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THE PHARMACOLOGICAL BASIS OF
THERAPEUTICS
FOURTEENTH EDITION
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THE PHARMACOLOGICAL BASIS OF
THERAPEUTICS
FOURTEENTH EDITION
Editor-in-Chief
Laurence L. Brunton, PhD
Professor of Pharmacology
School of Medicine
University of California, San Diego
La Jolla, California
Editor
Björn C. Knollmann, MD, PhD
William Stokes Professor of Medicine and Pharmacology
Fellowship Director, Division of Clinical Pharmacology
Director, Vanderbilt Center for Arrhythmia Research and
Therapeutics (VanCART)
Vanderbilt University School of Medicine
Nashville, Tennessee
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Contents
Contributors ix 18. Drug Therapy of Depression and Anxiety Disorders..................... 343

Preface xv James M. O’Donnell, Robert R. Bies, and Aislinn J. Williams
Acknowledgments xvii 19. Pharmacotherapy of Psychosis and Mania...................................... 357
Jonathan M. Meyer
20. Pharmacotherapy of the Epilepsies................................................... 385
Section I Cameron S. Metcalf, Misty D. Smith, and Karen S. Wilcox
General Principles 1 21. Treatment of Central Nervous System
1. Drug Discovery: From Medicinal Plants to Computer-Aided Degenerative Disorders...................................................................... 413
Drug Design ............................................................................................ 3 Erik D. Roberson and Talene A. Yacoubian
Michael K. Gilson and Laurence L. Brunton 22. Hypnotics and Sedatives.................................................................... 427
2. Pharmacokinetics: The Dynamics of Drug Absorption, S. John Mihic and Jody Mayfield
Distribution, Metabolism, and Elimination...................................... 23 23. Opioid Analgesics .............................................................................. 443
Iain L. O. Buxton Emily M. Jutkiewicz and John R. Traynor
3. Pharmacodynamics: Molecular Mechanisms of Drug Action........ 43 24. General Anesthetics and Therapeutic Gases................................... 471
David R. Manning and Donald K. Blumenthal Jerry Ingrande, Matthew L. Pearn, and Hemal H. Patel
4. Membrane Transporters and Drug Response................................... 79 25. Local Anesthetics................................................................................ 489
Kathleen M. Giacomini and Yuichi Sugiyama William A. Catterall and Kenneth Mackie
5. Drug Metabolism................................................................................ 101 26. Cannabinoids....................................................................................... 505
Frank J. Gonzalez and Michael Coughtrie Matthew N. Hill and Kenneth Mackie
6. The Gastrointestinal Microbiome and Drug Response................. 119 27. Ethanol.................................................................................................. 519
Shirley M. Tsunoda, Pieter C. Dorrestein, and Rob Knight Jody Mayfield and S. John Mihic
7. Pharmacogenetics and Pharmacogenomics.................................... 131 28. Drug Use Disorders and Addiction.................................................. 531
Dan M. Roden and Sara L. Van Driest Christine Konradi and Yasmin L. Hurd
8. Postmarketing Drug Safety................................................................ 145
C. Michael Stein and Wayne A. Ray
9. Principles of Clinical Toxicology...................................................... 155
Section III
Amberly R. Johnson and Kaitlyn M. Brown Modulation of Pulmonary, Renal,
and Cardiovascular 555
Section II 29. Drugs Affecting Renal Excretory Function..................................... 557
Edwin K. Jackson
Neuropharmacology 171 30. Renin and Angiotensin....................................................................... 585
10. Neurotransmission: The Autonomic and Somatic Motor Krishna Sriram and Paul A. Insel
Nervous Systems................................................................................. 173 31. Treatment of Ischemic Heart Disease............................................... 607
Rebecca Petre Sullivan, Steven R. Houser, and Walter J. Koch
Thomas Eschenhagen
11. Muscarinic Receptor Agonists and Antagonists............................. 207 32. Treatment of Hypertension................................................................ 625
Joan Heller Brown, Katharina Brandl, and Jürgen Wess
Thomas Eschenhagen
12. Anticholinesterase Inhibitors and Reactivators.............................. 221 33. Therapy of Heart Failure.................................................................... 647
Palmer Taylor
Thomas Eschenhagen
13. Neuromuscular Junction and Autonomic Ganglia; Nicotine, 34. Antiarrhythmic Drugs........................................................................ 667
Muscle Relaxants, and Spasmolytics ................................................ 235 Bjorn C. Knollmann, Dan M. Roden, and Katherine T. Murray
Ryan E. Hibbs and Alexander C. Zambon
35. Treatment of Pulmonary Arterial Hypertension............................ 695
14. Adrenergic Agonists and Antagonists.............................................. 251 Dustin R. Fraidenburg, Ankit A. Desai, Ayako Makino,
Douglas G. Tilley, Steven R. Houser, and Walter J. Koch and Jason X.-J. Yuan
15. 5-Hydroxytryptamine (Serotonin) and Dopamine........................ 285 36. Blood Coagulation and Anticoagulant, Fibrinolytic, and
Charles D. Nichols, Susan G. Amara, and David R. Sibley
Antiplatelet Drugs............................................................................... 709
16. Neurotransmission in the Central Nervous System....................... 305 Jeffrey I. Weitz
R. Benjamin Free, Suzanne M. Underhill, Susan G. Amara,
37. Drug Therapy for Dyslipidemias...................................................... 729
and David R. Sibley
Natalia Ruiz-Negrón and Donald K. Blumenthal
17. The Blood-Brain Barrier and Its Influence on Drug
Transport to the Brain........................................................................ 327
Richard Daneman, Margareta Hammarlund-Udenaes,
and Eric V. Shusta
viii Section IV 58. Cell Envelope Disruptors: β-Lactam, Glycopeptide, and
Lipopeptide Antibacterials.............................................................. 1147
Inflammation, Immunomodulation, Conan MacDougall
and Hematopoiesis 747 59. Miscellaneous Antibacterials: Aminoglycosides, Polymyxins,
38. Introduction to Immunity and Inflammation................................. 749 Urinary Antiseptics, Bacteriophages.............................................. 1167
Michael David Conan MacDougall and Robert T. Schooley
39. Immunosuppressants, Immunomodulation, and Tolerance......... 769 60. Protein Synthesis Inhibitors ............................................................ 1179
Carla V. Rothlin and J. Silvio Gutkind Conan MacDougall
Contents
40. Immune Globulins and Vaccines...................................................... 793 61. Antifungal Agents............................................................................. 1193
Roberto Tinoco and James E. Crowe, Jr. P. David Rogers and Damian J. Krysan
41. Lipid-Derived Autacoids: Eicosanoids and 62. Antiviral Agents (Nonretroviral).................................................... 1211
Platelet-Activating Factor................................................................... 815 Edward P. Acosta
Emanuela Ricciotti, Tilo Grosser, and Garret A. FitzGerald 63. Treatment of Viral Hepatitis (HBV/HCV).................................... 1227
42. Pharmacotherapy of Inflammation, Fever, Pain, and Gout........... 829 Jennifer J. Kiser
Tilo Grosser, Emanuela Ricciotti, and Garret A. FitzGerald 64. Antiretroviral Agents and Treatment of HIV Infection............... 1245
43. Histamine, Bradykinin, and Their Antagonists.............................. 857 Charles W. Flexner
Bruce L. Zuraw and Sandra C. Christiansen 65. Chemotherapy of Tuberculosis and Nontuberculous
44. Pulmonary Pharmacology................................................................. 875 Mycobacteria, Including Leprosy ................................................... 1267
Peter J. Barnes Elisa H. Ignatius and Kelly E. Dooley
45. Hematopoietic Agents: Growth Factors, Minerals, 66. Chemotherapy of Malaria................................................................ 1289
and Vitamins........................................................................................ 899 Abdoulaye A. Djimdé and Steve M. Taylor
Michael Choi and Thomas J. Kipps 67. Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis,
Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other
Protozoal Infections.......................................................................... 1309
Section V Dawn M. Wetzel and Margaret A. Phillips
Endocrine Pharmacology 921 68. Chemotherapy of Helminth Infections.......................................... 1325
46. Introduction to Endocrinology: Jennifer Keiser, James McCarthy, and Peter Hotez
The Hypothalamic-Pituitary Axis..................................................... 923
Dequina A. Nicholas and Mark A. Lawson
Section VIII
47. Thyroid and Antithyroid Drugs........................................................ 941
Ronald J. Koenig and Gregory A. Brent Pharmacotherapy of Neoplastic Disease 1335
Section Editor: Anton Wellstein
48. Estrogens, Progestins, and the Female Reproductive Tract........... 959
Ellis R. Levin, Wendy S. Vitek, and Stephen R. Hammes 69. General Principles in the Pharmacotherapy of Cancer................ 1337
49. Androgens and the Male Reproductive Tract................................. 991 Anton Wellstein
Peter J. Snyder 70. Cytotoxics and Antimetabolites...................................................... 1343
50. Adrenocorticotropic Hormone, Adrenal Steroids, Anton Wellstein and Edward A. Sausville
and the Adrenal Cortex.................................................................... 1003 71. Protein Kinase Inhibitors and Pathway-Targeted
Christopher J. Hupfeld and Jorge Iñiguez-Lluhí Small Molecules ................................................................................ 1381
51. Endocrine Pancreas and Pharmacotherapy of Anton Wellstein and Giuseppe Giaccone
Diabetes Mellitus and Hypoglycemia............................................. 1023 72. Antibodies, CAR T Cells, and Proteins to Treat Cancer.............. 1415
Alvin C. Powers and David D’Alessio Anton Wellstein and Michael B. Atkins
52. Agents Affecting Mineral Ion Homeostasis 73. Hormones, Hormone Receptor Antagonists, and
and Bone Turnover........................................................................... 1049 Related Agents in the Therapy of Cancer...................................... 1435
Thomas D. Nolin and Peter A. Friedman Claudine Isaacs, Kerry L. Burnstein, and Anna T. Riegel
Section VI Section IX
Gastrointestinal Pharmacology 1071 Special Systems Pharmacology 1451
53. Pharmacotherapy for Gastric Acidity, Peptic Ulcers, and 74. Ocular Pharmacology....................................................................... 1453
Gastroesophageal Reflux Disease................................................... 1073 Upneet K. Bains, Zeba A. Syed, Jeffrey D. Henderer,
Keith A. Sharkey and Wallace K. MacNaughton and Christopher J. Rapuano
54. Gastrointestinal Motility and Water Flux, Emesis, 75. Dermatological Pharmacology........................................................ 1475
Matthew J. Sewell and Dean S. Morrell
and Biliary and Pancreatic Disease................................................. 1085
Keith A. Sharkey and Wallace K. MacNaughton 76. Environmental Toxicology............................................................... 1507
Allison K. Ehrlich
55. Pharmacotherapy of Inflammatory Bowel Disease...................... 1111
Wallace K. MacNaughton and Keith A. Sharkey
Appendices
Section VII I. Design and Optimization of Dosage Regimens:
Pharmacokinetic Data...................................................................... 1533
Chemotherapy of Infectious Diseases 1125 Isabelle Ragueneau-Majlessi, Jingjing Yu, and Nina Isoherranen
Section Editor: Conan MacDougall
II. Drug-Drug Interactions................................................................... 1591
56. General Principles of Antimicrobial Therapy............................... 1127 Isabelle Ragueneau-Majlessi, Jingjing Yu, and Nina Isoherranen
Conan MacDougall
57. DNA Disruptors: Sulfonamides, Quinolones, Index 1595
and Nitroimidazoles ........................................................................ 1137
Conan MacDougall

Contributors
Edward Acosta, PharmD Kaitlyn Brown, PharmD, DABAT

Professor and Director, Clinical Pharmacology Clinical Supervisor
University of Alabama at Birmingham School of Medicine Adjunct Instructor–Utah Poison Control Center
Birmingham, Alabama Department of Pharmacotherapy
University of Utah College of Pharmacy
Susan G. Amara, PhD Salt Lake City, Utah
Scientific Director
National Institute of Mental Health Laurence L. Brunton, PhD
National Institutes of Health Emeritus Professor of Pharmacology
Bethesda, Maryland Department of Pharmacology, School of Medicine
Michael B. Atkins, MD La Jolla, California
Professor of Oncology and Medicine
Georgetown University School of Medicine Kerry L. Burnstein, PhD
Washington, DC Professor and Chair
Department of Molecular and Cellular Pharmacology
Upneet Kaur Bains, MD Miller School of Medicine
Assistant Professor of Ophthalmology University of Miami
Lewis Katz School of Medicine at Temple University Miami, Florida
Philadelphia, Pennsylvania
Iain L. O. Buxton, PharmD, FAHA
Peter J. Barnes, FRS, FMedSci Foundation Professor
Professor of Thoracic Medicine Department of Pharmacology
National Heart & Lung Institute University of Nevada, Reno School of Medicine
Imperial College London Reno, Nevada
London, United Kingdom
William A. Catterall, PhD
Robert R. Bies, PharmD, PhD Professor of Pharmacology
Associate Professor School of Medicine
School of Pharmacy and Pharmaceutical Sciences University of Washington
The State University of New York, Buffalo Seattle, Washington
Buffalo, New York
Michael Choi, MD
Donald K. Blumenthal, PhD Associate Clinical Professor
Associate Professor of Pharmacology Moores Cancer Center
College of Pharmacy University of California, San Diego
University of Utah La Jolla, California
Salt Lake City, Utah
Sandra Christiansen, MD
Katharina Brandl, PhD Clinical Professor of Health Sciences
Associate Professor University of California, San Diego
Skaggs School of Pharmacy and Pharmaceutical Sciences La Jolla, California
La Jolla, California Michael W. H. Coughtrie, PhD
Professor and Dean
Gregory A. Brent, MD Faculty of Pharmaceutical Sciences
Professor of Medicine and Physiology University of British Columbia
Chief, Division of Endocrinology, Diabetes and Metabolism Vancouver, Canada
David Geffen School of Medicine
University of California, Los Angeles James E. Crowe, Jr., MD
Los Angeles, California Professor of Pediatrics, Pathology, Microbiology and Immunology
Vanderbilt University Medical Center
Joan Heller Brown, PhD Nashville, Tennessee
Distinguished Professor, Emeritus Chair
Department of Pharmacology
x David D’Alessio, MD R. Benjamin Free, PhD
Professor, Department of Medicine Staff Scientist, Neuropharmacology Section
Director, Division of Endocrinology National Institute of Neurological Disorders and Stroke
Duke University Medical Center National Institutes of Health
Durham, North Carolina Bethesda, Maryland
Richard Daneman, PhD Peter A. Friedman, PhD

Associate Professor of Pharmacology and Neurosciences Professor
Contributors
University of California, San Diego Department of Pharmacology and Chemical Biology

La Jolla, California University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania
Michael David, PharmD, PhD
Professor Division of Biological Sciences and Kathleen M. Giacomini, PhD
Moores Cancer Center Professor of Bioengineering and Therapeutic Sciences
University of California, San Diego School of Pharmacy
La Jolla, California University of California, San Francisco
San Francisco, California
Ankit A. Desai, MD
Associate Professor of Medicine Giuseppe Giaconne, MD, PhD
Indiana University Professor of Medicine
Indianapolis, Indiana Associate Director of Clinical Research
Sandra and Edward Meyer Cancer Center
Abdoulaye Djimdé, PharmD, PhD Weill Cornell Medical Center
CAMES Professor of Parasitology and Mycology New York, New York
University of Science, Techniques and Technologies of Bamako
Bamako, Mali Michael K. Gilson, MD, PhD
Distinguished Professor
Kelly Dooley, MD, PhD, MPH Skaggs School of Pharmacy and Pharmaceutical Sciences
Professor of Medicine, Pharmacology & Molecular Sciences University of California, San Diego
Johns Hopkins University School of Medicine La Jolla, California
Baltimore, Maryland
Frank J. Gonzalez, PhD
Pieter C. Dorrestein, PhD Chief, Laboratory of Metabolism
Professor, Departments of Pharmacology and Pediatrics Center for Cancer Research
Skaggs School of Pharmacy & Pharmaceutical Sciences National Cancer Institute
University of California, San Diego National Institutes of Health
La Jolla, California Bethesda, Maryland
Allison K. Ehrlich, PhD Tilo Grosser, MD
Assistant Professor of Environmental Toxicology Research Associate Professor of Pharmacology
University of California, Davis Institute for Translational Medicine and Therapeutics
Davis, California University of Pennsylvania
Thomas Eschenhagen, MD Philadelphia, Pennsylvania
Professor and Chair of Pharmacology Silvio Gutkind, PhD
Department of Experimental Pharmacology and Toxicology Distinguished Professor and Chair
University Medical Center Hamburg-Eppendorf Department of Pharmacology
Hamburg, Germany University of California, San Diego
Garret A. FitzGerald, MD, FRS La Jolla, California
Director, Institute for Translational Medicine and Therapeutics Margareta Hammarlund-Udenaes, PhD
Perelman School of Medicine Professor of Pharmacokinetics and Pharmacodynamics
University of Pennsylvania Department of Pharmacy
Philadelphia, Pennsylvania Uppsala University
Charles W. Flexner, MD Uppsala, Sweden
Professor of Medicine, Pharmacology and Molecular Sciences, and Stephen R. Hammes, MD, PhD
International Health Professor of Medicine
Chief Scientific Officer, Institute for Clinical and Chief of Endocrinology and Metabolism
Translational Research School of Medicine and Dentistry
Johns Hopkins University University of Rochester
Baltimore, Maryland Rochester, New York
Dustin R. Fraidenburg, MD Jeffrey D. Henderer, MD
Assistant Professor of Medicine Professor of Ophthalmology
Director, Pulmonary Hypertension Program Dr. Edward Hagop Bedrossian Chair of Ophthalmology
University of Illinois Lewis Katz School of Medicine at Temple University
Chicago, Illinois Philadelphia, Pennsylvania

Ryan E. Hibbs, PhD Nina Isoherranen, MS, PhD xi
Associate Professor of Neuroscience Professor of Pharmaceutics
University of Texas Southwestern Medical School University of Washington School of Pharmacy
Dallas, Texas Seattle, Washington
Matthew N. Hill, PhD Edwin K. Jackson, PhD

Professor Professor of Pharmacology and Chemical Biology
Hotchkiss Brain Institute University of Pittsburgh
Contributors
Cumming School of Medicine Pittsburgh, Pennsylvania
University of Calgary
Calgary, Canada Amberly R. Johnson, PharmD, DABAT
Director, Utah Poison Control Center
Peter J. Hotez, MD, PhD Assistant Professor (Clinical)
Professor of Pediatrics and Molecular Virology and Microbiology University of Utah College of Pharmacy
Texas Children’s Hospital Endowed Chair in Tropical Pediatrics Salt Lake City, Utah
Dean, National School of Tropical Medicine
Baylor College of Medicine Emily M. Jutkiewicz, PhD
Houston, Texas Associate Professor of Pharmacology
University of Michigan
Steven R. Houser, PhD Ann Arbor, Michigan
Senior Associate Dean, Research
Vera J. Goodfriend Chair in Cardiovascular Research Jennifer Keiser, PhD
Director and Professor, Cardiovascular Research Center Associate Professor of Neglected Tropical Diseases
Professor, Cardiovascular Sciences and Medicine Unit Head
Lewis Katz School of Medicine Swiss Tropical & Public Health Institute
Temple University Allschwil, Switzerland
Philadelphia, Pennsylvania Thomas J. Kipps, MD, PhD
Christopher J. Hupfeld, MD Professor of Medicine, Moores Cancer Center
Clinical Professor of Medicine University of California, San Diego
Division of Endocrinology, School of Medicine La Jolla, California
University of California, San Diego Jennifer J. Kiser, PharmD, PhD
La Jolla, California Associate Professor
Yasmin L. Hurd, PhD Department of Pharmaceutical Sciences
Professor of Pharmacological Sciences, Neuroscience and Psychiatry University of Colorado Anschutz Medical Campus
Icahn School of Medicine at Mount Sinai Aurora, Colorado
New York, New York Rob Knight, PhD
Elisa H. Ignatius, MD, MSc Professor of Pediatrics
Assistant Professor of Medicine Affiliate Professor of Computer Science and Engineering
Division of Clinical Pharmacology and Infectious Diseases Director of the Center for Microbiome Innovation
Johns Hopkins University School of Medicine University of California, San Diego
Baltimore, Maryland La Jolla, California
Jerry Ingrande, MD, MS Bjorn C. Knollmann, MD, PhD

Associate Clinical Professor William Stokes Professor of Medicine and Pharmacology
Department of Anesthesiology, School of Medicine Fellowship Director, Division of Clinical Pharmacology
University of California, San Diego Director, Vanderbilt Center for Arrhythmia Research and
La Jolla, California Therapeutics (VanCART)
Vanderbilt University School of Medicine
Jorge Iniguez-Lluhi, PhD Nashville, Tennessee
Associate Professor of Pharmacology
University of Michigan Walter J. Koch, PhD
Ann Arbor, Michigan W.W. Smith Chair in Cardiovascular Medicine
Professor and Chair, Department of Cardiovascular Sciences
Paul A. Insel, MD Lewis Katz School of Medicine, Temple University
Distinguished Professor of Pharmacology and Medicine, Emeritus Philadelphia, Pennsylvania
Co-Director, Medical Scientist (MD/PhD) Training Program
University of California, San Diego Ronald J. Koenig, MD, PhD
La Jolla, California Professor Emeritus of Internal Medicine
Division of Metabolism, Endocrinology and Diabetes
Claudine Isaacs, MD, FRCPC University of Michigan
Professor of Medicine and Oncology Ann Arbor, Michigan
Associate Director for Clinical Research
Lombardi Comprehensive Cancer Center Christine Konradi, PhD
Georgetown University Professor of Pharmacology and Psychiatry
Washington, DC School of Medicine
Vanderbilt University
xii Damian J. Krysan, MD, PhD Jonathan M. Meyer, MD
Division Director, Pediatric Infectious Disease Psychopharmacology Consultant, California Department of
Samuel J. Fomon Chair in Pulmonology/Allergy/Infectious Diseases State Hospitals
Professor of Pediatrics and Microbiology/Immunology Assistant Clinical Professor of Psychiatry
Carver College of Medicine University of California, San Diego
University of Iowa La Jolla, California
Iowa City, Iowa
S. John Mihic, PhD
Contributors
Mark A. Lawson, PhD Associate Professor of Neuroscience

Professor of Obstetrics, Gynecology, and Reproductive Sciences University of Texas
School of Medicine Austin, Texas
La Jolla, California Dean S. Morrell, MD
Professor of Dermatology
Ellis R. Levin, MD University of North Carolina
Professor of Medicine Chapel Hill, North Carolina
Chief of Endocrinology, Diabetes and Metabolism
Veterans Affairs Long Beach Health Care System Katherine T. Murray, MD
University of California, Irvine Professor of Medicine and Pharmacology
Irvine, California Vanderbilt University School of Medicine
Conan MacDougall, PharmD, MAS
Professor of Clinical Pharmacy Dequina A. Nicholas, PhD
University of California, San Francisco Assistant Professor of Molecular Biology and Biochemistry
San Francisco, California School of Biological Sciences
University of California, Irvine
Kenneth P. Mackie, MD Irvine, California
Professor of Psychological and Brain Sciences
Director, Gill Center for Biomolecular Science Charles D. Nichols, PhD
Indiana University Professor
Bloomington, Indiana Department of Pharmacology and Experimental Therapeutics
Louisiana State University Health Sciences Center
Wallace K. MacNaughton, PhD, CAGF, FAPS New Orleans, Louisiana
Professor of Physiology and Pharmacology
University of Calgary Thomas D. Nolin, PharmD, PhD
Calgary, Canada Associate Dean for Research and Sponsored Programs
School of Pharmacy, University of Pittsburgh
Ayako Makino, PhD Pittsburgh, Pennsylvania
Associate Professor of Medicine
University of California, San Diego James M. O’Donnell, PhD
La Jolla, California Professor of Pharmaceutical Sciences
School of Pharmacy and Pharmaceutical Sciences
David R. Manning, PhD State University of New York at Buffalo
Emeritus Professor of Systems Pharmacology and Buffalo, New York
Translational Therapeutics
Perelman School of Medicine Hemal H. Patel, PhD
University of Pennsylvania Professor and Vice Chair of Research
Philadelphia, Pennsylvania Department of Anesthesiology, School of Medicine
Jody Mayfield, PhD La Jolla, California
Science Writer and Editor
Waggoner Center for Alcohol and Addiction Research Matthew L. Pearn, MD
University of Texas Associate Professor of Anesthesiology
Austin, Texas VA-San Diego Healthcare System
James McCarthy, MD La Jolla, California
Director, Victorian Infectious Diseases Service
Peter Doherty Institute Margaret A. Phillips, PhD
Royal Melbourne Hospital Professor and Chair
University of Melbourne Department of Biochemistry
Melbourne, Australia University of Texas Southwestern Medical Center
Dallas, Texas
Cameron S. Metcalf, PhD
Research Assistant Professor of Pharmacology & Toxicology Alvin C. Powers, MD
Associate Director, Epilepsy Therapy Screening Program Contract Site Joe C. Davis Chair in Biomedical Science
University of Utah Professor of Medicine, Molecular Physiology and Biophysics
Salt Lake City, Utah Director, Vanderbilt Diabetes Center
Chief, Division of Diabetes, Endocrinology and Metabolism
Vanderbilt University Medical Center

