Goodman and Gilmans the Pharmacological Basis of Therapeutics, 12th Edition

Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e [Vishal]1Front ................................................................................................................................................................................................................ 1Cover ....................................................................................................................................................................................................... 2Preface .................................................................................................................................................................................................... 3Preface to the Online Edition ........................................................................................................................................................ 4Copyright Information ....................................................................................................................................................................... 5Contributors ...........................................................................................................................................................................................
13Contents .............................................................................................................................................................................................. 15I. General Principles ....................................................................................................................................................................... 151. Drug Invention & the Pharmaceutical Industry .............................................................................................................. 302. Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism & Elimination ............. 623. Pharmacodynamics: Molecular Mechanisms of Drug Action .................................................................................. 984. Drug Toxicity & Poisoning .......................................................................................................................................................
1215. Membrane Transporters & Drug Response .................................................................................................................. 1566. Drug Metabolism ..................................................................................................................................................................... 1817. Pharmacogenetics .................................................................................................................................................................. 206II. Neuropharmacology .............................................................................................................................................................. 2068. Neurotransmission: The Autonomic & Somatic Motor Nervous Systems ....................................................... 2589. Muscarinic Receptor Agonists & Antagonists .............................................................................................................. 27710. Anticholinesterase Agents ................................................................................................................................................. 29611. Agents Acting at the Neuromuscular Junction & Autonomic Ganglia ............................................................. 32412. Adrenergic Agonists & Antagonists ................................................................................................................................ 38113. 5-Hydroxytryptamine (Serotonin) & Dopamine ........................................................................................................ 41814. Neurotransmission & the Central Nervous System ............................................................................................... 45315. Drug Therapy of Depression & Anxiety Disorders .................................................................................................. 46516. Pharmacotherapy of Psychosis & Mania .................................................................................................................... 50017. Hypnotics & Sedatives ....................................................................................................................................................... 52418. Opioids, Analgesia & Pain Management .................................................................................................................... 58119. General Anesthetics & Therapeutic Gases ................................................................................................................ 62320. Local Anesthetics .................................................................................................................................................................. 64421. Pharmacotherapy of the Epilepsies .............................................................................................................................. 68022. Treatment of Central Nervous System Degenerative Disorders ...................................................................... 70723. Ethanol & Methanol ............................................................................................................................................................. 73324. Drug Addiction ........................................................................................................................................................................ 762III. Modulation of Cardiovascular Function ............................................................................................................... 76225. Regulation of Renal Function & Vascular Volume ................................................................................................. 81826. Renin & Angiotensin ............................................................................................................................................................ 84627. Treatment of Myocardial Ischemia & Hypertension ............................................................................................... 88928. Pharmacotherapy of Congestive Heart Failure ....................................................................................................... 91429. Anti-Arrhythmic Drugs ......................................................................................................................................................... 94030. Blood Coagulation & Anticoagulant, Fibrinolytic & Antiplatelet Drugs ........................................................... 97931. Drug Therapy for Hypercholesterolemia & Dyslipidemia ....................................................................................
1012IV. Inflammation, Immunomodulation & Hematopoiesis .............................................................................. 101232. Histamine, Bradykinin & Their Antagonists ............................................................................................................ 104333. Lipid-Derived Autacoids: Eicosanoids & Platelet-Activating Factor ............................................................ 106734. Anti-inflammatory, Antipyretic & Analgesic Agents; Pharmacotherapy of Gout ...................................... 111435. Immunosuppressants, Tolerogens & Immunostimulants ................................................................................... 114036. Pulmonary Pharmacology .............................................................................................................................................. 117937. Hematopoietic Agents: Growth Factors, Minerals & Vitamins ........................................................................ 1224V. Hormones & Hormone Antagonists ........................................................................................................................ 122438. Introduction To Endocrinology: The Hypothalamic-Pituitary Axis .................................................................
124939. Thyroid & Anti-Thyroid Drugs ....................................................................................................................................... 129240. Estrogens & Progestins ................................................................................................................................................... 133541. Androgens ............................................................................................................................................................................. 135142. ACTH, Adrenal Steroids & Pharmacology of the Adrenal Cortex ................................................................. 137843. Endocrine Pancreas & Pharmacotherapy of Diabetes Mellitus & Hypoglycemia .................................. 141344. Agents Affecting Mineral Ion Homeostasis & Bone Turnover ......................................................................... 1449VI. Drugs Affecting Gastrointestinal Function ...................................................................................................... 144945. Pharmacotherapy of Gastric Acidity, Peptic Ulcers & Gastroesophageal Reflux Disease ................ 146746. Treatment of Disorders of Bowel Motility & Water Flux; .................................................................................. 149847. Pharmacotherapy of Inflammatory Bowel Disease ............................................................................................ 1508VII. Chemotherapy of Microbial Diseases .............................................................................................................. 150848. General Principles of Antimicrobial Therapy ......................................................................................................... 153049. Chemotherapy of Malaria .............................................................................................................................................. 156350. Chemotherapy of Protozoal Infections: Amebiasis, Giard ............................................................................... 159651. Chemotherapy of Helminth Infections ...................................................................................................................... 162552. Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolone .......................................................................... 164653. Penicillins, Cephalosporins & Other Beta-Lactam Antibiotics ........................................................................ 167154. Aminoglycosides ................................................................................................................................................................ 169355. Protein Synthesis Inhibitors & Miscellaneous Antibacterial Agents ............................................................. 172856. Chemotherapy of Tuberculosis, Mycobacterium Avium Complex Disease & Leprosy ....................... 175557. Antifungal Agents ............................................................................................................................................................... 178558. Antiviral Agents (Nonretroviral) .................................................................................................................................... 181659. Antiretroviral Agents & Treatment of HIV Infection ............................................................................................. 1845VIII. Chemotherapy of Neoplastic Diseases ......................................................................................................... 184560. General Principles of Cancer Chemotherapy ....................................................................................................... 185461. Cytotoxic Agents ................................................................................................................................................................ 191662. Targeted Therapies: Tyrosine Kinase Inhibitors, Monoclonal Antibodies & Cytokines ........................ 194663. Natural Products in Cancer Chemotherapy: Hormones & Related Agents .............................................. 1961IX. Special Systems Pharmacology ............................................................................................................................. 196164. Ocular Pharmacology ...................................................................................................................................................... 199365. Dermatological Pharmacology ..................................................................................................................................... 202566. Contraception & Pharmacotherapy of Obstetrical & Gynecological Disorders ...................................... 204767. Environmental Toxicology: Carcinogens & Heavy Metals ............................................................................... 2075X. Appendices ................................................................................................................................................................................ 2075I. Principles of Prescription Order Writing & Patient Compliance ........................................................................ 2087II. Design & Optimization of Dosage Regimens: Pharmacokinetic Data ..........................................................
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Preface
The publication of the twelfth edition of this book is a testament to the vision and ideals of the original authors, Alfred Gilman and Louis Goodman, who, in 1941 set forth the principles that have guided the book through eleven editions: to correlate pharmacology with related medical sciences, to reinterpret the actions and uses of drugs in light of advances in medicine and the basic biomedical sciences, to emphasize the applications of pharmacodynamics to therapeutics, and to create a book that will be useful to students of pharmacology and to physicians. These precepts continue to guide the current edition.
As with editions since the second, expert scholars have contributed individual chapters. A multiauthored book of this sort grows by accretion, posing challenges to editors but also offering memorable pearls to the reader. Thus, portions of prior editions persist in the current edition, and I hasten to acknowledge the contributions of previous editors and authors, many of whom will see text that looks familiar. However, this edition differs noticeably from its immediate predecessors. Fifty new scientists, including a number from outside the U.S., have joined as contributors, and all chapters have been extensively updated. The focus on basic principles continues, with new chapters on drug invention, molecular mechanisms of drug action, drug toxicity and poisoning, principles of antimicrobial therapy, and pharmacotherapy of obstetrical and gynecological disorders. Figures are in full color. The editors have continued to standardize the organization of chapters; thus, students should easily find the basic physiology, biochemistry, and pharmacology set forth in regular type; bullet points highlight important lists within the text; the clinician and expert will find details in extract type under clear headings.
Online features now supplement the printed edition. The entire text, updates, reviews of newly approved drugs, animations of drug action, and hyperlinks to relevant text in the prior edition are available on the Goodman & Gilman section of McGraw-Hill's websites, AccessMedicine.com and AccessPharmacy.com. An Image Bank CD accompanies the book and makes all tables and figures available for use in presentations.
