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P R IN C IP LE S o f P H A R M A C O LO G Y
T H E P AT H O P H YS I O LO G I C B A S I S O F D R U G T H E R A P Y

Fo u rt h Ed it io n
P R IN C IP LE S o f P H A R M A C O LO G Y
T H E P AT H O P H YS I O LO G I C B A S I S O F D R U G T H E R A P Y

Fo u rt h Ed it io n

David E. Go lan, MD, PhD

Editor-in-Chief

Ehrin J. Arm s tro ng , MD, MS c

April W. Arm s tro ng , MD, MPH
Associate Editors
Acquisitions Editor: Matthew Hauber
Product Development Editor: John Larkin
Marketing Manager: Mike McMahon
Production Project Manager: Bridgett Dougherty
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Manufacturing Coordinator: Margie Orzech
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Fourth edition

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Library of Congress Cataloging-in-Publication Data

Names: Golan, David E., editor. | Armstrong, Ehrin J., editor. | Armstrong,
April W., editor.
Title: Principles o pharmacology : the pathophysiologic basis o drug
therapy / David E. Golan, editor in chie ; Ehrin J. Armstrong, April W.
Armstrong, associate editors.
Other titles: Principles o pharmacology (Golan)
Description: Fourth edition. | Philadelphia : Wolters Kluwer Health, [2017] |
Includes bibliographical re erences and index.
Identif ers: LCCN 2015048962 | ISBN 9781451191004
Subjects: | MESH: Pharmacological Phenomena | Drug Therapy
Classif cation: LCC RM301 | NLM QV 38 | DDC 615/.1—dc23 LC record available at http://lccn.loc.gov/2015048962

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To our students and the patients they will serve
 Contents
Preface ........................................................................................... ix S e c t io n IIB
Preface to the First Edition............................................................. xi Principles of Autonomic and Peripheral
Nervous System Pharmacology 126
Acknowledgments........................................................................ xiii
Contributors....................................................................................xv 10 Cholinergic Pharmacology............................................. 127
Alireza Atri, Michael S. Chang, and Gary R. Strichartz
S E C T IO N I 11 Adrenergic Pharmacology ............................................. 150
Fundamental Principles of Pharmacology 1 Nidhi Gera, Ehrin J. Armstrong, and David E. Golan
12 Local Anesthetic Pharmacology ................................... 167
1 Drug–Receptor Interactions .............................................. 2 Quentin J. Baca, Joshua M. Schulman, and
Francis J. Alenghat and David E. Golan Gary R. Strichartz
2 Pharmacodynamics ........................................................... 17
Quentin J. Baca and David E. Golan S e c t io n IIC
3 Pharmacokinetics .............................................................. 27 Principles of Central Nervous System Pharmacology 183
Quentin J. Baca and David E. Golan
13 Pharmacology of GABAergic and
4 Drug Metabolism ............................................................... 43 Glutamatergic Neurotransmission................................ 184
F. Peter Guengerich
Stuart A. Forman, Hua-Jun Feng, Janet Chou, Jianren Mao,
5 Drug Transporters .............................................................. 56 and Eng H. Lo
Baran A. Ersoy and Keith A. Ho master
14 Pharmacology of Dopaminergic
6 Drug Toxicity ....................................................................... 70 Neurotransmission .......................................................... 206
Michael W. Conner, Catherine Dorian-Conner, David G. Standaert and Victor W. Sung
Vishal S. Vaidya, Laura C. Green, and David E. Golan
15 Pharmacology of Serotonergic and
7 Pharmacogenomics .......................................................... 87 Central Adrenergic Neurotransmission ....................... 227
Amber Dahlin and Kelan Tantisira Stephen J. Haggarty and Roy H. Perlis
16 Pharmacology of Abnormal Electrical
S E C T IO N II Neurotransmission in the Central Nervous System..... 249
Principles of Neuropharmacology 96 Susannah B. Cornes, Edmund A. Gri f n, Jr., and
Daniel H. Lowenstein
S e c t io n IIA 17 General Anesthetic Pharmacology............................... 265
Fundamental Principles of Neuropharmacology 97 Jacob Wouden and Keith W. Miller
18 Pharmacology of Analgesia ........................................... 288
8 Principles of Cellular Excitability and Robert S. Gri f n and Cli ord J. Wool
Electrochemical Transmission......................................... 98
19 Pharmacology of Drugs of Abuse ................................. 308
Elizabeth Mayne, Lauren K. Buhl, and Gary R. Strichartz
Peter R. Martin and Sachin Patel
9 Principles of Nervous System
Physiology and Pharmacology ...................................... 110 S E C T IO N III
Joshua M. Galanter, Susannah B. Cornes, and
Principles of Cardiovascular Pharmacology 335
Daniel H. Lowenstein
20 Pharmacology of Cholesterol and
Lipoprotein Metabolism.................................................. 336
Tibor I. Krisko, Ehrin J. Armstrong, and David E. Cohen

vii
viii Contents
21 Pharmacology o Volume Regulation ........................... 358
Hakan R. Toka and Seth L. Alper
22 Pharmacology o Vascular Tone ................................... 385
William M. Oldham and Joseph Loscalzo
23 Pharmacology o Hemostasis and Thrombosis .......... 403
Ehrin J. Armstrong and David E. Golan
24 Pharmacology o Cardiac Rhythm ................................ 433
Ehrin J. Armstrong and David E. Clapham
25 Pharmacology o Cardiac Contractility ........................ 454
Ehrin J. Armstrong
26 Integrative Cardiovascular Pharmacology:
Hypertension, Ischemic Heart Disease,
and Heart Failure ............................................................. 469
James M. McCabe and Ehrin J. Armstrong
S E C T IO N IV
Principles o Endocrine Pharmacology
27 Pharmacology o the Hypothalamus
and Pituitary Gland .......................................................... 498
Anand Vaidya and Ursula B. Kaiser
28 Pharmacology o the Thyroid Gland ............................. 514
Anthony Hollenberg and William W. Chin
29 Pharmacology o the Adrenal Cortex ........................... 524
Rajesh Garg and Gail K. Adler
30 Pharmacology o Reproduction..................................... 541
Ehrin J. Armstrong and Robert L. Barbieri
31 Pharmacology o the Endocrine Pancreas
and Glucose Homeostasis .............................................. 561
Giulio R. Romeo and Steven E. Shoelson
32 Pharmacology o Bone Mineral Homeostasis ............ 580
David M. Slovik and Ehrin J. Armstrong
S E C T IO N V
Principles o Chemotherapy
33 Principles o Antimicrobial and
Antineoplastic Pharmacology ....................................... 603
Donald M. Coen, Vidyasagar Koduri, and David E. Golan
34 Pharmacology o Bacterial In ections: DNA
Replication, Transcription, and Translation ................. 622
Alexander J. McAdam and Donald M. Coen
35 Pharmacology o Bacterial and Mycobacterial
In ections: Cell Wall Synthesis ...................................... 641
David W. Kubiak, Ramy A. Arnaout, and Sarah P. Hammond
36 Pharmacology o Fungal In ections .............................. 661
Chelsea Ma and April W. Armstrong
37 Pharmacology o Parasitic In ections .......................... 674
Louise C. Ivers and Edward T. Ryan
38 Pharmacology o Viral In ections .................................. 694
Jonathan Z. Li and Donald M. Coen
39 Pharmacology o Cancer: Genome Synthesis,
Stability, and Maintenance ............................................ 723
David A. Barbie and David A. Frank
40 Pharmacology o Cancer: Signal Transduction .......... 750
David A. Barbie and David A. Frank
41 Principles o Combination Chemotherapy ................... 770
Quentin J. Baca, Donald M. Coen, and David E. Golan
S E C T IO N V I
Principles o Inf ammation and Immune Pharmacology 782
42 Principles o Inf ammation and
the Immune System......................................................... 783
Eryn L. Royer and April W. Armstrong
43 Pharmacology o Eicosanoids ....................................... 794
David M. Dudzinski and Charles N. Serhan
44 Histamine Pharmacology ............................................... 819
Elizabeth A. Brezinski and April W. Armstrong
45 Pharmacology o Hematopoiesis
and Immunomodulation .................................................. 830
497
Andrew J. Wagner, Ramy A. Arnaout, and George D. Demetri
46 Pharmacology o Immunosuppression ........................ 844
Elizabeth A. Brezinski, Lloyd B. Klickstein, and
April W. Armstrong
47 Integrative Inf ammation Pharmacology:
Peptic Ulcer Disease ....................................................... 864
Dalia S. Nagel and Helen M. Shields
48 Integrative Inf ammation Pharmacology: Asthma ...... 877
Joshua M. Galanter and Stephen Lazarus
49 Integrative Inf ammation Pharmacology: Gout ........... 895
Ehrin J. Armstrong and Lloyd B. Klickstein
S E C T IO N V II
Environmental Toxicology 904
50 Environmental Toxicology............................................... 905
Laura C. Green, Sarah R. Armstrong, and
Joshua M. Galanter
602
S E C T IO N V III
Fundamentals o Drug Development and Regulation 918
51 Drug Discovery and Preclinical Development ............ 919
John L. Vahle, David L. Hutto, and Maarten Postema
52 Clinical Drug Evaluation and
Regulatory Approval........................................................ 933
Mark A. Goldberg and Alexander E. Kuta
53 Systematic Detection o Adverse Drug Events ........... 946
Jerry Avorn
S E C T IO N IX
Frontiers in Pharmacology 954
54 Protein Therapeutics ....................................................... 955
Quentin J. Baca, Benjamin Leader, and David E. Golan
55 Drug Delivery Modalities ................................................ 979
Joshua D. Moss and Robert Langer
Credit List .................................................................................... 987
Index............................................................................................ 991

The editors are grate ul or many help ul suggestions rom
readers o the f rst, second, and third editions o Principles
o Pharmacology: The Pathophysiologic Basis o Drug
Therapy. The ourth edition eatures many changes to re ect
the rapidly evolving nature o pharmacology and drug de-
velopment. We believe that these updates will continue to
contribute to the learning and teaching o pharmacology both
nationally and internationally:
■ Comprehensive updates o ull-color f gures throughout
the textbook—about 450 in all. Every f gure has been
updated and colorized, and over 50 f gures are new or
substantially modif ed to highlight advances in our un-
derstanding o physiologic, pathophysiologic, and phar-
macologic mechanisms. As in the f rst three editions, our
collaboration with a single illustrator creates a uni orm
“look and eel” among the f gures that acilitates under-
standing and helps the reader make connections across
broad areas o pharmacology.
■ Comprehensive updates and additions in the undamen-
tals o pharmacology. Along with extensive updates in
the chapters on drug–receptor interactions, pharmaco-
dynamics, pharmacokinetics, drug metabolism, drug
toxicity, and pharmacogenomics, a new chapter on drug
transporters has been added. The f rst section o the text-
book now provides a comprehensive ramework or the
undamental principles o pharmacology that serve as the
oundation or material in all subsequent chapters.
■ Comprehensive updates o all 37 drug summary tables.
These tables, which have been particularly popular with
readers, group drugs and drug classes according to mech-
anism o action and list clinical applications, serious and
common adverse e ects, contraindications, and therapeu-
tic considerations or each drug discussed in the chapter.
■ Comprehensive updates o all chapters, including new
drugs approved through 2014–2015. We have ocused
especially on newly discovered and revised mecha-
nisms that sharpen our understanding o the physiology,
Preface
pathophysiology, and pharmacology o the relevant sys-
tem. Sections throughout the book contain substantial
amounts o new and updated material, especially the chap-
ters on drug–receptor interactions; drug toxicity; pharma-
cogenomics; adrenergic pharmacology; local anesthetic
pharmacology; the pharmacology o serotonergic and
central adrenergic neurotransmission; the pharmacology
o analgesia; the pharmacology o cholesterol and lipopro-
tein metabolism; the pharmacology o volume regulation;
the pharmacology o vascular tone; the pharmacology
o hemostasis and thrombosis; the pharmacology o the
thyroid gland; the pharmacology o the endocrine pan-
creas and glucose homeostasis; the pharmacology o bone
mineral homeostasis; the pharmacology o bacterial DNA
replication, transcription, and translation; the pharmacol-
ogy o bacterial and mycobacterial cell wall synthesis;
the pharmacology o viral in ections; the pharmacology
o cancer; the pharmacology o eicosanoids; the pharma-
cology o immunosuppression; the undamentals o drug
development and regulation; and protein therapeutics.
As with the third edition, we have recruited a panel o
new, expert chapter authors who have added tremendous
strength and depth to the existing panel o authors, and the
editorial team has reviewed each chapter in detail to achieve
uni ormity o style, presentation, and currency across the
entire text.
Finally, we would like to acknowledge the immeasur-
able contributions o the late Armen H. Tashjian, Jr., MD,
to the conception, design, and implementation o this text.
Armen was our riend, mentor, and close colleague, and his
indomitable spirit lives on in this ourth edition o Principles
o Pharmacology: The Pathophysiologic Basis o Drug
Therapy.
David E. Golan, MD, PhD
Ehrin J . Armstrong, MD, MSc
April W. Armstrong, MD, MPH
ix

This book represents a new approach to the teaching o a
f rst or second year medical school pharmacology course.
The book, titled Principles of Pharmacology: The Patho-
physiologic Basis of Drug Therapy, departs rom standard
pharmacology textbooks in several ways. Principles of
Pharmacology provides an understanding o drug action
in the ramework o human physiology, biochemistry, and
pathophysiology. Each section o the book presents the
pharmacology o a particular physiologic or biochemical
system, such as the cardiovascular system or the in am-
mation cascade. Chapters within each section present the
pharmacology o a particular aspect o that system, such as
vascular tone or eicosanoids. Each chapter presents a clini-
cal vignette, illustrating the relevance o the system under
consideration; then discusses the biochemistry, physiology,
and pathophysiology o the system; and, f nally, presents the
drugs and drug classes that activate or inhibit the system by
interacting with specif c molecular and cellular targets. In
this scheme, the therapeutic and adverse actions o drugs are
understood in the ramework o the drug’s mechanism o ac-
tion. The physiology, biochemistry, and pathophysiology are
illustrated using clear and concise f gures, and the pharma-
cology is depicted by displaying the targets in the system
on which various drugs and drug classes act. Material rom
the clinical vignette is re erenced at appropriate points in the
discussion o the system. Contemporary directions in mo-
lecular and human pharmacology are introduced in chapters
on modern methods o drug discovery and drug delivery and
in a chapter on pharmacogenomics.
Preface
t o t h e Firs t Ed it io n
This approach has several advantages. We anticipate that
students will use the text not only to learn pharmacology but
also to review essential aspects o physiology, biochemistry,
and pathophysiology. Students will learn pharmacology in a
conceptual ramework that osters mechanism-based learning
rather than rote memorization, and that allows or ready incor-
poration o new drugs and drug classes into the student’s und
o knowledge. Finally, students will learn pharmacology in a
ormat that integrates the actions o drugs rom the level o an
individual molecular target to the level o the human patient.
The writing and editing o this textbook have employed a
close collaboration among Harvard Medical School students and
aculty in all aspects o book production, rom student– aculty
co-authorship o individual chapters to student– aculty editing o
the f nal manuscript. In all, 43 HMS students and 39 HMS ac-
ulty have collaborated on the writing o the book’s 52 chapters.
This development plan has blended the enthusiasm and per-
spective o student authors with the experience and expertise
o aculty authors to provide a comprehensive and consistent
presentation o modern, mechanism-based pharmacology.
David E. Golan, MD, PhD
Armen H. Tashjian, J r., MD
Ehrin J . Armstrong, MD, MSc
Joshua M. Galanter, MD
April W. Armstrong, MD, MPH
Ramy A. Arnaout, MD, DPhil
Harris S. Rose, MD
FOUNDING EDITORS
xi

The editors are grate ul or the support o students and aculty
rom around the world who have provided encouragement
and help ul suggestions.
Stuart Ferguson continued his exemplary work as an execu-
tive assistant by managing all aspects o project coordination,
including submission o chapter manuscripts, multiple layers
o editorial revisions, coordination o f gure generation and
revision, and delivery o the f nal manuscript. We are extraor-
dinarily grate ul or his unwavering dedication to this project.
Rob Duckwall did a superb job to update the ull-color
f gures. Rob’s standardization and coloration o the f gures in
this textbook re ect his creativity and expertise as a leading
medical illustrator. His artwork is a major asset and highlight
o this textbook.
Quentin Baca electronically rendered the striking image
on the cover o this textbook. We are most grate ul or his
creativity and expertise.
The editors would like to thank the publication, editorial,
and production sta at Wolters Kluwer or their expert man-
agement and production o this handsome volume.
David Golan would like to thank the many aculty, stu-
dent, and administrative colleagues whose support and un-
derstanding were critical or the success ul completion o
this project. Members o the Golan laboratory and aculty
and sta in the Department o Biological Chemistry and
Acknowledgments
Molecular Pharmacology at Harvard Medical School and in
the Hematology Division at Brigham and Women’s Hospital
and the Dana-Farber Cancer Institute were gracious and sup-
portive throughout. Deans Je rey Flier and John Czajkowski
were especially supportive and encouraging. Laura, Liza,
and Sarah provided valuable insights at many critical stages
o this project and were constant sources o support and love.
Ehrin Armstrong would like to thank colleagues at the
University o Colorado and the Denver Veterans Adminis-
tration Medical Center or providing academic support and
guidance. Greg Schwartz and Jim Beck were especially en-
couraging. Ki any, Larry, and Ginger were a constant source
o support and love throughout.
April Armstrong would like to thank Drs. David Golan
and Laura Green or their constant support over the years.
She thanks her dedicated coauthors Eryn Royer, Elizabeth
Brezinski, and Chelsea Ma or their hard work. She also
thanks Drs. David Norris, David West, and Fu-Tong Liu
or ostering her career. She is grate ul or the love o her
amily—Amy, Yanni, and Susan.
Credit lines identi ying the original source o a f gure or
table borrowed or adopted rom copyrighted material, and
acknowledging the use o noncopyrighted material, are gath-
ered together in a list at the end o the book. We thank all o
these sources or permission to use this material.
xiii

