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 Contents
Contributors ix
Preface xv
Acknowledgments xvii
Section I
General Principles
1. Drug Invention and the Pharmaceutical Industry............................. 3
Suzanne M. Rivera and Alfred Goodman Gilman
2. Pharmacokinetics: The Dynamics of Drug Absorption,
Distribution, Metabolism, and Elimination...................................... 13
Iain L. O. Buxton
3. Pharmacodynamics: Molecular Mechanisms of Drug Action........ 31
Donald K. Blumenthal
4. Drug Toxicity and Poisoning............................................................... 55
Michelle A. Erickson and Trevor M. Penning
5. Membrane Transporters and Drug Response................................... 65
Kathleen M. Giacomini and Yuichi Sugiyama
6. Drug Metabolism.................................................................................. 85
Frank J. Gonzalez, Michael Coughtrie, and Robert H. Tukey
7. Pharmacogenetics............................................................................... 101
Dan M. Roden
Section II
Neuropharmacology 113
8. Neurotransmission: The Autonomic and Somatic Motor
Nervous Systems................................................................................. 115
Thomas C. Westfall, Heather Macarthur, and David P. Westfall
9. Muscarinic Receptor Agonists and Antagonists............................. 149
Joan Heller Brown, Katharina Brandl, and Jürgen Wess
10. Anticholinesterase Agents.................................................................. 163
Palmer Taylor
11. Nicotine and Agents Acting at the Neuromuscular
Junction and Autonomic Ganglia..................................................... 177
Ryan E. Hibbs and Alexander C. Zambon
12. Adrenergic Agonists and Antagonists.............................................. 191
Thomas C. Westfall, Heather Macarthur, and David P. Westfall
13. 5-Hydroxytryptamine (Serotonin) and Dopamine........................ 225
David R. Sibley, Lisa A. Hazelwood, and Susan G. Amara
14. Neurotransmission in the Central Nervous System....................... 243
R. Benjamin Free, Janet Clark, Susan Amara, and David R. Sibley
15. Drug Therapy of Depression and Anxiety Disorders..................... 267
James M. O’Donnell, Robert R. Bies, and Richard C. Shelton
16. Pharmacotherapy of Psychosis and Mania...................................... 279
Jonathan M. Meyer
17. Pharmacotherapy of the Epilepsies................................................... 303
Misty D. Smith, Cameron S. Metcalf, and Karen S. Wilcox
18. Treatment of Central Nervous System
Degenerative Disorders...................................................................... 327
Erik D. Roberson
19. Hypnotics and Sedatives.................................................................... 339
S. John Mihic, Jody Mayfield, and R. Adron Harris
Brunton_FM_pi-pxviii.indd 7
20. Opioids, Analgesia, and Pain Management..................................... 355
Tony Yaksh and Mark Wallace
21. General Anesthetics and Therapeutic Gases................................... 387
Hemal H. Patel, Matthew L. Pearn, Piyush M. Patel,
and David M. Roth
22. Local Anesthetics................................................................................ 405
1 William A. Catterall and Kenneth Mackie
23. Ethanol.................................................................................................. 421
S. John Mihic, George F. Koob, Jody Mayfield,
and R. Adron Harris
24. Drug Use Disorders and Addiction.................................................. 433
Charles P. O’Brien
Section III
Modulation of Pulmonary, Renal, and
Cardiovascular Function 443
25. Drugs Affecting Renal Excretory Function..................................... 445
Edwin K. Jackson
26. Renin and Angiotensin....................................................................... 471
Randa Hilal-Dandan
27. Treatment of Ischemic Heart Disease............................................... 489
Thomas Eschenhagen
28. Treatment of Hypertension................................................................ 507
Thomas Eschenhagen
29. Therapy of Heart Failure.................................................................... 527
Thomas Eschenhagen
30. Antiarrhythmic Drugs........................................................................ 547
Bjorn C. Knollmann and Dan M. Roden
31. Treatment of Pulmonary Arterial Hypertension............................ 573
Dustin R. Fraidenburg, Ankit A. Desai, and Jason X.-J. Yuan
32. Blood Coagulation and Anticoagulant, Fibrinolytic, and
Antiplatelet Drugs............................................................................... 585
Kerstin Hogg and Jeffrey I. Weitz
33. Drug Therapy for Dyslipidemias....................................................... 605
Holly E. Gurgle and Donald K. Blumenthal
Section IV
Inflammation, Immunomodulation,
and Hematopoiesis 619
34. Introduction to Immunity and Inflammation................................. 621
Nancy Fares-Frederickson and Michael David
35. Immunosuppressants and Tolerogens.............................................. 637
Alan M. Krensky, Jamil R. Azzi, and David A. Hafler
36. Immune Globulins and Vaccines...................................................... 655
Roberto Tinoco and James E. Crowe, Jr.
37. Lipid-Derived Autacoids: Eicosanoids and
Platelet-Activating Factor................................................................... 673
Emer M. Smyth, Tilo Grosser, and Garret A. FitzGerald
38. Pharmacotherapy of Inflammation, Fever, Pain, and Gout........... 685
Tilo Grosser, Emer M. Smyth, and Garret A. FitzGerald
08/09/17 2:51 PM
 viii 39. Histamine, Bradykinin, and Their Antagonists.............................. 711 57. Penicillins, Cephalosporins, and Other
Randal A. Skidgel β-Lactam Antibiotics........................................................................ 1023
40. Pulmonary Pharmacology................................................................. 727 Conan MacDougall
Peter J. Barnes 58. Aminoglycosides............................................................................... 1039
41. Hematopoietic Agents: Growth Factors, Conan MacDougall
Minerals, and Vitamins...................................................................... 751 59. Protein Synthesis Inhibitors and Miscellaneous
Kenneth Kaushansky and Thomas J. Kipps Antibacterial Agents......................................................................... 1049
Conan MacDougall
Contents

Section V 60. Chemotherapy of Tuberculosis, Mycobacterium avium

Complex Disease, and Leprosy....................................................... 1067
Hormones and Hormone Antagonists 769 Tawanda Gumbo
42. Introduction to Endocrinology: 61. Antifungal Agents............................................................................. 1087
The Hypothalamic-Pituitary Axis..................................................... 771 P. David Rogers and Damian J. Krysan
Mark E. Molitch and Bernard P. Schimmer 62. Antiviral Agents (Nonretroviral).................................................... 1105
43. Thyroid and Antithyroid Drugs........................................................ 787 Edward P. Acosta
Gregory A. Brent and Ronald J. Koenig 63. Treatment of Viral Hepatitis (HBV/HCV).................................... 1119
44. Estrogens, Progestins, and the Female Reproductive Tract........... 803 Jennifer J. Kiser and Charles W. Flexner
Ellis R. Levin, Wendy S. Vitek, and Stephen R. Hammes 64. Antiretroviral Agents and Treatment of HIV Infection............... 1137
45. Androgens and the Male Reproductive Tract................................. 833 Charles W. Flexner
Peter J. Snyder
46. Adrenocorticotropic Hormone, Adrenal Steroids,
and the Adrenal Cortex...................................................................... 845
Section VIII
Bernard P. Schimmer and John W. Funder Pharmacotherapy of Neoplastic Disease 1159
47. Endocrine Pancreas and Pharmacotherapy of 65. General Principles in the Pharmacotherapy of Cancer................ 1161
Diabetes Mellitus and Hypoglycemia............................................... 863 Anton Wellstein
Alvin C. Powers and David D’Alessio 66. Cytotoxic Drugs................................................................................ 1167
48. Agents Affecting Mineral Ion Homeostasis and Anton Wellstein, Giuseppe Giaccone, Michael B. Atkins,
Bone Turnover.................................................................................... 887 and Edward A. Sausville
Thomas D. Nolin and Peter A. Friedman 67. Pathway-Targeted Therapies: Monoclonal Antibodies, Protein
Kinase Inhibitors, and Various Small Molecules.......................... 1203
Anton Wellstein, Giuseppe Giaccone, Michael B. Atkins,
Section VI and Edward A. Sausville
Gastrointestinal Pharmacology 907 68. Hormones and Related Agents in the Therapy of Cancer........... 1237
49. Pharmacotherapy for Gastric Acidity, Peptic Ulcers, and Claudine Isaacs, Anton Wellstein, and Anna T. Riegel
Gastroesophageal Reflux Disease...................................................... 909
Keith A. Sharkey and Wallace K. MacNaughton
Section IX
50. Gastrointestinal Motility and Water Flux, Emesis, and
Biliary and Pancreatic Disease.......................................................... 921
Special Systems Pharmacology 1249
Keith A. Sharkey and Wallace K. MacNaughton 69. Ocular Pharmacology....................................................................... 1251
Jeffrey D. Henderer and Christopher J. Rapuano
51. Pharmacotherapy of Inflammatory Bowel Disease........................ 945
Wallace K. MacNaughton and Keith A. Sharkey 70. Dermatological Pharmacology........................................................ 1271
Matthew J. Sewell, Craig N. Burkhart, and Dean S. Morrell
71. Environmental Toxicology: Carcinogens
Section VII and Heavy Metals.............................................................................. 1297
Chemotherapy of Infectious Diseases 955 Michael C. Byrns and Trevor M. Penning
52. General Principles of Antimicrobial Therapy................................. 957
Tawanda Gumbo
Appendices
53. Chemotherapy of Malaria.................................................................. 969
I. Principles of Prescription Order Writing
Joseph M. Vinetz
and Patient Compliance................................................................... 1317
54. Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Iain L. O. Buxton
Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other
II. Design and Optimization of Dosage Regimens:
Protozoal Infections............................................................................ 987
Pharmacokinetic Data...................................................................... 1325
Dawn M. Wetzel and Margaret A. Phillips
Kenneth E. Thummel, Danny D. Shen, and Nina Isoherranen
55. Chemotherapy of Helminth Infections.......................................... 1001
Jennifer Keiser, James McCarthy, and Peter Hotez
Index 1379
56. Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones,
and Agents for Urinary Tract Infections........................................ 1011
Conan MacDougall

Brunton_FM_pi-pxviii.indd 8 08/09/17 2:51 PM

 Contributors

Edward P. Acosta, PharmD Craig N. Burkhart, MD

Professor and Director, Division of Clinical Pharmacology Associate Professor of Dermatology, School of Medicine
University of Alabama at Birmingham School of Medicine University of North Carolina
Birmingham, Alabama Chapel Hill, North Carolina

Susan G. Amara, PhD Iain L. O. Buxton, PharmD

Scientific Director Foundation Professor and Chair
National Institute of Mental Health Department of Pharmacology
National Institutes of Health University of Nevada, Reno School of Medicine
Bethesda, Maryland Reno, Nevada

Michael B. Atkins, MD Michael C. Byrns, PhD

Professor of Oncology and Medicine Associate Professor of Environmental Health
Georgetown University, School of Medicine Illinois State University
Washington DC Normal, Illinois

Jamil Azzi, MD, FAST William A. Catterall, PhD

Assistant Professor of Medicine Professor and Chair of Pharmacology
Transplantation Research Center University of Washington School of Medicine
Harvard Medical School Seattle, Washington
Boston, Massachusetts
Janet A. Clark, PhD
Peter J. Barnes, DM, DSc, FRCP, FMedSci, FRS Director, Office of Fellowship Training
Professor and Head of Respiratory Medicine Intramural Research Program
National Heart & Lung Institute National Institute of Mental Health
Imperial College, London National Institutes of Health
Bethesda, Maryland
Robert R. Bies, PharmD, PhD
Associate Professor Michael W. H. Coughtrie, PhD
School of Pharmacy and Pharmaceutical Sciences Professor and Dean
University at Buffalo Faculty of Pharmaceutical Sciences
The State University of New York University of British Columbia
Buffalo, New York Vancouver, Canada

Donald K. Blumenthal, PhD James E. Crowe, Jr.