Isabelle Ragueneau-Majlessi, MD, MS Matthew J. Sewell, MD, PharmD xiii
Clinical Professor WISE Dermatology
Department of Pharmaceutics Houston, Texas
University of Washington
Seattle, Washington Keith A. Sharkey, PhD, CAGF, FACHS
Professor of Physiology and Pharmacology
Christopher J. Rapuano, MD Cumming School of Medicine
Chief, Cornea Service, Wills Eye Hospital University of Calgary
Contributors
Professor Calgary, Canada
Sidney Kimmel Medical College at Thomas Jefferson University
Philadelphia, Pennsylvania Eric V. Shusta, PhD
Howard Curler Distinguished Professor and
Wayne Ray, PhD R. Byron Bird Department Chair
Professor, Department of Health Policy Department of Chemical and Biological Engineering
Vanderbilt University Medical Center Department of Neurological Surgery
Nashville, Tennessee University of Wisconsin
Madison, Wisconsin
Emanuela Riciotti, PhD
Research Assistant Professor of Pharmacology David R. Sibley, PhD
Department of Systems Pharmacology and Translational Therapeutics Senior Investigator, Molecular Neuropharmacology Section
Perelman School of Medicine National Institute of Neurological Disorders and Stroke
University of Pennsylvania National Institutes of Health
Philadelphia, Pennsylvania Bethesda, Maryland
Anna Tate Riegel, PhD Misty D. Smith, PhD

Professor Research Assistant Professor
Departments of Oncology & Pharmacology Department of Pharmacology & Toxicology
Georgetown University School of Medicine College of Pharmacy and School of Dentistry
Washington, DC University of Utah
Salt Lake City, Utah
Erik D. Roberson, MD, PhD
Rebecca Gale Endowed Professor Peter J. Snyder, MD
Department of Neurology Professor of Medicine
University of Alabama at Birmingham Perelman School of Medicine
Birmingham, Alabama University of Pennsylvania
Dan M. Roden, MD
Professor of Medicine, Pharmacology, and Biomedical Informatics Krishna Sriram, PhD
Senior Vice President for Personalized Medicine Assistant Project Scientist
Vanderbilt University Medical Center Department of Pharmacology
Nashville, Tennessee University of California, San Diego
P. David Rogers, PharmD, PhD, FCCP
St. Jude Endowed Chair in Pharmaceutical Sciences C. Michael Stein, MBChB, FRCP(Edin)
Department of Pharmacy and Pharmaceutical Sciences Dan May Professor of Medicine
St. Jude Children’s Research Hospital Division of Clinical Pharmacology
Memphis, Tennessee Vanderbilt University Medical Center
Carla V. Rothlin, PhD
Dorys McConnell Duberg Professor of Immunobiology and Yuichi Sugiyama, PhD
Pharmacology Distinguished Professor
Yale University School of Medicine Graduate School of Pharmaceutical Sciences
New Haven, Connecticut Josai International University
Kioi-cho, Japan
Natalia Ruiz-Negrón, PharmD
Research Assistant Professor Rebecca Petre Sullivan, PhD
University of Utah College of Pharmacy Associate Professor of Physiology and Vice Chair
Salt Lake City, Utah Department of Biomedical Education and Data Science
Department of Cardiovascular Sciences
Edward A. Sausville, MD, PhD Lewis Katz School of Medicine
Professor of Medicine (Retired) Temple University
Greenebaum Comprehensive Cancer Center Philadelphia, Pennsylvania
University of Maryland
Baltimore, Maryland Zeba A. Syed, MD
Assistant Professor
Robert Schooley, MD Wills Eye Hospital
Distinguished Professor of Medicine Philadelphia, Pennsylvania
xiv Palmer Taylor, PhD Anton Wellstein, MD, PhD
Sandra & Monroe Trout Professor of Pharmacology, School of Medicine Professor of Oncology and Pharmacology
Dean Emeritus, Skaggs School of Pharmacy & Pharmaceutical Sciences Georgetown University School of Medicine
University of California, San Diego Washington, DC
Jürgen Wess, PhD
Steve M. Taylor, MD, PhD Chief, Molecular Signaling Section
Associate Professor of Medicine (Infectious Diseases) and Global Health Lab of Bioorganic Chemistry
Contributors
School of Medicine, Duke University National Institute of Diabetes and Digestive and Kidney Diseases
Durham, North Carolina National Institutes of Health
Bethesda, Maryland
Douglas G. Tilley, PhD
Professor Dawn Wetzel, MD, PhD
Department of Cardiovascular Sciences, and Center for Assistant Professor of Pediatrics and Biochemistry
Translational Medicine University of Texas Southwestern Medical Center
Lewis Katz School of Medicine at Temple University Dallas, Texas
Karen S. Wilcox, PhD
Roberto Tinoco, PhD Professor and Chair of Pharmacology & Toxicology
Assistant Professor College of Pharmacy
Department of Molecular Biology and Biochemistry University of Utah
School of Biological Sciences Salt Lake City, Utah
University of California, Irvine
Irvine, California Aislinn Williams, MD, PhD
Assistant Professor of Psychiatry
John Traynor, PhD Iowa Neuroscience Institute
Edward F. Domino Research Professor University of Iowa
Professor and Associate Chair for Research, Department of Iowa City, Iowa
Pharmacology, Medical School
Professor of Medicinal Chemistry, College of Pharmacy Talene A. Yacoubian, MD, PhD
Department of Pharmacology Professor
University of Michigan Department of Neurology
Ann Arbor, Michigan University of Alabama at Birmingham
Birmingham, Alabama
Shirley M. Tsunoda, PharmD
Professor of Clinical Pharmacy Jingjing Yu, MD, PhD
Skaggs School of Pharmacy & Pharmaceutical Sciences Clinical Associate Professor and Associate Director of UW Drug
University of California, San Diego Interaction Solutions
La Jolla, California Department of Pharmaceutics
University of Washington
Suzanne M. Underhill, PhD Seattle, Washington
Research Fellow
National Institute of Mental Health Jason X.-J. Yuan, MD, PhD
Bethesda, Maryland Professor of Medicine and Director of Physiology
Sara L. Van Driest, MD, PhD La Jolla, California
Associate Professor of Pediatrics, Division of General Pediatric
Associate Professor of Medicine, Division of Clinical Pharmacology Alexander C. Zambon, PhD
Vanderbilt University School of Medicine Assistant Professor of Biopharmaceutical Sciences
Nashville, Tennessee Keck Graduate Institute
Claremont, California
Wendy Vitek, MD
Associate Professor and Medicine Bruce L. Zuraw, MD
University of Rochester Medical Center Professor of Medicine
Rochester, New York University of California, San Diego
Jeffrey I. Weitz, MD, FRCPC, FRSC, FCAHS
Professor of Medicine and Biochemistry and Biomedical Sciences
Canada Research Chair (Tier I) in Thrombosis
Heart and Stroke Foundation J.F. Mustard Chair in
Cardiovascular Research
McMaster University
Hamilton, Canada

Preface
This is the 14th edition of book that began as a collaboration between or that are known only by a trade name. The full text is available online at
two friends and professors at Yale, Louis Goodman and Alfred Gilman. many medical, pharmacy, and nursing schools by institutional subscription
Over the years, “G&G” has been acclaimed as the “blue bible” of phar- to AccessMedicine.com and AccessPharmacy.com, where we publish regular
macology. Surely much of that acclaim reflects the book’s purpose, delin- updates. Feel free to contact the editors by email if you have comments on
eated by the original authors and steadily adhered to over 81 years: to the book or the websites.
correlate pharmacology with related medical sciences, to reinterpret the Editing this book brings to mind a number of larger issues, both
actions and uses of drugs in light of advances in medicine and the basic positive and negative, relating to health care; among them: the
biomedical sciences, to emphasize the application of pharmacodynamics remarkable explosion of molecular genetic techniques, the prolif-
to therapeutics, and to create a book that would be useful to students of eration of therapeutic agents affecting the immune system, and the
pharmacology and to healthcare practitioners. power of computer-aided drug design; antibiotic resistance promoted
Following these principles is demanding: the sheer volume and unre- by the continuing misuse and overuse of antibiotics in healthcare and
mitting growth of knowledge in the basic biomedical sciences and their animal husbandry; the adverse environmental effects of human activ-
clinical applications continue to amaze, challenging editors and contrib- ity to life on Earth; the effects of global warming and the sheer size of
utors who are trying to produce a one-volume work, and surely challeng- the human population on global health and nutrition; the ease with
ing students. To create a book that reflects our times, we have updated all which infectious diseases can spread around the world; the fragility of
chapters and have added five new chapters: drug response and the gas- truth and fact, and the difficulty of promoting health based on science
trointestinal biome, pharmacovigilance, the blood-brain barrier (it is not and data in the face of determined conspiracy theories and political
simply a lipid sheath), cannabinoids, and immunotherapies for cancer, ideology. A better world is possible.
plus a novel appendix on drug-drug interactions. Advances in immu- A number of people have contributed to the preparation of this edition
nomodulation are presented in most sections. In addition, we have con- of Goodman & Gilman. Many thanks to: my co-editor, Bjorn Knollmann,
tinued to reach out to younger contributors who are on the forefront of and to the clinical pharmacology fellows at Vanderbilt whom he recruited
pharmacological investigation and clinical practice. As a result, we have, to read the first drafts of chapters as they honed their editorial skills; our
in this edition, 56 new contributors, drawn from diverse backgrounds, attentive publisher at McGraw Hill, Michael Weitz, and his colleagues
who will ensure the book’s vigor into the future. Christina Thomas and Melinda Avelar; consulting pharmacist Nelda
A multi-authored work such as Goodman & Gilman grows by accre- Murri; Nitesh Sharma at KnowledgeWorks Global Ltd, who tirelessly
tion, deletion, addition, replacement, and repair. The current text reflects oversaw the transformation of Word documents into a printed book;
over eight decades of such activity, with wisdom, memorable pearls, new Jason McAlexander of MPS North America, whose rapid-response art-
material, and flashes of wit, hopefully edited to meet the present and to be work brightens the pages; and the eagle-eyed Becky Hainz-Baxter, who
forward looking. End-of-chapter notes acknowledge retired contributors saw what the editors had missed.
to the 13th edition, but I am happy to acknowledge that several genera- My special thanks to Lynne Larson, a novelist, artist, and grants
tions of editors and contributors have helped to bring this 14th edition to management specialist who managed this enterprise and kept the
its present form. As in the 13th edition, we have used a larger page size, no editors organized. Lynne managed the production of the 11th edition
extract type, and more mechanistic figures as we attempt to explain the of Goodman & Gilman when I first became the editor, when everything
pharmacodynamics of new agents. Some readers have complained that the was done with hard copy and Word files submitted by mail, when galley
book is getting too complex. We believe that a thorough understanding of proofs were actual long sheets of paper on which corrections were hand-
a drug’s actions and interactions at multiple physiological sites and with written and then transcribed to new Word files. I was delighted when
other drugs is essential to modern therapeutics. However, we also prom- Lynne agreed to manage this all-electronic project. We would not have
inently summarize the mechanisms of action, ADME, and clinical use of this 14th edition without her.
individual agents and drug classes. Not wanting to favor one manufactur-
er’s product over that of another, we continue generally to avoid using trade Laurence L. Brunton
names except as needed to distinguish multiple formulations of the same San Diego, CA
agent that have distinct pharmacokinetic or pharmacodynamic properties 14 July 2022

Acknowledgments
Melinda Avelar Becky Hainz-Baxter

Executive Assistant Editorial Specialist
McGraw Hill
Lynne Larson
Marijo Bilusic, MD, PhD Managing Editor
Sylvester Comprehensive Cancer Center
University of Miami Ali Manouchehri, MD
Clinical Pharmacology Fellow
Katherine Black, MD Vanderbilt University
Clinical Pharmacology Fellow Nashville, Tennessee
Pediatric Gastroenterology, Hepatology and Nutrition
Vanderbilt University Jason M. McAlexander
Nashville, Tennessee Biomedical Media Manager
MPS North America LLC
John Brannon, PhD
Clinical Pharmacology Fellow Nelda Murri, PharmD, MBA
Hadjifrangiskou Lab Consulting Pharmacist
Vanderbilt University Bin Ni, PhD
Nashville, Tennessee Clinical Pharmacology Fellow
John Cidlowski, PhD Vanderbilt University
Senior Investigator, NIEHS Nashville, Tennessee
Benjamin Coleman, PhD Jin-Woo Park, MD, PhD

Grueter Lab Graduate, 2022 Clinical Instructor in Neurology
Vanderbilt University Adjunct Instructor in Clinical Pharmacology
Nashville, Tennessee Korea University Medical Center
Seoul, Korea
Gwendolyn Davis, PhD
Clinical Pharmacology Fellow Brittany Spitznagel, PharmD, PhD
Madhur Lab Research Instructor
Vanderbilt University Weaver Lab
Nashville, Tennessee Vanderbilt University
Christian Egly, PharmD
Clinical Pharmacology Fellow Janaki Sharma, MD
Knollmann Lab Assistant Professor of Medicine
Vanderbilt University University of Miami
Nashville, Tennessee Nitesh Sharma
Erica Marie Garner, MD, MSCI Senior Project Manager
Instructor in Medicine KnowledgeWorks Global Ltd.
Vanderbilt University Christina Thomas
Nashville, Tennessee Senior Project Development Editor
Breanne Gibson, PhD McGraw Hill
Research Fellow
Schoenecker Lab
xviii Francisco Villarreal, MD, PhD Amr Tarek Wahba, MD
Professor of Medicine Instructor of Clinical Medicine
UC San Diego School of Medicine Division of Clinical Pharmacology
La Jolla, California Department of Medicine
Nataraja Sarma Vaitnadin, MBBS, PhD, MPH Nashville, Tennessee
Research Fellow
Acknowledgments
Department of Medicine Michael Weitz

Vanderbilt University Sr. Associate Global Publisher
Nashville, Tennessee Medical, Pharmacy & Allied Health Textbooks
McGraw Hill

Section I
General Principles
Chapter 1. Drug Discovery: From Medicinal Plants to
Computer-Aided Drug Design / 3
Chapter 2. Pharmacokinetics: The Dynamics of Drug Absorption,
Distribution, Metabolism, and Elimination / 23
Chapter 3. Pharmacodynamics: Molecular Mechanisms of Drug Action / 43
Chapter 4. Membrane Transporters and Drug Response / 79
Chapter 5. Drug Metabolism / 101
Chapter 6. The Gastrointestinal Microbiome and Drug Response / 119
Chapter 7. Pharmacogenetics and Pharmacogenomics / 131
Chapter 8. Postmarketing Drug Safety / 145
Chapter 9. Principles of Clinical Toxicology / 155
Brunton_Ch01_p0001-p0022.indd 1 29/07/22 2:46 PM

Chapter
1
FROM MEDICINAL PLANTS TO
COMPUTER-AIDED DRUG DESIGN
■■ Early Experiences With Plants
Drug Discovery: From Medicinal Plants to
Computer-Aided Drug Design
Michael K. Gilson and Laurence L. Brunton
DESIGNING LARGE MOLECULES AS DRUGS:

THE RISE OF BIOPHARMACEUTICALS
■■ Drug Discovery or Drug Invention? THE INVESTIGATIONAL NEW DRUG APPLICATION

■■ Target Identification
■■ Target Validation CLINICAL TRIALS
■■ Target Druggability ■■ Role of the FDA
■■ Beyond Single-Protein Drug Targets ■■ The Conduct of Clinical Trials
■■ Protein-Drug Binding: Affinity and Allostery ■■ Determining “Safe” and “Effective”
EXPERIMENTAL APPROACHES TO PERSONALIZED (INDIVIDUALIZED, PRECISION) MEDICINE

DRUG DISCOVERY
PUBLIC POLICY CONSIDERATIONS
■■ Medicinal Chemistry
■■ High Throughput Screening ■■ The Pharmaceutical Industry Operates in a Capitalist Economy
■■ Fragment-Based Drug Discovery ■■ Who Pays?
■■ Emerging Experimental Technologies ■■ Intellectual Property and Patents
■■ Bayh-Dole Act
COMPUTER-AIDED DRUG DISCOVERY ■■ Biosimilars
■■ Using Chemical Similarity to Discover Targeted Ligands ■■ Drug Promotion
■■ Structure-Based Drug Design ■■ Concerns About Global Injustice
■■ Artificial Intelligence in Drug Discovery ■■ Product Liability
■■ “Me Too” Versus True Innovation: The Pace of New Drug Development
The first edition of Goodman & Gilman, published in 1941, helped to

organize the field of pharmacology, giving it intellectual validity and an From Medicinal Plants to Computer-Aided
academic identity. That edition began: “The subject of pharmacology Drug Design
is a broad one and embraces the knowledge of the source, physical and
chemical properties, compounding, physiological actions, absorption, Early Experiences With Plants
fate, and excretion, and therapeutic uses of drugs. A drug may be broadly
The human fascination—and sometimes infatuation—with chemicals
defined as any chemical agent that affects living protoplasm, and few sub-
that alter biological function is ancient and begins with our long expe-
stances would escape inclusion by this definition.” In practice, of course,
rience with and dependence on plants. Because most plants are root-
a chemical or biological agent is considered a legal drug only if it has been
bound, many produce defensive compounds that animals learn to avoid
approved as such by a national regulatory agency, such as the U.S. Food
and humans to exploit or abuse. Thus, the prior of an Arabian convent
and Drug Administration (FDA) or the European Medicines Agency;
came to appreciate coffee (caffeine) after noting the behavior of goats that
these approved compounds are the focus of this book.
gamboled and frisked through the night after eating the berries of the
This first nine chapters of this book, General Principles, provide
coffee plant; women sought to enhance their beauty by using an extract
the underpinnings for these definitions of pharmacology and drugs by
of the deadly nightshade plant, Atropa belladonna (“beautiful lady”),
exploring the physiological, biochemical, and molecular mechanisms of
enriched in atropine, to produce pupillary dilation; the Chinese herb ma
drug action. This section covers drug invention, development, and reg-
huang (ephedrine) was used as a stimulant; indigenous people of South
ulation, as well as how drugs act in biological systems, i.e., pharmacody-
American used curare to paralyze and kill animals hunted for food; and
namics, pharmacokinetics (including drug transport and metabolism), the
poppy juice (opium), containing morphine (from the Greek Morpheus, the
influence of the gastrointestinal microbiome, and pharmacogenetics, with
god of dreams), has long been used for pain relief and control of diarrhea.
brief forays into pharmacovigilance and drug toxicity and poisoning. Sub-
Morphine, of course, has well-known addicting properties, as do other
sequent sections deal with the use of specific classes of drugs as therapeu-
psychoactive natural products, such as nicotine, cocaine, and ethanol.
tic agents in human subjects. The present chapter is an introduction to
Note that these drugs did not derive from a search for a druggable target
pharmaceuticals, their development, and the activities of the pharmaceu-
or any knowledge of a target. Rather, drug discovery in the past often
tical industry and government surrounding the discovery, production,
resulted from serendipitous observations of the effects of plant extracts or
and use of therapeutic agents. The processes of discovery and invention
individual chemicals on animals or humans. Drugs were selected based
of drugs have changed substantially with the general progress of bio-
on effect, with no understanding of mechanism as we use the term today.
medical sciences, the advent and improvement of computer-aided drug
In the 20th century, the hunt for natural products broadened, driven in
design, and technical advances in biochemistry and molecular biology.
part by the discovery of antibiotics, such as penicillin and the cephalospo-
Some of these new capabilities are reviewed below.
rins, which fungi and microbes make to compete with each other.
4
Abbreviations then use this information to steer the program of chemical synthesis and
testing toward increasingly potent compounds.
In the 1980s, it became practical to determine high-resolution
ADME: absorption, distribution, metabolism, and excretion three-dimensional structures of complex organic molecules and even
BLA: Biologics License Application larger molecules such as proteins, using and refining the techniques of
CADD: computer-aided drug discovery X-ray crystallography pioneered by Hodgkin, Kendrew, and Perutz in
CHAPTER 1 DRUG DISCOVERY: FROM MEDICINAL PLANTS TO COMPUTER-AIDED DRUG DESIGN
DEL: DNA-encoded compound library the mid-20th century. It was already known that many drugs worked
DHHS: U.S. Department of Health and Human Services by binding tightly to a disease-related protein and thereby modulating
DMPK: drug metabolism and pharmacokinetics (e.g., inhibiting or activating) its biological function, but the atomic
FBDD: fragment-based drug discovery details of these interactions had remained mysterious. As a consequence,
the only way to advance a drug discovery project had been by synthesizing
FDA: U.S. Food and Drug Administration
and testing one compound after another. Now, with the protein’s three-
GPU: graphics processing unit
dimensional structure in hand, one could finally hope to design a com-
HCV: hepatitis C virus
pound that would bind with high affinity by fitting snugly into a pocket
HDL: high-density lipoprotein
in the protein, such as an enzyme’s active site. Thus, protein crystallog-
HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A
raphy enabled structure-based drug design (SBDD), where the three-
HTS: high-throughput screening
dimensional structure of the drug target is used to guide creation of
IND: Investigational New Drug tight-binding compounds, often called ligands.
LDL: low-density lipoprotein Around the same time, computer technology began to advance
mRNA: messenger RNA rapidly. This accelerated the data processing needed to go from X-ray
NDA: New Drug Application diffraction patterns to protein structures (i.e., three-dimensional atomic
NIH: National Institutes of Health coordinates) and enabled interactive visualization of complex protein
NMEs: new molecular entities structures comprising thousands of atoms. It also opened new vistas in
PDUFA: Prescription Drug User Fee Act computer-aided drug discovery (CADD), including the use of molecular
SBDD: structure-based drug design simulations to model the physical interactions of compounds and pro-
siRNA: small interfering RNA teins, and the development of tools to encode, archive, share, and analyze
chemical and pharmacological data. In parallel, automation and minia-
turization have dramatically increased experimental throughput, notably
through robotic high-throughput screening (HTS), in which hundreds
Drug Discovery or Drug Invention? of thousands of compounds can be tested rapidly and at relatively low
The conventional phrase drug discovery makes sense for therapeutic com- cost in cellular or molecular activity assays. Today, excitement about the
pounds obtained from plants and other organisms. Today, however, only power of artificial intelligence motivates wide-ranging efforts to apply
a fraction of the new drugs introduced each year are discovered in nature. these technologies to drug discovery.
Instead, most drugs are not discovered, but are totally new compounds, The following section goes into more detail regarding the process of
painstakingly optimized against many criteria through an interplay of drug discovery, focusing on so-called small-molecule drugs, organic com-
design and experimentation. In that sense, today’s new drugs are more pounds with molecular weights typically less than 500 Da, which have
invented than discovered. traditionally been the most common type of drug. Subsequent sections
The current paradigm for drug development grew out of synthetic introduce biological drugs, such as antibodies and other engineered
organic chemistry, which arose as the dye industry in the late 19th biomolecules.
century and has continued to flourish. Dyes are colored compounds
with selective affinity across various biological tissues. Study of these Target Identification
interactions stimulated Paul Ehrlich to postulate the existence of Today, most small-molecule drug discovery projects grow out of basic
chemical receptors in tissues that interacted with and “fixed” the dyes. research that implicates a specific macromolecule, usually a protein, as a
Similarly, Ehrlich thought that unique receptors on microorganisms key player in a disease and, further, suggests that a small molecule which
or parasites might react specifically with certain dyes and that such binds this macromolecule could be used to treat the disease. The macro-
selectivity could spare normal tissue. Ehrlich’s work culminated in the molecule thus becomes a candidate drug target. Many small-molecule
invention of arsphenamine in 1907, which was patented as “salvarsan,” drugs are inhibitors (antagonists), which work by reducing the activity of
suggestive of the hope that the chemical would be the salvation of their macromolecular target. Examples include the statins, which reduce
humankind. This and other organic arsenicals were used to treat syph- cholesterol synthesis by binding and inhibiting the enzyme 3-hydroxy-3-
ilis until the discovery of penicillin. Gerhard Domagk demonstrated methylglutaryl (HMG) coenzyme A (CoA) reductase, and β-lactam antibi-
that another dye, prontosil (the first clinically useful sulfonamide), otics, which kill bacteria by inhibiting enzymes involved in the synthesis of
was dramatically effective in treating streptococcal infections, thereby bacterial cell walls. However, some small molecules are activators (agonists)
launching the era of antimicrobial chemotherapy. The collaboration of rather than inhibitors. Activators frequently target proteins whose normal
pharmacology with chemistry on the one hand and clinical medicine role involves cell signaling, such as hormone receptors. For example, the
on the other has been a major contributor to the effective treatment of asthma medication albuterol dilates bronchi by binding and activating β
disease, especially since the middle of the 20th century. adrenergic receptors on bronchial smooth muscle, thereby mimicking the
Early on, new compounds could be tested for their activities only in effect of adrenaline (epinephrine; see Chapter 10).
whole organisms. This is how the nonsteroidal anti-inflammatory drug Candidate drug targets have been identified in many ways
indomethacin was discovered, for example (Brune and Hinz, 2004). In (Hughes et al., 2011). For example, the enzymes targeted by the β-lactam
the past 70 years, researchers have begun to understand in considerable antibiotics were unknown in advance and were discovered precisely
detail the cellular and molecular mechanisms of disease. As a result of this because they are bound by these naturally occurring antibiotics. In con-
basic biomedical research, it is possible to do initial testing of compounds trast, the target of the statins, HMG-CoA reductase, was identified by
in vitro (“in glass”), using cellular and molecular assays. For example, elucidation of the pathways of cholesterol synthesis (Tobert, 2003), and
one could look for the cellular responses due to inhibition of a protein this information was used to help discover the first statins. Similarly, as
involved in a disease process. In this scenario, by testing enough appro- researchers have determined the regulatory functions of human protein
priately chosen compounds, one could develop at least a partial under- kinases—enzymes that change the activities of other proteins by cova-
standing of which types of compounds are most likely to be active and lently attaching phosphate groups to their hydroxyl-containing side