The process of editing brings into view many remarkable facts, theories, and realizations. Three stand out: the invention of new classes of drugs has slowed to a trickle; therapeutics has barely begun to capitalize on the information from the human genome project; and, the development of resistance to antimicrobial agents, mainly through their overuse in medicine and agriculture, threatens to return us to the pre-antibiotic era. We have the capacity and ingenuity to correct these shortcomings.
Many, in addition to the contributors, deserve thanks for their work on this edition; they are acknowledged on an accompanying page. In addition, I am grateful to Professors Bruce Chabner (Harvard Medical School/Massachusetts General Hospital) and Björn Knollmann (Vanderbilt University Medical School) for agreeing to be associate editors of this edition at a late date, necessitated by the death of my colleague and friend Keith Parker in late 2008. Keith and I worked together on the eleventh edition and on planning this edition. In anticipation of the editorial work ahead, Keith submitted his chapters before anyone else and just a few weeks before his death; thus, he is well represented in this volume, which we dedicate to his memory.
Laurence L. Brunton San Diego, California December 1, 2010
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Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th Edition Preface to the Online Edition
The first edition of Goodman & Gilman's The Pharmacological Basis of Therapeutics was published in 1941. Medicine has changed dramatically since then; so, too, has the delivery of information. The editors of the online version of 12th edition of Goodman & Gilman are hoping to be at the forefront of publishing technology in a project to enhance the premier text in pharmacology and bring it to your desktop. We hope to bring not just the text of the book but to enhance the text with additional features. The production of on-line resources for Goodman & Gilman will be guided by three complementary priorities:
1. To provide regular updates, particularly in areas of pharmacology and therapeutics where significant advances in basic or clinical research have occurred since publication of the printed version
2. To provide faculty and students with high-quality electronic resources to enhance teaching and learning of pharmacology
3. To provide comprehensive search results that allow users quick access to required content
We are currently working on the following online resources to enhance the 12th edition of Goodman & Gilman:
Updates: Regular updates, including new chapter content, a Clinical Pharmacist's Corner that discusses newly approved drugs or new therapeutic uses of approved drugs, and pieces that focus on emerging areas of pharmacological interest Grand Rounds: Occasional webcasts of lectures in areas of therapeutic importance by authorities Multimedia Content: To complement the text, we have started an ongoing series of interactive, animated versions of some of the more important figures from Goodman & Gilman, which are useful for interactive self-study by students
The Editors of Goodman & Gilman welcome your thoughts on improvements and corrections to the text, as well as suggestions and submissions for online updates. If you are a pharmacologist, pharmacist, physician, or medical scientist and you would are interested to contribute an update, please send an email to the Editors at [email protected].
The ENIAC (Electronical Numerical Integrator and Computer; circa 1945) was the first electronic computer. The invention of Dr. J. W. Mauchly and Mr. J. Presper Eckert, it containied close to 18,000 vacuum tubes, occupied a room 30 by 50 feet, weighed 30 tons and cost of more than $486,000. It was used at the War Department's Ballistics Research Laboratory to calculate artillery trajectories. (U.S. Army Photo, courtesy of http://ftp.arl.army.mil/~mike/comphist/ and http://ftp.arl.army.mil/ftp/historic- computers/.)
1st Edition Table of Contents
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Copyright Information
Goodman and Gilman's The Pharmacological Basis of Therapeutics, Twelfth Edition Copyright © 2011, 2006, 2001, 1996, 1990, 1985, 1980, 1975, 1970, 1965, 1955, 1941 by The McGraw-Hill Companies, Inc. All rights reserved. Printed in China. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher.
ISBN 978-0-07-162442-8 MHID 0-07-162442-2
Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.
Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e [Vishal] Copyright Information
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Contributors
Editor Laurence L. Brunton, PhD Professor of Pharmacology and Medicine School of Medicine, University of California, San Diego La Jolla, California
Associate Editors Bruce A. Chabner, MD Professor of Medicine Harvard Medical School Director of Clinical Research Massachusetts General Hospital Cancer Center Boston, Massachusetts
Björn C. Knollmann, MD, PhD Professor of Medicine and Pharmacology Oates Institute for Experimental Therapeutics Division of Clinical Pharmacology Vanderbilt University School of Medicine Nashville, Tennessee
Contributors (print) Edward P. Acosta, PharmD Professor of Clinical Pharmacology University of Alabama, Birmingham
Peter J. Barnes, DM, DSc, FRCP, FMedSci, FRS Professor and Head of Respiratory Medicine National Heart & Lung Institute Imperial College, London
Jeffrey A. Barnes, MD, PhD Fellow in Hematology-Oncology Dana-Farber Cancer Institute Boston, Massachusetts
Leslie Z. Benet, PhD Professor of Bioengineering and Therapeutic Sciences Schools of Pharmacy and Medicine University of California, San Francisco
John E. Bennett, MD Chief of Clinical Mycology National Institute of Allergy and Infectious Diseases Bethesda, Maryland
William Bennett, MD Professor (Emeritus) of Medicine and Pharmacology Oregon Health & Science University, Portland
Thomas P. Bersot, MD, PhD Professor of Medicine; Associate Investigator Gladstone Institute of Cardiovascular Disease University of California, San Francisco
Joseph R. Bertino, MD Professor of Medicine and Pharmacology Robert Wood Johnson Medical School University of Medicine & Dentistry of New Jersey New Brunswick
Donald K. Blumenthal, PhD Associate Professor of Pharmacology & Toxicology College of Pharmacy University of Utah, Salt Lake City
Viengngeun Bounkeua, PhD Medical Scientist Training Program, School of Medicine University of California, San Diego
Gregory A. Brent, MD Professor of Medicine and Physiology Geffen School of Medicine University of California, Los Angeles
Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e [Vishal] Contributors
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University of California, Los Angeles
Joan Heller Brown, PhD Professor and Chair of Pharmacology University of California, San Diego
Craig N. Burkhart, MD Assistant Professor of Dermatology, School of Medicine University of North Carolina, Chapel Hill
Iain L. O. Buxton, PharmD Professor of Pharmacology University of Nevada School of Medicine, Reno
Michael C. Byrns, PhD Fellow in Pharmacology University of Pennsylvania School of Medicine, Philadelphia
William A. Catterall, PhD Professor and Chair of Pharmacology University of Washington School of Medicine, Seattle
Bruce A. Chabner, MD Professor of Medicine, Harvard Medical School Director of Clinical Research, Massachusetts General Hospital Cancer Center Boston, Massachusetts
Henry F. Chambers, MD Professor of Medicine and Chief of Infectious Diseases San Francisco General Hospital University of California, San Francisco
Jérôme Clain, PharmD, PhD Research Fellow in Microbiology and Immunology College of Physicians and Surgeons Columbia University, New York
James M. Cleary MD, PhD Attending Physician Dana-Farber Cancer Institute Boston, Massachusetts
Michael W.H. Coughtrie, PhD Professor of Biochemical Pharmacology Division of Medical Sciences University of Dundee, Scotland
David D'Alessio, MD Professor of Endocrinology and Medicine University of Cinncinnati, Ohio
Richard T. Eastman, PhD Fellow in Microbiology Columbia University, New York
Ervin G. Erdös, MD Professor (Emeritus) of Pharmacology University of Illinois-Chicago
David A. Fidock, PhD Associate Professor of Microbiology and Medicine College of Physicians and Surgeons Columbia University, New York
Garret A. FitzGerald, MD Professor of Medicine, Pharmacology and Translational Medicine and Therapeutics Chair of Pharmacology University of Pennsylvania School of Medicine, Philadelphia
Charles W. Flexner, MD Professor of Medicine, Pharmacology and Molecular Sciences, and International Health The Johns Hopkins University School of Medicine and Bloomberg School of Public Health Baltimore, Maryland
Peter A. Friedman, PhD Professor of Pharmacology and Chemical Biology School of Medicine University of Pittsburgh, Pennsylvania
John W. Funder, AO, MD, BS, PhD, FRACP Professor of Medicine, Prince Henry's Institute
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Professor of Medicine, Prince Henry's Institute Monash Medical Centre ClaytonVictoria, Australia
James C. Garrison, PhD Professor of Pharmacology, School of Medicine University of Virginia, Charlottesville
Kathleen M. Giacomini, PhD Professor and Chair of Biopharmaceutical Sciences School of Pharmacy University of California, San Francisco
Alfred G. Gilman, MD, PhD Professor (Emeritus) of Pharmacology University of Texas Southwestern Medical School Chief Scientific Officer, Cancer Prevention and Research Institute of Texas, Dallas
Lowell A. Goldsmith, MD, MPH Professor of Dermatology, School of Medicine University of North Carolina, Chapel Hill, North Carolina
Frank J. Gonzalez, PhD Chief, Laboratory of Metabolism Center for Cancer Research, National Cancer Institute Bethesda, Maryland
