Cover Preface Preface to the Online Edition Copyright Information Contributors Contents 1. Drug Invention & the Pharmaceutical Industry 2. Pharmacokinetics: The Dynamics of Drug Absorption, Distribution,Metabolism & Elimination 3. Pharmacodynamics: Molecular Mechanisms of Drug Action 4. Drug Toxicity & Poisoning 5. Membrane Transporters & Drug Response 6. Drug Metabolism 7. Pharmacogenetics 8. Neurotransmission: The Autonomic & Somatic Motor NervousSystems 9. Muscarinic Receptor Agonists & Antagonists 10. Anticholinesterase Agents 11. Agents Acting at the Neuromuscular Junction & Autonomic Ganglia12. Adrenergic Agonists & Antagonists 13. 5-Hydroxytryptamine (Serotonin) & Dopamine 14. Neurotransmission & the Central Nervous System 15. Drug Therapy of Depression & Anxiety Disorders 16. Pharmacotherapy of Psychosis & Mania 17. Hypnotics & Sedatives 18. Opioids, Analgesia & Pain Management 19. General Anesthetics & Therapeutic Gases 20. Local Anesthetics 21. Pharmacotherapy of the Epilepsies 22. Treatment of Central Nervous System Degenerative Disorders

23. Ethanol & Methanol 24. Drug Addiction 25. Regulation of Renal Function & Vascular Volume 26. Renin & Angiotensin 27. Treatment of Myocardial Ischemia & Hypertension 28. Pharmacotherapy of Congestive Heart Failure 29. Anti-Arrhythmic Drugs 30. Blood Coagulation & Anticoagulant, Fibrinolytic & AntiplateletDrugs 31. Drug Therapy for Hypercholesterolemia & Dyslipidemia 32. Histamine, Bradykinin & Their Antagonists 33. Lipid-Derived Autacoids: Eicosanoids & Platelet-Activating Factor 34. Anti-inflammatory, Antipyretic & Analgesic Agents;Pharmacotherapy of Gout 35. Immunosuppressants, Tolerogens & Immunostimulants 36. Pulmonary Pharmacology 37. Hematopoietic Agents: Growth Factors, Minerals & Vitamins 38. Introduction To Endocrinology: The Hypothalamic-Pituitary Axis 39. Thyroid & Anti-Thyroid Drugs 40. Estrogens & Progestins 41. Androgens 42. ACTH, Adrenal Steroids & Pharmacology of the Adrenal Cortex 43. Endocrine Pancreas & Pharmacotherapy of Diabetes Mellitus &Hypoglycemia 44. Agents Affecting Mineral Ion Homeostasis & Bone Turnover 45. Pharmacotherapy of Gastric Acidity, Peptic Ulcers &Gastroesophageal Reflux Disease 46. Treatment of Disorders of Bowel Motility & Water Flux; Anti-Emetics; Agents Used in Biliary & Pancreatic Disease 47. Pharmacotherapy of Inflammatory Bowel Disease 48. General Principles of Antimicrobial Therapy

49. Chemotherapy of Malaria 50. Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis,Trichomoniasis, Trypanosomiasis, Leishmaniasis & Other ProtozoalInfections 51. Chemotherapy of Helminth Infections 52. Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones &Agents for UrinaryTract Infections 53. Penicillins, Cephalosporins & Other Beta-Lactam Antibiotics 54. Aminoglycosides 55. Protein Synthesis Inhibitors & Miscellaneous Antibacterial Agents 56. Chemotherapy of Tuberculosis, Mycobacterium Avium ComplexDisease & Leprosy 57. Antifungal Agents 58. Antiviral Agents (Nonretroviral) 59. Antiretroviral Agents & Treatment of HIV Infection 60. General Principles of Cancer Chemotherapy 61. Cytotoxic Agents 62. Targeted Therapies: Tyrosine Kinase Inhibitors, MonoclonalAntibodies & Cytokines 63. Natural Products in Cancer Chemotherapy: Hormones & RelatedAgents 64. Ocular Pharmacology 65. Dermatological Pharmacology 66. Contraception & Pharmacotherapy of Obstetrical & GynecologicalDisorders 67. Environmental Toxicology: Carcinogens & Heavy Metals I. Principles of Prescription Order Writing & Patient Compliance II. Design & Optimization of Dosage Regimens: Pharmacokinetic Data

