History of Pharmacology 3 Foundation reputation of pharmacology. Funda- vity relationship, drug receptor, an elective toxicity emerged from the work of, respectively, T. Frazer(1841 Ehrlich (1854-1915) in Germany. Alexander Clark(1885-1941)in England first for- 1920s by applying the Law of Mass Ac gether with the internist, bernhar founded the first journal of pharmacol d the first institute of pharm. (1857-1938)wa he University of Dorpat(Tartu, mericans to train in Schmiedeber adependent scientific discipline. In ad- nal of Pharmacology and experimental dition to a description of effects. he Therapeutics(published from 1909 until strove to explain the chemical proper- ties of drugs "The science of medicines is a theoretical Status Quo with knowledge by which our judgement about the utility of medicines can be vali. After 1920, pharmacological laborato- dated at the bedside” ries sprang up in the pl onsolidation-General Recognition clinical pharmacology were se甲 Oswald Schmiedeberg(1838-1921). together with his many disciples (12 of whom were appointed to chairs of phar- macology ) helped to establish the high LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
History of Pharmacology 3 Foundation Rudolf Buchheim (1820–1879) founded the first institute of pharmacology at the University of Dorpat (Tartu, Estonia) in 1847, ushering in pharmacology as an independent scientific discipline. In addition to a description of effects, he strove to explain the chemical properties of drugs. “The science of medicines is a theoretical, i.e., explanatory, one. It is to provide us with knowledge by which our judgement about the utility of medicines can be validated at the bedside.” Consolidation – General Recognition Oswald Schmiedeberg (1838–1921), together with his many disciples (12 of whom were appointed to chairs of pharmacology), helped to establish the high reputation of pharmacology. Fundamental concepts such as structure-activity relationship, drug receptor, and selective toxicity emerged from the work of, respectively, T. Frazer (1841– 1921) in Scotland, J. Langley (1852– 1925) in England, and P. Ehrlich (1854–1915) in Germany. Alexander J. Clark (1885–1941) in England first formalized receptor theory in the early 1920s by applying the Law of Mass Action to drug-receptor interactions. Together with the internist, Bernhard Naunyn (1839–1925), Schmiedeberg founded the first journal of pharmacology, which has since been published without interruption. The “Father of American Pharmacology”, John J. Abel (1857–1938) was among the first Americans to train in Schmiedeberg‘s laboratory and was founder of the Journal of Pharmacology and Experimental Therapeutics (published from 1909 until the present). Status Quo After 1920, pharmacological laboratories sprang up in the pharmaceutical industry, outside established university institutes. After 1960, departments of clinical pharmacology were set up at many universities and in industry. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
Drug Sources Drug and Active Principle upon the product's geographical origin Until the end of the 19th century, medi- cines were natural organic or inorganic tions and length of storage. For the sam oducts, mostly dried, but also asons, the relative proportion of indi- plants or plant parts. These might con- vidual constituents may vary consider ( therapeutic) properties or substances morphine from opium in 1804 by F w urner(1783-1841). the active prin oles of many other natural products cally useful products not merely at the were subsequently isolated in chemi- time of harvest but year-round, plants cally pure form by pharmaceutical la were preserved by drying or soaking oratories ve drogue"-dried herb). Colloquially. this 1. Identification of the active ingredi term nowadays often refers to chemical ent(s). substances with high potential for phys- 2. Analysis of the biological effects ical dependence and abuse. Used sci (pharmacodynamics)of individual in- tifically, this term implies nothing about gredients and of their fate in the body ng nal, wider sense, drug could refer equal- 3. Ensuring a precise and constant dos- ly well to the dried leaves of pepper- age in the therapeutic mint, dried lime blossoms, dried flowe (hashish, marijuana), or the dried milky which would afford independen exudate obtained by slashing the unripe limited natural supplies and create con- seed capsules of Papaver somniferum ditions for the analysis of structure-ac- (raw opium). Nowadays, the term is ap- plied quite generally to a chemical sub- Finally, derivatives of the original con stance that is used for pharmacothera- to optimize pharmacological Soaking plants parts in alcohol Thus, ives of the original dEities. (ethanol)creates a tincture. In this pro- uent with improved therapeutic useful- ness may nts of the plant are extracted by the hol Tinctures do not contain the com- plete spectrum of substances that exis that an plant or crude drug, only those soluble in alcohol. In the case of alkaloids(ie, basic substances of plant origin) including: morphine, codeine, arcotine noscapine, papaverine, na Using a natural product or extract administration of a number of substanc. possibly possessing very different vidual constituent contained within a given amount of the natural product is bject to large variations, depending LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Drug and Active Principle Until the end of the 19th century, medicines were natural organic or inorganic products, mostly dried, but also fresh, plants