J
`
`-.
`
`_.fi.‘J
`
`._
`
`DVD INCLUDED
`
`The Pharmacological
`Basis of
`
`LAURENCE L. BRUNTON
`
`BRUCE A. CHABNER
`
`BJCDRN c. KNOLLMANN
`
`Boehringer Ex. 2018
`Mylan v. Boehringer lngelheim
`|PR2016-01564
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`Page 1
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`

`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 pos(cid:173)
`sibility 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 par(cid:173)
`ticular, readers arc 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
`e
`
`s
`
`twelfth edition
`
`editor
`
`l.
`Professor of Pharmacology and Medicine
`School of Medicine, University of California, San Diego
`La Jolla, California
`
`associate editors
`
`Professor of Medicine
`Harvard Medical School
`Director of Clinical Research
`Massachusetts General Hospital Cancer Center
`Boston, Massachusetts
`
`Professor of Medicine and Pharmacology
`Oates Institute for Experimental Therapeutics
`Division of Clinical Pharmacology
`Vanderbilt University School of Medicine
`Nashville, Tennessee
`
`Medical
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`

`In Memoriam
`Keith L. Parker
`(1954-2008)
`
`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 Compa(cid:173)
`nies, 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.
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`ISBN 978-0-07-162442-8
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`Book ISBN 978-0-07-175352-4 Book MHID 0-07-175352-4
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`This book was set in Times by Glyph International.
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`This book is printed on acid-free paper.
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`Library of Congress Cataloging-in-Publication Data
`
`Goodman & Gilman's pharmacological basis of therapeutics.·-- 12th ed. I editor,
`Laurence L. Brunton ; associate editors, Bruce A. Chabner, Bjorn C. Knollmann.
`p.; em.
`Other title: Goodman and Gilman's pharmacological basis of therapeutics
`Other title: Pharmacological basis of therapeutics
`Rev. ed. of: Goodman & Gilman's the pharmacological basis of therapeutics. 11th ed. I editor,
`Laurence L. Brunton. c2006.
`Includes bibliographical references and index.
`ISBN-13: 978-0-07-162442-8 (hardcover: alk. paper)
`ISBN-10: 0-07-162442-2
`II. Brunton, Laurence L.
`I. Goodman, Louis Sanford, 1906-
`l. Pharmacology. 2. Therapeutics.
`III. Chabner, Bruce.
`IV. Knollmann, Bjorn C. V. Goodman & Gilman's the pharmacological
`basis of therapeutics. VI. Title: Goodman and Gilman's pharmacological basis of therapeutics.
`VII. Title: Pharmacological basis of therapeutics.
`[DNLM:
`1. Pharmacological Phenomena. 2. Drug Therapy. QV 4 G6532 2011]
`RM300.G644 2011
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`McGraw-Hill books are available at special quantity discounts to use as premiums or sales promotions, or for use in
`corporate training programs. To contact a representative, please email us at bulksales@mcgraw-hill.com.
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`Page 3
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`

`

`Contributors
`
`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 Califomia, 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
`
`lain L. 0. 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
`
`Boehringer Ex. 2018
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`IPR2016-01564
`Page 4
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`

`

`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
`
`Jerome 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
`
`RichardT. Eastman, PhD
`Fellow in Microbiology
`Columbia University, New York
`
`Ervin G. Erdos, 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
`
`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
`Monash Medical Centre
`Clayton Victoria, 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
`
`Garret A. fitzGerald, MD
`Professor of Medicine, Pharmacology and Translational
`Medicine and Therapeutics;
`Chair of Pharmacology
`University of Pennsylvania School of Medicine, Philadelphia
`
`Stephen R. Hammes, MD, PhD
`Professor of Medicine, Chief of Endocrinology and
`Metabolism
`School of Medicine and Dentistry
`University of Rochester, New York
`
`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
`
`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
`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 0. McNamara, MD
`Professor and Chair of Neurobiology
`Director of Center for Translational Neuroscience
`Duke University Medical Center
`Durham, North Carolina
`
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`