Preface The publication of the twelfth edition of this book is a testament to thevision and ideals of the original authors, Alfred Gilman and LouisGoodman, who, in 1941 set forth the principles that have guided the bookthrough eleven editions: to correlate pharmacology with related medicalsciences, to reinterpret the actions and uses of drugs in light of advancesin medicine and the basic biomedical sciences, to emphasize theapplications of pharmacodynamics to therapeutics, and to create a bookthat will be useful to students of pharmacology and to physicians. Theseprecepts continue to guide the current edition.

As with editions since the second, expert scholars have contributedindividual chapters. A multiauthored book of this sort grows by accretion,posing challenges to editors but also offering memorable pearls to thereader. Thus, portions of prior editions persist in the current edition, and Ihasten to acknowledge the contributions of previous editors and authors,many of whom will see text that looks familiar. However, this editiondiffers 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 basicprinciples continues, with new chapters on drug invention, molecularmechanisms of drug action, drug toxicity and poisoning, principles ofantimicrobial therapy, and pharmacotherapy of obstetrical andgynecological disorders. Figures are in full color. The editors havecontinued to standardize the organization of chapters; thus, studentsshould easily find the basic physiology, biochemistry, and pharmacologyset forth in regular type; bullet points highlight important lists within thetext; the clinician and expert will find details in extract type under clearheadings.

Online features now supplement the printed edition. The entire text,updates, reviews of newly approved drugs, animations of drug action, andhyperlinks to relevant text in the prior edition are available on theGoodman & Gilman section of McGraw-Hill's websites, AccessMedicine.comand AccessPharmacy.com. An Image Bank CD accompanies the book andmakes 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 drugshas slowed to a trickle; therapeutics has barely begun to capitalize on theinformation from the human genome project; and, the development ofresistance 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 onthis edition; they are acknowledged on an accompanying page. Inaddition, I am grateful to Professors Bruce Chabner (Harvard MedicalSchool/Massachusetts General Hospital) and Björn Knollmann (VanderbiltUniversity Medical School) for agreeing to be associate editors of thisedition at a late date, necessitated by the death of my colleague andfriend Keith Parker in late 2008. Keith and I worked together on theeleventh edition and on planning this edition. In anticipation of theeditorial work ahead, Keith submitted his chapters before anyone else andjust a few weeks before his death; thus, he is well represented in thisvolume, which we dedicate to his memory.

Laurence L. BruntonSan Diego, CaliforniaDecember 1, 2010

Goodman & Gilman's ThePharmacological Basis of Therapeutics,12th Edition

Preface to the Online Edition

The first edition of Goodman & Gilman's The PharmacologicalBasis of Therapeutics was published in 1941. Medicine haschanged dramatically since then; so, too, has the delivery ofinformation. The editors of the online version of 12th edition ofGoodman & Gilman are hoping to be at the forefront ofpublishing technology in a project to enhance the premier textin pharmacology and bring it to your desktop.We hope to bring not just the text of the book but to enhancethe text with additional features. The production of on-lineresources for Goodman & Gilman will be guided by threecomplementary priorities:

1. To provide regular updates, particularly in areas ofpharmacology and therapeutics where significant advancesin basic or clinical research have occurred since publicationof the printed version

2. To provide faculty and students with high-quality electronicresources to enhance teaching and learning ofpharmacology

3. To provide comprehensive search results that allow usersquick access to required content

We are currently working on the following online resources toenhance the 12th edition of Goodman & Gilman:

Updates: Regular updates, including new chapter content,a Clinical Pharmacist's Corner that discusses newlyapproved drugs or new therapeutic uses of approveddrugs, and pieces that focus on emerging areas ofpharmacological interest

Grand Rounds: Occasional webcasts of lectures in areas oftherapeutic importance by authorities

Multimedia Content: To complement the text, we have

1st

EditionTable ofContents

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started an ongoing series of interactive, animated versionsof some of the more important figures from Goodman &Gilman, which are useful for interactive self-study bystudents

The Editors of Goodman & Gilman welcome your thoughts onimprovements and corrections to the text, as well assuggestions and submissions for online updates. If you are apharmacologist, pharmacist, physician, or medical scientist andyou would are interested to contribute an update, please sendan email to the Editors at gg_updates@mhedu.com.