Tilo Grosser, MD Assistant Professor of Pharmacology Institute for Translational Medicine and Therapeutics University of Pennsylvania, Philadelphia
Tawanda Gumbo, MD Associate Professor of Internal Medicine University of Texas Southwestern Medical School, Dallas
Stephen R. Hammes, MD, PhD Professor of Medicine, Chief of Endocrinology and Metabolism School of Medicine and Dentistry University of Rochester, New York
R. Adron Harris, PhD Professor of Molecular Biology; Director, Waggoner Center for Alcohol and Addiction Research University of Texas, Austin
Lisa A. Hazelwood, PhD Research Fellow, Molecular Neuropharmacology Section National Institute of Neurological Disorders and Stroke Bethesda, Maryland
Jeffrey D. Henderer, MD Professor and Chair of Ophthalmology Temple University School of Medicine Philadelphia, Pennsylvania
Ryan E. Hibbs, PhD Research Fellow, Vollum Institute Oregon Health & Science University, Portland
Randa Hilal-Dandan, PhD Lecturer in Pharmacology University of California, San Diego
Brian B. Hoffman, MD Professor of Medicine, Harvard Medical School Physician, VA-Boston Health Care System Boston, Massachusetts
Peter J. Hotez, MD, PhD Professor and Chair of Microbiology, Immunology, and Tropical Medicine George Washington University Washington, DC
Nina Isoherranen, PhD Assistant Professor of Pharmaceutics, School of Pharmacy University of Washington, Seattle
Edwin K. Jackson, PhD Professor of Pharmacology and Chemical Biology School of Medicine University of Pittsburgh, Pennsylvania
Allen P. Kaplan, MD Clinical Professor of Medicine
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Clinical Professor of Medicine Medical University of South Carolina, Charleston
Robert S. Kass, PhD Professor and Chair of Pharmacology Vice Dean for Research College of Physicians and Surgeons Columbia University, New York
Kenneth Kaushansky, MD Dean, School of Medicine and Senior Vice President of Health Sciences SUNY Stony Brook, New York
Thomas J. Kipps, MD, PhD Professor of Medicine, Moores Cancer Center University of California, San Diego
Ronald J. Koenig, MD, PhD Professor of Metabolism, Endocrinology and Diabetes Department of Internal Medicine University of Michigan Health System, Ann Arbor
Alan M. Krensky, MD Senior Investigator, National Cancer Institute, Bethesda, Maryland
Nora Laiken, PhD Lecturer in Pharmacology and Medicine University of California, San Diego
Andrew A. Lane, MD, PhD Fellow, Dana-Farber Cancer Institute Massachusetts General Hospital Cancer Center, Boston
Richard J. Lee, MD, PhD Professor of Medicine, Harvard Medical School Physician, Massachusetts General Hospital Boston, Massachusetts
Ellis R. Levin, MD Professor of Medicine; Chief of Endocrinology Diabetes and Metabolism University of California, Irvine, and Long Beach VA Medical Center, Long Beach
Dan L. Longo, MD Scientific Director, National Institute on Aging National Institutes of Health, Bethesda, Maryland
Alex Loukas, PhD Professor of Public Health, Tropical Medicine and Rehabilitation Sciences James Cook University, Cairns, Australia
Conan MacDougall, PharmD, MAS Associate Professor of Clinical Pharmacy School of Pharmacy University of California, San Francisco
Kenneth P. Mackie, MD Professor of Neuroscience Indiana University, Bloomington
Bradley A. Maron, MD Fellow in Cardiovascular Medicine Harvard Medical School and Brigham and Women's Hospital Boston, Massachusetts
James McCarthy, MD Associate Professor of Clinical Tropical Medicine University of Queensland Brisbane, Australia
James O. McNamara, MD Professor and Chair of Neurobiology Director of Center for Translational Neuroscience Duke University Medical Center Durham, North Carolina
Jonathan M. Meyer, MD Assistant Adjunct Professor of Psychiatry University of California, San Diego
Thomas Michel, MD, PhD Professor of Medicine and Biochemistry Harvard Medical School Senior Physician in Cardiovascular Medicine Brigham and Women's Hospital
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Senior Physician in Cardiovascular Medicine Brigham and Women's Hospital Boston, Massachusetts
S. John Mihic, PhD Professor of Neurobiology Waggoner Center for Alcohol & Addiction Research Institute for Neuroscience and Cell & Molecular Biology University of Texas, Austin
Constantine S. Mitsiades, MD, PhD Professor of Medical Oncology Dana-Farber Cancer Institute, Harvard Medical School Boston, Massachusetts
Perry Molinoff, MD Professor of Pharmacology, School of Medicine University of Pennsylvania, Philadelphia
Dean S. Morrell, MD Associate Professor of Dermatology University of North Carolina, Chapel Hill
Beverly Moy, MD, MPH Assistant Professor of Medicine Harvard Medical School Massachusetts General Hospital, Needham
Hamza Mujagic, MD, MR. SCI, DR. SCI Visiting Professor of Hematology and Oncology Harvard Medical School Massachusetts General Hospital, Needham
Joel W. Neal, MD, PhD Assistant Professor of Medicine-Oncology, Stanford University School of Medicine, Palo Alto, California
Charles P. O'Brien, MD, PhD Professor of Psychiatry, School of Medicine University of Pennsylvania, Philadelphia
James O'Donnell, PhD Professor of Behavioral Medicine and Psychiatry School of Medicine West Virginia University, Morgantown
Erin M. Olson, MD Fellow in Medical Oncology Dana-Farber Cancer Institute Boston, Massachusetts
Taylor M. Ortiz, MD Clinical Fellow in Medical Oncology Dana-Farber Cancer Institute General Hospital Cancer Center Boston, Massachusetts
Kevin Osterhoudt, MD, MSCE, FAAP, FACMT Associate Professor of Pediatrics School of Medicine, University of Pennsylvania Medical Director, Poison Control Center, Children's Hospital of Philadelphia, Pennsylvania
Keith L. Parker, MD, PhD (deceased) Professor of Internal Medicine and Pharmacology Chief of Endocrinology and Metabolism University of Texas Southwestern Medical School, Dallas
Hemal H. Patel, PhD Associate Professor of Anesthesiology University of California, San Diego Dean, School of Medicine and Senior Vice President of Health Sciences SUNY Stony Brook, New York
Piyush M. Patel, MD, FRCPC Professor of Anesthesiology University of California, San Diego
Trevor M. Penning, PhD Professor of Pharmacology Director, Center of Excellence in Environmental Toxicology School of Medicine University of Pennsylvania, Philadelphia
William A. Petri, Jr, MD, PhD Professor of Medicine; Chief, Division of Infectious Diseases
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Professor of Medicine; Chief, Division of Infectious Diseases University of Virginia, Charlottesville
Margaret A. Phillips, PhD Professor of Pharmacology University of Texas Southwestern Medical School, Dallas
Alvin C. Powers, MD Professor of Medicine, Molecular Physiology and Biophysics Vanderbilt University Medical Center Nashville, Tennessee
Christopher Rapuano, MD Director, Cornea Service and Refractive Surgery Department, Wills Eye Institute Philadelphia, Pennsylvania
Robert F. Reilly, Jr, MD Professor of Internal Medicine University of Texas Southwestern Medical School, Dallas Chief of Nephrology VA-North Texas Health Care System, Dallas
Mary V. Relling, PharmD Chair of Pharmaceutical Sciences St. Jude Childrens' Research Hospital Memphis, Tennessee
Paul G. Richardson, MD Associate Professor of Medicine, Harvard Medical School Clinical Director, Lipper Center for Multiple Myeloma Dana-Farber Cancer Institute Boston, Massachusetts
Suzanne M. Rivera, PhD, MSW Assistant Professor of Clinical Sciences University of Texas Southwestern Medical Center, Dallas
Erik Roberson, MD, PhD Assistant Professor of Neurology and Neurobiology University of Alabama, Birmingham
Thomas P. Rocco, MD Associate Professor of Medicine Harvard Medical School VA-Boston Healthcare System Boston, Massachusetts
David M. Roth, MD, PhD Professor of Anesthesiology University of California, San Diego VA-San Diego Healthcare System
David P. Ryan, MD Associate Professor of Medicine Harvard Medical School Massachusetts General Hospital Cancer Center, Boston
Kevin J. Sampson, PhD Postdoctoral Research Scientist in Pharmacology Columbia University, New York
Elaine Sanders-Bush, PhD Professor (Emerita) of Pharmacology School of Medicine, Vanderbilt University Nashville, Tennessee
Bernard P. Schimmer, PhD Professor (Emeritus) of Medical Research and Pharmacology University of Toronto, Ontario
Marc A. Schuckit, MD Distinguished Professor of Psychiatry University of California, San Diego Director, Alcohol Research Center VA-San Diego Healthcare System
Lecia Sequist, MD, MPH Assistant Professor of Medicine Harvard Medical School, Massachusetts General Hospital Cancer Center, Boston
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Keith A. Sharkey, PhD Professor of Physiology & Pharmacology and Medicine University of Calgary, Alberta
Richard C. Shelton, MD Professor of Psychiatry and Pharmacology School of Medicine, Vanderbilt University Nashville, Tennessee
Danny Shen, PhD Professor and Chair of Pharmacy Professor of Pharmaceutics, School of Pharmacy University of Washington, Seattle
Randal A. Skidgel, PhD Professor of Pharmacology and Anesthesiology College of Medicine, University of Illinois-Chicago
Matthew R. Smith, MD, PhD Associate Professor of Medicine, Harvard Medical School Physician, Massachusetts General Hospital, Boston
Emer M. Smyth, PhD Research Assistant, Professor of Pharmacology University of Pennsylvania, Philadelphia
Peter J. Snyder, MD Professor of Medicine University of Pennsylvania, Philadelphia
David Standaert, MD, PhD Professor of Neurology Director, Center for Neurodegeneration and Experimental Therapeutics University of Alabama, Birmingham
Samuel L. Stanley, Jr, MD Professor of Medicine and President SUNY Stony Brook, New York
Yuichi Sugiyama, PhD Professor and Chair of Molecular Pharmacokinetics University of Tokyo, Japan