Associate Professor of Pharmacology & Toxicology Professor of Pediatrics, Pathology, Microbiology and Immunology
College of Pharmacy Director, Vanderbilt Vaccine Center
University of Utah Vanderbilt University Medical Center
Salt Lake City, Utah Nashville, Tennessee

Katharina Brandl, PhD David D’Alessio, MD

Assistant Professor of Pharmacy Professor, Department of Medicine
University of California San Diego Director, Division of Endocrinology
Skaggs School of Pharmacy and Pharmaceutical Sciences Duke University Medical Center
La Jolla, California Durham, North Carolina

Gregory A. Brent, MD Michael David, PharmD, PhD

Professor of Medicine and Physiology Professor of Biology and Moores Cancer Center
Geffen School of Medicine University of California, San Diego
University of California La Jolla, California
Los Angeles, California
Ankit A. Desai, MD
Joan Heller Brown, PhD Assistant Professor of Medicine
Professor and Chair of Pharmacology University of Arizona
University of California Tucson, Arizona
San Diego, California

Brunton_FM_pi-pxviii.indd 9 08/09/17 2:51 PM

 x Michelle Erickson, PhD Frank J. Gonzalez, PhD
Research Assistant Professor of Gerontology and Geriatric Chief, Laboratory of Metabolism
Medicine, School of Medicine Center for Cancer Research, National Cancer Institute
University of Washington Bethesda, Maryland
Seattle, Washington
Tilo Grosser, MD
Thomas Eschenhagen, MD Research Associate Professor of Pharmacology
Professor of Pharmacology and Toxicology Institute for Translational Medicine and Therapeutics
Contributors

Chair of Pharmacology University of Pennsylvania

University Medical Center Hamburg Eppendorf Philadelphia, Pennsylvania
Hamburg, Germany
Tawanda Gumbo, MD
Nancy Fares-Frederickson, PhD Director, Center for Infectious Diseases Research and
Division of Biology and Moores Cancer Center Experimental Therapeutics
University of California, San Diego Baylor Research Institute
La Jolla, California Baylor University Medical Center
Dallas, Texas
Garret A. FitzGerald, MD
Professor of Medicine, Pharmacology and Translational Medicine Holly Gurgle, PharmD, BCACP, CDE
and Therapeutics; Assistant Professor (Clinical) of Pharmacotherapy
Chair of Pharmacology College of Pharmacy
University of Pennsylvania School of Medicine University of Utah
Philadelphia, Pennsylvania Salt Lake City, Utah

Charles W. Flexner, MD David A. Hafler, MD

Professor of Medicine, Pharmacology and Molecular William S. and Lois Stiles Edgerly Professor of Neurology and
Sciences, and International Health Immunobiology
The Johns Hopkins University School of Medicine and Chairman, Department of Neurology
Bloomberg School of Public Health Yale School of Medicine
Baltimore, Maryland New Haven, Connecticut

Dustin R. Fraidenburg, MD Stephen R. Hammes, MD, PhD

Assistant Professor of Medicine Professor of Medicine, Chief of Endocrinology and Metabolism
University of Illinois at Chicago School of Medicine and Dentistry
Chicago, Illinois University of Rochester
Rochester, New York
R. Benjamin Free, PhD
Staff Scientist, Molecular Neuropharmacology Section R. Adron Harris, PhD
National Institute of Neurological Disorders and Stroke Professor of Neuroscience and Pharmacology
National Institutes of Health Waggoner Center for Alcohol and Addiction Research
Bethesda, Maryland University of Texas
Austin, Texas
Peter A. Friedman, PhD
Professor of Pharmacology and Chemical Biology, and Lisa A. Hazelwood, PhD
of Structural Biology Principal Research Scientist, Liver Disease and Fibrosis, AbbVie
University of Pittsburgh School of Medicine North Chicago, Illinois
Pittsburgh, Pennsylvania
Jeffrey D. Henderer, MD
John W. Funder, AC, MD, BS, PhD, FRACP Professor of Ophthalmology
Professor of Medicine, Prince Henry’s Institute Dr. Edward Hagop Bedrossian Chair of Ophthalmology
Monash Medical Centre Lewis Katz School of Medicine at Temple University
Clayton, Victoria, Australia Philadelphia, Pennsylvania

Giuseppe Giaccone, MD, PhD Ryan E. Hibbs, PhD

Professor of Medical Oncology and Pharmacology Assistant Professor of Neuroscience
Georgetown University University of Texas Southwestern Medical School
Washington DC Dallas, Texas

Kathleen M. Giacomini, PhD Randa Hilal-Dandan, PhD

Professor of Bioengineering and Therapeutic Sciences, Lecturer in Pharmacology
School of Pharmacy University of California
University of California San Diego, California
San Francisco, California
Peter J. Hotez, MD, PhD
Alfred G. Gilman, MD, PhD (deceased) Professor of Pediatrics and Molecular Virology & Microbiology
Professor (Emeritus) of Pharmacology Texas Children’s Hospital Endowed Chair in Tropical Pediatrics
University of Texas Southwestern Medical School Dean, National School of Tropical Medicine
Dallas, Texas Baylor College of Medicine
Houston, Texas

Brunton_FM_pi-pxviii.indd 10 08/09/17 2:51 PM

 Claudine Isaacs, MD, FRCPC Wallace K. MacNaughton, PhD xi
Professor of Medicine and Oncology Professor and Head of Physiology and Pharmacology
Georgetown University, School of Medicine Cumming School of Medicine,
Washington DC University of Calgary
Calgary, Alberta, Canada
Nina Isoherranen, PhD
Professor of Pharmaceutics, School of Pharmacy Kenneth P. Mackie, MD
University of Washington Professor of Psychological and Brain Sciences

Contributors
Seattle, Washington Indiana University
Bloomington, Indiana
Edwin K. Jackson, PhD
Professor of Pharmacology and Chemical Biology Jody Mayfield, PhD
University of Pittsburgh School of Medicine Science Writer and Editor
Pittsburgh, Pennsylvania Waggoner Center for Alcohol and Addiction Research
University of Texas
Kenneth Kaushansky, MD Austin, Texas
Dean, School of Medicine and Senior Vice President of Health Sciences
SUNY Stony Brook James McCarthy, MD
New York, New York Senior Scientist QIMR Berghofer Intitute of Medical Research
Department of Infectious Diseases, Royal Brisbane
Jennifer Keiser, PhD and Womens Hospital
Professor of Neglected Tropical Diseases Brisbane, Queensland, Australia
Swiss Tropical and Public Health Institute
Basel, Switzerland James O. McNamara, MD
Professor and Chair of Neurobiology
Thomas J. Kipps, MD, PhD Director of Center for Translational Neuroscience
Professor of Medicine, Moores Cancer Center Duke University Medical Center
University of California Durham, North Carolina
San Diego, California
Cameron S. Metcalf, PhD
Jennifer J. Kiser, PharmD Research Assistant Professor
Associate Professor, Pharmaceutical Sciences Associate Director, Anticonvulsant Drug Development Program
University of Colorado Department of Pharmacology & Toxicology
Denver, Colorado College of Pharmacy
University of Utah
Ronald J. Koenig, MD, PhD
Salt Lake City, Utah
Professor of Metabolism, Endocrinology and Diabetes
Department of Internal Medicine Jonathan M. Meyer, MD
University of Michigan Health System Psychopharmacology Consultant
Ann Arbor, Michigan California Department of State Hospitals
Assistant Clinical Professor of Psychiatry
George F. Koob, PhD
University of California
Director, National Institute on Alcohol Abuse and Alcoholism
San Diego, California
National Institutes of Health
Rockville, Maryland S. John Mihic, PhD
Professor of Neuroscience
Alan M. Krensky, MD
Waggoner Center for Alcohol & Addiction Research
Vice Dean
University of Texas
Professor of Pediatrics and Microbiology & Immunology
Austin, Texas
Feinberg School of Medicine
Northwestern University Mark E. Molitch, MD
Chicago, Illinois Martha Leland Sherwin Professor of Endocrinology
Northwestern University
Ellis R. Levin, MD
Chicago, Illinois
Professor of Medicine; Chief of Endocrinology
Diabetes and Metabolism Dean S. Morrell, MD
University of California, Irvine, and Long Beach Professor of Dermatology
VA Medical Center University of North Carolina
Long Beach, California Chapel Hill, North Carolina
Heather Macarthur, PhD Thomas D. Nolin, PharmD, PhD
Associate Professor of Pharmacology and Physiology Associate Professor of Pharmacy and Therapeutics, and of Medicine
Saint Louis University School of Medicine University of Pittsburgh School of Pharmacy and School of Medicine
St. Louis, Missouri Pittsburgh, Pennsylvania
Conan MacDougall, PharmD, MAS Charles P. O’Brien, MD, PhD
Professor of Clinical Pharmacy Professor of Psychiatry, School of Medicine
School of Pharmacy University of Pennsylvania
University of California Philadelphia, Pennsylvania
San Francisco, California

Brunton_FM_pi-pxviii.indd 11 08/09/17 2:51 PM

 xii James O’Donnell, PhD Dan M. Roden, MD
Dean and Professor Professor of Medicine, Pharmacology, and Biomedical Informatics
School of Pharmacy & Pharmaceutical Sciences Senior Vice President for Personalized Medicine
University at Buffalo Vanderbilt University Medical Center
The State University of New York Nashville, Tennessee
Buffalo, New York
P. David Rogers, PharmD, PhD, FCCP
Hemal H. Patel, PhD First Tennessee Endowed Chair of Excellence in Clinical Pharmacy
Contributors

