of the endplate 

– Action can be reversed by increasing AcCh concentrations (e.g. via AcCh-esterase inhibitors) 

• Agonists = Depolarizing blockers 

– AcCh mimetics that are not hydrolyzed by AcCh-esterase (but hydrolyzed by plasma esterases) 

– Act by triggering a sustained depolarization of the neuromuscular endplate 

– No new action potential can be generated 

– Can NOT be reversed increasing AcCh concentrations (would cause further depolarization)

BIMM118 



Nondepolarizing blockers 

• Curare: 

– Plant derived arrow poison in S-America 

– Active ingredient is d-Tubocurarine 

– Death occurs through respiratory paralysis 

– Tubocurarine is not absorbed orally => no risk eating the prey 

– Tubocurarine was used clinically as muscle relaxant during surgery 

but: Tubocurarine triggers histamine release => blood pressure drops

BIMM118 



Nondepolarizing blockers 

Synthetic quarternary ammonium compounds 

– Replaced tubocurarine as muscle relaxants 

– No or little histamine release 

• Pancuronium long-lasting action (1-2h) 

Used in lethal injection (together with barbiturate + KCl) 

• Vecuronium intermediate-lasting action (

BIMM118 



Depolarizing blockers 

• Succinylcholine = Suxamethonium 

– “dimeric” Acetylcholine 

– Acts agonistic like AcCh 

– NOT hydrolyzed by AcCh-esterase (only by plasmaesterases) 

– Initial depolarization triggers muscle twitching 

– Followed by persistant depolarization (~10min) 

– Used for brief procedures (e.g. intubation; shock therapy)

BIMM118 

Cholinergic System 

Parasympathetic Drugs - Summary

BIMM118 


BIMM118 


innervated organs 

• Myelinated axons 

• Note: 

Somatic nervous 

system has no 

ganglia! 



spinal column 

• Preganglionic axons 

are myelinated; 

postganglionic axons 

are unmyelinated

BIMM118 

Transmitters: 



– ALL preganglionic neurons 

– ALL parasympathetic postganglionic neurons 

• Norepinephrine (= Noradrenalin): 

– MOST sympathetic postganglionic neurons 

– Exceptions: Sweat glands (Acetylcholine); 

Renal arteries (Dopamine) 

• Epinephrine (= Adrenalin): 

– Adrenal medulla upon sympathetic impulses 

(no ganglion!)

BIMM118 

Adrenergic System 

Termination of (nor)epinephrine action: 

• Reuptake into presynaptic nerve ending 

– Predominant mechanism 

– active transport; inhibited by Cocaine 

• Catechol-O-methyltransferase (COMT) 

– In the cytoplasm of post-junctional cells 

• Monoamino-oxidase (MAO) 

– In mitochondria of nerve and post-junctional cells 

• Presynaptic α2-receptors 

– Negative feedback that inhibits norepinephrine 

release

BIMM118 

Adrenergic receptors: 

• alpha 1 

– most vascular smooth muscles 

– Activate PLCβ => Ca ++ => Contraction 

• alpha 2 

– mostly presynaptic 

– Inhibit adenylate cyclase (Gα i ) 

• beta 1 

– mostly heart 

– Activate adenylate cyclase 

• beta 2 

– respiratory and uterine smooth muscle 

– Activate adenylate cyclase 

• beta 3 

– mostly adipocytes 

– Activate adenylate cyclase => lipolysis 

• (Dopamine) 

Adrenergic System

BIMM118 

Sympathomimetics 

Adrenergic System - Agonists 

Indirect Sympathicomimetics: 

MAO - Inhibitors: 

– Inhibition of MAO causes increase in free Norepinephrine 

– In the CNS, MAO also metabolizes dopamine and serotonin => MAO inhibitors trigger 

increase in these “happy hormones” => uses as antidepressants 

– Irreversible inhibition of MAO => long-lasting effect (weeks!) 

• Tranylcypromine 

• Moclobemide 

Possibility of severe adverse interactions of MAO inhibitors with numerous other drugs 

=> fatal hypertension

BIMM118 



Indirect Sympathicomimetics : 

• Ephedrine 

– Chief alkaloid in Ephedra, no clinical use 

– Displace norepinephrine in storage vesicle => forced norepinephrine release 

– Found in many dietary supplements: “Energy-Boosters”, Diet pills (Metabolife®) etc. 

– Ingredient in many herbal preperations: Ephedra, Ma Huang 

Epinephrine Ephedrine 

The FDA has received more than 800 reports of adverse effects associated with use of products 

containing ephedrine alkaloid since 1994. These serious adverse effects, include hypertension (elevated 

blood pressure), palpitations (rapid heart rate), neurophathy (nerve damage), myopathy (muscle injury), 

psychosis, stroke, memory loss, heart rate irregularities, insomnia, nervousness, tremors, seizures, heart 

attacks, and death. 

In Feb ‘04, the agency has banned the marketing of dietary supplements containing 

ephedrine alkaloids (ban challenged by court order in April ‘05).

BIMM118 


Indirect Sympathicomimetics : 

Amphetamines 


– Displace norepinephrine in storage vesicle => forced epinephrine release 

– Also inhibit norepinephrine re-uptake and degradation by MAO (“triple action”) 

• Methylphenidate (Ritalin®) 

– Treatment of ADD 

• Fenfluramine 

– Appetite suppressant (now banned in US) 

(combined with Phentermine = “FenPhen”) 

• Metamphetamine/MDMA 

– Effectiveness disappears due to catecholamine depletion 

of vesicles => post-use depression 

=> urge for re-administration! 

Ephedrine

BIMM118 


Non-selective agonists: 

• Epinephrine (Adrenaline) 


– Activates both α and β receptors; 

– Blood pressure increase, but effect on systolic pressure dominant 

– Dilates bronchii 

– Potent vasopressor => Clinical uses limited 

– Used for: 

symptomatic treatment of anaphylactic shock (Epi-Pen®) 

adjuvant in local anesthetics (increases duration, reduces bleeding) 

• Norepinephrine (Noradrenaline) 

– Activates mostly α receptors => systolic and diastolic blood pressure increase 

– Very potent vasopressor => Clinical uses limited to severe shock treatment

BIMM118 


α 1 - selective agonists 


• Methoxamine 


– Treatment of hypotensive state 

• Phenylephrine 

– (Local) vasoconstrictor 

nasal decongestant 

Epinephrine Phenylephrine

BIMM118 


α 1 - selective agonists (cont’d) 



Nasal decongestants (mostly OTC): 

• Naphazoline (Privine®, Rhinon®) 

• Oxymetazoline (Afrin®, etc.) 

• Xylometazoline (Privin®) 

Should be used less than 10 days, otherwise reactive hyperemia (“rhinitis medicamentosa”) develops! 

Continued used can result in local hypoxia => atrophic damage of the nasal mucosa

BIMM118 


α 2 - selective agonists 


Phenotypically produce sympatholytic effects! 

Activate presynaptic α 2 receptors in the cardiovascular control center in the CNS 

=> reduced sympathetic nervous system activity => blood pressure decrease 


Hypertension 

• Clonidine 

• Guanfacine

BIMM118 

β 1 - receptors 

• Mostly in heart 


• Increase contractility = “positive inotrope” 

• Increase heart rate = “positive chronotrope” 

β 2 - receptors 

• Respiratory system – located in bronchial smooth muscle 

• Produce bronchial dilation

BIMM118 


β 1 - selective agonists 


• Dobutamine 


– Strong inotropic effect with little chronotropic effect => 

increase in cardiac output without significant increase in heart rate 

– Short-term treatment of impaired cardiac function after cardiac surgery, MI etc. 

– Also used in “Dobutamine Stress Test” = Heart sonogram: Dobutamine mimics exercise 

Epinephrine Dobutamine

BIMM118 


β 2 - selective agonists 


Asthma: 


• Non-selective sympathomimetics => strong cardiac side effects 

• β 2 - selective agonists target predominantly the respiratory system 

• Drugs differ in speed of onset and in duration of action => acute vs. long-term treatment 

• Additionally, preferential activation of pulmonary receptors due to application as aerosols 

• Metaproterenol (Alupent®) 

• Albuterol = Salbutamol (Ventolin®) 

• Formoterol (Foradil®) 

• Etc…

BIMM118 

Sympatholytics 

α - selective antagonists 

Adrenergic System - Antagonists 

Promote vasodilation => decreased peripheral resistance => blood pressure 

(Side effects: reflex tachycardia and postural hypotension) 

Relaxation of the smooth muscles in the bladder neck 


Hypertension; Urinary retention 

Non-selective α-antagonist: 

• Phentolamine (for pheochromocytoma) 

• Ergot alkaloids see 5HT receptor 

α 1 -selective antagonists: 

• Prazosin (Minipress®) 

first α 1 - selective antagonist 

• Terazosin longer half-life 

• Doxazosin longer half-life

BIMM118 


α 2 - selective antagonists 

• Yohimbine 


– Chief active compound in Pausinystalia yohimbine (bark) 

– Effects opposite of Clonidine 

– Enters CNS => increased sympathetic output => increased heart rate, blood 

pressure, can cause severe tremors 

– Ingredient in many weight loss products 

– Extensive (past) use in treatment of male sexual dysfunction

BIMM118 



β - selective antagonists (”β - blockers”) 

β 2 - selective antagonists would trigger bronchial constriction => no clinical use 

β 2 - antagonism is mostly an “undesired side effect” of β-selective antagonists 

(goal is to antagonize β 1 - receptors) 

Non-cardiac effects: CNS - anxiolytic; skeletal muscle - reduction of tremor 


• Angina pectoris 

• Hypertension 

• Cardiac dysrhythmias 

• MI 

• Heart failure 

• Familial tremor 

• “Stage fright”

BIMM118 


β - selective antagonists 


• First-generation β-receptor antagonists blocked β 1 and β 2 -receptors = 

noncardioselective (β-receptors in the heart are β 1 - receptors). 

• Many β-receptor antagonists posses intrinsic agonist activity 

• Basic conserved structure: Norepinephrine side chain linked to aromatic structure by 

a methylene-oxygen bridge. 

Prototype: 

• Propranolol 

Epinephrine

BIMM118 



β - selective, noncardioselective antagonists (cont’d): 

• Nadolol 

• Pindolol 

• Timolol 

• Labetalol - also antagonistic on α 1 - receptors => potent antihypertonic drug 

β 1 - specific “cardioselective” antagonists: 

• Metoprolol 

• Atenolol 

• Esmolol - quick onset / short duration => used in urgent settings

BIMM118 

β-Sympatholytics 

Epinephrine 

Adrenergic System - Antagonists

BIMM118 

Cardiovascular Pharmacology 

• Hypertension 

• Angina pectoris 

• Cardiac Arrhythmias 

• Heart Failure

BIMM118 


• Cardiovascular (=Circulatory) system – heart and blood vessels 

• Arteries – transport blood to tissues 

• Capillaries – sites of exchange, fluid O2, CO2, nutrients etc. 

• Venules – collect blood from capillaries 

• Veins – transport blood back to heart 

• Blood moves within vessels – higher pressure to lower pressure 

Resistance to flow depends on vessel diameter, length and 

viscosity of blood

BIMM118 

Cardiac blood flow 


• The mammalian heart is a double pump in which the right side 

operates as a low-pressure system delivering de-oxygenated blood 

to the lungs, while the left side is a high pressure system delivering 

oxygenated blood to the rest of the body. 

• The walls of the right ventricle are much thinner than those of the 

left, because the work load is lower for the right side of the heart. 

• The ventricular muscle is relatively stiff, and it would take some time 

to fill with venous blood during diastole. The thin, flexible atria serve 

to buffer the incoming venous supply, and their initial contraction at 

the begining of each cardiac cycle fills the ventricles efficiently in a 

short space of time.

BIMM118 

Cardiovascular Pharmacology

BIMM118 


Regulation of cardiac output 

~ 5L /minute; dependent on: 

• Heart rate 

• Stroke volume 

• Preload 

• Afterload 

Starling’s Law 

Ventricular contraction is proportional to muscle fiber stretch 

Aortic output pressure rises as the venous filling pressure is increased 

Increased venous return – increase cardiac output – up to a point!

BIMM118 


Cardiac electrical activity 

• Cardiac muscle does not require any nervous stimulation to contract. 

• Each beat is initiated by the spontaneous depolarisation of pacemaker 

cells in the sino-atrial (SA) node. These cells trigger the neighbouring atrial 

cells by direct electrical contacts and a wave of depolarisation spreads out 

over the atria, eventually exciting the atrio-ventricular (AV) node. 

• Contraction of the atria precedes that of the ventricles, forcing extra blood 

into the ventricles and eliciting the Starling response. 

• The electrical signal from the AV node is carried to the ventricles by a 

specialised bundle of conducting tissue (the bundle of His) 

• The conducting tissues are derived from modified 

cardiac muscle cells, the Purkinje fibers. 

The conducting bundles divide repeatedly through 

the myocardium to coordinate electrical and 

contractile activity across the heart. 

• Although each cardiac muscle cell is in electrical 

contact with most of its neighbours, the message 

normally arrives first via the Purkinje system.

BIMM118 

Venous return 


• Systemic filling pressure 

• Auxiliary muscle pump 

• Resistance to flow between peripheral vessels and right atrium 

• Right atrial pressure - elevation 

Regulation of Arterial Pressure 

• Arterial pressure = cardiac output + peripheral resistance 

• Arterial pressure affected by: 

– the autonomic nervous system (fast) 

– the renin-angiotensin system (hours or days) 

– the kidneys (days or weeks)

BIMM118 

Potential drug targets: 

Antihypertensive Drugs 

Hypertension: 

• Usually symptom-free 

• Consequences: Heart failure, kidney damage, 

stroke, blindness … 

• CNS, ANS: decrease sympathetic tone 

• Heart: decrease cardiac output 

• Veins: dilate => decrease preload 

• Arterioles: dilate => decrease afterload 

• Kidneys: increase diuresis; inhibit RAA system

BIMM118 

Antihypertensive Drugs 

Four major drug categories 

• Sympathetic nervous system suppressors: 

– α 1 and β 1 antagonists 

– α 2 agonists 

• Direct vasodilators: 

– Calcium channel antagonists 

– Potassium channel agonists 

• Renin-angiotensin system targeting drugs: 

– ACE inhibitors 

– Angiotensin II receptor antagonists 

• Diuretics: 

– Thiazides 

– Loop diuretics 

– K + - sparing diuretics

BIMM118 

Antihypertensive Drugs:Vasodilators 

Calcium channel blockers (= Calcium antagonists): 

– Inhibit calcium entry into cells of the arteries 

=> decreased afterload 

Dihydropyridines: 

– Target specifically L-type channels on vascular smooth muscle cells 

– No cardiac effects (“Vasoselective Ca ++ antagonists”) 

– Can cause peripheral edema 

• Nifedipine 

– Prototype 

• Nicardipine 

• Nimodipine 

• Nisoldipine 

• Amlodipine

BIMM118 

Antihypertensive Drugs: Vasodilators 

Potassium channel agonists: 

• Minoxidil 

– Increases outward K + current => membrane hyperpolarization, which 

inhibits Ca ++ channel activity 

– Used only for severe, treatment-resistant hypertension 

– Major side effect: Hirsutism => used topically to treat baldness (Rogaine®)

BIMM118 

Antihypertensive Drugs: Vasodilators 

• Nitroprusside 

– Very unstable (only iv) 

– Metabolized by blood vessels into NO 

=> activates cGMP production => vasodilation 

– Rapid action (30 sec !), short duration (effect ends after 3 min) => blood 

pressure “titration” 

– Used only to treat hypertensive emergencies

BIMM118 

Antihypertensive Drugs: RAAS-targeting drugs 

Renin-angiotensin system 

• Important role in regulating blood volume, arterial 

pressure, and cardiac and vascular function. 

• Most important site for renin release is the kidney: 

sympathetic stimulation (acting via β1- 

adrenoceptors), renal artery hypotension (e.g. 

stenosis), and decreased sodium delivery to the 

distal tubules stimulate the release of renin by the 

kidney. 

• Renin acts upon a circulating substrate, 

angiotensinogen (produced mainly by the liver) 

which undergoes proteolytic cleavage to form the 

decapeptide angiotensin I (AT I). 

• Vascular endothelium, particularly in the lungs, 

contains angiotensin converting enzyme (ACE), 

which cleaves off two amino acids to form the 

octapeptide, angiotensin II (AT II).

BIMM118 


Renin-angiotensin system 

Angiotensin II 

• Constricts vessels thereby increasing vascular 

resistance and arterial pressure 

• Stimulates the adrenal cortex to release 

aldosterone, which acts upon the kidneys to 

increase sodium and fluid retention 

• Stimulates the release of vasopressin (antidiuretic 

hormone, ADH) from the pituitary which acts upon 

the kidneys to increase fluid retention 

• Facilitates norepinephrine release and inhibits re- 

uptake from nerve endings, thereby enhancing 

sympathetic adrenergic function 

• Stimulates cardiac and vascular hypertrophy

BIMM118 


ACE - Inhibitors 

• Captopril 

– First ACE inhibitor 

– Given po 

– Frequent side effect: cough (reduced inactivation of kinins) 

• Enalapril 

• Benazepril 

• Ramipril 

• Lisinopril 

• Etc…

BIMM118 


AT II Receptor Antagonists 

Do not interfer with kinin processing => no cough 

• Losartan 

• Candesartan 

• Eprosartan 

• Valsartan 

• Irbesartan 

• Etc…

BIMM118 

Angina pectoris 

• Medical term for chest pain or discomfort due to coronary heart 

disease. Typical angina pectoris (=“tight heart” is uncomfortable 

pressure, fullness, squeezing or pain in the center of the chest 

• Angina is a symptom of myocardial ischemia, which occurs when the 

myocardium does not receive sufficient oxygen. 