The ENIAC (Electronical Numerical Integrator andComputer; circa 1945) was the first electronic computer.The invention of Dr. J. W. Mauchly and Mr. J. Presper Eckert, itcontainied close to 18,000 vacuum tubes, occupied a room 30by 50 feet, weighed 30 tons and cost of more than $486,000.It was used at the War Department's Ballistics ResearchLaboratory to calculate artillery trajectories. (U.S. Army Photo,courtesy of http://ftp.arl.army.mil/~mike/comphist/ andhttp://ftp.arl.army.mil/ftp/historic-computers/.)

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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 CopyrightAct of 1976, no part of this publication may be reproduced or distributedin any form or by any means, or stored in a database or retrieval system,without the prior written permission of the publisher.

ISBN 978-0-07-162442-8MHID 0-07-162442-2

Notice

Medicine is an ever-changing science. As new research and clinicalexperience broaden our knowledge, changes in treatment and drugtherapy are required. The authors and the publisher of this work havechecked with sources believed to be reliable in their efforts to provideinformation that is complete and generally in accord with the standardsaccepted at the time of publication. However, in view of the possibility ofhuman error or changes in medical sciences, neither the authors nor thepublisher nor any other party who has been involved in the preparation orpublication of this work warrants that the information contained herein isin every respect accurate or complete, and they disclaim all responsibilityfor any errors or omissions or for the results obtained from use of theinformation contained in this work. Readers are encouraged to confirm theinformation contained herein with other sources. For example and inparticular, readers are advised to check the product information sheetincluded in the package of each drug they plan to administer to be certainthat the information contained in this work is accurate and that changeshave not been made in the recommended dose or in the contraindicationsfor administration. This recommendation is of particular importance inconnection with new or infrequently used drugs.

Contributors

EditorLaurence L. Brunton, PhDProfessor of Pharmacology and MedicineSchool of Medicine, University of California, San DiegoLa Jolla, California

Associate EditorsBruce A. Chabner, MDProfessor of MedicineHarvard Medical SchoolDirector of Clinical ResearchMassachusetts General Hospital Cancer CenterBoston, Massachusetts

Björn C. Knollmann, MD, PhDProfessor of Medicine and PharmacologyOates Institute for Experimental TherapeuticsDivision of Clinical PharmacologyVanderbilt University School of MedicineNashville, Tennessee

Contributors (print)Edward P. Acosta, PharmDProfessor of Clinical PharmacologyUniversity of Alabama, Birmingham

Peter J. Barnes, DM, DSc, FRCP, FMedSci, FRSProfessor and Head of Respiratory MedicineNational Heart & Lung InstituteImperial College, London

Jeffrey A. Barnes, MD, PhDFellow in Hematology-OncologyDana-Farber Cancer InstituteBoston, Massachusetts

Leslie Z. Benet, PhDProfessor of Bioengineering and Therapeutic Sciences

Schools of Pharmacy and MedicineUniversity of California, San Francisco

John E. Bennett, MDChief of Clinical MycologyNational Institute of Allergy and Infectious DiseasesBethesda, Maryland

William Bennett, MDProfessor (Emeritus) of Medicine and PharmacologyOregon Health & Science University, Portland

Thomas P. Bersot, MD, PhDProfessor of Medicine; Associate InvestigatorGladstone Institute of Cardiovascular DiseaseUniversity of California, San Francisco

Joseph R. Bertino, MDProfessor of Medicine and PharmacologyRobert Wood Johnson Medical SchoolUniversity of Medicine & Dentistry of New JerseyNew Brunswick

Donald K. Blumenthal, PhDAssociate Professor of Pharmacology & ToxicologyCollege of PharmacyUniversity of Utah, Salt Lake City

Viengngeun Bounkeua, PhDMedical Scientist Training Program, School of MedicineUniversity of California, San Diego

Gregory A. Brent, MDProfessor of Medicine and PhysiologyGeffen School of MedicineUniversity of California, Los Angeles