chains—specific kinases have been targeted for small-molecule drug target validation aims to “de-risk” a project by lowering the probability 5
discovery (Cohen et al., 2021). Many kinase inhibitors are anticancer that a compound carefully developed to hit the targeted protein will fail
agents that work by inhibiting protein kinases that accelerate cell prolifer- in clinical trials, whether because hitting the target does not influence
ation. Some of these targeted kinases carry abnormal, cancer-associated the disease as expected or because the compound generates unanticipated
mutations that make them hyperactive, so inhibiting them returns their toxicity, termed on-target or mechanism-based toxicity.
SECTION I
regulatory activities toward normal. The pioneering example of this sce- There are no absolute criteria for target validation, nor is there a single
nario is the drug imatinib, which inhibits a cancer-associated mutant method. One approach is to use a chemical probe, a small molecule that
protein kinase, the Bcr-Abl tyrosine kinase, and is used to treat chronic binds the target, and study its biological effects (Quinlan and Brennan,
myelogenous leukemia (Buchdunger et al., 2002). 2021). This approach requires that such a probe be available, and the
In recent years, technological advances enabling genome-wide experi- fields of chemical genetics (Stockwell, 2000) and chemogenomics (Bredel
mentation (omics) have opened new approaches to identifying candidate and Jacoby, 2004) aim to create selective chemical probes for as many
targets (Lindsay, 2003; Paananen and Fortino, 2020). Fast, inexpensive proteins in the human genome as possible. Alternatively, one may use
GENERAL PRINCIPLES
genome sequencing facilitates genome-wide association studies, in which gene silencing via small interfering RNA (siRNA) to block production
variations in the susceptibility to a disease across many people are cor- of the target protein, thereby mimicking the effect of an inhibitor of the
related with variations in specific genes, leading to suggestions for gene protein’s activity. Additional insight into the biological role of a candidate
products (i.e., proteins), that may be suitable drug targets. The growing drug target may sometimes be obtained by studying genetically modified
availability of patient genomic data in the context of patients’ electronic mice, including knockout mice, in which the gene coding for the target
medical records will likely open new opportunities for data mining in has been disabled entirely, and transgenic mice, in which expression of
support of target discovery in the coming years. It has also become routine the target’s gene is placed under the control of a promoter that can be
to measure the quantities of messenger RNA (mRNA) transcribed from turned on by feeding the animals a specific compound, such as tetracycline
thousands of genes simultaneously (the transcriptome) and to quantify (Lindsay, 2003).
thousands of translated proteins (proteomics). By comparing such data
between, for example, cancer cells and normal cells, one can identify pro- Target Druggability
teins transcribed or present at elevated or depressed levels in the disease
It is important to know whether the candidate target is drug-
state. Mining data about these proteins from sources such as biomedi-
gable, that is, whether it can, in principle, bind a small molecule with suf-
cal databases, scientific articles, and patents, and integrating it with the
ficient affinity. If the protein has been the target of a prior drug discovery
omics data, may suggest certain proteins as candidate drug targets.
effort, there may be informative small-molecule binding data in a public
A totally different approach starts with the use of high-throughput
database, such as BindingDB (Gilson et al., 2016), PubChem (Kim et al.,
instrumentation and robotics to test a large collection of small molecules
2021), or ChEMBL (Gaulton et al., 2012), or in an article or patent not
(a chemical library) for biological activity in a phenotypic screen (Swinney
yet curated by one of these databases. One may also check the Protein
and Lee, 2020), which might use automated microscopy and image anal-
Data Bank (Berman et al., 2000; Berman and Gierasch, 2021) for a crystal
ysis to determine which compounds produce desired biological effects,
structure of the target, which may assist in locating a suitable binding
such as the activation of a desired gene in cultured human cells or the
pocket for the small molecule to be developed as a drug. This is frequently
death of a parasitic microorganism in culture. Various methods may then
true for metabolic enzymes and receptors that have evolved to bind small
be used for target deconvolution (i.e., to determine how the active small
substrate and transmitter molecules. Many proteins belong to families,
molecules work). For example, candidate targets of compounds found to
such as the protein kinases, whose members have similar properties
kill the malarial parasite Plasmodium falciparum were identified by cul-
(e.g., an ATP binding pocket), so that if one member of a family is drug-
tivating these organisms in gradually increasing concentrations of the
gable, then the others probably are also. In contrast, receptors for proteins
compound to select for resistant protozoa and then using omics methods
often have large, relatively flat binding surfaces, rather than small binding
to determine which genes had changed. The proteins encoded by these
pockets suitable for a small-molecule drug, and are thus less likely to
genes may then become candidate drug targets (Flannery et al., 2013).
be druggable and influenced by small molecules. Efforts are under
way to systematically search for all druggable targets encoded by the
Target Validation human genome (Nguyen et al., 2017; Finan et al., 2017; Hopkins and
After a candidate drug target has been identified, additional research is Groom, 2002) and to gain traction against targets hitherto considered
usually warranted to validate it by seeking stronger evidence that a small undruggable (Dang et al., 2017).
molecule that binds and modulates it will actually treat the disease (Jones, The ultimate validation of a candidate target is the successful devel-
2016; Lansdowne, 2018; see Box 1–1). For example, the fact that a protein opment of a novel drug that works by binding to it. Such a novel drug is
is more abundant in cancer cells than normal cells by no means proves termed first-in-class. A first-in-class drug is a true innovation and may
that it is a suitable drug target. Instead, this might be a correlate rather represent a medical breakthrough, so one might expect first-in-class to
than a cause, so further research is needed to assess its role. Accordingly, be the goal of every drug discovery project. In fact, however, pharma-
ceutical companies often engage in less innovative, more predictable
projects by developing me-too drugs against old targets that are already
BOX 1–1 ■ Target Validation: The Lesson of Leptin fully validated by a first-in-class drug. Such projects aim to improve on
the first-in-class drug through, for example, greater potency, reduced
Biological systems frequently contain redundant elements or can side effects, or more convenient dosing (e.g., oral instead of intravenous),
alter expression of drug-regulated elements to compensate for the and ideally to produce a new drug considered best-in-class. For example,
effect of the drug. In general, the more important the function, the Merck’s lovastatin broke ground as the first statin, the first in a class of
greater the complexity of the system. For example, many mechanisms drugs that lower cholesterol by inhibiting the enzyme HMG-CoA reduc-
control feeding and appetite, and drugs to control obesity have been tase (see Chapter 37); but other statins, such as atorvastatin, have also
notoriously difficult to find. The discovery of the hormone leptin, achieved enormous commercial success.
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 Beyond Single-Protein Drug Targets
a marvelous opportunity to treat obesity. However, on investigation, A number of drugs, whether by accident or by design, hit multiple pro-
it was discovered that obese individuals have high circulating tein targets, a phenomenon termed polypharmacology (Peters, 2013).
concentrations of leptin and appear insensitive to its action. This phenomenon is particularly common when the target is a mem-
ber of a family of proteins with similar binding sites. For example, the

6 full physiological effect of an adrenergic antagonist is determined by • The hydrophobic effect, in which nonpolar or “greasy” parts of the
its actions across the family of adrenergic receptor types and subtypes. drug and protein associate with each other to reduce their energeti-
Similarly, many protein kinase inhibitors inhibit multiple kinases, each cally unfavorable exposure to water, much as oil droplets coalesce in
to a different degree. There are instances where hitting multiple targets salad dressing
is fruitful, such as inhibiting sequential reactions in a series. Modulating • Dispersion forces—the attractive part of van der Waals interactions—
multiple proteins in a single biochemical pathway or signaling network short-ranged attractive interactions between the instantaneous elec-
overcomes the evolved redundancy of a robust biological system and trical dipoles that result from the constant fluctuations of negatively
hence leads to greater efficacy than modulating only one protein. A single charged atomic electron clouds around positively charged atomic
compound may, alternatively, hit two entirely different targets in different nuclei
pathways, although this is more challenging to achieve without going to
larger compounds. The analysis of complex molecular systems in relation These attractive forces need to overcome the entropic tendency of
to drug action is termed systems pharmacology. the drug and protein to wander apart, due to thermal energy. There are
Polypharmacology is not always beneficial, and indeed, it can lead to also, inevitably, forces that oppose binding and that must be overcome by
toxicity. Some of the unintended effects of a drug will be termed side the attractive ones. For example, there is an energy penalty for stripping
effects or even major adverse drug responses. For example, a number of water from polar chemical groups of the ligand and protein as they come
initially promising compounds have proven to bind and inhibit hERG, together to bind. Thus, the overall affinity of a drug-protein interaction
the K+ channel in the heart that mediates repolarization (the IKr current; reflects a delicate and hard-to-predict balance of attractive and repulsive
see Chapter 34); inhibition of hERG can lead to potentially fatal arrhyth- interactions.
mias. The hERG channel has, therefore, become a notorious anti- Small-molecule drugs do not bind to the relatively smooth, exterior
target that must be scrupulously avoided by drug discovery projects surfaces of their protein targets, but instead are enfolded by binding pock-
(Garrido et al., 2020). ets in the protein (see Figure 1–4). This structural arrangement makes it
Some small-molecule drugs do not bind to proteins at all. For exam- possible to form the extensive, short-ranged, physical interactions that
ple, platinum anticancer drugs, such as carboplatin, kill cancer cells by are needed to hold the two molecules together tightly. Druggable binding
binding covalently to DNA; the aminoglycoside antibiotics block bacte- pockets (i.e., ones that enable small-molecule binding) usually are avail-
rial protein synthesis by binding to RNA within the bacterial ribosome; able in enzymes whose substrates are small molecules and in receptors
and antiviral nucleoside analogues are incorporated into viral DNA in that bind small-molecule hormones and transmitters. However, many
place of normal nucleosides and then block DNA replication. The drug proteins lack a concave pocket and therefore are difficult or impossible
sugammadex has both an unusual purpose and an unusual mechanism. to drug with a small molecule. In such cases, one may instead consider
Surgical patients often receive not only general anesthesia but also the developing a protein therapeutic, such as an engineered antibody that
nondepolarizing neuromuscular blocking agent rocuronium, which targets the protein of interest. Because proteins are large, they can form
prevents involuntary movements of skeletal muscle during surgical extensive, short-ranged, physical interactions even with the relatively flat
procedures (see Chapter 13). Sugammadex, a larger, cup-shaped mole- exterior surface of a targeted protein, and thus can achieve adequate bind-
cule, binds and sequesters rocuronium. Thus, injection of sugammadex ing affinity where a small-molecule drug cannot. These considerations
rapidly reduces the concentration of unbound rocuronium in the blood also help explain why it is difficult to develop a small-molecule drug that
and promptly reverses paralysis when a procedure is complete. will block a protein-protein interaction: protein-protein binding usually
involves a large number of interactions on a relatively flat binding inter-
face between the two proteins, and a small molecule cannot get sufficient
Protein-Drug Binding: Affinity and Allostery purchase on such a flat surface.
A successful drug with a protein target must bind to its target with high Note that a drug must not only bind to its target but also have the
affinity so that even a small dose of the drug will yield a blood concen- desired effect upon it. If the goal is to inhibit an enzyme, then a drug
tration high enough to bind a large fraction of the targeted protein. If the that binds in the active site should easily accomplish this by simply
affinity were low, then a high concentration of drug would be needed for blocking association of the enzyme with molecules of substrate. In
a substantial fraction of the target sites to be occupied, and a large dose contrast, when a cell-surface receptor is the target, a small molecule
of drug would need to be administered, leading to inconvenience and might interact at the agonist binding site but without inducing an acti-
an increased risk of side effects. The affinity of a small molecule for a vating conformational change and thus might function as an antag-
protein is generally given as the dissociation constant, the concentration onist or inverse agonist (see Chapter 3). A drug may also inhibit the
of free drug molecules in solution at which 50% of the targeted protein function of a protein by binding in a pocket outside the active site, and
has bound drug; the lower this concentration, the higher the affinity (see thereby modifying the three-dimensional conformation of the targeted
Figure 3–3). Drug design projects typically aim for a dissociation con- protein; this is an allosteric effect. Such a drug must not only bind in
stant on the order of 10–9 mol/L (1 nM); such a “nanomolar drug” is typi- a suitable pocket but also induce the desired conformational change.
cally dosed in milligrams to grams per day. A successful drug should also Efavirenz and nevirapine, used in treating HIV-AIDS, are nonnucle-
exhibit a high degree of specificity for its target protein, meaning that the oside reverse transcriptase inhibitors that act allosterically to inhibit
drug does not interact with other proteins that could lead to undesired viral transcription of viral RNA to DNA (see Figure 65–5). Similarly,
side effects and toxicity. In some cases, the effectiveness of a drug may a number of ligands interact with allosteric sites on GABAA receptors
be influenced by not just the affinity but also the kinetic rate constants (see Figure 16–11) and other Cys-loop receptors to modulate receptor/
for drug-protein binding and dissociation, which determine the drug’s channel function. Allostery can also offer a sophisticated strategy to
residence time at its receptor (Copeland, 2016). target a single enzyme from among a family of similar enzymes. Thus,
Most drugs bind their targeted proteins via attractive, intermolecular inter- in designing a drug, one might take advantage of the fact that, even
actions that do not involve a covalent chemical bond. These noncovalent within a family of related proteins with similar active sites, the members
interactions typically include: will likely have other regions of their structure that are more variable
and possibly unique. Designing a small ligand that binds to such a site
• Hydrogen bonding, in which an electronegative atom with a bound might produce an agent that is a quite selective allosteric modifier of
hydrogen atom, such as a hydroxyl group, partly shares its hydrogen enzyme function. This approach is being used to target selected protein
with an electronegative atom on the other molecule phosphatases (Mullard, 2018).
• Attractive electrostatic interactions between atoms of opposite charge, A few small-molecule drugs react chemically with their protein targets
such as between a negatively charged carboxylic acid belonging to the to form irreversible, covalent bonds, rather than relying entirely on the
drug and a positively charged arginine side chain of the protein noncovalent attractions discussed above. Such covalent drugs bond to a

specific chemical group of the protein target, often a relatively reactive Medicinal Chemistry 7
amino acid side chain within an enzyme’s catalytic site. In principle,
Synthetic organic chemistry remains at the heart of small molecule drug
covalent drugs should require smaller, less frequent dosing, because a
discovery, where it is specialized and known as medicinal chemistry.
covalently bound drug will not dissociate from the protein as the con-
Medicinal chemists typically are part of a project team that includes,
centration of free drug dwindles over time following a dose (but note
among others, biologists, assay specialists, and computational chemists;
that some boron-containing compounds form reversible covalent bonds
SECTION I
their role is to reduce chemical concepts to practice by synthesizing and
[Diaz and Yudin, 2017]). Drug developers have tended to avoid cova-
purifying compounds that may ultimately lead to a new drug. In addition
lent drugs because they necessarily possess chemically reactive groups
to providing the expertise needed to synthesize compounds of interest,
that risk reacting not only with the desired target but also with other
they also help guide the design and selection of the compounds to be
proteins and biomolecules, with the potential for causing undesired
made. A key consideration is the complexity of a compound’s synthesis,
biological effects. However, selectivity can be achieved by specific non-
or “synthetic accessibility”, which must be balanced against the level of
covalent interactions between the drug and the protein that pull the
GENERAL PRINCIPLES
interest in the compound. For example, it can be difficult to generate
compound into a location and conformation where it is poised to form
pure stereoisomers of compounds with multiple chiral carbon atoms, and
the desired covalent bond.
certain chemical structures can by synthesized only via demanding, mul-
Covalent binding has been used to successfully target and inhibit
ti-step syntheses. A compound that is too difficult to make or purify will
a member of the RAS GTPase family, KRAS G12C, which had been
not only slow down the research effort but may also lead to a drug that is
viewed as virtually undruggable. As a result of such targeted posi-
too costly to manufacture.
tioning, the cancer drug sotorasib gains both potency and specificity
Medicinal chemists also inform the drug design process by providing
by forming a covalent bond with a cysteine side chain present in an
insights into the properties of various chemical groups that might be
oncogenic mutant form of KRAS but not in normal KRAS (Lanman
incorporated into a drug, such as the attractive or repulsive interactions
et al., 2020).
they may form with the targeted protein, their susceptibility to metabolic
changes following administration, their potential to spontaneously form
undesired covalent bonds with biomolecules, and their influence on the
Experimental Approaches to Drug Discovery compound’s ability to cross the blood-brain barrier (which may be desir-
Given a validated target, the next major milestone in a drug discovery able or undesirable, depending on the goal of the project). This expertise
project is arrival at a clinical candidate, a small molecule that binds the comes into play, for example, when a compound binds the target well but
target with high affinity and specificity, has the desired effect on it, is rapidly metabolized by the liver into an inactive product. In this setting,
and meets a range of other criteria for a safe, efficacious drug (Hefti, the medicinal chemist may try substituting the part of the compound that
2008). Some of these criteria relate to pharmacokinetics: How well will is metabolized with a “bioisostere”, a different chemical group with a sim-
the compound be absorbed if given orally? How well does it distribute ilar shape and ability to interact with the protein but with reduced suscep-
to the targeted organs and tissues? How rapidly and by what mecha- tibility to metabolic modification. More broadly, decades of experience
nisms is it eliminated? Is it metabolized to an active metabolite? These have led to a number of rules of thumb for what makes a compound
properties are often lumped together as absorption, distribution, “drug-like”, such as the “rule of five” (Lipinski, et al., 2001). These may
metabolism, and excretion (ADME) or drug metabolism and pharma- be useful guides during drug discovery projects, but there are also many
cokinetics (DMPK). exceptions to the rules (Zhang et al., 2007).
It is also essential to confirm that the compound does not show evi-
dence of toxicity. Both pharmacokinetics and toxicity can be initially High-Throughput Screening
studied in vitro. For example, there are in vitro methods that examine If nothing is known about the structure of the target protein and what
the ease with which the compound enters cells (see Chapter 4) and the small molecules can bind it, it is common to turn to HTS, in which thou-
likelihood that liver enzymes (see Chapter 5) will chemically modify the sands or millions of compounds are tested using automation and robotics
compound. Compounds also can be evaluated in vitro for evidence of (Wildley et al., 2017). Tiny samples of each compound are drawn from
toxicity and mutagenicity. However, in vitro studies cannot fully model a stored chemical library and deposited into multiwell plates for testing.
the complexities of a living organism; animal studies are still required to Substantial effort often must be invested to devise an assay that works reli-
minimize the chances that a compound will be problematic when first ably in miniature and without user intervention. Most provide an optical
given to human subjects. For example, toxicity is usually assessed by long- readout, such as a change in luminescence, fluorescence, or color, as these
term monitoring of the health of two species of animals, generally one can be efficiently measured with an optical plate reader. The compounds
rodent (usually mouse) and one nonrodent (often rabbit), when dosed screened can range from part of the vast, in-house compound collection
with the compound. A good clinical candidate should also meet some that a major pharmaceutical company has assembled over the years to a
nonbiological criteria. In particular, it must be amenable to large-scale smaller set purchased from a commercial vendor. A screening library is
synthesis and high-grade purification at acceptable cost, and it should be often designed for the particular application. For example, one can pur-
possible to create a formulation (e.g., a tablet or injection) that is suffi- chase libraries tuned for activity against protein kinases, libraries with
ciently water soluble and stable. reactive groups that can form covalent bonds to the protein, and libraries
Sophisticated technologies have been developed to speed the process designed to sample a wide range of compounds through high chemical
of generating a clinical candidate. These mainly focus on the discov- diversity. A compound chosen at random from a screening library has a
ery or design of compounds that will bind the protein target with high very low probability, typically 0.1% or less, of being active against a given
affinity (potent ligands). Less progress has been made toward designing target (Shun et al., 2011), and HTS measurements are subject to experi-
in safety and favorable pharmacokinetics. These properties pose more mental error. Therefore, many of the compounds that appear active on an
complex challenges, because they go far beyond how a small molecule initial screen (hit compounds) are false positives, so careful data analysis
and a protein interact with each other and instead involve the interac- and confirmatory testing are essential.
tions of the small molecule with thousands of different biomolecules in Even the confirmed hits from a high-throughput screen are far from
a living system. The technologies for ligand discovery are both experi- being drugs. Their affinity for the target usually is orders of magnitude
mental and computational, and different methods are applicable in dif- too weak, they may lack the desired specificity, and they do not meet
ferent settings. The following subsections touch on broad approaches DMPK or safety criteria. However, they offer an initial toehold on the
but are not comprehensive. Note, too, that various approaches can challenge of finding a potent drug candidate. The next step is to purchase
be used in combination, so the distinctions made here are ultimately (analogue by catalog) and/or synthesize (medicinal chemistry) similar
somewhat artificial. compounds that ultimately give a picture of how various changes in
8 1 O
Compound ALDH1A1 ALDH2 ALDH3A1
O
N 1 0.02 82 7.7
2 0.06 2.1 16
O
2 Cl 4 O
3 0.58 2.1 69
O
N O 4 0.07 3.5 0.45
N
5 0.07 >100 0.31
O 6 2.0 0.05 18
3 Br 5 O
O
N O
N
6 O
Br
O
N
Figure 1–1 Structure-activity relationship: scaffolds and substituents. Five inhibitors of the aldhyde dehydrogenase family of enzymes have a common chemical
scaffold (black) while having different chemical substituents at two positions (red, green). The table lists the IC50 (μM) of each compound for three members
of the aldehyde dehydrogenase family of enzymes: ALDH1A1, ALDH2, and ALDH3A1; i.e., the concentration of compound needed to provide 50% inhibition
of each enzyme. The lower the IC50, the more potently the compound inhibits the enzyme. Focusing first on compounds 1, 2, and 3, one can see that adding an
increasingly bulky halogen atom (Cl, Br) on the six-membered ring tends to reduce the compound’s potency against ALDH1A1 and ALDH3A1 but to increase
it against ALDH2. Focusing next on compounds 1, 4, and 5, one can see that adding increasingly bulky, nonpolar, aromatic substituents at the nitrogen modestly
reduces the potency against ALDH1A1, initially improves but then destroys potency against ALDH2, and consistently improves potency against ALD3A1. Such
patterns can guide the design of new compounds with desired potency and selectivity. For example, the substituents in compounds 3 and 4 each reduce potency
against ALDH1A1 while increasing potency against ALDH2, so it is not surprising that compound 6, which combines both substituents, has particularly low
potency against ALDH1A1 and high potency against ALDH2. Note, however, that this kind of reasoning can only offer guidelines; its predictions are not always
borne out by experiment. Data drawn from Kimble-Hill et al., 2014.
the chemical structure influence activity against the target (structure- to the protein. This information can be used to stitch together designed
activity relationships, or SAR) and other properties (Figure 1–1). This compounds that place the appropriate fragments at the right places in the
information is used to guide the synthesis of often hundreds of com- protein’s binding pocket (fragment linking) or to optimize and expand one
pounds with gradually improving properties. The most promising early selected fragment (fragment growing). In this way, FBDD avoids the com-
molecules (lead compounds) serve as starting points for further improve- binatorial explosion of possible compounds made from various chemical
ment (lead optimization), ultimately generating, hopefully, a clinical components and allows researchers to focus quickly on compounds made
candidate, potentially accompanied by several backup compounds in case from only a productive subset of chemical components. The drug vemu-
the leading candidate fails. rafenib, which targets an oncogenic mutation of B-Raf kinase and was
developed with a fragment-growing strategy, is usually referenced as the
Fragment-Based Drug Discovery first FBDD success story (Bollag et al., 2012).
Even a large-scale screen can fail to provide useful hits (Keserü and
Makara, 2009). This result becomes understandable when one recognizes Emerging Experimental Technologies
that the number of stable, drug-sized, organic compounds is on the order The difficulty and cost of drug discovery, coupled with the market and
of 1060 (Reymond et al., 2010), so a screen of even 106 compounds scarcely human need for new medications, have driven ongoing innovation in
touches the vastness of chemical space. This vastness results from the com- drug discovery technologies. For example, DNA-encoded compound
binatorial explosion of ways of connecting various chemical substruc- libraries (DELs) dramatically expand the number of compounds that
tures, such as benzene rings, hydroxyl groups, and cycloalkanes. To be can be tested, relative to conventional HTS (Halford, 2017). Unlike a
a good binder, a compound has to get multiple substructures positioned traditional HTS compound library, where each compound is kept in its
so they all form favorable interactions with complementary groups in the own separate container or well, a DEL is a mixture of compounds in a
targeted binding pocket. If it has two chemical components suitable for single container and can include far more compounds—into the billions
binding the target but a third that is inappropriate or in the wrong place and even trillions. Each unique compound in the mixture is covalently
on the compound, it may fail to bind the target. This perspective moti- bound to a corresponding unique short DNA molecule, which serves as
vates another method of discovering binders, fragment-based drug dis- an identification tag. Such libraries can be synthesized and tagged with
covery (FBDD) (Erlanson, 2012; Lamoree and Hubbard, 2017). In FBDD, the methods of combinatorial chemistry, where a mixture of compounds
one conceptually breaks down drug-sized compounds into their sub- is split into multiple portions, each portion is modified with a different
structures (fragments) and tests simple substructures against the target. chemical step and its DNA tags modified accordingly, and the portions
Although such fragment-like molecules can bind only very weakly, such are mixed again. This process is iterated until the synthesis is complete.
studies can, nonetheless, identify a small set of chemical substructures To screen the DEL for active compounds, one may immobilize the target
that are suitable for the target, and one can then buy or synthesize larger of interest on a solid surface, expose the surface to the DEL mixture, and
compounds assembled from these components. When either X-ray crys- then wash the surface to remove all the DEL compounds that have not
tallography (Patel et al., 2014) or nuclear magnetic resonance spectros- bound tightly to the target. The binders are then removed from the target
copy (Shuker et al., 1996) is used to detect or analyze fragment binding, by more aggressive washing, and the active compounds in the wash are
specific information is usually available about where each fragment binds identified by sequencing the DNA tags they carry.