Professor of Anesthesiology Vice-Chair for Research

University of California, San Diego Director, Clinical and Experimental Therapeutics
VA-San Diego Healthcare System Co-Director, Center for Pediatric Pharmacokinetics and Therapeutics
San Diego, California Professor of Clinical Pharmacy and Pediatrics
University of Tennessee College of Pharmacy
Piyush M. Patel, MD, FRCPC Memphis, Tennessee
Professor of Anesthesiology
University of California, San Diego David M. Roth, MD, PhD
VA-San Diego Healthcare System Professor of Anesthesiology
San Diego, California University of California, San Diego
VA-San Diego Healthcare System
Matthew L. Pearn, MD San Diego, California
Associate Professor of Anesthesiology
University of California, San Diego Edward A. Sausville, MD, PhD
VA-San Diego Healthcare System Professor of Medicine; Adjunct Professor, Pharmacology &
San Diego, California Experimental Therapeutics
University of Maryland School of Medicine
Trevor M. Penning, PhD Baltimore, Maryland
Professor of Systems Pharmacology & Translational Therapeutics
Director, Center of Excellence in Environmental Toxicology Matthew J. Sewell, MD
School of Medicine Pediatric Dermatology Fellow
University of Pennsylvania Department of Dermatology
Philadelphia, Pennsylvania University of North Carolina
Chapel Hill, North Carolina
Margaret A. Phillips, PhD
Professor of Pharmacology Bernard P. Schimmer, PhD
University of Texas Southwestern Medical School Professor (Emeritus) of Pharmacology and Toxicology
Dallas, Texas University of Toronto
Ontario, Canada
Alvin C. Powers, MD
Professor of Medicine, Molecular Physiology and Biophysics Keith A. Sharkey, PhD, CAGF, FCAHS
Director, Vanderbilt Diabetes Center Professor of Physiology and Pharmacology
Chief, Division of Diabetes, Endocrinology, and Metabolism Cumming School of Medicine
Vanderbilt University School of Medicine University of Calgary
Nashville, Tennessee Calgary, Alberta, Canada

Christopher J. Rapuano, MD Richard C. Shelton, MD

Director, Cornea Service and Refractive Surgery Professor, Department of Psychiatry and Behavioral Neurobiology
Wills Eye Hospital The University of Alabama at Birmingham
Philadelphia, Pennsylvania Birmingham, Alabama

Anna T. Riegel, PhD Danny Shen, PhD

Professor of Oncology and Pharmacology Professor of Pharmaceutics, School of Pharmacy
Georgetown University, School of Medicine University of Washington
Washington DC Seattle, Washington

Suzanne M. Rivera, PhD, MSW David R. Sibley, PhD

Assistant Professor of Bioethics Senior Investigator, Molecular Neuropharmacology Section
Case Western Reserve University National Institute of Neurological Disorders & Stroke
Cleveland, Ohio National Institutes of Health
Bethesda, Maryland
Erik D. Roberson, MD, PhD
Associate Professor of Neurology and Neurobiology Randal A. Skidgel, PhD
Co-Director, Center for Neurodegeneration and Professor of Pharmacology
Experimental Therapeutics College of Medicine, University of Illinois-Chicago
University of Alabama at Birmingham Chicago, Illinois
Birmingham, Alabama

Brunton_FM_pi-pxviii.indd 12 08/09/17 2:51 PM

 Misty D. Smith, PhD Jeffrey I. Weitz, MD, FRCP(C), FACP xiii
Research Assistant Professor, Department of Professor of Medicine
Pharmacology & Toxicology; Biochemistry and Biomedical Sciences McMaster University
Research Assistant Professor, School of Dentistry Executive Director, Thrombosis & Atherosclerosis
Co-Investigator, Anticonvulsant Drug Development Program Research Institute
University of Utah Hamilton, Ontario, Canada
Salt Lake City, Utah
Anton Wellstein, MD, PhD

Contributors
Emer M. Smyth, PhD Professor of Oncology and Pharmacology
Director, Cancer Research Alliances Georgetown University, School of Medicine
Assistant Dean for Cancer Research Washington DC
Assistant Professor, Pathology and Cell Biology
Herbert Irving Comprehensive Cancer Center Jürgen Wess, PhD
Columbia University Medical Center Chief, Molecular Signaling Section
New York, New York Lab. of Bioorganic Chemistry
National Institute of Diabetes and Digestive and Kidney Diseases
Peter J. Snyder, MD Bethesda, Maryland
Professor of Medicine
University of Pennsylvania David P. Westfall, PhD
Philadelphia, Pennsylvania Professor (Emeritus) of Pharmacology
University of Nevada School of Medicine
Yuichi Sugiyama, PhD Reno, Nevada
Head of Sugiyama Laboratory
RIKEN Innovation Center Thomas C. Westfall, PhD
RIKEN Yokohama Professor and Chair Emeritus, Department of Pharmacology
Yokohama, Japan and Physiology
Saint Louis University School of Medicine
Palmer Taylor, PhD St. Louis, Missouri
Sandra & Monroe Trout Professor of Pharmacology,
School of Medicine Dawn M. Wetzel, MD, PhD
Dean Emeritus, Skaggs School of Pharmacy and Assistant Professor of Pediatrics (Division of Infectious Diseases)
Pharmaceutical Sciences and Pharmacology
University of California University of Texas Southwestern Medical Center
San Diego, California Dallas, Texas

Kenneth E. Thummel, PhD Karen S. Wilcox, PhD

Professor and Chair, Department of Pharmaceutics Professor and Chair, Department of Pharmacology
University of Washington Director, Anticonvulsant Drug Development Program
Seattle, Washington University of Utah
Salt Lake City, Utah
Roberto Tinoco, PhD
Research Assistant Professor Kerstin de Wit, MD
Infectious and Inflammatory Diseases Center Department of Medicine
Sanford Burnham Prebys Medical Discovery Institute Divisions of Emergency and Haematology
La Jolla, California McMaster University, Canada;
Thrombosis and Emergency Physician
Robert H. Tukey, PhD Hamilton Health Sciences
Professor of Pharmacology and Chemistry/Biochemistry Hamilton, Ontario, Canada
University of California
San Diego, California Tony L. Yaksh, PhD
Professor of Anesthesiology and Pharmacology
Joseph M. Vinetz, MD University of California, San Diego
Professor of Medicine, Division of Infectious Diseases La Jolla, California
University of California
San Diego, California Jason X.-J. Yuan, MD, PhD
Professor of Medicine and Physiology;
Wendy Vitek, MD Chief, Division of Translational and Regenerative Medicine
Assistant Professor of Obstetrics and Gynecology University of Arizona
University of Rochester School of Medicine and Dentistry Tucson, Arizona
Rochester, New York
Alexander C. Zambon, PhD
Mark S. Wallace, MD Assistant Professor of Biopharmaceutical Sciences
Professor of Clinical Anesthesiology Keck Graduate Institute
University of California Claremont, California
San Diego, California

Brunton_FM_pi-pxviii.indd 13 08/09/17 2:51 PM

This page intentionally left blank
 Preface
The first edition of this book appeared in 1941, the product of a
collaboration between two friends and professors at Yale, Louis Goodman
and Alfred Gilman. Their purpose, stated in the preface to that edition, was
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 would be useful to students of
pharmacology and to physicians. We continue to follow these principles
in the 13th edition.
The 1st edition was quite successful despite its high price, $12.50,
and soon became known as the “blue bible of pharmacology.” The book
was evidence of the deep friendship between its authors, and when the
Gilmans’ son was born in 1941, he was named Alfred Goodman Gilman.
World War II and the relocation of both authors—Goodman to Utah,
Gilman to Columbia—postponed a second edition until 1955. The
experience of writing the second edition during a period of accelerating
basic research and drug development persuaded the authors to become
editors, relying on experts whose scholarship they trusted to contribute
individual chapters, a pattern that has been followed ever since.
Alfred G. Gilman, the son, served as an associate editor for the 5th
edition (1975), became the principal editor for the 6th (1980), 7th (1985),
and 8th (1990) editions, and consulting editor for the 9th and 10th editions
that were edited by Lee Limbird and Joel Hardman. After an absence in the
11th edition, Al Gilman agreed to co-author the introductory chapter in
the 12th edition. His final contribution to G&G, a revision of that chapter,
is the first chapter in this edition, which we dedicate to his memory.
A multi-authored text of this sort grows by accretion, posing challenges
to editors but also offering 75 years of wisdom, memorable pearls, and
flashes of wit. Portions of prior editions persist in the current edition,
and we have given credit to recent former contributors at the end of
each chapter. Such a text also tends to grow in length with each edition,
as contributors add to existing text and as pharmacotherapy advances.
To keep the length manageable and in a single volume, Dr. Randa
Brunton_FM_pi-pxviii.indd 15
Hilal-Dandan and I prepared a shortened version of each chapter and then
invited contributors to add back old material that was essential and to add
new material. We also elected to discard the use of extract (very small) type
and to use more figures to explain signaling pathways and mechanisms of
drug action. Not wanting to favor one company’s preparation of an agent
over that of another, we have ceased to use trade names except as needed
to refer to drug combinations or to distinguish multiple formulations of
the same agent with distinctive pharmacokinetic or pharmacodynamic
properties. Counter-balancing this shortening are five new chapters that
reflect advances in the therapeutic manipulation of the immune system,
the treatment of viral hepatitis, and the pharmacotherapy of cardiovascular
disease and pulmonary artery hypertension.
Editing such a book brings into view a number of overarching issues:
Over-prescribing of antibiotics and their excessive use in agricultural
animal husbandry continues to promote the development of antimicrobial
resistance; the application of CRISPR/cas9 will likely provide new
therapeutic avenues; global warming and the sheer size of the human
population require medical scientists and practitioners to promote
remedial and preventive action based on data, not ideology.
A number of people have made invaluable contributions to the
preparation of this edition. My thanks to Randa Hilal-Dandan and Bjorn
Knollmann for their editorial work; to Harriet Lebowitz of McGraw-Hill,
who guided our work, prescribed the updated style, and kept the project
moving to completion; to Vastavikta Sharma of Cenveo Publishers Services,
who oversaw the copy editing, typesetting, and preparation of the artwork;
to Nelda Murri, our consulting pharmacist, whose familiarity with clinical
pharmacy is evident throughout the book; to James Shanahan, publisher
at McGraw-Hill, for supporting the project; and to the many readers who
have written to critique the book and offer suggestions.
Laurence L. Brunton
San Diego, CA
1 September 2017
08/09/17 2:51 PM
This page intentionally left blank
 Acknowledgments

The editors appreciate the assistance of:

Harriet Lebowitz Joseph K. Prinsen, DO, PhD
Senior Project Development Editor Jason D. Morrow Chief Fellow in Clinical Pharmacology
McGraw-Hill Education Vanderbilt University School of Medicine

Laura Libretti David Aaron Rice

Administrative Assistant Administrative Assistant
McGraw-Hill Education University of California, San Diego