Gail K. Adler, MD, PhD
Associate Pro essor o Medicine
Harvard Medical School
Associate Physician
Division o Endocrinology, Diabetes
and Hypertension
Department o Medicine
Brigham and Women’s Hospital
Boston, Massachusetts
Francis J . Alenghat, MD, PhD
Assistant Pro essor
Department o Medicine, Section o
Cardiology
University o Chicago
Chicago, Illinois
Seth L. Alper, MD, PhD
Pro essor o Medicine
Harvard Medical School
Renal Division and Molecular and
Vascular Medicine Division
Department o Medicine
Beth Israel Deaconess Medical Center
Boston, Massachusetts
April W. Armstrong, MD, MPH
Associate Dean or Clinical Research
Director o Clinical Research, Southern
Cali ornia Clinical and Translational
Science Institute (SC CTSI)
Vice Chair, Department o Dermatology
Associate Pro essor o Dermatology
University o Southern Cali ornia
Los Angeles, Cali ornia
Ehrin J . Armstrong, MD, MSc
Associate Pro essor o Medicine
Division o Cardiology
University o Colorado School
o Medicine
Denver, Colorado
Sarah R. Armstrong, MS, DABT
Consultant in Toxicology
Amherst, Massachusetts
Ramy A. Arnaout, MD, DPhil
Assistant Pro essor o Pathology
Harvard Medical School
Associate Director, Clinical
Microbiology
Department o Pathology
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Alireza Atri, MD, PhD
Ray Dolby Endowed Chair in Brain
Health Research
Ray Dolby Brain Health Center
Cali ornia Pacif c Medical Center
San Francisco, Cali ornia
Visiting Scientist in Neurology
Harvard Medical School
Boston, Massachusetts
J erry Avorn, MD
Pro essor o Medicine
Harvard Medical School
Chie , Division o
Pharmacoepidemiology
Brigham and Women’s Hospital
Boston, Massachusetts
Quentin J . Baca, MD, PhD
Chie Resident in Anesthesia
Department o Anesthesiology,
Perioperative and Pain Medicine
Stan ord University School o
Medicine
Palo Alto, Cali ornia
David A. Barbie, MD
Assistant Pro essor o Medicine
Harvard Medical School
Associate Physician
Department o Medical Oncology
Dana-Farber Cancer Institute
Boston, Massachusetts
Contributors
Robert L. Barbieri, MD
Kate Macy Ladd Pro essor o
Obstetrics, Gynecology and
Reproductive Biology
Department o Obstetrics, Gynecology
and Reproductive Biology
Harvard Medical School
Chairman, Department o Obstetrics
and Gynecology
Brigham and Women’s Hospital
Boston, Massachusetts
Elizabeth A. Brezinski, MD
Resident in Dermatology
Harvard Combined Dermatology
Residency Training Program
Boston, Massachusetts
Lauren K. Buhl, MD, PhD
Clinical Fellow in Anaesthesia
Harvard Medical School
Resident in Anaesthesia
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Michael S. Chang, MD
Assistant Pro essor o Orthopedic
Surgery
University o Arizona College o
Medicine
Complex Spine Surgeon
Sonoran Spine Center
Phoenix, Arizona
William W. Chin, MD
Bertarelli Pro essor o Translational
Medical Science, Emeritus
Harvard Medical School
Boston, Massachusetts
Chie Medical O f cer and Executive
Vice President
Pharmaceutical Research and
Manu acturers o America
Washington, DC
xv
xvi Contributors
J anet Chou, MD
Instructor, Department of Pediatrics
Harvard Medical School
Assistant in Medicine
Department of Immunology
Children’s Hospital Boston
Boston, Massachusetts
David E. Clapham, MD, PhD
Aldo R. Castañeda Professor of
Cardiovascular Research
Professor of Neurobiology
Harvard Medical School
Chief, Basic Cardiovascular Research
Department of Cardiology
Children’s Hospital Boston
Boston, Massachusetts
Donald M. Coen, PhD
Professor of Biological Chemistry and
Molecular Pharmacology
Harvard Medical School
Boston, Massachusetts
David E. Cohen, MD, PhD
Robert H. Ebert Professor of Medicine
and Health Sciences and
Technology
Director, Harvard-Massachusetts
Institute of Technology Division of
Health Sciences and Technology
Harvard Medical School
Director of Hepatology
Division of Gastroenterology,
Hepatology and Endoscopy
Department of Medicine
Brigham and Women’s Hospital
Boston, Massachusetts
Michael W. Conner, DVM
Vice President
Theravance Biopharma, U.S., Inc.
South San Francisco, California
Susannah B. Cornes, MD
Assistant Professor, Department
of Neurology
University of California, San Francisco
Department of Neurology
UCSF Medical Center
San Francisco, California
Amber Dahlin, PhD, MMSc
Instructor in Medicine
Harvard Medical School
Associate Epidemiologist
Channing Division of Network
Medicine, Department of Medicine,
Brigham and Women’s Hospital
Boston, Massachusetts
George D. Demetri, MD
Professor of Medicine
Department of Medical Oncology
Co-Director, Ludwig Center
Harvard Medical School
Department of Medical Oncology
Dana-Farber Cancer Institute
Boston, Massachusetts
Catherine Dorian-Conner, PharmD, PhD
Consultant in Toxicology
Half Moon Bay, California
David M. Dudzinski, MD, J D
Clinical Fellow in Medicine
Harvard Medical School
Fellow, Department of Cardiology
Massachusetts General Hospital
Boston, Massachusetts
Baran A. Ersoy, PhD
Instructor in Medicine
Harvard Medical School
Investigator
Brigham and Women’s Hospital
Boston, Massachusetts
Hua-J un Feng, MD, PhD
Instructor in Anaesthesia
Harvard Medical School
Assistant in Pharmacology
Massachusetts General Hospital
Boston, Massachusetts
Stuart A. Forman, MD, PhD
Associate Professor of Anesthesia
Harvard Medical School
Boston, Massachusetts
David A. Frank, MD, PhD
Associate Professor of Medicine
Harvard Medical School
Departments of Medicine and
Medical Oncology
Dana-Farber Cancer Institute
Boston, Massachusetts
J oshua M. Galanter, MD
Assistant Professor, Department of
Medicine
University of California, San Francisco
San Francisco, California
Rajesh Garg, MD
Assistant Professor of Medicine
Harvard Medical School
Associate Physician
Division of Endocrinology, Diabetes
and Hypertension
Department of Medicine
Brigham and Women’s Hospital
Boston, Massachusetts
Nidhi Gera, PhD
Research Fellow
Department of Biological Chemistry
and Molecular Pharmacology
Harvard Medical School
Boston, Massachusetts
David E. Golan, MD, PhD
Professor of Biological Chemistry and
Molecular Pharmacology
George R. Minot Professor of Medicine
Dean for Basic Science and
Graduate Education
Special Advisor for Global Programs
Harvard Medical School
Senior Physician, Hematology
Division, Brigham and
Women’s Hospital and
Dana-Farber Cancer Institute
Department of Biological Chemistry
and Molecular Pharmacology,
Department of Medicine
Harvard Medical School
Boston, Massachusetts
Mark A. Goldberg, MD
Associate Professor of Medicine,
Part-time
Harvard Medical School
Boston, Massachusetts
Advisor
Medical and Regulatory Strategy
Synageva BioPharma Corp.
Lexington, Massachusetts
Laura C. Green, PhD, DABT
President and Senior Toxicologist
Green Toxicology, LLC
Brookline, Massachusetts
Edmund A. Gri f n, J r., MD, PhD
Assistant Professor of Clinical
Psychiatry
Department of Psychiatry
Columbia University
Attending Psychiatrist
New York-Presbyterian Hospital
New York, New York
Robert S. Gri f n, MD, PhD
Clinical Assistant Professor of
Anesthesiology
Weill Cornell Medical College
Assistant Attending Anesthesiologist
Hospital for Special Surgery
New York, New York
F. Peter Guengerich, PhD
Professor, Department of Biochemistry
Vanderbilt University School of
Medicine
Nashville, Tennessee

Stephen J . Haggarty, PhD
Associate Pro essor o Neurology
Harvard Medical School
Director, Chemical Neurobiology
Laboratory
Center or Human Genetic Research
Massachusetts General Hospital
Boston, Massachusetts
Sarah P. Hammond, MD
Assistant Pro essor o Medicine
Harvard Medical School
Associate Physician
Brigham and Women’s Hospital
Boston, Massachusetts
Keith A. Hoffmaster, PhD
Director, Global Program
Management
Translational Clinical Oncology
Novartis Institutes or Biomedical
Research
Cambridge, Massachusetts
Anthony Hollenberg, MD
Pro essor o Medicine
Harvard Medical School
Chie , Division o Endocrinology,
Diabetes and Metabolism
Beth Israel Deaconess Medical Center
Boston, Massachusetts
David L. Hutto, DVM, PhD, DACVP
Corporate Senior Vice President and
Chie Scientif c O f cer—Sa ety
Assessment
Charles River Laboratories, Inc.
Wilmington, Massachusetts
Louise C. Ivers, MD, MPH, DTM&H
Associate Pro essor o Medicine
Harvard Medical School
Associate Physician
Department o Medicine
Brigham and Women’s Hospital
Boston, Massachusetts
Ursula B. Kaiser, MD
Pro essor o Medicine
Harvard Medical School
Chie , Division o Endocrinology,
Diabetes and Hypertension
Brigham and Women’s Hospital
Boston, Massachusetts
Lloyd B. Klickstein, MD, PhD
Head o Translational Medicine
New Indications Discovery Unit
Novartis Institutes or
Biomedical Research
Cambridge, Massachusetts
Vidyasagar Koduri, MD, PhD
Clinical Fellow in Hematology/
Oncology
Dana Farber Cancer Institute/Harvard
Cancer Center
Boston, Massachusetts
Tibor I. Krisko, MD
Instructor
Department o Medicine
Harvard Medical School
Boston, Massachusetts
Sta Gastroenterologist
Department o Gastroenterology/
Medicine
Boston VA Medical Center
Jamaica Plain, Massachusetts
David W. Kubiak, PharmD
Adjunct Clinical Assistant Pro essor
o Pharmacy Practice
Massachusetts College o Pharmacy
and Health Sciences
Adjunct Assistant Pro essor o
Pharmacology
Massachusetts General Hospital
Institute o Health Pro essions
Adjunct Clinical Assistant Pro essor
o Pharmacy Practice
Northeastern University Bouvé
College o Heath Sciences
Co-Director o Antimicrobial
Stewardship and Advanced Practice
In ectious Diseases Pharmacy
Specialist
Brigham and Women’s Hospital
Boston, Massachusetts
Alexander E. Kuta, PhD
Vice President and Head o US
Regulatory A airs
EMD Serono, Inc.
Rockland, Massachusetts
Robert Langer, ScD
David H. Koch Institute Pro essor
Departments o Chemical Engineering
and Bioengineering
Massachusetts Institute o Technology
Cambridge, Massachusetts
Senior Lecturer on Surgery
Children’s Hospital Boston
Boston, Massachusetts
Stephen Lazarus, MD
Pro essor o Medicine
Division o Pulmonary and Critical
Care Medicine
Director, Training Program in Pulmonary
and Critical Care Medicine
University o Cali ornia, San Francisco
San Francisco, Cali ornia
xvii Contributors
Benjamin Leader, MD, PhD
Chie Executive O f cer
ReproSource
Woburn, Massachusetts
J onathan Z. Li, MD, MMSc
Assistant Pro essor o Medicine
Harvard Medical School
Brigham and Women’s Hospital
Boston, Massachusetts
Eng H. Lo, PhD
Pro essor o Radiology
Harvard Medical School
Director, Neuroprotection
Research Laboratory
Departments o Radiology
and Neurology
Massachusetts General Hospital
Boston, Massachusetts
J oseph Loscalzo, MD, PhD
Hersey Pro essor o the Theory and
Practice o Medicine
Harvard Medical School
Chairman, Department o Medicine
and Physician-in-Chie
Brigham and Women’s Hospital
Boston, Massachusetts
Daniel H. Lowenstein, MD
Pro essor, Department o Neurology
University o Cali ornia, San Francisco
Director, UCSF Epilepsy Center
UCSF Medical Center
San Francisco, Cali ornia
Chelsea Ma, MD
Resident Physician
Internal Medicine
Beth Israel Deaconess Medical Center
Harvard Medical School
Boston, Massachusetts
J ianren Mao, MD, PhD
Richard J. Kitz Pro essor o
Anaesthesia Research
Harvard Medical School
Chie , Division o Pain Medicine
Massachusetts General Hospital
Boston, Massachusetts
Peter R. Martin, MD
Pro essor, Departments o Psychiatry
and Pharmacology
Vanderbilt University
Director, Division o Addiction
Psychiatry and Vanderbilt
Addiction Center
Vanderbilt University Medical Center
Nashville, Tennessee
xviii Contributors
Elizabeth Mayne, MD, PhD
Resident in Pediatrics and Child
Neurology
Department of Pediatrics
Stanford University School of
Medicine
Palo Alto, California
Alexander J . McAdam, MD, PhD
Associate Professor of Pathology
Harvard Medical School
Medical Director
Infectious Diseases Diagnostic
Laboratory
Boston Children’s Hospital
Boston, Massachusetts
J ames M. McCabe, MD
Assistant Professor of Medicine
University of Washington
Director, Cardiac Catheterization
Laboratory
University of Washington Medical
Center
Seattle, Washington
Keith W. Miller, MA, DPhil
Edward Mallinckrodt Professor
of Pharmacology
Department of Anaesthesia
Harvard Medical School
Pharmacologist, Department of
Anesthesia, Critical Care and
Pain Medicine
Massachusetts General Hospital
Boston, Massachusetts
J oshua D. Moss, MD
Assistant Professor of Medicine
Heart Rhythm Center
University of Chicago Medical Center
Chicago, Illinois
Dalia S. Nagel, MD
Clinical Instructor, Department
of Ophthalmology
Mount Sinai School of Medicine
Attending Physician
Department of Ophthalmology
Mount Sinai Hospital
New York, New York
William M. Oldham, MD, PhD
Instructor in Medicine
Harvard Medical School
Associate Physician
Pulmonary and Critical Care Medicine
Brigham and Women’s Hospital
Boston, Massachusetts
Sachin Patel, MD, PhD
Assistant Professor, Departments
of Psychiatry and Molecular
Physiology and Biophysics
Vanderbilt University Medical Center
Nashville, Tennessee
Roy H. Perlis, MD, MSc
Director, Center for Experimental
Drugs and Diagnostics
Center for Human Genetic Research
and Department of Psychiatry
Massachusetts General Hospital
Associate Professor of Psychiatry
Harvard Medical School
Boston, Massachusetts
Maarten Postema, PhD
Director of Chemistry
EISAI Inc.
Andover, Massachusetts
Giulio R. Romeo, MD
Instructor in Medicine
Harvard Medical School
Staff Physician, Adult Diabetes
Section
Joslin Diabetes Center
Staff Physician, Division of
Endocrinology BIDMC
Boston, Massachusetts
Eryn L. Royer, BA
Medical Student
University of Colorado School of
Medicine
Aurora, Colorado
Edward T. Ryan, MD
Professor of Medicine
Harvard Medical School
Professor of Immunology and
Infectious Diseases
Harvard T.H. Chan School of
Public Health
Director, Tropical Medicine
Massachusetts General Hospital
Boston, Massachusetts
J oshua M. Schulman, MD
Assistant Professor of Dermatology
University of California, Davis
Director of Dermatopathology
Sacramento VA Medical Center
Sacramento, California
Charles N. Serhan, PhD
Simon Gelman Professor of
Anaesthesia (Biological Chemistry
and Molecular Pharmacology)
Department of Anesthesiology,
Perioperative and Pain Medicine
Harvard Medical School
Director, Center for Experimental
Therapeutics and Reperfusion Injury
Brigham and Women’s Hospital
Boston, Massachusetts
Helen M. Shields, MD
Professor of Medicine
Harvard Medical School
Physician, Department of Medicine
Brigham and Women’s Hospital
Boston, Massachusetts
Steven E. Shoelson, MD, PhD
Professor of Medicine
Harvard Medical School
Associate Director of Research,
Section Head, Cellular and
Molecular Physiology
Joslin Diabetes Center
Boston, Massachusetts
David M. Slovik, MD
Associate Professor of Medicine
Harvard Medical School
Endocrine Unit
Massachusetts General Hospital
Boston, Massachusetts
Chief, Division of Endocrinology
Newton-Wellesley Hospital
Newton, Massachusetts
David G. Standaert, MD, PhD
John N. Whitaker Professor and Chair,
Department of Neurology
University of Alabama at Birmingham
Director, Division of
Movement Disorders
University Hospital
Birmingham, Alabama
Gary R. Strichartz, PhD
Professor of Anaesthesia
(Pharmacology),
Harvard Medical School
Director, Pain Research Center,
Department of Anesthesiology,
Perioperative and Pain Medicine
Brigham and Women’s Hospital
Boston, Massachusetts

Victor W. Sung, MD
Associate Professor, Department of
Neurology, Division of Movement
Disorders
The University of Alabama at
Birmingham
Birmingham, Alabama
Kelan Tantisira, MD, MPH
Associate Professor of Medicine
Harvard Medical School
Associate Physician
Channing Division of Network
Medicine and Division of
Pulmonary and Critical Care
Medicine
Brigham and Women’s Hospital
Boston, Massachusetts
Hakan R. Toka, MD, PhD
Assistant Professor of Medicine
Division of Nephrology and
Hypertension
Eastern Virginia Medical School
Norfolk, Virginia
J ohn L. Vahle, DVM, PhD, DACVP
Senior Research Pathologist, Department
of Toxicology and Pathology
Lilly Research Laboratories
Indianapolis, Indiana
Anand Vaidya, MD
Assistant Professor of Medicine
(Endocrinology)
Harvard Medical School
Division of Endocrinology, Diabetes,
and Hypertension
Brigham and Women’s Hospital
Boston, Massachusetts
Vishal S. Vaidya, PhD
Associate Professor of Medicine
Head, Systems Toxicology
Program, Laboratory of Systems
Pharmacology
Harvard Medical School
Brigham and Women’s Hospital
Associate Professor of Environmental
Health
Harvard T.H. Chan School of
Public Health
Boston, Massachusetts
xix Contributors
Andrew J . Wagner, MD, PhD
Assistant Professor, Department of
Medicine
Harvard Medical School
Medical Director, Ambulatory Oncology
Center for Sarcoma and Bone Oncology
Dana-Farber Cancer Institute
Boston, Massachusetts
Clifford J . Woolf, MB, BCh, PhD
Professor of Neurology
and Neurobiology
Harvard Medical School
Director, F.M. Kirby
Neurobiology Center
Children’s Hospital Boston
Boston, Massachusetts
J acob Wouden, MD
Radiologist, Washington Hospital
Medical Staff
Washington Hospital Healthcare Group
Fremont, California
 I
Fundamental Principles of
Pharmacology
 B C

1
Drug–Receptor Interactions
Fra n c is J . Ale n g h a t a n d David E. Go la n
α β
γ
INTRODUCTION & CASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2–33
INTR Int GD
G DP
n racee llular Recep
nt e tors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
CONFORMATION AND D CH
CHE EMISTRY Y OF IInt
ntrra ce
cellllular Enzymes and Signal
DRUGS AND D RE
RECE
CEPT
PTOR
ORS S ..................................2 Traa ns
nsduduct
c ion Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
IImp
mpaa ctt of Drug Binding on the Receptor . . . . . . . . . . . . . . . . . . . 5 Transcription Factorss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Membrane Effects on Drug–Receptor Inter erac
acti tion
ons . . . . . . . . . . 6 Structural Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
MOLECULAR AND CEL LLU
LULA LAR R DETERMINANTS OF Nucleic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
DR
RUG SEL ELECECTI
TIVITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Extracellular Targetss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Cell Surface
Surfrfac
acc e Ad
Adhheesion
sion
sion R
Receptors
eceptors . . . . . . . . . . . . . . . . . . . . . . . . 14
MAJ OR TYPES OF DRUG RECEPTORS . . . . . . . . . . . . . . . . . . . . . . . 6
Tra
Trans
nsme
memb mbra
rane
ne Ion Cha hannels . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 PROCESSING OF SIGNALS RESULTING FROM
Transmembrane G Protein-Coupl pled
ed Recepec epto tors . . . . . . . . . . . . . 9 DRUG–RECEPTOR INTERACTIONS . . . . . . . . . . . . . . . . . . . . . . . . . 14
Tra
rans
nsme
memb mbra
rane
ne Receptors with Linked Enzymatic Domains . . . 11 CELLULAR REGULATION OF DRUG–RECEPTOR
Receptor Tyrosine Kinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 INTERACTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Receptor Tyrosine Phosphatases . . . . . . . . . . . . . . . . . . . . . . 12 DRUGS THAT DO NOT FIT THE DRUG–RECEPTOR MODEL. . . . . 16
Tyrosine
y Kinase-Associated Receptors p . . . . . . . . . . . . . . . . . 12 CONCLUSION
CONCL
ON CLUSUSIO IONNA AND
ND FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . . 16
Receptor Serine/Threonine Kinasess . . . . . . . . . . . . . . . . . . . 12 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Receptor Guanylyl Cyclasess . . . . . . . . . . . . . . . . . . . . . . . . . . 12

INTRODUCTION Drug receptors are macromolecules that, upon binding to a

Why is it that one drug a ects cardiac unction and another
alters the transport o specif c ions in the kidney? Why do
antibiotics e ectively kill bacteria but rarely harm patients?
These questions can be answered by f rst examining the in-
teraction between a drug and its specif c molecular target and
then considering the role o that action in a broader physi-
ologic context. This chapter ocuses on the molecular details
o drug–receptor interactions, emphasizing the variety o
receptors and their molecular mechanisms. This discussion
provides a conceptual basis or the action o the many drugs
and drug classes discussed in this book. It also serves as a
background or Chapter 2, Pharmacodynamics, which dis-
cusses the quantitative relationships between drug–receptor
interactions and pharmacologic e ect.
Although drugs can theoretically bind to almost any
three-dimensional target, most drugs achieve their desired
(therapeutic ) e ects by interacting selectively with target
molecules that play important physiologic or pathophysi-
ologic roles. In many cases, selectivity o drug binding to
receptors also determines the undesired (adverse ) e ects
o a drug. In general, drugs are molecules that interact with
specif c molecular components o an organism to cause bio-
chemical and physiologic changes within that organism.
drug, mediate those biochemical and physiologic changes.
CONFORMATION AND CHEMISTRY OF
DRUGS AND RECEPTORS
An understanding o why a drug binds to a particular receptor
can be ound in the structure and chemical properties o the
two molecules. This section discusses the basic determinants
o receptor structure and the chemistry o drug–receptor
binding. The discussion here ocuses primarily on the inter-
actions o drugs that are small molecules with target recep-
tors that are mainly macromolecules (especially proteins),
but many o these principles also apply to the interactions
o antibody- or other protein-based therapeutics with their
molecular targets (see Chapter 54, Protein Therapeutics).
Because many human and microbial drug receptors are
proteins, it is use ul to review the our major levels o protein
structure (Fig. 1-1). At the most basic level, proteins consist
o long chains o amino acids, the sequences o which are
determined by the sequences o the DNA that code or the
proteins. A protein’s amino acid sequence is re erred to as
its primary structure . Once a long chain o amino acids has
been synthesized on a ribosome, many o the amino acids