`

`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
`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
`
`DeanS. 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
`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 Childrcns' 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
`
`Keith A. Sharkey, PhD
`Professor of Physiology & Pharmacology and Medicine
`University of Calgary, Alberta
`
`Richard C. Shelton, MD
`Professor of Psyehiatty 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
`
`Bernard P. Schimmer, PhD
`Professor (Emeritus) of Medical Research and Pharmacology
`University of Toronto, Ontario
`
`Jeffrey G. Supko, PhD
`Associate Professor of Medicine, Harvard Medical School
`Massachusetts General Hospital, Boston
`
`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
`
`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
`
`Boehringer Ex. 2018
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`IPR2016-01564
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`
`

`

`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
`
`MarkS. 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
`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
`
`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 appli(cid:173)
`cations of pharmacodynamics to therapeutics, and to
`create a book that will be useful to students of pharma(cid:173)
`cology 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 con(cid:173)
`tributions of previous editors and authors, many of
`whom will see text that looks familiar. However, this
`edition differs noticeably from its immediate predeces(cid:173)
`sors. Fifty new scientists, including a number from out(cid:173)
`side 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 ther(cid:173)
`apy, and pharmacotherapy of obstetrical and gynecol(cid:173)
`ogical disorders. Figures are in full color. The editors
`have continued to standardize the organization of chap(cid:173)
`ters; thus, students should easily tlnd the basic physiol(cid:173)
`ogy, 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 edi(cid:173)
`tion. The entire text, updates, reviews of newly approved
`drugs, animations of drug action, and hyperlinks to rel(cid:173)
`evant text in the prior edition are available on the Good(cid:173)
`man & 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 acknowl(cid:173)
`edged on an accompanying page. In addition, I am
`grateful to Professors Bruce Chabner (Harvard Medical
`School/Massachusetts General Hospital) and Bjorn
`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 edi(cid:173)
`tion. 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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`