Bryan Mott, PhD James F. Shanahan

Consulting Medicinal Chemist
Nelda Murri, PharmD, MBA
Consulting Pharmacist
Christie Naglieri
Senior Project Development Editor
McGraw-Hill Education
Publisher, Medical Textbooks
McGraw-Hill Education
Vastavikta Sharma
Lead Project Manager
Cenveo Publisher Services
Roberto Tinoco, PhD
Research Assistant Professor
Sanford-Burnham-Prebys Medical Discovery Institute

Brunton_FM_pi-pxviii.indd 17 08/09/17 2:51 PM

This page intentionally left blank
 Section I
General Principles
Chapter 1. Drug Invention and the Pharmaceutical
Industry / 3
Chapter 2. Pharmacokinetics: The Dynamics of Drug Absorption,
Distribution, Metabolism, and Elimination / 13
Chapter 3. Pharmacodynamics: Molecular Mechanisms of Drug Action / 31
Chapter 4. Drug Toxicity and Poisoning / 55
Chapter 5. Membrane Transporters and Drug Response / 65
Chapter 6. Drug Metabolism / 85
Chapter 7. Pharmacogenetics / 101

Brunton_Ch01_p0001-p0012.indd 1 07/09/17 1:16 PM

This page intentionally left blank
 Chapter
1
FROM EARLY EXPERIENCES WITH PLANTS TO MODERN
CHEMISTRY
Drug Invention and the
Pharmaceutical Industry
Suzanne M. Rivera and Alfred Goodman Gilman*
SOURCES OF DRUGS
■■ Small Molecules Are the Tradition
■■ From Hits to Leads
■■ Large Molecules Are Increasingly Important
TARGETS OF DRUG ACTION
■■ Is the Target Drugable?
■■ Has the Target Been Validated?
■■ Is This Drug Invention Effort Economically Viable?
ADDITIONAL PRECLINICAL RESEARCH
The first edition of Goodman & Gilman, published in 1941, helped to
organize the field of pharmacology, giving it intellectual validity and an
academic identity. That edition began: “The subject of pharmacology is a
broad one and embraces the knowledge of the source, physical and chem-
ical 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.” This General Principles sec-
tion provides the underpinnings for these definitions by exploring the
processes of drug invention, development, and regulation, followed by
the basic properties of the interactions between the drug and biological
systems: pharmacodynamics, pharmacokinetics (including drug transport
and metabolism), and pharmacogenomics, with a brief foray into drug
toxicity and poisoning. Subsequent sections deal with the use of drugs as
therapeutic agents in human subjects.
Use of the term invention to describe the process by which a new drug
is identified and brought to medical practice, rather than the more con-
ventional term discovery, is intentional. Today, useful drugs are rarely
discovered hiding somewhere waiting to be found. The term invention
emphasizes the process by which drugs are sculpted and brought into
being based on experimentation and optimization of many independent
properties; there is little serendipity.
From Early Experiences With Plants to
Modern Chemistry
The human fascination—and sometimes infatuation—with chemicals that
alter biological function is ancient and results from long experience with
and dependence on plants. Because most plants are root bound, many of
them produce harmful compounds for defense that animals have learned
to avoid and humans to exploit (or abuse).
Earlier editions of this text described examples: the appreciation of cof-
fee (caffeine) by the prior of an Arabian convent, who noted the behavior
*
Deceased, December 23, 2015. AGG served on the Board of Directors of Regeneron
Pharmaceuticals, Inc., a potential conflict of interest.
Brunton_Ch01_p0001-p0012.indd 3
CLINICAL TRIALS
■■ Role of the FDA
■■ The Conduct of Clinical Trials
■■ Determining “Safe” and “Effective”
PERSONALIZED MEDICINE
PUBLIC POLICY CONSIDERATIONS AND CRITICISMS OF THE
PHARMACEUTICAL INDUSTRY
■■ Who Pays?
■■ Intellectual Property and Patents
■■ Drug Promotion
■■ Concerns about Global Injustice
■■ Product Liability
■■ “Me Too” Versus True Innovation: The Pace of New Drug Development
of goats that gamboled and frisked through the night after eating the
berries of the coffee plant; the use of mushrooms and the deadly night-
shade plant by professional poisoners; of belladonna (“beautiful lady”) to
dilate pupils; of the Chinese herb ma huang (containing ephedrine) as a
circulatory stimulant; of curare by South American Indians to paralyze
and kill animals hunted for food; and of poppy juice (opium) containing
morphine (from the Greek Morpheus, the God of dreams) for pain relief
and control of dysentery. Morphine, of course, has well-known addicting
properties, mimicked in some ways by other problematic (“recreational”)
natural products—nicotine, cocaine, and ethanol.
Although terrestrial and marine organisms remain valuable sources
of compounds with pharmacological activities, drug invention became
more allied with synthetic organic chemistry as that discipline flour-
ished over the past 150 years, beginning in the dye industry. Dyes 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 and
other organic arsenicals were used for the chemotherapy of syphilis until
the discovery of penicillin. The work of Gerhard Domagk demonstrated
that another dye, prontosil (the first clinically useful sulfonamide), was
dramatically effective in treating streptococcal infections, launching the
era of antimicrobial chemotherapy.
The collaboration of pharmacology with chemistry on the one hand and
with clinical medicine on the other has been a major contributor to the effec-
tive treatment 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 (e.g., insulin),
most drugs were small organic molecules (typically <500 Da) until
07/09/17 1:16 PM
 4
Abbreviations This approach was driven largely by instinct and trial and error in the
past; modern drug development frequently takes advantage of determi-
nation of a high-resolution structure of the putative drug bound to its
ADME: absorption, distribution, metabolism, excretion target. X-ray crystallography offers the most detailed structural informa-
AHFS-DI: American Hospital Formulary Service-Drug tion if the target protein can be crystallized with the lead drug bound to
Information it. Using techniques of molecular modeling and computational chemistry,
CHAPTER 1 DRUG INVENTION AND THE PHARMACEUTICAL INDUSTRY

BLA: Biologics License Application the structure provides the chemist with information about substitutions
CDC: Centers for Disease Control and Prevention likely to improve the “fit” of the drug with the target and thus enhance
CDER: Center for Drug Evaluation and Research the affinity of the drug for its target. Nuclear magnetic resonance (NMR)
DHHS: U.S. Department of Health and Human Services studies of the drug-receptor complex also can provide useful information
(albeit usually at lower resolution), with the advantage that the complex
FDA: U.S. Food and Drug Administration
need not be crystallized.
HCV: hepatitis C virus
The holy grail of this approach to drug invention is to achieve success
HMG CoA: 3-hydroxy-3-methylglutaryl coenzyme A
entirely through computation. Imagine a database containing detailed
IND: Investigational New Drug
chemical information about millions of chemicals and a second database
LDL: low-density lipoprotein
containing detailed structural information about all human proteins. The
NDA: New Drug Application
computational approach is to “roll” all the chemicals over the protein of
NIH: National Institutes of Health interest to find those with high-affinity interactions. The dream becomes
NMEs: New Molecular Entities bolder if we acquire the ability to roll the chemicals that bind to the target
NMR: nuclear magnetic resonance of interest over all other human proteins to discard compounds that have
PCSK9: proprotein convertase subtilisin/kexin type 9 unwanted interactions. Finally, we also will want to predict the structural
PDUFA: Prescription Drug User Fee Act and functional consequences of a drug binding to its target (a huge chal-
PhRMA: Pharmaceutical Research and Manufacturers of lenge), as well as all relevant pharmacokinetic properties of the molecules
America of interest. Indeed, computational approaches have suggested new uses
R&D: research and development for old drugs and offered explanations for recent failures of drugs in the
SCHIP: State Children’s Health Insurance Program later stages of clinical development (e.g., torcetrapib; see Box 1-2)
siRNAs: small interfering RNAs (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
recombinant DNA technology permitted synthesis of proteins by various
treatment of diabetes following the experiments of Banting and Best in
organisms (bacteria, yeast) and mammalian cells. The usual approach to
1921. Insulins purified from porcine or bovine pancreas are active in
invention of a small-molecule drug is to screen a collection of chemicals
humans, although antibodies to the foreign proteins are occasionally
(“library”) for compounds with the desired features. An alternative is to
problematic. Growth hormone, used to treat pituitary dwarfism, exhib-
synthesize and focus on close chemical relatives of a substance known to
its more stringent species specificity. Only the human hormone could be
participate in a biological reaction of interest (e.g., congeners of a spe-
used after purification from pituitary glands harvested during autopsy,
cific enzyme substrate chosen to be possible inhibitors of the enzymatic
and such use had its dangers—some patients who received the human
reaction), a particularly important strategy in the discovery of anticancer
hormone developed Creutzfeldt-Jakob disease (the human equivalent
drugs.
of mad cow disease), a fatal degenerative neurological disease caused by
Drug discovery in the past often resulted from serendipitous observa-
prion proteins that contaminated the drug preparation. Thanks to gene
tions of the effects of plant extracts or individual chemicals on animals
cloning and the production of large quantities of proteins by expressing
or humans; today’s approach relies more on high-throughput screening
the cloned gene in bacteria or eukaryotic cells, protein therapeutics now
of libraries containing hundreds of thousands or even millions of com-
use highly purified preparations of human (or humanized) proteins. Rare
pounds for their capacity to interact with a specific molecular target or
proteins can be produced in quantity, and immunological reactions are
elicit a specific biological response. Ideally, the target molecules are of
minimized. Proteins can be designed, customized, and optimized using
human origin, obtained by transcription and translation of the cloned
genetic engineering techniques. Other types of macromolecules may also
human gene. The potential drugs that are identified in the screen (“hits”)
be used therapeutically. For example, antisense oligonucleotides are used
are thus known to react with the human protein and not just with its rela-
to block gene transcription or translation, as are siRNAs.
tive (ortholog) obtained from the mouse or another species.
Proteins used therapeutically include hormones; growth factors (e.g.,
Among the variables considered in screening are the “drugability” of
erythropoietin, granulocyte colony-stimulating factor); cytokines; and a
the target and the stringency of the screen in terms of the concentrations
number of monoclonal antibodies used in the treatment of cancer and
of compounds that are tested. Drugability refers to the ease with which the
autoimmune diseases (Chapters 34–36 and 67). Murine monoclonal anti-
function of a target can be altered in the desired fashion by a small organic
bodies can be “humanized” (by substituting human for mouse amino acid
molecule. If the protein target has a well-defined binding site for a small
sequences). Alternatively, mice have been engineered by replacement of
molecule (e.g., a catalytic or allosteric site), chances are excellent that hits
critical mouse genes with their human equivalents, such that they make
will be obtained. If the goal is to employ a small molecule to mimic or dis-
completely human antibodies. Protein therapeutics are administered par-
rupt the interaction between two proteins, the challenge is much greater.
enterally, and their receptors or targets must be accessible extracellularly.
From Hits to Leads
Initial hits in a screen are rarely marketable drugs, often having mod-
est affinity for the target and lacking the desired specificity and pharma-
Targets of Drug Action
cological properties. Medicinal chemists synthesize derivatives of the Early drugs came from observation of the effects of plants after their inges-
hits, thereby defining the structure-activity relationship and optimizing tion by animals, with no knowledge of the drug’s mechanism or site of
parameters such as affinity for the target, agonist/antagonist activity, per- action. Although this approach is still useful (e.g., in screening for the
meability across cell membranes, absorption and distribution in the body, capacity of natural products to kill microorganisms or malignant cells),
metabolism, and unwanted effects. modern drug invention usually takes the opposite approach, starting with