Another emerging technology, sometimes termed clinical trials in a dish instead computes tens or hundreds of quantitative descriptors for each 9
(Alpeeva et al., 2017; Fermini et al., 2018; Strauss and Blinova, 2017), aims compound. Examples include simple descriptors, such as molecular
to predict the effects of a compound in humans more accurately than is pos- weight or number of aromatic rings, and more complex descriptors such
sible with standard cell culture or animal models. This approach involves as electrical dipole and quadrupole moments. If one imagines descriptors
creating specific cell types of interest from human pluripotent stem cells and as Cartesian coordinates in a multidimensional space, one can then quan-
SECTION I
using them to create three-dimensional organoids in culture (Fligor et al., tify the similarity of two molecules in terms of how close they are in this
2018; Liu et al., 2021; Sato and Clevers, 2013) or artificial tissue architectures descriptor space (Wale et al., 2008).
via three-dimensional bioprinting (Ferrer and Simeonov, 2017). These rela- Similarity metrics such as these enable virtual screening, a fast, inex-
tively intricate in vitro constructs promise to better recapitulate the proper- pensive, computational alternative to experimental HTS (Figure 1–3).
ties of the corresponding in vivo tissues and may be used to test compounds In this approach, every compound in a chemical library—a large set of
for activity, DMPK properties, compound metabolism, and toxicity. compounds that are available or synthesizable—is assessed for its simi-
larity to one or more known ligands of the protein target. The most sim-
GENERAL PRINCIPLES
ilar compounds are tested in an experimental assay, and confirmed hits
Computer-Aided Drug Discovery become candidates for further chemical optimization. This approach is
most relevant when the three-dimensional structure of the targeted pro-
The rise of information technology has enabled the research community
tein has not been determined. When the structure is known, powerful
to store and move large quantities of information, to write and maintain
structure-based methods become applicable.
complex software, and to do calculations at unprecedented speed and
scale. These continually improving capabilities are used in a variety of
ways to support and accelerate drug discovery. Thus, chemical informat-
Structure-Based Drug Design
ics enables compact databasing of information on hundreds of millions The detailed three-dimensional structure of a targeted protein opens up a
of compounds and rapid recovery of chemical data for a specific com- range of additional computational methods for designing a small molecule
pound and/or chemically similar compounds (Willett et al., 1998), while that binds the target with high affinity (Figure 1–4). The applicability of
the Internet makes chemical (Gaulton et al., 2012; Gilson et al., 2016; Kim such SBDD methods has grown continually, due to rapid increases in com-
et al., 2021), macromolecular (Benson et al., 1994; Berman et al., 2000; puter power and the development of technologies that make determining
Berman and Gierasch, 2021; UniProt Consortium, 2015), biomolecu- protein structures easier and faster. One example is the use of synchrotrons
lar pathway (Croft et al., 2014; Ogata et al., 2000; Oughtred et al., 2021; (e.g., the Advanced Photon Source at Argonne National Laboratory) to
Wishart et al., 2020), and other databases readily accessible to researchers generate high-quality X-ray beams for use in protein X-ray crystallography.
worldwide. These data are useful in their own right and also support the Another is the development of methods to solve the structures of mem-
development and evaluation of computer models used in drug discovery. brane-bound proteins, such as ion channels and cell-surface receptors.
In parallel, exponential increases in computer speed, measured as These can be high-quality drug targets because a drug does not need to
the number of mathematical operations executed per second, have enter the cell to access them and because they regulate many cellular pro-
made more and more detailed molecular simulations feasible. Ideally, a cesses. However, their structures were virtually impossible to solve until
computational chemist could design a compound, hand the design to a methods were developed in recent years to grow three-dimensional crystals
medicinal chemist to synthesize, and the compound would prove to bind of them. Since at least the 1980s, the promise of advances in SBDD methods
the target with nanomolar affinity. When this level of accuracy becomes has inspired the founding of multiple companies.
feasible, one might go further and compute the affinity of a candidate The field of physical chemistry tells us how to compute the binding
drug to all known human proteins in order to check for unwanted inter- affinity of two molecules in water (Gilson and Zhou, 2007). Ideally,
actions. This level of accuracy is not possible today, but existing methods one could use numerical solutions of SchrÖdinger’s equation to obtain
have predictive value, and growing computer power may make this vision the electronic wave function for the compound, the target protein,
achievable in the coming years. and the aqueous solvent, for any given conformation of the system
Approaches to predicting the interactions of a small molecule with (i.e., given the Cartesian coordinates of all atoms). From the wave func-
a protein may be broadly divided into ligand-based and structure-based tion, one could then compute the instantaneous force on every atom.
approaches, as explained below. Given this method of computing atomic forces, one could simulate the
system at atomistic detail, computing the reversible work of gradually
Using Chemical Similarity to Discover pulling the compound out of the protein binding site as all the atoms
wiggled, jiggled, and shifted due to thermal motion (Feynman et al.,
Targeted Ligands 1963). This reversible work would equal the free energy of binding, DGo,
If the targeted protein is an enzyme with a small-molecule substrate which is directly related to the dissociation constant, KD:
or a receptor for a small-molecule transmitter (e.g., histamine), then
compounds chemically similar to the substrate or transmitter may be ∆ G o = RTlnK D (Equation 1–1)
active against the target and thus useful starting points for drug design
(Figure 1–2). For some targets, more extensive information about ligands This would be a prohibitively massive calculation with existing com-
for the target may be available from prior drug discovery efforts and may puter technology. However, researchers have created fast approximations
be used to guide a new project. As noted above, even if a drug has already to such an ideal calculation, each with its own strengths and weaknesses
been developed against the target, there may still be room for a me-too in terms of accuracy, range of applicability, and the computer power
drug with better properties, such as less frequent oral dosing or reduced required (Figure 1–5).
side effects. Large quantities of data to support this ligand-based drug dis- An important approximation used in molecular modeling is the
covery approach are available in the scientific literature, patents, and public force field or potential function, a mathematical model for the atomic
databases (Gaulton et al., 2012; Gilson et al., 2016; Kim et al., 2019). forces that can be evaluated orders of magnitude faster than solving
Metrics of chemical similarity abstract the detailed chemical structures SchrÖdinger’s equation (Dauber-Osguthorpe and Hagler, 2019). Force
of compounds into characteristics that can be computed and compared fields often contain adjustable parameters fitted to give agreement with
across molecules. One approach computes a compound’s molecular reference solutions of SchrÖdinger’s equation. With a force field in hand,
fingerprint, which indicates whether various molecular substructures are it becomes practical to use molecular simulations to estimate protein-
present (Muegge and Mukherjee, 2016). Other similarity metrics jetti- ligand binding free energies (Tembe and McCammon, 1984; Kollmann,
son such details and, instead, compute and compare the overall shapes 1993; Gilson et al., 1997; Simonson et al., 2002). Such free energy methods
of the two molecules and the electrical fields they generate (Bajorath, are among the most accurate approaches available to predict protein-li-
2017). In a third approach, even molecular shape is set aside, and one gand binding affinities (Schindler et al., 2020), and their use by the drug
10 A. Statins
O OH O OH O OH O OH
HO HO HO HO
O OH OH OH OH
OH F F
F
N
N
O N
O
HN
Mevastatin Fluvastatin Cerivastatin Atorvastatin
B. SGLT Inhibitors
SGLT IC50 (nM) IC50 (nM) Relative selectivity

HO OH OH
inhibitor at SGLT1 at SGLT2 for SGLT2 (col2/col3)
Phlorizin 290 21 ~14
O O
HO O Canagliflozin 710 2.7 ~260
HO OH Dapagliflozin 1400 1.2 ~1200
OH Empagliflozin 8300 3.1 ~2700
Phlorizin
Ertugliflozin 2000 0.9 ~2200
F
Cl O
S
O O
HO HO
HO OH HO OH
OH Canagliflozin OH Dapagliflozin
O O
Cl
Cl O
OH O
O O
HO
HO OH HO OH
OH Empagliflozin OH Ertugliflozin
Figure 1–2 Using chemical similarity to develop ligands. A. Statins. Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase),
the rate-limiting enzyme in cholesterol synthesis. These inhibitors are widely used to lower blood levels of cholesterol (see Chapter 37). Mevastatin is a natural
product that inspired development of the three FDA-approved statins shown here. Each compound has a polycyclic lower part linked to a common hydroxyacid
moiety, which can also exist as a cyclic lactone. B. SGLT inhibitors. Sodium-glucose cotransporters (SGLTs) facilitate glucose ingress in the gastrointestinal tract
(SGLT1) and the kidney (SGLT2). The natural product phlorizin inhibits both SGLTs to varying extents. Modifications of the phlorizin structure led to the four
FDA-approved relatively specific SGLT2 inhibitors, the gliflozins, shown here. Gliflozins reduce renal reabsorption of glucose, thereby lowering blood sugar
concentrations, and thus are used to treat type 2 diabetes (see Chapter 51). Each compound has a glucose moiety (except ertugliflozin, which has a glucose-similar
moiety), sensible for compounds that interact with transporters that bind glucose. Phenyl-containing moieties endow each inhibitor with varying activities against
each of the two protein forms, as shown in the table. Activities are given as IC50, the concentration of drug (nM) that reduces the transporter’s activity by 50%. Data
adapted from Fediuk et al. (2020) and Wright (2021).
discovery community has been enabled by the acceleration of molecu- Another computational approach, molecular docking (Guedes et
lar simulations on graphics processing units (GPUs) (Salomon-Ferrer al., 2014; Huang, 2010; Meng, 2011), is fast enough to substitute for
R, et al., 2013). Even with GPUs, though, the simulations are too slow (or supplement) a large-scale experimental high-throughput screen.
to replace an experimental high-throughput screen of millions of com- In docking, most or all of the protein is held rigid, and the software
pounds. Instead, simulations are most commonly used to help medici- tries a vast number of different locations and conformations—poses—
nal chemists decide which chemical variations on a promising starting of a small molecule in the target’s binding site, searching for the one
compound are worth synthesizing and testing. Fast molecular simula- that is lowest in energy and hence most stable. Because docking leaves
tions also are used to explore the various conformations that a protein out so many known contributions to the free energy of binding (e.g.,
can adopt. For example, if a simulation shows that a new binding pocket protein flexibility and entropy), the energy model usually must be
could form as a result of thermal protein motions, it may be possible to tuned against experimental binding data to make it more predictive.
design a drug that will bind this hitherto unrecognized site. The resulting model is often called a docking score, to differentiate

A. Screening based on concepts of chemical similarity 11
Compound Library Known Ligands
SECTION I
Similar?
GENERAL PRINCIPLES
Candidate ligands
Optimization
(Med chem, Assay
crystallography, modeling)
Actives Potent drug candidates
B. Screening based on protein-ligand docking
3D structure of target
Compound database
(crystallography, NMR, modeling)
Protein-ligand docking
Favorable score?
Candidate ligands
Ligand optimization
Med chem, Experimental assay
crystallography, modeling
Ligands Drug candidates
Figure 1–3 Virtual screening. A. Virtual compound screening based on concepts of chemical similarity. Using available similarity metrics, the compounds in
a database (green) are computationally tested for chemical similarity to the known ligands (binders) of the targeted protein. Compounds that are above some
threshold similarity are considered candidate ligands and so are experimentally assayed for binding to the protein target. Those found to be inactive are set aside,
while “actives” are subjected to iterative rounds of ligand optimization where structure-activity relationships are defined and used to guide the design of new
compounds by medicinal chemists. When sufficiently active compounds are found, these become early-stage drug candidates. B. Virtual compound screening
based on protein-ligand docking. The compounds in a database (green) are computationally docked; i.e., optimally fitted into the binding site of a target protein of
known three-dimensional structure. Compounds whose computed stabilizing interactions with the binding site are above a threshold similarity are considered
candidate ligands and so are experimentally assayed for binding to the protein target. Those found to be inactive are set aside, while “actives” are subjected to
iterative rounds of ligand optimization. This typically involves using the protein structure to design new compounds that can form better interactions with the
binding site and solving crystal structures of the protein with selected compounds to determine whether the designed compounds bind as hoped and to guide
further rounds of chemical design and synthesis. Advanced computational methods, such as simulation-based free energy calculations, may also be used at this
stage. When sufficiently active compounds are found, these become early-stage drug candidates.

12
Figure 1–4 Crystal structure of the human immunodeficiency virus 1 protease (HIV-1 protease) with the protease inhibitor darunavir bound in the active site. Colored
tubes: protein backbone of the enzyme, a symmetric dimer made up of two identical subunits, where color indicates secondary structure (yellow, β-sheet; red,
α-helix; blue, turn; white, none). Translucent gray: overall surface of the protein, including both side-chain and backbone atoms. Ball and stick: darunavir in the
tunnel-shaped active site, with atoms colored by element (gray, carbon; red, oxygen; blue, nitrogen), with hydrogen atoms omitted for simplicity. Key hydrogen
bonds are shown as dashed green lines, and the oxygen of a water molecule that bridges between the drug and the protein is shown as a red ball. Atomic coordi-
nates from Protein Data Bank (Wang et al., 2011).
it from a true force field. Docking calculations are typically used for methods may be trained on existing data, such as on existing collections
virtual HTS (see Figure 1–3), in which thousands or millions of com- of protein–small-molecule binding data, the results of DELs, and protein
pounds in a chemical library are rapidly fitted into the binding site of structures, to enable direct prediction of protein–small-molecule binding
the targeted protein. Tens or hundreds of the top-scoring compounds and automated design of ligands for a targeted protein. They may also
may then be subjected to more detailed calculations or tested exper- support drug discovery in other ways, such as by predicting the three-
imentally. Although not all of the top-scoring compounds will be dimensional structures of proteins (AlQuraishi, 2021; Baek et al., 2021;
good binders, the fraction of binders will normally be enriched rel- Jumper et al., 2021), the energies of molecules as a function of confor-
ative to the chemical library as a whole. In addition, the predicted mation (Smith et al., 2017), and molecular properties such as whether a
binding poses may provide mechanistic insight and serve as starting compound is water soluble (Francoeur and Koes, 2021). Artificial intelli-
points for molecular simulations (Guest et al., 2022; Heinzelmann and gence and machine learning will undoubtedly play an expanding role in
Gilson, 2021). The empirically tuned scoring functions used in dock- drug discovery in the coming years.
ing can also be used to guide manual chemical editing of a known
binder with graphical molecular modeling software. For example, one
may manually edit an existing compound in the context of a three- Designing Large Molecules as Drugs:
dimensional rendering of the binding pocket to design a new com-
pound that reaches into a neighboring subpocket and forms stabilizing The Rise of Biopharmaceuticals
hydrophobic and hydrogen-bonding interactions with the protein. This Large molecules are increasingly important as therapeutic agents. For
interactive work may be aided by immersive visualization and manipu- example, antisense oligonucleotides are used to block gene transcription
lation technologies, such as virtual reality. or translation, as are siRNAs and modified mRNAs (as in several vaccines
for SARS-CoV-2 [severe acute respiratory syndrome coronavirus 2]).
Artificial Intelligence in Drug Discovery Important proteins used therapeutically include monoclonal antibodies,
Deep neural networks have proven their power in wide-ranging artifi- enzymes, and peptide hormones. Protein therapeutics were uncommon
cial intelligence tasks such as image recognition and language transla- before the advent of recombinant DNA technology except for the few
tion, and researchers are now exploring their use in drug discovery. These peptide hormones that could be isolated and purified in bulk. Insulin was

monoclonal antibodies can be “humanized” (by substituting human for 13
L + P KA PL mouse amino acid sequences). Alternatively, mice have been engineered
by replacement of critical mouse genes with their human equivalents,
such that they make completely human antibodies. Protein therapeu-
tics are administered parenterally, and their receptors or targets must be
SECTION I
accessible extracellularly.
Using some of the strategies outlined above, nonantibody therapeu-
tic proteins and peptides can now be optimized for stability, activity, and
targeting to particular cell types. Peptides are being developed as ther-
apeutics, especially in the area of interrupting protein-protein interac-
Simple, fast Detailed, time-consuming tions where the large contact surfaces may defy small-molecule action.
Computational methods are proving very useful in the design of peptide
GENERAL PRINCIPLES
therapeutics (Belvisi et al., 2021). Therapeutic proteins are usually close
Protein-ligand MMGBSA Free energy copies of naturally occurring proteins that are optimized for high stabil-
docking MMPBSA calculations ity (both during manufacture and after administration) and optimized to
Mining Minima avoid rapid degradation, to have low immunogenicity, and to have high
Figure 1–5 Physics-based computational methods for estimating protein- potency when administered to a patient. Strategies include optimizing
ligand binding affinities. These methods provide an estimate of the associ- expression of a protein’s gene sequence in multiple hosts, exploring close
ation constant, KA, for binding of a ligand, L, to a protein of known three- relatives of the protein of interest and mutations (random and rational),
dimensional structure, P, to form a protein-ligand complex, PL, held together introduction of posttranslational modifications, and exploring biolog-
typically by noncovalent interactions such as hydrogen bonding and the ical modifications such as fusion with macromolecules (Dellas et al.,
hydrophobic effect. The equation relates KA to the standard free energy of 2021). Conjugation strategies (e.g., PEGylation) can be used to improve
binding ΔGo, the gas constant R, and the absolute temperature T, and fur- pharmacokinetic properties of therapeutic proteins (Moncalvo et al.,
ther relates the binding free energy to the standard concentration Co, and 2020). The roster of recently engineered proteins that are not antibod-
the configuration integrals of the protein-ligand complex (ZPL), the unbound ies includes agents for cancers, gout, clotting disorders and hemophilia,
protein (ZP), and the unbound ligand (ZL). As more low-energy conforma- inherited metabolic diseases, lysosomal storage disorders, pancreatic
tions are accessible to each molecular species (PL, P, L), the corresponding exocrine deficiency, insufficiencies of hormones and growth factors,
value of Z increases. Therefore, if the protein-ligand complex can access more and macular degeneration, among others. The number of nonantibody
low-energy conformations than the separate protein and ligand, the equilib- FDA-approved therapeutic proteins and peptides is growing rapidly (see
rium constant will be large, favoring binding. Direct calculation of these con- a database of FDA-approved proteins and peptides at https://webs.iiitd.
figuration integrals is a computational challenge; however, researchers have edu.in/raghava/thpdb/index.html; Usmani et al., 2017). A few protein
created a spectrum of computational methods, ranging from fast, approxi-
therapeutics are administered topically or orally, but most are adminis-
mate methods that are expected to be less accurate, to more detailed, more
tered by injection. However, this is changing with the development of
computationally demanding methods that are typically more accurate (Gilson
liposomal drug delivery systems, which are administered parenterally but
and Zhou, 2007). Docking, discussed in the text, is at the fast end of the spec-
are proving amenable to inhalation, ocular, and topical routes.
trum; it treats the protein as mainly rigid, along with other approximations.
Free energy calculations, also discussed in the text, are at the slow end of
the spectrum; they treat the protein and ligand as fully flexible. In the mid-
dle of the spectrum are the molecular mechanics generalized Born/surface The Investigational New Drug Application
area (MMGBSA) (Srinivasan et al., 1998), molecular mechanics Poisson-
Before the drug candidate can be administered to human subjects in a
Boltzmann/surface area (MMPBSA) (Gouda et al., 2003), and Mining
clinical trial, the sponsor must file an Investigational New Drug (IND)
Minima methods (Chen et al., 2010). These use various approaches to directly
application, a request to the FDA for permission to use the drug for
estimate the configuration integrals, ZPL, ZP, and ZL. For example, Mining
human research (see Clinical Trials, below). The IND describes the
Minima searches for low-energy conformations of the protein, the ligand, and
the complex; estimates their individual contributions to Z; and sums these rationale and preliminary evidence for efficacy in experimental systems,
contributions to provide an overall estimate of the configuration integral. as well as pharmacology, toxicology, chemistry, manufacturing, and so
forth. It also describes the plan (protocol) for investigating the drug in
human subjects. The FDA has 30 days to review the IND application,
introduced into clinical medicine for the treatment of diabetes following the by which time the agency may disapprove it, ask for more data, or allow
experiments of Banting and Best in 1921. Insulins purified from porcine or initial clinical testing to proceed.
bovine pancreas are active in humans, although antibodies to the foreign
proteins are occasionally problematic. Growth hormone, used to treat pitu-
itary dwarfism, exhibits more stringent species specificity. Only the human Clinical Trials
hormone could be used after purification from pituitary glands harvested
during autopsy, and such use had its dangers—some patients who received Role of the FDA
the human hormone developed Creutzfeldt-Jakob disease (the human equiv- The FDA, a federal regulatory agency within the U.S. Department of Health
alent of mad cow disease), a fatal degenerative neurological disease caused by and Human Services (DHHS), is responsible for protecting the public
prion proteins that contaminated the drug preparation. health by ensuring the safety, efficacy, and security of human and veteri-
Thanks to gene cloning, expression of the cloned gene in bacteria or nary drugs, biological products, medical devices, our nation’s food supply,
eukaryotic cells, and large-scale production techniques, protein thera- cosmetics, and products that emit radiation (FDA, 2018). The FDA also is
peutics now use highly purified preparations of human (or humanized) responsible for advancing public health by helping to speed innovations
proteins. Rare proteins can be produced in quantity, and immunological that make medicines and foods more effective, safer, and more affordable
reactions are minimized. Proteins can be designed, customized, and opti- and by helping people obtain the accurate, science-based information they
mized using genetic engineering techniques. need to use medicines and foods to improve their health.
Proteins used therapeutically include hormones, growth factors The first drug-related legislation in the U.S., the Federal Pure Food
(e.g., erythropoietin, granulocyte colony-stimulating factor), cytokines, and Drugs Act of 1906, was concerned only with the interstate trans-
and a number of monoclonal antibodies used in the treatment of can- port of adulterated or misbranded foods and drugs. Motivations for
cer and autoimmune diseases (see Chapters 38–40, 45, and 72). Murine federal regulation included the prominence of “patent medicines” and
14 their adulteration, the journalism of S. H. Adams (via articles in Colliers The FDA-regulated clinical trials typically are conducted in four
Weekly), and Upton Sinclair’s novel The Jungle (Law, 2004). In the 1906 phases. Phases I to III are designed to establish safety and efficacy.
act, there were no obligations to establish drug efficacy or safety. This act Phase IV postmarketing trials and surveys gather additional data from
was amended in 1938 after the deaths of over 100 children from “elixir larger populations and increasing numbers of administered doses. This
sulfanilamide,” a solution of sulfanilamide in diethylene glycol, an excellent phase provides information regarding new indications, risks, and optimal
but highly toxic solvent and an ingredient in antifreeze. The enforcement doses and schedules, as presented in Chapter 8. Table 1–1 and Figure 1–6
of the amended act was entrusted to the FDA, which began requiring summarize the important features of each phase of clinical trials; note
toxicity studies as well as approval of a New Drug Application (NDA) (see the attrition at each successive stage over a relatively long and costly
The Conduct of Clinical Trials, below) before a drug could be promoted process. When initial phase III trials are complete, the sponsor (usually a
and distributed. Although a new drug’s safety had to be demonstrated, no pharmaceutical company) applies to the FDA for approval to market the
proof of efficacy was required. drug; this application is called either an NDA or a BLA (Biologics License
In the 1960s, thalidomide, a hypnotic drug with no obvious advantages Application). These applications contain comprehensive information,
over others, was introduced in Europe. Epidemiological research even- including individual case report forms from the hundreds or thousands
tually established that this drug, taken early in pregnancy, was respon- of individuals who have received the drug during its phase III testing.
sible for an epidemic of what otherwise is a relatively rare and severe Applications are reviewed by teams of specialists, and the FDA may call
birth defect, phocomelia, in which limbs are malformed. In reaction on the help of panels of external experts in complex cases.
to this catastrophe, the U.S. Congress passed the Harris-Kefauver Under the provisions of the Prescription Drug User Fee Act (PDUFA;
amendments to the Food, Drug, and Cosmetic Act in 1962. These enacted in 1992 and renewed every 5 years, most recently in 2017), phar-
amendments established the requirement for proof of efficacy as well maceutical companies now provide a significant portion of the FDA
as documentation of relative safety in terms of the risk-to-benefit budget via user fees, a legislative effort to expedite the drug approval
ratio for the disease entity to be treated (the more serious the dis- review process by providing increased resources. The PDUFA also broad-
ease, the greater the acceptable risk). Today, the FDA faces an enor- ened the FDA’s drug safety program and increased resources for review
mous challenge, especially in view of the widely held belief that its of television drug advertising. Under PDUFA, review typically takes
mission cannot possibly be accomplished with the resources allocated 6 to 10 months after an NDA is submitted to the FDA. During this time,
by Congress. Moreover, harm from drugs that cause unanticipated numerous review functions are usually performed, including advisory
adverse effects is not the only risk of an imperfect system; harm also committee meetings, amendments, manufacturing facility inspections,
occurs when the approval process delays the approval of a new drug and proprietary name reviews (FDA, 2013). Before a drug is approved
with important beneficial effects. for marketing, the company and the FDA must agree on the content of
the “label” (package insert)—the official prescribing information. This
The Conduct of Clinical Trials label describes the approved indications for use of the drug and clinical
Clinical trials of drugs are designed to acquire information about the pharmacological information, including dosage, adverse reactions, and
pharmacokinetic and pharmacodynamic properties of a candidate drug special warnings and precautions (sometimes posted in a “black box”).
in humans and to establish the efficacy and safety of the drug prior to its Promotional materials used by pharmaceutical companies cannot devi-
sale in the U.S. The U.S. National Institutes of Health (NIH) identifies ate from information contained in the package insert. Importantly, the
seven ethical principles that must be satisfied before a clinical trial can physician is not bound by the package insert; a physician in the U.S.
begin (NIH, 2021): may legally prescribe a drug for any purpose that he or she deems rea-
sonable. However, third-party payers (insurance companies, Medicare,
1. Social and clinical value and so on) generally will not reimburse a patient for the cost of a drug
2. Scientific validity used for an “off-label” indication unless the new use is supported by a
3. Fair selection of subjects statutorily named compendium (e.g., the American Hospital Formulary
4. Informed consent Service–Drug Information [AHFS-DI]). Furthermore, a physician may
5. Favorable risk-benefit ratio be vulnerable to litigation if untoward effects result from an unapproved
6. Independent review use of a drug.
7. Respect for potential and enrolled subjects
TABLE 1–1 ■ TYPICAL CHARACTERISTICS OF THE PHASES OF CLINICAL TRIALS REQUIRED BY THE FDA BEFORE THE
MARKETING OF NEW DRUGS*
PHASE I PHASE II PHASE III PHASE IV
FIRST IN HUMAN FIRST IN PATIENT MULTISITE TRIAL POSTMARKETING
10–100 participants 50–500 participants A few hundred to a few thousand participants Many thousands of
participants
Usually healthy volunteers; Patient-subjects receiving Patient-subjects receiving experimental drug Patients in treatment with
occasionally patients with experimental drug approved drug
advanced or rare disease
Open label Randomized and controlled (can be Randomized and controlled (can be placebo Open label
placebo controlled); may be blinded controlled) or uncontrolled; may be blinded
Safety and tolerability Efficacy and dose ranging Confirm efficacy in larger population Adverse events, compliance,
drug-drug interactions
1–2 years 2–3 years 3–5 years No fixed duration
U.S. $10 to 15 million U.S. $20 to 40 million U.S. $50–150 million Variable
Success rate: 50% Success rate: 30% Success rate: 25%–50% —
Costs of clinical trial phases vary widely with a drug’s therapeutic area, size and complexcity of trial, whether trial must prove non-inferiority to existing agents, etc.
*
Overall cost to develop a new molecular entity (NME) from laboratory to FDA approval is estimated at $1 billion to $4 billion.