• People with stable angina have episodes of chest discomfort that are 

usually predictable, such as on exertion or under stress (Treatment: 

Nitrates, β-blockers). 

• In people with unstable angina, the chest pain is unexpected and usually 

occurs while at rest. The discomfort may be more severe and prolonged 

than typical angina (Treatment: Nitrates). 

• Variant angina is also called Prinzmetal's angina. Unlike typical angina, it 

nearly always occurs when a person is at rest, and does not follow 

physical exertion or emotional stress. Variant angina is due to coronary 

artery spasm (Treatment: Ca ++ channel blockers).

BIMM118 

• Nitroglycerin 

– Organic nitrate 

Angina pectoris - Nitrates 

– Acts on vascular smooth muscle to promote vasodilation 

– Primarily works on veins, only modest dilation of arterioles 

– Decreases oxygen demand by decreasing venous return => 

use in stable angina 

It was originally believed that nitrates and nitrites dilated coronary blood vessels, 

thereby increasing blood flow to the heart. It is now believed that atherosclerosis 

limits coronary dilation and that the benefits of nitrates and nitrites are due to 

dilation of arterioles and veins in the periphery. The resultant reduction in preload, 

and to a lesser extent in afterload, decreases the workload of the heart and lowers 

myocardial oxygen demand. 

– Oral, sublingual, IV, buccal and transdermal administration 

– Adverse effects – headache, tachycardia, hypotension 

– Never to be combined with other drugs causing 

vasodilation (Viagra®) or hypotension

BIMM118 

Angina pectoris - Nitrates 

• Isosorbide-dinitrate (ISDN) 

– More stable than nitroglycerol 

– Longer lasting effect 

– Tolerance can occur – give lowest dose possible 

• Nitroprusside

BIMM118 

Arrhythmias: 

Cardiac Arrhythmia 

Abnormal rhythms of the heart that cause the heart to pump less effectively 

Arrhythmia occurs: 

– when the heart’s natural pacemaker develops an abnormal rate or rhythm 

– when the normal conduction path is interrupted 

– when another part of the heart takes over as pacemaker 

Types of arrhythmia: 

– Tachycardia: unusually fast heartbeat 

– Bradycardia: unusually slow heartbeat 

– Atrial fibrillation: the atria quiver rather than contract normally because of rapid and irregular 

electrical signals in the heart. Beside the abnormal heart beat, there is also a risk that blood 

will pool in the atria, possibly causing the formation of blood clots. 

– Ventricular fibrillation: life threatening condition in which the heart ceases to beat regularly 

and instead “quivers” or fibrillates very rapidly – sometimes at 350 beats per minute or more 

(causes 350,000 death/year in the US - “sudden cardiac arrest”)

BIMM118 

Arrhythmias: 

Drug Classes: 

• Class I: Sodium channel blockers 

• Class II: β-blockers 


• Class III: Potassium channel blockers 

• Class IV: Calcium channel blockers 

• Other arrhythmic drugs

BIMM118 

Arrhythmias: 


Class I - Sodium channel blockers: 

Block Na + entry during depolarization phase 

For atrial and ventricular arrhythmias (“all-purpose”) 

• Procainamide 

• Quinidine 

For acute treatment of ventricular arrhythmias 

• Lidocaine 

For chronic treatment of ventricular arrhythmias 

• Flecainide 

• Propofenone

BIMM118 

Arrhythmias: 

Class II - β-blockers: 

For tachycardia 

• Propranolol 


Class III - Potassium channel blockers: 

Prolong repolarization phase by blocking outward potassium flux 

For treatment of intractable ventricular arrhythmias 

• Bretylium 

• Amiodarone 

Class IV - Calcium channel blockers: 

Prolong repolarization phase by blocking inward calcium current 

Predominantly for treatment of atrial arrhythmias 

• Verapamil

BIMM118 

Arrhythmias: 

Other antiarrhythmics: 

• Adenosine 


For paroxysmal supraventricular tachycardia 

• Digoxin 

iv only, extremely short half-life 

used to terminate arrhythmias (blocks reentrant pathway) 

For atrial fibrillation 

• Epinephrine, Isoproterenol 

For bradycardia 

(Paroxysmal = an arrhythmia that suddenly begins and ends)

BIMM118 

Congestive heart failure: 

Congestive Heart Failure 

• characterised by inadequate contractility, so that the ventricles have 

difficulty in expelling sufficient blood => rise in venous blood pressures 

• Raised venous pressures impair fluid drainage from the tissues and 

produce a variety of serious clinical effects: 

– Right sided heart failure causes lower limb oedema. Blood pooling in the lower 

extremities is associated with intravascular clotting and thromboembolism 

– Left sided heart failure produces pulmonary oedema and respiratory distress 

– Causes: Blocked coronary arteries; viral infections; hypertension; MI; leaky heart valves

BIMM118 


Classification of severity 

• I – no limitation of physical activity 

• II – slight limitation 

• III – marked limitation 

• IV – symptoms occur at rest

BIMM118 


Treatment options: 

• Diuretics 

– Loop diuretics 

– Thiazides 

– Spironolactone 

• ACE inhibitors & AT II antagonists 

• Vasodilators 

– Nitrates 

• Cardiac Glycosides

BIMM118 

Cardiac Glycosides: 


• Chief active ingredient in several plant families and animals:

BIMM118 


• Two main categories: 


– Cardenolides (Digitalis, Convallaria, Oleandra) 

– Bufadienolides (Helleborus, Poison Arrow Frog)

BIMM118 



• Cardiac glycosides slow the heart rate and increase the force of 

contraction 

• Extracts of D. purpurea have been used clinically for over 200 years to 

treat heart failure and edema (“dropsy”) 

• The cardiac glycosides inhibit the Na + /K + -ATPase pump, which causes an 

increase in intracellular Na + => slowing of the Na + /Ca ++ -exchanger => 

increase in intracellular Ca ++ . 

• Low therapeutic index => Associated with an appreciable risk of toxicity 

• Digoxin is the most widely used preparation of digitalis (half-life = 1-2 

days), although digitoxin (half-life = 7 days) is used in situations where 

long half-life may be an advantage. 

• Digitalis is the drug of choice for heart failure associated with atrial 

fibrillation

BIMM118 



• Improve cardiac performance (=positive inotrope) 

• Increases cardiac output 

• Decreased sympathetic tone 

• Increase urine output 

• Decreased renin release 

• Does not prolong life (only symptom relief) 

Toxicity: 

• Overdose; drug interaction; accidental ingestion of plants (children!) 

• Potassium competes with cardiac glycoside for binding to Na + /K + -ATPase 

pump => potassium is an “antidot” for cardiac glycoside poisoning 

• Injection of anti-cardiac glycoside antibodies

BIMM118 

Renal Pharmacology 

Diuretics: 

• Carbonic Anhydrase Inhibitors 

• Thiazides 

• Loop Diuretics 

• Potassium-sparing Diuretics

BIMM118 

Kidneys: 


• Represent 0.5% of total body weight, 

but receive ~25% of the total arterial 

blood pumped by the heart 

• Each contains from one to two million 

nephrons: 

– The glomerulus 

– The proximal convoluted tubule 

– The loop of Henle 

– The distal convoluted tubule

BIMM118 

Functions 


• Clean extracellular fluid and maintain ECF volume 

and composition 

• Acid-base balance 

• Excretion of wastes and toxic substances 

• Renal processes 

• Filtration - glomerulus 

• Reabsorption 

• Tubular secretion 

In 24 hours the kidneys reclaim: 

– ~ 1,300 g of NaCl 

– ~ 400 g NaHCO 3 

– ~ 180 g glucose 

– almost all of the 180 L of water that entered the tubules

BIMM118 


• Blood enters the glomerulus under pressure 

• This causes water, small molecules (but not 

macromolecules like proteins) and ions to filter 

through the capillary walls into the Bowman's capsule 

• This fluid is called nephric filtrate 

– Not much different from interstitial fluid 

• Nephric filtrate collects within the Bowman's capsule 

and flows into the proximal tubule: 

• Here all of the glucose and amino acids, >90% of the 

uric acid, and ~60% of inorganic salts are reabsorbed by active transport 

– The active transport of Na + out of the proximal tubule is controlled by angiotensin II. 

– The active transport of phosphate (PO 4 ) 3- is regulated (suppressed by) the parathyroid hormone. 

• As these solutes are removed from the nephric filtrate, a large volume of the 

water follows them by osmosis: 

– 80–85% of the 180 liters deposited in the Bowman's capsules in 24 hours 

• As the fluid flows into the descending segment of the loop of Henle, water 

continues to leave by osmosis because the interstitial fluid is very hypertonic: 

– This is caused by the active transport of Na + out of the tubular fluid as it moves up the ascending 

segment of the loop of Henle 

• In the distal tubules, more sodium is reclaimed by active transport, and still more 

water follows by osmosis.

BIMM118 

Diuretics: 

• Increase output of urine 


• Primary indications are hypertension and mobilization of 

edematous fluid (e.g. kidney problems, heart failure, 

cirrhosis,…) 

Basic mechanism: 

• Block reabsorption of sodium and chloride => water will 

also stay in the nephron 

• Diuretics that work on the earlier nephron have greatest 

effect, since they are able to block more sodium and 

chloride reabsorption

BIMM118 

Diuretics: 


Carbonic anhydrase inhibitors: 

• Azetazolamide 

– Can trigger metabolic acidosis 

– Not in use as diuretic anymore 

– Primary indications is glaucoma 

(prevents production of aequous humor) 

• Dorzolamide 

CA-inhibitors are sulfonamides => 

cross-allergenic with antibiotics etc.

BIMM118 

Diuretics: 


Loop diuretics (= high ceiling diuretics): 

– Strong, but brief diuresis (within 1 hr, lasts ~ 4hrs) 

– Used for moderate to severe fluid retention and hypertension 

– Most potent diuretics available 

– Act by inhibiting the Na + /K + /2Cl - symporter in the ascending limb in the loop of Henle 

– Major side effects: loss of K + (and Ca ++ and Mg ++ ) 

• Furosemide 

• Bumetanide 

• Torasemide

BIMM118 

Diuretics: 

Thiazide diuretics: 


– Used for mild to moderate hypertension, mild heart failure, 

– Medium potency diuretics 

– Act by inhibiting the Na + /Cl - symporter in the distal convoluted tube 

– Major side effects: loss of K + (and Mg ++ , but not Ca ++ ) 

• Hydrochlorothiazide 

• Benzthiazide 

• Cyclothiazide …

BIMM118 


Major side effects of these diuretics: 

• Hypokalemia, hyponatremia, hypochloremia 

• Hypotension and dehydration 

• Interaction with Cardiac Glycosides 

=> Potassium can be given orally or IV 

or 

Potassium-sparing diuretics: 

• Often used in combination with high-ceiling diuretics or 

thiazides due to potassium-sparing effects 

• Produce little diuresis on their own

BIMM118 

Diuretics: 

Potassium-sparing diuretics: 


– Act on the distal portion of the distal tube (where Na + is exchanged for K + ) 

– Aldosterone promotes reabsorption of Na + in exchange for K + 

(transcriptionally upregulates the Na + /K + pump and sodium channels) 

• Spironolactone 

– Aldosterone receptor antagonist 

– Onset of action requires several days 

• Amiloride; Trimterene 

– Block sodium channels 

– Quick onset 

Aldosterone Spironolactone

BIMM118 

Diuretics: 

Osmotic diuretics: 


– Small, non-reabsorbable molecules that inhibit passive reabsorption of water 

– Predominantly increase water excretion without significantly increasing Na + 

excretion => limited use 

– Used to prevent renal failure, reduction of intracranial pressure 

(does not cross blood-brain barrier => water is pulled out of the brain into the blood) 

• Mannitol 

– Only given IV – can crystallize (=> given with filter needle or in-line filter)

BIMM118 

Renal Pharmacology

BIMM118 


Uric acid 

• only slightly soluble in water and easily precipitates out of solution forming needlelike 

crystals of sodium urate 

– sodium urate crystals contribute to the formation of kidney stones and 

– produce the excruciating pain of gout when deposited in the joints. 

• Curiously, our kidneys reclaim most of the uric acid filtered at the glomeruli. Why, if it 

can cause problems? 

– Uric acid is a potent antioxidant and thus can protect cells from damage by reactive oxygen 

species (ROS). 

– The concentration of uric acid is 100-times greater in the cytosol than in the extracellular 

fluid. So when lethally-damaged cells release their contents, crystals of uric acid form in the 

vicinity. These enhance the ability of nearby dendritic cells to "present" any antigens 

released at the same time to T cells leading to a stronger immune response. 

=> risk of kidney stones and gout may be the price we pay for these protections. 

• Most mammals have an enzyme — uricase — for breaking down uric acid into a 

soluble product. However, during the evolution of great apes and humans, the gene 

encoding uricase became inactive. 

– Uric acid is the chief nitrogenous waste of insects, lizards, snakes and birds 

(the whitish material that birds leave on statues)

BIMM118 

Uricosuric agents: 


– At therapeutic doses promote excretion and inhibit reabsorption of uric acid 

(normally, only 8-12% of the initially filtered urates are eliminated) 

– At low, subtherapeutic doses, both excretion and reabsorption are inhibited 

=> possibility of an increase in uric acid concentration 

• Probenicid 

– Inhibits reabsorption of urates in the proximal convoluted tubule 

– Strong inhibitory effect on penicillin excretion 

• Sulfinpyrazone

BIMM118 

Gastrointestinal Pharmacology 

• Antacids 

– Peptic ulcer therapy 

• Antiemetics 

• Laxatives 

• Antidiarrheal drugs

BIMM118 

Acid production: 

• 2.5 L per day 

• Isotonic HCl solution 

• pH < 1 


• Produced by parietal cells 

Mucus production: 

• Produced by mucus-secreting cells 

• Also produce bicarbonate, which becomes 

trapped in the mucus layer => pH gradient 

across the mucus layer (can become 

destroyed by alcohol)

BIMM118 

Antacids: 


Weak bases: 

• Aluminum hydroxide 

– Cause constipation 

• Magnesium hydroxide 

– Cause diarrhea 

=> often combined 

Usally taken 5-7 times per day

BIMM118 

Antacids: 


• Histamine stimulates acid production by parietal cells 

• Mast cells produce a steady basal level of histamine, 

which increases in response to gastrin or acetylcholine 

• Parietal cells express histamine H 2 receptors => 

H 2 receptor blockers: 

• Cimetidine (Tagamet®) 

– First H 2 -blocker available 

– Inhibits P450 => Drug interaction 

• Ranitidine (Zantac®) 

– Does not inhibit P450 => fewer side effects 

• Nizatidine (Axid®) 

• Famotidine (Pepcid®)

BIMM118 

Antacids: 


Proton pump inhibitors: 

– Irreversibly inhibit the H + /K + - ATPase in gastric parietal cells 

– Drugs are inactive at neutral pH, but since they are weak bases, 

are activated in the acidic stomach milieu => restricted activity 

– Acid production abliterated for 24-48 hours 

• Omeprazole (Prilosec®) 

• Lansoprazole (Prevacid®) 

• Esomeprazole (Nexium®) 

• Rabeprazole

BIMM118 


Gastroesophageal reflux disease (GERD): 

– Backflow of stomach acid into the esophagus 

– Esophagus is not equipped to handle stomach acid => scaring 

– Usual symptom is heartburn, an uncomfortable burning sensation behind the 

breastbone (MI often mistaken for GERD !) 

– More severe symptoms: difficulty swallowing, chest pain 

– Reflux into the throat can cause sore throat 

– Complications include esophageal erosions, esophageal ulcer and narrowing of 

the esophagus (esophageal stricture) 

– In some patients, the normal esophageal lining or epithelium may be replaced 

with abnormal (Barrett's) epithelium. This condition 

(Barrett's esophagus) has been linked to cancer of 

the esophagus. 

– Primary treatment option are proton pump inhibitors

BIMM118 


Mucosal protective agents: 

• Misoprostol 

– Prostaglandin E 1 analog (PG stimulate mucus and bicarbonate production) 

– Used when treatment with NSAIDs inhibits 

endogenous PG synthesis 

• Sucralfate 

– Complex of aluminum hydroxide and sulfated sucrose 

– Forms complex gels with mucus => mucus stabilized => diffusion of H + impaired 

– Not absorbed => essentially free of side effects 

– Must be taken every 6 hours

BIMM118 


Peptic Ulcer Disease 

Imbalance between defenses and aggressive factors 

• Defensive factors: 

Prevent the stomach and duodenum from self-digestion 

– Mucus: continually secreted, protective effect 

– Bicarbonate: secreted from endothelial cells 

– Blood flow: good blood flow maintains mucosal integrity 

– Prostaglandins: stimulate secretion of bicarbonate and mucus, promote blood flow, 

suppress secretion of gastric acid 

• Aggressive factors: 

– Helicobacter pylori: gram negative bacteria, can live in stomach and duodenum, 

may breakdown mucus layer => inflammatory response to presence of the bacteria also 

produces urease – forms CO 2 and ammonia which are toxic to mucosa 

– Gastric Acid: needs to be present for ulcer to form => activates pepsin and injures 

mucosa 

– Decreased blood flow: causes decrease in mucus production and bicarbonate synthesis, 

promote gastric acid secretion 

– NSAIDS: inhibit the production of prostaglandins 

– Smoking: nicotine stimulates gastric acid production

BIMM118 


Peptic Ulcer Disease 

(~25 mill. Americans will have an ulcer in their life) 

Most common cause (> 85%): Helicobacter pylorii 

(not stress or hot sauce!) 