Brunton_Ch01_p0001-p0012.indd 4 07/09/17 1:16 PM

 a statement (or hypothesis) that a certain protein or pathway plays a crit-
ical role in the pathogenesis of a certain disease, and that altering the
protein’s activity would 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?
The effort expended to find the desired drug will be determined by the
degree of confidence in the answers to the last 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 exhibits consid-
erable affinity and selectivity.
If the target is an enzyme or a receptor for a small ligand, one is encour-
aged. 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?
The question of whether the target has been validated is obviously a crit-
ical one. A negative answer, frequently obtained only retrospectively, is a
common cause of failure in drug invention (Box 1–1). Modern techniques
of molecular biology offer 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 ben-
eficial 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 (encod-
ing proprotein convertase subtilisin/kexin type 9) greatly lower concen-
trations of LDL cholesterol in blood and reduce the risk of myocardial
infarction (Horton et al., 2009; Poirier and Mayer, 2013). Based on these
findings, two companies now market antibodies that inhibit the action
of PCSK9. These antibodies lower the concentration of LDL cholesterol
in blood substantially and are essentially additive to the effects of statins;
long-term outcome studies are in progress to determine whether the risk
of significant cardiovascular events also is reduced. Additional molecules
are in the queue.
BOX 1–1 ■ Target Validation: The Lesson of Leptin
Biological systems frequently contain redundant elements or can
alter expression of drug-regulated elements to compensate for the
effect of the drug. 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,
on investigation, it was discovered that obese individuals have high
circulating concentrations of leptin and appear insensitive to its
action.
Brunton_Ch01_p0001-p0012.indd 5
Is This Drug Invention Effort Economically Viable? 5
Drug invention and development is expensive (see Table 1-1), and economic
realities influence the direction of pharmaceutical research. For example,
investor-owned companies generally cannot afford to develop products for
rare diseases or for diseases that are common only in economically under-
SECTION I GENERAL PRINCIPLES
developed parts of the world. Funds to invent drugs targeting rare diseases
or diseases primarily affecting developing countries (especially parasitic
diseases) often come from taxpayers or wealthy philanthropists.
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 fash-
ion. Now, one must consider all aspects of the molecule in question—its
affinity and selectivity for interaction with the target; its pharmacokinetic
properties (ADME); issues of its large-scale synthesis or purification; 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 gen-
eral toxicity by long-term monitoring of the activity of various systems in
two species of animals, generally one rodent (usually the mouse) and one
nonrodent (often the rabbit). Compounds also are evaluated for carcino-
genicity, genotoxicity, and reproductive toxicity (see Chapter 4). In vitro
and ex vivo assays are used 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 caused by an off-target effect of the drug, which
might be minimized by further optimization of the molecule.
Before the drug candidate can be administered to human subjects in
a clinical trial, the sponsor must file an IND application, a request to the
U.S. FDA (see “Clinical Trials”) for permission to use the drug for human
research. 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 (proto-
col) for investigating the drug in human subjects. The FDA has 30 days to
review the IND application, by which time the agency may disapprove it,
ask for more data, or allow initial clinical testing to proceed.
Clinical Trials
Role of the FDA
The FDA is a federal regulatory agency within the U.S. DHHS. It is respon-
sible for protecting the public health by ensuring the safety, efficacy, and
security of human and veterinary drugs, biological products, medical
devices, our nation’s food supply, cosmetics, and products that emit radi-
ation (FDA, 2014). The FDA also is responsible for advancing public
health by helping to speed innovations that make medicines and foods
more effective, safer, and more affordable and by helping people obtain
the accurate, science-based information they need to use medicines and
foods to improve their health.
New governmental regulations often result from tragedies. 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 over
100 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, which began requiring toxicity studies as well as approval of an NDA
(see “The Conduct of Clinical Trials”) before a drug could be promoted
and distributed. Although a new drug’s safety had to be demonstrated, no
proof of efficacy was required.
07/09/17 1:16 PM
 6 In the 1960s, thalidomide, a hypnotic drug with no obvious advantages
over others, was introduced in Europe. Epidemiological research eventu-
ally established that this drug, taken early in pregnancy, was responsible
for an epidemic of what otherwise is a relatively rare and severe birth
defect, phocomelia, in which limbs are malformed. In reaction to this
catastrophe, the U.S. Congress passed the Harris-Kefauver amendments
CHAPTER 1 DRUG INVENTION AND THE PHARMACEUTICAL INDUSTRY
specialists, and the FDA may call on the help of panels of external experts
in complex cases.
Under the provisions of the PDUFA (enacted in 1992 and renewed
every 5 years, most recently in 2012), pharmaceutical companies now
provide a significant portion of the FDA budget via user fees, a legislative
effort to expedite the drug approval review process by providing increased

to the Food, Drug, and Cosmetic Act in 1962. These amendments estab-
lished the requirement for proof of efficacy as well as 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).
Today, the FDA faces an enormous challenge, especially in view of the
widely held belief that its mission cannot possibly be accomplished with
the resources allocated by Congress. 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 approval
of a new drug with important beneficial effects.
The Conduct of Clinical Trials
Clinical trials of drugs are designed to acquire information about the
pharmacokinetic and pharmacodynamic properties of a candidate drug
in humans. 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. NIH identifies seven ethical principles that must be satisfied
before a clinical trial can begin:
1. Social and clinical value
2. Scientific validity
3. Fair selection of subjects
4. Informed consent
5. Favorable risk-benefit ratio
6. Independent review
7. Respect for potential and enrolled subjects (NIH, 2011).
The FDA-regulated clinical trials typically are conducted in four phases.
Phases I-III are designed to establish safety and efficacy, while phase IV
postmarketing trials delineate additional information regarding new indi-
cations, risks, and optimal doses and schedules. Table 1–1 and Figure 1–1
summarize the important features of each phase of clinical trials; note the
attrition at each successive stage over a relatively long and costly process.
When initial phase III trials are complete, the sponsor (usually a pharma-
ceutical company) applies to the FDA for approval to market the drug;
this application is called either an NDA or a BLA. These applications con-
tain comprehensive information, including individual case report forms
from the hundreds or thousands of individuals who have received the
drug during its phase III testing. Applications are reviewed by teams of
resources. The PDUFA also broadened the FDA’s drug safety program and
increased resources for review of television drug advertising. Under the
PDUFA, once an NDA is submitted to the FDA, review typically takes
6–10 months. During this time, numerous review functions are usu-
ally performed, including advisory committee meetings, amendments,
manufacturing facility inspections, and proprietary name reviews (FDA,
2013a). 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 dos-
age, adverse reactions, and special warnings and precautions (sometimes
posted in a “black box”).
Promotional materials used by pharmaceutical companies cannot devi-
ate 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 he or she 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 a statutorily
named compendium (e.g., the AHFS-DI). Furthermore, a physician may
be vulnerable to litigation if untoward effects result from an unapproved
use of a drug.
Determining “Safe” and “Effective”
Demonstrating efficacy to the FDA requires performing “adequate and
well-controlled investigations,” generally interpreted to mean two repli-
cate clinical trials that are usually, but not always, randomized, double
blind, and placebo (or otherwise) controlled.
Is a placebo the proper control? The World Medical Association’s Dec-
laration of Helsinki (World Medical Association 2013) discourages use of
placebo controls when an alternative treatment is available for compari-
son because of the concern that study participants randomized to placebo
in such a circumstance would, in effect, be denied treatment during the
conduct of the trial.
What must be measured in the trials? In a straightforward trial, a read-
ily 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

TABLE 1–1 ■ TYPICAL CHARACTERISTICS OF THE VARIOUS PHASES OF THE CLINICAL TRIALS REQUIRED FOR
MARKETING OF NEW DRUGS
PHASE I PHASE II PHASE III PHASE IV
FIRST IN HUMAN FIRST IN PATIENT MULTISITE TRIAL POSTMARKETING SURVEILLANCE
10–100 participants 50–500 participants A few hundred to a few thousand Many thousands of participants
participants
Usually healthy volunteers; Patient-subjects receiving Patient-subjects receiving Patients in treatment with
occasionally patients with experimental drug experimental drug approved drug
advanced or rare disease
Open label Randomized and controlled Randomized and controlled Open label
(can be placebo controlled); (can be placebo controlled) or
may be blinded uncontrolled; may be blinded
Safety and tolerability Efficacy and dose ranging Confirm efficacy in larger Adverse events, compliance,
population drug-drug interactions
1–2 years 2–3 years 3–5 years No fixed duration
U.S. $10 million U.S. $20 million U.S. $50–100 million —
Success rate: 50% Success rate: 30% Success rate: 25%–50% —