2

In te n t o n e n jo yin g h is n e w ly o u n d
re tire m e n t, Mr. B h a s m a d e a p o in t o
p la yin g te n n is a s o te n a s p o s s ib le d u r-
in g th e p a s t ye a r. Fo r th e p a s t 3 m o n th s ,
h o w e ve r, h e h a s n o te d in cre a s in g a -
tig u e . Mo re o ve r, h e is n o w u n a b le to
f n is h a m e a l, d e s p ite h is typ ica lly vo ra cio u s a p -
p e tite . Wo rrie d a n d w o n d e rin g w h a t th e s e s ym p -
to m s m e a n , Mr. B s ch e d u le s a n a p p o in tm e n t w ith
h is d o cto r. On p hys ica l e xa m in a tio n , th e p hys icia n
n o te s th a t Mr. B h a s a n e n la rg e d s p le e n , e xte n d in g
a p p ro xim a te ly 10 cm b e lo w th e le t co s ta l m a rg in ;
th e p hys ica l e xa m is o th e rw is e w ith in n o rm a l lim -
its . Blo o d te s ts s h o w a n in cre a s e d to ta l w h ite b lo o d
ce ll co u n t (70,0 0 0 ce lls /m m 3 ) w ith a n a b s o lu te in -
cre a s e in n e u tro p h ils , b a n d o rm s , m e ta m ye lo cyte s ,
a n d m ye lo cyte s , b u t n o b la s t ce lls (u n d i e re n tia te d
p re cu rs o r ce lls ). Cyto g e n e tic a n a lys is o m e ta p h a s e
ce lls d e m o n s tra te s th a t 90% o Mr. B’s m ye lo id ce lls
p o s s e s s th e Ph ila d e lp h ia ch ro m o s o m e (in d ica tin g a
tra n s lo ca tio n b e tw e e n ch ro m o s o m e s 9 a n d 22), co n -
f rm in g th e d ia g n o s is o ch ro n ic m ye lo id le u ke m ia .
Th e p hys icia n in itia te s th e ra p y w ith imatinib, a h ig h ly
s e le ctive in h ib ito r o th e BCR-Ab l tyro s in e kin a s e
u s io n p ro te in th a t is e n co d e d b y th e Ph ila d e lp h ia
ch ro m o s o m e . Ove r th e n e xt m o n th , th e ce lls
begin to interact with nearby amino acids in the polypeptide
chain. These interactions, which are typically mediated by
hydrogen bonding, give rise to the secondary structure o a
protein by orming well-def ned con ormations such as the
helix, pleated sheet, and barrel. As a result o their
highly organized shape, these structures o ten pack tightly
with one another, urther def ning the overall shape o the
protein. Tertiary structure results rom the interaction o
amino acids more distant rom one another along a single
amino acid chain. These interactions include hydrogen bond
and ionic bond ormation as well as the covalent linkage
o sul ur atoms to orm intramolecular disulf de bridges.
Finally, polypeptides may oligomerize to orm more com-
plex structures. The con ormation that results rom the
interaction o separate polypeptides is re erred to as the qua-
ternary structure .
Di erent portions o a protein’s structure generally have
di erent a f nities or water, and this eature has an additional
e ect on the protein’s shape. Because both the extracellular
and intracellular environments are composed primarily o
water, hydrophobic protein segments are o ten drawn to the
inside o the protein or shielded rom water by insertion into
lipid bilayer membranes. Conversely, hydrophilic protein
segments are o ten located on a protein’s exterior sur ace.
A ter all o this twisting and turning is completed, each pro-
tein has a unique shape that determines its unction, location
in the body, relationship to cellular membranes, and binding
interactions with drugs and other macromolecules.
The site on the receptor at which the drug binds is
called its binding site . Each binding site has unique chemi-
cal characteristics that are determined by the specif c
properties o the amino acids that make up the site. The
C h a p t e r 1 Drug–Receptor Interactions 3
co n ta in in g th e Ph ila d e lp h ia ch ro m o s o m e d is a p p e a r
co m p le te ly ro m Mr. B’s b lo o d , a n d h e b e g in s to e e l
w e ll e n o u g h to co m p e te in a s e n io rs te n n is to u rn a -
m e n t. Mr. B co n tin u e s to ta ke im a tin ib e ve ry d a y,
a n d h e h a s a co m p le te ly n o rm a l b lo o d co u n t a n d n o
a tig u e . He is n o t s u re w h a t th e u tu re w ill b rin g , b u t
h e is g la d to h a ve b e e n g ive n th e ch a n ce to e n jo y a
h e a lthy re tire m e n t.
Questions
1 . How does imatinib interrupt the activity o the BCR-Abl
tyrosine kinase usion protein?
2 . Unlike imatinib, most o the older therapies or chronic
myeloid leukemia (such as inter eron- ) had signif cant
“ u-like” adverse e ects. Why did these therapies
cause signif cant adverse e ects in most patients,
whereas (as in this case) imatinib causes adverse
e ects in very ew patients?
3 . Why is imatinib a selective therapy or chronic myeloid
leukemia? Is this selectivity related to the lack o ad-
verse e ects associated with imatinib therapy?
4 . How does the BCR-Abl protein a ect intracellular
signaling pathways?
three-dimensional structure, shape, and reactivity o the
site, and the inherent structure, shape, and reactivity o the
drug, determine the orientation o the drug with respect to
the receptor and govern how tightly these molecules bind to
one another. Drug–receptor binding is the result o multiple
chemical interactions between the two molecules, some
o which are airly weak (such as van der Waals orces)
and some o which are extremely strong (such as covalent
bonding). The sum total o these interactions provides the
specif city o the overall drug–receptor interaction. The a-
vorability o a drug–receptor interaction is re erred to as the
a f nity o the drug or its binding site on the receptor. This
concept is discussed in more detail in Chapter 2. The chem-
istry o the local environment in which these interactions
occur—such as the hydrophobicity, hydrophilicity, and pKa
o amino acids near the binding site—may also a ect the
a f nity o the drug–receptor interaction. The primary orces
that contribute to drug–receptor a f nity are described below
and in Table 1-1.
van der Waals orces , resulting rom the polarity induced
in a molecule by the shi ting o its electron density in re-
sponse to the close proximity o another molecule, provide
a weak attractive orce or drugs and their receptors. This
induced polarity is a ubiquitous component o all molecular
interactions. Hydrogen bonds have substantial strength and
are o ten important or drug–receptor association. This type
o bond is mediated by the interaction between positively
polarized hydrogen atoms (which are covalently attached
to more electronegative atoms such as nitrogen or oxygen)
and negatively polarized atoms (such as oxygen, nitrogen,
or sul ur that are covalently attached to less electronega-
tive atoms such as carbon or hydrogen). Ionic interactions ,
4 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
Primary
Amino a cids
Secondary
Be ta ple a te d Alpha he lix
s he e t
Tertiary
Be ta ple a te d s he e t
Alpha he lix
Quaternary
FIGURE 1-1. Levels of protein structure. Protein structure can be divided
into our levels o complexity, re erred to as primary, secondary, tertiary,
and quaternary structure. Primary structure is determined by the sequence
o amino acids that make up the polypeptide chain. Secondary structure is
determined by the interaction o positively polarized hydrogen atoms with
negatively polarized atoms (such as oxygen) on the same polypeptide chain.
These interactions result in a number o characteristic secondary patterns
o protein con ormation, including the helix and pleated sheet. Tertiary
structure is determined by the interactions o amino acids that are relatively
ar apart on the protein backbone. These interactions, which include ionic
bonds and covalent disulf de linkages (among others), give proteins their
characteristic three-dimensional structure. Quaternary structure is deter-
mined by the binding interactions among two or more independent protein
subunits.
which occur between atoms with opposite charges, are
stronger than hydrogen bonds but less strong than covalent
bonds. Covalent bonding results rom the sharing o a pair o
electrons between two atoms on di erent molecules. Cova-
lent interactions are so strong that, in most cases, they are
essentially irreversible. Table 1-1 indicates the mechanism
o interaction and relative strength o each o these types o
bonds. As noted above, the environment in which drugs and
receptors interact also a ects the avorability o binding.
The hydrophobic effect re ers to the mechanism by which the
unique properties o the ubiquitous solvent water cause the
interaction o a hydrophobic molecule with a hydrophobic
binding site to be enhanced.
Rarely is drug–receptor binding caused by a single type
of interaction; rather, it is a combination of these binding
interactions that provides drugs and receptors with the
forces necessary to form a stable drug–receptor complex.
In general, multiple weak orces comprise the majority o
drug–receptor interactions. For example, imatinib orms
many van der Waals interactions and hydrogen bonds with
the ATP-binding site o the BCR-Abl tyrosine kinase. The
sum total o these relatively weak orces creates a strong
(high a f nity) interaction between this drug and its recep-
tor (Fig. 1-2). Ionic and hydrophobic interactions exert
orce at a greater distance than van der Waals interactions
and hydrogen bonds; or this reason, the ormer interac-
tions are o ten critical to initiate the association o a drug
and receptor.
Although relatively rare, covalent interactions between
a drug and its receptor are a special case. The ormation
o a covalent bond is o ten essentially irreversible, and in
such cases, the drug and receptor orm an inactive complex.
To regain activity, the cell must synthesize a new receptor
molecule to replace the inactivated protein; and the drug
molecule, which is also part o the inactive complex, is
generally not available to inhibit other receptor molecules.
Drugs that modi y their target receptors (o ten enzymes)
through this mechanism are sometimes called suicide sub-
strates . Aspirin is an example o such a drug; it irrevers-
ibly acetylates cyclooxygenases to reduce the production
o prostaglandins (anti-in ammatory e ect) and thrombox-
anes (antiplatelet e ect) (see Chapter 43, Pharmacology o
Eicosanoids).
The molecular structure o a drug dictates the physical
and chemical properties that contribute to its specif c bind-
ing to the receptor. Important actors include hydrophobicity,
ionization state (pKa), con ormation, and stereochemistry o
the drug molecule. All o these actors combine to determine
the complementarity o the drug to the binding site. Recep-
tor binding pockets are highly specif c, and small changes
in the drug can have a large e ect on the a f nity o the
drug–receptor interaction. For example, the stereochemistry
o the drug has a great impact on the strength o the bind-
ing interaction. Warfarin is synthesized and administered as
a racemic mixture (a mixture containing 50% o the right-
handed molecule and 50% o the le t-handed molecule);
however, the S enantiomer is our times more potent than
the R because o a stronger interaction o the S orm with its
binding site on vitamin K epoxide reductase. Stereochem-
istry can also a ect toxicity in cases where one enantiomer
o a drug causes the desired therapeutic e ect and the other
enantiomer causes an undesired toxic e ect, perhaps due to
an interaction with a second receptor or to metabolism to a
toxic species. Although it is sometimes di f cult or pharma-
ceutical companies to synthesize and puri y individual en-
antiomers on a large scale, a number o currently marketed
drugs are produced as individual enantiomers in cases where
one enantiomer has higher e f cacy and/or lower toxicity
than its mirror image.
 C h a p t e r 1 Drug–Receptor Interactions 5

TABLE 1-1 Relative Strength o Bonds between Receptors and Drugs

BOND TYPE MECHANISM BOND STRENGTH
van der Waals Shi ting electron density in areas o a molecule, or in a molecule as a whole, results in the generation o
transient positive or negative charges. These areas interact with transient areas o opposite charge
on another molecule.

Hydrogen Hydrogen atoms bound to nitrogen or oxygen become more positively polarized, allowing them to bond
to more negatively polarized atoms such as oxygen, nitrogen, or sul ur.

Ionic Atoms with an excess o electrons (imparting an overall negative charge on the atom) are attracted to
atoms with a def ciency o electrons (imparting an overall positive charge on the atom).

Covalent Two bonding atoms share electrons.

Impact o Drug Binding on the Receptor The principle o induced f t suggests that drug–receptor
binding can have pro ound e ects on the con ormation o
How does drug binding produce a biochemical and/or physi-
the receptor. By inducing con ormational changes in the re-
ologic change in the organism? In the case o receptors with
ceptor, many drugs not only improve the quality o the bind-
enzymatic activity, the binding site o the drug is o ten the
ing interaction but also alter the action o the receptor. The
active site at which an enzymatic trans ormation is cata-
change in shape induced by the drug is sometimes identi-
lyzed, and the catalytic activity o the enzyme is inhibited
cal to that caused by the binding o an endogenous ligand.
by drugs that prevent substrate binding to the site or that
For example, exogenously administered insulin analogues
covalently modi y the site. In cases where the binding site is
all stimulate the insulin receptor to the same extent, despite
not the active site o the enzyme, drugs can cause a change
their slightly di erent amino acid sequences. In other cases,
by preventing the binding o endogenous ligands to their
drug binding alters the shape o the receptor so as to make it
receptor binding pockets. In many drug–receptor interac-
more or less unctional than normal. For example, imatinib
tions, however, the binding o a drug to its receptor results
binding to the BCR-Abl tyrosine kinase causes the protein to
in a change in the con ormation o the receptor. Altering the
assume an enzymatically inactive con ormation, thus inhib-
shape o the receptor can a ect its unction, including en-
iting the kinase activity o the receptor.
hancing the a f nity o the drug or the receptor. Such an
Another way to describe the induced f t principle is to
interaction is o ten re erred to as induced f t, because the re-
consider that many receptors exist in multiple con orma-
ceptor’s con ormation changes so as to improve the quality
tional states—such as inactive (or closed), active (or open),
o the binding interaction.
and desensitized (or inactivated)—and that the binding o a

A B Glu 286
C
Me t 290 Imatinib

Ile 313

Imatinib P he 382
Ala 269
Gly 383
As p 381
As n 368 Activa tion loop
of kina s e
Thr 315

P he 382 Lys 271

As p 363

Le u 248 P he 317
As p 381 Arg 367 Tyr 393
Tyr 253 Va l 256

Me t 318
Gly 321

Le u 370

FIGURE 1-2. Structural basis o specif c enzyme inhibition: imatinib interaction with the BCR-Abl kinase. A. The kinase portion o the BCR-Abl tyrosine
kinase is shown in a ribbon ormat (gray). An analogue o imatinib, a specif c inhibitor o the BCR-Abl tyrosine kinase, is shown as a space-f lling model (blue ).
B. Detailed diagram o the intermolecular interactions between the drug (shaded in purple ) and amino acid residues in the BCR-Abl protein. Hydrogen bonds
are indicated by dashed lines, while van der Waals interactions (indicated by halos around the amino acid name and its position in the protein sequence)
are shown or nine amino acids with hydrophobic side chains. C. The interaction o the drug (blue ) with the BCR-Abl protein (gray) inhibits phosphorylation
o a critical activation loop (green-highlighted ribbon format), thus preventing catalytic activity.
6 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
drug to the receptor stabilizes one or more o these con or-
mations. Quantitative models that incorporate these concepts
o drug–receptor interactions are discussed in Chapter 2.
Membrane E ects on Drug–Receptor
Interactions
The structure o the receptor also determines where the pro-
tein is located in relationship to cellular boundaries such as
the plasma membrane. Proteins that have large hydrophobic
domains are able to reside in the plasma membrane because
o the membrane’s high lipid content. Many receptors that
span the plasma membrane have lipophilic domains that are
located in the membrane and hydrophilic domains that re-
side in the intracellular and extracellular spaces. Other drug
receptors, including a number o transcription regulators
(also called transcription actors ), have only hydrophilic do-
mains and reside in the cytoplasm, nucleus, or both.
Just as the structure o the receptor determines its loca-
tion in relationship to the plasma membrane, the structure o
a drug a ects its ability to gain access to the receptor. For
example, many drugs that are highly water-soluble are un-
able to pass through the plasma membrane and bind to target
molecules in the cytoplasm. Certain hydrophilic drugs are
able to pass through transmembrane channels (or use other
transport mechanisms) and gain ready access to cytoplasmic
receptors. Drugs that are highly lipophilic, such as many
steroid hormones, are o ten able to pass through the hydro-
phobic lipid environment o the plasma membrane without
special channels or transporters and thereby gain access to
intracellular targets.
Drug-induced alterations in receptor shape can allow
drugs bound to cell sur ace receptors to a ect unctions
inside cells. Many cell sur ace receptors have extracellular
domains that are linked to intracellular e ector molecules by
receptor domains that span the plasma membrane and extend
into the cytoplasm. In some cases, changing the shape o
the extracellular domain can alter the con ormation o the
membrane-spanning and/or intracellular domains o the
receptor, resulting in a change in receptor unction. In other
cases, drugs can cross-link the extracellular domains o two
receptor molecules, orming a dimeric receptor complex that
activates e ector molecules inside the cell.
All o these actors—drug and receptor structure, the
chemical orces in uencing drug–receptor interaction, drug
solubility in water and in the plasma membrane, and the
unction o the receptor in its cellular environment—con er
substantial specif city on the interactions between drugs
and their target receptors. This book discusses numerous
examples o drugs that can gain access and bind to receptors,
induce con ormational changes in the receptors, and thereby
produce biochemical and physiologic e ects. Specif city o
drug–receptor binding suggests that, armed with the knowl-
edge o the structure o a receptor, one could theoretically
design a drug that interrupts or enhances receptor activity.
This process, known as rational drug design, could poten-
tially increase the e f cacy and reduce the toxicity o drugs
by optimizing their structure so that they bind more selec-
tively to their targets. Rational drug design was f rst used to
develop highly selective agents such as the antiviral prote-
ase inhibitor ritonavir and the antineoplastic tyrosine kinase
inhibitor imatinib. Indeed, urther rounds o rational drug
design have led to the development o second-generation
protease inhibitors and antineoplastics with high a f nity or
the mutated drug targets that can evolve in patients who de-
velop resistance to f rst-generation drugs. The rational drug
design approach is discussed in greater detail in Chapter 51,
Drug Discovery and Preclinical Development.
MOLECULAR AND CELLULAR
DETERMINANTS OF DRUG SELECTIVITY
The ideal drug would interact only with a molecular target
that causes the desired therapeutic e ect but not with molec-
ular targets that cause unwanted adverse e ects. Although
no such drug has yet been discovered (i.e., all drugs cur-
rently in clinical use have the potential to cause adverse
e ects as well as therapeutic e ects; see Chapter 6, Drug
Toxicity), pharmacologists can take advantage o several de-
terminants o drug selectivity in an attempt to reach this goal.
Selectivity o drug action can be con erred by at least two
classes o mechanisms, including (1) the cell-type specif c-
ity o receptor subtypes and (2) the cell-type specif city o
receptor–e ector coupling.
Although many potential receptors or drugs are widely
distributed among diverse cell types, some receptors are
more limited in their distribution. Systemic administration o
drugs that interact with such localized receptors can result in
a highly selective therapeutic e ect. For example, drugs that
target ubiquitous processes such as DNA synthesis are likely
to cause signif cant toxic side e ects; this is the case with
many currently available chemotherapeutics or the treat-
ment o cancer. Other drugs that target cell-type restricted
processes such as acid generation in the stomach may have
ewer adverse e ects. Imatinib, or example, is an extremely
selective drug because the BCR-Abl protein is not expressed
in normal (noncancerous) cells. In general, the more re-
stricted the cell-type distribution o the receptor targeted by
a particular drug, the more selective the drug is likely to be.
Similarly, even though many di erent cell types may ex-
press the same molecular target or a drug, the e ect o that
drug may di er in the various cell types because o di er-
ential receptor–e ector coupling mechanisms or di erential
requirements or the drug target in the various cell types.
For example, although voltage-gated calcium channels are
ubiquitously expressed in the heart, cardiac pacemaker cells
are relatively more sensitive to the e ects o calcium chan-
nel blocking agents than are cardiac ventricular muscle cells.
This di erential e ect is attributable to the act that action po-
tential propagation depends mainly on the action o calcium
channels in cardiac pacemaker cells, whereas sodium chan-
nels are more important than calcium channels in the action
potentials o ventricular muscle cells. In general, the more
the receptor–e ector coupling mechanisms di er among the
various cell types that express a particular molecular target
or a drug, the more selective the drug is likely to be.
MAJ OR TYPES OF DRUG RECEPTORS
Given the great diversity o drug molecules, it might seem
likely that the interactions between drugs and their molecular
targets would be equally diverse. This is only partly true. In act,
most o the currently understood drug–receptor interactions
can be classif ed into six major groups. These groups com-
prise the interactions between drugs and (1) transmembrane
 C h a p t e r 1 Drug–Receptor Interactions 7

A B C D

α β
γ
GDP

FIGURE 1-3. Major types of interactions between drugs and receptors. Most drug–receptor interactions can be divided into six groups, our o which are
shown here. A. Drugs can bind to ion channels spanning the plasma membrane, causing an alteration in the channel’s conductance. B. Heptahelical recep-
tors spanning the plasma membrane are unctionally coupled to intracellular G proteins. Drugs can in uence the actions o these receptors by binding to
the extracellular sur ace or transmembrane region o the receptor. C. Drugs can bind to the extracellular domain o a transmembrane receptor and cause a
change in signaling within the cell by activating or inhibiting an enzymatic intracellular domain (rectangular box) o the same receptor molecule. D. Drugs can
di use through the plasma membrane and bind to cytoplasmic or nuclear receptors. This is o ten the pathway used by lipophilic drugs (e.g., drugs that bind
to steroid hormone receptors). Additionally, drugs can bind to enzymes and other targets in the extracellular space and to cell sur ace adhesion receptors
without the need to cross the plasma membrane (not shown).

ion channels; (2) transmembrane receptors coupled to intra-
cellular G proteins; (3) transmembrane receptors with linked
enzymatic domains; (4) intracellular receptors, including en-
zymes, signal transduction molecules, transcription actors,
structural proteins, and nucleic acids; (5) extracellular targets;
and (6) cell sur ace adhesion receptors (Fig. 1-3). Table 1-2
provides a summary o each major interaction type.
Knowing whether and to what extent a drug activates or
inhibits its target provides valuable in ormation about the in-
teraction. Although pharmacodynamics (the e ects o drugs
on the human body) is covered in detail in the next chapter, it
is use ul to state brief y the major pharmacodynamic relation-
ships between drugs and their targets be ore examining the mo-
lecular mechanisms o drug–receptor interactions. Agonists are
molecules that, upon binding to their targets, cause a change
in the activity of those targets. Full agonists bind to and acti-
vate their targets to the maximal extent possible. For example,
acetylcholine binds to the nicotinic acetylcholine receptor and
induces a con ormational change in the receptor-associated ion
channel rom a nonconducting to a ully conducting state. Par-
tial agonists produce a submaximal response upon binding to
their targets. Inverse agonists cause constitutively active targets
to become inactive. Antagonists inhibit the ability of their tar-
gets to be activated (or inactivated) by physiologic or pharma-
cologic agonists. Drugs that directly block the binding site o
a physiologic agonist are called competitive antagonists ; drugs
that bind to other sites on the target molecule, and thereby pre-
vent the con ormational change required or receptor activation
(or inactivation), may be either noncompetitive or uncompetitive
antagonists (see Chapter 2). As the mechanism o each drug–
receptor interaction is outlined in the next several sections, it
will be use ul to consider at a structural level how these di er-
ent pharmacodynamic e ects could be produced.
Transmembrane Ion Channels
Many cellular unctions require the passage o ions and
other hydrophilic molecules across the plasma membrane.

