Introduction to Pharmacology © 1997, 2003 Taylor & Francis In the ocean depths off Madagascar, obsolete fish keep their laggard appointments. In the depths of the human mind, obsolete assumptions go their daily rounds. And there is little difference between the two, except that the fish do no harm. Robert Ardrey African Genesis, 1967 That which in the beginning may be just like poison, but at the end is like nectar, and which awakens one to self-realization, is said to be happiness in the mode of goodness. Bhagavad Gita Nothing in life is to be feared, it is only to be understood. Marie Curie © 1997, 2003 Taylor & Francis Introduction to Pharmacology Second Edition Mannfred A. Hollinger, Ph.D. Professor Emeritus, Department of Medical Pharmacology and Toxicology University of California, Davis © 1997, 2003 Taylor & Francis First published 1997 by Taylor & Francis Second edition published 2003 by Taylor & Francis 11 New Fetter Lane, London EC4P 4EE Simultaneously published in the USA and Canada by Taylor & Francis Inc, 29 West 35th Street, New York, NY 10001 Taylor & Francis is an imprint of the Taylor & Francis Group © 1997, 2003 Taylor & Francis Typeset in 10/12 pt Sabon by Graphicraft Limited, Hong Kong Printed and bound in Great Britain by TJ International Ltd, Padstow, Cornwall All rights reserved. No part of this book may be reprinted or reproduced or utilised in any form or by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying and recording, or in any information storage or retrieval system, without permission in writing from the publishers. Every effort has been made to ensure that the advice and information in this book is true and accurate at the time of going to press. However, neither the publisher nor the authors can accept any legal responsibility or liability for any errors or omissions that may be made. In the case of drug administration, any medical procedure or the use of technical equipment mentioned within this book, you are strongly advised to consult the manufacturer’s guidelines. British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging in Publication Data Hollinger, Mannfred A. Introduction to pharmacology / Mannfred A. Hollinger.—2nd ed. p. cm. Includes bibliographical references and index. 1. Pharmacology. I. Title. [DNLM: 1. Pharmacology. 2. Pharmaceutical Preparations. QV 4 H74li 2003] RM300 .H65 2003 615′.1—dc21 2002072005 ISBN 0-415-28033-8 (hbk) ISBN 0-415-28034-6 (pbk) © 1997, 2003 Taylor & Francis Contents Acknowledgements vii Preface to the first edition viii Preface to the second edition x PART 1 Fundamentals of pharmacokinetics 1 1 Introduction 3 2 Absorption and distribution 23 3 Metabolism and elimination 44 4 Drug interactions 61 PART 2 Fundamentals of pharmacodynamics and toxicodynamics 73 5 Drug receptors 75 6 Dose–response relationship 90 7 Drug toxicity 101 8 Treating drug overdose 137 PART 3 Drugs that replace, cure, or treat symptoms 147 9 Hormones 149 10 Chemotherapeutic agents 164 11 Drug treatment of symptoms: neuropharmacology and substance abuse 181 12 Cardiovascular drugs 241 © 1997, 2003 Taylor & Francis PART 4 Drug development 265 13 Drug discovery by the pharmaceutical industry 267 14 Pharmaceutical development of drugs and the FDA 299 15 Animals in research 316 16 Alternative medicine 341 Appendix: The History of drug abuse laws in the United States 351 Glossary 376 Answers to questions 393 vi Contents © 1997, 2003 Taylor & Francis Acknowledgements The author would like to express his thanks for the continuing support of his wife Georgia throughout this project. In addition, the always-present commiseration of sons Randy and Chris served as a never-ending source of insight and intellectual stimulation. The author would also like to acknowledge the excellent graphic design provided by Tsunami Graphics, Sacramento, CA. Much of the Appendix has been reproduced with kind permission from PJD Publica- tions Limited, Westbury, NY 11590, USA, from M. A. Hollinger, Res. Commun Alc. Sbst. Abuse, vol. 16, pp. 1–23, 1995. Copyright 1995 by PJD Publications Ltd. © 1997, 2003 Taylor & Francis Preface to the first edition The topic of pharmacology usually escapes the attention of many college students by virtue of the fact that pharmacology itself is rarely taught on the undergraduate level. It generally is reserved for postbaccalaureate students who are enrolled in health curricula associated with medicine, dentistry, nursing, and the veterinary sciences; however, certain upper level undergraduates are interested in the subject. This book is the product of teaching undergraduates the principles of pharmacology over the last 20 years. During that period the author continually searched for an appropriate textbook for students who normally had some background in biochemistry and physio- logy. Medical school texts were of no use since their coverage