Brunton_Ch01_p0001-p0012.indd 6 07/09/17 1:16 PM

 12
Introduction
11 Registration
10 1
9 Development
8 2
7 Phase II
2–5
Years 6 5–10
5 Preclinical tests
4
10–20
3
Basic research
2 examination,
1
10,000–25,000
0
Number of chemical entities
Figure 1–1 The phases, time lines, and attrition that characterize the invention of new drugs. See also Table 1–1.
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 that the
candidate drug is intended to treat.
Some of the difficulties are well illustrated by experiences with eze-
timibe, a drug that inhibits absorption of cholesterol from the gastrointes-
tinal tract and lowers LDL cholesterol concentrations in blood, 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, and the drug
was approved based on such data. Surprisingly, a subsequent clinical
trial (ENHANCE) demonstrated that the combination of ezetimibe and
a statin did not reduce intima media thickness of carotid arteries (a more
direct measure of subendothelial 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 argued that the patients in the study had famil-
ial 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 (see below). A
follow-up 7-year study involving over 18,000 patients (IMPROVE-IT)
vindicated the decision to approve ezetimibe (Jarcho and Keaney, 2015).
Taken in conjunction with a statin, the drug significantly reduced the inci-
dence of myocardial infarction and stroke in high-risk patients (Box 1–2).
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 (see 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
Brunton_Ch01_p0001-p0012.indd 7
7
Postmarketing Phase IV
surveillance
Clinical tests Phase III
SECTION I GENERAL PRINCIPLES
(human)
Phase I
(animal)
Synthesis,
screening
incidence of untoward effects become known only after a drug is released
to the broader market and used by a large number of people (phase IV,
postmarketing surveillance). Drug development costs and 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 pharmaceu-
tical 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
are not simple and can become issues for great debate.
Several strategies exist to detect adverse reactions after marketing of a
drug. 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, in which the fre-
quency of drug use in cases of adverse responses is compared to controls;
and meta-analysis of pre- and postmarketing studies. Voluntary reporting
of adverse events has proven to be an effective way to generate an early sig-
nal that a drug may be causing an adverse reaction (Aagard and Hansen,
2009). The primary sources for the reports are responsible, alert physi-
cians; third-party payers (pharmacy benefit managers, insurance com-
panies) and consumers also play important roles. Other useful sources
are nurses, pharmacists, and students in these disciplines. In addition,
hospital-based pharmacy and therapeutics committees and quality assur-
ance committees frequently are charged with monitoring adverse drug
reactions in hospitalized patients. In 2013, the reporting system in the
U.S., called MedWatch, celebrated its 20th anniversary and announced
improvements designed to encourage reporting by consumers (FDA,
2013b). The simple forms for reporting may be obtained 24 hours a day,
7 days a week, by calling 800-FDA-1088; alternatively, adverse reactions
BOX 1–2 ■ A Late Surprise in the Development of a Blockbuster
Torcetrapib elevates high-density lipoprotein (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. In this case, approval of the drug based on this
secondary end point would have been a mistake (Cutler, 2007). A
computational systems analysis suggested a mechanistic explanation
of this failure (Xie et al., 2009).
07/09/17 1:16 PM
Another random document with
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 “Sure, people buying things for school. Grouchy Greenway was in,
he bought a lot of homework paper—pity the fellers in the third
grade. Ruth Binney’s scared of that ladder that rolls along—oh
bimbo, that’s my middle name. I can take a running jump and ride it
all the way to the back of the store.” He did not mention that he
played the harmonica for the girls to dance; he was a good sport and
did not tell tales out of school.
“I think Ruth and Annie Terris will miss you when you go to
Montana,” said Mr. Walton playfully.
“Such nonsense,” said Mrs. Walton. “Don’t put those ideas back
into his head.”
“I may go sooner than you think,” said Hervey.
He stood in the doorway to the dining room, pausing before
making his late evening attack on the apple barrel. A blithe, carefree
figure he seemed, his eyes full of a kind of gay madness. One
rebellious lock of hair sprawled over his forehead as he suddenly
pulled off his outlandish hat in deference to his stepmother. He never
remembered to do this as a regular duty; he remembered each time
separately, and then with lightning inspiration. He could not for the
life of him adapt his manners or phraseology to his elders.
“You know me, Al,” he said.
“Are you going to wash your face when you go in the kitchen?”
Mrs. Walton inquired.
“Sure, is there any pie?” he asked.
They heard him fumbling in the kitchen, then trudging up the
stairs.
“I think it would be just as well not to harp on Montana,” said Mrs.
Walton. “It’s odd how he hit on Montana.”
“One place is as good as another,” said Mr. Walton. “I’m glad it’s
Montana, it costs so much to get there. If he had Harlem in mind, or
Coney Island, I might worry.”
“He talks of them both,” said Mrs. Walton. “Yes, but I think his
heart is in the big open spaces, where the fare is about a hundred
dollars. If it were the Fiji Islands I’d be content.”
“Do you think he’d like to go to Europe with us next summer?”
Mrs. Walton asked. “I can’t bear to leave him alone.”
 “No, I’m afraid he’d want to dive from the Rock of Gibraltar,” said
Mr. Walton. “He’ll be safe at Temple Camp.”
“He seems to have just no balance-wheel,” Mrs. Walton mused.
“When I look in his eyes it seems to me as if they saw joys, but never
consequences.”
“Sort of near-sighted in a way, eh?”
“I do wish he had stayed in the Scouts, don’t you?”
“No, I don’t,” said Mr. Walton in a matter-of-fact way. “He didn’t
see it. Some day he’ll see it, but it won’t be because anybody tells
him. The only way Hervey can learn that a tree is high is for him to
fall out of it. That’s what I mean by his being near-sighted in a way.”
“Do you think those railroad workers are a good set?”
“Oh, they’re a good lot; good, strong men.”
“Well, I don’t care for that Hinkey, do you?”
Mr. Walton did not go into raptures over anybody from New York.
He was a good New Englander. Nor had he been carried off his feet
by the “million dollar theatre.” But being a true New Englander he
was fair in judgment and of few words, especially in the field of
criticism. His answer to this last question was to resume reading his
book.
 CHAPTER XXIV
IN THE SILENT NIGHT
In his own room Hervey opened the satchel which circumstances
had caused him to carry home. He thought that since kind fate had
brought the opportunity, he would like to give one exceedingly low
blast on a real musical instrument. He was astonished to find that
there was no musical instrument in the satchel, but a tin box
containing a small account book, a number of bills with a rubber
band around them, and an envelope containing some loose change.
He contemplated this treasure aghast. Counting the bills he found
them to be in amount a trifle over a hundred dollars. Never before
had he handled so much money. He was a little afraid of it. He shook
the sealed envelope which was fat with coins; that alone seemed to
contain a fortune. He glanced at the book and found it to full of
figures, entries of receipts and expenditures. On the flyleaf was
written:
Farrelton Merry Medley Serenaders,
Horton Manners, Treasurer.
He was greatly excited by this revelation. Here was a serious
business, a very grave consequence of a mischievous act. To be
sure, the bringing home of the satchel that did not belong to him
would have been the same in any case regardless of its contents.
But just the same the sight of so much money come into his
possession in such a way, frightened him. He had not thought of
such a thing as this. You see Hervey never thought at all—ever.
But he thought now. He had “colloped” (whatever that meant) the
treasury funds of this musical organization and he felt uneasy that he
should have to be the custodian of such a princely sum over night.
Money that did not belong to him! Would his wanton act be
construed as just harmless mischief? He had always wanted to have
a hundred dollars, but now he was almost afraid to touch it. He
replaced the box in the satchel and put the satchel under his bed.
Then he pulled it out again and put it in his dresser. Then he closed
and locked the window. When he was half undressed, he took the
satchel out of his dresser and stood holding it not knowing where to
put it. Then he put it back in the dresser.
He thought of going downstairs and telling his stepfather and
getting this awful fortune off his hands. But then he would have to tell
how he had come by it. Well, was that so very bad? Tripping a fellow
up? But would any one understand? He was very angry at the
deserter Hinkey. And he was equally angry that this dextrous little
tripping stunt should bear such consequences. It seemed to him that
even poor Horton Manners had taken a mean advantage.
He resolved that he would hunt up the musical treasurer in the
morning and return the satchel to him. He would hang on to it pretty
carefully going down the street, too. He did not know Horton
Manners, but he could find him. Of course, he would have to tell the
man that he was sorry he had tripped him up. And his explanation of
why he had carried the satchel home might sound rather queer. He
was not too considerate of the tripping treasurer. He was doomed to
a sleepless night on account of that “bimbo.” It was odd, more than it
was significant, that Hervey, who was afraid of no peril, was in panic
fear of this hundred and some odd dollars. He was just afraid of it.
Several times during that long night, he arose and groped his way
to the dresser to make sure that the satchel was safe. In the wee
hours of the night he was sorry that he had not hunted up Horton
Manners immediately after his escapade. But then he might have got
home too late. On every hand he seemed confronted with the high
cost of mischief.
He wondered if the tripping treasurer was searching for the culprit
with the aid of the police. He felt sure that no one dreamed he was
the culprit. Would they, might they not already, have traced Hinkey?
And what would Hinkey say? He had a reassuring feeling that
Hinkey could not be identified as one of the culprits. He certainly
would not tell on Hinkey. And he hoped that Hinkey would not be
incriminated and tell on him before he had a chance to return the
satchel. But surely Mr. Horton Manners had not gone home and to
bed, doing nothing about the theft of more than a hundred dollars. To
the young treasurer the affair was a plain robbery. Of course, Hervey
could not sleep when his imagination pictured the whole police and
detective force of the town aroused by a bold hold-up.
In the hour just before dawn Hervey, in his troubled half-sleep,
heard a knocking sound. Trembling all over, he pulled on his shirt
and trousers, crept stealthily downstairs and with a shaking hand
and pounding heart opened the front door.
 CHAPTER XXV
LIFE, LIBERTY⸺
No one was there. Hervey looked out upon the dissolving night;
already the familiar scene was emerging in the gray drawn—the
white rail fence, the gravel walk with its bordering whitewashed
stones, the big whitewashed tub that caught the rain-water from the
roof trough. He smelled the mist. There was no one anywhere about;
no sound but the slow dripping into the tub. Drop, drop, drop; it was
from the rain of two or three days ago. How audible it was in the
stillness! He crept upstairs again and went to bed. But he did not
sleep. He wished that dreadful satchel were off his hands. Over a
hundred dollars!
He arose in the morning before the household was astir and stole
out with his guilty burden. He knew that Kipp’s Railroad Lunch was
open all night and that it had a telephone. He would look in the
telephone book for Manners. That way he would find the address.
He thought of leaving the satchel at the Manners’ door, ringing the
bell, and running away. The recovery of the money would end the
trouble. But suppose the satchel should be stolen again—not again;
but suppose it should be stolen? Of course, it had not been stolen
before.... Just the same he was desperate to get it off his hands.
Things looked strange about the station so early in the morning;
there were so few people to be seen, and no shops open. Somehow
the very atmosphere imparted a guilty feeling to Hervey. He felt a
little like a fugitive.
He could not find the name of Manners in the ’phone book and