Joan Heller Brown, PhDProfessor and Chair of PharmacologyUniversity of California, San Diego

Craig N. Burkhart, MDAssistant Professor of Dermatology, School of Medicine

University of North Carolina, Chapel Hill

Iain L. O. Buxton, PharmDProfessor of PharmacologyUniversity of Nevada School of Medicine, Reno

Michael C. Byrns, PhDFellow in PharmacologyUniversity of Pennsylvania School of Medicine, Philadelphia

William A. Catterall, PhDProfessor and Chair of PharmacologyUniversity of Washington School of Medicine, Seattle

Bruce A. Chabner, MDProfessor of Medicine, Harvard Medical SchoolDirector of Clinical Research, Massachusetts General Hospital CancerCenterBoston, Massachusetts

Henry F. Chambers, MDProfessor of Medicine and Chief of Infectious DiseasesSan Francisco General HospitalUniversity of California, San Francisco

Jérôme Clain, PharmD, PhDResearch Fellow in Microbiology and ImmunologyCollege of Physicians and SurgeonsColumbia University, New York

James M. Cleary MD, PhDAttending PhysicianDana-Farber Cancer InstituteBoston, Massachusetts

Michael W.H. Coughtrie, PhDProfessor of Biochemical PharmacologyDivision of Medical SciencesUniversity of Dundee, Scotland

David D'Alessio, MDProfessor of Endocrinology and MedicineUniversity of Cinncinnati, Ohio

Richard T. Eastman, PhDFellow in MicrobiologyColumbia University, New York

Ervin G. Erdös, MDProfessor (Emeritus) of PharmacologyUniversity of Illinois-Chicago

David A. Fidock, PhDAssociate Professor of Microbiology and MedicineCollege of Physicians and SurgeonsColumbia University, New York

Garret A. FitzGerald, MDProfessor of Medicine, Pharmacology and TranslationalMedicine and TherapeuticsChair of PharmacologyUniversity of Pennsylvania School of Medicine, Philadelphia

Charles W. Flexner, MDProfessor of Medicine, Pharmacology and Molecular Sciences, andInternational HealthThe Johns Hopkins University School of Medicine and Bloomberg School ofPublic HealthBaltimore, Maryland

Peter A. Friedman, PhDProfessor of Pharmacology and Chemical Biology School of MedicineUniversity of Pittsburgh, Pennsylvania

John W. Funder, AO, MD, BS, PhD, FRACPProfessor of Medicine, Prince Henry's InstituteMonash Medical CentreClaytonVictoria, Australia

James C. Garrison, PhDProfessor of Pharmacology, School of MedicineUniversity of Virginia, Charlottesville

Kathleen M. Giacomini, PhDProfessor and Chair of Biopharmaceutical Sciences School of PharmacyUniversity of California, San Francisco

Alfred G. Gilman, MD, PhDProfessor (Emeritus) of PharmacologyUniversity of Texas Southwestern Medical SchoolChief Scientific Officer, Cancer Prevention and Research Institute ofTexas, Dallas

Lowell A. Goldsmith, MD, MPHProfessor of Dermatology, School of MedicineUniversity of North Carolina, Chapel Hill, North Carolina

Frank J. Gonzalez, PhDChief, Laboratory of MetabolismCenter for Cancer Research, National Cancer InstituteBethesda, Maryland

Tilo Grosser, MDAssistant Professor of PharmacologyInstitute for Translational Medicine and TherapeuticsUniversity of Pennsylvania, Philadelphia

Tawanda Gumbo, MDAssociate Professor of Internal MedicineUniversity of Texas Southwestern Medical School, Dallas

Stephen R. Hammes, MD, PhDProfessor of Medicine, Chief of Endocrinology and MetabolismSchool of Medicine and DentistryUniversity of Rochester, New York

R. Adron Harris, PhDProfessor of Molecular Biology; Director, Waggoner Center for Alcohol andAddiction ResearchUniversity of Texas, Austin

Lisa A. Hazelwood, PhDResearch Fellow, Molecular Neuropharmacology SectionNational Institute of Neurological Disorders and StrokeBethesda, Maryland

Jeffrey D. Henderer, MDProfessor and Chair of OphthalmologyTemple University School of Medicine