• Antibiotics 

• Antisecretory agents 

• Mucosal protectants 

• Antisecretory agents that enhance mucosal defenses 

• Antacids

BIMM118 


Antibiotic ulcer therapy: 

Combinations must be used: 

• Bismuth (PeptoBismol®) – disrupts cell wall of H. pylori 

• Clarithromycin – inhibits protein synthesis 

• Amoxicillin – disrupts cell wall 

• Tetracyclin – inhibits protein synthesis 

• Metronidazole – used often due to bacterial resistance to 

amoxicillin and tetracyclin, or due to intolerance by the patient 

Standard treatment regimen for peptic ulcer: 

Omeprazole + amoxicillin + metronidazole

BIMM118 


Antiemetic drugs: 

Vomiting: 

– Infection, pregnancy, motion sickness, adverse drug effects,… 

– Triggered by the “vomiting center” or “chemoreceptor trigger zone (CTZ)” in 

the medulla (CTZ is on the ‘blood side’ of the blood-brain barrier). 


– H 1 antagonists: Meclizine, promethazine, dimenhydramine… 

– Muscarinic receptor antagonists: Scopolamine (motion sickness) 

– Benzodiazepines: Lorazepam (during chemotherapy) 

– D 2 antagonists: have also peripheral prokinetic effects => increase motility of 

the GI tract => increases the rate of gastric emptying. 

Caution in patients with Parkinson’s disease! 

Metoclopramide 

Domperidone 

– Cannabinoids: 

Marihuana ? 

Synthetic cannabinoids: during chemotherapy 

Nabilone 

Dronabinol

BIMM118 

Laxatives: 


• Laxative – production of a soft formed stool over a period of 1 or more days 

• Catharsis – prompt, fluid evacuation of the bowel, more intense 

Indications for laxative use: 

• Pain associated with bowel movements 

• To decrease amount of strain under certain conditions 

• Evacuate bowel prior to procedures or examinations 

• Remove poisons 

• To relieve constipation caused by pregnancy or drugs 

Contraindications: 

• Inflammatory bowel diseases 

• Acute surgical abdomen 

• Chronic use and abuse

BIMM118 


Laxatives: 

• Stimulate peristalsis 

• Soften bowel content 

Classification: 

• Bulk laxatives 

– Non-absorbable carbohydrates 

– Osmotically active laxatives 

• Irritant laxatives = purgatives 

– Small bowel irritants 

– Large bowel irritants 

• Lubricant laxatives 

– Paraffin 

– Glycerol

BIMM118 


Laxatives: 

Bulk laxatives: 

Increase in bowel content volume triggers stretch receptors in the intestinal wall 

=> causes reflex contraction (peristalsis) that propels the bowel content forward 

Carbohydrate-based laxatives 

– Insoluble and non-absorbable 

– Non digestable; take several days for effect 

– Expand upon taking up water in the bowel 

– Must be taken with lots of water 

• Vegetable fibers (e.g. Psyllium, lineseed) 

• Bran (husks = milling waste product) 

Osmotically active laxatives 

– Partially soluble, but not absorbable 

– Saline-based (mostly sulfates) 

– Effect in 1-3 hrs => used to purge intestine (e.g. surgery, poisoning) 

• MgSO 4 (= Epsom salt) 

• Na 2 SO 4 (= Glauber’s salt)

BIMM118 


Laxatives: 

Irritant laxatives: 

Cause irriatation of the enteric mucosa => more water is secreted than absorbed 

=> softer bowel content and increased peristaltic due to increase volume 

Small bowel irritants 

• Ricinoleic acid (Castor oil) 

– Active ingredient of Ricinus communis 

– The oil (triglyceride) is inactive 

– Ricinoleic acid released from oil through lipase activity 

Ricin: 

– Lectin from the beans of R.communis 

– Potent toxin: inhibits protein synthesis 

– Potential bioterrorism agent (LD ~100µg) 

In 1978, ricin was used to assassinate Georgi Markov, 

a Bulgarian journalist who spoke out against the 

Bulgarian government. He was stabbed with the point 

of an umbrella while waiting at a bus stop near Waterloo 

Station in London. They found a perforated metallic 

pellet embedded in his leg that had presumably 

contained the ricin toxin.

BIMM118 


Laxatives: 


Large bowel irritants 

Anthraquinones 

Active ingredient of Senna sp. (Folia and fructus sennae), 

Rhamnus frangulae (cortex frangulae) and Rheum sp. (rhizoma rhei): 

contain inactive glycosides => active anthraquinones released in colon 

take 6-10 hours to act

BIMM118 


Laxatives: 


Large bowel irritants 

Diphenolmethanes 

– Derivatives of phenolphtalein 

• Bisacodyl 

– Oral administration: effect in 6-8 hrs 

– Rectal administration: effect in 1 hr 

– Often used to prepare for intestinal surgery 

• Sodium picosulfate

BIMM118 


Laxative abuse: 

Most common cause of constipation! 

– Longer interval needed to refill 

colon is misinterpreted as 

constipation => repeated use 

– Enteral loss of water and salts 

causes release of aldosterone 

=> stimulates reabsorption in 

intestine, but increases renal 

excretion of K + => double loss of 

K + causes hypokalemia, which 

in turn reduces peristalsis. This 

is then often misinterpreted as 

constipation => repeated use

BIMM118 


Antidiarrheal drugs: treat only symptoms! 

– Diarrhea is usually caused by infection (Salmonella, shigella, campylobacter, 

clostridium, E. coli), toxins, anxiety, drugs… 

– In healthy adults mostly discomfort and inconvenience 

– In children (particularly mal-nourished) a principal cause of death due to 

excessive loss of water and minerals. 

Antimotility agents: 

– Muscarinic receptor antagonists (not useful due to side effects) and opiates: 

• Morphine 

• Codeine 

• Diphenoxylate 

– All have CNS effects - NOT useful for diarrhea treatment 

• Loperamide 

– Selective action on the GI tract 

– Does not produce CNS effects 

– First choice antidiarrheal opoid 

– Combined with Dimethicone 

(Silicon-based gas-absorbent)

BIMM118 

Drugs for Metabolic Disorders 

• Diabetes mellitus 

• Hyperlipidemia

BIMM118 

Diabetes mellitus 

Pancreas: 

• Islets of Langerhans: site of hormone production 

– A (alpha) cells – produce Glucagon 

– B (beta) cells – produce Insulin 

– D (delta) cells – produce Somatostatin 

Insulin and Glucagon are the major regulators of blood glucose

BIMM118 


Blood glucose levels are tightly regulated:

BIMM118 

Diabetes mellitus

BIMM118 


Insulin: 

• First protein whose sequence was identified (1955) 

• 51 amino acids; synthesized as proinsulin (84 aa) 

• 6-10 mg stored in the pancreas 

• ~ 2 mg released per day 

• Liver, brain and red blood cells do not require Insulin for glucose uptake 

(only muscle and fat cells depend on insulin) 

• Main release stimulus: elevated blood sugar 

• Main effect: promote storage of glucose (increase in glucose uptake 

(GLUT4) and glycogen synthesis) 

• Also inhibits lipolysis, and promotes lipogenesis and amino acid uptake 

Glucagon: 

• 29 amino acids 

• Main release stimulus: hunger (= low blood sugar)

BIMM118 

Diabetis mellitus: 


• Group of metabolic diseases characterized by high blood sugar 

• Elevated levels of blood glucose (hyperglycemia) lead to spillage of 

glucose into the urine (diabetes mellitus means “sweet urine”) 

Two distinct clinical forms: 

• Type I (= insulin-dependent diabetes = juvenile onset diabetes) 

– Caused by destruction of the B cells 

– Generally appears in childhood 

– Absolutely dependent on insulin replacement 

• Type II (= insulin-independent diabetes = adult onset diabetes) 

– Caused by target cell resistance to insulin (InsR decreased, signaling defect) 

– Mostly obese patients (likely genetic predisposition) 

– Obesity appears to reduce the number of insulin receptors 

– Can be treated with oral hypoglycemic drugs

BIMM118 

Complications: 

• Short-term 

– Hyperglycemia, (hypoglycemia) 

– Ketoacidosis 


• Long-term 

– Disruptions in blood flow => Cardiovascular complications => Amputations 

Microvascular disease: blood flow to microvasculature lowered (kidney, eye) 

– Retinopathy – blindness 

– Nephropathy – primary cause of morbidity and mortality 

– Neuropathy – nerve damage 

– Erectile dysfunction

BIMM118 

Insulin: 


Therapeutic insulin used to be purified from porcine or bovine pancreas => 

functionally active, but many patients developed an immune response 

Today, human insulin is produced by recombinant DNA technology 

Main side effect: Hypoglycemia (requires immediate attention!) 

“Natural” insulin and four modified insulins are used clinically: 

• Regular (Natural) Insulin 

– Unmodified human insulin 

– rapid acting with short duration (half-life 9 min) 

– Only one that can be given IV (infusions, since injections are too brief acting) 

– Useful for emergencies (hyperglycemic coma) 

• Insulin Lispro (Humalog®) 

– reversal of the order of the 28 th and 29 th amino acids of the Beta-chain 

– Mutation prevents dimer formation 

– more rapid acting – effects 5-15 minutes 

– Usually given right before meals

BIMM118 

Insulin: 


Main problem with using natural and rapid acting insulin: wide fluctuations in concentration 

=> Longer lasting formulations: 

• Insulin Lente 

– mixed with zinc => forms micro-precipitates => 

takes longer to absorb => longer acting 

– Only for s.c. administration 

– Ultra-lente: longest acting 

• NPH Insulin 

– regular insulin mixed with protamine (large positively charged protein) 

=> delayed absorption 

– NPH = neutral protamine Hagedorn 

– Long acting

BIMM118 

Insulin: 

• Insulin Glargine (Lantus®) 


– amino acid asparagine at position A21 is replaced by glycine and two arginines 

are added to the C-terminus of the B-chain 

– low aqueous solubility at neutral pH, but it is completely soluble at pH 4 (as in the 

LANTUS injection solution). After injection into the subcutaneous tissue, the acidic 

solution is neutralized, leading to formation of microprecipitates from which small 

amounts of insulin glargine are slowly released, resulting in a relatively constant 

concentration/time profile over 24 hours with no pronounced peak.

BIMM118 

Insulin administration: 


• Subcutaneously (oral application impossible due to degradation) 

• Only Regular Insulin can be given IV if needed 

• Jet injectors 

• Pen injectors 

• Implantable insulin pumps 

• Intranasal insulin - mucosal atrophy (abandoned) 

• Pulmonary insulin (inhalation) - in clinical trial

BIMM118 


Oral hypoglycemic agents: 

Useful only in Type II diabetes! 

Sulfonylureas 

Stimulate insulin release (increase sensitivity of B cell towards glucose: block ATPgated 

K + channel => membrane depolarization => Ca ++ increase => insulin secretion), 

reduce serum glucagon levels, increase insulin binding on target cells 

First generation sulfonylureas: 

• Tolbutamide (t 1/2 = 6-12h) 

• Chlorpropamide (not used anymore) 

• Tolazamide 

• Acetohexamide 

Second generation sulfonylureas: 

• Glimepiride (t 1/2 = 18-24h), 100x more 

potent than Tolbutamide 

• Glipizide 

• Glyburide

BIMM118 



-glitazones (Thiozolidinediones) 

Increase insulin sensitivity of target cells: 

function as PPARγ agonists => promote transcription of insulin receptor signaling 

components and of glucose transporters 

Main side effect: hypoglycemia 

• Troglitazone 

– First of its class 

– Hepatotoxic! 

– No longer in use 

• Rosiglitazone 

• Pioglitazone 

– Half-life ~ 7hrs 

– Half-life of active metabolites up to 150 hrs !

BIMM118 



Biguanides 

• Metformine 

– Only drug in this class in use 

– Increase glucose uptake and inhibit gluconeogenesis in the liver 

– Mechanism unclear 

– Also lowers LDL and VLDL 

– Adverse side effects: Diarrhea, nausea 

– Benefitial side effect: appetite suppressant! 

– Does not cause hypoglycemia 

– Not for patients with liver or kidney 

disease (predisposition to lactic acidosis)

BIMM118 

Novel concepts: 

Alpha-Glucosidases: 


– Intestinal enzymes in the small intestine 

– Break down complex carbohydrates (Starch, Glygogen) 

Alpha-Glucosidase Inhibitors: 

– Inhibit carbohydrate breakdown => less monosaccherides available for absorption 

– Saccharides that act as competitive enzyme inhibitors 

– DO NOT increase insulin levels !! 

– Maybe useful in Type I diabetes as well? 

• Acarbose 

– Also inhibits alpha-amylases 

– No significant absorption => no systemic side effects 

– Used to prevent postprandial hyperglycemia 

– Side effects: Diarrhea, flatulence (intestinal bacteria digest the carbohydrates!) 

• Miglitol 

– Systemically absorbed 

– No effect on alpha-amylases

BIMM118 

Novel concepts (cont’d): 

Incretins: 


– Gastrointestinal hormones: Glucagon-Like Peptide 1 (GLP1) 

Gastric Inhibitory Peptide (GIP) 

– Both are inactivated by Dipeptidyl Peptidase 4 (DPP4) 

– Insulin released before glucose levels become elevated 

– Reduce gastric emptying => slower carbohydrate absorption 

– Inhibit Glucagon release 

– Reduce food intake 

Incretin mimetic: 

• Exenatide 

– Originally identified in the saliver of the Gila Monster (“Lizard spit”) 

– No effect if glucose levels are normal => no risk of hypoglycemic shock 

– Long-term weight loss 

– Only for s.c.injection 

DPP4-Inhibitors: 

No effect if glucose levels are normal => no risk of hypoglycemic shock 

Oral administration! 

• Sitagliptin 

• Vildagliptin

BIMM118 

Novel concepts (cont’d): 


Amylin: 

– Pancreatic hormone (also from β-Islet cells) 

– Reduces gastric emptying 

– Inhibit Glucagon release 

– Promotes satiety (=> decreased food intake) 

Amylin mimetics: 

• Pramlintide 

– Only drug other than insulin approved for Type I Diabetes !! 

– Used in combination with insulin

BIMM118 

Artherosclerosis: 

Hyperlipidemia

BIMM118 


Hyperlipidemia

BIMM118 


Hyperlipidemia 

Initiating mechanism: 

– Endothelial cells (EC) bind LDL 

– When activated (e.g. injury), EC and attached macrophages produce ROS 

– ROS oxidize LDL, which results in lipid peroxidation 

– This leads to the destruction of the LDL receptors which normally clear LDL 

– Oxidized LDL is phagocytosed by macrophages via “scavenger receptors” 

– Upon ingestion of oxidized LDL, macrophages become foam cells 

– One species of LDL, lipoprotein(a) contains apoprotein(a) which is structually 

similar to plasminogen. Plasminogen activator on EC processes plasminogen into 

the fibrinolytic enzyme plasmin. 

– LDL displaces plasminogen on EC => plasmin reduced => thrombosis promoted

BIMM118 

Lipoprotein metabolism: 

– Absorbed lipids released by enterocytes 

in form of chylomicrones 

– Chylomicrones bypass the liver, enter the 

circulation via lymph and are hydrolyzed 

in target tissues by lipoprotein lipases 

– 60-70% of the cholesterol in the liver 

stems from de novo synthesis 

– Liver requires cholesterol to produce 

VLDL particles, which are released into 

the blood stream 

– VLDL particles provide target tissues 

with fatty acids => become LDL particles 

– HDL particles transfer cholesterol from 

tissues to LDL particles 

Hyperlipidemia

BIMM118 

Cholesterol: 

– 60-70% (=1000 mg) synthesized (not from 


food!): Liver, intestines, reproductive organs… 

– Rate-limiting enzyme: HMG-CoA reductase 

(3-hydroxy-3-methyl-glutaryl-CoA reductase) 

< 200mg/dl: no risk 

200-240 mg/dl: moderate risk 

> 240 mg/dl: high risk

BIMM118 

Lipid-lowering drugs: 


HMG-CoA reductase inhibitors (Statins): 

– Bear structural resemblance to HMG-CoA 

– Reversible competitive inhibitors of HMG-CoA reductase 

– Isolated from Aspergillus sp. 