thus baffled, he felt nervous. For while he was losing time, the victim
and the authorities were probably not wasting any time. He thought
he would wait in the station a little while and try to decide what to do.
He knew that the family of Denny Crothers, a scout, was identified
with the big white church. There was an idea! Denny would know
where Horton Manners lived, or could soon find out. Perhaps he
might even take Denny into his confidence. It is worth considering
that in his extremity he was willing not only to use, but to trust, this
scout whose troop he had repudiated.
Well, he would sit in the station a little while (it was still very early)
and if he could not think of any other plan, he would go to Denny’s
house. It would seem strange to the Crothers, seeing him there so
early. And it would seem stranger still to Denny to be approached by
an arch enemy. But Hervey’s troubled thoughts could not formulate
any better plan.
The station was not yet open and he strolled back and forth on the
platform where a very few people were waiting for the early train—a
workman wearing a reefer jacket and carrying a dinner-pail, a little
group of girls who worked in the paper mill at Brierly, and a couple of
youngish men near the end of the platform. These two were chatting
and one of them gave a quick glance at Hervey. It seemed to him
that the talk which followed had reference to himself. He wished that
the station would open, for it was a raw fall morning; there was a
penetrating chill in the air. He wanted to sit down; he was tired of
holding that dreadful satchel, yet he would not set it down for so
much as a moment.
Suddenly, a rattling old car drove up and a brisk young man in an
overcoat got out and dragged two huge oilcloth grips to the platform.
He looked as if he might be a salesman who had completed his
assault on Farrelton. He stopped and lighted a cigarette, and while
he was doing this the two men strolled over and spoke to him. He
seemed annoyed, then laughed as he took out some papers which
the two men examined. Hervey overheard the word hardware. And
he overheard one of the men say, “K.O., Buddy.” They handed back
the papers, nodded sociably, and moved away. It seemed by the
most casual impulse that they approached Hervey. But he trembled
all over.
“You’re out early, kiddo,” said one of them. “Waiting for the train?”
Why, oh why, did he flush and stammer and answer without
thinking? “No—y-yes—I guess it’s late, hey?”
 “Guess not,” said the man with a kind of leisurely pleasantry.
“What you got in the bag, kiddo?”
“Bimbo, do I have to tell you?” Hervey demanded with the air of
one whose rights are outraged.
“Might be just as well,” said the man. “What’s your name
anyway?”
“My name is Hervey Willetts and you let go of that!” Hervey
shouted, tugging at the satchel. “You let go of that, do you hear!” He
not only pulled, but he kicked. “You let go of that or you’ll get in
trouble, you big⸺”
He was the center of a little group now; it was astonishing what a
number of persons were presently on the scene considering the few
early morning stragglers. The men put a quick end to Hervey’s ill-
considered struggle by taking the satchel while one held him firmly
by the collar. There is not a decent person in the world but rebels
against this collar grip which seems the very essence of effrontery.
Few boys so held will fail to use that potent weapon, the foot, and
Hervey, squirming, administered a kick upon his captor’s shin which
made the burly fellow wince and swear.
But it was all to no avail. They opened the satchel and noted its
contents. Hervey’s sense of indignity now quite obliterated every
other feeling. His struggles subsided into a wrathful sullenness; he
could not, or he would not, explain. He knew only that he was being
held and that fact alone aroused the demon in him. Of course, if
Walton could not manage him, and the Scouts could not win and
hold him, it was hardly to be expected that these low-bred detectives
could get closer to him than to hold him by the collar. A dog would
have understood him better. He was not the kind of boy to grab by
the collar.
These two detectives, apprised of the “robbery,” had taken their
stand at the station to note if any suspicious looking strangers were
leaving town on the first train. The boy had almost escaped, because
of his youth.
And escape was the one thought in his mind now. Twice he might
have explained; first to his good stepfather, and again to these
minions of the law. But they had the grabbing instinct and (oh, the
pity of it) had diverted his thoughts from honest restitution to a
maniac desire to beat them and baffle them, to steal indeed his
liberty if nothing else, and let the satchel with its fortune go hang! He
would steal; yes, he would forget all else now in this crazy mixup! He
would steal what was the very breath of life to him—his freedom. He
forgot the whole sorry business in this dominant thought—Horton
Manners, the satchel, everything. They had grabbed him by the
collar and he could feel the tightness in his neck.
As long as the squirrel has teeth to bite, he will bite. You cannot
tame a squirrel. The fact that he is caught stealing in your tree is
quite a secondary matter. Hervey Willetts never thought of stealing
anything in his life—but just the one thing.
Freedom!
So he did a stunt. With both hands he tore open his shirt in front,
and as he felt the loosening grip in back he sprang forward only to
feel a vice-like hand catch hold of his arm. And that hand he bit with
all his vicious might and main. Like lightning he dodged both men
and was off like a deer while the circle of onlookers stood aghast.
Around the end of the freight platform he sped and those who
hurried there beheld no sign of him—only a milk-can lying on its side
which he had probably knocked over.
Off bounded one of the detectives; the other lingered, sucking the
cut in his hand. He didn’t know much about wild life, poor man. This
was a kind of stealing he had never seen before—the only kind that
interested Hervey Willetts. The only thing that interested him—
freedom. As long as the squirrel has teeth to bite, he will bite.
You cannot tame a squirrel.
 CHAPTER XXVI
OUT OF THE FRYING PAN
But they caught him, and caged him. They found him in the camp
of railroad workers near Clover Valley where he had spent a week or
so of happy days. And they left nothing undone. They investigated
the histories of that rough and ready crew, for they were after the
man higher up, the “master mind” in back of the robbery.
They unearthed the fact that one of them, Nebraska Ned, had
been a sailor and had deserted his ship to assist in a revolution in
South America. It was then that Hervey made a most momentous
decision. He abandoned Montana quite suddenly and chose South
America as the future theatre of his adventurous career.
No master mind was discovered, not even the true master mind,
Harlem Hinkey. He was not implicated and he neglected to uphold
the chivalrous honor of Harlem by coming forward as the originator
of the prank which had such a grave sequel. In the hearing in court,
Hervey never mentioned his name. And there you have Hervey
Willetts. You may take your choice between the “million dollar
theatre” and South America.
There was a pathos about the quiet resignation, the poise and
fairness in face of all, which Mr. Walton presented in that memorable
scene at the hearing. I like Mr. Walton, good man that he was. He
sat, a tall, gaunt figure, one lanky limb across the other, and listened
without any outward show of humiliation. His tired gray eyes, edged
by crow’s-foot wrinkles singularly deep, rested tolerantly on the prim
young man, Horton Manners, who was having his day in court with a
vengeance.
And Hervey, too, looked upon the young treasurer musician with
interest, with dismay indeed, for he recognized in him the very same
young man into whose lap he had stumbled on the train coming
home after his triumphal season at helpless Temple Camp. Horton
Manners looked down from his throne on the witness box, gazing
through Hervey rather than at him, and adjusted his horn spectacles
in a way that no one should do who is under fifty years old. He held
one lapel of his coat and this simple posture, so common with his
elders, gave him somehow the absurd look of an experienced
business man of about twenty-two years.
He was not in the least embarrassed. He testified that he was
treasurer of the Farrelton Band and confessed that he played a small
harp. If he had said that he played a drum nobody would have
believed him. He said that he had lived in Farrelton but a short while
and made his home with his married sister. Then, on invitation of the
likely looking young man representing the prosecutor, he told how
Hervey had mentioned on the train that he was going to Montana
and that he was going to “collop” the money to get there.
“And when did you next see him?”
“Not till this very day; in fact—here in court.”
“When he spoke of Montana, did he ask you how much it would
cost to get there?”
“He did, and I informed him that it would cost at least a hundred
dollars. I advised him against going.” There was a slight titter of the
spectators at this.
“I think that’s all, your Honor,” said the interrogator. “Since the boy
admits he took the satchel, we need not prove that.”
“Just one moment,” drawled Mr. Walton, drawing himself slowly to
his feet. He had employed no lawyer, and would not, unless his
stepson were held for trial on the serious charge of robbery.
“You say you live with your married sister?” he drawled
ruminatively.
“Mrs. Winton C. DeGraw, yes.”
“Then your name would not be in the ’phone book?”
“Presumably not.”
“Hmph.”
“I don’t see any significance in that,” said the young prosecutor.
“I simply want to find out if my boy has told me the truth,” said Mr.
Walton. “This isn’t a trial, of course. When I have satisfied myself
about certain matters I will ask the court to hear me. One more
question, Mr. Horton—I mean Mr. Manners. Do you know the
meaning of the word collop?”
“I never investigated it.”
“Well, I have investigated it,” said Mr. Walton, with the faintest
twinkle in his eye. Hervey looked rather surprisedly at his stepfather.
“It does not mean to steal. It means to earn or to get by the
performance of a foolhardy act—what boys call a stunt. Do you know
what a stunt is?”
“I suppose when I was knocked down⸺”
“You mean tripped.”
“Well, tripped. I suppose that was a stunt.”
“Exactly,” said Mr. Walton. “That’s all it was and nothing more. I
have talked with boys and I find that if a boy jumps from a high fence
to get another boy’s jack-knife, he collops it. It’s a long time since
you and I were boys, Mr. Horton Manners,” Mr. Walton added with a
smile. “Do you really want to charge this youngster with a felony?” he
continued in a tone of quiet kindness. “Isn’t the case hard enough
without that? Did you never perform a stunt?”
Oh, Hervey Willetts, if you had no thrill in that moment for the
patient, kindly, harassed man—your friend and counselor; then
indeed was there no hope for you! But he had a thrill. For the first
time in all his life his eyes filled and brimmed over as he looked at
the man who wanted only to make sure of him, to know that he was
not dishonest; who could stand for anything save that.
“I think, your Honor,” said Mr. Walton quietly, “that this affair
simmers down to a piece of mischief with an unintendedly serious
consequence. I know, of course, about the recent affair of the fire.
My boy gave himself up because he would not be despicable. He
does not lie, much less steal. I believe the story he told me; that he
thought the satchel contained a musical instrument and that he
intended to blow it and cause panic to those gathered in the church.
He saw the police officer, thought he was watched, and carried out
the part of innocence by bringing the satchel home. It proved an
elephant on his hands, a guilty burden to one really innocent. He told
me he could not find this young man’s name in the ’phone book and
it develops that the name is not there. I have here two men who saw
him looking in the ’phone book in a lunch room near the station⸺”
The judge interrupted and surprised him. “I think we need not
prolong this,” said he. “I think the boy had no intention of committing
a serious crime, or any crime at all. I believe the story he told when
arrested. I’d like to think the consequence will prove a lesson to him.
But do you think it will?”
“I’m afraid it will not,” said Mr. Walton. “And I may say now that it is
my intention to send him somewhere where he will be under rigid
discipline. I think I may be left to deal with him.”
“Well, the charge of robbery is dismissed,” said the judge. Then he
appeared to ruminate. “But the boy is still with us and there’s the
problem. This is the second time he has been brought into court. He
kicked up quite a rumpus and bit an officer. Where is this kind of