12 15
Introduction Postmarketing Phase IV
11 Registration surveillance
10 1
9 Development Clinical tests Phase III
SECTION I
(human)
8 2
7 Phase II
2–5
Years 6 Phase I
5–10
5 Preclinical tests
(animal)
GENERAL PRINCIPLES
4
10–20
3
Basic research Synthesis,
2 examination,
screening
1
104–107
0
Number of chemical entities
Figure 1–6 The phases, timelines, and attrition that characterize the development of new drugs. See also Table 1–1.
Determining “Safe” and “Effective” especially when used in combination with a statin. Lowering of LDL
cholesterol was assumed to be an appropriate surrogate end point for
Demonstrating efficacy to the FDA requires performing “adequate
the effectiveness of ezetimibe to reduce myocardial infarction and stroke,
and well-controlled investigations,” generally interpreted to mean two
and the drug was approved based on such data. Surprisingly, a subse-
replicate clinical trials that are usually, but not always, randomized,
quent clinical trial (ENHANCE) demonstrated that the combination of
double-blind, and placebo (or otherwise) controlled. Is a placebo the
ezetimibe and a statin did not reduce intima media thickness of carotid
proper control? The World Medical Association’s Declaration of Helsinki
arteries (a more direct measure of subendothelial cholesterol accumula-
(World Medical Association, 2013) discourages use of placebo controls
tion) compared with the statin alone, despite the fact that the drug com-
when an alternative treatment is available for comparison because of the
bination lowered LDL cholesterol concentrations substantially more than
concern that study participants randomized to placebo in such a circum-
did either drug alone (Kastelein et al., 2008). Critics of ENHANCE argued
stance would, in effect, be denied treatment during the conduct of the
that the patients in the study had familial hypercholesterolemia, had been
trial. What must be measured in the trials? In a straightforward trial,
treated with statins for years, and did not have carotid artery thicken-
a readily quantifiable parameter (a secondary or surrogate end point),
ing at the initiation of the study. Should ezetimibe have been approved?
thought to be predictive of relevant clinical outcomes, is measured in
Must we return to measurement of true clinical end points (e.g., myocar-
matched drug- and placebo-treated groups. Examples of surrogate end
dial infarction) before approval of drugs that lower cholesterol by novel
points include low-density lipoprotein (LDL) cholesterol as a predictor of
mechanisms? The costs involved in such extensive and expensive trials
myocardial infarction, elevated high-density lipoprotein (HDL) choles-
must be borne somehow (see below). A follow-up 7-year study involving
terol as a predictor of reduced risk of myocardial infarction (see Box 1–2),
over 18,000 patients (IMPROVE-IT) vindicated the decision to approve
bone mineral density as a predictor of fractures, or hemoglobin A1c as a
ezetimibe (Jarcho and Keaney, 2015). Taken in conjunction with a statin,
predictor of the complications of diabetes mellitus. More stringent trials
the drug significantly reduced the incidence of myocardial infarction and
would require demonstration of reduction of the incidence of myocar-
stroke in high-risk patients.
dial infarction in patients taking a candidate drug in comparison with
No drug is totally safe; all drugs produce unwanted effects in at least
those taking an HMG-CoA reductase inhibitor (statin) or other LDL
some people at some dose. Many unwanted and serious effects of drugs
cholesterol–lowering agent or reduction in the incidence of fractures in
occur so infrequently, perhaps only once in several thousand patients,
comparison with those taking a bisphosphonate. Use of surrogate end
that they go undetected in the relatively small populations (a few thou-
points significantly reduces cost and time required to complete trials, but
sand) in the standard phase III clinical trial (see Table 1–1). To detect and
there are many mitigating factors, including the significance of the surro-
verify that such comparatively rare effects are, in fact, drug-related would
gate end point to the disease that the candidate drug is intended to treat.
require administration of the drug to tens or hundreds of thousands of
Some of the difficulties are well illustrated by experiences with
people during clinical trials, adding enormous expense and time to drug
ezetimibe, a drug that inhibits absorption of cholesterol from the
development and delaying access to potentially beneficial therapies. In
gastrointestinal tract and lowers LDL cholesterol concentrations in blood,
general, the true spectrum and 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
BOX 1–2 ■ A Late Surprise in the Search for a Blockbuster development costs and drug prices could be reduced substantially if the
Torcetrapib elevates HDL cholesterol (the “good cholesterol”). public were willing to accept more risk. This would require changing the
Higher levels of HDL cholesterol are statistically associated with way we think about a pharmaceutical company’s liability for damages
(are a surrogate end point for) a lower incidence of myocardial from an unwanted effect of a drug that was not detected in clinical tri-
infarction. Surprisingly, clinical administration of torcetrapib caused a als deemed adequate by the FDA. Would the public accept a drug with
significant increase in mortality from cardiovascular events, ending a extremely severe unwanted effects, including death, if its therapeutic
development path of 15 years and $800 million. In this case, approval effect were sufficiently unique and valuable? Such dilemmas are not sim-
of the drug based on this secondary end point would have been a ple and can become issues for great debate.
mistake (Cutler, 2007). A computational systems analysis suggested a Several strategies exist to detect adverse reactions after marketing of a
mechanistic explanation of this failure (Xie et al., 2009). drug. Formal approaches for estimation of the magnitude of an adverse
drug response include the follow-up or cohort study of patients who
16 are receiving a particular drug; the case-control study, in which the fre- Not surprisingly, there is tension between those who treat drugs as enti-
quency of drug use in cases of adverse responses is compared to controls; tlements and those who view drugs as high-tech products of a capitalistic
and meta-analysis of pre- and postmarketing studies. Voluntary report- society. Supporters of the entitlement position argue that a constitutional
ing of adverse events has proven to be an effective way to generate an right to healthcare should guarantee access to drugs, and they are critical
early signal that a drug may be causing an adverse reaction (Aagard and of pharmaceutical companies and others who profit from the business
Hansen, 2009). The primary sources for the reports are responsible, alert of making and selling drugs. Free-marketeers point out that, without a
physicians and third-party payers (pharmacy benefit managers, insurance profit motive, it would be difficult to generate the resources and inno-
companies); consumers also play important roles. Other useful sources vation required for new drug development. Clearly, drug development
are nurses, pharmacists, and students in these disciplines. In addition, is both a scientific process and a political one, and also a process about
hospital-based pharmacy and therapeutics committees and quality assur- which attitudes can change quickly. Critics of the pharmaceutical indus-
ance committees frequently are charged with monitoring adverse drug try frequently begin from the position that people (and animals) need
reactions in hospitalized patients. In the U.S., the FDA sponsors MedWatch, to be protected from greedy and unscrupulous companies and scientists
a drug safety information and adverse event reporting program. The website (Angell, 2015; Kassirer, 2005; Ryan and DeSanctis, 2005). In the absence
for MedWatch (http://www.fda.gov/Safety/MedWatch/default.htm) proof a government-controlled drug development enterprise, our current
vides simple forms for reporting and lists recent safety alerts about specific system relies predominantly on investor-owned pharmaceutical compa-
medications. In addition to online access, the service may be reached by nies that, like other companies, have a profit motive and an obligation
calling 800-FDA-1088. Health professionals also may contact the pharma- to shareholders. The price of prescription drugs causes great consterna-
ceutical manufacturer, who is legally obligated to file reports with the FDA. tion among consumers, especially as many health insurers seek to con-
trol costs by choosing not to cover certain “brand-name” products (see
below). Further, a few drugs (especially for treatment of cancer) have been
Personalized (Individualized, Precision) introduced to the market in recent years at prices that greatly exceeded
the costs of development, manufacture, and marketing of the product.
Medicine Many of these products were discovered in government laboratories or in
Drug inventors strive to “fit” the drug to the individual patient. To realize university laboratories supported by federal grants. The U.S. is the only
the full potential of this approach, however, requires intimate knowledge large country that places no controls on drug prices and where price plays
of the considerable heterogeneity of both the patient population and the no role in the drug approval process. Many U.S. drugs cost much more in
targeted disease process. Why does one antidepressant appear to amelio- the U.S. than overseas; thus, U.S. consumers subsidize drug costs for the
rate depression in a given patient, while another drug with the same or rest of the world, and they are irritated by that fact. The example of newer
very similar presumed mechanism of action does not? Is this a difference agents for the treatment of hepatitis C infection brings many conflicting
in the patient’s response to the drug; in patient susceptibility to the drug’s priorities into perspective (Box 1–3).
unwanted effects; in the drug’s ADME; or in the etiology of the depres-
sion? How much of this variability is attributable to environmental factors
BOX 1–3 ■ The Cost of Treating Hepatitis C
and possibly their interactions with patient-specific genetic variability?
Recent advances, especially in genetics and genomics, provide powerful Infection with hepatitis C virus (HCV) is a chronic disease afflicting
tools for understanding this heterogeneity. The single most powerful tool millions of people. Some suffer little from this condition; many
for unraveling these myriad mysteries is the ability to sequence DNA others eventually develop cirrhosis or hepatocellular carcinoma.
rapidly and economically. The cost of sequencing a human’s genome is Who should be treated? The answer is unknown. Until recently, the
now less than $1000, about six orders of magnitude lower than at the treatment of choice for people with genotype 1 HCV involved year-
start of the 21st century (National Human Genome Research Institute, long administration of an interferon (by injection) in combination
2021). The current focus is on the extraordinarily complex analysis of with ribavirin and a protease inhibitor. Unwanted effects of this
the enormous amounts of data now being obtained from many thou- regimen are frequent and severe (some say worse than the disease);
sands of individuals, ideally in conjunction with deep knowledge of their cure rates range from 50% to 75%. A newer treatment involves an
phenotypic characteristics, especially including their medical histories. oral tablet containing a combination of sofosbuvir and ledipasvir (see
Readily measured biomarkers of disease are powerful adjuncts to DNA Chapter 63). Treatment usually requires daily ingestion of one tablet
sequence information. Simple blood or other tests can be developed to for 8 to 12 weeks; cure rates exceed 95%, and side effects are minimal.
monitor real-time progress or failure of treatment; many such examples Controversy surrounds the price of the treatment, about $1000/day.
already exist. Similarly, chemical, radiological, and genetic tests may be Some insurers refused to reimburse this high cost, relegating many
useful not only to monitor therapy but also to predict success or failure, patients to less effective, more toxic, but less expensive treatment.
anticipate unwanted effects of treatment, or appreciate pharmacokinetic However, these third-party payers have negotiated substantial
variables that may require adjustments of dosage or choice of drugs. Such discounts of the price, based on the availability of a competing
tests already play a significant role in the choice of drugs for cancer che- product. Is the cost exorbitant? Should insurers, rather than patients
motherapy, and the list of drugs specifically designed to “hit” a mutated and their physicians, be making such important decisions?
target in a specific cancer is growing. Such information is also becoming Continued and excessive escalation of drug and other healthcare
increasingly useful in the choice of patients for clinical trials of specific costs will bankrupt the healthcare system. The question of appropriate
agents, thereby reducing the time required for such trials and their cost, to cost involves complex pharmacoeconomic considerations. What are
say nothing of better defining the patient population who may benefit from the relative costs of the two treatment regimens? What are the savings
the drug. These important subjects are discussed in detail in Chapter 7, from elimination of the serious sequelae of chronic HCV infection?
Pharmacogenetics, and in Chapter 8, Postmarketing Drug Safety. How does one place value to the patient on the less toxic and more
effective and convenient regimen? What are the profit margins of
the company involved? Who should make decisions about costs
and choices of patients to receive various treatments? How should
Public Policy Considerations we consider cases (unlike that for HCV) for which the benefits are
quite modest, such as when a very expensive cancer drug extends
The Pharmaceutical Industry Operates in a life only briefly? One astute observer (and an industry critic of many
Capitalist Economy drug prices) summarized the situation as follows: “great, important
Drugs can save lives, prolong lives, and improve the quality of people’s problem; wrong example.”
lives. However, in a free-market economy, access to drugs is not equitable.

The drug development process is long, expensive, and risky (see The U.S. patent protection system provides protection for 20 years 17
Figure 1–6 and Table 1–1). Consequently, drugs must be priced to from the time the patent is filed. During this period, the patent owner of
recover the substantial costs of invention and development and to fund a drug has exclusive rights to market and sell the drug. When the patent
the marketing efforts needed to introduce new products to physicians expires, equivalent nonproprietary products can come on the market. A
and patients. Depending on the methods of accounting for sales and dis- generic product must be therapeutically equivalent to the original, con-
SECTION I
pensing, prescription drugs account for 9% to 13% of total U.S. healthcare tain equal amounts of the same active chemical ingredient, and achieve
expenditures (Conti et al., 2021). equal concentrations in blood when administered by the same routes.
Although the increase in prices is significant in certain classes of drugs These generic preparations are sold much more cheaply than the origi-
(e.g., anticancer agents), the total price of prescription drugs is growing at nal drug and without the huge development costs borne by the original
a slower rate than other healthcare costs. Even drastic reductions in drug patent holder. The long time course of drug development, often more
prices that would severely limit new drug invention would not lower the than 10 years (see Figure 1–6), reduces the time during which patent
overall healthcare budget by more than a few percent. Are profit margins protection functions as intended. The Drug Price Competition and Pat-
GENERAL PRINCIPLES
excessive among the major pharmaceutical companies? There is no objec- ent Term Restoration Act of 1984 (Public Law 98-417, informally called
tive answer to this question. Pragmatic answers come from the markets the Hatch-Waxman Act) permits a patent holder to apply for extension
and from company survival statistics. The U.S. free-market system provides of a patent term to compensate for delays in marketing caused by FDA
greater rewards for particularly risky and important fields of endeavor, and approval processes; nonetheless, the average new drug brought to market
many people argue that the rewards should be greater for those willing to now enjoys only about 10 to 12 years of patent protection. Some argue
take the risk. The pharmaceutical industry is clearly one of the more risky: that patent protection for drugs should be shortened, so that earlier
generic competition will lower healthcare costs. The counterargument is
• The costs to bring products to market are enormous.
that new drugs would have to carry even higher prices to provide ade-
• The success rate of drug development is low (accounting for much of
quate compensation to companies during a shorter period of protected
the cost).
time. If that is true, lengthening patent protection would actually permit
• Accounting for the long development time, effective patent protec-
lower prices. Recall that patent protection is worth little if a superior com-
tion for marketing a new drug is only about a decade (see Intellectual
petitive product is invented and brought to market.
Property and Patents).
• Regulation is stringent.
• Product liability is great.
Bayh-Dole Act
• Competition is fierce. The Bayh-Dole Act (35 U.S.C. § 200) of 1980 created strong incentives for
• With mergers and acquisitions, the number of companies in the phar- federally funded scientists at academic medical centers to approach drug
maceutical world is shrinking. invention with an entrepreneurial spirit. The act transferred intellectual
property rights to the researchers and their respective institutions (rather
Many feel that drug prices should be driven more by their therapeu- than to the government) to encourage partnerships with industry that
tic impact and their medical need, rather than by simpler free-market would bring new products to market for the public’s benefit. While the
considerations; there is movement in this direction. There are many need to protect intellectual property is generally accepted, this encourage-
components and points of contention in estimating a drug’s value ment of public-private research collaborations has given rise to concerns
(Schnipper et al., 2015), and, as a consequence, there is no well-accepted about conflicts of interest by scientists and universities (Kaiser, 2009).
approach to answer the question of value.
Biosimilars
Who Pays?
The path to approval of a chemically synthesized small molecule that is
The cost of prescription drugs is borne by consumers (“out of pocket”), identical to an approved compound whose patent protection has expired
private insurers, and public insurance programs such as Medicare, is relatively straightforward. The same is not true for large molecules
Medicaid, and the State Children’s Health Insurance Program (SCHIP). (usually proteins), which are generally derived from a living organism
Some major retailers and mail-order pharmacies run by private insur- (e.g., eukaryotic cell or bacterial culture). Covalent modification of
ers offer consumer incentives for purchase of generic drugs, and these proteins (e.g., glycosylation) or conformational differences may influ-
initiatives have helped to contain the portion of household expenses ence pharmacokinetics, pharmacodynamics, immunogenicity, or other
spent on pharmaceuticals; however, more than one-third of total retail properties, and demonstration of therapeutic equivalence may be a com-
drug costs in the U.S. are paid with public funds—tax dollars. Health- plex process. The Biologics Price Competition and Innovation Act was
care in the U.S. is more expensive than everywhere else, but it is not, on enacted as part of the Affordable Care Act in 2010. The intent was to
average, demonstrably better than everywhere else. One way in which implement an abbreviated licensure pathway for certain “similar” biologi-
the U.S. system falls short is with regard to healthcare access. Although cal products. Biosimilarity is defined to mean “that the biological product
the Patient Protection and Affordable Care Act of 2010 (“Obamacare”) is highly similar to a reference product notwithstanding minor differ-
has reduced the percentage of Americans without health insurance to ences in clinically inactive components” and that “there are no clinically
a historic low, practical solutions to the challenge of providing health- meaningful differences between the biological product and the reference
care for all who need it must recognize the importance of incentivizing product in terms of the safety, purity, and potency of the product.” In
innovation. general, an application for licensure of a biosimilar must provide satisfac-
tory data from analytical studies, animal studies, and one or more clinical
Intellectual Property and Patents
studies. However, the interpretation of this language has involved endless
Drug invention produces intellectual property eligible for patent protec- discussion, and hard-and-fast rules seem unlikely.
tion, protection that is enormously important for innovation. As noted
by Abraham Lincoln, the only U.S. president to ever hold a patent (for a Drug Promotion
device to lift boats over shoals; never commercially produced):
In an ideal world, physicians would learn all they need to know about
Before [patent laws], any man might instantly use what another had drugs from the medical literature, and good drugs would sell themselves.
invented; so that the inventor had no special advantage from his own Instead, we have print advertising, visits from salespeople directed at phy-
invention. The patent system changed this; secured to the inventor, for sicians, and extensive direct-to-consumer advertising aimed at the public
a limited time, the exclusive use of his invention; and thereby added the (in print, on the radio, and especially on television). There are roughly
fuel of interest to the fire of genius, in the discovery and production of 80,000 pharmaceutical sales representatives in the U.S. who target about
new and useful things. (Lincoln, 1859) 10 times that number of physicians. The number of salespeople is down
18 from about 100,000 in 2010, a decline possibly related to increased atten- Product Liability
tion to conflicts of interest. The amount spent on promotion of drugs
Product liability laws are intended to protect consumers from defective
approximates or perhaps even exceeds that spent on research and devel-
products. Pharmaceutical companies can be sued for faulty design or
opment. Pharmaceutical companies have been especially vulnerable to
manufacturing, deceptive promotional practices, violation of regulatory
criticism for some of their marketing practices (Angell, 2015). Pro-
requirements, or failure to warn consumers of known risks. Failure-
motional materials used by pharmaceutical companies cannot deviate
to-warn claims can be made against drug makers even when the prod-
from information contained in the FDA-approved package insert. In
uct is approved by the FDA. With greater frequency, courts are finding
addition, there must be an acceptable balance between presentation of
companies that market prescription drugs directly to consumers respon-
therapeutic claims for a product and discussion of unwanted effects.
sible when advertisements fail to provide an adequate warning of poten-
Such requirements notwithstanding, direct-to-consumer advertising
tial adverse effects. Although injured patients are entitled to pursue legal
of prescription drugs remains controversial and is permitted only in
remedies, the negative effects of product liability lawsuits against phar-
the U.S. and New Zealand. Canada allows a modified form of adver-
maceutical companies may be considerable. First, fear of liability may
tising in which either the product or the indication can be mentioned,
cause pharmaceutical companies to be overly cautious about testing,
but not both. The efficacy of direct televised marketing is measurable
thereby delaying access to the drug. Second, the cost of drugs increases
(Gray et al., 2020; Sullivan et al., 2021), and physicians frequently suc-
for consumers when pharmaceutical companies increase the length and
cumb, albeit with misgivings, to patients’ advertising-driven requests
number of trials they perform to identify even the smallest risks and
for specific medications.
when regulatory agencies increase the number or intensity of regulatory
The counterargument to such marketing is that patients are educated
reviews. Third, excessive liability costs create disincentives for develop-
by such marketing efforts and are thereby encouraged to seek medi-
ment of so-called orphan drugs, pharmaceuticals that benefit a small num-
cal care, especially for conditions (e.g., depression) that they may have
ber of patients. Should pharmaceutical companies be liable for failure to
been denying (Avery et al., 2012). A major criticism of drug marketing
warn when all of the rules were followed, and the product was approved
involves some of the unsavory approaches used to influence physician
by the FDA but the unwanted effect was not detected because of its rarity
behavior. Gifts of value (e.g., sports tickets) are now forbidden, but
or another confounding factor? The only way to find “all” of the unwanted
dinners where drug-prescribing information is presented by non–sales
effects that a drug may have is to market it—to conduct a phase IV “clinical
representatives are widespread. Large numbers of physicians are paid as
trial” or observational study. This basic friction between risk to patients and
“consultants” to make presentations in such settings. The acceptance of
the financial risk of drug development does not seem likely to be resolved
any gift, no matter how small, from a drug company by a physician is
except on a case-by-case basis, in the courts. The U.S. Supreme Court
now forbidden at many academic medical centers and by law in several
added further fuel to these fiery issues in 2009 in the case Wyeth v. Levine. A
states. In 2009, the board of directors of the Pharmaceutical Research
patient (Levine) suffered gangrene of an arm following inadvertent arterial
and Manufacturers of America (PhRMA) adopted an enhanced Code
administration of the antinausea drug promethazine, subsequently losing
on Interactions With Healthcare Professionals that prohibits the distribu-
her hand. The healthcare provider had intended to administer the drug by
tion of noneducational items, prohibits company sales representatives
so-called intravenous push. The FDA-approved label for the drug warned
from providing restaurant meals to healthcare professionals (although
against, but did not prohibit, administration by intravenous push. The state
exceptions are granted when a third-party speaker makes the presenta-
court and then the U.S. Supreme Court held both the healthcare provider
tion), and requires companies to ensure that their representatives are
and the company liable for damages. Specifically, the Vermont court found
trained about laws and regulations that govern interactions with health-
that Wyeth, the drug’s maker, had inadequately labeled the drug. This
care professionals.
means that FDA approval of the label does not protect a company from
Concerns About Global Injustice liability or prevent individual states from imposing regulations more strin-
gent than those required by the federal government.
Drug discovery is expensive (see Table 1–1), and economic realities influ-
ence the direction of pharmaceutical research. For example, investor-
owned companies generally cannot afford to develop products for rare
“Me Too” Versus True Innovation: The Pace of New
diseases or for diseases that are common only in economically underde- Drug Development
veloped parts of the world. Funds to invent drugs targeting rare diseases As noted previously, the term me-too drug describes a pharmaceutical
or diseases primarily affecting developing countries (e.g., malaria, schis- that is usually structurally similar to a drug already on the market. Other
tosomiasis, and other parasitic diseases) often come from taxpayers or names used are derivative medications, molecular modifications, and
wealthy philanthropists. follow-up drugs. In some cases, a me-too drug is a different molecule
Because development of new drugs is so expensive, private-sector developed deliberately by a competitor company to take market share
investment in pharmaceutical innovation has focused on products that from the company with existing drugs on the market. When the market
will have lucrative markets in wealthy countries such as the U.S., which for a class of drugs is especially large, several companies can share the
combines patent protection with a free-market economy. Accordingly, market and make a profit. Other me-too drugs result coincidentally from
there is concern about the degree to which U.S. and European patent pro- the simultaneous development of products by several companies with-
tection laws have restricted access to potentially lifesaving drugs in devel- out knowing which drugs will be approved for sale (Box 1–4). There are
oping countries. To lower costs, pharmaceutical companies increasingly
test their experimental drugs outside the U.S. and the E.U., in developing
countries where there is less regulation and easier access to large num- BOX 1–4 ■ A Not-So-New Drug
bers of patients. According to the U.S. DHHS, there has been a 2000% Some me-too drugs are only slightly altered formulations of a
increase in foreign trials of U.S. drugs over the past 25 years. When these company’s own drug, packaged and promoted as if really offering
drugs are successful in obtaining marketing approval, consumers in the something new. An example is the heartburn medication esomeprazole,
countries where the trials were conducted often cannot afford them. marketed by the same company that makes omeprazole. Omeprazole is
Some ethicists have argued that this practice violates the justice principle a mixture of two stereoisomers; esomeprazole contains only one of the
articulated in the Belmont Report (DHHS, 1979, p. 10), which states that isomers and is eliminated less rapidly. Development of esomeprazole
“research should not unduly involve persons from groups unlikely to be created a new period of market exclusivity, although generic versions
among the beneficiaries of subsequent applications of the research.” A of omeprazole are marketed, as are branded congeners of omeprazole/
counterargument is that the conduct of trials in developing nations also esomeprazole. Both omeprazole and esomeprazole are now available over
frequently brings needed medical attention to underserved populations. the counter—narrowing the previous price difference.
This is another controversial issue.