TABLE 1-2 Six Major Types of Drug–Receptor Interactions

RECEPTOR TYPE SITE OF DRUG–RECEPTOR INTERACTION SITE OF RESULTANT ACTION EXAMPLES
Transmembrane ion Extracellular, intrachannel, or intracellular Cytoplasm Amlodipine, diazepam,
channel lidocaine, omeprazole

Transmembrane linked to Extracellular or intramembrane Cytoplasm Albuterol, loratadine,

intracellular G protein losartan, metoprolol

Transmembrane with Extracellular or intracellular Cytoplasm Erlotinib, insulin, nesiritide,

linked enzymatic sunitinib
domain

Intracellular Cytoplasm or nucleus Cytoplasm or nucleus Atorvastatin, doxycycline,

levothyroxine, paclitaxel

Extracellular target Extracellular Extracellular Dabigatran, donepezil,

etanercept, lisinopril

Adhesion Extracellular Extracellular Eptif batide, natalizumab

8 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
Specialized transmembrane channels regulate these pro-
cesses. The unctions o ion channels are diverse, including
undamental roles in neurotransmission, cardiac conduction,
muscle contraction, and secretion. Because o this, drugs tar-
geting ion channels can have a substantial impact on major
body unctions.
Three major mechanisms are used to regulate the activ-
ity o transmembrane ion channels. In some channels, the
conductance is controlled by ligand binding to the channel.
In other channels, the conductance is regulated by changes in
voltage across the plasma membrane. In still other channels,
the conductance is controlled by ligand binding to plasma
membrane receptors that are linked to the channel in some
way. The f rst group o channels is re erred to as ligand-
gated, the second as voltage-gated, and the third as second
messenger-regulated. Table 1-3 summarizes the mechanism
o activation and unction o each channel type.
Channels are generally highly selective or the ions they
conduct. For example, action potential propagation in neu-
rons o the central and peripheral nervous systems occurs as
a result o the synchronous stimulation o voltage-gated ion
channels that permit the selective passage o Na ions into
the cell. When the membrane potential in such a neuron be-
comes su f ciently positive, the voltage-gated Na channels
open, allowing a large in ux o extracellular sodium ions
that urther depolarizes the cell. The role o ion-selective
channels in action potential generation and propagation is
discussed in Chapter 8, Principles o Cellular Excitability
and Electrochemical Transmission.
Most ion channels share some structural similarity, re-
gardless o their ion selectivity, the magnitude o their
conductance, or their mechanism o activation (gating) or
inactivation. Ion channels are pore- orming macromolecules
consisting o one or more protein subunits that pass through
the plasma membrane. The ligand-binding domain can be ex-
tracellular, within the channel, or intracellular, whereas the
domain that interacts with other receptors or modulators is
most o ten intracellular. The structures o several ion chan-
nels have been determined to atomic resolution; the nico-
tinic acetylcholine (ACh) receptor provides an example o
the structure o an important ligand-gated ion channel. This
receptor consists o f ve subunits, each o which crosses the
TABLE 1-3 Three Major Types of Transmembrane Ion
Channels
MECHANISM OF
CHANNEL TYPE ACTIVATION FUNCTION
Ligand-gated Binding o ligand to Altered ion
channel conductance
Voltage-gated Change in Altered ion
transmembrane conductance
voltage gradient
Second messenger- Binding o ligand to Second
regulated transmembrane messenger
receptor with regulates ion
G protein-coupled conductance
cytosolic domain, o channel
leading to second
messenger generation
plasma membrane (Fig. 1-4). Two o the subunits have been
designated ; each contains a single extracellular binding
site or ACh. In the ree (nonliganded) state o the recep-
tor, the channel is occluded by amino acid side chains and
does not allow the passage o ions. Binding o two molecules
o acetylcholine to the receptor induces a con ormational
change that opens the channel and allows ion conductance.
Although the nicotinic ACh receptor appears to assume
only two states, open or closed, many ion channels assume
other states as well. For example, some ion channels are able
to become refractory or inactivated. In this state, the chan-
nel’s permeability cannot be altered or a certain period o
time, known as the channel’s re ractory period. The volt-
age-gated sodium channel undergoes a cycle o activation,
channel opening, channel closing, and channel inactiva-
tion. During the inactivation (re ractory) period, the channel
A
α α
γ
Liga nd binding s ite s
B
α α
O
Re ce ptor ga te clos e d
+
N
O
Ace tylcholine
Na +
α α
Na +
Re ce ptor ga te ope n
FIGURE 1-4. Ligand-gated nicotinic acetylcholine receptor. A. The plasma
membrane acetylcholine (ACh) receptor is composed o f ve subunits—two
subunits, a subunit, a subunit, and a subunit. B. The subunit has
been removed to show an internal schematic view o the receptor, demon-
strating that it orms a transmembrane channel. In the absence o ACh, the
receptor gate is closed, and cations (most importantly, sodium ions [Na ])
are unable to traverse the channel. C. When ACh is bound to both subunits,
the channel opens, and sodium can pass down its concentration gradient
into the cell.
 C h a p t e r 1 Drug–Receptor Interactions 9

cannot be reactivated or a number o milliseconds, even i
the membrane potential returns to a voltage that normally
stimulates the channel to open. Some drugs bind with di er-
ent a f nities to di erent states o the same ion channel. This
state-dependent binding is important in the mechanism o
action o some local anesthetic and antiarrhythmic drugs, as
discussed in Chapters 12 (Local Anesthetic Pharmacology)
and 24 (Pharmacology o Cardiac Rhythm), respectively.
Two important classes o drugs that act by altering the
conductance o ion channels are the local anesthetics and the
benzodiazepines. Local anesthetics block the conductance
o sodium ions through voltage-gated sodium channels in
neurons that transmit pain in ormation rom the periphery to
the central nervous system, thereby preventing action poten-
tial propagation and, hence, pain perception (nociception).
Benzodiazepines also act on the nervous system, but by a
di erent mechanism. These drugs inhibit neurotransmission
in the central nervous system by potentiating the ability o
the neurotransmitter gamma-aminobutyric acid (GABA) to
increase the conductance o chloride ions across neuronal
membranes, thereby driving the membrane potential urther
away rom its threshold or activation.
Transmembrane G Protein-Coupled Receptors
G protein-coupled receptors are the most abundant class o
receptors in the human body. These receptors are exposed at
the extracellular sur ace o the plasma membrane, traverse
the membrane, and possess intracellular regions that acti-
vate a unique class o signaling molecules called G proteins .
(G proteins are so named because they bind the guanine nu-
cleotides GTP and GDP.) G protein-coupled signaling mech-
anisms are involved in many important processes, including
vision, ol action, and neurotransmission.
G protein-coupled receptors have seven transmembrane
regions within a single polypeptide chain. Each transmem-
brane region consists o a single helix, and the heli-
ces are arranged in a characteristic structural moti that is
similar in all members o this receptor class. The extracel-
lular domain o this class o proteins usually contains the
ligand-binding region, although some G protein-coupled
receptors bind ligands within the transmembrane domain
o the receptor. G proteins have and subunits that are
noncovalently linked in the resting state. Stimulation o a
G protein-coupled receptor causes its cytoplasmic domain to
bind and activate a nearby G protein, whereupon the sub-
unit o the G protein exchanges GDP or GTP. The -GTP
subunit then dissociates rom the subunit, and the or
subunit di uses along the inner lea et o the plasma mem-
brane to interact with a number o di erent e ectors. These
e ectors include adenylyl cyclase, phospholipase C, various
ion channels, and other classes o proteins. Signals medi-
ated by G proteins are usually terminated by the hydrolysis
o GTP to GDP, which is catalyzed by the inherent GTPase
activity o the subunit (Fig. 1-5).
One major role o the G proteins is to activate the production
o second messengers ; that is, signaling molecules that convey
the input provided by the f rst messenger—usually an endog-
enous ligand or an exogenous drug—to cytoplasmic e ectors
(Fig. 1-6). The activation o cyclases such as adenylyl cyclase ,
which catalyzes the production o the second messenger cyclic
adenosine-3′,5′-monophosphate (cAMP), and guanylyl cyclase ,
which catalyzes the production o cyclic guanosine-3′,5′-
monophosphate (cGMP), constitutes the most common path-
way linked to G proteins. In addition, G proteins can activate the
enzyme phospholipase C (PLC), which, among other unctions,
plays a key role in regulating the concentration o intracellular

Re ce ptor
Effe ctor
A

1 Agonis t unbinding 1 Agonis t binding

2 GTP hydrolys is 2 GTP -GDP e xcha nge
α β
3 He te rotrime ric γ 3 G prote in a ctiva tion
G prote in re cons titute d GDP

Agonis t
Effe ctor a ctiva te d GTP

C B

1 α -GTP diffus ion to e ffe ctor

β α 2 Effe ctor a ctiva tion α β
γ γ
GTP GTP

GDP

FIGURE 1-5. Receptor-mediated activation of a G protein and the resultant effector interaction. A. In the resting state, the and subunits o a G protein
are associated with one another, and GDP is bound to the subunit. B. Binding o an extracellular ligand (agonist) to a G protein-coupled receptor causes
the exchange o GTP or GDP on the subunit. C. The subunit dissociates rom the subunit, which di uses to interact with e ector proteins. Interac-
tion o the GTP-associated subunit with an e ector activates the e ector. In some cases (not shown), the subunit can also activate e ector proteins.
Depending on the receptor subtype and the specif c G iso orm, G can also inhibit the activity o an e ector molecule. The subunit possesses intrinsic
GTPase activity, which leads to hydrolysis o GTP to GDP. This leads to reassociation o the subunit with the subunit, and the cycle can begin again.
10 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

A Agonis t
TABLE 1-4 The Major G Protein Families and Examples
Re ce ptor Ade nylyl cycla s e of Their Actions
G PROTEIN ACTIONS
G-stimulatory (Gs ) Activates Ca 2 channels, activates adenylyl
cyclase
β αs
γ G-inhibitory (Gi) Activates K channels, inhibits adenylyl cyclase
GTP
ATP cAMP Go Inhibits Ca 2 channels

Gq Activates phospholipase C
PKA
G12/13 Diverse ion transporter interactions

P rote in phos phoryla tion

B be grouped into f ve major amilies—G-stimulatory (Gs),

P LC G-inhibitory (Gi), Go, Gq, and G12/13. Examples o the e ects
o these iso orms are shown in Table 1-4. The di erential
unctioning o these G proteins, some o which may couple
PIP2 DAG
in di erent ways to the same receptor in di erent cell types,
P KC is likely to be important or the potential selectivity o uture
(a ctive )
β αq drugs. The subunits o G proteins can also act as sec-
γ
GTP ond messenger molecules, although their actions are not as
P KC
completely characterized.
IP3
One important class in the G protein-coupled receptor
Ca 2+ amily is the -adrenergic receptor group. The most thor-
oughly studied o these receptors have been designated 1,
Ca 2 + 2, and 3. As discussed in more detail in Chapter 11, Ad-

P rote in phos phoryla tion

renergic Pharmacology, 1 receptors play a role in control-
ling heart rate; 2 receptors are involved in the relaxation o
smooth muscle; and 3 receptors play a role in the mobiliza-
FIGURE 1-6. Activation of adenylyl cyclase (AC) and phospholipase C tion o energy by at cells. Each o these receptors is stimu-
(PLC) by G proteins. G proteins can interact with several di erent types o lated by the binding o endogenous catecholamines, such as
e ector molecules. The subtype o G protein that is activated o ten deter- epinephrine and norepinephrine , to the extracellular domain
mines which e ector the G protein will activate. Two o the most common G o the receptor. Epinephrine binding induces a con orma-
subunits are G s and G q, which stimulate adenylyl cyclase and phospholi- tional change in the receptor and thereby activates G pro-
pase C, respectively. A. When stimulated by G s , adenylyl cyclase converts teins associated with the cytoplasmic domain o the receptor.
ATP to cyclic AMP (cAMP). cAMP then activates protein kinase A (PKA), The activated (GTP-bound) orm o the G protein activates
which phosphorylates a number o specif c intracellular proteins. B. When
adenylyl cyclase, resulting in increased intracellular cAMP
stimulated by G q, phospholipase C (PLC) cleaves the membrane phospho-
lipid phosphatidylinositol-4,5-bisphosphate (PIP2) into diacylglycerol (DAG)
levels and downstream cellular e ects. Table 1-5 indicates
and inositol-1,4,5-trisphosphate (IP3). DAG di uses in the membrane to acti-
vate protein kinase C (PKC), which then phosphorylates specif c cellular pro-
teins. IP3 stimulates release o Ca 2 rom the endoplasmic reticulum into the
TABLE 1-5 Tissue Localization and Action of
cytosol. Calcium release also stimulates protein phosphorylation events that
lead to changes in protein activation. Although not shown, the subunits
-Adrenergic Receptors
o G proteins can also a ect certain cellular signal transduction cascades.
TISSUE
RECEPTOR LOCALIZATION ACTION
calcium. Upon activation by a G protein, PLC cleaves the mem- 1 Sinoatrial (SA) node Increases heart rate
brane phospholipid phosphatidylinositol-4,5-bisphosphate o heart
(PIP2) to the second messengers diacylglycerol (DAG) and Cardiac muscle Increases contractility
inositol-1,4,5-trisphosphate (IP3). IP3 triggers the release o Adipose tissue Increases lipolysis
Ca2 rom intracellular stores, thereby dramatically increasing
Bronchial smooth Dilates bronchioles
the cytosolic Ca2 concentration and activating downstream 2
muscle
molecular and cellular events. DAG activates protein kinase Gastrointestinal Constricts sphincters and
C, which then mediates other molecular and cellular events smooth muscle relaxes gut wall
including smooth muscle contraction and transmembrane ion Uterus Relaxes uterine wall
transport. All o these events are dynamically regulated, so that Bladder Relaxes bladder
the di erent steps in the pathways are activated and inactivated Liver Increases gluconeogenesis
with characteristic kinetics. and glycolysis
A large number o G protein iso orms have been identi- Pancreas Increases insulin release
f ed, each with unique e ects on its targets. Based on the Adipose tissue Increases lipolysis
3
primary sequence o the G subunit, these iso orms can
 C h a p t e r 1 Drug–Receptor Interactions 11

FIGURE 1-7. Major types of transmembrane receptors with linked

enzymatic domains. There are f ve major categories o transmembrane re-
A ceptors with linked enzymatic domains. A. The largest group is composed
o receptor tyrosine kinases . A ter ligand-induced activation, these recep-
tors dimerize and transphosphorylate tyrosine residues in the receptor and,
o ten, on target cytosolic proteins. Examples o receptor tyrosine kinases
include the insulin receptor and many growth actor receptors. B. Some
Tyr Tyr
receptors can act as tyrosine phosphatases. These receptors dephos-
P Tyr Tyr P
phorylate tyrosine residues either on other transmembrane receptors or on
cytosolic proteins. Many cells o the immune system have receptor tyro-
Tyros ine kina s e Cytopla s mic sine phosphatases. C. Some tyrosine kinase-associated receptors lack a
a ctivity prote in def nitive enzymatic domain, but binding o ligand to the receptor triggers
Tyr P Tyr
activation o receptor-associated protein 1 (termed nonreceptor tyrosine
kinases ) that then phosphorylate tyrosine residues on certain cytosolic
proteins. D. Receptor serine/threonine kinases phosphorylate serine and
B threonine residues on certain target cytosolic proteins. Members o the
TGF- super amily o receptors are in this category. E. Receptor guanylyl
cyclases contain a cytosolic domain that catalyzes the ormation o cGMP
rom GTP. The receptor or B-type natriuretic peptide is one o the receptor
guanylyl cyclases that has been well characterized.

Tyros ine phos pha ta s e some o the diverse tissue localizations and actions o the
a ctivity
P Tyr Tyr
-adrenergic receptors.

Transmembrane Receptors with Linked

C
Enzymatic Domains
The third major class o cellular drug targets consists o
transmembrane receptors that transduce an extracellular li-
Activa te d kina s e gand-binding interaction into an intracellular action through
the activation o a linked enzymatic domain. The enzymatic
Ina ctive
kina s e Tyros ine kina s e domain may be part o the receptor itsel or part o a cyto-
a ctivity solic protein that is recruited to the receptor in response to
Tyr P Tyr receptor activation. Such receptors play roles in a diverse set
o physiologic processes, including cell metabolism, growth,
and di erentiation. Receptors that have a linked enzymatic
D domain can be grouped into f ve major classes based on their
cytoplasmic mechanism o action (Fig. 1-7). All o these
receptors are single–membrane-spanning proteins, in con-
trast to the seven–membrane-spanning moti present in G
protein-coupled receptors. Many receptors with enzymatic
S e r/Thr P S e r/Thr cytosolic domains orm dimers or multisubunit complexes
to transduce their signals.
Many receptors with linked enzymatic domains modi y
S e rine /thre onine
kina s e a ctivity proteins by adding or removing phosphate groups to or rom
S e r/Thr P S e r/Thr
specif c amino acid residues. Phosphorylation is a ubiq-
uitous mechanism of protein signaling. The large negative
charge o phosphate groups can dramatically alter the three-
E dimensional structure o a protein and thereby change that
protein’s activity. In addition, phosphorylation is easily re-
versible, thus allowing this signaling mechanism to act spe-
cif cally in time and space.

