G R V d e t i n U vip.persianss.ir G R V RdANG AND DALE’S Pharmacology e t i n U vip.persianss.ir G R V d e t i n U Content Strategist: Meghan Ziegler Content Development Specialist: Alexandra Mortimer Content Coordinator: Sam Crowe, Trinity Hutton Project Manager: Joanna Souch Design: Christian Bilbow Illustration Manager: Brett MacNaughton Illustrator: Peter Lamb, Antbits, Jason McAlexander Marketing Manager: Melissa Darling vip.persianss.ir RANG AND DALE’S Pharmacology EIGHTH EDITION G H P Rang MB BS MA DPhil Hon FBPharmacolS FMedSci FRS R Emeritus Professor of Pharmacology, University College London, London, UK V J M Ritter DPhil FRCP FBPharmacolS FMedSci d Emeritus Professor of Clinical Pharmacology, King’s College London, and Medicael Research Director, Quintiles, London, UK t R J Flower i PhD DSc FBPharmacolS FMedSci FRS n Professor, Biochemical Pharmacology, The William Harvey ResU earch Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK G Henderson BSc PhD FBPharmacolS FSB Professor of Pharmacology, University of Bristol, Bristol, UK For additional online content visit studentconsult Student CONSULT vip.persianss.ir an imprint of Elsevier Limited © 2016, Elsevier Ltd. All rights reserved. First edition 1987 Second edition 1991 Third edition 1995 Fourth edition 1999 Fifth edition 2003 Sixth edition 2007 Seventh edition 2012 The right of H P Rang, J M Ritter, R J Flower and G Henderson to be identified as authors of this work has been asserted by them in accordance with the Copyright, Designs and Patents Act 1988. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements G with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright bRy the Publisher (other than as may be noted herein). Notices V Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experiendce and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety e of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each t product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the reisponsibility of practitioners, relying on their own experience and knowledge of their patients, to mnake diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/Uor damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN: Main edition ISBN-13 978-0-7020-5362-7 International edition ISBN-13 978-0-7020-5363-4 Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1 vip.persianss.ir Rang and Dale’s Pharmacology Eighth Edition Preface In this edition, as in its predecessors, we set out not just therapeutic effects; (3) the action of drugs on specific to describe what drugs do but also to emphasise the mech- organ systems; (4) the action of drugs on the nervous anisms by which they act. This entails analysis not only system; (5) the action of drugs used to treat infectious at the cellular and molecular level, where knowledge and diseases and cancer; (6) a range of special topics such as techniques are advancing rapidly, but also at the level of adverse effects, non-medical uses of drugs, etc. This physiological mechanisms and pathological disturbances. organisation reflects our belief that drug action needs to Pharmacology has its roots in therapeutics, where the aim be understood, not as a mere description of the effects of is to ameliorate the effects of disease, so we have attempted individual drugs and their uses, but as a chemical inter- to make the link between effects at the molecular and cel- vention that perturbs the network of chemical and cellular lular level and the range of beneficial and adverse effects signalling that underlies the function of any living organ- that humans experience when drugs are used for thera- ism. In addition to updating all of the chapters, we have peutic or other reasons. Therapeutic agents have a high covered the receptor-related topics of biased agonism, rate of obsolescence, and more than 100 new ones have allosteric modulation and desensitisation in more detail G been approved since the last edition of this book. An in Chapters 2 and 3, as well as revamping the section on appreciation of the mechanisms of action of the class of nuclear receptors. A new Chapter 27 on the pharmacology drugs to which a new agent belongs provides a good start- of the skin has been added, and Chapters 17 and 18 ing point for understanding and using a new compound on local hormonesR have been revised. Additional material intelligently. on cognition-enhancing drugs has been included in Pharmacology is a lively scientific discipline in its own Chapter 48. right, with an importance beyond that of providing a basis Despite the fact that pharmacology, like