– Side effects: Hepatotoxicity, GI disturbances, myopathy 

• Simvastatin (Zocor®) 

• Lovastatin (Mevacor®) 

– Both drugs are precursors => 

activated in the liver 

– Lactone ring is hydrolyzed 

Lovastatin

BIMM118 




• Fluvastatin (Lescol®) 

• Pravastatin (Pravachol®) 

– Both drugs are already in active form 

• Atorvastatin (Lipitor®) 

– Long-lasting inhibition if HMGR 

Atorvastatin 

Fluvastatin 

Pravastatin

BIMM118 




• Statins accumulate in the liver (usually an undesired drug effect) 

• Cholesterol synthesis is predominantly effected in the liver => 

hepatocytes must meet their cholesterol requirements through 

different mechanisms => 

• Hepatic upregulation of the LDL-receptors => increase in LDL 

uptake => decrease in circulating LDL

BIMM118 



Fibrates: 

– Fibric acid derivates 

– PPARα agonists: stimulate β-oxidation of fatty acids 

– Also stimulate lipoprotein lipase activity 

– Reduce hepatic VLDL production 

– Affect predominantly VLDL levels (little effect on LDL) 

– Increase in HDL ! 

– Side effects: Myositis (unusual, but severe) 

• Clofibrate 

• Bezafibrate (Cedur®) 

• Fenofibrate (Tricor®) 

• Ciprofibrate 

• Gemfibrozil (Lopid®)

BIMM118 


Bile acid binding resins: 

– Anion exchange resins 


– Prevent reabsorption and enterohepatic recirculation of bile acids 

=> increase in hepatic LDL receptors => increase in hepatic LDL uptake 

=> Reduced LDL in the plasma 

– Side effects: resins are not absorbed => no systemic side effects 

mostly bloating, constipation, diarrhea 

– Interfer with absorption of drugs (e.g. digoxin) and fat-soluble vitamins 

– Not particularly appetizing 

• Cholestyramine 

• Colestipol

BIMM118 

Hyperlipidemia

BIMM118 

Steroid-based Drugs 

• Adrenocortical 

Hormones

BIMM118 

Adrenal gland: 

• Medulla: 

Adrenocortical Hormones 

– produces Epinephrine 

(stimulated by sympathetic impulse) 

• Cortex: 

– Zona glomerulosa – produces Aldosterone 

(stimulated by Angiotensin II and ACTH) 

– Zona fasciculata – produces Glucocorticoids 

(stimulated by ACTH = Corticotropin) 

– Zona reticularis – produces Androgens 

(physiological role unclear)

BIMM118 

Steroid hormone synthesis: 


• Pregnenolone synthesis is rate-limiting step 

• C21 hydroxylase: 

– Prevents hydroxylation of C17 (-> c) 

=> Only mineralocorticoids 

• C17 hydroxylase: 

– Hydroxylation of C17 (-> f, g) can be followed 

by hydroxylation of C11 and C21 (-> h, j, k) 

=> Sex hormones and glucocorticoids 

• P450 C17α hydroxylase: 

– Produces 17-Keto-steroids (-> l) 

=> Sex hormones

BIMM118 


Steroid hormone classification: 

• Progesterone: 

– C21 

– C 3: =O 

– C17: -OH or =O 

• Mineralocorticoids: 

– C21 

– C21: -OH 

– C3: =O 

• Glucocorticoids : 

– C21 

– C21, C17: -OH 

– C 3: =O 

– C11: -OH or =O 

• Estrogens : 

– C18 

– C17: -OH or =O 

– C 3: -OH 

• Androgens : 

– C19 

– C17: -OH 

– C 3: =O

BIMM118 

Glucocorticoids (GC): 


• Inhibit all phases of inflammatory reaction 

• Promote fetal development (lungs) 

• Inhibit NFκB nuclear translocation => transcription of proinflammatory 

mediators is prevented 

• Upregulate lipocortin => inhibits PLA 2 => no PG and LT synthesis 

• Undesirable effects of increased GC: 

– Immune suppression 

– Increased glucose release (=> “steroid diabetes”) 

– Glucose coverted to fat => adiposity 

– Increased protein catabolism => muscle atrophy 

– Salt and water retention (increased GC lead to reduction in ACTH => decreases 

levels of aldosterone) => hypertension 

– Osteoporosis

BIMM118 



• Adrenal cortex failure (= Addison’s disease) 

Lack of GC production: 

– Chronic fatigue and muscle weakness. 

– Loss of appetite, inability to digest food, and weight loss. 

– Low blood pressure (hypotension) 

– Blotchy, dark tanning and freckling of the skin 

(feedback missing => increased corticotropin) 

– Blood sugar abnormalities 

– Inability to cope with stress 

• Adrenal cortex tumors (= Cushing Syndrome) 

GC overproduction 

– Upper body obesity 

– “Buffalo hump” 

– Red, round face 

– Hypertension 

– Water retention 

– Thin skin and bruising 

– Poor wound healing

BIMM118 



Clinical uses: 

• Allergic Rhinitis 

• Rheumatoid Arthritis 

• Asthma 

• Multiple Sclerosis 

• Carpal Tunnel Syndrome 

• Dermatitis 

• COPD 

• Osteoarthritis 

• Gout 

• Psoriasis 

• Inflammatory Bowel Disease 

• Sinusitis 

• Lupus Erythematosus 

• Many conditions flare up if GC therapy is discontinued due 

to adreno-corticol atrophy

BIMM118 


• Hydrocortison (= Cortisol) 

– Main glucocortocoid in humans 


– Also binds mineralocorticoid receptor 

(Cortison does NOT) 

– Used for replacement therapy (Addison’s Disease) 

– Otherwise mostly topical application due to 

sodium-retaining effects

BIMM118 


• Prednisone 

– Inactive until converted to 

• Prednisolone 


– Drug of choice for systemic application 

– Lower sodium-retaining effects 

O 

Prednisolone 

HO 

CH 3 

O 

CH 3 

OH 

OH 

O 

Prednisone 

O 

CH 3 

O 

CH 3 

OH 

OH

BIMM118 


• Triamcinoline 


– Stronger anti-inflammatory (5x) than cortisol 

– No sodium-retaining effect 

Halogenated GC 

• Betamethasone 

• Dexamethasone 

– 30x more potent than cortisol 

– No water and sodium retaining effects 

O 

O 

O 

HO 

CH 3 

HO 

HO 

CH 3 

F 

CH 3 

F 

O 

CH 3 

O 

CH 3 

O 

CH 3 

OH 

O 

O 

OH 

OH 

OH 

CH 3 

OH 

CH 3

BIMM118 


• Administration 

– Oral 

– Nasal 

– Cutaneous 

– IV 

– Inhalation 

Adrenocortical Hormones

BIMM118 

Steroid-based Drugs 

• Sex Steroids

BIMM118 

Sex Steroids 

• Female reproductive cycle 

– Gonadotropin Releasing Hormone 

(GnRH) = Gonadoliberin 

stimulates release of 

– Follicle stimulating hormone 

(FSH) = Follitropin 

and 

– Luteinising Hormone 

(LH) = Lutropin 

which trigger production of 

– Estrogens (E) and Gestagens (G) 

which in turn negatively regulate 

– Pituitary (E+G) and Hypothalamus (G) 

hormone production

BIMM118 

Sex Steroids 


– Cycle length varies from 21-35 days 

• Menstruation 3-6 days 

– First (= Proliferative) phase: 

• Variable (7-21 days) 

• FSH and LH promote follicle development 

• One follicle becomes the Graafian follicle 

(the rest degenerate) 

• Graaffian Follicle: 

– Consists of thecal and granulosa cells 

which surround the ovum 

• FSH-stimulated granulosa cells produce 

estrogens from androgen precursors 

generated by LH-stimulated thecal cells 

• Estrogens are responsible for the 

proliferative phase: increase in thickness 

and vascularity of endometrium; secretion 

of protein+ carbo-rich mucus 

• Constant low estrogen inhibits LH/FSH production BUT high estrogen cause 

surge of LH production => swellign and rupture of Graafian follicle = Ovulation

BIMM118 

Sex Steroids 


– Second (= Secretory) phase: 

• Secretory phase constant (~ 14 days) 

• LH-stimulated ruptured follicle develops 

into Corpus luteum which secrets 

Progesterone 

• Progesterone (Pg) is responsible for the 

secretory phase: endometrium becomes 

suitable for implantation; mucus thickens 

• Thermogenic effects of Pg => 

body temperature increase 0.5º C 

• Without implantation: Pg secretion stops 

=> menstuation is triggered 

• With implantation: continued Pg production 

which (via inhibition of LH and FSH prod.) 

blocks further ovulation 

• Chorion (“precursor” of placenta) secretes 

human chorionic gonadotropin (HCG) which 

maintains endometrium lining throughout 

pregnancy (HCG -> see pregnancy test)

BIMM118 

Sex Steroids 

• Female reproductive cycle

BIMM118 

Sex Steroids 

Estrogens 

All produced from androgen precursors 

Three main endogenous estrogens: 

• Estradiol 

– Primary estrogen in humans 

– Breast development 

– Improving bone density 

– Growth of the uterus 

– Accelerating bone maturation and epiphyses closure 

– Development of the endometrium to support pregnancy 

– Promoting vaginal mucosal thickness and secretions 

– Increase HDL 

• Estrone 

• Estriol 

– only during pregnancy (made by fetus)

BIMM118 

Sex Steroids 

Estrogens 

– Estrogens induce expression of progesterone receptors 

– Progesterone inhibits expression of estrogen receptors 

– Two types of estrogen receptors => potential for selective drugs 

• Estradiol 

– Not suitable for oral administration (rapid hepatic elimination) 

=> stable derivatives: 

• Ethinylestradiol 

• Diethyl-Stilbestrol 

– Stilbene derivative

BIMM118 

Estrogens 

• Mestranol 

Sex Steroids 

– Used in oral contraceptives 

– Inactive => Cleavage of C3-methoxy group 

yields ethinylestradiol 

• Raloxifene 

– Selective estrogen receptor modifier (=SERM) 

– Antiestrogenic effects on breast and endometrium 

– Estrogenic effects on bone and lipid metabolism 

=> use in postmenopausal osteoporosis 

Clinical uses of estrogens: 

– Replacement therapy (Turner syndrome; menopause) 

– Contraception 

– Cancer therapy

BIMM118 

Anti-Estrogens 

• Tamoxifen 

Sex Steroids 

– Antiestrogenic effects on mammary tissue 

– Weak estrogenic effects on bone and lipid metabolism 

• Clomiphene 

– Inhibits estrogen binding in the pituitary 

=> prevention of negative feedback=> ovulation 

Clinical uses of anti-estrogens: 

– Breast cancer therapy (Tamoxifen) 

– Infertility (Clomiphen)

BIMM118 

Progesterons 

• Progesterone 

Sex Steroids 

– Inhibits rhythmic contractions of the myometrium 

– Not suitable for oral administration 

(rapid hepatic elimination) => stable derivatives: 

• Hydroxyprogesterone 

• Medroxyprogesterone

BIMM118 

Progesterons 

Sex Steroids 

Testosterone derivatives with progesterone activity: 

• Norethindrone 

• Norgestrel 

• Desogestrel

BIMM118 

Anti-Progesterons 

• Mifepristone (RU486) 

Sex Steroids 

– developed during the early 1980s by the French company Roussel Uclaf 

– while investigating glucocorticoid receptor antagonists, they discovered compounds 

that blocked the similarly shaped progesterone receptor. Further refinement led to the 

production of RU 486 

– Clinical testing of mifepristone as a means of inducing medical abortion began in 

France in 1982. Results from these trials showed that when used as a single agent, 

mifepristone induced a complete abortion in up to 80% of women up to 49 days’ 

gestation. 

– Addition of small doses of a prostaglandin analogue (=> see misoprostol) a few days 

later to stimulate uterine contractions, a complete medical abortion is achieved in 

nearly 100 percent of women 

– approved in the US in 2000 for the termination of 

early pregnancy (defined as 49 days or less)

BIMM118 

Sex Steroids 

• Male reproductive system 

– Gonadotropin Releasing Hormone 

(GnRH) = Gonadoliberin 

stimulates release of 

– Follicle stimulating hormone (FSH) 

(Stimulates Sertoli cells => 

promotes gametogenesis) 

and 

– Luteinising Hormone (LH) = 

Interstitial Cell Stimulating Hormone (ICSH) 

which triggers production of 

– Testosterone (T) (by Leydig cells) 

which in turn negatively regulates 

– Pituitary and Hypothalamus hormone production

BIMM118 

Androgens 

Sex Steroids 

• Testosterone 

– Primary androgen in humans 

– Possesses androgenic and anabolic effects: 

Androgenic effects: 

• Growth and development of male sex organs 

• Important for (male) sex drive and performance 

• Development of secondary sexual characteristics 

• Important role in spermatogenesis 

Anabolic effects: 

• Development of muscle mass 

• Reverse catabolic or tissue-depleting processes 

• Dihydro-Testosterone 

– Active metabolite 

– Mediates most of testosterone actions 

O 

O 

CH 3 

CH 3 

H 

CH 3 

CH 3 

OH 

OH

BIMM118 

Androgens 

Sex Steroids 

• Testosterone 

– Hepatic elimination after oral administration 

– Also short half-life after injection => ester derivatives: 

Proprionate, enanthate, cypionate… 

• Fluoxymesterone 

– Hepatic elimination after oral administration 

O 

O 

HO 

CH 3 

CH 3 

F 

CH 3 

CH 3 

OH 

OHR 

CH 3

BIMM118 

Anabolic Androgens 

Sex Steroids 

Testosterone derivatives: anabolic effects dominant 

• Nandrolone 

– Injection 

• Stanozolol 

– oral administration 

HN 

N 

O 

CH 3 

H 

H 

CH 3 

OH 

CH OH 

3 

CH3 

O 

CH 3 

CH 3 

OH

BIMM118 

Anabolic Androgens 

• Dehydroepiandrosterone (DHEA) 

Sex Steroids 

– Popular item in health food stores: DHEA was prescription only until 

recently when changes in federal law labeled it as a nutritional 

supplement (DHEA sales now equal that of melatonin) 

– Is actually a testosterone precursor 

– Supposedly by maintaining youthful DHEA levels one can improve mood, 

memory, energy and libido, while preserving lean body mass and counteracting 

the effects of stress hormones. 

– DHEA may have serious side effects: 

• If it abnormally increases testosterone, then testosterone side effects may be 

expected, including acne, testicular atrophy and increased risk of prostate cancer. 

• Women taking excessive doses of DHEA have reported acne and facial hair. 

– DHEA can also be converted into estrogen, so high levels of DHEA can lead to 

estrogen side effects as well, including gynaecomasty and increased risk of 

breast cancer. 

– DHEA is often marketed as an anabolic steroid: This is misleading since as an 

androgen precursor its metabolism will produce testosterone which has anabolic 

properties

BIMM118 

Anti-Androgens 

• Flutamide 

– Non-steroidal receptor antagonist 

– Used in prostate cancer treatment 

Sex Steroids 

• Finasteride 

– Inhibits 5α-reductase => prevent conversion of 

testosterone into the more potent dihydrotestosterone (DHT) 

– Used to treat prostate gland enlargement and hair loss 

(bald man have higher average levels of DHT) 

O 

N 

H 

CH 3 

H 

CH 3 

O 

N 

H 

CH 3 

CH 3 

CH 3 

CF 3 

HN 

O 

NO 2 

CH 3 

CH 3

BIMM118 

GnRH analogs/modifiers 

Sex Steroids 

• Danazol 

– Inhibits GnRH release => no FSH/LH production 

=> no steroid production 

– Used to treat endometriosis 

(growth of endometrial tissue outside of the uterus) 

• Synthetic GnRH (Gonadorelin, Buserelin, Leuprorelin…) 

– Up to 200x more potent than GnRH 

– If given in pulses (s.c.) stimulate gonadotropin release => induce ovulation 

– If given continously they desensitize the GnRH receptors => gonadal 

suppression (“medical castration”) 

– Used in sex hormone-dependent conditions (prostate, breast cancer; 

endometriosis; uterine fibroids…) 

– Side effects: menopausal symptoms 

N 

O 

CH 3 

CH 3 OH 

CH

BIMM118 

Oral Contraceptives 

• History 

Sex Steroids 

– 1937: Investigators demonstrated that the female 

hormone progesterone could halt ovulation in rabbits 

– 1949: Scientists at the University of Pennsylvania 

achieved the production of synthetic progestins 

– 1953: Margaret Sanger, Katherine McCormick and Gregory Pincus team up to 

develop a reliable contraceptive 

– 1950s: Large scale testing of “the pill” was successful 

– 1960: FDA approves first oral contraceptive 

(Early pill formulations contained up to 150 micrograms (mcg) of estrogen!) 

– 1982/84: Introduction of the bi- and tri-stage formulation 

– 1988: FDA recognized several severe long-term side effects (high estrogen!) 

– Currently used by 16 mill. women in the US (40% of women between 18 and 24

BIMM118 


Sex Steroids 

Either combination estrogen/progesterone of progesterone alone 

• Combination pills: 

– Highly effective 

– Estrogen component is mostly ethinylestradiol, sometimes mestranol 

– Progesterone component varies 

– 21 day cycle with 7 day break (causes withdrawal bleeding) 

– Can be mono- or biphasic 

Mechanism: 

– Estrogen inhibits FSH secretion (neg. feedback loop!) 

=> suppression of follicle development 

– Progesterone inhibits LH secretion (neg. feedback loop!) 