Philadelphia, Pennsylvania

Ryan E. Hibbs, PhDResearch Fellow, Vollum InstituteOregon Health & Science University, Portland

Randa Hilal-Dandan, PhDLecturer in PharmacologyUniversity of California, San Diego

Brian B. Hoffman, MDProfessor of Medicine, Harvard Medical SchoolPhysician, VA-Boston Health Care SystemBoston, Massachusetts

Peter J. Hotez, MD, PhDProfessor and Chair of Microbiology, Immunology, and Tropical MedicineGeorge Washington University Washington, DC

Nina Isoherranen, PhDAssistant Professor of Pharmaceutics, School of PharmacyUniversity of Washington, Seattle

Edwin K. Jackson, PhDProfessor of Pharmacology and Chemical Biology School of MedicineUniversity of Pittsburgh, Pennsylvania

Allen P. Kaplan, MDClinical Professor of MedicineMedical University of South Carolina, Charleston

Robert S. Kass, PhDProfessor and Chair of Pharmacology Vice Dean for ResearchCollege of Physicians and Surgeons Columbia University, New York

Kenneth Kaushansky, MDDean, School of Medicine and Senior Vice President of Health SciencesSUNY Stony Brook, New York

Thomas J. Kipps, MD, PhDProfessor of Medicine, Moores Cancer CenterUniversity of California, San Diego

Ronald J. Koenig, MD, PhDProfessor of Metabolism, Endocrinology and DiabetesDepartment of Internal MedicineUniversity of Michigan Health System, Ann Arbor

Alan M. Krensky, MDSenior Investigator, National Cancer Institute, Bethesda, Maryland

Nora Laiken, PhDLecturer in Pharmacology and MedicineUniversity of California, San Diego

Andrew A. Lane, MD, PhDFellow, Dana-Farber Cancer InstituteMassachusetts General Hospital Cancer Center, Boston

Richard J. Lee, MD, PhDProfessor of Medicine, Harvard Medical SchoolPhysician, Massachusetts General HospitalBoston, Massachusetts

Ellis R. Levin, MDProfessor of Medicine; Chief of EndocrinologyDiabetes and MetabolismUniversity of California, Irvine, and Long BeachVA Medical Center, Long Beach

Dan L. Longo, MDScientific Director, National Institute on AgingNational Institutes of Health, Bethesda, Maryland

Alex Loukas, PhDProfessor of Public Health, Tropical Medicine and Rehabilitation SciencesJames Cook University, Cairns, Australia

Conan MacDougall, PharmD, MASAssociate Professor of Clinical Pharmacy School of PharmacyUniversity of California, San Francisco

Kenneth P. Mackie, MDProfessor of NeuroscienceIndiana University, Bloomington

Bradley A. Maron, MDFellow in Cardiovascular MedicineHarvard Medical School and Brigham and Women's HospitalBoston, Massachusetts

James McCarthy, MDAssociate Professor of Clinical Tropical MedicineUniversity of QueenslandBrisbane, Australia

James O. McNamara, MDProfessor and Chair of NeurobiologyDirector of Center for Translational NeuroscienceDuke University Medical CenterDurham, North Carolina

Jonathan M. Meyer, MDAssistant Adjunct Professor of PsychiatryUniversity of California, San Diego

Thomas Michel, MD, PhDProfessor of Medicine and Biochemistry Harvard Medical SchoolSenior Physician in Cardiovascular Medicine Brigham and Women'sHospitalBoston, Massachusetts

S. John Mihic, PhDProfessor of NeurobiologyWaggoner Center for Alcohol & Addiction ResearchInstitute for Neuroscience and Cell & Molecular BiologyUniversity of Texas, Austin

Constantine S. Mitsiades, MD, PhDProfessor of Medical OncologyDana-Farber Cancer Institute, Harvard Medical SchoolBoston, Massachusetts

Perry Molinoff, MDProfessor of Pharmacology, School of MedicineUniversity of Pennsylvania, Philadelphia

Dean S. Morrell, MDAssociate Professor of Dermatology

University of North Carolina, Chapel Hill

Beverly Moy, MD, MPHAssistant Professor of MedicineHarvard Medical SchoolMassachusetts General Hospital, Needham