other branches V for the use of drugs in therapy, and we aim to provide a of biomedical science, advances steadily, with the acquisi- good background, not only for future doctors but also for tion of new information, the development of new con- scientists in other disciplines who need to understand cepts and the introduction of new drugs for clinical use, how drugs act. We have, therefore, where appropriate, wde have avoided making the 8th edition any longer than described how drugs are used as probes for elucidating its predecessor by cutting out-dated and obsolete mate- cellular and physiological functions, even when the com- rial, and have made extensive use of small print text to e pounds have no clinical use. cover more specialised and speculative information that Names of drugs and related chemicals are established is not essential to understanding the key message, but through usage and sometimes there is more thtan one will, we hope, be helpful to students seeking to go into name in common use. For prescribing purposes, it is greater depth. In selecting new material for inclusion, we i important to use standard names, and we follow, as far as have taken into account not only new agents but also n possible, the World Health Organization’s list of recom- recent extensions of basic knowledge that presage further mended international non-proprietary names (rINN). drug development. And where possible, we have given a Sometimes these conflict with the familiar names of drugs brief outline of new treatments in the pipeline. Reference U (e.g. amphetamine becomes amfetamine in the rINN list), lists are largely restricted to guidance on further reading, and the endogenous mediator prostaglandin I – the together with review articles that list key original papers. 2 standard name in the scientific literature – becomes ‘epo- prostenol’ – a name unfamiliar to most scientists – in the rINN list. In general, we use rINN names as far as possible in the context of therapeutic use, but often use the common name in describing mediators and familiar drugs. Sometimes English and American usage varies (as with adrenaline/epinephrine and noradrenaline/ norepinephrine). Adrenaline and noradrenaline are the official names in EU member states and relate clearly to terms such as ‘noradrenergic’, ‘adrenoceptor’ and ‘adrenal gland’ and we prefer them for these reasons. Drug action can be understood only in the context of what else is happening in the body. So at the beginning of most chapters, we briefly discuss the physiological and biochemical processes relevant to the action of the drugs described in that chapter. We have included the chemical structures of drugs only where this information helps in understanding their pharmacological and pharmacoki- netic characteristics, secure in the knowledge that chemi- cal structures are readily available online. The overall organisation of the book has been retained, with sections covering: (1) the general principles of drug action; (2) the chemical mediators and cellular mecha- nisms with which drugs interact in producing their xv vip.persianss.ir G R V d e t i n U ACKNOWLEDGEMENTS We would like to thank the following for their help and advice in the preparation of this edition: Dr Alistair Corbett, Dr Hannah Gill, Professor Eamonn Kelly, Professor Alastair Poole, Dr Emma Robinson, Dr Maria Usowicz and Professor Federica Marelli-Berg. We would like to put on record our appreciation of the team at Elsevier who worked on this edition: Meghan Ziegler (commissioning editor), Alexandra Mortimer (develop- ment editor), Joanna Souch (project manager), Brett MacNaughton (illustration manager), Peter Lamb, Antbits and Jason McAlexander (freelance illustrators), Elaine Leek (freelance copyeditor), Marcela Holmes (freelance proofreader) and Innodata Inc. (freelance indexing services). London 2014 H. P. Rang J. M. Ritter R. J. Flower G. Henderson vip.persianss.ir GENERAL PRINCIPLES    SECTION 1 1 What is pharmacology? pharmacopoeias were written, and the apothecaries’ trade  OVERVIEW flourished. However, nothing resembling scientific prin- ciples was applied to therapeutics, which was known at  In this introductory chapter we explain how phar- that time as materia medica.2 Even Robert Boyle, who laid  macology came into being and evolved as a scien- the scientific foundations of chemistry in the middle of the  tific discipline, and describe the present day structure 17th century, was content, when dealing with therapeu- of the subject and its links to other biomedical tics (A Collection of Choice Remedies, 