=> inhibition of ovulation; also increases mucus viscosity 

– Both steroids alter endometrium => prevent implantation

BIMM118 


Sex Steroids 

Estrogen 

Progesterone

BIMM118 

Contraceptives 

Sex Steroids 

• “Mini Pill”: 

– Contains only a progesterone (Levonorgestrel, Ethynodiol…) 

– Used when estrogen in contraindicated (e.g. thrombosis) 

– Taken daily without interruption 

– Acts mainly by increasing viscosity of mucus 

(Mucolytica in cough medicine can cause failure) 

– Less reliable than combination pill 

• Postcoital contraceptives (“Morning after pill”) 

– High dose of progesterone (Levonorgestrel) 

– Must be taken within 72 hrs 

– Nausea and vomiting are common side effects 

• Depot and patch formulations 

– Injection of oily depot formulations every 3 month 

– Transdermal delivery systems

BIMM118 


Side effects: 

– Thrombosis 

– Hypertension 

– Intermittant bleeding 

– Weight gain 

– Depression 

– Nausea 

– Loss of libido 

Sex Steroids 

Drug interactions: 

– Steroids are metabolized by P450 enzymes 

– Minimal dose of steroid is used to prevent risk of thrombosis 

– Any increase in clearance by P450-inducing drugs can result in contraception failure 

– Frequent cause of OC failure is diarrhea (diminished time for absorption)

BIMM118 

Drugs against Allergies 

• Antihistamines 

• Leukotriene Modulators 

• Glucocorticoids 

• Epinephrine

BIMM118 

Allergy 

Allergy: 

represents a sensitivity to a specific substance, called an 

allergen, that is contacted through the skin, inhaled into the 

lungs, swallowed, or injected. 

Anaphylaxis: 

is a severe whole-body allergic reaction that occurs within minutes of 

exposure, progresses rapidly and can lead to anaphylactic shock and death.

BIMM118 

Allergy - Symptoms

BIMM118 

Allergy - Pathophysiology

BIMM118 

Allergy - Food 

• Allergic reactions to foods almost always occur immediately 

• The majority of reactions are not fatal 

• In general, reactions worsen with age

Allergy - Latex 

BIMM118 Latex: milky sap from the rubber tree hevea brasiliensis

BIMM118 

Latex has cross-reactive epitopes 

with foods: banana, avocado, 

chestnut 

Allergy - Latex

BIMM118 

Allergy - Hymenoptera stings 

Hymenoptera (hymen=membrane; ptera=wings): ants, bees, wasps 

Bee 

Wasp 

Bumble Bee 

Yellow jacket

BIMM118 

Allergy - Drugs 

Predominantly against beta-lactam antibiotics and NSAIDs:

BIMM118 

Allergy - Diagnosis

BIMM118 

Allergy - Mediators

BIMM118 

Allergy - Histamine 

Receptors: 

part of the super family of G-protein coupled receptors 

•H1-Receptor 

–Gq coupled to Phospholipase C 

–CNS, smooth muscle cells of airways, GI tract, cardiovascular system, endothelial 

cells and lymphocytes => Vasodilation, bronchoconstriction, seperation of 

endothelial cells, pain and itching, allergic rhinitis, motion sickness. 


–Gs coupled to Adenylyl Cyclase 

–Parietal cells; vascular smooth muscle cells => mediate histamine induced gastric 

acid secretion; vasodilation 


–Gi/o coupled to AC, also to N-type voltage gated Ca channels and reduce Ca influx 

–CNS => Presynaptic, feedback inhibition of histamine synthesis and release; also 

controls release of other neurotransmitters 


–coupled to Gi/o in mast cells, can trigger calcium mobilization 

–found primarily in bone marrow and immune cells => mast cell chemotaxis

BIMM118 

Allergy - Histamine 

Histamine: 

Endogenous bioactive amine: synthesized, stored and released in 

–mast cells, which are abundant in the skin, GI, and the respiratory tract 

–basophils in the blood 

–neurons in the CNS and peripheral NS 

•Physiological actions 

–Primary stimulant for gastric acid and pepsin secretion 

(acid secretion is further enhanced by gastrin and vagal stimulation) 

–Neurotransmitter (both in the CNS and peripheral sites) 

•Pathophysiological actions 

–Mediator of immediate hypersensitivity reactions and acute inflammatory responses 

–Anaphylaxis 

–Duodenal ulcers

BIMM118 

Allergy - Histamine Effects 

Actions of Histamine: 

Vascular: 

H 1 - vasodilation mediated by NO and PGs (via endothelial cells) 

H 2 - vasodilation mediated by cAMP (vascular smooth muscle cells) 

H 1 - coronary vasoconstriction 

H 1 - increased permeability of post capillary venules => edema 

Heart: 

H 1 - decreased AV conduction 

H 2 - increased chronotropy 

H 2 - increased inotropy 

Lung: 

H 1 - bronchoconstriction 

H 1 - increased mucus viscosity 

H 1 - stimulation of vagal sensory nerve endings: cough and bronchospasm 

Gastrointestinal System: 

H 2 - acid, fluid and pepsin secretion 

H 1 - increased intestinal motility and secretions 

Cutaneous Nerve Endings: 

H 1 - pain and itching 

Symptoms range from mild allergic symptoms to anaphylactic shock: 

• mild/cutaneous: erythema, urticaria, and/or itching 

• moderate: skin reactions, tachycardia, dysrhythmias, moderate 

hypotension, mild respiratory distress 

• severe/anaphylactic: severe hypotension, ventricular fibrillations, cardiac arrest, 

bronchospasm, respiratory arrest

BIMM118 

Allergy - Drugs Targeting Histamine 

• H1 Receptor Antagonists 

Actually inverse agonists (H-receptors display baseline activity!) 

– 1 st Generation (Sedating): 

• Ethylenediamines: 1st antihistamines => obsolete 

• Ethanolamines: Diphenhydramine, Doxylamine, Clemastine 

• Alkylamines: Chlorpheniramine 

• Piperazines: Meclizine, Hydroxyzine 

– 2 nd Generation (Non-sedating): 

• Piperazines: Cetirizine 

• Piperidines: Loratadine, Fexofenadine 

• (H2 Receptor Antagonists => GI drugs) 

• (H3 Receptor Agonist and Antagonists: potential new drugs being developed) 

• Mast Cell Stabilizers

BIMM118 

H1-Antagonists (“Antihistamines”) 

First generation drugs: 

• Applications: 

– Adjunctive in anaphylaxis (H 2 antagonists and epinephrine also used) 

– Antiallergy (allergic rhinitis, allergic dermatoses, contact dermatitis) 

– Sedative/sleep aid 

– Prevention of motion sickness 

• Adverse effects: 

– Sedation (Paradoxical Excitation in children) 

– Dizziness, Fatigue 

– Peripheral anti-muscarinic effects: (also block muscarinic Ach receptors) 

• Dry Mouth 

• Blurred Vision 

• Constipation 

• Urinary Retention 

• Drug interactions: 

– Additive with classical muscarinic Ach receptor antagonists 

– Potentiate CNS depressants 

• opioids 

• sedatives 

• general and narcotic analgesics 

• alcohol

BIMM118 



• Diphenhydramine (Benadryl®): 

– Allergic rhinitis (=seasonal allergies); 

skin allergies (=contact dermatitis); cough relief 

– Penetrates blood/brain barrier => Sedative/sleep aid 

• Dimenhydrinate (Dramamine®): 

– 1:1 ratio Diphenhydramine : 8-Cl-Theophylline => Slower action 

– Anti H1 and anti-muscarinic activity => good antiemetic 

– Used to treat nausea, motion sickness

BIMM118 



• Doxylamine (Unisom®, Nyquil®): 

– Antiallergy: as good as diphenhydramine 

– Most potent OTC sedative/sleep aid (better than barbiturates!) 

• Clemastine (Tavist®):

BIMM118 



• Chlorpheniramine (Chlor-Trimeton®): 

– Also anti-depressant (inhibits serotonin re-uptake) 

• Meclizine (Dramamine II®): 

– Antiemetic: Less drowsiness than original Dramamine 

• Hydroxyzine (Atarax®): 

– Antihistamine action due to metabolite: Cetirizine 

Second generation drugs: 

• Cetirizine (Zyrtec®):

BIMM118 


Second generation drugs: 

• Loratadine (Claritin®): 

– Does not enter CNS => NO drowsiness! 

– t1/2=8h => Active metabolite: Desloratadine (t1/2=28h) 

• Desloratadine (Clarinex®): 

• Fexofenadine (Allegra®): 

– Highly selective for H1-Receptor 

– $ 2B in sales/year !!

BIMM118 

Mast Cell Stabilizers 

• Cromolyn=Cromoglycate (Intal®, Nasalcrom®): 

– Only prevents asthma, but can NOT stop an attack in progress 

– Acts by preventing mediator release from mast cells (likely by 

preventing Ca++ influx) 

– Usually applied via inhalation or as eye drops 

• Nedocromil (Tilade®):

BIMM118 

Allergy - Leukotrienes 

Leukotrienes: 

Generated by 5-Lipoxygenase: 

Converts AA into 5-HPETE, which in turn is converted into 

– LTB4: potent mediator of inflammation 

and 

– Cysteinyl-LTs (LTC4, LTD4, LTE4 = SRS-A): mediate asthmatic responses 

• Physiological actions: 

– LTB4: 

• Mediated by specific LTB4 receptor 

• Adherence, chemotaxis and activation of macrophages 

• Stimulates cytokine and chemokine production 

• Present in inflammatory exsudates (RA, ulcerative colititis, psoriasis) 

– Cys-LTs: 

• Mediated by shared receptor for LTC4, LTD4 and LTE4 

• Contraction of bronchial muscles (longer lasting than histamine) 

• Peripheral vasodilation, coronary vasoconstriction 

• Found in sputum of chronic bronchitis, asthmatic lung; lavage of allergic rhinitis

BIMM118 

Allergy - Leukotrienes 

Cys-LTs-R antagonists: 

Used as add-on therapy for mild to moderate asthma: 

• Prevent exercise and aspirin-induced asthma 

• Decrease response to allergens 

• Montelukast (Singulair®): 

– Oral application 

– t1/2=5h 

• Zafirlukast (Accolate®): 

– Oral application 

– t1/2=10h 

LTB4

BIMM118 

5-Lipoxygenase inhibitor: 

• Zileuton (Zyflo®): 

– Only approved LO inhibitor 

– Prevents production of all LTs 

– Not useful for treatment of attacks 

Allergy - Leukotrienes

BIMM118 

Drugs Targeting the CNS 

• Hypnotics/Anxiolytics 

• Antidepressants 

• Neuroleptics 

• Parkinson 

• Epilepsy

BIMM118 

Neurotransmitters in the CNS 

• Norepinephrine: 

– Excitory or inhibitory 


– Targeted by: MAO inhibitors (); tricyclic antidepressant (); amphetamines () 


– Excitory (M1; N) or inhibitory (M2) 

– Targeted by: M inhibitors (); Acetylcholine-esterase inhibitors () 

• Glutamate: 

– Excitory 

– Targeted by: antiepileptics, ketamine, phencyclidine () 

• GABA (γ-amino-butyric acid): 

– Inhibitory (increases g Cl - and g K +, but not g Na + => hyperpolarization (higher threshold for 

activation 

– Targeted by: hypnotics, sedative, anti-epileptics () 

• Dopamine: 

– Inhibitory 

– Targeted by: older neuroleptics (); anti-parkinson drugs, amphetamines () 

• Serotonin: 

– Excitory or inhibitory 

– Targeted by: MAO inhibitors, SSRIs, Tricyclic antidepressants, hallucinogens ()

BIMM118 


Glutamate 

• Excitatory amino acid: 

– Uniformly distributed throughout the brain 

– Mainly derived from glutamine or glucose 

– Stored in synaptic vesicles 

– Four distinct receptors exist - 

(NMDA receptor subtype most significant for drug action: needs to be 

“co-occupied” by glycine to become activated) 

– Termination mainly by re-uptake into nerve terminal and astrocytes 

– Astrocytes convert it to glutamine (lack activity) and return it to nerve cells

BIMM118 


GABA (γ-amino-butyric acid) 

• Inhibitory amino acid: 

– Only found in the brain 

– Mainly derived from glutamate via glutamic acid decarboxylase (GAD) 

– Stored in synaptic vesicles 

– Two distinct receptors exist - GABA A and GABA B 

(GABA A receptor subtype most significant for drug action: mostly post-synaptic: 

Cl - - influx hyperpolarizes the cell => inhibitory) 

– Termination mainly by deamination (GABA transaminase)

BIMM118 

Dopamine 

• Inhibitory amino acid: 

– Precursor to (nor)epinephrine 


– Termination mainly by reuptake (dopamine transporter - inhibited by Cocaine) 

and metabolism via MAO B and COMT 

– Two distinct receptor groups exist (coupled to heterotrimeric G proteins): 

D 1 -group (D 1 ,D 5 : stimulate Adenylate cyclase: CNS, renal arteries) 

D 2 -group (D 2 ,D 3, D 4 : inhibit Adenylate cyclase: CNS) 

– Three main dopaminergic pathways: 

• Nigrostriatal (substantia nigra): motor control (Parkinson’s disease) 

• Mesolimbic/mesocortical: emotion and reward system 

• Tuberohypophysal: from hypothalamus to pituitary 

• (Medulla oblongata: Vomiting center: D2 receptors) 

– Schizophrenia: increased dopamine levels and 

D 2 receptors

BIMM118 


5-Hydroxytryptamine (5-HT = Serotonin) 

• Excitatory or Inhibitory amino acid: 

– Generated from tryptophane 

– Termination mainly by reuptake and MAO B 

– Seven distinct receptor types exist (7-TM): 

5-HT 1 group (CNS, blood vessels) (cAMP) 

5-HT 2 group (CNS, blood vessels) (IP 3 /DAG) 

5-HT 3 group (peripheral nervous system) 

5-HT 4 group (enteric nervous system) 

– Main functions: 

• Intestine: increases motility 

• Blood vessel: constriction (large vessels) 

dilation (arterioles) 

• Nerve ending: triggers nociceptive receptors 

5-HT injection causes pain 

(5-HT found in nettle stings) 

• Neurons: excites some neurons, inhibits others 

inhibition mostly presynaptic (inhibit transmitter release) 

LSD = agonist of 5-HT 2A receptor

BIMM118 


Sites of drug action in the CNS:

BIMM118 

Anxiety: 


Panic disorder (panic attacks) - rapid-onet attacks of extreme fear and feelings of heart 

palpitations, choking and shortness of breath. 

Phobic anxiety is triggered by a particular object, for example; spiders, 

snakes, heights, or open spaces. 

Obsessive-compulsive disorder - uncontrollable recurring anxiety-producing thoughts and 

uncontrollable impulses (compulsive hand-washing, checking that doors are locked: “Monk”) 

Generalized anxiety disorder - extreme feeling of anxiety in the absence 

of any clear cause 

Post-traumatic stress disorder (PTSD) - recurrent recollections of a 

traumatic event of unusual clarity which produce intense psychological distress.

BIMM118 

Hypnotics / Anxiolytics 

Barbiturates 

– Derivatives of barbituric acid 

– Hypnotic/anxiolytic effect discovered in the early 20th century (Veronal®, 1903) 

– Until the 60s the largest group of hypnotics (more hypnotic than anxiolytic) 

– Act by both enhancing GABA responses and mimicking GABA (open Cl-channels 

in the absence of GABA) => increased inhibition of the CNS (also block 

glutamate receptors) 

– High risk of dependence (severe withdrawal symptoms) 

– Strong depressent activity on the CNS => anesthesia 

– At higher doses respiratory (inhibit hypoxic and CO 2 response of 

chemoreceptors) and cardiovascular depression => 

very little use today as hypnotics (only for epilepsy and anesthesia) 

– Potent inducers of the P450 system in the liver => high risk of drug interactions 

(oral contraceptives)

BIMM118 


Barbiturates 

Different barbiturates vary mostly in their duration of action 

• Phenobarbital 

– Long-acting: used for anticonvulsive therapy 

• Thiopental 

– Very short acting (very lipophilic => redistributed from the brain into the fat tissue 

=> CNS concentration falls below effective levels: used for i.v. anesthesia 

• Amobarbital 

• Pentobarbital 

• Secobarbital

BIMM118 


Benzodiazepines 

– Derivatives of Benzodiazepin 

– Valium (diazepam) in 1962 

– Characteristic seven-membered ring fused to aromatic ring 

– Selectively activates GABA receptor operated 

chloride channels (bind to the benzodiazepin 

receptor which is part of the GABA-receptor/ 

chloride channel complex) 

– Increase the affinity of GABA for its receptor 

– Used to treat anxieties of all kinds (phobias, 

preoperative anxiety, myocardial infarction 

(prevent cardiac stress due to anxiety…) 

– Significantly fewer side effects than barbiturates 

=> much safer => more widespread use 

– Cause anterograde amnesia (useful 

for minor surgeries)

BIMM118 

Benzodiazepines 


Different benzodiazepines vary mostly in their duration of action 

• Chlordiazepoxide (Librium®) 

– introduced in 1960, first benzodiazepine 

• Diazepam (Valium®), Clonazepam, 

– Strongly anticonvulsive => therapy of status epilepticus 

• Lorazepam 

• Flunitrazepam (Rohypnol®) 

– Known as “date-rape drug”, “roofie” 

– Color- and tasteless, 

– Disinhibiting effect (particularly with EtOH), amnesia ! 