or plant parts. These might contain substances possessing healing (therapeutic) properties or substances exerting a toxic effect. In order to secure a supply of medically useful products not merely at the time of harvest but year-round, plants were preserved by drying or soaking them in vegetable oils or alcohol. Drying the plant or a vegetable or animal product yielded a drug (from French “drogue” – dried herb). Colloquially, this term nowadays often refers to chemical substances with high potential for physical dependence and abuse. Used scientifically, this term implies nothing about the quality of action, if any. In its original, wider sense, drug could refer equally well to the dried leaves of peppermint, dried lime blossoms, dried flowers and leaves of the female cannabis plant (hashish, marijuana), or the dried milky exudate obtained by slashing the unripe seed capsules of Papaver somniferum (raw opium). Nowadays, the term is applied quite generally to a chemical substance that is used for pharmacotherapy. Soaking plants parts in alcohol (ethanol) creates a tincture. In this process, pharmacologically active constituents of the plant are extracted by the alcohol. Tinctures do not contain the complete spectrum of substances that exist in the plant or crude drug, only those that are soluble in alcohol. In the case of opium tincture, these ingredients are alkaloids (i.e., basic substances of plant origin) including: morphine, codeine, narcotine = noscapine, papaverine, narceine, and others. Using a natural product or extract to treat a disease thus usually entails the administration of a number of substances possibly possessing very different activities. Moreover, the dose of an individual constituent contained within a given amount of the natural product is subject to large variations, depending upon the product‘s geographical origin (biotope), time of harvesting, or conditions and length of storage. For the same reasons, the relative proportion of individual constituents may vary considerably. Starting with the extraction of morphine from opium in 1804 by F. W. Sertürner (1783–1841), the active principles of many other natural products were subsequently isolated in chemically pure form by pharmaceutical laboratories. The aims of isolating active principles are: 1. Identification of the active ingredient(s). 2. Analysis of the biological effects (pharmacodynamics) of individual ingredients and of their fate in the body (pharmacokinetics). 3. Ensuring a precise and constant dosage in the therapeutic use of chemically pure constituents. 4. The possibility of chemical synthesis, which would afford independence from limited natural supplies and create conditions for the analysis of structure-activity relationships. Finally, derivatives of the original constituent may be synthesized in an effort to optimize pharmacological properties. Thus, derivatives of the original constituent with improved therapeutic usefulness may be developed. 4 Drug Sources Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
Drug Sources 5 Raw opium pium tincture Morphine Narcotine Opium tincture(laudanum) A From poppy to morphine LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Drug Sources 5 A. From poppy to morphine Raw opium Preparation of opium tincture Morphine Codeine Narcotine Papaverine etc. Opium tincture (laudanum) Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
6 Drug Development evelopment herapeutic efficacy in those diseas This process starts with the synthesis of Should a beneficial action be evident novel chemical compounds. Substances and the incidence of adverse effects be with complex structures may be ob- acceptably small, Phase Ill is entered, ined from various sources, e. g. plan (cardiac glycosides), animal tissues whom the new drug will be heparin. microbial cultures(penicillin with standard treatments in or human cells(urokinase), or by therapeutic outcome. As a form of hu of lin). As more insight is gained into struc- trials are subject to review and approval re-activity relationships, the search by institutional ethics committees ac- or new agents becomes more clearly cording to international codes of cor duct( Declarations of Helsinki, Tokyo, Preclinical testing yields informa- and Venice). During clinical testing tion on the biological effects of new sub- many drugs are revealed to be unusabl stances. Initial screening may employ Ultimately, only one new drug remains iochemical-pharmacological investiga- from approximately 10,000 newly syn- tions (e.g. receptor-binding p. 56) or experiments on cell culture The decision to approve a new olated cells, and isolated organs. Since drug is made by a national regulatory these models invariably fall short of od Drug Adm replicating complex biological process he U.S.A, the Health Protection Branch organism, any rugs Directorate in Canada, UK, Euro- ug must be te mal Only animal experiments can re required to submit their applica real whether the desired effects will ac- tions. Applicants must document by tually occur at dosages that produce lit- means of appropriate test data(from or no toxicity. Toxicological investiga- preclinical and clinical trials) that the tions serve to evaluate the potential for: criteria of efficacy and safety have been (1) toxicity associated with acute met and that product forms(tablet, cap- hronic administration; (2) genetic sule, etc. )satisfy general standards of amage (genotoxicity, mutagenicity ) quality control. ()production of tumors(onco-or car- oval, cinogenicity): and(4)causation