Receptor Tyrosine Kinases

Gua nylyl cycla s e
The largest group o transmembrane receptors with enzy-
a ctivity matic cytosolic domains is the receptor tyrosine kinase am-
GTP cGMP
ily. These receptors transduce signals rom many hormones
and growth actors by phosphorylating tyrosine residues on
the cytoplasmic tail o the receptor. This leads to recruitment
and subsequent tyrosine phosphorylation o cytosolic signal-
ing molecules. When aberrantly expressed or overexpressed,
growth actor-responsive receptor tyrosine kinases (such as
epidermal growth actor receptor [EGFR], HER2/neu, and
vascular endothelial growth actor receptor [VEGFR]) are
12 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
associated with a wide array o cancers; these receptor tyro-
sine kinases are the targets o several monoclonal antibody
and small-molecule inhibitor drugs (see Chapter 40, Phar-
macology o Cancer: Signal Transduction).
The insulin receptor is a well-characterized receptor
tyrosine kinase. This receptor consists o two extracellular
subunits that are covalently linked to two membrane-
spanning subunits. Binding o insulin to the subunits
results in a change in con ormation o the adjacent subunits,
causing the subunits to move closer to one another on the
intracellular side o the membrane. The proximity o the
two subunits promotes a transphosphorylation reaction,
in which one subunit phosphorylates the other (autophos-
phorylation). The phosphorylated tyrosine residues then act
to recruit other cytosolic proteins, known as insulin receptor
substrate (IRS) proteins. Type 2 diabetes mellitus may, in
some cases, be associated with de ects in post-insulin recep-
tor signaling; thus, understanding the insulin receptor signal-
ing pathways is relevant or the potential design o rational
therapeutics. The mechanism o insulin receptor signaling is
discussed in more detail in Chapter 31, Pharmacology o the
Endocrine Pancreas and Glucose Homeostasis.
Receptor Tyrosine Phosphatases
Just as receptor tyrosine kinases phosphorylate the tyro-
sine residues o cytoplasmic proteins, receptor tyrosine
phosphatases remove phosphate groups rom specif c tyro-
sine residues. In some cases, this may be an example o re-
ceptor convergence (discussed later), where the di erential
e ects o two receptor types can negate one another. How-
ever, receptor tyrosine phosphatases possess novel signaling
mechanisms as well. Many receptor tyrosine phosphatases
are ound in immune cells, where they regulate cell activa-
tion. These receptors are discussed urther in Chapter 46,
Pharmacology o Immunosuppression.
Tyrosine Kinase-Associated Receptors
Tyrosine kinase-associated receptors constitute a diverse
amily o proteins that, although lacking inherent cata-
lytic activity, recruit active cytosolic signaling proteins in a
ligand-dependent manner. These cytosolic proteins are also
called (somewhat con usingly) nonreceptor tyrosine kinases .
Ligand activation o cell sur ace tyrosine kinase-associated
receptors causes the receptors to cluster together. This clus-
tering event recruits cytoplasmic proteins that are then acti-
vated to phosphorylate other proteins on tyrosine residues.
Thus, the downstream e ect is much like that o receptor
tyrosine kinases, except that tyrosine kinase-associated re-
ceptors rely on a nonreceptor kinase to phosphorylate target
proteins. Important examples o tyrosine kinase-associated
receptors include cytokine receptors and a number o other
receptors in the immune system. These receptors are dis-
cussed in detail in Chapter 46.
Receptor Serine/Threonine Kinases
Some transmembrane receptors are capable o catalyzing the
phosphorylation o serine or threonine residues on cytoplas-
mic protein substrates. Ligands or such receptors are typi-
cally members o the trans orming growth actor (TGF- )
super amily. Many receptor serine/threonine kinases are
important mediators o cell growth and di erentiation that
have been implicated in cancer progression and metastasis.
While there are many approved drugs that target cytosolic
serine/threonine kinases (see Intracellular Receptors below),
drugs selective or receptor serine/threonine kinases are
mainly in development.
Receptor Guanylyl Cyclases
As illustrated in Figure 1-6, the stimulation o G protein-
coupled receptors may cause activation and release o
G subunits, which, in turn, alter the activity o adenylyl and
guanylyl cyclases. In contrast, receptor guanylyl cyclases
have no intermediate G protein. Instead, ligand binding
stimulates intrinsic receptor guanylyl cyclase activity, in
which GTP is converted to cGMP. This is the smallest am-
ily o transmembrane receptors. B-type natriuretic peptide,
a hormone secreted by the ventricles in response to volume
overload, acts via a receptor guanylyl cyclase. Nesiritide ,
a recombinant version o the native peptide ligand, is ap-
proved or the treatment o decompensated heart ailure (al-
though it does not reliably improve outcomes), as discussed
in Chapter 21, Pharmacology o Volume Regulation.
Intracellular Receptors
The plasma membrane provides a unique barrier or drugs
that have intracellular receptors. Many such drugs are small
or lipophilic and are thus able to cross the membrane by
di usion. Others require specialized protein transporters or
acilitated di usion or active transport into the cell.
Intracellular Enzymes and Signal Transduction
Molecules
Enzymes are common intracellular drug targets. Many drugs
that target intracellular enzymes exert their e ect by altering
the enzyme’s production o critical signaling or metabolic
molecules. Vitamin K epoxide reductase, a cytosolic enzyme
involved in the post-translational modif cation o glutamate res-
idues in certain coagulation actors, is the target o the antico-
agulant drug warfarin. HMG-CoA reductase, the rate-limiting
enzyme in cholesterol synthesis, is the target o atorvastatin and
the other lipid-lowering statins. Many inhibitors o cytosolic
signal transduction molecules are approved or in development.
For example, inhibitors o the serine/threonine kinase mTOR
(such as everolimus ) are used to prevent rejection o trans-
planted organs, to treat certain cancers, and to prevent resteno-
sis in drug-eluting coronary stents.
Many other intracellular kinases play important roles in
cellular growth and di erentiation, and it is not surprising
that “gain-o - unction” mutations in these proteins can lead
to uncontrolled cell growth and cancer. Recall rom the in-
troductory case that chronic myeloid leukemia is associated
with the Philadelphia chromosome, which results rom a
reciprocal translocation between the long arms o chromo-
somes 9 and 22. The mutant chromosome codes or a con-
stitutively active tyrosine kinase re erred to as the BCR-Abl
protein. (BCR and Abl are short or “break-point cluster
region” and “Abelson,” respectively, the two chromosomal
regions that undergo translocation with high requency in
this orm o leukemia.) The constitutive activity o this kinase
results in phosphorylation o a number o cytosolic proteins,
leading to dysregulated myeloid cell growth and chronic
myeloid leukemia. Imatinib is a selective therapy or chronic
myeloid leukemia because it selectively targets the BCR-Abl
protein; the drug inhibits BCR-Abl activity by neutralizing
its ability to phosphorylate substrates. Imatinib was the f rst
example o a drug targeted selectively to tyrosine kinases,

and its success has led to the development o a number o
drugs that act by similar mechanisms. Such drugs include
second-generation drugs such as dasatinib and nilotinib
that are used to treat CML patients with imatinib-resistant
BCR-Abl iso orms, as well as the inhibitors o growth
actor-responsive receptor tyrosine kinases discussed above.
Indeed, the kinase targets o antineoplastic drugs are diverse.
For instance, sorafenib targets both receptor tyrosine kinases
and intracellular serine/threonine kinases, and vemurafenib
is a recently approved late-stage melanoma treatment that
targets a specif c mutant o the serine/threonine kinase
B-RAF. As a f nal example, idelalisib is a recently approved
phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) in-
hibitor used to treat certain leukemias and lymphomas (see
Chapter 40).
Transcription Factors
The transcription regulatory actors are important intracel-
lular receptors that are targeted by lipophilic drugs. All pro-
teins in the body are encoded by DNA. The transcription
o DNA into RNA and the translation o RNA into protein
are controlled by a diverse set o molecules. Transcription o
many genes is regulated, in part, by the interaction between
lipid-soluble signaling molecules and transcription regu-
latory actors. Because o the undamental role played by
control o transcription in many biological processes, tran-
scription regulators (also called transcription factors ) are the
targets o some important drugs. Steroid hormones are a class
o lipophilic drugs that di use readily through the plasma
membrane and act by binding to transcription actors in the
cytoplasm or nucleus (Fig. 1-8).
Just as the shape o a transcription actor governs the
drugs to which it binds, the shape also determines where on
the genome the transcription actor attaches and which co-
activator or corepressor molecules bind to it. By activating or
inhibiting transcription, thereby altering the intracellular or
extracellular concentrations o specif c gene products, drugs
that target transcription actors can have pro ound e ects
on cellular unction. The cellular responses to such drugs,
and the e ects that result rom these cellular responses in
tissues and organ systems, provide links between the mo-
lecular drug–receptor interaction and the e ects o the drug
on the organism as a whole. Because gene transcription is a
relatively slow and long-lasting process (minutes to hours),
drugs that target transcription actors o ten require a longer
period o time or the onset o action to take place, and have
longer lasting e ects, than do drugs that alter more transient
processes such as ion conductance (seconds to minutes).
Structural Proteins
Structural proteins are another important class o intracellu-
lar drug targets. For example, the antimitotic vinca alkaloids
bind to tubulin monomers and prevent the polymerization o
this molecule into microtubules. Inhibition o microtubule
ormation arrests the a ected cells in metaphase, making the
vinca alkaloids use ul antineoplastic drugs.
Nucleic Acids
Nucleic acids are a ourth subset o intracellular drug tar-
gets. Some small-molecule drugs bind directly to RNA or
ribosomes; these include important antibiotics (such as
doxycycline and azithromycin) that block translation in target
microorganisms. DNA- and RNA-binding chemotherapeutic
C h a p t e r 1 Drug–Receptor Interactions 13
S te roid hormone
Hormone
re ce ptor
A Cha pe rone
Nucle us
B
DNA
C
FIGURE 1-8. Lipophilic molecule binding to an intracellular transcription
factor. A. Small lipophilic molecules can diffuse through the plasma mem-
brane and bind to intracellular transcription factors. In this example, steroid
hormone binding to a cytosolic hormone receptor is shown, although some
receptors of this class may be located in the nucleus before ligand binding.
B. Ligand binding triggers a conformational change in the receptor (and
often, as shown here, dissociation of a chaperone repressor protein) that
leads to transport of the ligand–receptor complex into the nucleus. In the
nucleus, the ligand–receptor complex typically dimerizes. In the example
shown, the active form of the receptor is a homodimer (two identical recep-
tors binding to one another), but heterodimers (such as the thyroid hormone
receptor and the retinoid Xreceptor) may also form. C. The dimerized ligand–
receptor complex binds to DNA and may then recruit coactivators or core-
pressors (not shown). These complexes alter the rate of gene transcription,
leading to a change (either up or down) in cellular protein expression.
agents (such as doxorubicin) are mainstays o treatment or
many cancers. Drugs composed o nucleic acids can also tar-
get nucleic acids. Antisense therapeutics (such as the recently
approved drug mipomersen) bind target mRNA to block tran-
scription o specif c proteins. With continued development
o such antisense approaches and o related RNA inter er-
ence (RNAi) therapeutics, such targeting could someday en-
able physicians to routinely modi y the expression levels o
specif c gene transcripts. To date, technical challenges in de-
livering such therapeutics to their targets have limited their
utility to specialized applications.
Extracellular Targets
Many important drug receptors are enzymes with active sites
located outside the plasma membrane. The extracellular
environment consists o a milieu o proteins and signaling
molecules. Many o these proteins serve a structural role,
and others are used to communicate in ormation between
cells. Enzymes that modi y the molecules mediating these
important signals can in uence physiologic processes such
as vasoconstriction and neurotransmission. One example o
this class o receptors is the angiotensin converting enzyme
(ACE), which converts angiotensin I to the potent vasocon-
strictor angiotensin II. ACE inhibitors are drugs that inhibit
14 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

this enzymatic conversion and thereby lower blood pressure
(among other e ects; see Chapter 21). Another example is
acetylcholinesterase , which degrades acetylcholine a ter
this neurotransmitter is released rom cholinergic neurons.
Acetylcholinesterase inhibitors enhance neurotransmis-
sion at cholinergic synapses by preventing neurotransmit-
ter degradation at these sites (see Chapter 10, Cholinergic
Pharmacology).
Some extracellular targets are not enzymes. For example,
several proteins, including monoclonal antibodies, are used
to target soluble cytokines and block them rom interacting
with their endogenous receptors. One set o such drugs is the
anti-TNF- agents, including etanercept, in iximab, adalim-
umab, and others, which are commonly used to treat autoim-
mune diseases such as rheumatoid arthritis (see Chapter 46).
Cell Sur ace Adhesion Receptors
Cells o ten interact directly with other cells to per orm spe-
cif c unctions or to communicate in ormation. The orma-
tion o tissues and the migration o immune cells to a site
o in ammation are examples o physiologic processes that
require cell–cell adhesive interactions. A region o contact
between two cells is termed an adhesion, and cell–cell adhe-
sive interactions are mediated by pairs o adhesion receptors
on the sur aces o the individual cells. In many cases, several
such receptor–counter-receptor pairs combine to secure a
f rm adhesion, and intracellular regulators control the activ-
ity o the adhesion receptors by changing their a f nity or
by controlling their expression and localization on the cell
sur ace. Adhesion receptors also mediate adhesion o cells to
the extracellular matrix. Several adhesion receptors involved
in the in ammatory response are attractive targets or selec-
tive inhibitors. Inhibitors o a specif c class o adhesion re-
ceptors, known as integrins , have entered the clinic in recent
years, and these drugs are used in the treatment o a range
o conditions including thrombosis (abciximab, eptif batide ),
in ammatory bowel disease (vedolizumab), and multiple
sclerosis (natalizumab) (see Chapter 23, Pharmacology o
Hemostasis and Thrombosis, and Chapter 46).
PROCESSING OF SIGNALS
RESULTING FROM DRUG–RECEPTOR
INTERACTIONS
Many cells in the body are continuously inundated with mul-
tiple inputs, some stimulatory and some inhibitory. How do
cells integrate these signals to produce a coherent response?
G proteins and other second messengers appear to provide
important points o integration. As noted above, relatively
ew second messengers have been identif ed, and it is un-
likely that many more remain to be discovered. Thus, second
messengers are an attractive candidate mechanism or pro-
viding cells with a set o common points upon which numer-
ous outside stimuli could converge to generate a coordinated
cellular e ect (Fig. 1-9).
Ion concentrations provide another point o integra-
tion or cellular e ects because the cellular concentration
o a particular ion is the result o the integrated activity o
multiple ionic currents that both increase and decrease the
concentration o the ion within the cell. For example, the
contractile state o a smooth muscle cell is a unction o
the intracellular calcium ion concentration, which is de-
termined by several di erent Ca2 conductances. These
conductances include calcium ion leaks into the cell and
calcium currents into and out o the cytoplasm through
specialized channels in the plasma membrane and smooth
endoplasmic reticulum.
Because the magnitude o cellular response is o ten
considerably greater than the magnitude o the stimulus
that caused the response, cells appear to have the ability
to ampli y the e ects o receptor binding. G proteins pro-
vide an excellent example o signal amplif cation. Ligand
binding to a G protein-coupled receptor activates a single
G protein molecule. This G protein molecule can then bind
to and activate many e ector molecules, such as adenylyl
cyclase, which can then generate an even greater number
o second messenger molecules (in this example, cAMP).
Another example o signal amplif cation is “trigger Ca2 ”
or calcium-induced calcium release, in which a small in ux

Liga nd 1 Ade nylyl cycla s e Liga nd 2

Re ce ptor Re ce ptor

αs β αs αs αi αi β αi
γ γ
GDP GTP GTP GTP GTP GDP
ATP cAMP cAMP ATP

Ne t re s ult = inte gra te d e ffe ct

FIGURE 1-9. Signaling convergence o two receptors. A limited number of mechanisms are used to transduce intracellular signal cascades. In some
cases, this allows for convergence, where two different receptors have opposite effects that tend to negate one another in the cell. In a simple example, two
different G protein-coupled receptors could be stimulated by different ligands. The receptor shown on the left is coupled to G s , a G protein that stimulates
adenylyl cyclase to catalyze the formation of cAMP. The receptor shown on the right is coupled to G i, a G protein that inhibits adenylyl cyclase. When both
of these receptors are activated simultaneously, they can attenuate or even neutralize each other, as shown. Sometimes, signaling through a pathway may
alternate as the two receptors are sequentially activated.

o Ca2 through voltage-gated Ca2 channels in the plasma
membrane “triggers” the release o larger amounts o Ca2
rom intracellular stores into the cytoplasm.
CELLULAR REGULATION OF DRUG–
RECEPTOR INTERACTIONS
Drug-induced activation or inhibition o a receptor o ten
has a lasting impact on the receptor’s subsequent respon-
siveness to drug binding. Mechanisms that mediate such
e ects are important because they prevent overstimulation
that could lead to cellular damage or adversely a ect the
organism as a whole. Many drugs show diminishing e -
ects over time; this phenomenon is called tachyphylaxis .
In pharmacologic terms, the receptor and the cell become
desensitized to the action o the drug. Mechanisms o de-
sensitization can be divided into two types: homologous ,
in which the e ects o agonists at only one type o re-
ceptor are diminished, and heterologous , in which the e -
ects o agonists at two or more types o receptors are
coordinately diminished. Heterologous desensitization is
thought to be caused by drug-induced alteration in a com-
mon point o convergence in the signaling pathways acti-
vated by the involved receptors, such as a shared e ector
molecule.
Many receptors exhibit desensitization. For example, the
cellular response to repeated stimulation o -adrenergic
receptors by epinephrine diminishes steadily over time
(Fig. 1-10). -Adrenergic receptor desensitization is medi-
ated by epinephrine-induced phosphorylation o the cyto-
plasmic tail o the receptor. This phosphorylation promotes
the binding o -arrestin to the receptor; in turn, -arrestin
inhibits the receptor’s ability to stimulate the G protein Gs.
With lower levels o activated Gs present, adenylyl cyclase
produces less cAMP. In this manner, repeated cycles o
ligand–receptor binding result in smaller and smaller cel-
lular e ects. Other molecular mechanisms have even more
pro ound e ects, completely turning o the receptor to
stimulation by ligand. The latter phenomenon, re erred to
as inactivation, may also result rom phosphorylation o the
receptor; in this case, the phosphorylation completely blocks
the signaling activity o the receptor or causes removal o the
receptor rom the cell sur ace.
Another mechanism that can a ect the cellular response
caused by drug–receptor binding is called refractoriness.
Receptors that assume a refractory state ollowing activa-
tion require a period o time to pass be ore they can be
stimulated again. As noted above, voltage-gated sodium
channels, which mediate the f ring o neuronal action po-
tentials, are subject to re ractory periods. A ter channel
opening induced by membrane depolarization, the voltage-
gated sodium channel spontaneously closes and cannot
be reopened or some period o time (called the refractory
period). This inherent property o the channel determines
the maximum rate at which neurons can be stimulated and
transmit in ormation.
The e ect o drug–receptor binding can also be in uenced
by drug-induced changes in the number o receptors on or
in a cell. One example o a molecular mechanism by which
receptor number can be altered is called down-regulation.
In this phenomenon, prolonged receptor stimulation by li-
gand induces the cell to endocytose and sequester receptors
C h a p t e r 1 Drug–Receptor Interactions 15
P
A P hos phoryla tion by
P
P P
β-a rre s tin P
P KA a nd/or β ARK P P
P binding
β-a rre s tin
Agonis t
G prote in binding
pre ve nte d
B S e que s tra tion
C De gra da tion
Endos ome
Lys os ome
FIGURE 1-10. -Adrenergic receptor regulation. Agonist-bound
-adrenergic receptors activate G proteins, which then stimulate adeny-
lyl cyclase activity (not shown). A. Repeated or persistent stimulation of
the receptor by agonist results in phosphorylation of amino acids at the
C-terminus of the receptor by protein kinase A (PKA) and/or -adrenergic
receptor kinase ( ARK). -Arrestin then binds to the phosphorylated domain
of the receptor and blocks Gs binding, thereby decreasing adenylyl cyclase
(effector) activity. B. Binding of -arrestin also leads to receptor sequestra-
tion into endosomal compartments via clathrin-mediated endocytosis (not
shown), effectively neutralizing -adrenergic receptor signaling activity.
The receptor can then be recycled and reinserted into the plasma mem-
brane. C. Prolonged receptor occupation by an agonist can lead to receptor
down-regulation and eventual receptor degradation. Cells can also reduce
the number of receptors by inhibiting the transcription or translation of the
gene coding for the receptor (not shown).
in endocytic vesicles. This sequestration prevents the re-
ceptors rom coming into contact with ligands, resulting
in cellular desensitization. When the stimulus that caused
the receptor sequestration subsides, the receptors can be
recycled to the cell sur ace and thereby rendered unctional
again (Fig. 1-10). Cells also have the ability to alter the
rates o synthesis or degradation o receptors and thereby
to regulate the number o receptors available or drug
binding. Receptor sequestration and alterations in recep-
tor synthesis and degradation occur on a longer time scale
than does phosphorylation and have longer lasting e ects
as well. Table 1-6 provides a summary o the mechanisms
by which the e ects o drug–receptor interactions can be
regulated.
16 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
TABLE 1-6 Mechanisms of Receptor Regulation
MECHANISM DEFINITION
Tachyphylaxis Repeated administration of the same dose of a
drug results in a diminishing effect of the drug
over time
Desensitization Decreased ability of a receptor to respond to
stimulation by a drug or ligand
Homologous Decreased response at a single type of
receptor
Heterologous Decreased response at two or more types of
receptor
Inactivation Loss of ability of a receptor to respond to
stimulation by a drug or ligand
Refractory After a receptor is stimulated, a period of time
is required before the next drug–receptor
interaction can produce an effect
Down-regulation Repeated or persistent drug–receptor interaction
results in removal of the receptor from sites
where subsequent drug–receptor interactions
could take place
DRUGS THAT DO NOT FIT THE DRUG–
RECEPTOR MODEL
Although most drugs interact with one o the basic recep-
tor types outlined above, others act by nonreceptor-mediated
mechanisms. Two examples are the osmotic diuretics and
the antacids.
Diuretics control uid balance in the body by altering the
relative rates o water and ion absorption and secretion in
the kidney. Many o these drugs act on ion channels. One
class o diuretics, however, alters water and ion balance not
by binding to ion channels or G protein-coupled receptors
but by changing the osmolarity in the nephron directly. The
sugar mannitol, which is used mainly to treat increased in-
tracranial pressure, is secreted into the lumen o the nephron
and increases the osmolarity o the urine to such a degree
that water is drawn rom the peritubular blood into the
lumen. This uid shi t serves to increase the volume o urine
while decreasing the blood volume.
Another class o drugs that does not f t the drug–receptor
model is the antacids, which are used to treat gastroesopha-
geal re ux disease and peptic ulcer disease. Unlike antiul-
cer agents that bind to receptors involved in the physiologic
generation o gastric acid, antacids act nonspecif cally by
absorbing or chemically neutralizing stomach acid. Ex-
amples o these agents include bases such as NaHCO3 and
Mg(OH)2.
CONCLUSION AND FUTURE
DIRECTIONS
Although the molecular details o drug–receptor interactions
vary widely among drugs o di erent classes and receptors
o di erent types, the undamental mechanisms o action
described in this chapter serve as paradigms or the principles
o pharmacodynamics. The ability to classi y drugs based on
their receptors and mechanisms o action makes it possible
to simpli y the study o pharmacology, because the molecu-
lar mechanism o action o a drug can usually be linked to its
cellular, tissue, organ, and system levels o action. In turn, it
becomes easier to understand how a given drug mediates its
therapeutic e ects and its unwanted or adverse e ects in a
particular patient. The major aim o modern drug develop-
ment is to identi y drugs that are highly selective by tailoring
drug molecules to unique targets responsible or disease. As
knowledge o drug development and the genetic and patho-
physiologic basis o disease progresses, physicians and sci-
entists will learn to combine the molecular specif city o a
drug with the genetic and pathophysiologic specif city o the
drug target to provide more and more selective therapies.
Acknowledgment
We thank Jose B. Simon, Christopher W. Cairo, and Zachary
S. Morris or their valuable contributions to this chapter in
the First, Second, and Third Editions o Principles o Phar-
macology: The Pathophysiologic Basis o Drug Therapy.
Suggested Reading
Alexander SP, Mathie A, Peters JA. Guide to Receptors and Channels
(GRAC), 5th ed. Br J Pharmacol 2011;164(suppl 1):S1–S324. (Brie over-
views o molecular targets or drugs, organized by types o receptors.)
Katritch V, Cherezov V, Stevens RC. Structure- unction o the G protein-
coupled receptor super amily. Annu Rev Pharmacol Toxicol 2013;53:
531–556. (Reviews recent structural insights into G protein-coupled
receptors.)
Kole R, Krainer AR, Altman S. RNA therapeutics: beyond RNA inter-
erence and antisense oligonucleotides. Nat Rev Drug Discov 2012;11:
125–140. (Highlights early successes, therapeutic mechanisms, and re-
maining challenges in the development o RNA-based therapies.)
Lagerström MC, Schiöth HB. Structural diversity o G protein-coupled
receptors and signif cance or drug discovery. Nat Rev Drug Discov
2008;7:339–357. (Discusses the f ve amilies o G protein-coupled recep-
tors, with an eye toward uture drug development.)
Pratt WB, Taylor P, eds. Principles o drug action: the basis o pharmacol-
ogy. 3rd ed. New York: Churchill Livingstone; 1990. (Contains a detailed
discussion o drug–receptor interactions.)
Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF, Babu
MM. Molecular signatures o G protein-coupled receptors. Nature 2013;
494:185–194. (Comparative analysis o structures, ligand binding, and
con ormational changes o G protein-coupled receptors.)
Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase
inhibitors. Nat Rev Cancer 2009;9:28–39. (Discusses dysregulation o
protein kinases in cancer and targeting o these molecules by drugs such
as imatinib.)
 Agon
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a n ta g o n is t
C D
2
Pharmacodynamics
Q u e n t in J . Ba c a a n d David E. Go la n