– Death unlikely, but high risk of dependence 

• Alprazolam 

– Has also antidepressive properties 

• Triazolam 

– Causes paradoxical irritability (=> withdrawn in the UK) 

Alprazolam

BIMM118 

Antidepressants 

Clinical Depression 

Characterized by feelings of misery, guilt, low self-esteem without cause 

Lack of motivation, missing drive to act 

Mania: opposite symptoms 

Unipolar depression: Depressive phase only 

Bipolar disorder: Depression alternates with mania 

“Amine hypothesis of depression”: 

States that a functional decrease in brain norepinephrine and/or serotonin is 

responsible for the disorder (maybe over-simplified, BUT => 

Most anti-depressive drugs facilitate the activity of these brain amines 

• Several drug classes 

– MAO inhibitors 

– Tricyclic antidepressants (TCAs) 

– Selective Serotonine Reuptake Inhibitors (SSRIs) 

– Misc. Heterocyclic antidepressants 

– Lithium (bipolar disorder only)

BIMM118 

MAO Inhibitors: 


– Increase levels of norepinephrine, serotonin and dopamine by preventing their 

metabolism 

– Use is declining due to side effects (can cause fatal hypertensive crisis) => 

Last choice of treatment today (only if other drugs fail) 

– Possibility of severe food-drug interaction (“cheese reaction”: Tyramine is usually 

metabolized and inactivated in the gut by MAOs. MAO-inhibition allows for 

uptake of tyramine, which displaces norepinephrine in the storage vesicles => 

NE released => hypertension and cardiac arrhythmias. 

• Tranylcypromine 

• Phenelzine

BIMM118 

Tricyclic antidepressants: 


– Increase levels of norepinephrine and serotonin by preventing their neuronal 

reuptake => extended duration of post-synaptic effects 

– Strong interaction with alcohol 

– Side effect: Sedation (H1-block) 

• Imipramine 

• Desipramine 

• Clomipramine 

• Amitriptyline 

• Nortriptyline

BIMM118 


Selective Serotonin Reuptake Inhibitors (SSRIs): 

– Increase levels of serotonin specifically by preventing their neuronal reuptake => 

extended duration of post-synaptic effects 

– Same efficacy as TCAs, but fewer side effects 

– Main side effect: inhibition of sexual climax 

– Rare, but severe side effect: aggression, violence 

• Fluoxetine (Prozac®) 

Most widely prescribed antidepressant 

Sales exceed 1 bill. $ / year 

• Paroxetine (Paxil®) 

• Sertraline (Zoloft®) 

• Clotalopram (Celexa®)

BIMM118 

Schizophrenia 

Endogenous psychosis characterized by: 

Neuroleptics 

Positive symptoms: thought disorder (illogical, incoherent, garbled sentences), 

mood inappropriation, paranoia (persecution mania) and hallucinations (voices) 

and 

Negative symptoms: withdrawal from society, flattened emotional responses, defect 

in selective attention (can’t distinguish between important and insignificant) 

Affects up to 1% of population, high suicide rate (10%) 

Amphetamines promote dopamine release => mimic schizophrenia 

“Dopamine hypothesis of schizophrenia”: 

States that a functional increase in brain dopamine is responsible for the disorder. 

In addition, 5-HT might play a role, possibly by modulating dopamine responses. 

Anti-psychotic drugs act as dopamine D2 (and 5-HT) receptor blockers 

• Several drug classes 

– Typical (older, pre-1980s) neuroleptics: phenothiazines, butyrophenones 

relieve mostly positive symptoms 

– Atypical (newer) neuroleptics: fewer extrapyramidal side effects 

relieve both positive and negative symptoms

BIMM118 

Classical neuroleptics: 

Phenothiazines 

• Chlorpromazine 

• Triflupromazine 

• Fluphenazine… 

Butyrophenones 

• Haloperidol 

• Trifluperidol 

• Spiroperidol 

Neuroleptics

BIMM118 

Classical neuroleptics: 

Adverse effects: 

Neuroleptics 

– Mostly extensions of dopamine-receptor antagonism (extrapyramidal effects due 

to dopamine blockage in the striatum): 

• Acute dystonia: Motor impairment, involuntary movements of face, tongue, neck.. 

(reversible; develops immediately after start of treatment) 

• Akathesia (Pseudo-Parkinsonism): motor restlessness, rigidity, tremor 

(reversible; develops days to month after start of treatment) 

• Tardive Dyskinesia: involuntary movements of most body parts (head, lips, limbs..) 

– Sedation (results from H1-receptor blockage) 

(irreversible; develops after extended treatment in 20-40% of 

patients) - main problem of classical neuroleptic therapy 

– Also block muscarinic cholinergic and α-adrenergic receptors (=> dry mouth, 

constipation, urinary retention) 

– Lactation (dopamine suppresses prolactin release) 

– Strong interaction with alcohol

BIMM118 

Atypical neuroleptics: 

– Inhibit 5-HT and D2 receptors 

Neuroleptics 

– Act predominantly in the limbic system, but not in the striatum => fewer 

extrapyramidal side effects (might also be due to adrenergic receptor blockage) 

• Clozapine 

– Can cause agranulocytosis 

(=> strict monitoring required) 

• Olanzapine 

– Same efficacy as Clozapine, but no agranulocytosis 

• Risperidone 

• Olanzapine

BIMM118 

Pathology: 

Parkinson’s Disease 

• Loss of dopaminergic neurons in the Pars compacta of the Substantia nigra 

• The excitatory influence of ACh becomes unopposed => movement disorders 

(tremor, muscle stiffness, slow movements, and difficulty walking) 

• Symptoms: stooped and rigid posture, shuffling gait, tremor, a masklike facial 

appearance, and "pill rolling"

BIMM118 

Pathology: 


• Loss of dopaminergic suppression of the cholinergic neurons in the striatum => 

increased GABA output to the thalamus => suppression of stimulating input into the 

motor cortex => movement disorder 

• Treatment strategies: Dopamine replacement 

Dopamine agonists 

Cholinergic antagonists (Atropine - see Lecture 6)

BIMM118 

Dopamine replacement: 


Dopamine does not cross blood-brain barrier => use of 

• Levodopa (L-Dopa) 

– Metabolic precursor of dopamine 

– High concentrations required, as most of L-Dopa is decarboxylated in the 

periphery => high concentration of peripheral dopamine => side effects! 

– L-Dopa combined with 

• Carbidopa 

– L-Dopa decarboxylase - inhibitor 

– Does not cross blood-brain barrier => 

only peripheral effect => increases the amount 

of L-Dopa that reaches the brain

BIMM118 

Dopamine agonists: 


Actions and side effects similar to L-Dopa 

• Bromocriptine 

– Derived from ergot alkaloids 

– Potent D2 agonist 

– Initially used to treat galactorrhoea (inhibit Prl release) 

• Pergolide 

• Pramipexole 

Indirect dopamine agonists: 

• Selegiline 

– Inhibitor of MAO B (mostly in the CNS => few peripheral side effects, e.g. cheese 

reaction etc.) 

– Extends half-life of dopamine

BIMM118 

Pathology: 

Epilepsy 

– Group of disorders characterized by excessive excitability of neurons within the 

central nervous system (CNS) 

– Characteristic syptom is seizure 

– ~0.5% of population is affected 


– Simple (patient remains conscious, often involves brain lesions) or complex 

(patient looses consciousness) 

– Partial (only localized brain region is affected) or generalized 

Generalized seizures are devided into: 

• Tonic clonic seizures (grand mal): strong contraction of entire musculature 

=> rigid spasm, often accompanied by salivation, defaecation and 

respiratory arrest. Tonic phase is followed by series of violent jerks, which 

slowly die out in a few minutes 

• Absence seizures (petite mal): often in children. Less dramatic, but more 

frequent (several seizures/day): patient stops abruptly what (s)he was doing 

and “spaces out”

BIMM118 

Epilepsy 

Treatment strategies: 

Enhancement of GABA action 

Mostly for partial and generalized convulsive seizures (not effective in absence seizures) 

• Carbamazepine 

– Benzodiazepine => increases Cl - -influx in response to GABA => counteracts 

depolarization 

• Tiagabin 

– Prevents GABA re-uptake 

Inhibition of sodium channels 

• Phenytoin 

– Blocks voltage-gated Na + -channels in the inactivated (refractory) state => preferential 

inhibition of high-frequency discharges 

(very limited effect on normal frequency excitation 

= “use-dependent inhibition”) 

– Eliminated following zero-order kinetics 

– Used for convulsive seizures (not effective in 

absence seizures) 

– gingival hyperplasia (fairly high percentage)

BIMM118 


Inhibition of calcium channels 

• Ethosuximide 

– Blocks T-type channels 

– Drug of choice for absence seizures 

• Valproate 

Epilepsy 

– Exact mechanism unclear (causes GABA increase in the brain) 

– Useful for convulsive and absence seizures 

– Teratogenic 

– Hepatotoxic (elevated liver enzymes, even fatal hepatic failure)

BIMM118 

Glycine receptor antagonist 

Glycine: 

– Non-essential amino acid 

Strychnine 

– Major inhibitory neurotransmitter (similar to GABA) 

– Binds NMDA receptor (not strychnine sensitive) 

– Glycine receptor (Cl - ion channel) - binding is Strychnine sensitive 

Strychnine: 

– Main alkaloid in Strychnos nux-vomica seeds 

– Among the most bitter substances known 

– Poisoning causes most severe muscle spasm (“arching”): 

Convulsions progress to death by asphyxiation (LD 50 =10mg) 

(Considered one of the most painful deaths: horrific seizures without losing consciousness) 

– Popular use as a rodent pesticide 

– Antidotes: Anticonvulsants (Diazepines) 

Muscle relexants

BIMM118 

Ethanol 

Most widely consumed “drug”: 

1 drink = ~ 8-12g ethanol (= 0.17-0.26 mole) => 

not unusual to consume >1mole/session 

(equivalent to ~ 0.5 kg of most other drugs) 

• Biological effects 

Resembles actions of general, volatile anesthetics 

Acts on many different levels: 

– Low concentrations: 

• enhancement of excitatory effects of N-ACh and 5-HT 3 receptors => 

agitation 

– Higher concentrations: 

• Inhibition of neurotransmitter release by blocking Na + and Ca 2+ channels 

• Inhibition of NMDA receptor function 

• Enhancement of GABA-mediated inhibition (similar to benzodiazepines) 

Peripheral effects: 

• Cutaneous vasodilation (heat loss!!) 

• Increased salvary and gastric secretion (=> hunger) 

• Increased glucocorticoid release 

• Inhibition of anti-diuretic hormone (ADH) secretion => diuresis 

• Inhibition of Oxytocin release (=> delay of labor induction)

BIMM118 

• Alcoholism 

– Long-term effect: 

Ethanol - Alcoholism 

– Liver damage: increased fat accumulation due to increased “stress” => increased release of 

fatty acids from fat tissue, and impaired fatty acid oxidation due to “metabolic competition” 

– Chronic malnutrition (ethanol satisfies the 

– Addiction: 

“caloric requirement”, but no vitamins etc.) 

– Alcohol use linked to endorphine system (AA Wistar rats more sensitive to endorphine 

release after alcohol consumption => proned to alcoholism) 

– Endorphines are part of the bodies “reward system” =>re-inforced behavior 

– Withdrawal: 

– Long-term alcohol use leads to reduced GABA levels 

– Abrupt stop of alcohol consumption => lack of GABA input => 

Seizures, halluzinations, tremor, convulsions, “Delirium tremens” 

– More than 15 mill. Americans are considered Alcoholics !!!

BIMM118 


• Disulfiram (Antabuse®) 

– Blocks Aldehyde-dehydrogenase => 

Ethanol - Alcoholism 

accumulation of Acetaldehyde after alcohol consumption: 

nausea, vomiting,”hang-over” 

– Also inhibits dopamine-hydroxylase => 

blocks dopamine->NE conversion => 

rise in dopamine: schizophrenic symptoms 

• Naltrexone (“Sinclair Method”) 

– Opioid receptor antagonist 

– Prevents the “reward response” 

– Patient is allowed to consume alcohol in usual setting => 

BUT: urge to drink diminishes over time 

– Very simple and successful (~80%) regimen

BIMM118 

Drugs against Pain 

• Anesthesia 

• Narcotic Analgetics 

• Local Anesthetics 

• NSAIDs

BIMM118 

General Anesthetics 

State of drug-induced absence of perception of all sensations: 

Unconciousness, analgesia, amnesia and muscle relaxation 

General anesthesia is usually induced with intravenous anesthetics, 

and maintained with inhalation anesthetics 

1846 - first surgery under ether-anethesia; 1847 - introduction of chloroform 

Originally, anesthesia was achieved with a single agent (e.g ether, nitrous oxide). 

However, to satisfy all four anesthesia requirements with one agent necessitates 

high dosage => increased risk of suppression of vital functions.

BIMM118 


Inhalation anesthetics: 

• Very diverse drugs: ether, nitrous oxide, halogenated hydrocarbons 

• Mechanism of action largely unknown (probably inhibition of glutamate receptors and 

increased activity of GABA receptors) 

• Actions are affected by cardiac output and ventilation rate 

• Elimination predominantly through exhalation of the unchanged gas 

Potency and speed of induction/recovery depend on two properties of the anesthetic: 

• Solubility in blood (blood:gas partition coefficient) 

– Speed of onset is inversely correlated with the solubility in blood (more soluble => slower 

onset): blood acts as a reservoir that “needs to be filled” 

• Solubility in lipid (oil:gas partition coefficient) 

– Determines the potency of the anesthetic 

– Minimal alveolar concentration (MAC) 

= alveolar concentration at 1 atm that produces immobility 

in 50% of the patients exposed to a painful stimulus 

(usually expressed in Vol%) 

– More lipophilic anesthetics have higher potency 

– Lipophilic anesthetics gradually accumulate in body fat 

=> prolonged “hang-over”

BIMM118 



• Ether 

– Obsolete (except in underdeveloped regions) 

– Slow onset and recovery 

– Post-operative nausea, vomiting 

– Highly explosive 

• Nitrous oxide 

– Low potency (must be combined with other agents) 

– Rapid induction and recovery 

– Good analgesic properties 

• Halothane 

– Widely used agent 

– Potent, non-explosive and non-irretant 

– 30% metabolized in liver 

=> repeated use can cause liver damage 

– No analgetic properties 

– Causes hypotension (vasodilation, cardio-suppression)

BIMM118 



• Enflurane 

– Similar to halothane 

– Less metabolized => smaller risk of liver damage 

• Isoflurane 

• Desflurane 

• Sevoflurane

BIMM118 


Intravenous anesthetics: 

• Thiopental 

– Barbiturate with very high lipid solubility 

– Rapid action, but accumulates in fat with extended use 

– No analgesic effect 

– Narrow therapeutic range 

• Propofol 

– Rapidly metabolized => quick recovery 

– Drug of choice for day-case surgery 

– Used as continuous infusion 

• Ketamine 

– Phencyclidine analogue 

– Good analgesia and amnesia 

– High incidence of hallucinations during recovery 

• Midazolame 

– Benzodiazepine

BIMM118 


Modern anesthesia: 

Employs a combination of drugs to achieve the goals of a “balanced anesthesia”: 

– Anxiolytic premedication (Diazepines) 

– Autonomic stabilization (Atropin: prevents visceral reflexes) 

– Analgetics (Opioids: Fentanyl) 

– Muscle relaxant (Pancuronium)

BIMM118 

Opioid Analgesics 

Opiates: 

– Alkaloids derives from Papaver somniferum 

– Already used 4000 B.C. (opius greek: “little juice”) 

– 1805: Morphine isolated (morpheus: Greek god of dreams) 

– 1874: synthesis of heroin (introduced in 1898 by Bayer as a cough medicine) 

– Opium tincture heavily used during civil war 

– Opiates freely available in the US until 1914 

– 1914: Harrison Act 

Prevented physicians from maintaining addiction

BIMM118 


Opiates: 

– Act through receptors (7TM, coupled to Gα i or ion-channels) for endogenous opioids: 

Enkephalins, endorphines,… 

– Reduce cAMP, but countereffect: upregulation of adenylate cyclase => tolerance 

Endorphine Morphin 

– Three receptor subtypes: 

• mu (µ): account for most of the morphin effects 

• delta (δ): mediate reduced GI motility and respiratory suppression (in addition to µ) 

• kappa (κ): mediate dysphoria and contribute to sedation, weak analgesic effect 

– Most opiods are full agonists for all receptors 

(exception: Pentazocine, buprenorphine, which are mixed a(nta)gonists based on receptor type)

BIMM118 

Opiates: 

Mechanism of analgesic action: 


– Spinal analgesia: 

Activation of presynaptic opioid receptors => decreased Ca ++ flux => decreased 

neurotransmitter (Substance P) release => decreased transmission of pain signal from 

nocireceptors 

– Supraspinal analgesia: 

Activation of postsynaptic opioid receptors in the medulla and midbrain => increased K + 

flux => hyperpolarization => inhibition of neurons in the pain pathway 

– Oral opioids are subject to first-pass 

elimination => low oral bioavailability 

– Morphine is metabolized and eliminated 

via glucuronidation 

– Heroin, Fentanyl: very lipophilic => 

rapid accumulation in the CNS

BIMM118 

Opiates: 

Morphine: 

– CNS: 

– Eyes: 

• Sedation and drowsiness 


• Nausea (direct stimulation of the chemoreceptor trigger zone) 

• Cough suppressant (suppressive effect on medulla; independent of analgesic effect) 

• Pupillary constriction (stimulate parasympathetic portion of the oculomotor nucleus) 

– Respiratory system: 

• Strongly suppressive on all phases (frequency; volume) 

• Also depression of hypoxic drive 

– GI: 

• Increases resting tone of the smooth muscle of the entire GI tract => segmentation 

• Decreased peristaltic movements, increased sphincter tonus => constipation 

– Urinary tract: 

• Increased smooth muscle cell tone => urinary retention 

Withdrawal symptoms: 

– Mostly autonomic hyperactivity: diarrhea, vomiting, chills, cramps, pain…

BIMM118 

Codeine (3-methoxy-morphine): 


– Better oral absorption than morphine 

– Only 20% of analgesic effect of morphine 

(does not increase significanly by increasing the dose) 

– Prodrug: Converted into morphine by demethylation via CYP2D6 

(mutated in ~10% of the population => resistance to the analgesic effect) 

– CYP2D6 inhibitors (e.g. Fluoxetine) reduce efficacy of Codeine 

– Little euphoria => rarely addictive 

– GI and respiratory effects similar to morphine 

(=> codeine and dihydrocodeine are widely used as antitussiva) 

Dextromethorphane (DXM): 

– Synthetic morphine derivative 

– Equally antitussive as codeine 

– Does not act through opioid receptors 

– No analgesic or GI effects

BIMM118 

Heroin (diamorphine): 

– Diacetylated morphine 


– Greater lipophilicity => crosses blood/brain barrier better 

=> greater “rush” 

– Used in UK as analgesic 

(~2x more potent than morphine) 

Hydrocodone (Vicodin®): 

– Often combined with NSAIDs 

– Contained in over 200 preparations in the US 

Oxycodone (OxyContin®): 

– Used in slow-release formulation to treat chronic pain 

– People seeking an alternative to heroin often try OxyContin. 