valid criticisms of me-too drugs. First, an excessive emphasis on profit investment in research and development grew 45-fold, from $2 bil- 19
may stifle true innovation. Second, some me-too drugs are more expen- lion to $91 billion. This disconnect between research and develop-
sive than the older versions they seek to replace, increasing the costs ment investment and new drugs approved occurred at a time when
of healthcare without corresponding benefit to patients. Nevertheless, combinatorial chemistry was blooming, the human genome was being
for some patients, me-too drugs may have better efficacy or fewer side sequenced, highly automated techniques of screening were being devel-
SECTION I
effects or promote compliance with the treatment regimen. For exam- oped, and new techniques of molecular biology and genetics were
ple, the me-too drug that can be taken once a day rather than more fre- offering novel insights into the pathophysiology of human disease. A
quently is convenient and promotes compliance. Some me-too drugs continued increase in productivity will be needed to sustain today’s
add great value from a business and medical point of view. For instance, pharmaceutical companies as they face waves of patent expirations.
atorvastatin was the seventh statin to be introduced to market; it sub- There are strong arguments that development of much more targeted,
sequently became the best-selling drug in the world. Critics argue that individualized drugs, based on a new generation of molecular diagnos-
pharmaceutical companies are not innovative and do not take risks and, tic techniques and improved understanding of disease in individual
GENERAL PRINCIPLES
further, that medical progress is actually slowed by their excessive con- patients, will improve both medical care and the survival of pharma-
centration on me-too products. ceutical companies. Many of the advances in genetics and molecular
Figure 1–7 summarizes a few of the facts behind this and other biology are still new, particularly when measured in the time frame
arguments. Clearly, only a modest number of new molecular entities required for drug development. Moreover, the techniques of computa-
(NMEs), about two dozen a year, achieved FDA approval between 1980 tional chemistry and computerized drug design described earlier in this
and 2016. In recent years (2017 through 2021), the annual number chapter are still advancing and being integrated into the process. One
of approved NMEs has averaged 38 (and approval of biologicals has can hope that modern molecular medicine will sustain the development
averaged 13 a year). Thus, there is a recent uptick in FDA-approved of more efficacious and more specific pharmacological treatments for
NMEs and BLAs. However, from 1980 to 2021, the industry’s annual an ever-wider spectrum of human diseases.
100 100
90 90
80 80
)
)
) or Biologicals (
70 70
PhRMA R&D expenditures (in billions) (

60 PDUFA 60
spike
50 50
Number of approved NMEs (
40 40
30 30
20 20
10 10
0 0
1980 1990 2000 2010 2020
Year
Figure 1–7 The cost of drug invention is rising. Is productivity rising accordingly? Tally includes enzymes, antibodies, peptides, and small molecules and excludes
vaccines and blood products. Sources: Center for Drug Evaluation and Research, 2022; Congressional Budget Office, 2021; McClung, 2021; Mullard, 2022.
20 Acknowledgment: Suzanne M. Rivera and Alfred Goodman Gilman Subjects of Biomedical and Behavioral Research. DHHS, Washington,
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Mullard A. Phosphatases start shedding their stigma of undruggability. Acids Res, 2015, 43:D204–D212.
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Chapter
2
PASSAGE OF DRUGS ACROSS MEMBRANE BARRIERS
Pharmacokinetics: The Dynamics of Drug
Absorption, Distribution, Metabolism,
and Elimination
Iain L. O. Buxton
■■ The Plasma Membrane Is Selectively Permeable

■■ A Few Principles of Metabolism and Elimination
■■ Prodrugs
■■ Modes of Permeation and Transport ■■ Pharmacogenetics
EXCRETION OF DRUGS
DRUG ABSORPTION, BIOAVAILABILITY, AND ROUTES OF
■■ Renal Excretion
ADMINISTRATION
■■ Biliary and Fecal Excretion
■■ Absorption and Bioavailability ■■ Excretion by Other Routes
■■ Routes of Administration
■■ Novel Methods of Drug Delivery CLINICAL PHARMACOKINETICS
■■ Clearance
BIOEQUIVALENCE ■■ Distribution
■■ Steady-State Concentration
DISTRIBUTION OF DRUGS ■■ Half-Life
■■ Not All Tissues Are Equal ■■ Extent and Rate of Absorption
■■ Binding to Plasma Proteins ■■ Nonlinear Pharmacokinetics
■■ Tissue Binding ■■ Design and Optimization of Dosage Regimens
METABOLISM OF DRUGS THERAPEUTIC DRUG MONITORING
The human body restricts access to foreign molecules; therefore, to reach oriented outward. Individual lipid molecules in the bilayer vary accord-
its target within the body and have a therapeutic effect, a drug molecule ing to the particular membrane and can move laterally and organize
must cross several restrictive barriers en route to its target site. Following themselves into microdomains (e.g., regions with sphingolipids and
administration, the drug must be absorbed and distributed, usually via cholesterol, forming lipid rafts), endowing the membrane with fluidity,
vessels of the circulatory and lymphatic systems. In addition to cross- flexibility, functional organization, high electrical resistance, and relative
ing membrane barriers, the drug must survive metabolism (primar- impermeability to highly polar molecules. Membrane proteins embed-
ily hepatic) and elimination (by the kidney and liver and in the feces). ded in the bilayer serve as structural anchors, receptors, ion channels,
ADME, the absorption, distribution, metabolism, and elimination of or transporters to transduce electrical or chemical signaling pathways
drugs, are the processes of pharmacokinetics (Figure 2–1). Understand- and provide selective targets for drug actions. Far from being a sea of
ing these processes and their interplay and employing pharmacokinetic lipids with proteins floating randomly about, membranes are ordered
principles increase the probability of therapeutic success and reduce the and compartmented (Banani et al., 2017; Kitamata et al., 2020) with
occurrence of adverse drug events and drug-drug interactions. structural scaffolding elements linking to the cell interior. Membrane
The absorption, distribution, metabolism, and excretion of a drug proteins may be associated with caveolin and sequestered within cave-
involve its passage across numerous cell membranes. Mechanisms by olae, excluded from caveolae, or organized in signaling domains rich in
which drugs cross membranes and the physicochemical properties of cholesterol and sphingolipids not containing caveolin or other scaffold-
molecules and membranes that influence this transfer are critical to ing proteins.
understanding the disposition of drugs in the human body. The char-
acteristics of a drug that predict its movement and availability at sites of Modes of Permeation and Transport
action are its molecular size (i.e., molecular weight) and structural fea- Passive diffusion dominates transmembrane movement of most drugs.
tures, degree of ionization, the relative lipid solubility of its ionized and However, carrier-mediated mechanisms (active transport and facilitated
nonionized forms, and its binding to serum and tissue proteins. Although diffusion) play important roles (Figure 2–2; Figure 4–4).
physical barriers to drug movement may be a single layer of cells (e.g.,
intestinal epithelium) or several layers of cells and associated extracellular
Passive Diffusion
In passive transport, the drug molecule usually penetrates by diffusion
protein (e.g., skin), the plasma membrane is the basic barrier.
along a concentration gradient by virtue of its solubility in the lipid bilayer.
Such transfer is directly proportional to the magnitude of the concentration
gradient across the membrane, to the lipid:water partition coefficient of the
Passage of Drugs Across Membrane Barriers drug, and to the membrane surface area exposed to the drug. At steady
state, the concentration of the unbound drug is the same on both sides of
The Plasma Membrane Is Selectively Permeable the membrane if the drug is a nonelectrolyte. For ionic compounds, the
The plasma membrane consists of a bilayer of amphipathic lipids with steady-state concentrations depend on the electrochemical gradient for
their hydrocarbon chains oriented inward to the center of the bilayer the ion and on differences in pH across the membrane, which will influ-
to form a continuous hydrophobic phase, with their hydrophilic heads ence the state of ionization of the molecule disparately on either side of
Brunton_Ch02_p0023-p0042.indd 23 29/07/22 9:39 AM
24
Abbreviations is the pH at which half the drug (weak acid or base electrolyte) is in its
ionized form. The ratio of nonionized to ionized drug at any pH may be
calculated from the Henderson-Hasselbalch equation:
ABC: ATP-binding cassette
ACE: angiotensin-converting enzyme [protonated form]
log = p K a − pH (Equation 2–1)
AUC: area under the concentration-time curve of drug [unprotonated form]
CHAPTER 2 PHARMACOKINETICS: THE DYNAMICS OF DRUG ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION
absorption and elimination

BBB: blood-brain barrier Equation 2–1 relates the pH of the medium around the drug and the
drug’s acid dissociation constant (pKa) to the ratio of the protonated (HA
CL: clearance
or BH+) and unprotonated (A− or B) forms, where
CNS: central nervous system
CNT1: concentrative nucleoside transporter 1 [A − ][H+ ]
Cp: plasma concentration HA ↔ A − + H+ , where K a =
[HA]
CSF: cerebrospinal fluid
Css: steady-state concentration describes the dissociation of an acid, and
CYP: cytochrome P450
F: bioavailability [B][H+ ]
BH+ ↔ B + H+ , where K a =
FDA: Food and Drug Administration [BH+ ]
GI: gastrointestinal
h: hours describes the dissociation of the protonated form of a base.
k: a rate constant At steady state, an acidic drug will accumulate on the more basic side
MDR1: multidrug resistance protein of the membrane and a basic drug on the more acidic side. This phenom-
MEC: minimum effective concentration enon, known as ion trapping, is an important process in drug distribution
min: minutes with potential therapeutic benefit and in management of the poisoned
PLLR: Pregnancy and Lactation Labeling Rule patient (Ornillo and Harbord, 2020). Figure 2–3 illustrates this effect and
SLC: solute carrier shows the calculated values for the distribution of a weak acid between
T, t: time the plasma and gastric compartments.
t1/2: half-life The effects of pH on transmembrane partitioning can be utilized to
V: volume of distribution alter drug excretion. In the kidney tubules, urine pH can vary over a wide
Vss: volume of distribution at steady state range, from 4.5 to 8. As urine pH drops (as [H+] increases), weak acids
(A–) and weak bases (B) will exist to a greater extent in their protonated
forms (HA and BH+); the reverse is true as pH rises, where A– and B will
be favored. Thus, alkaline urine favors excretion of weak acids; acidic
the membrane and can effectively trap ionized drug on one side of the
urine favors excretion of weak bases. Elevation of urine pH (by giving
membrane.
sodium bicarbonate) will promote urinary excretion of weak acids such
Influence of pH on Ionizable Drugs as aspirin (pKa ~3.5) and urate (pKa ~5.8). Another useful consequence
Many drugs are weak acids or bases that are present in solution as both of a drug being ionized at physiological pH is illustrated by the relative
the lipid-soluble, diffusible nonionized form and the ionized species that lack of sedative effects of second-generation histamine H1 antagonists
is relatively lipid insoluble and poorly diffusible across a membrane. (e.g., loratadine): Second-generation antihistamines are ionized molecules
Common ionizable groups are carboxylic acids and amino groups (pri- (less lipophilic, more hydrophilic) that poorly cross the BBB compared to
mary, secondary, and tertiary; quaternary amines hold a permanent pos- first-generation agents such as diphenhydramine, which are now used as
itive charge). The transmembrane distribution of a weak electrolyte is sleep aids. Also of note, most bacterial urinary tract infections cause the
influenced by its pKa and the pH gradient across the membrane. The pKa urine to become alkaline, potentially altering therapy (Huang et al., 2020).
TISSUE RESERVOIRS
bound free
THERAPEUTIC
UNWANTED SITE
SITE OF ACTION
OF ACTION
“Receptors”
CENTRAL bound free
bound free
COMPARTMENT
ABSORPTION CLEARANCE
DRUG [FREE DRUG]
DOSE
LIBERATION EXCRETION
protein bound metabolites

drug
BIOTRANSFORMATION
Figure 2–1 The interrelationship of the absorption, distribution, binding, metabolism, and excretion of a drug and its concentration at its sites of action. Possible
distribution and binding of metabolites in relation to their potential actions at receptors are not depicted.

ACTIVE TRANSPORT 25
PASSIVE TRANSPORT
Primary Secondary
Paracellular Diffusion Facilitated
Na+ X Na+ Y
transport diffusion K+
SECTION I
[Na+] ~ 140 mm
[K+] ~ 4 mm
+++ out
anti sym
––– in
ATP
[Na+] ~ 10 mm
[K+] ~ 150 mm
ADP Na+ X Na+ Y
GENERAL PRINCIPLES
+ K+
Pi
SLC ABC Na+,K+ - SLC co-transporters

transporter transporter ATPase
Figure 2–2 Drugs move across membrane and cellular barriers in a variety of ways. See details in Figures 4–1 through 4–4.
Carrier-Mediated Membrane Transport of heart failure (see Chapter 29). A group of primary active transporters,
Proteins in the plasma membrane mediate transmembrane movements of the ABC family, hydrolyze ATP to export substrates across membranes.
many physiological solutes; these proteins also mediate transmembrane For example, the P-glycoprotein, also called ABCB1 or MDR1, exports
movements of drugs and can be targets of drug action. Mediated trans- bulky neutral or cationic compounds from cells; its physiologic substrates
port is broadly characterized as facilitated diffusion or active transport include steroid hormones such as testosterone and progesterone. MDR1
(see Figure 2–2; Figure 4–4). Membrane transporters and their roles in exports many drugs as well, including digoxin, and a great variety of
drug response are presented in detail in Chapter 4. other agents (see Table 4–4). P-glycoprotein in the enterocyte limits the
absorption of some orally administered drugs by exporting compounds
Facilitated Diffusion. Facilitated diffusion is a carrier-mediated
into the lumen of the GI tract subsequent to their absorption (Gessner
transport process in which the driving force is simply the electro-
et al., 2019). ABC transporters perform a similar function in the cells of
chemical gradient of the transported solute; thus, these carriers can
the BBB, effectively reducing net accumulation of some compounds in the
facilitate solute movement either in or out of cells, depending on the
brain (see Chapters 4 and 17). By the same mechanism, P-glycoprotein
direction of the electrochemical gradient. The carrier protein may be
also can confer resistance to some cancer chemotherapeutic agents
highly selective for a specific conformational structure of an endoge-
(see Chapters 69–73).
nous solute or a drug whose rate of transport by passive diffusion
Members of the SLC superfamily can mediate secondary active trans-
through the membrane would otherwise be quite slow. For instance,
port using the electrochemical energy stored in a gradient (usually Na+)
the organic cation transporter OCT1 (SLC22A1) facilitates the move-
to translocate both biological solutes and drugs across membranes. For
ment of a physiologic solute, thiamine (Jensen et al., 2020), and drugs,
instance, the Na+/Ca2+ exchange protein (SLC8 or NCX) uses the energy
including metformin, which is used in treating type 2 diabetes. Chapter 4
stored in the Na+ gradient established by Na+/K+-ATPase to export cyto-
describes OCT1 and other members of the human SLC superfamily
solic Ca2+ and maintain it at a low basal level, about 100 nM in most
of transporters.
cells. SLC8 is thus an antiporter, using the inward flow of Na+ to drive an
Active Transport. Active transport is characterized by a direct require- outward flow of Ca2+. SLC8 also helps to mediate the positive inotropic
ment for energy, capacity to move solute against an electrochemical effects of digoxin and other cardiac glycosides that inhibit the activity of
gradient, saturability, selectivity, and competitive inhibition by cotrans- Na+/K+-ATPase and thereby reduce the driving force for the extrusion
ported compounds. Na+/K+-ATPase is an important example of an active of Ca2+ from the ventricular cardiac myocyte. Other SLC cotransport-
transport mechanism, which simultaneously exports three sodium ions ers are symporters, in which the driving force ion and solute move in
in exchange for two potassium ions using ATP as the energy substrate. the same direction. The CNT1 (SLC28A1), driven by the Na+ gradi-
Digoxin is an important Na+/K+-ATPase inhibitor used in the treatment ent, moves pyrimidine nucleosides and the cancer chemotherapeutic
agents gemcitabine and cytarabine into cells. DAT, NET, and SERT,
[1]
pKa = 4.4
[1000] 1001 = [HA] + [A–] transporters for the neurotransmitters dopamine, norepinephrine, and
– + serotonin, respectively, are secondary active transporters that also rely
HA A+H on the energy stored in the transmembrane Na+ gradient. These sym-
Plasma pH = 7.4 porters coordinate movement of Na+ and neurotransmitter in the same
direction (into the neuron). DAT, NET, and SERT are also the targets of
Lipid Mucosal Barrier CNS-active agents used to treat depression and/or anxiety. Members of
Gastric juice pH = 1.4 the SLC superfamily are active in drug transport in the GI tract, liver, and
kidney, among other sites, and play a significant role in drug disposition
[1] [0.001] 1.001 = [HA] + [A–] (Liu, 2019).
– +
HA A+H Paracellular Transport
Figure 2–3 Influence of pH on the distribution of a weak acid (pKa = 4.4) In the vascular compartment, paracellular passage of solutes and fluid
between plasma and gastric juice separated by a lipid barrier. A weak acid through intercellular gaps is sufficiently large that passive transfer across
dissociates to different extents in plasma (pH 7.4) and gastric acid (pH 1.4): the endothelium of capillaries and postcapillary venules is generally lim-
The higher pH facilitates dissociation; the lower pH reduces dissociation. The ited by blood flow. Evidence of this phenomenon can readily be seen in
uncharged form, HA, equilibrates across the membrane. Blue numbers in the dependent edema that forms in the ankles of heart failure patients.
brackets show relative equilibrium concentrations of HA and A−, as calculated Capillaries of the CNS and a variety of epithelial tissues have tight junc-
from Equation 2–1. tions that limit paracellular movement of drugs (Spector et al., 2015).
26 Factors modifying bioavailability also apply to prodrugs, in which case
Drug Absorption, Bioavailability, and Routes availability results from metabolic processes that produce the active form
of Administration of the drug.
Absorption and Bioavailability Routes of Administration