Agonis
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iiss t b iinding
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C omp mpe p e ttiti
& CASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 18
itivveeNoncncom
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nntta vege Rooni nnis
ecep
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itsorrtAntagonistss . . . . . . . . N o n c o m p e tit
. . . . . . . . . 22
DRUG–RECEPTOR BI N ING. . . . . . . . . . . . . . . . . . . bindin
BIND bindd in g Partial
binding Nonreceptor Antagonists . . . . . . . . . . . . . . . . . . . .
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bind i n d in g
DOSE–RESPONSE RELA ATITIONSHIPS . . . . . . . . . . . . . . . . . . . . . . . . 18 Agonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Graded Dose–Respponnse s e Relat
elatiionships . . . . . . . . . . . . . . . . . . . 18 Invee rs
rsee Agonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
Quan
Qu anta
tall Dose–Response Re Relalationships . . . . . . . . . . . . . . . . . . . 19 Spare Recept ptor
orss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
DRUG–RECEPTOR INTERACTIONS . . . . . . . . . . . . . . . . . . . . . . . . . 20 CONCEPTS IN THERAPEUTICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
A i t . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Agonists Therapeutic Index and Therapeutic Wi Window
ndow
d w . . . . . . . . . . . . . . 25
Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 CONCLUSION AND FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . . 26
Competitive Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . 21 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

INTRODUCTION Consider the simpsimplest

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Pharma
Pharmacodynamics
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o a drug on the body. These e ects are typically described kon
in quantitative terms. The previous chapter considered the L RÆ
¨ LR Equation 2-1
molecular interactions by which pharmacologic agents exert koff

their e ects. The integration o these molecular actions into

an e ect on the organism as a whole is the subject addressed
in this chapter. It is important to describe the e ects o a drug
quantitatively in order to determine appropriate dose ranges
or patients, as well as to compare the potency, e f cacy,
and sa ety o one drug to that o another.
DRUG–RECEPTOR BINDING
The study o pharmacodynamics is based on the concept o
drug–receptor binding. When either a drug or an endogenous
ligand (such as a hormone or neurotransmitter) binds to its
receptor, a response may result rom that binding interac-
tion. When a su f cient number o receptors are bound (or
“occupied”) on or in a cell, the cumulative e ect o receptor
“occupancy” may become apparent in that cell. At some point,
all o the receptors may be occupied, and a maximal response
may be observed (an exception is the case o spare receptors;
see below). When the response occurs in many cells, the e ect
can be seen at the level o the organ or even the patient. But
this all starts with the binding o drug or ligand to a recep-
tor ( or the purpose o discussion, “drug” and “ligand” will
be used interchangeably or the remainder o this chapter).
A model that accurately describes the binding o drug to re-
ceptor would there ore be use ul in predicting the e ect o the
drug at the molecular, cellular, tissue (organ), and organism
(patient) levels. This section describes one such model.
where L is ligand (drug), R is ree receptor, and LR is bound
drug–receptor complex. At equilibrium, the raction o re-
ceptors in each state is dependent on the dissociation con-
stant, Kd, where Kd ko /kon. Kd is an intrinsic property o
any given drug–receptor pair. Although Kd varies with tem-
perature, the temperature o the human body is relatively
constant, and it can there ore be assumed that Kd is a con-
stant or each drug–receptor combination.
According to the law o mass action, the relationship be-
tween ree and bound receptor can be described as ollows:
[L][R] [L][R]
Kd , rearranged to [LR] Equation 2-2
[LR] Kd
where [L] is ree ligand concentration, [R] is ree receptor con-
centration, and [LR] is ligand–receptor complex concentration.
Because Kd is a constant, some important properties o the
drug–receptor interaction can be deduced rom this equation.
First, as ligand concentration is increased, the concentration
o bound receptors increases. Second, and not so obvious, is
that as ree receptor concentration is increased (as may happen,
or example, in disease states or upon repeated exposure to a
drug), bound receptor concentration also increases. There ore,
an increase in the effect of a drug can result from an increase in
the concentration of either the ligand or the receptor.
The remainder o the discussion in this chapter, how-
ever, assumes that the total concentration o receptors is a

17
18 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
Ad m ira l X is a 66-ye a r-o ld re tire d s u b -
m a rin e ca p ta in w ith a 70 p a ck–ye a r
s m o kin g h is to ry (tw o p a cks a d a y o r
35 ye a rs ) a n d a a m ily h is to ry o co ro -
n a ry a rte ry d is e a s e . He ta ke s d a ily a to r-
va s ta tin to re d u ce h is ch o le s te ro l le ve l a n d a s p irin to
re d u ce h is ris k o co ro n a ry a rte ry o cclu s io n .
On e d a y, w h ile w o rkin g in h is w o o d s h o p , Ad m i-
ra l X b e g in s to e e l tig h tn e s s in h is ch e s t. Th e e e lin g
ra p id ly b e co m e s p a in u l, a n d th e p a in ra d ia te s d o w n
h is le t a rm . He ca lls 911, a n d a n a m b u la n ce tra n s -
p o rts h im to th e lo ca l e m e rg e n cy d e p a rtm e n t. A te r
e va lu a tio n , it is d e te rm in e d th a t Ad m ira l X is h a vin g
a n a n te rio r m yo ca rd ia l in a rctio n . Be ca u s e Ad m ira l X
ca n n o t b e tra n s e rre d to a h o s p ita l w ith a ca rd ia c
ca th e te riza tio n la b o ra to ry w ith in 120 m in u te s o
f rs t m e d ica l co n ta ct, a n d h e h a s n o re la tive co n -
tra in d ica tio n s to th ro m b o lytic th e ra p y (s u ch a s u n -
co n tro lle d hyp e rte n s io n , h is to ry o s tro ke , o r re ce n t
s u rg e ry), th e p h ys icia n in itia te s th e ra p y w ith b o th
a th ro m b o lytic a g e n t, tis s u e -typ e p la s m in o g e n a cti-
va to r (tPA), a n d a n a n tico a g u la n t, h e p a rin . Be ca u s e
o th e ir lo w th e ra p e u tic in d ice s , im p ro p e r d o s in g o
constant, so that [LR] [R] [Ro]. This allows Equation
2-2 to be arranged as ollows:
[L][R]
[Ro] [R] [LR] [R]
Kd
[L] ˆ
[R] Ê1 Equation 2-3
Ë Kd ¯
Solving or [R] and substituting Equation 2-3 into Equation
2-2 yields:
[Ro] [L]
[LR] , rearranged to
[L] Kd
[LR] [L]
Equation 2-4
[Ro] [L] Kd
Note that the le t side o this equation, [LR]/[Ro], represents
the raction o all available receptors that are bound to ligand.
Figure 2-1 shows two plots o Equation 2-4 or the bind-
ing o two hypothetical drugs to the same receptor. These
plots are known as drug–receptor binding curves . Figure 2-1A
shows a linear plot, and Figure 2-1B shows the same plot on
a semilogarithmic scale. Because drug responses occur over
a wide range o doses (concentrations), the semilog plot is
o ten used to display drug–receptor binding data. The two
drug–receptor interactions are characterized by di erent val-
ues o Kd. In this case, KdA KdB.
Notice rom Figure 2-1 that maximal drug–receptor bind-
ing occurs when [LR] is equal to [Ro], or [LR]/[Ro] 1. Also
notice that, according to Equation 2-4, when [L] Kd, then
[LR]/[Ro] Kd/2Kd ½. Thus, Kd can be def ned as the con-
centration o ligand at which 50% o the available receptors
are occupied.
b o th o th e s e d ru g s ca n h a ve d ire co n s e q u e n ce s
(h e m o rrh a g e a n d d e a th ). Th e re o re , Ad m ira l X is
clo s e ly m o n ito re d , a n d th e p h a rm a co lo g ic e e ct o
th e h e p a rin is m e a s u re d p e rio d ica lly b y te s tin g th e
p a rtia l th ro m b o p la s tin tim e (PTT). Ad m ira l X’s s ym p -
to m s re s o lve ove r th e n e xt s e ve ra l h o u rs , a lth o u g h
h e re m a in s in th e h o s p ita l o r m o n ito rin g . He is d is -
ch a rg e d a te r 4 d a ys in th e h o s p ita l; h is d is ch a rg e
m e d ica tio n s in clu d e a to rva s ta tin , a s p irin , a te n o lo l,
lis in o p ril, a n d clo p id o g re l o r s e co n d a ry p re ve n tio n
o m yo ca rd ia l in a rctio n .
Questions
1 . How does the molecular interaction o a drug with its re-
ceptor determine the potency and e f cacy o the drug?
2 . Why does the act that a drug has a low therapeutic
index mean that the physician must use greater care
in its administration?
3 . What properties o certain drugs, such as aspirin,
allow them to be taken without monitoring o plasma
drug levels, whereas other drugs, such as heparin, re-
quire such monitoring?
DOSE–RESPONSE RELATIONSHIPS
The pharmacodynamics o a drug can be quantif ed by the
relationship between the dose (concentration) o the drug
and the organism’s (patient’s) response to that drug. One
might intuitively expect the dose–response relationship to
be related closely to the drug–receptor binding relationship,
and this turns out to be the case or many drug–receptor
combinations. Thus, a use ul assumption at this stage o dis-
cussion is that the response to a drug is proportional to the
concentration o receptors that are bound (occupied) by the
drug. This assumption can be quantif ed by the ollowing
relationship:
response [DR] [D]
Equation 2-5
max response [Ro] [D] Kd
where [D] is the concentration o ree drug, [DR] is the
concentration o drug–receptor complexes, [Ro] is the con-
centration o total receptors, and Kd is the equilibrium disso-
ciation constant or the drug–receptor interaction. (Note that
the right side o Equation 2-5 is equivalent to Equation 2-4,
with [D] substituted or [L].) The generalizability o this as-
sumption is examined below.
There are two major types o dose–response relationships—
graded and quantal. The di erence between the two types is
that graded dose–response relationships describe the e ect
o various doses o a drug on an individual, whereas quantal
relationships show the e ect o various doses o a drug on a
population o individuals.
Graded Dose–Response Relationships
Figure 2-2 shows graded dose–response curves or two hy-
pothetical drugs that elicit the same biological response.

A Line a r
1.0
Drug A
Drug B
[LR]
0.5
[R o ]
0 0
KdA KdB
[L]
B S e miloga rithmic
1.0
Drug A
Drug B
[LR]
0.5
[R o ]
0 0
KdA KdB
[L]
FIGURE 2-1. Ligand–receptor binding curves. A. Linear graphs o drug–
receptor binding or two drugs with di erent values o Kd. B. Semilogarithmic
graphs o the same drug–receptor binding. Kd is the equilibrium dissocia-
tion constant or a given drug–receptor interaction—a lower Kd indicates
a tighter drug–receptor interaction (higher a f nity). Because o this rela-
tionship, Drug A, which has the lower Kd, will bind a higher proportion o
total receptors than Drug B at any given drug concentration. Notice that Kd
corresponds to the ligand concentration [L] at which 50% o the receptors
are bound (occupied) by ligand. [L] is the concentration o ree (unbound)
ligand (drug), [LR ] is the concentration o ligand–receptor complexes, and
[Ro] is the total concentration o occupied and unoccupied receptors. Thus,
[LR]/[Ro] is the fractional occupancy o receptors, or the raction o total
receptors that are occupied (bound) by ligand.
The curves are presented on both linear and semilogarithmic
scales. The curves are similar in shape to those in Figure 2-1,
consistent with the assumption that response is proportional
to receptor occupancy.
Two important parameters—potency and e f cacy—can
be deduced rom the graded dose–response curve. The po-
tency (EC50) o a drug is the concentration at which the drug
elicits 50% of its maximal response. The e f cacy (E max) is
the maximal response produced by the drug. In accordance
with the assumption stated above, e f cacy can be thought o
as the state at which receptor-mediated signaling is maximal
and, there ore, additional drug will produce no additional
response. This usually occurs when all the receptors are oc-
cupied by the drug. Some drugs, however, are capable o elic-
iting a maximal response when less than 100% o the drug’s
receptors are occupied; the remaining receptors can be called
spare receptors . This concept is discussed urther in the text
C h a p t e r 2 Pharmacodynamics 19
A Line a r
1.0
Drug A
Drug B
E
0.5
E MAX
EC 50 (A) EC 50 (B)
[L]
B S e miloga rithmic
1.0
Drug A
Drug B
E
0.5
E MAX
EC 50 (A) EC 50 (B)
[L]
FIGURE 2-2. Graded dose–response curves. Graded dose–response
curves demonstrate the e ect o a drug as a unction o its concentration.
A. Linear graphs o graded dose–response curves or two drugs. B. Semilog-
arithmic graphs o the same dose–response curves. Note the close resem-
blance to Figure 2-1: the raction o occupied receptors [LR]/[Ro] has been
replaced by the ractional e ect E/Emax, where E is a quantif able response to
a drug (e.g., an increase in blood pressure). EC50 is the potency o the drug, or
the concentration at which the drug elicits 50% o its maximal e ect. In the
f gure, Drug A is more potent than Drug B because it elicits a hal -maximal
e ect at a lower concentration than Drug B. Drugs A and B exhibit the same
e f cacy (the maximal response to the drug). Note that potency and e f cacy
are not intrinsically related—a drug can be extremely potent but have little
e f cacy, and vice versa. [L] is drug concentration, E is e ect, Emax is e f cacy,
and EC50 is potency.
that ollows. Note again that the graded dose–response curve
o Figure 2-2 bears a close resemblance to the drug–receptor
binding curve o Figure 2-1, with EC50 replacing Kd and Emax
replacing Ro.
Quantal Dose–Response Relationships
The quantal dose–response relationship plots the fraction
of the population that responds to a given dose of drug
as a function of the drug dose. Quantal dose–response
relationships describe the concentrations o a drug that pro-
duce a given e ect in a population. Figure 2-3 shows an
example o quantal dose–response curves. Because o di er-
ences in biological response among individuals, the e ects
o a drug are seen over a range o doses. The responses are
def ned as either present or not present (i.e., quantal, not
graded). Endpoints such as “sleep/no sleep” or “alive at
20 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

Cumula tive % e xhibiting Agonists

The ra pe utic e ffe ct Toxic e ffe ct Le tha l e ffe ct
An agonist is a molecule that binds to a receptor and stabi-
100 lizes the receptor in a particular conformation (usually, the
g
active conformation). When bound by an agonist, a typical
n
i
receptor is more likely to be in its active con ormation than
d
n
% Requiring dose to achieve
o
its inactive con ormation. Depending on the receptor, ago-
p
Therapeutic Toxic effect Lethal effect
s
nists may be drugs or endogenous ligands. A use ul model
e
effect
r
50 or understanding the relationship between agonist binding
s
l
a
and receptor activation is shown in Equation 2-6:
u
d
vi
R Æ
i
D ¨ D R*
d
n
I
Ø≠ Ø≠ Equation 2-6
%
0 Æ
DR ¨ DR*
ED50 TD50 LD50

