BIMM118“One of the features which is thought todistinguish man from other animals is hisdesire to take medicines”(Sir William Osler, 1849-1919)BIMM118Definitions• Pharmacology is the science of the interaction of chemicals with livingsystems 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 aphysiological, biochemical or molecular level• Pharmacogenetics examines the effects of genetic factors to variations in thedrug response (“Asian Flush”, Codeine “resistance”)• 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 formedicinal useBIMM118Definitions• 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 establisheddose 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 effecte.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.BIMM118History of Pharmacology• Initially most medicines were ofbotanical or zoological origin• Since 1950’s, large increase insynthetic organic chemicals• Recent introduction of recombinantDNA technology has extendedsynthesis to molecules of human originBIMM118History of Pharmacology• Early agents were naturally occurring inorganic salts and plantalkaloids– Opium– Foxglove– Mercury, arsenic or lead compounds• Most ineffective or actually dangerous• Standardization of dose very difficult– Narrow therapeutic index with foxgloveBIMM118Homeopathy• 1790-96: Dr. Samuel Hahnemann:To discover the true mode of action by which cinchona bark curedmalaria, he ingested cinchona juice twice daily for a few days. To hisgreat astonishment, he very soon developed symptoms very similarto malarial fever.– Postulated a new principle of treatment: “Likes cure likes”– Drug is called the remedy, obtained through serial dilutions of thechemicalThe remedy is mainly extracted from the plants, animals and minerals. The medicinal extract is diluted andpotentiated to such an extent that not even an atom of the mother material can be detected in the remedy by thetime it reaches the 12th potency. Dilutions are done in steps. For example: In the centi scale, one drop of mothertincture is mixed with 99 drops of alcohol and shaken rigorously using pre-determined strokes. This is termed as1c. 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 withpotency (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 along standing side effect.BIMM118History of Pharmacology• Major advance in safe use of naturally derived agentswas the isolation, purification and chemicalcharacterization of the active compound:– Allowed administration of a controlled dose– Allowed administration of the active component of herbalmixtures to be given alone– Identification and characterization of active componentallowed definition of mechanism of action, leading tosynthesis of improved agents with greater selectivity,potency, altered duration of action, etc.BIMM118History of Pharmacology• Aspirin® - first synthetic drug– Hippocrates: pain relief treatments with powder made from the bark and leaves ofthe willow tree (Salix sp.)– Johann Buchner (1829): isolated Salicin as theactive 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 Bayersynthezised 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 yearBIMM118History of Pharmacology• 20th Century: Dramatic change in antimicrobial therapy– Survival of patients with severe infections with historically highmortality– Introduction of sulfonamides (Gelmo 1908: Sulfanilamide) andarsenic compounds (Ehrlich 1908/10: arsephenamine= Salvarsan)and subsequently penicillins (Fleming 1928/29)BIMM118New 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 becomeevident when the compounds are tested in humans• Sulfanilamide --> thiazide diuretics• Sulfanilamide --> sulfonylurea hypoglycemics• Aspirin® --> Anti-aggregatory --> CardioprotectiveBIMM118New Drug Discovery• Synthesis and screening of new chemical entities• Subject new chemicals to a battery of tests designed to detecta particular type of biological activity (“Drug screening”)• Chemicals produced by direct synthesis, or isolation frombiological sources (or combination of both: semi-synthetic)• Apparently not an efficient method since huge numbers ofchemicals may need to be screened, however, new roboticinstruments are now screening millions of compounds againstdefined receptors or enzymesBIMM118New Drug Discovery• 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 developinteracting compounds• Examples:– STI571 (Glevec®): Bcr-Abl specific inhibitor, but high pK, also resistance =>2nd generation Bcr-Abl inhibitors are being designed based on the structure of the Bcr-Abl/STI571 complex– Cloning of
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