thing going to end?” He seemed kindly and spoke rather sociably
and not as an official. “Why don’t you put him in the Boy Scouts?” he
added.
“The Boy Scouts haven’t given him a knockout blow yet,” smiled
Mr. Walton. “I’m always hoping they’ll reach him. But I suppose
they’ll have to do a stunt that pleases him. Meanwhile, I’m going to
send him to a military school. It seems like a confession of defeat,
but I’m afraid it’s the only thing to do.”
The judge turned to Hervey. “You’d better go home with your
father,” said he. “And you take my advice and get into the Boy
Scouts while there is time, or the first thing you know you’ll land in a
reformatory. So you want to go to Montana, eh?”
“Sure, they have train robbers out there?” said Hervey.
“And how do you like having a hundred dollars that doesn’t belong
to you?”
“Nix on that stuff,” Hervey said gayly.
“Yet you like train robbers.”
“Bimbo, that’s different.”
Mr. Horton Manners, still sitting like an owl on the witness stand,
gazed at Hervey with a look of utter bewilderment.
“But in South America they have rebellions,” said Hervey.
“Well, let us have no more rebellion here,” smiled the judge.
And he winked at Mr. Walton.
 CHAPTER XXVII
AT LAST
Of course, Hervey was never in any danger of being sent to prison
for robbery. As soon as he was arrested and made to tell his story,
Mr. Walton annoyed, but unruffled, saw the thing in its true light. He
went to the all night lunch room near the station and made sure that
Hervey had gone there; then he verified the boy’s statement that the
name of Manners was not in the ’phone book.
Quietly he even inquired among boys the meaning of collop. And
he learned on the highest juvenile authority that it did not signify
stealing nor an intent to steal. But Horton Manners had made the
charge of robbery and so the whole business had to be aired in
court. Mr. Walton was a man of few words; it would be interesting to
know what he really thought of Horton Manners.
As for Hervey, he quite forgot the affair within an hour of the time it
was over. He had been appalled to find himself the custodian of a
hundred and more dollars, but now that he had got it off his hands,
he went upon his way rejoicing. He never looked either backward or
forward; the present was good enough for him. It is significant that
he bore no malice toward Horton Manners. Once or twice he referred
to him as Arabella; then he forgot all about him. He could not be
bothered hating anybody; nor caring a great deal about anybody
either.
A few prominent townspeople financed the Firemen’s Carnival
and it was held after all. Shows and acts were engaged, the merry-
go-round revolved to the accompaniment of its outlandish music, the
peanut and lemonade men held form; you could see the five-legged
calf for “a dime ten cents,” and Biddle’s field presented a gala scene.
The boys of Farrelton went round and round trying to stab the brass
ring, they drank red lemonade and time after time gazed spellbound
at the five-legged calf.
Hervey did not care about seeing the five-legged calf unless he
could sneak in under the canvas fence, and he could not manage
that because of the man who kept shouting and slapping the canvas
with his stick. In common with all the other boys he was thrilled at the
sight of Diving Denniver who ascended a ladder to a dizzy height
and dived from it into a small tank directly below. Diving Denniver did
this thing twice a day, and his night performance was the more
thrilling because it was in the glare of a searchlight whose long beam
followed him in his slow ascent of the frail looking ladder and showed
him in a circle of light when he paused for one thrilling moment at the
top. He earned his living in this way, going around exhibiting at
carnivals and amusement parks, and he was the big feature of the
Farrelton carnival.
Hervey was not content simply to behold this daredevil exploit. He
saw it twice in the daytime and once at night, and he could not stand
the strain of being restricted to the enjoyment afforded a gaping
audience. That is where he differed from other boys. It was this
something in his nature that prevented him from reading boys’
books; he could not intrude into the hair-raising adventures and so
he had no use for them. The most thrilling stories were utterly dead
stuff to Hervey.
But here he could intrude. It was after he saw the night
performance that he felt the urge to penetrate to the hallowed spot
whence that enchanted daredevil emerged in his theatrically
cautious ascent of the ladder. The nature of the spectacular feat
required that it be performed at a distance from the body of the
carnival. As soon as the band started playing Up in the air mid the
stars, the long column of light was directed on the ladder which
appeared as if by magic a hundred yards or so from the thronged
area of the carnival. Every eye was then fixed with expectancy as a
white figure arose into view, moving up, up, up, to a little
surmounting platform. Then the sensational dive, after which the
pleasure seekers ate, drank and were merry again.
But Hervey could not go back to any merry-go-round after that,
and red lemonade had no solace for him. He wandered off from
those festoons of electric lights, away from the festive groups, into
the darkness. Before him, down near the edge of Biddle’s field, was
a tiny light. Soon he came to a rope fence which cut off the end of
the field from the public. Beyond this were wagons and huge cases
standing in the darkness, the packing and transporting paraphernalia
of the motley shows. In a monstrous truck that stood there the multi-
colored prancing horses of the merry-go-round would be loaded and
have a ride themselves.
On an upright of this rope fence was a sign which read
POSITIVELY NO ADMITTANCE. Hervey entered just where the sign
was placed. A hundred or so paces brought him to the holy of holies,
a little tent at the foot of the towering, slender ladder. In the darkness
its wire braces, extending away on each side to their anchorages in
the earth, could not be seen. Almost at the foot of the ladder was a
tank perhaps fifteen or eighteen feet square. Close by the tent was a
Ford sedan, and Hervey crept reverently up to it and read the words
on the spare tire cover DIVING DENNIVER. On the lower part of the
circumference was printed THREE HUNDRED FOOT DIVE. Diving
Denniver believed in advertising. In that tent lived the enchanted
mortal.
Hervey lingered in awe as a pilgrim might linger at a shrine before
entering. Then he walked rather hesitatingly to the open flap of the
tent. On a mattress which lay atop a huge red chest reclined Diving
Denniver in a bath robe. The chest had DIVING DENNIVER printed
on it, as also did a large leather grip, which bore the additional
information WONDER OF TWO CONTINENTS. If the world could
not see Diving Denniver on his dizzy perch, it at least could read
about him. Besides the makeshift divan the tent contained a rough
table formed by a red board laid on two saw horses.
On this was a greasy oil-stove and one or two plates and cups. In
his illicit wanderings, Hervey had at last trespassed through the
golden gates into heaven.
“I was walking around,” said he, rather unconvincingly.
Diving Denniver, a slim young man of about thirty, was smoking a
cigarette and looking over a magazine. It seemed incredible that he
should be thus engaged so soon after his spectacular descent.
 “Bimbo, that was some pippin of a dive,” said Hervey. Then, as
Diving Denniver made no attempt to kill him, he ventured to add, “Oh
bambino, that’s one thing I’m crazy about—diving.”
“Didn’t the cop see you?” the marvel asked.
“Leave it to me,” said Hervey. “There isn’t any cop there anyway.
Cops, that’s one thing I have no use for—nix.”
“Yere?” queried Diving Denniver, aroused to slight amusement.
“Do you—do you feel funny?” Hervey ventured as he gazed upon
the wonder of two continents.
“Where did yer git that hat?” asked the god of the temple. “What’s
all them buttons you got on it?”
“I climbed way down a cellar shaft to get one of those buttons,”
said Hervey, anxious to establish a common ground of professional
sympathy with this celebrity. “That’s the one,” he indicated, as he
handed Denniver his hat; “the one that says VOTE FOR TINNEY. He
didn’t get elected and I’m glad, because his chauffeur’s a big fool; he
chased me, but he couldn’t catch me. Some of those holes I cut out
with a real cartridge shell, like you cut cookies. I bet you feel funny,
hey?”
“Yere?” said Diving Denniver, examining the hat. “Well, do you
think yer could go back up there where the big noise is and then
come back here again—without gettin’ stopped?”
“You mean you dare me to?”
Diving Denniver roused himself sufficiently to reach over to a box
and grope in the pocket of a pair of ordinary trousers, the kind that
mortals wear. Then he tossed a quarter to Hervey. “Chase yourself
back there and get a frankfurter,” he said; “get a couple of ’em. And
don’t leave the cop see yer.”
So the wonder of two continents ate frankfurters—and scorned
cops. More than that, he and Hervey were going to eat a couple of
frankfurters together. At last Hervey felt that he had not lived in vain.
 CHAPTER XXVIII
THE LAW AGAIN
Hervey felt that he and Diving Denniver were pretty much alike
after all. The wonder of two continents beat all the boy scouts put
together. And he had now a fine precedent for his repudiation of
authority. Diving Denniver cared naught for cops and signs. Hervey
would have been glad to go into any court and cite this high
authority, confounding the powers with this frankfurter episode. He
was sorry he had not told Diving Denniver of his swimming across
the lake at Temple Camp (during rest period which was against the
rules). Instead of an honor he had received a reprimand for that. He
was a little afraid that some of the other boys would visit the wonder
in his tent, but in fact there wasn’t much danger of that. The wonder
was too much off the beaten track for most boys. Their thoughts did
not carry behind the scenes.
Hervey was now in much perplexity whether to witness the thrilling
exploit from the audience the next night or to view it from the
sanctum of the hero. In either case he intended to visit the remote
scene of enchantment with two frankfurters. He decided that he
would not demean himself by gazing at his hero with the idle throng.
He even negotiated an extra hour out from Mr. Walton in anticipation
of his second visit to the hermit of the ladder.
He could not possibly reach the place in the daytime, and besides,
he had to take up some bulbs for his stepmother the next day. For
this and other services he was to receive fifty cents. Twenty-five of
this would pay his admission to the carnival. With the other twenty-
five he intended to furnish forth a banquet of frankfurters for his hero
and brother daredevil. He could not afford to go twice in the day. He
had some thought of effecting an entrance over the high fence into
the field and having his entire fifty cents for the post-exploit feast. But
reckless as he was, he was cautious in this matter of reaching the
tent—there was so much at stake! So he decided to go respectably
in through the entrance and then cross the rope fence where the
“Positively No Admittance” sign was placed. It was not often that he
showed such a conservative spirit.
At half past eight, he found Diving Denniver strolling around in his
bathrobe outside the tent. Within, the odor of fried bacon and coffee
still lingered.
“You back again?”
“Sure, I want to see you from right here, and afterward I’m going
to go and get some more frankfurters. After you’re finished will you
let me go about ten or fifteen steps up the ladder and try it?”
Diving Denniver did not trouble himself to answer, but he ruffled
Hervey’s hair good-humoredly as he ambled about smoking his
cigarette. “Much of a crowd over there?” he asked.
“Oh bimbo, they’re all waiting. They stop dancing even when you
go up,” Hervey said.
“You’re a pretty slippery kid, all right, ain’t yer?” Denniver said.
“Ain’t there no guy up there at the rope?”
The words were scarcely out of his mouth when both he and
Hervey became aware of a policeman who had just come around the
side of the tent. But Hervey, though astonished, was not perturbed,
for he believed that the wonder of two continents would protect him.
One word from Diving Denniver and he would be safe. He even
ventured a defense himself.
“I’m going to do an errand for him,” he said.
“You can ask him yourself. So I’ve got a right to be here.”
But it appeared that it was Diving Denniver with whom the officer
had business. “Are you Charles McDennison?” he asked.
“Yere, what’s the dope?” the wonder asked, with a kind of
weariness in his voice.
Hervey was astonished, not to say shocked, that Diving Denniver
acknowledged the name of Charles McDennison.
“Let’s look at your permit,” said the officer.
Mr. McDennison entered the tent, presently emerging with a
paper.