Jeffrey G. Supko, PhD Associate Professor of Medicine, Harvard Medical School Massachusetts General Hospital, Boston
Palmer W. Taylor, PhD Professor of Pharmacology, School of Medicine Dean, Skaggs School of Pharmacy and Pharmaceutical Sciences University of California, San Diego
Kenneth E. Thummel, PhD Professor and Chair, Department of Pharmaceutics University of Washington, Seattle
Robert H. Tukey, PhD Professor of Pharmacology and Chemistry/Biochemistry University of California, San Diego
Flavio Vincenti, MD Professor of Clinical Medicine Medical Director, Pancreas Transplant Program University of California, San Francisco
Joseph M. Vinetz, MD Professor of Medicine, Division of Infectious Diseases University of California, San Diego
Mark S. Wallace, MD Professor of Clinical Anesthesiology University of California, San Diego
John L. Wallace, PhD, MBA, FRSC Professor and Director, Farncombe Family Digestive Health Research Institute McMaster University, Hamilton, Ontario
Jeffrey I. Weitz, MD, FRCP(C), FACP Professor of Medicine, Biochemistry and Biomedical Sciences McMaster University Executive Director, Thrombosis & Atherosclerosis
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Executive Director, Thrombosis & Atherosclerosis Research Institute, Hamilton, Ontario
David P. Westfall, PhD Professor (Emeritus) of Pharmacology University of Nevada School of Medicine, Reno
Thomas C. Westfall, PhD Professor and Chair of Pharmacological and Physiological Science St. Louis University School of Medicine, Missouri
Wyndham Wilson, MD, PhD Senior Investigator and Chief of Lymphoid Therapeutics Section Center for Cancer Research, National Cancer Institute Bethesda Maryland
Tony L. Yaksh, PhD Professor of Anesthesiology and Pharmacology University of California, San Diego
Alexander C. Zambon, PhD Assistant Professor of Pharmacology University of California, San Diego
Contributors (online)
Donald K. Blumenthal Nelda Murri Randa Hilal-Dandan Lecturer in Pharmacology University of California, San Diego
Consulting Editor
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Section I. General Principles Chapter 1 Drug Invention & the Pharmaceutical Industry Chapter 2 Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism &
Elimination Chapter 3 Pharmacodynamics: Molecular Mechanisms of Drug Action Chapter 4 Drug Toxicity & Poisoning Chapter 5 Membrane Transporters & Drug Response Chapter 6 Drug Metabolism Chapter 7 Pharmacogenetics
Section II. Neuropharmacology Chapter 8 Neurotransmission: The Autonomic & Somatic Motor Nervous Systems Chapter 9 Muscarinic Receptor Agonists & Antagonists Chapter 10 Anticholinesterase Agents Chapter 11 Agents Acting at the Neuromuscular Junction & Autonomic Ganglia Chapter 12 Adrenergic Agonists & Antagonists Chapter 13 5-Hydroxytryptamine (Serotonin) & Dopamine Chapter 14 Neurotransmission & the Central Nervous System Chapter 15 Drug Therapy of Depression & Anxiety Disorders Chapter 16 Pharmacotherapy of Psychosis & Mania Chapter 17 Hypnotics & Sedatives Chapter 18 Opioids, Analgesia & Pain Management Chapter 19 General Anesthetics & Therapeutic Gases Chapter 20 Local Anesthetics Chapter 21 Pharmacotherapy of the Epilepsies Chapter 22 Treatment of Central Nervous System Degenerative Disorders Chapter 23 Ethanol & Methanol Chapter 24 Drug Addiction
Section III. Modulation of Cardiovascular Function Chapter 25 Regulation of Renal Function & Vascular Volume Chapter 26 Renin & Angiotensin Chapter 27 Treatment of Myocardial Ischemia & Hypertension Chapter 28 Pharmacotherapy of Congestive Heart Failure Chapter 29 Anti-Arrhythmic Drugs Chapter 30 Blood Coagulation & Anticoagulant, Fibrinolytic & Antiplatelet Drugs Chapter 31 Drug Therapy for Hypercholesterolemia & Dyslipidemia
Section IV. Inflammation, Immunomodulation & Hematopoiesis Chapter 32 Histamine, Bradykinin & Their Antagonists Chapter 33 Lipid-Derived Autacoids: Eicosanoids & Platelet-Activating Factor Chapter 34 Anti-inflammatory, Antipyretic & Analgesic Agents; Pharmacotherapy of Gout Chapter 35 Immunosuppressants, Tolerogens & Immunostimulants Chapter 36 Pulmonary Pharmacology Chapter 37 Hematopoietic Agents: Growth Factors, Minerals & Vitamins
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Section V. Hormones & Hormone Antagonists Chapter 38 Introduction To Endocrinology: The Hypothalamic-Pituitary Axis Chapter 39 Thyroid & Anti-Thyroid Drugs Chapter 40 Estrogens & Progestins Chapter 41 Androgens Chapter 42 ACTH, Adrenal Steroids & Pharmacology of the Adrenal Cortex Chapter 43 Endocrine Pancreas & Pharmacotherapy of Diabetes Mellitus & Hypoglycemia Chapter 44 Agents Affecting Mineral Ion Homeostasis & Bone Turnover
Section VI. Drugs Affecting Gastrointestinal Function Chapter 45 Pharmacotherapy of Gastric Acidity, Peptic Ulcers & Gastroesophageal Reflux
Disease Chapter 46 Treatment of Disorders of Bowel Motility & Water Flux; Anti-Emetics; Agents Used in
Biliary & Pancreatic Disease Chapter 47 Pharmacotherapy of Inflammatory Bowel Disease
Section VII. Chemotherapy of Microbial Diseases Chapter 48 General Principles of Antimicrobial Therapy Chapter 49 Chemotherapy of Malaria Chapter 50 Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Trichomoniasis,
Trypanosomiasis, Leishmaniasis & Other Protozoal Infections Chapter 51 Chemotherapy of Helminth Infections Chapter 52 Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones & Agents for
UrinaryTract Infections Chapter 53 Penicillins, Cephalosporins & Other β-Lactam Antibiotics Chapter 54 Aminoglycosides Chapter 55 Protein Synthesis Inhibitorsand Miscellaneous Antibacterial Agents Chapter 56 Chemotherapy of Tuberculosis, Mycobacterium Avium Complex Disease & Leprosy Chapter 57 Antifungal Agents Chapter 58 Antiviral Agents (Nonretroviral) Chapter 59 Antiretroviral Agents & Treatment of HIV Infection
Section VIII. Chemotherapy of Neoplastic Diseases Chapter 60 General Principles of Cancer Chemotherapy Chapter 61 Cytotoxic Agents Chapter 62 Targeted Therapies: Tyrosine Kinase Inhibitors, Monoclonal Antibodies & Cytokines Chapter 63 Natural Products in Cancer Chemotherapy: Hormones & Related Agents
Section IX. Special Systems Pharmacology Chapter 64 Ocular Pharmacology Chapter 65 Dermatological Pharmacology Chapter 66 Contraception & Pharmacotherapy of Obstetrical & Gynecological Disorders Chapter 67 Environmental Toxicology: Carcinogens & Heavy Metals
Section X. Appendices
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Goodman & Gilman's The Pharmacological Basis of Therapeutics > Section I. General Principles > Chapter 1. Drug Invention and the Pharmaceutical Industry >
DRUG INVENTION AND THE PHARMACEUTICAL INDUSTRY: INTRODUCTION The first edition of this textbook, published in 1941, is often credited with organizing the field of pharmacology, giving it intellectual validity and an academic identity. That first edition began: "The subject of pharmacology is a broad one and embraces the knowledge of the source, physical and chemical properties, compounding, physiological actions, absorption, fate, and excretion, and therapeutic uses of drugs. A drug may be broadly defined as any chemical agent that affects living protoplasm, and few substances would escape inclusion by this definition." These two sentences still serve us well. This first section of the 12th edition of this textbook provides the underpinnings for these definitions by exploring the processes of drug invention and development into a therapeutic entity, followed by the basic properties of the interactions between the drug and biological systems: pharmacodynamics, pharmacokinetics (including drug transport and metabolism), and pharmacogenomics. Subsequent sections deal with the use of drugs as therapeutic agents in human subjects. We intentionally use the term invention to describe the process by which a new drug is identified and brought to medical practice, rather than the more conventional term discovery. This significant semantic change was suggested to us by our colleague Michael S. Brown, MD, and it is appropriate. In the past, drugs were discovered as natural products and used as such. Today, useful drugs are rarely discovered hiding somewhere waiting to be found; rather, they are sculpted and brought into being based on experimentation and optimization of many independent properties. The term invention emphasizes this process; there is little serendipity. *Alfred G. Gilman serves on the Board of Directors of Eli Lilly & Co. and Regeneron Pharmaceuticals, and acknowledges potential conflicts of interests. FROM EARLY EXPERIENCES WITH PLANTS TO MODERN CHEMISTRY Man's fascination—and sometimes infatuation—with chemicals (i.e., drugs) that alter biological function is ancient and arose as a result of experience with and dependence on plants. Most plants are root-bound, and many have become capable of elaborate chemical syntheses, producing harmful compounds for defense that animals learned to avoid and man learned to exploit. Many examples are described in earlier editions of this text: the appreciation of coffee (caffeine) by the prior of an Arabian convent who noted the behavior of goats that gamboled and frisked through the night after eating the berries of the coffee plant, the use of mushrooms or the deadly nightshade plant (containing the belladonna alkaloids atropine and scopolamine) by professional poisoners, and a rather different use of belladonna ("beautiful lady") to dilate pupils. Other examples include the uses of the Chinese herb ma huang (containing ephedrine) for over 5000 years as a circulatory stimulant, curare-containing arrow poisons used for centuries by South American Indians to paralyze and kill animals hunted for food, and poppy juice (opium) containing morphine (from the Greek Morpheus, the god of