1692), to recommend  sciences. The structure that has emerged forms the concoctions of worms, dung, urine and the moss from a  basis of the organisation of the rest of the book. dead man’s skull. The impetus for pharmacology came  Readers in a hurry to get to the here-and-now of G pharmacology can safely skip this chapter. from the need to improve the outcome of therapeutic  intervention by doctors, who were at that time skilled at  clinical observation and diagnosis but broadly ineffectual  WHAT IS A DRUG? when it came to treatment.3 Until the late 19th century,  R knowledge of the normal and abnormal functioning of the  For the purposes of this book, a drug can be defined as a body was too rudimentary to provide even a rough basis  chemical substance of known structure, other than a nutrient for understanding drug effects; at the same time, disease  or an essential dietary ingredient,1 which, when administered and deathV were regarded as semisacred subjects, appro- to a living organism, produces a biological effect. priately dealt with by authoritarian, rather than scientific,  A few points are worth noting. Drugs may be synthetic  doctrines. Clinical practice often displayed an obedience  chemicals, chemicals obtained from plants or animals, or  tod authority and ignored what appear to be easily ascer- products of genetic engineering. A medicine is a chemical  tainable facts. For example, cinchona bark was recognised  preparation, which usually, but not necessarily, contains  as a specific and effective treatment for malaria, and a  one or more drugs, administered with the intention oef  sound protocol for its use was laid down by Lind in 1765.  producing a therapeutic effect. Medicines usually contain  In 1804, however, Johnson declared it to be unsafe until  other  substances  (excipients,  stabilisers,  solvents,  etc.)  the fever had subsided, and he recommended instead the  besides the active drug, to make them more convetnient to  use of large doses of calomel (mercurous chloride) in   use. To count as a drug, the substance must bie adminis- the early stages – a murderous piece of advice that was  tered as such, rather than released by physionlogical mech- slavishly followed for the next 40 years. anisms. Many substances, such as insulin or thyroxine, are  The motivation for understanding what drugs can and  endogenous hormones but are also drugs when they are  cannot do came from clinical practice, but the science  administered intentionally. Many drUugs are not used in  could be built only on the basis of secure foundations in  medicines but are nevertheless useful research tools. In  physiology, pathology and chemistry. It was not until  everyday parlance, the word drug is often associated with  1858 that Virchow proposed the cell theory. The first use  addictive, narcotic or mind-altering substances – an unfor- of a structural formula to describe a chemical compound  tunate negative connotation that tends to bias uninformed  was in 1868. Bacteria as a cause of disease were discovered  opinion against any form of chemical therapy. In this book  by Pasteur in 1878. Previously, pharmacology hardly had  we focus mainly on drugs used for therapeutic purposes  the legs to stand on, and we may wonder at the bold  but also describe important examples of drugs used as  vision of Rudolf Buchheim, who created the first pharma- experimental tools. Although poisons fall strictly within  cology institute (in his own house) in Estonia in 1847. the definition of drugs, they are not covered in this book. In its beginnings, before the advent of synthetic organic  chemistry,  pharmacology  concerned  itself  exclusively  with  understanding  the  effects  of  natural  substances,  ORIGINS AND ANTECEDENTS mainly plant extracts – and a few (mainly toxic) chemicals  such as mercury and arsenic. An early development in  Pharmacology can be defined as the study of the effects  chemistry was the purification of active compounds from  of drugs on the function of living systems. As a science,  plants. Friedrich Sertürner, a young German apothecary,  it was born in the mid-19th century, one of a host of new  purified morphine from opium in 1805. Other substances  biomedical sciences based on principles of experimenta- quickly followed, and, even though their structures were  tion  rather  than  dogma  that  came  into  being  in  that  unknown, these compounds showed that chemicals, not  remarkable period. Long before that – indeed from the  magic or vital forces, were responsible for the effects that  dawn of civilisation – herbal