Some characteristics of the major administration routes employed for
CHAPTER 2 PHARMACOKINETICS: THE DYNAMICS OF DRUG ABSORPTION, DISTRIBUTION, METABOLISM, AND ELIMINATION
Absorption is the movement of a drug from its site of administration

into the central compartment (e.g., bloodstream; see Figure 2–1). For systemic drug effect are compared in Table 2–1.
solid dosage forms, absorption first requires dissolution of the tablet or Oral Administration
capsule, thus liberating the drug. Except in cases of malabsorption syn- Oral ingestion is the most common method of drug administration. It
dromes, the clinician is concerned primarily with bioavailability rather also is the safest, most convenient, and most economical. Its disadvan-
than absorption (Tran et al., 2013). tages include limited absorption of some drugs because of their physical
Bioavailability describes the fractional extent to which an adminis- characteristics (e.g., low water solubility or poor membrane permeabil-
tered dose of drug reaches its site of action or a biological fluid (usually ity), emesis as a result of irritation to the GI mucosa, destruction of some
the systemic circulation) from which the drug has access to its site of drugs by digestive enzymes or low gastric pH, irregularities in absorp-
action. A drug given orally must be absorbed first from the GI tract, tion or propulsion in the presence of food or other drugs, and the need
but net absorption may be limited by the characteristics of the dosage for cooperation on the part of the patient. In addition, drugs in the GI
form, by the drug’s physicochemical properties, by metabolic attack tract may be metabolized by the enzymes of the intestinal microbiome,
in the intestine, and by transport across the intestinal epithelium and mucosa, or liver before they gain access to the general circulation. The
into the portal circulation. The absorbed drug then passes through gut microbiome comprises over 1000 species; its alteration may impact
the liver, where metabolism and biliary excretion may occur before the disease progression and therapeutic outcomes (see Chapter 6 and
drug enters the systemic circulation. Accordingly, less than all of the Ding et al., 2020).
administered dose may reach the systemic circulation and be distrib- Absorption from the GI tract is governed by factors such as surface
uted to the drug’s sites of action. If the metabolic or excretory capacity area for absorption; blood flow to the site of absorption; the physical state
of the liver and the intestine for the drug is large, bioavailability will be of the drug (solution, suspension, or solid dosage form); its aqueous sol-
reduced substantially (first-pass effect). This decrease in availability is ubility; and the drug’s concentration at the site of absorption. For drugs
a function of the anatomical site from which absorption takes place; given in solid form, the rate of dissolution may limit their absorption.
for instance, intravenous administration generally permits all of a drug Because most drug absorption from the GI tract occurs by passive dif-
to enter the systemic circulation. Other anatomical, physiological, and fusion, absorption is favored when the drug is in the nonionized, more
pathological factors can influence bioavailability (described further in lipophilic form. Based on the pH-partition concept (see Figure 2–3), one
this chapter), and the route of drug administration should be chosen would predict that drugs that are weak acids would be better absorbed
based on an understanding of these conditions. We can define bioavail- from the stomach (pH 1–2) than from the upper intestine (pH 3–6), and
ability F as: vice versa for weak bases. However, the surface area of the stomach is
relatively small, and a mucus layer covers the gastric epithelium. By con-
Quantity of drug reaching systemic circulation trast, the villi of the upper intestine provide an extremely large surface area
F= (Equation 2–2)
Quantity of drug administered (~200 m2). Accordingly, the rate of absorption of a drug from the intestine
will be greater than that from the stomach even if the drug is predom-
where 0 < F ≤ 1. inantly ionized in the intestine and largely nonionized in the stomach.
TABLE 2–1 ■ SOME CHARACTERISTICS OF COMMON ROUTES OF DRUG ADMINISTRATIONa

ROUTE AND
BIOAVAILABILTY (F) ABSORPTION PATTERN SPECIAL UTILITY LIMITATIONS AND PRECAUTIONS
Intravenous Absorption circumvented Valuable for emergency use Increased risk of adverse effects
F = 1 by definition Potentially immediate effects Permits titration of dosage Must inject solutions slowly as a rule
Suitable for large volumes and for Usually required for high-molecular- Not suitable for oily solutions or poorly
irritating substances, or complex weight protein and peptide drugs soluble substances
mixtures, when diluted
Subcutaneous Prompt from aqueous solution Suitable for some poorly soluble Not suitable for large volumes
0.75 < F < 1 suspensions and for instillation of slow-
release implants
Slow and sustained from Possible pain or necrosis from irritating
repository preparations substances
Intramuscular Prompt from aqueous solution Suitable for moderate volumes, oily Precluded during anticoagulant therapy
0.75 < F < 1 vehicles, and some irritating substances
Slow and sustained from Appropriate for self-administration (e.g., May interfere with interpretation of
repository preparations insulin) certain diagnostic tests (e.g., creatine
kinase)
Oral ingestion Variable, depends on many Most convenient and economical; usually Requires patient compliance
0.05 < F < 1 factors (see text) safer
Bioavailability potentially erratic and
incomplete
See text for more complete discussion and for other routes.
a

Thus, any factor that accelerates gastric emptying (recumbent position indiscriminate diffusion of molecules regardless of their lipid solubility. 27
right side) will generally increase the rate of drug absorption, whereas Larger molecules, such as proteins, slowly gain access to the circulation
any factor that delays gastric emptying will have the opposite effect. by way of lymphatic channels. Drugs administered into the systemic cir-
The gastric emptying rate is influenced by numerous factors, including culation by any route, excluding the intra-arterial route, are subject to
the caloric content of food; volume, osmolality, temperature, and pH of possible first-pass elimination in the lung prior to distribution to the rest
SECTION I
ingested fluid; diurnal and interindividual variation; metabolic state (rest of the body. The lungs also serve as a filter for particulate matter that
or exercise); and the ambient temperature. Gastric emptying is influenced may be given intravenously and provide a route of elimination for volatile
in women by the effects of estrogen (i.e., compared to men, emptying is substances.
slower for premenopausal women and those taking estrogen replacement Intravenous. Factors limiting absorption are circumvented by intra-
therapy). venous injection of drugs in aqueous solution because bioavailability is
Drugs that are destroyed by gastric secretions and low pH or that cause complete (F = 1.0) and distribution is rapid. Also, drug delivery is con-
gastric irritation sometimes are administered in dosage forms with an trolled and achieved with an accuracy and immediacy not possible by
GENERAL PRINCIPLES
enteric coating that prevents dissolution in the acidic gastric contents. any other procedures. Certain irritating solutions can be given only in
Enteric coatings are useful for drugs that can cause gastric irritation and this manner because the drug, when injected slowly, is greatly diluted by
for presenting a drug such as mesalamine to sites of action in the ileum the blood.
and colon (see Figure 55–4). There are advantages and disadvantages to intravenous administra-
Controlled-Release Preparations. The rate of absorption of a drug tion. Unfavorable reactions can occur because high concentrations of
administered as a tablet or other solid oral dosage form is partly depen- drug may be attained rapidly in plasma and tissues. There are therapeu-
dent on its rate of dissolution in GI fluids. This is the basis for con- tic circumstances for which it is advisable to administer a drug by bolus
trolled-release, extended-release, sustained-release, and prolonged-action injection (e.g., tissue plasminogen activator) and other circumstances
pharmaceutical preparations that are designed to produce slow, uniform where slower or prolonged administration of drug is advisable (e.g., anti-
absorption of the drug for 8 h or longer. Potential advantages of such biotics). Intravenous administration of drugs warrants careful determi-
preparations are reduction in the frequency of administration compared nation of dose and close monitoring of the patient’s response; once the
with conventional dosage forms (often with improved compliance by the drug is injected, there is often no retreat. Repeated intravenous injections
patient), maintenance of a therapeutic effect overnight, and decreased depend on the ability to maintain a patent vein. Drugs in an oily vehi-
incidence and intensity of undesired effects (by dampening of the peaks cle, those that precipitate blood constituents or hemolyze erythrocytes,
in drug concentration) and nontherapeutic blood levels of the drug (by and drug combinations that cause precipitates to form must not be given
elimination of troughs in concentration) that often occur after admin- intravenously.
istration of immediate-release dosage forms. Controlled-release dosage
Subcutaneous. Injection into a subcutaneous site can be done only
forms are most appropriate for drugs with short half-lives (t1/2 <4 h) or
with drugs that are not irritating to tissue; otherwise, severe pain, necro-
in select patient groups, such as those receiving antiepileptic or antipsy-
sis, and tissue sloughing may occur. The rate of absorption following
chotic agents (Bera, 2014). Women have also benefited from long-acting
subcutaneous injection of a drug is generally constant and slow, provid-
hormonal contraception produced by implanted (Friend, 2016) or oral
ing a sustained effect. Moreover, altering the period over which a drug is
(Conley et al., 2006) controlled-release devices.
absorbed may be varied intentionally, as is accomplished with insulin for
Sublingual Administration. Absorption from the oral mucosa has spe- injection using particle size, protein complexation, and pH. The incor-
cial significance for certain drugs despite the fact that the surface area poration of a vasoconstrictor agent in a solution of a drug to be injected
available is small. Venous drainage from the mouth directly enters the subcutaneously also retards absorption. Absorption of drugs implanted
superior vena cava, thus bypassing the portal circulation. As a conse- under the skin in a solid pellet form occurs slowly over a period of weeks
quence, a drug held sublingually and absorbed from that site is protected or months; some hormones (e.g., contraceptives) are administered effec-
from rapid intestinal and hepatic first-pass metabolism. For example, tively in this manner.
sublingual nitroglycerin (see Chapter 31) is rapidly effective because it
is nonionic, has high lipid solubility, and is not subject to the first-pass Intramuscular. Absorption of drugs in aqueous solution after intra-
effect prior to reaching the heart and regions of the circulatory system muscular injection depends on the rate of blood flow to the injection site
where nitroglycerin acts to relieve myocardial ischemia. and can be relatively rapid. Absorption may be modulated to some extent
by local heating, massage, or exercise. Generally, the rate of absorption
Parenteral Injection following injection of an aqueous preparation into the deltoid or vastus
Parenteral (i.e., not via the GI tract) injection of drugs has distinct advan- lateralis is faster than when the injection is made into the gluteus max-
tages over oral administration. In some instances, parenteral administra- imus. The rate is particularly slower for females after injection into the
tion is essential for delivery of a drug in its active form, as in the case of gluteus maximus, a feature attributed to the different distribution of sub-
monoclonal antibodies and vaccine formulations. Availability is usually cutaneous fat in males and females and because fat is relatively poorly
more rapid, extensive, and predictable when a drug is given by injection; perfused. Slow, constant absorption from the intramuscular site results
the effective dose can be delivered more accurately to a precise dose; this if the drug is injected in solution in oil or suspended in various other
route is suitable for the loading dose of medications prior to initiation of repository (depot) vehicles.
oral maintenance dosing (e.g., digoxin). In emergency therapy and when
a patient is unconscious, uncooperative, or unable to retain anything
Intra-arterial. Occasionally, a drug is injected directly into an artery
to localize its effect in a particular tissue or organ, such as in the treat-
given by mouth, parenteral therapy may be necessary. Parenteral admin-
ment of liver tumors and head and neck cancers. Diagnostic agents
istration also has disadvantages: Asepsis must be maintained, especially
sometimes are administered by this route (e.g., technetium-labeled
when drugs are given over time (e.g., intravenous or intrathecal admin-
human serum albumin). Inadvertent intra-arterial administration can
istration); pain may accompany the site of injection; and it is sometimes
cause serious complications and requires careful management (Ellis
difficult for patients to perform the injections themselves if self-medication
et al., 2015).
is necessary.
The major routes of parenteral administration are intravenous, sub- Intrathecal. The BBB and the blood-CSF barrier often preclude
cutaneous, and intramuscular. Absorption from subcutaneous and intra- or slow the entrance of drugs into the CNS, reflecting the activity of
muscular sites occurs by simple diffusion along the gradient from drug P-glycoprotein (MDR1) and other transporters to export xenobiotics from
depot to plasma. The rate is limited by the area of the absorbing capillary the CNS. Therefore, when local and rapid effects of drugs on the meninges
membranes and by the solubility of the substance in the interstitial fluid. or cerebrospinal axis are desired, as in spinal anesthesia, drugs sometimes
Relatively large aqueous channels in the endothelial layer account for the are injected directly into the spinal subarachnoid space. Brain tumors or
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cases collected by Mouchet, 3 ended in recovery. Another success
has been recently recorded by Turretta. The écraseur has been
used, but its employment cannot be recommended. Compression by
clamps is advised by Schatz of Rostock. Ligation is best adapted to
cases occurring in the cervical and dorsal regions, in which, as
pointed out by Giraldès, nerve-elements are less likely to be
involved. Excision, supplemented by transplantation of a strip of
periosteum from a rabbit, has been successfully resorted to by
Mayo-Robson and by R. T. Hayes of Rochester, N. Y.; and simple
excision, with suture in separate lines of the sac and integuments, by
Mayo-Robson, Atkinson, and Jessop. The Clinical Society's
committee in all refers to 23 cases treated by excision, 16 of which
are said to have been successful.
ANÆMIA AND HYPERÆMIA OF THE BRAIN AND

SPINAL CORD.
BY E. C. SPITZKA, M.D.
Cerebral Hyperæmia.
Up to within a few years it was a favorite mode of explaining the
results of the administration of certain narcotic and stimulant drugs,
and certain of the active symptoms of mental derangement, to
attribute them to an increased blood-supply of the nerve-centres.
This view seemed to harmonize so thoroughly with the physiological
dictum that functional activity depends on the supply of oxygenated
blood that the first attempts at questioning it were treated as
heresies. To-day, however, few authorities can be found to adhere
unreservedly to this once-popular and easy explanation. The drift of
physiological and medical opinion is in the direction of regarding
some subtle molecular and dynamic state of the nerve-elements as
the essential factor in intoxications as well as in maniacal and other
forms of insane excitement: if they be complicated by active or
passive congestions, this is probably a secondary occurrence of
modifying but not of intrinsic determining power. While this change in
our views is the natural result of progress in experimental
pharmacology and pathology, it does not justify the extreme
assertion that there is no disorder of the brain functions deserving
the name of congestion and hyperæmia. This assertion seems to
have been provoked by the careless manner in which these terms
have been employed to designate conditions which are in reality the
most different in nature that can be well conceived. No one familiar
with the extent to which the term “congestion of the base of the
brain” has been abused in this country will marvel that the reaction
provoked by it has overstepped the boundaries of cautious criticism.
That there are physiological hyperæmias of the brain is now
universally admitted; the most recent experimental observations,
indeed, conform most closely to the claims of the older investigators.
It naturally follows that pathological hyperæmias are both possible
and probable, and even if the observations in the dead-house do not
strongly sustain the existence of pathological hyperæmias and
congestions independently of gross disease, clinical analysis and the
gratifying results of appropriate treatment justify us in retaining these
designations in our nomenclature with the limitation here implied.
One great difficulty in determining the precise nature of the disorders

which the physician is called upon to treat on the theory of
hyperæmia lies in the number of factors which may contribute to or
modify its development. If, for example, the action of the heart be
increased through hypertrophy, the result to the cerebral circulation
will obviously be different in a plethoric and in an anæmic person; it
will be also very much different in the event of the stimulation of the
centres which contract the calibre of the cerebral blood-vessels from
what it would be if there were a state of vascular relaxation. Should
the cardiac hypertrophy be associated with renal disease, other
disturbing elements may be introduced, such as arterio-fibrosis, or
the presence in the blood of certain toxic substances having direct
effects of their own on the nerve-elements. The picture may be still
more complicated by variations in the intracranial pressure. It is
impossible to prove, either by direct or indirect evidence, that there is
such a pathological state as a simple cerebral hyperæmia; indeed,
there is one fact which militates strongly against, if it be not fatal to,
such an assumption. Were a physiological hyperæmia to become
intensified to a pathological degree, we should have corresponding
clinical phenomena. In other words, the culmination of the morbid
process should be preceded by an exaggerated physiological
excitation similar to that observed with intoxications. But this is rarely
the case, and we accordingly find that the more cautious writers, like
Nothnagel,1 do not commit themselves to the view that the results of
mental overstrain2 are to be classed as simple cerebral hyperæmia.
Similar restrictions are to be made regarding the established
congestive states, such as those following sunstroke. It has been
usually supposed that insolation directly produces cerebral
hyperæmia, even to the degree of engorgement, and that the after
symptoms in persons who recover are due to the non-return of the
meningeal and cerebral blood-vessels to their normal calibre, and to
other more remote results of vascular stasis. The latter half of this
proposition is in part correct; the former is contradicted by numerous
pathological observations. Thus, Arndt,3 who had the opportunity of
studying over one hundred cases occurring in the course of a forced
march of a division of infantry from Berlin to Pankow, many of which
terminated fatally, found almost uniformly a pale brain, with peculiar
color-changes, denoting rather structural than circulatory trouble.4
The whole list of causes of what is commonly designated cerebral
hyperæmia, congestion, and engorgement may be gone through
with and similar modifying statements be found to apply to them. The
nearest approach to an ideal cerebral congestion is that found with
acute alcoholic intoxication. This is at first accompanied by cerebral
hyperæmia, which, with the comatose climax, becomes an
engorgement; accordingly, many of the results of acute alcoholic
intoxication are attributed to the circulatory condition alone. The
congestive troubles due to alcoholism which come to the special ken
of the physician, however, are those found with the chronic form, and
here a more complex pathological condition is found to underlie it;
the organization of the brain is altered, the vascular channels more
or less diseased, and the vaso-motor mechanism continuously
deranged. This disorder, as well as the apoplectiform states
attributed to vascular stasis, and the active and passive hyperæmias
associated with tumors, meningitic and other gross diseases of the
brain, as well as with the status epilepticus, are usually included in
the discussion of cerebral congestion, and serve to swell up the
chapters devoted to it. They will be found discussed in more
appropriate situations in this volume. In this place it is proposed to
consider only those congestive states which present themselves to
the physician, independently of conditions which, if associated,
preponderate in clinical and therapeutic importance.5
1 Ziemssen's Cyclopædia, “Nervous System,” i. p. 39, 2d German ed.
2 It has repeatedly happened during the past decade that young persons competing
for admission to higher institutions of learning in New York City through the channel of
a competitive examination died with symptoms of cerebral irritation; the death
certificates in several such cases assigned meningitis or cerebral congestion as the
cause of death, and attributed the disorder to mental overstrain. It is not so much the
intellectual effort that has proved hurtful to the pupils as the emotional excitement
attending on all competitive work, the dread of failure, the fear of humiliation, and
anxiety developed by the evident futility of the cramming process. Some years ago I
recorded the results of some inquiries on this head in the following words: “The
mental-hygiene sensationalists, who periodically enlighten the public through the
columns of the press whenever an opportune moment for a crusade against our
schools and colleges seems to have arrived, are evidently unaware of the existence
of such a disease as delirium grave, and ignorant of the fact that the disorder which
they attribute to excessive study is in truth due to a generally vitiated mental and
physical state, perhaps inherited from a feeble ancestry. Our school system is
responsible for a good deal of mischief, but not for meningitis” (Insanity, its
Classification, Diagnosis, and Treatment). Since then I had an opportunity of obtaining
an excellent description of such a case which had been attributed to the combined
effects of malaria and educational overstrain, presenting opisthotonos, fulminating
onset, and an eruption!
3 Virchow's Archiv, lxiv.
4 The observations of Gärntner (Medicinische Jahrbucher, 1884, 1) harmonize with

this. He found that radiant heat contracts the blood-vessels of the frog's mesentery.
5 The same applies to conditions which are discussed under this head in textbooks,
although they have either only a medico-legal bearing or are inconstant factors, such
as the injection of the brain in death from strangulation. I need but instance the
vascular condition of brains of criminals executed by hanging. In the case of one
where the strangulation had been slow I found an engorgement of all the vessels and
arachnoidal as well as endymal hemorrhages; in a second, where the criminal had
been carried half fainting to the drop, and death ensued quickly and without signs of
distress, the brain was decidedly anæmic.
It has been also considered best to omit treating of the collateral hyperæmia of the
brain sometimes found with erysipelas of the face and scalp. This I regard as
essentially of the same nature as the metastatic meningitis of erysipelas, if it be not in
reality a first stage of the latter.
ETIOLOGY.—An individual predisposition to cerebral congestion was

one of the unquestioned facts of the older medical writers. It
undoubtedly exists, and to-day we attribute it to inherited vascular
conditions either affecting the calibre and coats of the blood-vessels
or the vigor of the vaso-motor apparatus. I have remarked the
transmission of that weakness of the latter which underlies the
congestive phenomena of later life much more frequently in the
female than in the male sex.
It has been claimed that external refrigeration produces hyperæmia
of the brain, as of other internal organs, and that this accounts for
the greater frequency of the disorder in cold weather. Niemeyer
indeed speaks of persons who, suffering from this condition, appear
and act in such a way as to convince the laity that they are
intoxicated; and Andral, Falret, and Hammond note the occurrence
of a much larger number of cases in the winter than in the summer
months. I apprehend that the condition described by Niemeyer must
be extremely uncommon, both from individual experience and the
rarity of its mention as an independently observed fact. With regard
to the alleged greater frequency of the disorder in winter, it must be
remembered that all the three observers cited include in their
computation a number of cases in which congestion was a collateral
feature; they did not limit themselves to the disorder as spoken of
here. Certainly, the physician will see few if any persons who consult
him because of the hyperæmia-producing effects of a cold day.
The suppression of habitual discharges, of the hemorrhoidal flux,

and the cessation of menstruation are associated in many instances
with the more formidable grades of cerebral hyperæmia. Many
phenomena of so-called climacteric insanity depend on congestive
states. The sudden closure of an old ulcer or the removal of
hemorrhoids in advanced life has in some well-established instances
provoked alarming seizures not unlike those noted with paretic
dementia. The chain of proof establishing the direct influence of
physiological and pathological discharges on the vascular controlling
apparatus of the brain is most complete. Not alone cumulative
clinical observation, but the occasional happy result of therapeutical
procedure based on this supposed interdependence, support it.
Thus, the congestive cerebral state is recovered from when the
menstrual or hemorrhoidal flow is re-established, or an issue is
formed in the nape of the neck, or an old ulcer is allowed to reopen.6
6 The treatment of paretic dementia, particularly of the congestive type, is also based
on this relation. The irritating antimonial ointment and issues in the nape of the neck,
etc. have been lauded by older observers, and in two of my own cases had the best
results—in one, indeed, with established restitutio ad integrum of now nearly two
years' duration. I am inclined to suppose that its abandonment is due to an improper
selection of cases; in the ordinary premature senility and syphilitic types such
treatment is altogether ineffective. It is applicable to but a minority of cases at best,
and to them only at an early period. It is probably to a similar form of congestion that
Bouchut refers when (“Les Nèvroses congestives de l'Encéphale,” Gazette des
Hôpitaux, 1869) he speaks of a cerebral hyperæmia developing under the mask of a
meningitis—an expression that may be allowed if understood in the same sense as
the comparison between hydrocephaloid and hydrocephalus.
The origin of most cases that are brought to the physician's attention
is more or less complicated. A business-man, lawyer, or student
suffering from worry incident to his profession, living so irregularly as
to provoke gastric disturbances, becomes afflicted with insomnia,
and in addition is also constipated. Straining at stool, he finds a dull,
heavy sensation affecting the upper part of his head; attempting to
resume his work, this is aggravated, and after a series of temporary
remissions the condition to be later described becomes continuous.
In such a case the insomnia, usually due to neural irritability, if not
aggravated by an existing dyspepsia, leads to such a one, and a
circulus vitiosus familiar to all physicians is established. Each of the
factors concerned involves strain of the cerebral vaso-motor
apparatus, but none more so than the insomnia. It is not so much the
intensity of the strain as its long duration and the exhaustion of the
centre which in sleep is supposed to be at comparative rest. This
rest is not obtained, and, in conformity to the laws of neural
exhaustion, that centre becomes morbidly irritable. Now, gastric
irritation is competent to produce a reflex influence on even the
healthy cerebral organ; to do so it must be a severe one; but with the
class of persons alluded to the slightest indiscretion in food or drink
is sufficient to set up reflex vertigo or headache. The current theory
regarding these symptoms is that they are due to stimulation of the
vaso-constrictors and ensuing cerebral anæmia; but the subjects
before us will usually be found to flush up instead of becoming pale,
as in simple vertigo a stomacho læso, or if there be initial paleness,
there is a secondary flush, as if the tired arterial muscle had become
exhausted by the effort at obeying the reflex stimulus. In addition, a
profuse perspiration sometimes breaks out on the upper part of the
body.
The influence of traumatic causes and insolation in producing a

tendency to repeated and severe cerebral congestion is recognized,
particularly among alienists. It is supposed that an abnormal
irritability of the vaso-motor apparatus is provoked by these causes.
Abundant evidences are sometimes found in the brains of such
persons of an altered state of nutrition of the brain and its
membranes, and which point in the direction of congestion.
In the conditions thus far alluded to it can be fairly assumed that the
determination of blood to the cerebral blood-vessels is more or less
active. Passive congestion due to impeded return circulation is of
secondary interest, as the primary disease, be it a pertussis or a
laryngeal, cardiac, pulmonary, or surgical condition, will constitute
the main object of recognition and management. Certain quasi-
physiological acts, as coughing, hurried breathing, holding the breath
while straining at stool, and placing the head in a dependent position
while acting in the direction of passive hyperæmia, are to be
considered in connection with the active forms of congestion which
they may momentarily aggravate.
MORBID ANATOMY.—Owing to the non-fatality of the commoner forms