dreams) for pain relief and control of dysenteries. Morphine, of course, has well-known addicting properties, mimicked in some ways by other problematic ("recreational") natural products—nicotine, cocaine, and ethanol. While many terrestrial and marine organisms remain valuable sources of naturally occurring compounds with various pharmacological activities, especially including lethal effects on both microorganisms and eukaryotic cells, drug invention became more allied with synthetic organic chemistry as that discipline flourished over the past 150 years. This revolution began in the dye industry. Dyes, by definition, are colored compounds with selective affinity for biological tissues. Study of these interactions stimulated Paul Ehrlich to postulate the existence of chemical receptors in tissues that interacted with and "fixed" the dyes. Similarly, Ehrlich thought that unique receptors on microorganisms or parasites might react specifically with certain dyes and that such selectivity could spare normal tissue. Ehrlich's work culminated in the invention of arsphenamine in 1907, which was patented as "salvarsan," suggestive of the hope that the chemical would be the salvation of humankind. This arsenic-containing compound and other organic arsenicals were invaluable for the chemotherapy of syphilis until the discovery of penicillin. During that period and thanks to the work of Gerhard Domagk, another dye, prontosil (the first clinically useful sulfonamide) was shown to be dramatically effective in treating streptococcal infections. The era of antimicrobial chemotherapy was born, and the fascination with dyes soon spread to the entire and nearly infinite spectrum of organic chemicals. The resulting collaboration of pharmacology with chemistry on the one hand, and with clinical medicine on the other, has been a major contributor to the effective treatment
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of disease, especially since the middle of the 20th century. SOURCES OF DRUGS Small Molecules Are the Tradition With the exception of a few naturally occurring hormones such as insulin, most drugs were small organic molecules (typically <500 Da) until recombinant DNA technology permitted synthesis of proteins by various organisms (bacteria, yeast) and mammalian cells, starting in the 1980s. The usual approach to invention of a small-molecule drug is to screen a collection of chemicals ("library") for compounds with the desired features. An alternative is to synthesize and focus on close chemical relatives of a substance known to participate in a biological reaction of interest (e.g., congeners of a specific enzyme substrate chosen to be possible inhibitors of the enzymatic reaction), a particularly important strategy in the discovery of anticancer drugs. While drug discovery in the past often resulted from serendipitous observations of the effects of plant extracts or individual chemicals administered to animals or ingested by man, the approach today relies on high-throughput screening of libraries containing hundreds of thousands or even millions of compounds for their ability to interact with a specific molecular target or elicit a specific biological response (see "Targets of Drug Action" later in the chapter). Chemical libraries are synthesized using modern organic chemical synthetic approaches such as combinatorial chemistry to create large collections of related chemicals, which can then be screened for activity in high-throughput systems. Diversity-oriented synthetic approaches also are of obvious value, while natural products (plant or marine animal collections) are sources of novel and sometimes exceedingly complex chemical structures. Automated screening procedures employing robotic systems can process hundreds of thousands of samples in just a few days. Reactions are carried out in small trays containing a matrix of tiny wells (typically 384 or 1536). Assay reagents and samples to be tested are coated onto plates or distributed by robots, using ink-jet technology. Tiny volumes are used and chemical samples are thus conserved. The assay must be sensitive, specific, and designed to yield a readily detectable signal, usually a change in absorption or emission of light (fluorescence, luminescence, phosphorescence) or alteration of a radioactive substrate. The signal may result from the interaction of a candidate chemical with a specific protein target, such as an enzyme or a biological receptor protein that one hopes to inhibit or activate with a drug. Alternatively, cell-based high-throughput screens may be performed. For example, a cell may be engineered to emit a fluorescent signal when Ca2+ fluxes into the cell as a result of a ligand-receptor interaction. Cellular engineering is accomplished by transfecting the necessary genes into the cell, enabling it to perform the functions of interest. It is of enormous value that the specific protein target in an assay or the molecules used to engineer a cell for a high-throughput screen are of human origin, obtained by transcription and translation of the cloned human gene. The potential drugs that are identified in the screen ("hits") are thus known to react with the human protein and not just with its relative (ortholog) obtained from mouse or another species. Several variables affect the frequency of hits obtained in a screen. Among the most important are the "drugability" of the target and the stringency of the screen in terms of the concentrations of compounds that are tested. The slang term "drugability" refers to the ease with which the function of a target can be altered in the desired fashion by a small organic molecule. If the protein target has a well-defined binding site for a small molecule (e.g., a catalytic or allosteric site), chances are excellent that hits will be obtained. If the goal is to employ a small molecule to mimic or disrupt the interaction between two proteins, the challenge is much greater. From Hits to Leads Only rarely do any of the initial hits in a screen turn out to be marketable drugs. Initial hits often have modest affinity for the target, and lack the desired specificity and pharmacological properties of a successful pharmaceutical. Skilled medicinal chemists synthesize derivatives of the hits, making substitutions at accessible positions, and begin in this way to define the relationship between chemical structure and biological activity. Many parameters may require optimization, including affinity for the target, agonist/antagonist activity, permeability across cell membranes, absorption and distribution in the body, metabolism of the drug, and unwanted effects. While this approach was driven largely by instinct and trial and error in the past, modern drug development frequently takes advantage of determination of a high- resolution structure of the putative drug bound to its target. X-ray crystallography offers the most detailed structural information if the target protein can be crystallized with the lead drug bound to it. Using techniques of molecular modeling and computational chemistry, the structure provides the chemist with
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information about substitutions likely to improve the "fit" of the drug with the target and thus enhance the affinity of the drug for its target (and, hopefully, optimize selectivity of the drug simultaneously). Nuclear magnetic resonance (NMR) spectroscopy is another valuable technique for learning the structure of a drug-receptor complex. NMR studies are done in solution, with the advantage that the complex need not be crystallized. However, the structures obtained by NMR spectroscopy usually are not as precise as those from X-ray crystallography, and the protein target must not be larger than roughly 35–40 kDa. The holy grail of this approach to drug invention will be to achieve success entirely through computation. Imagine a database containing detailed chemical information about millions of chemicals and a second database containing detailed structural information about all human proteins. The computational approach is to "roll" all the chemicals over the protein of interest to find those with high-affinity interactions. The dream gets bolder if we acquire the ability to roll the chemicals that bind to the target of interest over all other human proteins to discard compounds that have unwanted interactions. Finally, we also will want to predict the structural and functional consequences of a drug binding to its target (a huge challenge), as well as all relevant pharmacokinetic properties of the molecules of interest. We are a long way from realization of this fabulous dream; however, we are sufficiently advanced to imagine it and realize that it could someday be a reality. Indeed, computational approaches have suggested new uses for old drugs and offered explanations for recent failures of drugs in the later stages of clinical development (e.g., torcetrapib; see below) (Kim et al., 2010; Kinnings et al., 2009; Xie et al., 2007, 2009). Large Molecules Are Increasingly Important Protein therapeutics were uncommon before the advent of recombinant DNA technology. Insulin was introduced into clinical medicine for the treatment of diabetes following the experiments of Banting and Best in 1921. Insulin could be produced in great quantities by purification from porcine or bovine pancreas obtained from slaughter houses. These insulins are active in man, although antibodies to the foreign proteins are occasionally problematic. Growth hormone, used to treat pituitary dwarfism, is a case of more stringent species specificity: only the human hormone could be used after purification from pituitary glands harvested during autopsy. The danger of this approach was highlighted when patients