remedies were widely used,  2The name persists today in some ancient universities, being attached to  1Like most definitions, this one has its limits. For example, there are a  chairs of what we would call clinical pharmacology. number of essential dietary constituents, such as iron and various  3Oliver Wendell Holmes, an eminent physician, wrote in 1860: ‘[I]  vitamins, that are used as medicines. Furthermore, some biological  firmly believe that if the whole materia medica, as now used, could be  products (e.g. epoietin) show batch-to-batch variation in their chemical  sunk to the bottom of the sea, it would be all the better for mankind  1 constitution that significantly affects their properties. and the worse for the fishes’ (see Porter, 1997). vip.persianss.ir 1 SECTION 1 GENERAL PRINCIPLES plant extracts produced on living organisms. Early phar- and therapeutics. Biochemistry also emerged as a distinct  macologists focused most of their attention on such plant- science early in the 20th century, and the discovery of  derived drugs as quinine, digitalis, atropine, ephedrine,  enzymes and the delineation of biochemical pathways  strychnine and others (many of which are still used today  provided yet another framework for understanding drug  and will have become old friends by the time you have  effects. The picture of pharmacology that emerges from  finished reading this book).4 this brief glance at history (Fig. 1.1) is of a subject evolved  from ancient prescientific therapeutics, involved in com- merce from the 17th century onwards, and which gained  PHARMACOLOGY IN THE 20TH AND respectability by donning the trappings of science as soon  21ST CENTURIES as this became possible in the mid-19th century. Signs of  its carpetbagger past still cling to pharmacology, for the  Beginning in the 20th century, the fresh wind of synthetic  pharmaceutical industry has become very big business  chemistry  began  to  revolutionise  the  pharmaceutical  and  much  pharmacological  research  nowadays  takes  industry, and with it the science of pharmacology. New  place in a commercial environment, a rougher and more  synthetic drugs, such as barbiturates and local anaesthet- pragmatic place than the glades of academia.5 No other  ics, began to appear, and the era of antimicrobial chemo- biomedical ‘ology’ is so close to Mammon. therapy began with the discovery by Paul Ehrlich in 1909  of  arsenical  compounds  for  treating  syphilis.  Further  ALTERNATIVE THERGAPEUTIC PRINCIPLES breakthroughs came when the sulfonamides, the first anti- bacterial drugs, were discovered by Gerhard Domagk in  Modern medicine relies heavily on drugs as the main   1935, and with the development of penicillin by Chain  tool of therapeutics. Other therapeutic procedures, such  and Florey during the Second World War, based on the  as surgery, diet, exercise, psychological treatments etc.,  R earlier work of Fleming. are  also  important,  of  course,  as  is  deliberate  non- These few well-known examples show how the growth  intervention, but none is so widely applied as drug-based  of synthetic chemistry, and the resurgence of natural  therapeutics. product chemistry, caused a dramatic revitalisation of  BefoVre the advent of science-based approaches, repeated  therapeutics in the first half of the 20th century. Each new  attempts were made to construct systems of therapeutics,  drug class that emerged gave pharmacologists a new chal- many of which produced even worse results than pure  lenge, and it was then that pharmacology really estab- dempiricism. One of these was allopathy, espoused by James  lished its identity and its status among the biomedical  Gregory (1735–1821). The favoured remedies included  sciences. blood letting, emetics and purgatives, which were used  In parallel with the exuberant proliferation of theraepeu- until the dominant symptoms of the disease were sup- tic molecules – driven mainly by chemistry – which gave  pressed. Many patients died from such treatment, and it  pharmacologists so much to think about, physiology was  was in reaction against it that Hahnemann introduced the  t also making rapid progress, particularly in relation to  practice  of  homeopathy  in  the  early  19th  century.  