Dos e
FIGURE 2-3. Quantal dose–response curves. Quantal dose–response
curves demonstrate the average e ect o a drug, as a unction o its con-
centration, in a population o individuals. Individuals are typically observed
or the presence or absence o a response (e.g., sleep or no sleep), and this
result is then used to plot the percentage o individuals who respond to each
dose o drug. Quantal dose–response relationships are use ul or predicting
the e ects o a drug when it is administered to a population o individuals
and or determining population-based toxic doses and lethal doses. These
doses are called the ED50 (dose at which 50% o subjects exhibit a therapeu-
tic response to a drug), TD50 (dose at which 50% o subjects experience a
toxic response), and LD50 (dose at which 50% o subjects die). Note that ED50
is the dose at which 50% o subjects respond to a drug, whereas EC50 (as
described in the previous f gure) is the dose at which a drug elicits a hal -
maximal e ect in an individual subject.
12 months/not alive at 12 months” are examples o quantal
responses; in contrast, graded dose–response relationships
are generated using scalar responses such as change in blood
pressure or heart rate. The goal is to generalize a result to a
population rather than to examine the graded e ect o di -
erent drug doses on a single individual. Types o responses
that can be examined using the quantal dose–response re-
lationship include e ectiveness (therapeutic e ect), toxicity
(adverse e ect), and lethality (lethal e ect). The doses that
produce these responses in 50% o a population are known
as the median effective dose (ED50), median toxic dose (TD50),
and median lethal dose (LD50), respectively.
DRUG–RECEPTOR INTERACTIONS
Many receptors or drugs can be modeled as having two con-
ormational states that are in reversible equilibrium with one
another. These two states are called the active state and the
inactive state . Many drugs unction as ligands or such recep-
tors and a ect the probability that the receptor exists pre er-
entially in one con ormation or the other. The pharmacologic
properties o drugs are o ten based on their e ects on the
state o their cognate receptors. A drug that, upon binding to
its receptor, avors the active receptor con ormation is called
an agonist; a drug that prevents agonist-induced activation
o the receptor is re erred to as an antagonist. Some drugs
do not f t neatly into this simple def nition o agonist and an-
tagonist; these include partial agonists and inverse agonists .
The ollowing sections describe these pharmacologic clas-
sif cations in more detail.
where D and R are unbound ( ree) drug and receptor concen-
trations, respectively, DR is the concentration o the agonist–
receptor complex, and R* indicates the active con ormation
o the receptor. For most receptors and agonists, R* and DR
are unstable species that exist only brie y and are quantita-
tively insignif cant compared to R and DR*. There ore, in
most cases, Equation 2-6 simplif es to
D RÆ
¨ DR** Equation 2-7
Note that Equation 2-7 is identical to Equation 2-1, which
was used or the analysis o drug–receptor binding. This
suggests that, or most receptors, agonist binding is propor-
tional to receptor activation. Some receptors, however, do
have limited stability in the R* and/or DR con ormations;
in these cases, Equation 2-6 must be revisited (see below).
Equation 2-6 can also be used to illustrate quantitatively
the concepts o potency and e f cacy. Recall that potency is
the agonist concentration required to elicit a hal -maximal
e ect, and e f cacy is the maximal e ect o the agonist.
Assuming that a receptor is not active unless bound to a drug
(i.e., R* is insignif cant compared to DR*), Equation 2-8
provides a quantitative description o potency and e f cacy:
kon k
D R Æ DR Æ DR* Equation 2-8
¨ ¨
koff k
Potency Efficacy
Here, k is the rate constant or receptor activation, and k
is the rate constant or receptor deactivation. This equation
demonstrates the relationship between potency (Kd ko /kon)
and agonist binding (D R ← → DR), as well as the relation-
ship between e f cacy (k /k ) and the con ormational change
→ DR*). These
required or activation o the receptor (DR ←
relationships are intuitive when we consider that more potent
drugs are those that have a higher a f nity or their receptors
(lower Kd), and more e f cacious drugs are those that cause a
higher raction o receptors to be activated.
Antagonists
An antagonist is a molecule that inhibits the action of an ago-
nist but has no effect in the absence of the agonist. Figure 2-4
shows one approach to classi ying the various types o an-
tagonists. Antagonists can be divided into receptor and non-
receptor antagonists. A receptor antagonist binds to either
the active site (agonist binding site) or an allosteric site on a
receptor. Binding o an antagonist to the active site prevents
the binding o the agonist to the receptor, whereas binding
 C h a p t e r 2 Pharmacodynamics 21

Anta gonis ts

Re ce ptor Nonre ce ptor

a nta gonis ts a nta gonis ts

Active s ite Allos te ric

binding binding

Re ve rs ible Irre ve rs ible Re ve rs ible Irre ve rs ible

Compe titive Noncompe titive Noncompe titive Che mica l P hys iologic
a nta gonis t a ctive s ite a llos te ric a nta gonis t a nta gonis t
a nta gonis t a nta gonis t

FIGURE 2-4. Antagonist classif cation. Antagonists can be categorized based on whether they bind to a site on the receptor or agonist (receptor antago-
nists) or interrupt agonist–receptor signaling by other means (nonreceptor antagonists). Receptor antagonists can bind either to the agonist (active) site
or to an allosteric site on the receptor; in either case, they do not a ect basal receptor activity (i.e., the activity o the receptor in the absence o agonist).
Agonist (active) site receptor antagonists prevent the agonist rom binding to the receptor. I the antagonist competes with the ligand or agonist site binding,
it is termed a competitive antagonist; high concentrations o agonist are able to overcome competitive antagonism. Noncompetitive active site antagonists
bind covalently or with very high a f nity to the agonist site, so that even high concentrations o agonist are unable to activate the receptor. Allosteric recep-
tor antagonists bind to the receptor at a site other than the agonist site. They do not compete directly with agonist or receptor binding, but rather alter the
Kd or agonist binding or inhibit the receptor rom responding to agonist binding. High concentrations o agonist are generally unable to reverse the e ect
o an allosteric antagonist. Nonreceptor antagonists all into two categories. Chemical antagonists sequester agonist and thus prevent the agonist rom
interacting with the receptor. Physiologic antagonists induce a physiologic response opposite to that o an agonist, but by a molecular mechanism that does
not involve the receptor or agonist.

o an antagonist to an allosteric site either alters the Kd or
agonist binding or prevents the con ormational change re-
quired or receptor activation. Receptor antagonists can also
be divided into reversible and irreversible antagonists ; that
is, antagonists that bind to their receptors reversibly and
those that bind irreversibly. Figure 2-5 illustrates the general
e ects o these antagonist types on agonist binding; more
detail is provided in the ollowing sections.
A nonreceptor antagonist does not bind to the same re-
ceptor as an agonist, but it nonetheless inhibits the ability o
an agonist to initiate a response. At the molecular level, this
inhibition can occur by inhibiting the agonist directly (e.g.,
using antibodies), by inhibiting a downstream molecule in
the activation pathway, or by activating a pathway that op-
poses the action o the agonist. Nonreceptor antagonists can
be divided into chemical antagonists and physiologic antag-
onists. Chemical antagonists inactivate an agonist be ore it
has the opportunity to act (e.g., by chemical neutralization);
physiologic antagonists cause a physiologic e ect opposite
to that induced by the agonist.
Competitive Receptor Antagonists
A competitive antagonist binds reversibly to the active site
of a receptor. Unlike an agonist, which also binds to the ac-
tive site o the receptor, a competitive antagonist does not
stabilize the con ormation required or receptor activation.
There ore, the antagonist blocks an agonist rom binding to
its receptor, while maintaining the receptor in the inactive
con ormation. Equation 2-9 is a modif cation o Equation 2-7
that incorporates the e ect o a competitive antagonist (A).
AR Æ
¨ A D RÆ
¨ DR* Equation 2-9
In this equation, a raction o the ree receptor molecules (R)
are unable to orm a drug (agonist)–receptor complex (DR*),
because receptor binding to the antagonist results in the

Agonis t
Agonis t Agonis t
Agonis t Allos te ric Compe titive
binding s ite a nta gonis t a nta gonis t
binding s ite Noncompe titive
A B C D a nta gonis t

Unbound re ce ptor Agonis t binding Compe titive a nta gonis t Noncompe titive a nta gonis t
binding binding

FIGURE 2-5. Types o receptor antagonists. A schematic illustrating the di erences between agonist (active) site and allosteric antagonists. A. The un-
bound inactive receptor. B. The receptor activated by agonist. Note the con ormational change induced in the receptor by agonist binding, or example, the
opening o a transmembrane ion channel. C. Agonist site antagonists bind to the receptor’s agonist site but do not activate the receptor; these agents block
agonist binding to the receptor. D. Allosteric antagonists bind to an allosteric site (di erent rom the agonist site) and thereby prevent receptor activation,
even when the agonist is bound to the receptor.
22 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

ormation o an antagonist–receptor complex (AR) instead.

In e ect, the ormation o the AR complex sets up a second A Compe titive a nta gonis t
equilibrium reaction that competes with the equilibrium or
agonist–receptor binding. Note that AR is incapable o un- 100
Agonis t a lone
dergoing a con ormational change to the active (R*) state o
the receptor.

e
s
n
Quantitative analysis yields the ollowing equation or

o
Agonis t + Anta gonis t

p
agonist (D) binding to the receptor in the presence o a com-

s
50

e
petitive antagonist (A):

R
%
[DR] [D]
Equation 2-10
[A]ˆ Anta gonis t a lone
[Ro] [D] Kd Ê1 0
Ë KA ¯

Equation 2-10 is similar to Equation 2-4, except that the e - B Noncompe titive a nta gonis t
ective Kd has been increased by a actor o (1 [A]/KA),
where KA is the dissociation constant or binding o the an-
tagonist to the receptor (i.e., KA [A][R]/[AR]). Because 100
Agonis t a lone
an increase in Kd is equivalent to a decrease in potency, the

e
presence o a competitive antagonist (A) reduces the potency

s
n
Agonis t + Anta gonis t
o an agonist (D) by a actor o (1 [A]/KA). Although the

o
p
s
potency o an agonist decreases as the concentration o com- 50

e
R
petitive antagonist increases, the e f cacy o the agonist is un-

a ected. This occurs because the agonist concentration [D]
can be increased to counteract (“outcompete”) the antago-
nist, thereby “washing out” or reversing the e ect o the
antagonist. Figure 2-6A shows the e ect o a competitive
antagonist on the agonist dose–response relationship. Note
that the competitive antagonist has the e ect o shi ting the
agonist dose–response curve to the right, causing a decrease
in agonist potency while maintaining agonist e f cacy.
Atorvastatin, the drug used in the case at the beginning o
this chapter to lower Admiral X’s cholesterol, is an example
o a competitive antagonist. Atorvastatin is a member o the
HMG-CoA reductase inhibitor (statin) class o lipid-lowering
drugs. HMG-CoA reductase is an enzyme that catalyzes the
reduction o HMG-CoA, which is the rate-limiting step in
cholesterol biosynthesis. The similarity between the chemi-
cal structures o statins and HMG-CoA allows the statin
molecule to bind to the active site o HMG-CoA reductase
and thereby to prevent HMG-CoA rom binding. This inhi-
bition is reversible because no covalent bonds are ormed
between the statin and the enzyme. Inhibition o HMG-CoA
reductase decreases endogenous cholesterol synthesis and
lowers the patient’s cholesterol levels. For a more detailed
discussion o the mechanism o action o atorvastatin and
other HMG-CoA reductase inhibitors, see Chapter 20, Phar-
macology o Cholesterol and Lipoprotein Metabolism.
Noncompetitive Receptor Antagonists
Noncompetitive antagonists can bind to either the active site
or an allosteric site o a receptor (Fig. 2-4). A noncompetitive
antagonist that binds to the active site o a receptor can bind
either covalently or with very high a f nity; in either case, the
binding is e ectively irreversible. Because an irreversibly
bound active site antagonist cannot be “outcompeted,” even
at high agonist concentrations, such an antagonist exhibits
noncompetitive antagonism.
A noncompetitive allosteric antagonist acts by prevent-
ing the receptor rom being activated, even when the agonist
is bound to the active site. An allosteric antagonist exhibits
noncompetitive antagonism regardless o the reversibility o
its binding, because such an antagonist acts not by competing
%
Anta gonis t a lone
0
Agonis t or a nta gonis t conce ntra tion
FIGURE 2-6. Antagonist effects on the agonist dose–response
relationship. Competitive and noncompetitive antagonists have di erent
e ects on potency (the concentration o agonist that elicits a hal -maximal
response) and e f cacy (the maximal response to an agonist). A. A competi-
tive antagonist reduces the potency o an agonist, without a ecting agonist
e f cacy. B. A noncompetitive antagonist reduces the e f cacy o an agonist.
As shown here, most allosteric noncompetitive antagonists do not a ect
agonist potency.
with the agonist or binding to the active site, but rather by
preventing receptor activation. The reversibility o antago-
nist binding is nonetheless important, because the e ect o
an irreversible antagonist does not diminish when the ree
(unbound) drug is eliminated rom the body, whereas the
e ect o a reversible antagonist can be “washed out” over
time as it dissociates rom the receptor (see Equation 2-9).
A receptor that is bound by a noncompetitive antago-
nist can no longer be activated by the binding o an agonist.
There ore, the maximal response (e f cacy) o the agonist is
reduced. A characteristic di erence between competitive and
noncompetitive antagonists is that competitive antagonists
reduce agonist potency, whereas noncompetitive antagonists
reduce agonist e f cacy. This di erence can be explained by
considering that a competitive antagonist continuously com-
petes or receptor binding, e ectively reducing the recep-
tor’s a f nity or an agonist without limiting the number o
available receptors. In contrast, a noncompetitive antagonist
removes unctional receptors rom the system, thereby lim-
iting the number o available receptors. Figures 2-6A and
2-6B compare the e ects o competitive and noncompetitive
antagonists on the agonist dose–response relationship.
Aspirin is one example o a noncompetitive antagonist.
This agent irreversibly acetylates cyclooxygenase, the enzyme
 C h a p t e r 2 Pharmacodynamics 23

responsible or generating thromboxane A2 in platelets. In the

absence o thromboxane A2 generation, platelet aggregation A
is inhibited. Because the inhibition is irreversible and plate-
100
lets are not capable o synthesizing new cyclooxygenase
molecules, the e ects o a single dose o aspirin last or 7 to
10 days (the time required or the bone marrow to generate Butyl
new platelets), even though the ree drug is cleared rom the He xyl
He ptyl
body much more rapidly.

n
o
i
t
Nonreceptor Antagonists

c
a
50

r
Nonreceptor antagonists can be divided into chemical an-

t
n
Octyl

o
tagonists and physiologic antagonists. A chemical antagonist

C
inactivates the agonist o interest by modi ying or sequester-

%
ing it, so that the agonist is no longer capable o binding
to and activating the receptor. Protamine is an example o a
chemical antagonist; this basic protein binds stoichiometri-
cally to the acidic heparin class o anticoagulants and thereby
0
inactivates these agents (see Chapter 23, Pharmacology o 10 -7 10 -6 10 -5 10 -4 10 -3
Hemostasis and Thrombosis). Because o this chemical an-
tagonism, protamine can be used to terminate the e ects o [D] (Mola r)
B
heparin rapidly.
A physiologic antagonist either blocks a receptor that me-
100
diates the physiologic response o the receptor or agonist or
activates a receptor that mediates a response physiologically Morphine
opposite to that o the receptor or agonist. For example, in
a
the treatment o hyperthyroidism, -adrenergic antagonists i
s
e
are used as physiologic antagonists to counteract the tachy-
g
l
50
a
cardic e ect o excess thyroid hormone. Excess thyroid hor-
n
Bupre norphine
A
mone produces tachycardia, at least in part, via up-regulation
%
o cardiac -adrenoceptors, and blocking -adrenergic stim-
ulation relieves the tachycardia (see Chapter 11, Adrenergic
Pharmacology, and Chapter 28, Pharmacology o the Thy- 0
roid Gland). 0.01 0.1 ED50 (B) ED50 (M) 10

Partial Agonists
A partial agonist is a molecule that binds to a receptor at its
active site but produces only a partial response, even when
all of the receptors are occupied (bound) by the agonist.
Figure 2-7A shows a amily o dose–response curves or
several ull and partial agonists. Each agonist acts by bind-
ing to the same site on the muscarinic acetylcholine (ACh)
receptor. Note that butyl trimethylammonium (TMA) is not
only more potent than longer chain derivatives at stimulating
muscle contraction but also more e f cacious than some o
the derivatives (e.g., the heptyl and octyl orms) at produc-
ing a greater maximal response. For this reason, butyl TMA
is a full agonist at the muscarinic ACh receptor, whereas the
octyl derivative is a partial agonist at this receptor.
Because partial agonists and ull agonists bind to the
same site on a receptor, a partial agonist can reduce the re-
sponse produced by a ull agonist. In this way, the partial
agonist can act as a competitive antagonist. For this reason,
partial agonists are sometimes called partial antagonists or
even mixed agonist-antagonists.
It is interesting to consider how an agonist could pro-
duce a less-than-maximal response i a receptor can exist
in only the active or the inactive state. This is an area o
current investigation, or which several hypotheses have
been proposed. Recall that Equation 2-6 was simplif ed to
Equation 2-7 based on the assumption that R and DR* are
much more stable than R* and DR. But what would happen
i a drug (call it a partial agonist) could stabilize DR as well
[D] (mg/kg)
FIGURE 2-7. Full and partial agonist dose–response curves. There are
many instances in which drugs that all act at the agonist site on the same
receptor produce di erent maximal e ects. A. Various alkyl derivatives o
trimethylammonium all stimulate muscarinic acetylcholine (ACh) recep-
tors to cause muscle contraction in the gut, but they produce di erent
maximal responses, even when all receptors are occupied. In this example,
the butyl and hexyl trimethylammonium derivatives are ull agonists—
although they have di erent potencies, they are both capable o eliciting
a maximal response. Agonists that produce only a partial response, such
as the heptyl and octyl derivatives, are called partial agonists . Note that
the dose–response curves o these partial agonists plateau at values less
than those o ull agonists. ACh acts as a ull agonist in this system (not
shown). B. Partial agonists may be more or less potent than ull agonists. In
this case, buprenorphine (ED50 0.3 mg/kg) is more potent than morphine
(ED50 1.0 mg/kg), although it cannot achieve the same maximal response
as the ull agonist. Buprenorphine is used clinically in the treatment o opioid
addiction, where it is desirable to use a partial agonist that is less e f cacious
than an addicting opioid such as heroin or morphine. Low concentrations
o the partial agonist buprenorphine bind tightly to the opioid receptor and
competitively inhibit the binding o the more e f cacious opioids. Very high
doses o buprenorphine show a paradoxically diminished analgesic e ect
that may be due to lower a f nity interactions o the drug with non–mu-opioid
receptors (not shown).
Another random document with
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of society gives the power to the mass of people to assert its own
tastes and demand its own enjoyments. To such a development the
universal success of Herz and Thalberg is related. It is because of
still further development that their wonders have become
commonplaces, not because either their purpose or their music is
intrinsically contemptible. Both these are respectable as
manifestations of energy and great labor; and that the two great
players achieved a victory which won the applause of the whole
world, indicates a streak of the hero in the cosmos of both.

III
We may conceive Herz and Thalberg each to be an infant Hercules,
strangling serpents in his cradle, if we compare them with Franz
Liszt, who, above all else, represents virtuosity grown to fully heroic
proportions. He was the great and universal hero in the history of
music. He cannot be dissociated from the public, the general world
over which he established his supremacy by feats of sheer muscular
or technical skill. Even the activity of his mind was essentially
empirical. Especially in the realm of pianoforte music he won his
unique place by colossal energy put to test or to experiment upon
the public through the instrument. The majority of his compositions in
this branch of music are tours de force.

His manifold activities in music all reveal the truly great virtuoso,
whom we may here define as an agent of highest efficiency between
a created art and the public to which it must be related. We will
presently analyze some of his compositions for the pianoforte, but
without presuming to draw from features of them so discovered any
conclusions as to their musical vitality or their æsthetic value. These
conclusions must be left to the wisdom and sense of posterity;
whatever they may prove to be, one cannot at present but recognize
in Liszt first and foremost the intermediary. He so conducted himself
in all his musical activities, which, taken in the inverse order of their
importance, show him as a writer upon subjects related to music, as
a conductor, as a composer, and as a pianist. He worked in an
indissoluble relation with the public, and by virtue of this relation
appears to us a hero of human and comprehensible shape, though
enormous, whose feet walked in the paths of men and women, and
whose head was not above the clouds in a hidden and secret
communion which we can neither define nor understand.

Many qualities in his character and in his person, which, of course,

are of no importance in estimating the value of his compositions,
made his peculiar relation with the public secure. His face was very
handsome, brilliantly so; he had a social charm which won for him a
host of friends in all the capitals of Europe; he was fascinating to
men and women in private, and in public exercised a seemingly
irresistible personal magnetism over his audiences. He was,
moreover, exceedingly generous and charitable, quick to befriend all
musicians, especially men younger than he, and to lend his aid in,
movements of public benefaction. He was an accomplished linguist,
and cosmopolitan, indeed international in his sympathies. As a
teacher he inspired his many pupils with an almost passionate
affection and feeling of loyal devotion. All these qualities set him
quite apart from the wizard Paganini, with whom alone his technical
mastery of his instrument was comparable. Paganini was wrapped in
mystery, whether he wove the veil himself or not; Liszt was
thoroughly a man of the world.

Liszt’s playing was stupendous. At least two influences fired him not
only to develop a technique which was limited only by the physically
impossible, but to establish himself as the unequalled player of the
age. Already as a youth when he first came to Paris this technique
was extraordinary, though probably not unmatched. It was the
wizardry of Paganini, whom he heard in Paris, that determined him
to seek an attainment hitherto undreamed of in skill with the
keyboard. This he achieved before he left Paris to journey away from
the world in Switzerland and Italy. During his absence Thalberg
came to Paris and took it by storm. Back came Liszt post-haste to
vanquish his rival and establish more firmly his threatened position.
The struggle was long and hotly fought, but the victory remained with
Liszt, who, though he had not that skill in a kind of melody playing
which was peculiar to Thalberg, towered far above his rival in virility,
in fire, and in variety.