of cerebral hyperæmia, no pathological observations of them are at
our disposal, nor can we assume from analogy that the appearances
would be well marked if they could be made. What little knowledge
we have is derived from a study of more serious conditions of which
cerebral hyperæmia is an initial, collateral, or episodial feature.
In pronounced cerebral hyperæmia the entire brain is, as it were,

tumefied, so that the dura appears tensely stretched over its surface
and the gyri are flattened; both the meningeal vessels proper and
those of the pia are injected. According as the hyperæmia is active
or passive the color of this injection varies, being of a brighter red in
the former, of a purple or bluish color in the latter case. The purest
instances of active cerebral hyperæmia which I have seen were
found in patients dying in the apoplectiform phases of paretic
dementia (progressive paralysis of the insane). Here the cortex on
section exhibited a beautiful rosy tint, which was distributed in darker
and lighter strata in correspondence with the distributional areas of
the short and the long cortical arteries; there were numerous puncta
vasculosa both in the cortex and in the white substance, and in some
instances the arachnoid or the ventricular fluid was tinged with blood,
albeit no vascular rupture could be discovered. The red blood-
corpuscles undoubtedly escape by diapedesis from the surface as
well as the endymal vessels; the same thing occurs in the
intracerebral blood-vessels, whose adventitial spaces are often
crowded with accumulations of red blood-discs, while groups or
single ones are found scattered in the surrounding parenchyma, and
even in the periganglionic spaces. Occasionally accumulations of
pigment found near the vascular channels remain to attest the
former existence of other hyperæmias, and indeed slight
accumulations of this kind are found in the brains of most persons
who have reached adult life. These are to be regarded as remnants
of the physiological hyperæmias to which all active individuals are
subject. It is only when the accumulations become considerable and
numerous, as in the chronic insane, or are associated with those
changes in the blood-vessels which are discussed in the articles on
thrombotic and hemorrhagic cerebral disease, that they can be
regarded as indications of a pathological condition.
Acute simple meningitis is ushered in by cerebral hyperæmia of the

active form. This is not alone demonstrated by the early symptoms of
this disease, but also by the fact, which I have observed in two
cases, that where this form of meningitis originates on one side, as
from extension of the middle-ear trouble, the opposite cerebral
hemisphere exhibited intense congestion of the ideal type.
In that serious form of mental disease known variously as grave or

acute delirium and typhomania (Luther Bell) a form of cerebral
hyperæmia is observed which in its intensity approximates
inflammatory congestion. The surface of the brain appears marbled
and mottled; blood seems to exude from the gyri after the pia is
removed; the cortical lamination is invisible, owing to the hyperæmic
discoloration of the gray substance; and the parenchymatous
elements themselves appear to be in a state of cloudy swelling. In
one case I have observed transudation of a hyaline proteinaceous
substance and an exudation of fibrin around the larger arterioles. In
some cases of typhus fever a less intense but similar congestive
hyperæmia is found. The hyperæmias of paretic dementia, of acute
delirium, and of typhus fever agree in this one feature: that all
districts of the brain, from the cortex and white substance of the
cerebral hemispheres to the medulla oblongata, are involved nearly
to the same degree. In the hyperæmia of simple meningitis of the
convexity it is chiefly confined to the pia mater and the most
superficial cortical strata.
Congestion of the brain from stagnation of the venous return

circulation should not be confounded with active hyperæmia. With
this condition, which may be due to thrombosis of the sinuses,
morbid growths near the jugular foramen or in the neck around the
internal jugular veins, or, finally, to certain cardiac and pulmonary
disorders, there is rather a lesser than a greater amount of blood
sent to the brain; and it is not infrequently found that while the
surface of the brain appears congested, owing to the prominence of
the cerebral veins, the deeper parts are quite anæmic; and if the
injection be general, it will be found that the blood, whether in
arteries or veins, has the venous character. An excellent example of
this form of congestion is afforded by persons dying in the status
epilepticus. In their brains the venous channels stand out, filled to
their extreme capacity with blood almost black in color; and in
prepared sections, particularly such as are taken from the pons and
medulla oblongata, a beautiful natural injection of the vessels is
found. But that rosy color which is so characteristic of active
hyperæmia is absent, the tissues appearing purplish, bluish, or
chocolate-colored.
SYMPTOMATOLOGY.—There are few symptoms attributable to the

nervous system which have not been enumerated among the
characteristics or the occasional manifestations of cerebral
hyperæmia. Thus, Hammond not only follows Andral in enumerating
apoplectic, convulsive, comatose, and maniacal symptoms as acute
manifestations of active cerebral congestion, but assures us that
aphasia may occur under the same circumstances. In the course of
his work on the subject, “an absolute want of power to get correct
ideas of even simple matters,” confusion of ideas, weakening of the
judgment, vacillation of purpose, diminished logical power, illusions
and hallucinations of every sense, delusions, morbid apprehension
of impending evil, imperative, suicidal, and other impulses,
suspicion, hypochondriasis, furious delirium, and the use of profane
and obscene language, are enumerated among the characteristic or
prominent symptoms of various forms and cases of cerebral
hyperæmia.7 Not one but several of the recognized forms of insanity
have yielded a fair quota of their symptoms to this long array. Among
somatic signs he in like manner names neuralgic pains, numbness,
spasms, paralysis, false impotence, hyperæmia of the tympanum,
choked disc, abolition or perversion of the sense of smell, taste, and
sight, fibrillary or fascicular twitches, various states of the urinary
excretions, diplopia, and monoplegias. It is here equally evident that
the initial symptoms of a considerable number of organic and clearly
defined affections have been included. It is on account of the
confusion engendered by this wide interpretation of the meaning of
the term congestion of the brain that I have determined to limit the
term as previously indicated, and to consider only the active form
here.
7 A Treatise on the Diseases of the Nervous System, 7th ed., pp. 1-53. The natural
inference following a perusal of this chapter, as well as the monographs to which their
author refers, is that he has gathered together all states in which cerebral hyperæmia
was an associated factor, as well as those in which he appears to assume its
existence on theoretical grounds, and designated them as cerebral congestion. In
some instances he uses the terms hypochondria and cerebral hyperæmia
interchangeably (p. 50, loc. cit.).
A feeling of head-pressure, associated with a more or less severe

dull pain, aggravated by mental exertion, by stooping down, by
straining at stool, or when out of breath, and accompanied by a
subjective sense of mental dulness, is the most constant feature of
the ordinary cases. There is usually a vertiginous sensation, and an
irritability of the eye and ear not unlike that described in the article on
Cerebral Anæmia. Sleep is at first disturbed by vivid and sometimes
frightful dreams; later, it becomes interrupted, and ultimately
complete insomnia may develop. The action of the heart is
accelerated and exaggerated in some cases; in that event increased
pulsation of the carotids, flushing of the face, injection of the
conjunctiva, and a subjective sense of heat in the head and face are
experienced. Hammond, in accord with Hasse and Krishaber,
believes that febrile symptoms may develop under these
circumstances; most authorities, however, deny this for the
uncomplicated form. I have never found an objective rise of the
general temperature.
Such a condition as that described is usually slowly produced,

several weeks, or even months, being occupied in its development.
At first the unpleasant symptoms occur only at certain hours of the
day, with temporary exacerbations and remissions. It may be
arrested with comparative ease at any time; if neglected, the mental
faculties become affected, not in the grave sense in which Hammond
and the older authors describe it, so as to carry the patient into
actual dementia or delusional insanity, but rather in the way of
diminished working-power. It is more difficult to fix attention, to
recollect words, names, and figures, or to keep up a protracted
mental effort, than in health, but the formal judgment does not suffer.
I have known patients to be in this condition for many months, and
several for more than one year, without any grave deterioration. It is
true that in the prodromal periods of some forms of insanity, such as
acute mania, there is a condition very similar to that of these
patients; and this has led to regarding mania as a possible phase of
cerebral hyperæmia. But the very fact that, typically, mania is
preceded by such a stage—which is always of brief duration—that
maniacal excitement is a constant and unavoidable consequence
upon it, while, as far as known, the condition here described may last
for years without leading to a true psychosis, should prevent one
regarding the two conditions as identical, however similar they may
be for the time being.
In sufferers from cerebral hyperæmia who pass into the chronic state
of this disorder the disturbance of sleep and of the digestive organs
becomes very prominent, and continually reinforces the acting
causes of the disorder. In a large number of cases the head-
sensations become more or less localized; that is, while the general
feeling of pressure or dull ache may continue, a special area, which
can be covered by the palm of one hand, either in the middle part or
to one side—usually the left—of that part of the vertex, is the seat of
a more severe pain, complained of as a hot pressure. The patients
frequently claim that the temperature is higher at this spot, and,
contrary to what might be anticipated on a priori grounds, the
statement will be confirmed, not alone by the coarse method of using
the hand, but by the surface thermometer. The locality where this
occasional rise of temperature and the more common sense of
pressure are experienced corresponds to that part of the longitudinal
sinus where the largest cerebral veins enter. It is a noteworthy fact
that nearly all the important admunctories of this sinus empty into it
within the short space of two inches at this point.
Not all sufferers from cerebral hyperæmia give a history of a gradual

development of their symptoms. A few date their trouble from some
single intellectual, physical, or emotional strain. In one case,
complicated by marked evidences of cerebro-spinal exhaustion, the
patient, a lady, had during an illness of her husband, being deserted
by her servants, and the water-supply having been cut off, carried all
the water required for the invalid and domestic as well as sanitary
purposes up three flights of stairs for two unusually hot days in July.
In two others, strikingly similar in many details of their cases, both
being cornet-players, both attributing their illness to an extra call
upon their instrument, it was brought on in the older patient within a
few hours after playing on a hot day at the State Camp at Peekskill,
and in the second at Narragansett Pier as he left the sultry concert-
room and became exposed to a draught. In both these cases, as in a
large number since examined, some stomach trouble could be
positively determined to have antedated these symptoms. I mention
this because it is only in such cases that I have found the nausea or
vomiting which some writers regard as an occasional occurrence of,
and due to, the lighter form of cerebral hyperæmia.
There are no ophthalmoscopic evidences of cerebral hyperæmia of

this form. I have never found the optic disc presenting variations in
tint beyond those found within normal limits, except in a case of
saturnine encephalopathy with predominant signs of cerebral
congestion. I believe that the statement of Hammond8 as to the
existence of choked disc in cerebral hyperæmia is generally
regarded as due to the interpretation of organic diseases as
congestive states. It is not confirmed by authorities.
8 Loc. cit., p. 41, lines 29-36.
I have never found the tympanic membrane hyperæmic

independently of ear disease, even when tinnitus was marked. It is
claimed to exist by Hammond, and he adduces as analogous the
observation of Roosa that quinine produces an injection around the
handle of the malleus.9
9 It certainly is not necessary to look to the injection of the tympanum as an
explanation for the tinnitus of cerebral hyperæmia, based on such an analogy. The
tinnitus of cinchonism is more central in location, being producible in persons who
have pathological or no tympanic membranes, just as the tinnitus of cerebral
hyperæmia occurs indifferently under like circumstances.
The congestive states which follow traumatism and insolation are

properly considered in connection with the traumatic neuroses and
certain forms of insanity. But there are some milder cases in which
the symptoms remain within such compass as is comprised in this
section. The patient, after a fall or a blow on the head, suffers from
insomnia, has a sensation of fulness and ache in the head,
complains of a pulsating feeling in the occipital region and an
inability to concentrate his thoughts on subjects which previously
were parts of his routine. Under appropriate treatment recovery
ensues, but there remains behind an intolerance of alcoholic
beverages, and at times the patient experiences momentary fits of
abstraction, which may be regarded as mild analogies of the more
serious episodes of the full-blown traumatic neurosis. Thus, he may
be walking along the street and suddenly lose his train of thought for
an instant, to regain it on observing that he has inadvertently made a
misstep. Or in the midst of an address a previously fluent orator in
attempting to find a certain by-law in the rules of a society is unable
to recollect which he was in search of, and is compelled to take his
seat with a rambling apology. But for the fact that similar sequelæ
are noted in cerebral hyperæmia from other causes, it would be
questionable whether it be proper to attribute them to the congestive
element engendered by the traumatic influence. They are usually
noted when the hyperæmic phenomena proper have become latent
or disappear, and, with other symptoms customarily treated of as
mere results of circulatory trouble, may be regarded as signs of
neural exhaustion or inadequacy rather than of insufficient
ensanguination.
A more serious form of cerebral hyperæmia occurs in females in

conjunction with the climacteric period, and in both sexes in
consequences of the suppression of any habitual discharge in
advanced, and exceptionally in middle and juvenile, life. The advent
of the symptoms is rapid, a few hours or days sufficing for the
development of the attack. The face is flushed, the carotids throb
violently, the general cutaneous surface is congested, and the
patient is incoherently talkative. The one side, usually the right, is
heavy and tremulous, the fingers are devoid of their usual skill, and
the speech is more or less thick. The sleep is disturbed or replaced
by a stuporous condition, whose similitude to an apoplectiform
seizure is sometimes heightened by stertorous breathing. After one
or several days the patient emerges from this condition by degrees
or suddenly with complete restitutio ad integrum. But the attack may
recur, and ultimately it is noted in the event of repeated attacks that
the return to the normal state is slower and less complete: the
disorder then undergoes a transition into the congestive type of
paretic dementia described in another portion of this volume.
DIFFERENTIAL DIAGNOSIS.—In some of its clinical aspects cerebral

hyperæmia closely resembles cerebral anæmia. This is not
surprising when we bear in mind that both constitute nutritive
disturbances of the same organ, and that, notwithstanding the
apparent difference in the surface injection of an anæmic and a
hyperæmic brain, the state of affairs in the ultimate capillary districts
may be much more alike than might be anticipated on theoretical
grounds. In congestion we have wider vessels, and perhaps, though
not necessarily, a better quality of blood; but at the same time the
intracranial pressure may be such that the venous emunctories can
labor but slowly: the result will be that although there is more blood
in the brain, the lessened rate of flow places the nerve-elements
under nearly the same nutritive disadvantage that they are placed
under with the narrower and vitiated but more rapid blood-column of
ordinary anæmia.10 It is particularly the symptoms dependent on
those nerve-centres and tracts which are, so to speak, dynamically
sensitive, which resemble each other so much that an intrinsic
difference—both being placed side by side—is not always
determinable. This is true of the aural and optic symptoms. Tinnitus,
photophobia, scotomata, and blurring or darkening of the visual field
occur in both, and in about the same varieties. In my experience the
acuteness of hearing is more apt to be interfered with by the
subjective sounds with hyperæmic than with anæmic tinnitus. The
scotomata of hyperæmia are more distinct and coarser than those of
anæmia; darkening of the visual field is more apt to occur with
sudden rising in anæmia, while in hyperæmia it is provoked by
coughing, straining at stool, or other cause operating directly or
indirectly on the return circulation. It may be stated, as a general
rule, that if any of these symptoms are aggravated on lying down or
stooping, they are due to hyperæmia; while if the same procedures
are resorted to in anæmia, amelioration ensues. But in many chronic
cases these symptoms seem to continue as indications of a
permanently altered activity of the nerve-elements themselves; that
is, as a sort of pathological habit. In that case the position test may
not be decisive. In one respect there is a decided difference between
the anæmic and hyperæmic forms; there is never amaurosis in the
latter, while it is approached, and occasionally fully developed, in the
former. Much more importance attaches to the differentiation of
tinnitus due to nutritive brain disorders and that due to aural disease.
As a rule, the tinnitus from cerebral hyperæmia is symmetrical; if
unilateral, it is of short duration. The procedure of Valsalva11
aggravates the tinnitus of hyperæmia, and relieves that which is due
to the commoner forms of ear disease; the former is aggravated and
the latter relieved by noise.
10 It is also admitted that the blood stagnating in the larger veins and accumulating in
the arteries, the limits of compressibility of the other cerebral contents being passed,
the capillaries will suffer, so that with injected and turgescent arterioles and venules
there may be capillary anæmia.
11 I would caution against Politzer's method in cases of ear disease coexisting with
cerebral congestion. In a patient now under my treatment each session at the aurist's
was followed by a distinct exacerbation of the cerebral symptoms.
In the table on p. 773 I have attempted to formulate the principal

differential relations of the protracted forms of cerebral anæmia and
hyperæmia.
There are a number of so-called functional nervous states which,

aside from the fact that they are unwarrantably confounded with
cerebral congestion, do not require mention in a differential relation.
Such are the masturbatory neurosis, certain hysterical states, and
the asthenia resulting from nervous shock and overwork. These
states have found a provisional resting-place under the
comprehensive and non-committing title of neurasthenia or nervous
exhaustion—a term which includes conditions fully recognized by
Robert Whytt and Isenflamm in the last century.
Symptomatic State. In Cerebral Anæmia. In Cerebral Hyperæmia.

Pupils. Usually dilated and mobile. Usually small or medium.
Respiration. Often interrupted by sighing or Normal.
by a deep breath, even when at
rest.
Headache. Either sharp and agonizing, and If localized, accompanied by a
then in a limited area, or a subjective and objective
general dull ache, intensified in (always?) feeling of heat; if
the temples and over or behind general, is compared to a bursting
the eyes. or steady pressure.
Activity. There is lassitude. There is indisposition to exertion,
yet patient is restless.
Temperament. Lethargic, with exceptions. Choleric, with exceptions.
Intellect. Inability to exert. Rather confusion than inability of.
Sleep. Insomnia, interrupted by trance- Insomnia, with great restlessness,
like conditions, in which the variegated by unpleasant and
patient is comparatively confused dreams.
comfortable. Dreams often
pleasant.
Influence of upright Aggravates all the symptoms. Either without influence or
position of body. beneficial.
Influence of Amelioration. Aggravation.
recumbent position of
body and dependent
position of head.
Influence of acts If any, a sharp headache may Aggravated.
involving deep ensue, but the other symptoms
inspiration, such as are not aggravated.
blowing, straining at
stool, sneezing, etc.
TREATMENT.—Ergot of rye with its preparations may be regarded as

the cardinal drug in cerebral hyperæmia. There are few drugs in the
domain of neurological therapeutics which are so directly antithetical
to the pathological state as this one. There is scarcely a case of
cerebral hyperæmia that is brought to the physician's attention but
may be regarded as being in part due to an over-distension of the
cerebral vascular tubes. This is directly overcome by ergot, and the
quantity which such patients will sometimes bear without showing
signs of ergotism is something remarkable, in notable contrast with
the subjects of cerebral anæmia, who are usually very sensitive to it.
About three grains of Bonjean's ergotin may be regarded as a safe
trial-dose for an adult, and unless a distinct effect is produced within
two or three days this dose may be raised to six grains twice or three
times within twenty-four hours. It is not advisable to combine
strychnia with the ergotin, as is often done; the effect of that alkaloid
is to increase the psychical and sensorial irritability of the patient.
Chloral hydrate or bromide, or both in combination, is as useful an
adjuvant here as it would be hurtful in cerebral anæmia.
It is not usually necessary to employ special hypnotics in cerebral

congestion. The same drug whose beneficial effect is so potently
marked during the daytime that tinnitus, cerebral pressure, and
subjective drowsiness will disappear before it, if not as rapidly, more
enduringly, than the symptoms of cerebral anæmia disappear before
nitrate of amyl, will also overcome the insomnia in the majority of
cases. Where it fails, warm pediluvia or sitz-baths will prove more
efficient than the majority of hypnotics. Their use, at all events,
involves no hurtful effect on a—possible already—disordered
stomach, and their certainty of action is much more even. Their
temperature should be about 40-42° Centigrade, and the immersion
continue from fifteen to twenty-five minutes.12
12 A number of experiments, the most recent of which were by Musso and Bergesio
(Rivista sperimentale di Freniatria e di Medicina legale, 1885, xi. p. 124), have shown
that in such baths the cerebral pulsations become less excursive and that the volume
of the brain decreases. The same applies to general warm baths.
In those cases where the subject sensations accompanying

hyperæmia, active or passive, are intensified in the posterior
segment of the head or the nuchal region, leeches at the mastoid
process, or cupping, wet or dry according to the severity of the
symptoms, will often give immediate relief. Burning with the actual
cautery, or, what is equivalent and a much neater application, the
heated glass rod, has an equally happy effect in that class of cases
where throbbing and pain are intensified low down. It should be done
as near the spot indicated by the patient's complaints as possible.13
13 In a case of gliomatous hypertrophy of the pons oblongata transition marked by the
development of numerous tortuous and enlarged blood-vessels the episodes of the
disease were found to be of the congestive type, and yielded to no other treatment
than that with the cautery.
The diet of patients who are suffering from or subject to cerebral
hyperæmia should not be stimulating nor difficult of digestion. It is
much more important to avoid distension or overstrain of the
stomach than to reduce the nutritive value of the food in the majority
of cases, for true plethora is much less common than is supposed.
The bowels should be so regulated that the patient have at least
one, and that an easy, movement a day. The saline cathartics,
particularly the Carlsbad salt, are to be used to effect this if
necessary. The clothing around the neck should be free and not
compress the parts.
In those severe forms of cerebral congestion attending the

climacteric period, or occurring in consequence of the suppression of
discharges, and similar causes, the symptoms are often so alarming
as to render energetic measures, such as bleeding, immediately
necessary. This may be affected by applying leeches to the nose,
the temples, or by bleeding at the arm. If due to the suppression of
hemorrhoidal discharges or menstruation, the leeches should be
applied to the anus and hot sitz-baths taken. In the milder forms a pill
composed of aloes, podophyllin, and ox-gall, recommended by
Schroeder van der Kolk, will be found effective.
Cerebral Anæmia.
The oft-confirmed observation of Treviranus, that the brain is paler in

the sleeping than in the waking state, supplemented as it has been
by more elaborate observations, which show that the difference
between the intracranial blood-amounts, as estimated in these
opposite states, is equivalent to one-twenty-fourth part of the total
blood-amount of the body, has been made the basis of much
dazzling theory and premature speculation. Hyperæmia of the
central nervous apparatus or of certain of its provinces becomes
regarded as synonymous with over-activity, and anæmia, general or
provincial, as the expression of the opposite functional state.
Elaborate directions may be found, even in recent treatises on the

Goodman and Gilmans The Pharmacological Basis of Therapeutics 14Th Edition Laurence Brunton Full Chapter

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Goodman and Gilman's The

Pharmacological Basis of Therapeutics,

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Contributors ix 18. Drug Therapy of Depression and Anxiety Disorders..................... 343

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Edward Acosta, PharmD Kaitlyn Brown, PharmD, DABAT

Richard Daneman, PhD Peter A. Friedman, PhD

University of California, San Diego Department of Pharmacology and Chemical Biology

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Matthew N. Hill, PhD Edwin K. Jackson, PhD

Jerry Ingrande, MD, MS Bjorn C. Knollmann, MD, PhD

Mark A. Lawson, PhD Associate Professor of Neuroscience

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Anna Tate Riegel, PhD Misty D. Smith, PhD

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Brunton_FM_p00i-pxviii.indd 16 28/07/22 5:19 PM

Melinda Avelar Becky Hainz-Baxter

Benjamin Coleman, PhD Jin-Woo Park, MD, PhD

Department of Medicine Michael Weitz

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DESIGNING LARGE MOLECULES AS DRUGS:

■■ Drug Discovery or Drug Invention? THE INVESTIGATIONAL NEW DRUG APPLICATION

EXPERIMENTAL APPROACHES TO PERSONALIZED (INDIVIDUALIZED, PRECISION) MEDICINE

The first edition of Goodman & Gilman, published in 1941, helped to

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Mevastatin Fluvastatin Cerivastatin Atorvastatin

SGLT IC50 (nM) IC50 (nM) Relative selectivity

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Compound Library Known Ligands

Actives Potent drug candidates

B. Screening based on protein-ligand docking

Ligands Drug candidates

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9 Development Clinical tests Phase III

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PhRMA R&D expenditures (in billions) (

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■■ The Plasma Membrane Is Selectively Permeable

METABOLISM OF DRUGS THERAPEUTIC DRUG MONITORING

absorption and elimination

protein bound metabolites

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SLC ABC Na+,K+ - SLC co-transporters

Absorption and Bioavailability Routes of Administration

Absorption is the movement of a drug from its site of administration

TABLE 2–1 ■ SOME CHARACTERISTICS OF COMMON ROUTES OF DRUG ADMINISTRATIONa

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ANÆMIA AND HYPERÆMIA OF THE BRAIN AND

One great difficulty in determining the precise nature of the disorders

3 Virchow's Archiv, lxiv.

4 The observations of Gärntner (Medicinische Jahrbucher, 1884, 1) harmonize with

ETIOLOGY.—An individual predisposition to cerebral congestion was

The suppression of habitual discharges, of the hemorrhoidal flux,