They chew the time-release tablets for a quicker high. Some crush the tablet 

to snort or inject it. Prescriptions are often obtained fraudulently, and in many 

robberies of pharmacies, only Oxycontin is stolen.

BIMM118 

Meperidine (Pethidine): 

– Actions similar to morphine 


– Much shorter duration => used during labour 

Methadone: 

– Actions similar to morphine 

– Significantly longer duration (t 1/2 = >24 h) => less psychological dependence 

– Used to treat morphine and heroin addiction 

Etorphine: 

– 1000x more potent than morphine, but similar efficacy 

– No clinical advantage 

– Used to immobilize wild animals (high potency permits small volumes in darts) 

Fentanyl: 

– High potency (allows use in transdermal delivery systems) 

– Short lasting: used in anesthesia and in patient-controlled infusion systems

BIMM118 

Opiate antagonists: 

• Naloxone: 

– Short acting 


– Rapidly reversed opoid-induced analgesia and 

respiratory suppression 

– No effect if no opioids are present 

– Used to treat opiate overdoses and to improve breathing 

in newborns whose mothers received opioids 

– Induces severe withdrawal symptoms in opioid addicts 

• Naltrexone: 

– Similar to naloxone, but much longer duration of action 

– Used to “protect” detoxified addicts by preventing any 

opioid effect if the patient relapses

BIMM118 

Mode of action: 

Local Anesthetics 

– Block generation of action potential by reversibly inhibiting Na + -influx 

– Are weak bases (pK=8-9) => mainly ionized at physiological pH 

– Act in their ionized form, but penetrate the cell membrane in the non-ionized form 

– Preferentially block activated Na + -channels = “Use dependence” 

(higher affinity for open/inactivated channel; easier access to open channel)

BIMM118 

Mode of action: 


• Different nerve fibers show differential sensitivity towards LA: 

– High sensitivity: 

thin, non-myelinated nerve fibers (sensory roots): Pain, touch, 

temperature 

– Medium sensitivity: 

thin->medium, myelinated nerve fibers (sympathetic nerves): vasomotor, 

visceromotor function 

– Low sensitivity: 

Thick, myelinated nerve fibers (somatic nervous system): motor function

BIMM118 



• Aromatic part linked by ester or amide bond to basic side chain: 

• Esters: 

– Inactivated quickly by non-specific esterases in the plasma and tissue 

• Amides: 

– More stable, longer plasma half-lifes

BIMM118 


• Cocaine 

– First local anesthetic 

– Isolated in 1860 from Coca 

(Indians, who chewed Coca 

leaves for their psychotropic 

effects, knew about the numbing 

effect they produced on the mouth 

and tongue) 

• Procaine 

– First synthetic local anesthetic 

• Many more …caines today 

Local Anesthetics

BIMM118 

Clinical use and 

Administration: 

– LA often combined 

with vasoconstrictors 

to extend duration of 

action (also to 

minimize bleeding) 

Local Anesthetics

BIMM118 

NSAIDs 

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): 

• Act by inhibiting CycloOXygenases (COX) => no PG production 

– COX-1: Constitutively expressed => house-keeping function 

– COX-2: Induced by pro-inflammatory factors (TNFα, IL-1) 

– COX-3: Just recently discovered 

• PGs do not cause pain, but sensitize nocireceptors to stimulation 

(e.g. by 5-HT, Bradykinine, capsaicin, …) 

• IL-1 release from activated macrophages (bacteria, etc.) induces COX-2 in 

the brain => PG E produced => affects thermoregulation => fever 

=> NSAIDs have anti-pyretic effects 

• Classical NSAIDs: inhibit both COX-1 and COX-2 (inhibition is reversible, 

with the exception of Aspirin) => housekeeping PGs reduced => side 

effects (gastrointestinal, bronchospasms,…) 

• 2nd generation NSAIDs: COX-2 specific => only the inflammatory response 

is inhibited => fewer side effects

BIMM118 

NSAIDs 


• Aspirin (= Acetyl-Salicylic Acid = ASA) 

– Oldest NSAID 

– Irreversible, non-selective COX inhibitor 

(causes acetylation of COX) 

– Can cause Reye’s Syndrome in children: 

(Combined encephalopacy and liver disorder - 20-40% lethality!!) 

=> Avoid Aspirin in children 

– Anti-rheumatic activity requires high doses => 

CNS effects possible (tinnitus, nausea, etc.) => 

other NSAIDs have been developed

BIMM118 

NSAIDs 


• Acetaminophen = Paracetamol (Tylenol®) 

– Most commonly used analgesic/antipyretic 

– Weak anti-inflammatory activity 

– Mechanism still debated (COX-3 inhibitor ??) 

– Overdose can produce fatal hepatotoxicity: 

at high doses (2-3x max. therapeutic dose), a toxic metabolite is produced that is 

conjugated to glutathione in the liver. If glutathione is depleted, metabolites 

accumulate => liver necrosis : more than 100 deaths/year in the US !

BIMM118 

NSAIDs 


• Ibuprofen (Advil®, Motrin®) 

• Naproxen (Aleve®) 

• Diclofenac (Voltaren®) 

• Indomethacine (Indocid®)

BIMM118 

COX-2 specific NSAIDs: 

• Rofecoxib (Vioxx®) 

– Launched in 1999 

NSAIDs 

– Marketed in 86 countries: 2.5 bill.$ /year 

– Recent trial to test Rofecoxib for efficacy in colorectal polyps treatment revealed 

an increased risk of heart disease (+ 50%) after 18 month continuous use 

– Sept. 2004: Merck voluntarily withdrew Vioxx® from the market pending further 

investigation. 

• Celecoxib (Celebrex®) 

– April 2005: FDA required Pfizer to include a “boxed warning” indicating a 

potential risk of cardiovascular side effects 

• Valdecoxib (Bextra®) 

– April 2005: FDA required Pfizer to withdraw Bextra® from the market due to 

unfavorable risk vs. benefit profile (mostly already known adverse skin reactions)

BIMM118 

Chemotherapeutic Agents 


• Antifungals 

• Antivirals 

• Antiprotozoal 

• Antihelmintics 

• Anticancer drugs

BIMM118 

General Aspects: 

Antibiotics 

• Principle: 

inhibit growth of bacteria without harming the host 

– Drug must penetrate body tissue to reach bacteria (exception: GI infection) 

(unique targets: cell wall, protein synthesis, metabolic pathways…) 

– Bacteria targeted must be within the spectrum of the AB 

– Drug can be bactericidal or bacteriostatic 

– Different agents can be combined for synergistic effect 

(Note: not all combinations are useful, e.g. cell wall synthesis inhibitors loose effectiveness 

when combined with bacteriostatic drugs) 

– Identification of the invasive microorganism necessary for optimal treatment 

• General side effect: 

Alteration in normal body flora 

– GI tract harbors symbiotic bacteria which are killed by AB => 

resistant bacteria repopulate the niche = secondary or superinfection 

(most common: overgrowth of Clostridium difficile)

BIMM118 

Antibiotics 

• Resistance: 

loss of efficacy of a given AB against a particular strain 

– Frequently: Staphylococcus aureus, pseudomonas aeruginosa, mycobacterium 

tuberculosii 

Acquisition: 

– Spontaneous mutation 

– Adaption: drug metabolism (β-lactamase); alternative metabolic pathways 

– Gene transfer: plasmids (via conjugation and transduction); transposons 

Manifestation: 

– Microbes may increase manufacture of drug-metabolizing enzymes (penicillins) 

– Microbes may cease active uptake of certain drugs (tetracyclines) 

– Changes in receptors which decrease antibiotic binding and action 

– Microbes may synthesize compounds that antagonize drug actions 

– Antibiotic use promotes the emergence of drug-resistant microbes 

(especially the use of broad-spectrum antibiotics) 

!!! The more ABs are used, the greater the chance of resistance !!!

BIMM118 

• Resistance avoided/delayed by: 

Antibiotics 

– Using AB only when absolutely needed and indicated: 

AB often abused for viral infections (diarrhea, flu-symptoms, etc.) 

– Starting with narrow-spectrum drugs 

– Limiting use of newer drugs 

– (Minimizing giving antibiotics to livestock) 

– Identifying the infecting organism 

– Defining the drug sensitivity of the infecting organism 

– Considering all host factors: 

site of infection, inability of drug of choice to penetrate the site of infection, etc. 

– Using AB combinations only when indicated: 

Severe or mixed infections, prevention of resistance (tuberculosis) 

Worldwide more than 500 metric tons antibiotics are used anually !!!

BIMM118 


• Cell wall synthesis inhibitors 

Antibiotics 

– Beta-lactams (penicillins, cephalosporins, aztreonam, imipenem) 

– Poly-peptides (bacitracin, vancomycin) 

• Protein synthesis inhibitors 

– Aminoglycosides 

– Tetracyclins 

– Macrolides 

– Chloramphenicol 

– Clindamycin 

• Folate antagonists 

– Sulfonamides 

– Trimethoprim 

• Quinolones

BIMM118 

Antibiotics - Cell wall synthesis inhibitors 

Bacterial cell wall: 

Three types: 

• Gram-negative (e.g. E.coli, Salmonella) 

– Few peptidoglycan layers 

(Lipopolysaccheride) 

• Gram-positive (e.g. Staphylococci, Listeria) 

– Many peptidoglycan layers 

(Lipoteichoic acid) 

– Stains w/ crystal-violet/iodine 

• Acid-fast positive (Mycobacteria) 

– Cell wall contains waxy substance 

(Mycolic acid) 

– Stain w/ acid fast test (heating required)

BIMM118 


Beta-lactam antibiotics: 

1928 - Alexander Fleming observes the antibacterial effects of Penicillin 

1940 - Florey and Chain extract Penicillin 


• Penicillins 

– Narrow spectrum – penicillinase sensitive 

– Narrow spectrum – penicillinase resistant 

– Broad spectrum penicillins 

– Extended-spectrum penicillins 

• Cephalosporines 

• Carbapenems 

• Monobactams 

• Vancomycin, Bacitracin

BIMM118 

Penicillins 


Inhibit transpeptidase required for cross-linking peptidoglycan chains 

Also inactivate an inhibitor of an autolytic bacterial enzyme => lysis 

Narrow spectrum – penicillinase (= β-lactamase) sensitive 

• Benzylpenicillin 

– Naturally occuring 

– Poor oral availability (sensitive to stomach acid) 

=> given by injection 

– Active against gram-positive bacteria 

• Phenoxymethylpenicillin 

– Better oral availability (acid resistant)

BIMM118 


Narrow spectrum – penicillinase (= β-lactamase) resistant 

• Methicillin 

– Semisynthetic 

– Poor oral availability (only parenteral) 

– Active against gram-pos bacteria 

– Mostly used for Staphylococcus aureus 

• Oxacillin 

– Good oral availability 

• Cloxacillin 

• Dicloxacillin

BIMM118 


Broad spectrum – penicillinase (= β-lactamase) sensitive 

(= Aminopenicillins) 

• Ampicillin 


– Good oral availability 

– Active against gram-pos and gram-neg bacteria 

– Active against enterobacteria 

• Amoxicillin 

– Excellent oral availability

BIMM118 


Extended spectrum – penicillinase (= β-lactamase) sensitive 

(= Carboxypenicillins) 

• Carbenicillin 


– Poor oral availability 

– Active against gram-pos and gram-neg bacteria 

– Active against Pseudomonas aeruginosa, Klebsiella 

• Ticarcillin 

• Mezlocillin 

• Pipercillin

BIMM118 


Cephalosporines 

Derived from Cephalosporium sp. (same antibiotic mechanism as penicillins) 

Cross-allergies with penicillins are common 

Some CSs antagonize Vitamin K => bleeding 

Some CSs block alcohol oxidation => disulfiram effect 

Classified into generations: 

• 1-4 

• Increasing activity against gram-negative bacterial and anaerobes 

• Increasing resistance to destruction by beta-lactamases 

• Increasing ability to reach cerebrospinal fluid

BIMM118 


First generation – β-lactamase sensitive 

• Cefazolin 

– Naturally occuring 

– Active against gram-positive bacteria 

• Cephalexin 

Second generation – β-lactamase sensitive 

• Cefaclor 

– Some activity against gram-neg bacteria 

• Cefamandole 

• Cefoxitin

BIMM118 


Third generation – mostly β-lactamase resistant 

• Cefotaxime 

– Active against gram-negative bacteria 

– Active against Pseudomonas aeruginosa 

– Active against enterobacteria, gonococcus 

– Penetrates the CNS => used for meningitis 

• Ceftriaxone 

Fourth generation – mostly β-lactamase restistant 

• Cefepime 

– Broadest antimicrobial spectrum of any drug 

– Used for MDR bacteria and mixed 

infections 

• Cefpirome

BIMM118 


Beta-lactamase inhibitors 

• Clavulanic acid 

– Irreversible inhibitor of β-lactamase 

– Good oral absorption 

– Combined with amoxicillin or ticarcillin 

• Sulbactam

BIMM118 


Vancomycin 

• Only effective against gram-positive bacteria 

• Poor oral absorption => used for GI infections 

• Used to be the “Magic bullet” for methicillin-resistant 

staphylococci, but now staph are becoming V-resistant. 

• Dose-related ototoxocity: 

Tinnitus, high-tone deafness; can progress to total deafness 

Bacitracin 

• Mixture of polypeptides 

• Serious nephrotoxicity => only topical use

BIMM118 

Antibiotics - Protein synthesis inhibitors 

Protein synthesis inhibitors: 

Inhibit either the 30s or 50s ribosomal subunit 

(bacterial ribosomal subunits differ from 

mammalian ones => drugs are selective 

for bacterial protein synthesis) 

Class based on chemical structure 

of the compounds 

Drugs need to enter bacteria => 

entry inhibition is a point of drug resistance 

• Classification: 

– Aminoglycosides (bactericidal) 

– Tetracyclins 

– Macrolides 

– Chloramphenicol 

– Clindamycin

BIMM118 


Aminoglycosides 

– Broad spectrum antibiotics (bactericidal) 

– Penetration into cell requires an oxygen-dependent transport => anaerobes are 

resistant 

(Chloramphenicol blocks this transport => inhibits AG uptake into bacteria; 

Penicillins weaken the cell wall => promote AG uptake) 

– Poor oral absorption (very polar) => parenteral administration 

– Narrow therapeutic range - severe side effects: 

Ototoxicity: destruction of outer hair cells in organ of Corti 

Nephrotoxicity: killing of proximal tubular cells 

Neuromuscular toxicity: blockage of presynaptic ACh release => respiratory suppression 

– Elimination almost completely by glomerular filtration 

(impaired kidney function => concentration of AG increases => toxicity)

BIMM118 


Aminoglycosides 

• Gentamicin 

• Tobramycin 

• Streptomycin 

• Neomycin 

• Kanamycin 

• Amikacin

BIMM118 


Tetracyclines 

Penetration into cell requires an energy-dependent transport not present in mammals 

Oral absorption impaired by food (insoluble chelates with Ca, Mg => caution w/ antacids) 

Side effects: 

Incorporation into teeth and bone => staining of teeth; retardation of bone growth 

(not used in children and during pregnancy) 

Photosensitivity 

Broad spectrum antibiotics (bacteriostatic) 

Also useful for treating rickettsial diseases (Rocky mountain spotted fever), Spirochetes 

(Lyme disease), Mycoplasma (pneumonia)

BIMM118 


Tetracyclines 

• Tetracycline 

– From Streptomyces sp. 