The  chemical mediators, which are discussed iin depth else- implausible guiding principles of homeopathy are: where in this book. Many hormones, nneurotransmitters  • like cures like and  inflammatory  mediators  were  discovered  in  this  • activity can be enhanced by dilution. period, and the realisation that chemical communication  plays a central role in almost everUy regulatory mechanism  The system rapidly drifted into absurdity: for example,  that our bodies possess immediately established a large  Hahnemann recommended the use of drugs at dilutions  area of common ground between physiology and phar- of 1 : 1060, equivalent to one molecule in a sphere the size  macology, for interactions between chemical substances  of the orbit of Neptune. and living systems were exactly what pharmacologists  Many other systems of therapeutics have come and  had been preoccupied with from the outset. The concept  gone, and the variety of dogmatic principles that they  of ‘receptors’ for chemical mediators, first proposed by  embodied have tended to hinder rather than advance sci- Langley in 1905, was quickly taken up by pharmacologists  entific progress. Currently, therapeutic systems that have  such as Clark, Gaddum, Schild and others and is a con- a basis that lies outside the domain of science are actually  stant theme in present-day pharmacology (as you will  gaining ground under the general banner of ‘alternative’  soon discover as you plough through the next two chap- or  ‘complementary’  medicine.  Mostly,  they  reject  the  ters). The receptor concept, and the technologies devel- ‘medical model’, which attributes disease to an underlying  oped from it, have had a massive impact on drug discovery  derangement of normal function that can be defined in  biochemical or structural terms, detected by objective  means, and influenced beneficially by appropriate chemi- 4A handful of synthetic substances achieved pharmacological  cal or physical interventions. They focus instead mainly  prominence long before the era of synthetic chemistry began. Diethyl  on subjective malaise, which may be disease-associated or  ether, first prepared as ‘sweet oil of vitriol’ in the 16th century, and  nitrous oxide, prepared by Humphrey Davy in 1799, were used to liven  up parties before being introduced as anaesthetic agents in the  mid-19th century (see Ch. 41). Amyl nitrite (see Ch. 21) was made in  5Some of our most distinguished pharmacological pioneers made  1859 and can claim to be the first ‘rational’ therapeutic drug; its  their careers in industry: for example, Henry Dale, who laid the  therapeutic effect in angina was predicted on the basis of its  foundations of our knowledge of chemical transmission and the  physiological effects – a true ‘pharmacologist’s drug’ and the smelly  autonomic nervous system (Ch. 12); George Hitchings and Gertrude  forerunner of the nitrovasodilators that are widely used today. Aspirin  Elion, who described the antimetabolite principle and produced   (Ch. 26), the most widely used therapeutic drug in history, was first  the first effective anticancer drugs (Ch. 56); and James Black, who  synthesised in 1853, with no therapeutic application in mind. It was  introduced the first β-adrenoceptor and histamine H-receptor  2 2 rediscovered in 1897 in the laboratories of the German company Bayer,  antagonists (Chs 13 and 17). It is no accident that in this book, where  who were seeking a less toxic derivative of salicylic acid. Bayer  we focus on the scientific principles of pharmacology, most of our  commercialised aspirin in 1899 and made a fortune. examples are products of industry, not of nature. vip.persianss.ir 1 WhAt IS PhARmACoLoGy? (cid:36)(cid:83)(cid:83)(cid:85)(cid:82)(cid:91)(cid:76)(cid:80)(cid:68)(cid:87)(cid:72)(cid:3)(cid:71)(cid:68)(cid:87)(cid:72)(cid:86) (cid:33)(cid:22)(cid:19)(cid:19)(cid:19)(cid:3)(cid:37)(cid:38) (cid:55)(cid:75)(cid:72)(cid:85)(cid:68)(cid:83)(cid:72)(cid:88)(cid:87)(cid:76)(cid:70)(cid:86) (cid:48)(cid:68)(cid:74)(cid:76)(cid:70)(cid:68)(cid:79)(cid:3)(cid:83)(cid:82)(cid:87)(cid:76)(cid:82)(cid:81)(cid:86) (cid:43)(cid:72)(cid:85)(cid:69)(cid:68)(cid:79)(cid:3)(cid:85)(cid:72)(cid:80)(cid:72)(cid:71)(cid:76)(cid:72)(cid:86) (cid:97)(cid:20)(cid:25)(cid:19)(cid:19)(cid:3)(cid:36)(cid:39) (cid:38)(cid:82)(cid:80)(cid:80)(cid:72)(cid:85)(cid:70)(cid:72) (cid:36)(cid:83)(cid:82)(cid:87)(cid:75)(cid:72)(cid:70)(cid:68)(cid:85)(cid:76)(cid:72)(cid:86) (cid:38)(cid:75)(cid:72)(cid:80)(cid:76)(cid:86)(cid:87)(cid:85)(cid:92) (cid:97)(cid:20)(cid:27)(cid:19)(cid:19) (cid:49)(cid:68)(cid:87)(cid:88)(cid:85)(cid:68)(cid:79) (cid:37)(cid:76)(cid:82)(cid:80)(cid:72)(cid:71)(cid:76)(cid:70)(cid:68)(cid:79) (cid:83)(cid:85)(cid:82)(cid:71)(cid:88)(cid:70)(cid:87)(cid:86) (cid:86)(cid:70)(cid:76)(cid:72)(cid:81)(cid:70)(cid:72)(cid:86) (cid:51)(cid:68)(cid:87)(cid:75)(cid:82)(cid:79)(cid:82)(cid:74)(cid:92) G (cid:51)(cid:75)(cid:68)(cid:85)(cid:80)(cid:68)(cid:70)(cid:72)(cid:88)(cid:87)(cid:76)(cid:70)(cid:68)(cid:79) (cid:51)(cid:75)(cid:68)(cid:85)(cid:80)(cid:68)(cid:70)(cid:82)(cid:79)(cid:82)(cid:74)(cid:92) (cid:76)(cid:81)(cid:71)(cid:88)(cid:86)(cid:87)(cid:85)(cid:92) (cid:38)(cid:75)(cid:72)(cid:80)(cid:76)(cid:70)(cid:68)(cid:79) (cid:51)(cid:75)(cid:92)(cid:86)(cid:76)(cid:82)(cid:79)(cid:82)(cid:74)(cid:92) (cid:86)(cid:87)(cid:85)(cid:88)(cid:70)(cid:87)(cid:88)(cid:85)(cid:72) R (cid:54)(cid:92)(cid:81)(cid:87)(cid:75)(cid:72)(cid:87)(cid:76)(cid:70) (cid:97)(cid:20)(cid:28)(cid:19)(cid:19) (cid:70)(cid:75)(cid:72)(cid:80)(cid:76)(cid:86)(cid:87)(cid:85)(cid:92) (cid:37)(cid:76)(cid:82)(cid:70)(cid:75)(cid:72)(cid:80)(cid:76)(cid:86)(cid:87)(cid:85)(cid:92) (cid:54)(cid:92)(cid:81)(cid:87)(cid:75)(cid:72)(cid:87)(cid:76)(cid:70) V (cid:71)(cid:85)(cid:88)(cid:74)(cid:86) (cid:48)(cid:82)(cid:79)(cid:72)(cid:70)(cid:88)(cid:79)(cid:68)(cid:85) (cid:97)(cid:20)(cid:28)(cid:26)(cid:19) (cid:69)(cid:76)(cid:82)(cid:79)(cid:82)(cid:74)(cid:92) (cid:37)(cid:76)(cid:82)(cid:83)(cid:75)(cid:68)(cid:85)(cid:80)(cid:68)(cid:70)(cid:72)(cid:88)(cid:87)(cid:76)(cid:70)(cid:68)(cid:79)(cid:86) d (cid:21)(cid:19)(cid:19)(cid:19) (cid:51)(cid:75)(cid:68)(cid:85)(cid:80)(cid:68)(cid:70)(cid:82)(cid:79)(cid:82)(cid:74)(cid:92) Fig. 1.1  The development of pharmacology.  e t i not. Abandoning objectivity in defining and measuring  duced into the body, are very different from those of  n disease goes along with a similar departure from scientific  drug-based therapeutics and will require a different con- principles in assessing therapeutic efficacy and risk, with  ceptual framework, which texts such as this will increas- the result that principles and practicesU can gain acceptance  ingly need to embrace if they are to stay abreast of modern  without satisfying any of the criteria of validity that would  medical treatment. convince a critical scientist, and that are required by law  to be satisfied before a new drug can be introduced into  PHARMACOLOGY TODAY therapy. Demand for ‘alternative’ therapies by the general  public, alas, has little to do with demonstrable efficacy.6 As with other biomedical disciplines, the boundaries of  pharmacology  are  not  sharply  defined,  nor  are  they   constant. Its exponents are, as befits pragmatists, ever  THE EMERGENCE OF BIOTECHNOLOGY ready to poach on the territory and techniques of other  Since the 1980s, biotechnology has emerged as a major  disciplines.  If  it  ever  had  a  conceptual  and  technical   source of new therapeutic agents in the form of antibod- core that it could really call its own, this has now dwindled  ies, enzymes and various regulatory proteins, including  almost to the point of extinction, and the subject is defined  hormones, growth factors and cytokines (see Buckel, 1996;  by its purpose – to understand what drugs do to living  Walsh, 2003). Although such products (known as biophar- organisms, and more particularly how their effects can   maceuticals) are generally produced by genetic engineer- be applied to therapeutics – rather than by its scientific  ing rather than by synthetic chemistry, the pharmacological  coherence. principles are essentially the same as for conventional  Figure 1.2 shows the structure of pharmacology as it  drugs. Looking further ahead, gene- and cell-based thera- appears today. Within the main subject fall a number of  pies (Ch. 59), although still in their infancy, will take  compartments (neuropharmacology, immunopharmacol- therapeutics into a new domain. The principles governing  ogy, pharmacokinetics, etc.), which are convenient, if not  the design, delivery and control of functioning artificial  watertight,  subdivisions.  These  topics  form  the  main  genes introduced into cells, or of engineered cells intro- subject matter of this book. Around the edges are several  interface disciplines, not covered in this book, which form  important two-way bridges between pharmacology and  6The UK Medicines and Healthcare Regulatory Agency (MHRA)  other fields of biomedicine. Pharmacology tends to have  requires detailed evidence of therapeutic efficacy based on controlled  more of these than other disciplines. Recent arrivals on  clinical trials before a new drug is registered, but no clinical trials data  the fringe are subjects such as pharmacogenomics, phar- 3 for homeopathic products or for the many herbal medicines that were  on sale before the Medicines Act of 1968. macoepidemiology and pharmacoeconomics. vip.persianss.ir