who had received the human hormone developed Creutzfeldt-Jakob disease (the human equivalent of mad cow disease), a fatal degenerative neurological disease caused by prion proteins that contaminated the drug preparation. Thanks to gene cloning and the ability to produce large quantities of proteins by expressing the cloned gene in bacteria or eukaryotic cells grown in enormous (30,000-liter) bioreactors, protein therapeutics now utilize highly purified preparations of human (or humanized) proteins. Rare proteins can now be produced in quantity, and immunological reactions are minimized. Proteins can be designed, customized, and optimized using genetic engineering techniques. Other types of macromolecules may also be used therapeutically. For example, antisense oligonucleotides are used to block gene transcription or translation, as are small interfering RNAs (siRNAs). Proteins utilized therapeutically include various hormones, growth factors (e.g., erythropoietin, granulocyte-colony stimulating factor), and cytokines, as well as a rapidly increasing number of monoclonal antibodies now widely used in the treatment of cancer and autoimmune diseases. Murine monoclonal antibodies can be "humanized" (by substituting human for mouse amino acid sequences). Alternatively, mice have now been "engineered" by replacement of critical mouse genes with their human equivalents, such that they make completely human antibodies. Protein therapeutics are administered parenterally, and their receptors or targets must be accessible extracellularly. TARGETS OF DRUG ACTION The earliest drugs came from observation of the effects of plants after their ingestion by animals. One could observe at least some of the effects of the chemical(s) in the plant and, as a side benefit, know that the plant extract was active when taken orally. Valuable drugs were discovered with no knowledge of their mechanism or site of action. While this approach is still useful (e.g., in screening for the ability of natural products to kill microorganisms or malignant cells), modern drug invention usually takes the opposite approach—starting with a statement (or hypothesis) that a certain protein or pathway plays a critical role in the pathogenesis of a certain disease, and that altering the protein's activity would therefore be effective against that disease. Crucial questions arise:
can one find a drug that will have the desired effect against its target? does modulation of the target protein affect the course of disease? does this project make sense economically?
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The effort that may be expended to find the desired drug will be determined by the degree of confidence in the answers to the latter two questions. Is the Target "Drugable"? The drugability of a target with a low-molecular-weight organic molecule relies on the presence of a binding site for the drug that can be approached with considerable affinity and selectivity. If the target is an enzyme or a receptor for a small ligand, one is encouraged. If the target is related to another protein that is known to have, for example, a binding site for a regulatory ligand, one is hopeful. However, if the known ligands are large peptides or proteins with an extensive set of contacts with their receptor, the challenge is much greater. If the goal is to disrupt interactions between two proteins, it may be necessary to find a "hot spot" that is crucial for the protein-protein interaction, and such a region may not be detected. Accessibility of the drug to its target also is critical. Extracellular targets are intrinsically easier to approach and, in general, only extracellular targets are accessible to macromolecular drugs. Has the Target Been Validated? This question is obviously a critical one. A negative answer, frequently obtained only retrospectively, is a common cause of failure in drug invention. Based on extensive study of a given biological process, one may believe that protein X plays a critical role in pathological alterations of that process. However, biological systems frequently contain redundant elements, and they are adaptable. When the activity of protein X is, e.g., inhibited by a drug, redundancy in the system may permit compensation. The system also may adapt to the presence of the drug, perhaps by regulating the expression of the target or of functionally related gene products. In general, the more important the function, the greater the complexity of the system. For example, many mechanisms control feeding and appetite, and drugs to control obesity have been notoriously difficult to find. The discovery of the hormone leptin, which suppresses appetite, was based on mutations in mice that cause loss of either leptin or its receptor; either kind of mutation results in enormous obesity in both mice and people. Leptin thus appeared to be a marvelous opportunity to treat obesity. However, obese individuals have high circulating concentrations of leptin and appear quite insensitive to its action. Modern techniques of molecular biology offer new and powerful tools for validation of potential drug targets, to the extent that the biology of model systems resembles human biology. Genes can be inserted, disrupted, and altered in mice. One can thereby create models of disease in animals or mimic the effects of long-term disruption or activation of a given biological process. If, for example, disruption of the gene encoding a specific enzyme or receptor has a beneficial effect in a valid murine model of a human disease, one may believe that the potential drug target has been validated. Mutations in humans also can provide extraordinarily valuable information. For example, loss-of-function mutations in the PCSK9 gene (encoding proprotein convertase subtilisin/kexin type 9) greatly lower concentrations of LDL cholesterol in plasma and reduce the risk of myocardial infarction (Horton et al., 2009). This single powerful observation speaks to a well-validated drug target. Based on these findings, many drug companies are actively seeking inhibitors of PCSK9 function. Is This Drug Invention Effort Economically Viable? Drug invention and development is extraordinarily expensive, as discussed later in the chapter. Economic realities influence the direction of science. For example, investor-owned companies generally cannot afford to develop products for rare diseases or for diseases that are common only in economically underdeveloped parts of the world. Funds to invent drugs targeting rare diseases or diseases primarily affecting developing countries (especially parasitic diseases) can come from taxpayers or very wealthy philanthropists; such funds generally will not come from private investors involved in running for-profit companies. ADDITIONAL PRECLINICAL RESEARCH Following the path just described can yield a potential drug molecule that interacts with a validated target and alters its function in the desired fashion (either enhancing or inhibiting the functions of the target). Now one must consider all aspects of the molecule in question—its affinity and selectivity for interaction with the target, its pharmacokinetic properties (absorption, distribution, excretion, metabolism), issues with regard to its large-scale synthesis or purification from a natural source, its pharmaceutical properties (stability, solubility, questions of formulation), and its safety. One hopes to correct, to the extent possible, any obvious deficiencies by modification of the molecule itself or by changes in the way the molecule is presented for use. Before being administered to people, potential drugs are tested for general toxicity by monitoring the
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activity of various systems in two species of animals for extended periods of time. Compounds also are evaluated for carcinogenicity, genotoxicity, and reproductive toxicity. Animals are used for much of this testing, although the predictive value of results obtained in nonhuman species is certainly not perfect. Usually one rodent (usually mouse) and one non-rodent (often rabbit) species are used. In vitro and ex vivo assays are utilized when possible, both to spare animals and to minimize cost. If an unwanted effect is observed, an obvious question is whether it is mechanism-based (i.e., caused by interaction of the drug with its intended target) or due to an off-target effect of the drug. If the latter, there is hope of minimizing the effect by further optimization of the molecule. Before clinical trials of a potential new drug may proceed in the U.S. (that is, before the drug candidate can be administered to a human subject), the sponsor must file an IND (Investigational New Drug) application, which is a request to the U.S. Food and Drug Administration (FDA; see the next section) for permission to administer the drug to human test subjects. The IND describes the rationale and preliminary evidence for efficacy in experimental systems, as well as pharmacology, toxicology, chemistry, manufacturing, and so forth. It also describes the plan for investigating the drug in human subjects. The FDA has 30 days to review the application, by which time the agency may disapprove the application, ask for more data, or allow initial clinical testing to proceed. In the absence of an objection or request for more information within 30 days by the FDA, a clinical trial may begin. CLINICAL TRIALS AND THE ROLE OF THE FDA The FDA is a regulatory agency within the U.S. Department of Health and Human Services. As its mission statement indicates, the FDA:
is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation's food supply, cosmetics, and products that emit radiation. The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health (FDA, 2009).