• Oxytetracycline 

• Minocycline 

• Doxycycline 

– Used to treat rosacea and prevent rhinophyma 

– No food interaction

BIMM118 

Macrolides 


Narrow spectrum antibiotics similar to penicillin (bacteriostatic or bactericidal) 

=> good alternative for patients w/ penicillin allergy 

Few side effects (GI disturbances), similar food interaction as tetracyclines 

Also used for treating Mycoplasma (pneumonia) and Legionella (Legionnaire’s disease) 

• Erythromycin 

– From Streptomyces erythreus 

• Azithromycin 

– Very long half-life (>24 h) 

– Convient use (Z-Pak®, Zithromax®) - 6 pill regimen 

• Clarithromycin 

– Used for H. pylori infection

BIMM118 


Chloramphenicol 

Very broad spectrum (almost all bacteria except Pseudomonas aeruginosa) 

Very severe side effects 

– Bone marrow depression => fatal aplastic anemia 

Reserved for life-threatening, otherwise treatment-resistant infections 

Clindamycin 

Medium broad spectrum (gram-positive organisms, anaerobes) 

Used for treatment of penicillin-resistant cocci 

Side effects: Colitis (triggered by toxin from clindamycin-resistant Clostridium difficile => 

combined w/ vancomycin to kill C. difficile)

BIMM118 

Folate antagonists 

Antibiotics - Folate Antagonsits 

Bacteria can not absorb folic acid => synthesis from p-amino-benzoic acid (PABA) 

required (Folic acid is a vitamin for humans => synthesis pathway is restricted to 

bacteria => selective drug target) 

Folate antagonsists block folate synthesis => inhibition of nucleotide synthesis => 

bacteriostatic effect 

(pus provides alternative source for nucleotides => drugs are inactive in the presence 

of pus or necrotic tissue)

BIMM118 

Sulfonamides 

Antibiotics - Folate Antagonists 

Structural analogues of PABA => compete with PABA for Dihydropteroate-synthase 

Used for infected burns, STDs, toxoplasmosis… 

Note: 

Many local anesthetics are PABA-esters => they antagonize folate antagonists 

• Sulfadiazine 

• Sulfadimidine 

• Sulfamethoxazole

BIMM118 

Trimethoprim 

Antibiotics - Folate Antagonists 

Resembles pteridine moiety of folates => compete with folates for Dihydrofolatereductase 

Use similar to sulfonamides 

Combined with Sulfomethoxazole (synergistic effect) = Co-trimoxazole (Bactrim®) 

Used for urinary tract infections

BIMM118 

Quinolones 

Antibiotics - Quinolones 

Synthetic inhibitors of DNA-Gyrase (= Topoisomerase II), a bacterial enzyme that 

winds and unwinds DNA (required for supercoiling the bacterial genome) => 

inhibition of DNA synthesis and transcription 

Very broad spectrum, bactericidal - well tolerated 

Al and Mg interfer with absorption (antacids!) 

Mostly fluorinated = Fluoroquinolones (except nalidixic acid = first quinolone)

BIMM118 

Quinolones 

• Nalidixic acid 

– Oldest quinolone 

Antibiotics - Quinolones 

– Only used for urinary tract infections 

– Improvement through structure-activity relationship: 

• Ciprofloxacin 

• Adding fluorine at position 6 will significantly increase activity 

• Substitution of piperazinyl-ring at position-7 will give the drug antipseudomonal activity 

– Most commonly used quinolone (Cipro®) 

– Very broad spectrum => used for emergencies 

(B. anthracis attacks in 2001) 

• Levofloxacin 

• Ofloxacin 

• Norfloxacin 

• Travofloxacin …

BIMM118 

Antibiotics - Summary

BIMM118 

Chemotherapeutic Agents 


• Antifungals 

• Antivirals 

• Antihelmintics 

• Antiprotozoal 

• Anticancer drugs

BIMM118 

Fungal Growth Patterns 

• Yeasts 

– Unicellular fungi, reproduce by budding 

– Moist mucoid or waxy colonies that resemble bacteria 

• Molds (=Filamentous Fungi) 

– Multicellular filamentous, “fluffy” colonies consisting of branching tubular structures 

called hyphae 

– Collection of intertwined hyphae called mycelium 

– Vegetative hyphae act like roots, penetrating the supporting medium and absorbing 

nutrients 

– Aerial hyphae project above the surface of the mycelium and bear the reproductive 

structures of the mold (often spread through the air) 

Aspergillus 

Candida albicans

BIMM118 

Fungal Growth Patterns 

• Dimorphic Fungi 

– Grow as molds at ambient environmental 

temperatures (e.g. 25˚ C) where they form 

reproductive spore structures. 

– Spores are aerosolized and infectious 

– Inhaled spores grow as yeasts at body 

temperature (37˚ C) in the host 

Yeast form Mold form 

Coccidioides immitis

BIMM118 

Fungal Habitats 

• Most clinically relevant fungi reside in the soil, in bird feces, on 

vegetation, or on the skin and mucous membranes of mammals. 

• Some have distinctive ecologic and geographical niches.

BIMM118 

Mycosis 

• Fungal infections (= mycosis) 

– spread generally from the environment to people (or animals) with limited 

person-to-person spread. 

– Skin and lungs are prominent entry site for many fungi 

– Patients with impaired cell-mediated immunity (e.g. AIDS, organ transplant) 

at heightened risk for severe disease. 

• Types of fungal infections 

– Superficial: Outer skin layer - no immune response 

caused mostly by yeasts (Dandruff) 

– Cutenous: Epidermal layers - evoke immune response 

Tinea (Ringworm, Athlete’s foot, jock itch) 

caused by Dermatophytes: 

– Subcutenous: Chronic infection of subdermal tissues 

may require surgical intervention 

– Systemic: Mostly originating in the lung 

caused by virulent dimorphic fungi 

– Opportunistic: In immunocompromised conditions 

(AIDS; altered mucosal flora due to antibiotics): 

mostly Candidiasis and Aspergillosis (often cause of epidemic death in birds)

BIMM118 

Superficial Mycoses 

• Tinea versicolor (= Pityriasis versicolor) 

– Caused by a lipophilic yeast, Malassezia furfur 

– Normal flora of skin and scalp 

– Growth on media markedly enhanced by adding fat 

(Clinical mycology labs routinely stock olive oil!) 

• Dandruff (= Scurf = Pityriasis capitis) 

– Caused by a lipophilic yeast, Malassezia globosa 

– Accellerated shedding of skin cells

BIMM118 

Cutaneous Mycosis 

– Also known as “ringworm” and tinea (latin “worm”) because of round shape 

of lesions 

– Infections confined to skin,hair and nails 

– Caused by Dermatophyte molds (Trychophytum; Microsporum) 

Clinical classification based on location: 

• Tinea capitis 

– Ringworm of scalp and hair 

• Tinea barbae 

– Ringworm of beard region

BIMM118 

• Tinea corporis 


– Ringworm of the smooth skin of the body 

• Tinea cruris 

– Starts in groin area (“Jock itch”) 

– Causes by Trychophytum rubrum

BIMM118 

• Tinea pedis 

– Classically interdigital (”Athlete’s foot”) 


– key risk factor for invasive bacterial 

infections in diabetics through disruption 

of normal skin barriers 

• Tinea unguium 

– Infection of finger and toe nails 

– Often associated with T. pedis

BIMM118 

• Sporotrichosis 

Subcutaneous Mycoses 

– Sporothrix schenckii - Dimorphic fungus 

– Found on vegetation, especially rose bushes 

– Introduced into skin by trauma (gardening!) 

– Initial ulcer develops into granulomatous nodule

BIMM118 

Systemic Mycosis 

– Infections are rare (high natural immunity) 

– Usually requires large inoculum 

– Often endemic to specific aereas 

Mostly associated with four fungi: 

• Coccidioides immitis -> Coccidioidomycosis 

– Soil fungus (dry, dusty soil => inhalation of spores) 

– SW USA (Arizona and Central Valley of CA) and Mexico 

(“Valley fever”) 

– Epidemic after (Northridge) earthquake or sandstorms 

– Considered most virulent fungus 

(select agent: BSL-3) 

– Starts with flu-like symptoms, meningitis 

– Striking racial/ethnic differences in rate of dissemination: 

Filipinos>African Americans>Hispanics>Asians>Caucasians 

(Kern County, Filipinos 0.23% of population but 22% of cases) 

Likely due to genetic differences in blood group/ HLA

BIMM118 


• Histoplasma capsulatum -> Histoplasmosis (“Cave disease”) 

– Soil fungus (soil containing guano (bird, bat droppings)! => spores inhaled) 

(In 1890 European starlings were introduced into Central Park, NYC in an effort to bring all of 

the birds mentioned by Shakespeare to the US => Now there are 200M-1B starlings in N. 

America, whose droppings are a major route of transmission for histoplasma) 

– S-SE USA (Ohio and Mississippi Valley) 

– Starts with flu-like symptoms, meningitis 

– Fungus lives intracellular in macrophages => 

immune-evasion 

– 95% of infected individuals asymptomatic 

(chronic infection can lead to lung fibrosis) 

– In immunecompromised patients systemic infection develops => 

multiorgan failure, sepsis

BIMM118 


• Blastomyces dermatitides -> Blastomycosis 

– Soil fungus (=> spores inhaled) 

– S-SE USA 

– Predominantly in lung and skin 

• Paracoccidioides brasiliensis 

– Soil fungus (=> spores inhaled) 

– Central and South America (Brazil—death rate up to 1.5/1000)

BIMM118 

Opportunistic Mycosis 

– Some fungi are commensal (mucosal flora of mouth, gut, vagina etc.) 

– Usually growth balanced by microorganisms (lactobacilli) 

– Only a problem in situations of compromised immune responses 

(AIDS, antibiotics, chemotherapy, radiation, alcoholism, etc.) 

• Candida albicans -> Candidiasis 

– Dimorphic fungus BUT also mold at 37˚ C 

– Also other Candida species 

– Cutanous candidiasis: mostly in moist skin folds (obese patients):

BIMM118 


• Candida albicans -> Candidiasis (cont.) 

– Oral candidiasis (“Thrush”) 

• Babies; denture users 

• Can progress into 

Candida esophagitis 

– Vaginal candidiasis (“Yeast infection”) 

• Does NOT require immune dysfunction 

• Severe itching/burning 

• Commonly associated with antibiotica use 

• Bacterial infection often falsly self-diagnosed as candidiasis 

(2/3 of self-diagnosed “yeast infections” actually bacterial!)

BIMM118 


• Candida albicans -> Candidiasis (cont.) 

– Systemic candidiasis 

• Mucocutaneous barriers breached in patients after surgery, burns 

• Dissemination to kidneys, skin, eye, heart, bone, liver, etc. 

• Often fatal !

BIMM118 


• Cryptococcus neoformans -> Cryptococcosis 

– Ubiquitous, but especially abundant in pigeon droppings 

– Cryptococcal meningitis most common manifestation 

– Complication in AIDS patients 

• Aspergillus sp. -> Aspergillosis 

– Mostly pulmonary infections 

– Allergenic 

(Allergic sinusitis and allergic bronchopulmonary aspergillosis) 

– Infections common in birds

BIMM118 

Differences between fungi and mammalian cells 

ANIMALS FUNGI 

Cell structure Eukaryotic Eukaryotic 

DNA Diploid Haploid 

Ribosomes 80S 80S 

Cell wall No chitin, mannans, glucans 

Cell membrane Predominantly cholesterol Predominantly ergosterol 

Microtubule affinity for griseofulvin No Yes 

Cytosine deaminase No Yes 

Squalene epoxidase No Yes

BIMM118 

Polyenes (Amphotericin, Nystatin) 

Azoles (Ketoconazole, Miconazole, 

Fluconazole, Itraconazole, 

Voriconazole, Posaconazole) 

5-Flucytosine 

Griseofulvin 

Echinocandins (Caspofungin, 

Micafungin, Anidulofungin) 

Allylamines (Terbinafine) 

Overview of Antifungal Drugs 

MECHANISM OF ACTION 

Selectively bind to ergosterol in fungal cell membrane, 

altering membrane fluidity and producing pores and 

osmotic cell death. Much less binding to cholesterol. 

Selectively block ergosterol synthesis by inhibiting 

demethylation of lanosterol. Fungal P450 enzyme much 

more sensitive than mammalian counterpart. 

Converted by fungal cytosine deaminase into 5-fluorouracil; 

inhibits DNA synthesis. Mammalian cells lack cytosine 

deaminase. 

Inhibit fungal growth by binding to microtubules, disrupting 

mitotic spindles. Mammalian microtubules less sensitive. 

Inhibit fungal Beta glucan synthesis, disrupting cell wall 

integrity. Mammalian cells have no cell walls. 

Selectively blocks ergosterol synthesis by inhibiting 

squalene epoxidase (not found in animals)

BIMM118 

Antifungal Drugs - Polyenes 

Polyenes 

– bind to fungal membrane sterols (ergosterol) 

– alter selectively permeability to K + (and Mg 2+ ) => Fungicidal 

– Resistance due to altered sterols 

• Amphotericin B 

– Isolated from Streptomyces nodosus 

– Given iv, it (poor oral absorption) and topical 

– Active against most systemic fungi 

– iv not well tolerated (chills, headaches, nausea) 

– Pronounced renal toxicity => 

Encapsulated into liposomes 

(less drug reaches the kidneys?) 

• Nystatin 

– Only for topical application 

(Canidida, dermatophytes)

BIMM118 

Antifungal Drugs - Azoles 

Azoles 

– inhibit the synthesis of ergosterol 

(block demethylation of lanosterol by inhibiting fungal CYP3A 

= 14-demethylase) 

– Fungistatic 

– Active against systemic fungi and dermatophytes 

– Resistance due to altered 14-demethylase 

• Two groups 

– Imidazoles 

– Triazoles

BIMM118 

Imidazoles 

• Clotrimazole 

– Only used topical 

– Candidiasis, tinea 


• Ketoconazole 

– Tinea, candidiasis, blastomycosis, coccidioidomycosis 

– Also for dandruff (Nizoral®) 

– First oral -azole (mostly replaced by fluconazole and itraconazole) 

– Absorption best at low pH (antacids interfer !) 

– Does not enter CNS well

BIMM118 

Imidazoles 

• Miconazole 

– Used topical and p.o. 

(intestinal fungal infections) 

– Also used in E6 slide film processing 

• Tioconazole 

Antifungal Drugs - Azoles

BIMM118 


Triazoles 

Newer, less toxic, more effective! 

• Fluconazole (Diflucan®) 

– Used i.v. and p.o. 

– Reaches high CSF concentrations 

– 90% excreted unchanged 

– t1/2 = 25 hrs 

– Used against Candidiasis, Coccoidosis (meningitis) 

– Well tolerated 

• Itraconazole (Sporanox ®) 

– Used i.v. and p.o.(p.o. poor absorption) 

– Absorption increased by acids (Orange juice, Coke!) 

– Absorption decreased by antacids 

– Does not reach CSF 

– Highly lipophilic => fatty tissue accumulation 

– Very broad spectrum 

• Voriconazole (Vfend ®) 

– Used for severe systemic infections and emerging fungi (very broad spectrum) 

• Posaconazole (Noxafil ®) 

– Very broad spectrum (tested against >18,000 fungi!)

BIMM118 

Antifungal Drugs - Antimetabolites 

5’-Flucytosine (Ancobon ®) 

– Only available antimetabolite drug 

– Activated by deamination within the fungal cells to 5-fluorouracil 

– 5-fluorouracil inhibits thymidylate synthetase 

– Also inhibits fungal protein synthesis by replacing uracil with 

5-flurouracil in fungal RNA 

– Resistance common (=> used in combination with other 

antifungals) 

– Broad range (only in the treatment of serious infections caused by 

susceptible strains of Candida and/or Cryptococcus) 

– Well orally absorbed

BIMM118 

Antifungal Drugs - Antimetabolites 

Griseofulvin (Grisactin®, Fulvicin®) 

– Inhibit fungal growth by binding to microtubules => 

disruption of mitotic spindles => fungistatic 

(mammalian microtubules less sensitive) 

– Mainly effective against dermatophytes (tinea) 

(incorporates into keratin => requires several weeks of therapy) 

– Oral administration (use declining due to better drugs - e.g. Triazoles) 

– Side effects: Nausea, hepato- and renal toxicity, photosensitivity,… 

– Veterinary use common

BIMM118 

Antifungal Drugs - Echinocandins 

– Inhibit synthesis of glucan in the fungal cell wall 

(likely block 1,3-beta glucan synthase) 

– Newest antifungals 

– Well tolerated 

• Caspofungin 

– Used i.v. 

– Active against Candida and Aspergillus 

– Approved 2001 

– Approved 2005 for invasive Aspergillosis 

• Anidulafungin 

– Used i.v. 

– Active against Candida and Aspergillus 

– Approved 2006 for invasive Aspergillosis 

• Micafungin

BIMM118 

Antifungal Drugs - Allylamines 

Allylamines 

– inhibit fungal sterol synthesis (ergosterol) by 

inhibiting squalene epoxidase 

• Terbinafine (Lamasil®) 

– Synthetic antifungal 

(mostly topical; p.o. for tinea unguium) 

– Lipophilic: accumulates in fat, skin and nails 

– Active against most dermatophytes (tinea, ringworm) 

• Butenafine (Lotrimin® Ultra) 

– Also anti-inflammatory activity 

– Superior antifungal activity over Terbinafine 

• Naftifine (Naftin®) 

• Amorolfine (Loceryl®)

BIMM118 

Antifungals - Summary

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