Hamza Mujagic, MD, MR. SCI, DR. SCIVisiting Professor of Hematology and OncologyHarvard Medical SchoolMassachusetts General Hospital, Needham

Joel W. Neal, MD, PhDAssistant Professor of Medicine-Oncology, Stanford University School ofMedicine, Palo Alto, California

Charles P. O'Brien, MD, PhDProfessor of Psychiatry, School of MedicineUniversity of Pennsylvania, Philadelphia

James O'Donnell, PhDProfessor of Behavioral Medicine and Psychiatry School of MedicineWest Virginia University, Morgantown

Erin M. Olson, MDFellow in Medical OncologyDana-Farber Cancer InstituteBoston, Massachusetts

Taylor M. Ortiz, MDClinical Fellow in Medical OncologyDana-Farber Cancer InstituteGeneral Hospital Cancer CenterBoston, Massachusetts

Kevin Osterhoudt, MD, MSCE, FAAP, FACMTAssociate Professor of Pediatrics School of Medicine, University ofPennsylvaniaMedical Director, Poison Control Center, Children's Hospital ofPhiladelphia, Pennsylvania

Keith L. Parker, MD, PhD (deceased)Professor of Internal Medicine and Pharmacology

Chief of Endocrinology and MetabolismUniversity of Texas Southwestern Medical School, Dallas

Hemal H. Patel, PhDAssociate Professor of AnesthesiologyUniversity of California, San Diego Dean, School of Medicine and SeniorVice President of Health SciencesSUNY Stony Brook, New York

Piyush M. Patel, MD, FRCPCProfessor of AnesthesiologyUniversity of California, San Diego

Trevor M. Penning, PhDProfessor of PharmacologyDirector, Center of Excellence in Environmental Toxicology School ofMedicineUniversity of Pennsylvania, Philadelphia

William A. Petri, Jr, MD, PhDProfessor of Medicine; Chief, Division of Infectious DiseasesUniversity of Virginia, Charlottesville

Margaret A. Phillips, PhDProfessor of PharmacologyUniversity of Texas Southwestern Medical School, Dallas

Alvin C. Powers, MDProfessor of Medicine, Molecular Physiology and BiophysicsVanderbilt University Medical CenterNashville, Tennessee

Christopher Rapuano, MDDirector, Cornea Service and Refractive SurgeryDepartment, Wills Eye InstitutePhiladelphia, Pennsylvania

Robert F. Reilly, Jr, MDProfessor of Internal MedicineUniversity of Texas Southwestern Medical School, DallasChief of NephrologyVA-North Texas Health Care System, Dallas

Mary V. Relling, PharmDChair of Pharmaceutical SciencesSt. Jude Childrens' Research HospitalMemphis, Tennessee

Paul G. Richardson, MDAssociate Professor of Medicine, Harvard Medical SchoolClinical Director, Lipper Center for Multiple MyelomaDana-Farber Cancer InstituteBoston, Massachusetts

Suzanne M. Rivera, PhD, MSWAssistant Professor of Clinical SciencesUniversity of Texas Southwestern Medical Center, Dallas

Erik Roberson, MD, PhDAssistant Professor of Neurology and NeurobiologyUniversity of Alabama, Birmingham

Thomas P. Rocco, MDAssociate Professor of MedicineHarvard Medical SchoolVA-Boston Healthcare SystemBoston, Massachusetts

David M. Roth, MD, PhDProfessor of AnesthesiologyUniversity of California, San DiegoVA-San Diego Healthcare System

David P. Ryan, MDAssociate Professor of MedicineHarvard Medical SchoolMassachusetts General Hospital Cancer Center, Boston

Kevin J. Sampson, PhDPostdoctoral Research Scientist in PharmacologyColumbia University, New York

Elaine Sanders-Bush, PhDProfessor (Emerita) of PharmacologySchool of Medicine, Vanderbilt UniversityNashville, Tennessee

Bernard P. Schimmer, PhDProfessor (Emeritus) of Medical Research and PharmacologyUniversity of Toronto, Ontario

Marc A. Schuckit, MDDistinguished Professor of PsychiatryUniversity of California, San DiegoDirector, Alcohol Research CenterVA-San Diego Healthcare System