The first drug-related legislation in the U.S., the Federal Food and Drug Act of 1906, was concerned only with the interstate transport of adulterated or misbranded foods and drugs. There were no obligations to establish drug efficacy or safety. This act was amended in 1938, after the deaths of 105 children from "elixir sulfanilamide," a solution of sulfanilamide in diethylene glycol, an excellent but highly toxic solvent and an ingredient in antifreeze. The enforcement of the amended act was entrusted to the FDA. Toxicity studies as well as approval of a New Drug Application (NDA; see the next section) were required before a drug could be promoted and distributed. Although a new drug's safety had to be demonstrated, no proof of efficacy was required. In the 1960s, thalidomide, a hypnotic drug with no obvious advantages over others, was introduced in Europe. Epidemiological research eventually established that this drug, taken early in pregnancy, was responsible for an epidemic of a relatively rare and severe birth defect, phocomelia. In reaction to this catastrophe, the U.S. Congress passed the Harris-Kefauver amendments to the Food, Drug, and Cosmetic Act in 1962. These amendments established the requirement for proof of efficacy as well of documentation of relative safety in terms of the risk-to-benefit ratio for the disease entity to be treated (the more serious the disease, the greater the acceptable risk).
One of the agency's primary responsibilities is to protect the public from harmful medications. However, the FDA clearly faces an enormous challenge, especially in view of the widely held belief that its mission cannot possibly be accomplished with the available resources. Moreover, harm from drugs that cause unanticipated adverse effects is not the only risk of an imperfect system; harm also occurs when the approval process delays the marketing of a new drug with important beneficial effects. Determining safety and efficacy prior to mass marketing requires careful consideration. The Conduct of Clinical Trials Clinical trials (as applied to drugs) are investigations in human subjects intended to acquire information about the pharmacokinetic and pharmacodynamic properties of a potential drug. Depending on the nature and phase of the trial, it may be designed to evaluate a drug's safety, its efficacy for treatment or prevention of specific conditions in patients, and its tolerability and side effects. Efficacy must be proven and an adequate margin of safety established for a drug to be approved for sale in the U.S. The U.S. National Institutes of Health notes seven ethical requirements that must be met before a clinical trial can begin. These include social value, scientific validity, fair and objective selection of subjects, informed
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consent, favorable ratio of risks to benefits, approval and oversight by an independent review board (IRB), and respect for human subjects. FDA-regulated clinical trials typically are conducted in four phases. The first three are designed to establish safety and efficacy, while Phase IV post-marketing trials delineate additional information regarding new indications, risks, and optimal doses and schedules. Table 1–1 and Figure 1–1 summarize the important features of each phase of clinical trials, especially the attrition at each successive stage over a relatively long and costly process.
Table 1–1 Typical Characteristics of the Various Phases of the Clinical Trials Required for Marketing of New Drugs.
PHASE I First in Human
PHASE II First in Patient
PHASE III Multi-Site Trial
PHASE IV Post-Marketing Surveillance
10-100 participants 50-500 participants A few hundred to a few thousand participants
Many thousands of participants
Usually healthy volunteers; occasionally patients with advanced or rare disease
Patient-subjects receiving experimental drug
Patient-subjects receiving experimental drug
Patients in treatment with approved drug
Open label Randomized and controlled (can be placebo-controlled); may be blinded
Randomized and controlled (can be placebo-controlled) or uncontrolled; may be blinded
Open label
Confirm efficacy in larger population
Adverse events, compliance, drug- drug interactions
Months to 1 year 1-2 years 3-5 years No fixed duration U.S. $10 million US $20 million US $50-100 million — Success rate: 50% Success rate: 30% Success rate: 25-50% —
Figure 1–1.
The phases, time lines, and attrition that characterize the invention of new drugs. See also Table 1–1.
When initial Phase III trials are complete, the sponsor (usually a pharmaceutical company) applies to the FDA for approval to market the drug; this application is called either a New Drug Application (NDA) or a Biologics License Application (BLA). These applications contain comprehensive information, including individual case-report forms from the hundreds or thousands of individuals who have received the drug
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during its Phase III testing. Applications are reviewed by teams of specialists, and the FDA may call on the help of panels of external experts in complex cases. The use of such external advisory committees greatly expands the talent pool available to assist in making important and difficult decisions. Under the provisions of the Prescription Drug User Fee Act (PDUFA, enacted initially in 1992 and renewed in 2007), pharmaceutical companies now provide a significant portion of the FDA budget via user fees, a legislative effort to expedite the drug approval review process. PDUFA also broadened the FDA's drug safety program and increased resources for review of television drug advertising. The larger FDA staffing now in place has shortened the time required for review; nevertheless, the process is a lengthy one. A1-year review time is considered standard, and 6 months is the target if the drug candidate is granted priority status because of its importance in filling an unmet need. Unfortunately, these targets are not always met. Before a drug is approved for marketing, the company and the FDA must agree on the content of the "label" (package insert)—the official prescribing information. This label describes the approved indications for use of the drug and clinical pharmacological information including dosage, adverse reactions, and special warnings and precautions (sometimes posted in a "black box"). Promotional materials used by pharmaceutical companies cannot deviate from information contained in the package insert. Importantly, the physician is not bound by the package insert; a physician in the U.S. may legally prescribe a drug for any purpose that she or he deems reasonable. However, third-party payers (insurance companies, Medicare, and so on) generally will not reimburse a patient for the cost of a drug used for an "off-label" indication unless the new use is supported by one of several compendia such as the U.S. Pharmacopeia. Furthermore, a physician may be vulnerable to litigation if untoward effects result from an unapproved use of a drug. Determining "Safe" and "Effective" To demonstrate efficacy to the FDA requires performing "adequate and well-controlled investigations," generally interpreted to mean two replicate clinical trials that are usually, but not always, randomized, double-blind, and placebo-controlled. Is a placebo the proper control? The World Medical Association's Declaration of Helsinki (2000) discourages use of placebo controls when an alternative treatment is available for comparison. What must be measured in the trials? In a straightforward trial, a readily quantifiable parameter (a secondary or surrogate end point), thought to be predictive of relevant clinical outcomes, is measured in matched drug- and placebo-treated groups. Examples of surrogate end points include LDL cholesterol as a predictor of myocardial infarction, bone mineral density as a predictor of fractures, or hemoglobin A1c as a predictor of the complications of diabetes mellitus. More stringent trials would require demonstration of reduction of the incidence of myocardial infarction in patients taking a candidate drug in comparison with those taking an HMG-CoA reductase inhibitor (statin) or other LDL cholesterol-lowering agent, or reduction in the incidence of fractures in comparison with those taking a bisphosphonate. Use of surrogate end points significantly reduces cost and time required to complete trials but there are many mitigating factors, including the significance of the surrogate end point to the disease or condition that the candidate drug is intended to treat.