is far too extensive. Alternatively, “softer” texts tended to overemphasize certain areas, such as drug abuse, which were often the driving force behind their creation. Although both types of texts were good in their own right, they missed the mark. Students frequently expressed a desire for more “hard” science that would not inundate them with boiler plate text. It is because I agree with this sentiment that this book was created. The goal of this book is not to be a mini-medical school pharmacology text. Rather, it is intended to address a wider audience of advanced undergraduate students who have an interest in learning about the diverse aspects of pharmacology in society—not simply about the curative aspects of drugs. It is hoped that not only students in the biological sciences but also those in the social sciences will find some, if not all, of the book’s contents informative and useful. This book has been organized to provide a logical continuum of information relat- ing to drugs, beginning with the inevitable historical discovery of drugs in food. With this background, important pharmacological principles will be considered relating to drug absorption, distribution, metabolism, and elimination. This material forms the corpus of the chapters that constitute Part 1. In essence, the emphasis is placed upon pharmacokinetic aspects of drug action. Having gained access to the body, how do drugs produce an effect and how can the effect be quantified for comparative purposes? In Part 2, the student is exposed to the concepts of drug–receptor inter- action and the transduction of drug binding into pharmacodynamic or toxicodynamic responses. Factors influencing drug toxicity, as well as underlying principles of man- aging drug overdose, also will be presented as the inevitable “other side of the coin.” Part 3 reiterates, in more detail, the concept introduced in Part 1 that drugs can be classified into four broad categories: (1) drugs that replace physiological inadequa- cies, (2) drugs that cure, (3) drugs that treat symptoms, and (4) drugs that alter mood or behavior. In this regard, hormones, antibiotics, and neuroactive agents provide © 1997, 2003 Taylor & Francis examples, respectively, in their own chapters. In addition, the pharmacology of sub- stance abuse as well as the evolution of drug abuse laws and the use of drugs in sports are also discussed. In Part 4, the final three chapters deal with the development of drugs by the pharmaceutical industry and the challenges they face in new drug discovery as well as dealing with the FDA. The section concludes with a discussion of the controversial use of experimental animals in research, an area often neglected in the study of pharmacology. Mannfred A. Hollinger Davis, California Preface to the first edition ix © 1997, 2003 Taylor & Francis Preface to the second edition Since the publication of the first edition I have reevaluated the content of the book as well as its purpose. It became clear over the years that certain important areas that had been omitted in the first edition needed to be included in a revision, if a revision was to be meaningful. Therefore, additional areas added to the second edition include cardiovascular drugs, anticancer drugs, neuroleptics, designer drugs, bioterrorism, placebos, recombinant DNA technology, apoptosis, gaseous anesthetics, local anesthetics, vitamins, and the cigarette industry Master Settlement Agreement. In the intervening period since the publication of the first edition, the issue of alternative medicine has also become very topical, and a new chapter on this subject has been added. Although identifying areas of omission was relatively straightforward, the question of how to make the book more attractive to my intended audience was more illusive. It has always been my goal to reach upper-level undergraduate students beyond those in the traditional “hard” science paths. Surely there must be students and faculties in the humanities, in fields such as sociology and psychology, for example, who would find certain aspects of the study of drugs interesting and perhaps even provocative? Areas such as animal experimentation, the development of drug laws, drugs in sports, the drug discovery process, and bioterrorism are not typical subjects expanded upon in graduate level texts. These are stand-alone subjects that do not require mastery of pharmacokinetics and pharmacodynamics, which are covered essentially in the introductory chapters in Parts 1 and 2. In order to assist the student in evaluating his/her progress in dealing with the subject matter, I have included a set of 10 self-assessment questions at the end of each chapter (answers are provided at the back of the book). These questions are intended to emphasize the important facts, principles, and personalities that the student should become familiar with in the field of pharmacology. To further enhance the teaching power of the book the new edition contains 41 new tables and 33 new figures. Finally, in the hope of helping students and faculty, wherever, I encourage con- structive input and am willing to try to answer any questions. My email is mahollinger@ucdavis.edu. Mannfred A. Hollinger Oro Valley, Arizona © 1997, 2003 Taylor & Francis [...]