of bi defects (teratogenicity ). In animals, (p. 333)and thus become available for mpounds under investigation also prescription by ph have to be studied with respect to their ing by pharmacists. As the drug gains absorption, distribution, metabolism, more widespread use, regulator netics). veillance continues in the form of post. Even at the level of preclinical testing. only a very small fraction of new com- < perience will the risk: benefit ratio be properly assessed and, thus, the thera- Pharmaceutical technology pro- peutic value of the new drug be deter linical testing starts with Phase studies on healthy subjects and seeks to determine whether effects observed in so occur in hu. determined In Phase Il, potential drugs are first tested on selected patients for LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Drug Development This process starts with the synthesis of novel chemical compounds. Substances with complex structures may be obtained from various sources, e.g., plants (cardiac glycosides), animal tissues (heparin), microbial cultures (penicillin G), or human cells (urokinase), or by means of gene technology (human insulin). As more insight is gained into structure-activity relationships, the search for new agents becomes more clearly focused. Preclinical testing yields information on the biological effects of new substances. Initial screening may employ biochemical-pharmacological investigations (e.g., receptor-binding assays p. 56) or experiments on cell cultures, isolated cells, and isolated organs. Since these models invariably fall short of replicating complex biological processes in the intact organism, any potential drug must be tested in the whole animal. Only animal experiments can reveal whether the desired effects will actually occur at dosages that produce little or no toxicity. Toxicological investigations serve to evaluate the potential for: (1) toxicity associated with acute or chronic administration; (2) genetic damage (genotoxicity, mutagenicity); (3) production of tumors (onco- or carcinogenicity); and (4) causation of birth defects (teratogenicity). In animals, compounds under investigation also have to be studied with respect to their absorption, distribution, metabolism, and elimination (pharmacokinetics). Even at the level of preclinical testing, only a very small fraction of new compounds will prove potentially fit for use in humans. Pharmaceutical technology provides the methods for drug formulation. Clinical testing starts with Phase I studies on healthy subjects and seeks to determine whether effects observed in animal experiments also occur in humans. Dose-response relationships are determined. In Phase II, potential drugs are first tested on selected patients for therapeutic efficacy in those disease states for which they are intended. Should a beneficial action be evident and the incidence of adverse effects be acceptably small, Phase III is entered, involving a larger group of patients in whom the new drug will be compared with standard treatments in terms of therapeutic outcome. As a form of human experimentation, these clinical trials are subject to review and approval by institutional ethics committees according to international codes of conduct (Declarations of Helsinki, Tokyo, and Venice). During clinical testing, many drugs are revealed to be unusable. Ultimately, only one new drug remains from approximately 10,000 newly synthesized substances. The decision to approve a new drug is made by a national regulatory body (Food & Drug Administration in the U.S.A., the Health Protection Branch Drugs Directorate in Canada, UK, Europe, Australia) to which manufacturers are required to submit their applications. Applicants must document by means of appropriate test data (from preclinical and clinical trials) that the criteria of efficacy and safety have been met and that product forms (tablet, capsule, etc.) satisfy general standards of quality control. Following approval, the new drug may be marketed under a trade name (p. 333) and thus become available for prescription by physicians and dispensing by pharmacists. As the drug gains more widespread use, regulatory surveillance continues in the form of postlicensing studies (Phase IV of clinical trials). Only on the basis of long-term experience will the risk: benefit ratio be properly assessed and, thus, the therapeutic value of the new drug be determined. 6 Drug Development Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license
Drug Development 7 Clinical sa sn § Long-term benefit-risk evaluation Phase 1 Phase 2 Phase 3 atient groups. dose definition, pharmacokinetics safety, efficacy, dose, dard therapy ECG Substances 鹅 Cells Animals solated organs homogenate A From drug synthesis to approval LOllmann, Color Atlas of Pharmacology e 2000 Thieme All rights reserved Usage subject to terms and conditions of license
Drug Development 7 Clinical trial Phase 4 Approval § General use Long-term benefit-risk evaluation Healthy subjects: effects on body functions, dose definition, pharmacokinetics Selected patients: effects on disease; safety, efficacy, dose, pharmacokinetics Patient groups: Comparison with standard therapy Substances Cells Animals Isolated organs (bio)chemical synthesis Tissue homogenate A. From drug synthesis to approval § § § 10 10,000 Substances Preclinical testing: Effects on body functions, mechanism of action, toxicity ECG EEG Blood sample Blood pressure Substance 1 Phase 1 Phase 2 Phase 3 Clinical trial § Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license