Lecia Sequist, MD, MPHAssistant Professor of MedicineHarvard Medical School, Massachusetts General Hospital Cancer Center,Boston

Keith A. Sharkey, PhDProfessor of Physiology & Pharmacology and MedicineUniversity of Calgary, Alberta

Richard C. Shelton, MDProfessor of Psychiatry and PharmacologySchool of Medicine, Vanderbilt UniversityNashville, Tennessee

Danny Shen, PhDProfessor and Chair of PharmacyProfessor of Pharmaceutics, School of PharmacyUniversity of Washington, Seattle

Randal A. Skidgel, PhDProfessor of Pharmacology and AnesthesiologyCollege of Medicine, University of Illinois-Chicago

Matthew R. Smith, MD, PhDAssociate Professor of Medicine, Harvard Medical SchoolPhysician, Massachusetts General Hospital, Boston

Emer M. Smyth, PhDResearch Assistant, Professor of PharmacologyUniversity of Pennsylvania, Philadelphia

Peter J. Snyder, MD

Professor of MedicineUniversity of Pennsylvania, Philadelphia

David Standaert, MD, PhDProfessor of NeurologyDirector, Center for Neurodegeneration and Experimental TherapeuticsUniversity of Alabama, Birmingham

Samuel L. Stanley, Jr, MDProfessor of Medicine and PresidentSUNY Stony Brook, New York

Yuichi Sugiyama, PhDProfessor and Chair of Molecular PharmacokineticsUniversity of Tokyo, Japan

Jeffrey G. Supko, PhDAssociate Professor of Medicine, Harvard Medical SchoolMassachusetts General Hospital, Boston

Palmer W. Taylor, PhDProfessor of Pharmacology, School of MedicineDean, Skaggs School of Pharmacy and Pharmaceutical SciencesUniversity of California, San Diego

Kenneth E. Thummel, PhDProfessor and Chair, Department of PharmaceuticsUniversity of Washington, Seattle

Robert H. Tukey, PhDProfessor of Pharmacology and Chemistry/BiochemistryUniversity of California, San Diego

Flavio Vincenti, MDProfessor of Clinical MedicineMedical Director, Pancreas Transplant ProgramUniversity of California, San Francisco

Joseph M. Vinetz, MDProfessor of Medicine, Division of Infectious DiseasesUniversity of California, San Diego

Mark S. Wallace, MD

Professor of Clinical AnesthesiologyUniversity of California, San Diego

John L. Wallace, PhD, MBA, FRSCProfessor and Director, Farncombe Family Digestive Health ResearchInstituteMcMaster University, Hamilton, Ontario

Jeffrey I. Weitz, MD, FRCP(C), FACPProfessor of Medicine, Biochemistry and Biomedical Sciences McMasterUniversityExecutive Director, Thrombosis & AtherosclerosisResearch Institute, Hamilton, Ontario

David P. Westfall, PhDProfessor (Emeritus) of PharmacologyUniversity of Nevada School of Medicine, Reno

Thomas C. Westfall, PhDProfessor and Chair of Pharmacological and Physiological ScienceSt. Louis University School of Medicine, Missouri

Wyndham Wilson, MD, PhDSenior Investigator and Chief of Lymphoid Therapeutics SectionCenter for Cancer Research, National Cancer InstituteBethesda Maryland

Tony L. Yaksh, PhDProfessor of Anesthesiology and PharmacologyUniversity of California, San Diego

Alexander C. Zambon, PhDAssistant Professor of PharmacologyUniversity of California, San Diego

Contributors (online)

Editor-in-Chief

Laurence L. Brunton

Associate Editors

Donald K. Blumenthal

Nelda Murri

Randa Hilal-DandanLecturer in PharmacologyUniversity of California, San Diego

Consulting Editor

Björn C. Knollmann

Preface Preface to the Online Edition Copyright Contributors

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

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 RefluxDisease

Chapter 46 Treatment of Disorders of Bowel Motility & Water Flux; Anti-Emetics; AgentsUsed 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 forUrinaryTract 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

Appendix I Principles of Prescription Order Writing & PatientCompliance

Appendix II Design & Optimization of Dosage Regimens:Pharmacokinetic Data