`

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`Wong W, Scott JD. AKAP signalling complexes: Focal points in
`space and time. Nat Rev Mol Cell Bioi, 2004, 5:959- 970.
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`Drug Toxicity and Poisoning
`Kevin C. Osterhoudt
`and Trevor M. Penning
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`Pharmacology deals with drugs and their chemical
`properties or characteristics, their mode of action, the
`physiological response to drugs, and the clinical uses
`of drugs. Pharmacology intersects with toxicology
`when the physiological response to a drug is an adverse
`effect. Toxicology is often regarded as the science of
`poisons or poisoning, but developing a strict definition
`for poison is problematic. A poison is any substance,
`including any drug, that has the capacity to harm a
`living organism. The Renaissance physician Paracelsus
`(1493-1541) is famously credited with offering the
`philosophical definition of poisons: "What is there that
`is not poison? All things are poison and nothing is
`without poison. Solely the dose determines that a thing
`is not a poison." However, poisoning inherently implies
`that damaging physiological effects result from
`exposure to pharmaceuticals, illicit drugs, or chemicals.
`So each drug in the pharmacopeia is a potential poison,
`and individual dose-, situation-, environment-, and gene(cid:173)
`related factors contribute to a drug's ability to achieve
`its adverse potential.
`
`Some chemicals may inherently be poisons, such as lead,
`which has no known necessary physiological role in the human body,
`and which is known to cause neuronal injury even at very low
`exposure levels. Most pharmaceuticals are threshold poisons; at
`therapeutic dosing the drug is used to confer a health advantage, but
`at higher doses the drug may produce a toxic effect. For instance,
`iron is a nutrient essential for heme synthesis and numerous
`physiological enzyme functions, but overdose of ferrous sulfate can
`lead to life-threatening multi-organ dysfunction.
`
`DOSE-RESPONSE
`Evaluation of the dose-response or the dose-effect
`~elationship is crucially important to toxicologists. There
`1s a graded dose-response relationship in an individual and
`a quanta! dose-response relationship in the population
`(see Chapters 2 and 3). Graded doses of a drug given to
`
`an individual usually result in a greater magnitude of
`response as the dose is increased. In a quanta! dose(cid:173)
`response relationship, the percentage of the population
`affected increases as the dose is raised; the relationship
`is quanta! in that the effect is specified to be either present
`or absent in a given individual (Figure 4-1 ). This quanta!
`dose-response phenomenon is extremely important in
`toxicology and is used to determine the median lethal
`) of drugs and other chemicals.
`dose (LD50
`The LD
`of a compound is determined experi(cid:173)
`50
`mentally, usually by administration of the chemical to
`mice or rats (orally or intraperitoneally) at several doses
`in the lethal range (Figure 4-1A).
`
`To linearize such data, the response (death) can be converted
`to units of deviation from the mean, or probits (probability units). The
`probit designates the deviation from the median; a probit of 5
`corresponds to a 50% response, and because each probit equals one
`standard deviation, a probit of 4 equals 16% and a probit of 6 equals
`84%. A plot of the percentage of the population responding, in probit
`units, against log close yields a straight line (Figure 4- lB). The LD50
`is determined by drawing a vertical line from the point on the line
`where the probit unit equals 5 (50% mortality). The slope of the close(cid:173)
`effect curve also is important. The LD50 for both compounds depicted
`in Figure 4- 1 is the same ( - 10 mg/kg); however, the slopes of the
`dose-response curves are quite different. At a close equal to one-half the
`LD
`(5 mg/kg), less than 5% of the animals exposed to compound B
`50
`would die, but 30% of the animals given compound A would die.
`
`Figure 4-2 illustrates the relationship between a
`quanta! dose-response curve for the therapeutic effect of
`a drug to generate a median effective dose (ED50), the
`concentration of drug at which 50% of the population
`will have the desired response, and a quanta! dose(cid:173)
`response curve for lethality by the same agent. These
`two curves can be used to generate a therapeutic index
`(TI), which quantifies the relative safety of a drug.
`Clearly, the higher the ratio, the safer the drug.
`
`Boehringer Ex. 2018
`Mylan v. Boehringer Ingelheim
`IPR2016-01564
`Page 8
`
`

`

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`Figure 4-1. Dose-response relationships. A. The toxic response
`to a chemical is evaluated at several doses in the toxic or lethal
`range. The midpoint of the curve representing percent of
`population responding (response here is death) versus dose (log
`scale) represents the LD 50
`, or the concentration of drug that is
`lethal in 50% of the population. B. A linear transformation of the
`data in panel A, obtained by plotting the log of the dose
`administered versus the percent of the population kj\led, in
`probit units.
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`Figure 4-2. Comparison of effective dose (ED), and lethal dose
`(LD). See text for explanation of probit units. Note that abscissa
`is a logarithmic scale.
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`DOSE
`Figure 4-3. U-Shaped dose-response curve for essential metals
`and vitamins. Vitamins and essential metals are essential for life
`and their lack can cause adverse responses (plotted on the
`vertical axis), as can their excess, giving rise to a U-shaped
`concentration-dependence curve.
`
`Drugs show a wide range of TI, from 1-2 to
`> 100. Drugs with a low TI must be administered with
`caution. Agents that fall into this category include the
`cardiac glycoside digitalis and cancer chemotherapeutic
`agents. Agents with very high TI are extremely safe and
`include some antibiotics (e.g., penicillin), unless there
`is a known allergic response.
`The use of median effective and median lethal
`doses is not without disadvantages, because median
`doses do not consider that the slopes of the dose(cid:173)
`response curves for therapeutic and lethal (toxic)
`effects may differ. As an alternative the ED99 for the
`therapeutic effect can be compared to the LD 1 for
`leth