Some of the difficulties are well illustrated by recent experiences with ezetimibe, a drug that inhibits absorption of cholesterol from the gastrointestinal tract and lowers LDL cholesterol concentrations in plasma, especially when used in combination with a statin. Lowering of LDL cholesterol was assumed to be an appropriate surrogate end point for the effectiveness of ezetimibe to reduce myocardial infarction and stroke, consequences of cholesterol accumulation in foam cells beneath the endothelium of vessels. Surprisingly, the ENHANCE trial demonstrated that the combination of ezetimibe and a statin did not reduce intima-media thickness of carotid arteries (a more direct measure of sub-endothelial cholesterol accumulation) compared with the statin alone, despite the fact that the drug combination lowered LDL cholesterol concentrations substantially more than did either drug alone (Kastelein et al., 2008). Critics of ENHANCE argue that the patients in the study had familial hypercholesterolemia, had been treated with statins for years, and did not have carotid artery thickening at the initiation of the study. Should ezetimibe have been approved? Must we return to measurement of true clinical end points (e.g., myocardial infarction) before approval of drugs that lower cholesterol by novel mechanisms? The costs involved in such extensive and expensive trials must be borne somehow (costs are discussed later in the chapter). Such a study (IMPROVE-IT) is now in progress; thousands of patients are enrolled and we will know the outcome in a few years.
The drug torcetrapib provides a related example in the same therapeutic area. Torcetrapib elevates
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HDL cholesterol (the "good cholesterol"), and higher levels of HDL cholesterol are statistically associated with (are a surrogate end point for) a lower incidence of myocardial infarction. Surprisingly, clinical administration of torcetrapib caused a significant increase in mortality from cardiovascular events, ending a development path of 15 years and $800 million. (For a recent computational-systems biologic analysis that may explain this failure, see Xie et al., 2009.) In this case, approval of the drug based on this secondary end point would have been a mistake (Cutler, 2007).
The concept of drug safety is perhaps even more complex (Institute of Medicine, 2007). No drug is totally safe; all drugs produce unwanted effects in at least some people at some dose. Many unwanted and serious effects of drugs occur so infrequently, perhaps only once in several thousand patients, that they go undetected in the relatively small populations (a few thousand) in the standard Phase III clinical trial (Table 1–1). To detect and verify that such events are in fact drug-related would require administration of the drug to tens or hundreds of thousands of people during clinical trials, adding enormous expense and time to drug development and delaying access to potentially beneficial therapies. In general, the true spectrum and incidence of untoward effects becomes known only after a drug is released to the broader market and used by a large number of people (Phase IV, post-marketing surveillance). Drug development costs, and thus drug prices, could be reduced substantially if the public were willing to accept more risk. This would require changing the way we think about a pharmaceutical company's liability for damages from an unwanted effect of a drug that was not detected in clinical trials deemed adequate by the FDA. While the concept is obvious, many lose sight of the fact that extremely severe unwanted effects of a drug, including death, may be deemed acceptable if its therapeutic effect is sufficiently unique and valuable. Such dilemmas can become issues for great debate. The sufficiency of a therapeutic effect in the presence of an unwanted effect of a drug may be quite subjective. One person's meat may indeed be another person's poison. Great effort may be made to quantify the ratio of risks to benefits, but the answers are frequently not simple.
Several strategies exist to detect adverse reactions after marketing of a drug, but debate continues about the most efficient and effective method. Formal approaches for estimation of the magnitude of an adverse drug response include the follow-up or "cohort" study of patients who are receiving a particular drug; the "case-control" study, where the frequency of drug use in cases of adverse responses is compared to controls; and meta-analysis of pre- and post-marketing studies. Because of the shortcomings of these types of studies to detect what may be a relatively rare event, additional approaches must be used. Spontaneous reporting of adverse reactions has proven to be an effective way to generate an early signal that a drug may be causing an adverse event (Aagard and Hansen, 2009). It is the only practical way to detect rare events, events that occur after prolonged use of drug, adverse effects that are delayed in appearance, and many drug-drug interactions. Recently, considerable effort has gone into improving the reporting system in the U.S., called MedWatch (Brewer and Colditz, 1999; Kessler et al., 1993; see also Appendix 1). Still, the voluntary reporting system in the U.S. is not nearly as robust as the legally mandated systems of some other countries. A disturbing number of physicians are not aware that the FDA has a reporting system for adverse drug reactions, even though the system has been repeatedly publicized in major medical journals (Trontell, 2004). Relatively few physicians actually file adverse drug response reports; those received frequently are incomplete or of such poor quality that the data are not considered reliable (Fontarosa et al., 2004).
The most important spontaneous reports are those that describe serious reactions. Reports on newly marketed drugs (within the first 5 years of a drug's introduction) are the most significant, even though the physician may not be able to attribute a causal role to a particular drug. This system provides early warning signals of unexpected adverse effects that can then be investigated by more formal techniques. However, the system also serves to monitor changes in the nature or frequency of adverse drug reactions due to aging of the population, changes in the disease itself, or the introduction of new, concurrent therapies. The primary sources for the reports are responsible, alert physicians; other potentially useful sources are nurses, pharmacists, and students in these disciplines. In addition, hospital-based pharmacy and therapeutics committees and quality assurance committees frequently are charged with monitoring adverse drug reactions in hospitalized patients, and reports from these committees should be forwarded to the FDA. The simple forms for reporting may be obtained 24 hours a day, 7 days a week by calling 800-FDA-1088; alternatively, adverse reactions can be reported directly using the Internet (www.fda.gov/medwatch). Health professionals
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also may contact the pharmaceutical manufacturer, who is legally obligated to file reports with the FDA. With this facile reporting system, the clinician can serve as a vital sentinel in the detection of unexpected adverse reactions to drugs.
PUBLIC POLICY CONSIDERATIONS AND CRITICISMS OF THE PHARMACEUTICAL INDUSTRY There is no doubt that drugs can save lives, prolong lives, and improve the quality of people's lives. Like adequate nutrition, vaccinations and medications are important for public health. However, in a free- market economy, access to safe and effective drugs (or any kind of healthcare, for that matter) is not equitable. Not surprisingly, there is a substantial tension between those who would treat drugs as entitlements and those who view drugs as high-tech products of a capitalistic society. Supporters of the entitlement position argue that the constitutional right to life should guarantee access to drugs and other healthcare, and they are critical of pharmaceutical companies and others who profit from the business of making and selling drugs. Free-marketers point out that, without a profit motive, it would be difficult to generate the resources and innovation required for new drug development. The media tend to focus on public policy with regard to the ethics of drug testing, the effectiveness of government regulations, and conflicts of interest on the part of researchers, physicians, and others who may have a personal stake in the success of a drug. In addition, high-profile legal battles have been waged recently over access to experimental (non-FDA-approved) drugs and over injuries and deaths resulting from both experimental and approved drugs. Clearly the public has an interest in both the pharmaceutical industry and its oversight. Consequently, drug development is not only a scientific process but also a political one in which attitudes can change quickly. Little more than a decade ago Merck was named as America's most admired company by Fortune magazine seven years in a row—a record that still stands. Today, Johnson and Johnson is the only pharmaceutical company in the top 50 of the most- admired list, and this likely reflect their sales of consumer products, such as band-aids and baby oil, rather than pharmaceuticals. The next sections explore some of the more controversial issues surrounding drug invention and development and consider some of the more strident criticisms that have been leveled at the pharmaceutical industry (Angell, 2004). Mistrust of Scientists and Industry Those critical of the pharmaceutical industry frequently begin from the position that people (and animals) need to be protected from greedy and unscrupulous companies and scientists (Kassirer, 2005). They can point to the very unfortunate (and highly publicized) occurrences of graft, fraud, and misconduct by scientists and industry executives, and unethical behavior in university laboratories and community physicians' offices. These problems notwithstanding, development of new and better drugs is good for people and animals. In the absence of a government-controlled drug development enterprise, our current system relies predominan

Goodman and Gilmans the Pharmacological Basis of Therapeutics, 12th Edition

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Transcript of Goodman and Gilmans the Pharmacological Basis of Therapeutics, 12th Edition