... Another of Baer’s contributions to the field involved a method to sterilize the maggots Today, commercial and research laboratories produce sterile larvae The ability of maggots to promote healing of lacerations on skin wounds is the result of their secretion of the chemical allantoin A less offensive source of allantoin is the synthetic form Synthetic allantoin is available today to accelerate wound healing... libido (presumably structurally related to either estrogen or progesterone) Mistletoe has, of course, become a contemporary symbol to Yuletide merrymakers as a license to kiss The Celts, and others, also used mistletoe for medical purposes The Roman historian Pliny the Younger wrote that mistletoe was “deemed a cure for epilepsy; carried about by women it assisted them to conceive, and it healed ulcers most... preparations of the late 1800s (see Appendix) In addition to providing drugs, plants have also been recently utilized for ecological purposes via the process of phytoremediation Phytoremediation refers to the ability of some plants to remove toxic compounds from the soil, concentrate them in their own tissues, and thus, achieve a certain degree of detoxification Current interest has specifically focused on... product—Salivart®), artificial tears, placebos, or tetrodotoxin drugs? However, with this official orientation behind us, we may now proceed to investigate the world(s) of drugs and their diverse influences on the human experience BACKGROUND The roots of pharmacology extend backward in time to our earliest Pleistocene hominid ancestors on the African savanna, approximately five to ten million years ago These primitive... heart attacks to prevent further damage, investigators noticed that patients who took placebo pills regularly had a lower death rate than patients who took placebos sporadically Therefore, the placebo effect is not unique to psychiatric illness Conversely, what types of patients are not really amenable to a placebo effect? If you are a type I (insulin-dependent) diabetic (Chapter 9) who goes into hypoglycemic... Haitians do not fear zombies, they fear being turned into one According to one theory, victims are “converted” into a zombie in a two-step process Initially, the intended victim is treated with the nerve toxin tetrodotoxin applied surreptitiously to an open wound As the toxin does its work, the victim presents with all the symptoms of death Often not realizing this error in diagnosis, the victim is... job is to reduce the level of the toxin so that the meal is not fatal but retains enough of the toxin to produce some of its effects These include a mild numbing or tingling of the tongue and lips, sensations of warmth, a flushing of the skin, and a general feeling of euphoria If the dose is too high, difficulty in breathing occurs and a coma-like state develops In some cases, people have seemed to have... pharmacoepidemiology e pharmacoeconomics 9 Extracts from which of the following were believed to confer the gift of flight? a mistletoe b tobacco c tomatoes d thorn apple e cannabis 10 Which of the following produces a steroid precursor that was used in the synthesis of progesterone? a mistletoe b coca plant c North American potatoes d Southwestern mushrooms e Mexican yam © 1997, 2003 Taylor & Francis Chapter 2... usually have to gain entrance into the body in order to produce an effect, the exception being those that produce a topical (skin) effect Today, there are a number of methods that can be used to introduce a drug into the body Because of its convenience, the most common delivery system is the oral route However, sometimes the oral route is not the most appropriate In addition to the oral route, some of the... inflammatory mediators Modern pharmacology owes part of its development to Friedrich Worler, who inaugurated the field of synthetic organic chemistry in 1828 with the synthesis of urea This achievement catalyzed the formation of an entire industry (the German dye industry), which ultimately led to the synthesis of NCEs, many of which were subsequently introduced as possible therapeutic agents Prior to this . & Francis Introduction to Pharmacology Second Edition Mannfred A. Hollinger, Ph.D. Professor Emeritus, Department of Medical Pharmacology and Toxicology University. Francis Contents Acknowledgements vii Preface to the first edition viii Preface to the second edition x PART 1 Fundamentals of pharmacokinetics 1 1 Introduction 3 2 Absorption