We may thus imagine him established by force of arms as king of all

pianists. He never relinquished his royal prerogatives nor could he
tolerate a challenge of his power; but he proved himself most a hero
in the use to which he put this enormous power. He chose the
master’s highest privilege and made himself a public benefactor. It is
true that he never wholly discarded the outward trappings of royal
splendor. He played operatic fantasias like the rest; made, of his
own, fabrics which were of a splendor that was blinding. But the true
glory of his reign was the tribute he paid to men who had been
greater than kings in music and the service he rendered to his own
subjects in making known to them the masterpieces of these men,
the fugues of Bach, the last sonatas of Beethoven, the works of
Chopin. It was largely owing to Liszt that the general public was
educated to an appreciation of these treasures, even that it became
aware of its possession of them. It may be added that the pupils of
this man, who was the most outstanding and overpowering of all the
pianoforte virtuosi, made wholly familiar to the world a nobler
practice of virtuosity in service to great music. Here, however, must
be mentioned one great contemporary of Liszt’s, Clara Schumann,
who, possessed of greatest skill, made her playing, in even greater
degree than Liszt, the interpreter of great music. It is one of the
richest tributes to Liszt as a pianist that he may in some respects be
compared with that noble woman.

It seems to have been above all else the fire in Liszt’s playing which
made it what it was, a fire which showed itself in great flames of
sound, spreading with incredible rapidity up and down the keyboard,
which, like lightning, was followed by a prodigious thunder. Yet it was
a playing which might rival all the elements, furious winds,
tumultuous waters, very phenomena of sounds. Caricatures show
him in all sorts of amazing attitudes, and many draw him with more
than two hands, or more than five fingers to a hand. At the piano he
was like Jupiter with the thunder-bolts, Æolus with the winds of
heaven, Neptune with the oceans of the earth in his control. And at
the piano he made his way to the throne which perhaps no other will
ever occupy again.

Just what was the effect of Liszt’s accomplishments upon pianoforte

technique must be carefully considered, and such a consideration
will bring us to problems which we may venture to assert are of
profound interest to the pianist and to the musician. Broadly
speaking he expanded the range of technique enormously, which is
to say that he discovered many new effects and developed others
which had previously been but partially understood. The Douze
Études d’exécution transcendante may be taken to constitute a
registry of his technical innovations.

First, in these, and in all his music, he makes a free and almost
constant use of all the registers of the keyboard, the very low and the
very high more than they had been used before, and the middle with
somewhat more powerful scoring than was usual with any other
composers excepting Schumann. Particularly his use of the low
registers spread through the piano an orchestral thunder.

The ceaseless and rapid weaving together of the deepest and the
highest notes made necessary a wide, free movement of both arms,
and more remarkably of the left arm, because such rapid flights had
hardly been demanded of it before. The fourth étude, a musical
reproduction of the ride of Mazeppa, is almost entirely a study in the
movement of the arms, demanding of them, especially in the playing
of the inner accompaniment, an activity and control hardly less rapid
or less accurate than what a great part of pianoforte music had
demanded of the fingers.

It is in fact by recognizing the possibilities of movement in the arm

that Liszt did most to expand pianoforte technique. One finds not
only such an interplaying of the arms as that in ‘Mazeppa’ and other
of his compositions, but a playing of the arms together in octave
passages which leap over broadest distances at lightning speed.
Sometimes these passages are centred, or rather based, so to
speak, on a fixed point, from and to which the arms shoot out and
back, touching a series of notes even more remote from the base,
often being expected to cover the distance of nearly two octaves, as
in the beginning of the first concerto. There are samples of this
difficulty in ‘Mazeppa’; and also of other runs in octaves for both
hands, which are full of irregular and wide skips.

In the long and extremely rapid tremolos with which his music is
filled, it is again the arm which is exerted to new efforts. The last of
the études is a study in tremolo for the arm, and so is the first of the
Paganini transcriptions. The tremolo, it need hardly be said, is no
invention of Liszt’s, but no composer before him demanded either
such rapidity in executing it, or such a flexibility of the arm. The
tremolo divided between the two hands, as here in this last study,
and the rapid alternation of the two hands in the second study,
depend still further on the freedom of the arm. It is the arm that is
called upon almost ceaselessly in the tenth study; and the famous
Campanella in the Paganini series is only a tour de force in a lateral
movement of the arm, swinging on the wrist.

The series, usually chromatic, of free chords which one finds surging
up and down the keyboard, often for both hands, may well paralyze
the unpracticed arm; the somewhat bombastic climaxes, in which, à
la Thalberg, he makes a huge noise by pounding chords, are a task
for the arm. All of the last part of the eleventh étude, Harmonies du
soir, is a study for the arm. Indeed even the wide arpeggios, running
from top to bottom of the keyboard in bolder flight than Thalberg
often ventured upon, the rushing scales, in double or single notes,
the countless cadenzas and runs for both hands, all of these, which
depend upon velocity for their effect, are possible only through the
unmodified liberation of the arm.

All this movement of the arm over wide distances and at high speed
makes possible the broad and sonorous effects which may be said
to distinguish his music from that of his predecessors and his
contemporaries. It makes possible his thunders and his winds, his
lightnings and his rains. Thus he created a sort of grand style which
every one must admit to be imposing.
Beyond these effects it is difficult to discover anything further so
uniquely and so generally characteristic in his pianoforte style. He
demands an absolutely equal skill in both hands, frequently
throughout an entire piece. He calls for the most extreme velocity in
runs of great length, sometimes in whole pages; and for as great
speed in executing runs of double notes as in those of single. A
study like the Feux-Follets deals with a complex mixture of single
and double notes. All these things, however, can be found in the
works of Schumann, or Chopin, or even Beethoven. Yet it must be
said that no composer ever made such an extended use of them, nor
exacted from the player quite so much physical endurance and
sustained effort. Moreover, against the background of his effects of
the arm, they take on a new light, no matter how often they had a
share in the works of other composers.

It can hardly be denied, furthermore, that this new light which they
seem to give his music, by which it appears so different from that of
Schumann and even more from that of Chopin, is also due to the use
to which he puts them. With Liszt these things are indisputably used
wholly as effects. Liszt follows Thalberg, or represents a further
development of the idea of pianoforte music which Thalberg
represents. He deals with effects,—with, as we have said elsewhere
of Thalberg, masses of sound. Very few of his compositions for the
pianoforte offer a considerable exception, and with these we shall
have to do presently. The great mass of études, concert or salon
pieces, and transcriptions, those works in which he displays this
technique, are virtuoso music. He shows himself in them a
sensationalist composer. Therefore the music suffers by the
necessary limitations mentioned in connection with Herz and
Thalberg, with the difference that within these limitations Liszt has
crowded the utmost possible to the human hand.

His great resources still remain speed and noise. He can do no more
than electrify or stupefy. It must not be forgotten that in these
limitations lies the glory of his music, its quality that is heroic
because it wins its battles in the world of men and women. It is
superb in its physical accomplishment. It shows the mighty Hercules
in a struggle with no ordinary serpent, but with the hundred-headed
Hydra. Yet if he will electrify he must do so with speed that is
reckless, and if he will overpower with noise he must be brutal.
Hence the great sameness in his material, trills, arpeggios, scales,
and chromatic scales, which are no more than these trills, arpeggios,
scales, etc., even if they be filled up with all the notes the hand can
grasp. Hence also the passages of rapidly repeated chords in places
where he wishes to be imposing to the uttermost.

It would be an interesting experiment to take from Liszt’s pianoforte

music all these numerous effects and put them together in a volume;
then to classify them, and, having mastered three or four of the
formulas, to try to find any further difficulties. It is doubtful if, having
so mastered the few types, one would need to make great effort to
play the whole volume from cover to cover. And these effects
constitute the great substance of Liszt’s music. He fills piece after
piece with solid blocks of them. The page on which they are printed
terrifies the eye, yet they demand of the player only speed and
strength. Inasmuch as these may be presupposed in a theoretical
technique, the music is, theoretically, not technically difficult. The
higher difficulties of pianoforte playing are not to be met in music that
conforms to technical types, but in music the notes of which appear
in ever changing combinations and yet are of separate and individual
importance. Such music presents a new difficulty almost in every
measure. In playing it the mind must control each finger in its every
move, and may not attend in general but must attend in particular.
The player who can play the twelve études of Liszt will find the Well-
tempered Clavichord and the Preludes of Chopin more difficult to
play. In the tours de force of Liszt his technique is of itself effective;
in the music of Bach or Chopin it must be effectual. Having a
colossal technique he can play Liszt, but he must ever practise Bach
and Chopin.

IV
Liszt wrote a vast amount of music for the pianoforte. There is not
space to discuss it in detail, and, in view of the nature of it and the
great sameness of his procedures, such a discussion is not
profitable. For a study of its general characteristics it may be
conveniently and properly divided into three groups. These are made
up respectively of transcriptions, of a sort of realistic music heavily
overlaid with titles, and of a small amount of music which we may
call absolute, including a sonata and two concertos.

The transcriptions are well-nigh innumerable. Some he seems to

have made with the idea of introducing great orchestral
masterpieces into the family circle by means of the pianoforte. So we
may consider the transcriptions, or rather the reductions of the nine
symphonies of Beethoven, of the septet by the same composer, and
of the Symphonie Fantastique and the ‘Harold in Italy’ of Berlioz. He
has succeeded in making these works playable by ten fingers; but he
did not pretend to make them pianoforte music. He had an
astonishing skill in reading from full score at sight, and in these
reductions he put this skill at the service of the public.

In rearranging smaller works for the piano, such as songs of

Schumann, Chopin, Schubert, Mendelssohn, and Franz, he worked
far more for the pianist. He saw clearly the great problem which such
a rearrangement involved, that qualities in the human voice for which
these songs were conceived were wholly lacking in the pianoforte,
and that he must make up for this lack by an infusion of new material
which brought out qualities peculiar to the instrument. In so far as
possible he took the clue to these infusions from the accompaniment
to the songs he worked on. In some songs the accompaniment was
the most characteristic feature, or the most predominant element.
There his task was light. The transcription of the Erl King, for
example, meant hardly more than a division of the accompaniment
as Schubert wrote it between the two hands in such a way that the
right would be able to add the melody. There is practically nothing of
Liszt in the result. Schubert’s accompaniment was a pianoforte piece
in itself. Again, the accompaniment of ‘Hark, Hark, the Lark’ was
originally highly pianistic. But here the piano could sing but a dry
imitation of the melody; and Liszt therefore enriched the
accompaniment, preserving always its characteristic motive, but
expanding its range and adding little runs here and there, which by
awakening the harmonious sonority of the piano concealed its lack of
expressive power in singing melody. The result was a masterpiece of
pianoforte style in which the melody and graceful spirit of the song
were held fast.

Those songs the accompaniments of which were effective on the

pianoforte seemed to blossom again under his hand into a new
freshness. His skill was delicate and sure. Even in the case where
the accompaniment was without distinction he was often able so to
add arabesques in pianoforte style as to make the transcription
wholly pleasing to the ear. The arrangement of Chopin’s song, ‘The
Maiden’s Wish,’ offers an excellent example. Here, having little but a
charming melody and varied harmonies to work on, he made a little
piece of the whole by adding variations in piquant style. But often
where he had no accompaniment to suggest ideas to him, he was
either unsuccessful, as in the transcription of Wolfram’s air from
Tannhäuser, or overshot the mark in adding pianistic figuration, as in
that of Mendelssohn’s Auf Flügeln des Gesanges. He touched the
Schumann and Franz songs, too, only to mar their beauty.

It may be that these transcriptions served a good end by making at

least the names and the melodies of a number of immortal songs
familiar to the public, but there can be no doubt that these
masterpieces have proved more acceptable in their original form.
Most of Liszt’s transcriptions have fallen from the public stage.
Amateurs who have the skill to play them have the knowledge that,
for all their cleverness, they are not the songs themselves. And
those which have been kept alive owe their present state of being to
the favor of the pianist, who conceives them to be only pieces for his
own instrument.

The number of Liszt’s transcriptions in the style of fantasias is very

great. Like his predecessors and his contemporaries he made use of
any and every tune, and the airs or scenes from most of the favorite
operas. There are fantasias on ‘God Save the King’ and Le Carnaval
de Venise, on Rigoletto, Trovatore, and Don Giovanni. The name of
the rest is legion. The frequency with which a few of them are still
heard, would seem to prove that they at least have some virtue
above those compositions of Herz and Thalberg in a similar vein; but
most of them are essentially neither a better nor a worthier addition
to the literature of the instrument and have been discarded from it.
Those who admire Liszt unqualifiedly have said of these fantasias
that they are great in having reproduced the spirit of the original
works on which they were founded, that Liszt not only took a certain
melody upon which to work, but that he so worked upon it as to
intensify the original meaning which it took from its setting in the
opera. The Don Giovanni fantasia is considered a masterpiece in
thus expanding and intensifying at once.

But what, after all, is this long fantasia but a show piece of the
showiest and the emptiest kind? How is it more respectable than
Thalberg’s fantasia on themes from ‘Moses,’ except that it contains
fifty times as many notes and is perhaps fifty times louder and
faster? It is a grand, a superb tour de force; but the pianist who plays
it—and he must wield the power of the elements—reveals only what
he can do, and what Liszt could do. It can be only sensational. There
is no true fineness in it. It is massive, almost orchestral. The only
originality there is in it is in making a cyclone roar from the strings, or
thunder rumble in the distance and crash overhead. On the whole
the meretricious fantasia on Rigoletto is more admirable, because it
is more naïve and less pretentious.

This Reminiscenses de Don Juan par Franz Liszt, dedicated to his

Majesty Christian Frederick VIII of Denmark with respectueux et
reconnaissant hommage, begins with a long and stormy introduction,
the predominant characteristic of which is the chromatic scale. This
one finds blowing a hurricane; and there are tremolos like thunder
and sharp accents like lightning. The storm, however, having
accomplished its purpose of awe, is allowed to die away, and in its
calm wake comes the duet La ci darem la mano, which, if it needed
more beauty than that which Mozart gave it, may here claim that of
being excellently scored for the keyboard. Liszt has interpolated long
passages of pianistic fiorituri between the sections of it, at which one
cannot but smile. Then follow two variations of these themes, amid
which there is a sort of cadenza loosing the furious winds again, and
at the end of which there is a veritable typhoon of chromatic scales,
here divided between the two hands in octaves, there in thirds for the
right hand. The variations are rich in sound, but commonplace in
texture. Finally there is a Presto, which may be taken as a coda,
founded upon Don Giovanni’s air, Finch’ han dal vino, an exuberant
drinking song. The scoring of this is so lacking in ingenuity as well as
in any imposing feature as to be something of an anti-climax. It trips
along in an almost trivial manner, with a lot of tum-tum and a lot of
speed. Toward the end there is many a word of hair-raising import:
sotto voce, martellato, rinforzando, velocissimo precipitato,
appassionato energico, arcatissimo, strepitoso, and a few others, all
within the space of little over three pages. There is also another blast
or two of wind. In the very last measures there is nothing left but to
pound out heavy, full chords with a last exertion of a battle-scarred
but victorious gladiator. And in spite of all this the last section of the
work is wanting in weight to balance the whole, and it seems like a
skeleton of virtuosity with all its flesh gone. It must be granted that
the recurrence of the opening motives at moments in the middle of
the fray, and at the end, gives a theoretical unity of structure which
similar fantasias by Herz and Thalberg did not have; but on the
whole it might well be dispensed with from the work, which, in spite
of such a sop to the dogs of form, remains nothing but a pot-pourri
from a favorite opera.

This huge transcription, as well as the delicate arrangements of

songs, the transcriptions of the overtures to ‘William Tell’ and
Tannhäuser, and of Mendelssohn’s ‘Midsummer Night’s Dream’
music, as well as the elaborations of Schubert’s Waltzes and other
short pieces may, if you will, be taken as an instance of a
professional courtesy or public benefaction on the part of Liszt; but
they stand out none the less most conspicuously as virtuoso music.
What Liszt really did in them was to exploit the piano. They effect but
one purpose: that of showing what the piano can do. At the present
day, when the possibilities of the instrument are commonly better
known, they are a sort of punching bag for the pianist. Surely no one
hears a pianist play Liszt’s arrangement of the overture to
Tannhäuser with any sense of gratitude for a concert presentation of
Wagner’s music. Nor does one feel that the winds and thunders in
the Don Giovanni fantasia may cause Mozart to turn in his grave with
gratitude. One sees the pianist gather his forces, figuratively hitch up
his sleeves, and if one is not wholly weary of admiring the prowess
of man, one wets one’s lips and attends with bated breath.
Something is to be butchered to make a holiday in many ways quite
Roman.

V
The second group of music to be observed consists of original
pieces of a more or less realistic type. Nearly all have titles. There
are Impressions et Poésies, Fleurs mélodiques des Alpes,
Harmonies poétiques et réligieuses, Apparitions, Consolations,
Légendes and Années de pèlerinage. There are even portraits in
music of the national heroes of Hungary. In the case of some the title
is an after-thought. It indicates not what suggested the music but
what the music suggested. There are two charming studies, for
example, called Waldesrauschen and Gnomenreigen, which are
pure music of captivating character. They are no more program
music than Schumann’s ‘Fantasy Pieces,’ nor do they suffer in the
slightest from the limitations which a certain sort of program is held
to impose upon music. First of all one notices an admirable
treatment of the instrument. There is no forcing, no reckless speed
nor brutal pounding. Then the quality of the music is fresh and
pleasing, quite spontaneous; and both are delightful in detail.

Others are decidedly more realistic than most good music for the
pianoforte which had been written up to that time. Take, for example,
the two Legends, ‘The Sermon of the Birds to St. Francis of Assisi,’
and ‘St. Francis of Paule Walking on the Waves.’ These are picture
music. In the one there is the constant twitter and flight of birds, in
the other the surging of waters. Both are highly acceptable to the
ear, but perhaps more as sound than as music. They depend upon
effects, and the effects are those of imitation and representation. The
pieces lose half their charm if one does not know what they are
about.

There seems to be no end of the discussion which has raged over

the relative merits of so-called program music and absolute music. It
has little relation to the beauty of sound in both kinds; else the
triumphant beauty of much program music would have long since put
an end to it. The Liszt Legends are as delightful to the ear as any
other of his pieces which have no relation to external things. What
we have to observe is that they deal with effects, that is with masses
of sound—trills, scales and other cumulative figures; that, finely as
these may be wrought, they have no beauty of detail nor any
detailed significance. Here is no trace of that art of music which
Chopin practised, an art of weaving many strands of sound in such a
way that every minute twist of them had a special beauty, a music in
which every note had an individual and a relative significance. The
texture of the ‘Legends’ is perhaps brilliantly colored, but it is solid or
even coarse in substance, relatively unvaried, and only generally
significant. But it serves its purpose admirably.

In the Années de pèlerinage one finds a great deal of Liszt in a nut-

shell. The three years of wandering through Switzerland and Italy
netted twenty-three relatively short pieces, to which were later added
three more, of Venetian and Neapolitan coloring, a gondoliera, a
canzona, and a tarantella. All these pieces bear titles which are of
greater or lesser importance to the music itself. It must be admitted
that only a title may explain such poor music as Orage, Vallée
d’Obermann and Marche funèbre (in memory of Emperor Maximilian
of Mexico). These pieces are inexcusable bombast. The Vallée
d’Obermann, which may claim to be the most respectable of them, is
not only dank, saturated with sentimentality, but lacks spontaneous
harmony and melody, and toward the end becomes a mountain of
commonplace noise to which one can find a parallel only in such
songs as ‘Palm Branches’ (Les Rameaux). The ‘Chapel of William
Tell,’ the ‘Fantasia written after a reading of Dante,’ the three pieces
which claim a relation to three sonnets of Petrarch, and the two Aux
cyprès de la villa d’Este, are hardly better. There is an Éclogue, a
piece on homesickness, one on the Bells of Geneva, an ‘Angelus’
and a Sursum Corda as well. Three, however, that deal with water in
which there is no trace of tears—Au lac du Wallenstedt, Au bord
d’une source, and Les jeux d’eaux à la Villa d’Este—are wholly
pleasing and even delightful pianoforte music. Especially the second
of these is a valuable addition to the literature of the instrument. The
suggested melody is spontaneous, the harmonies richly though not
subtly colored, the scoring exquisite.

Yet, though in looking over the Années de pèlerinage one may find
but a very few pieces of genuine worth, though most are pretentious,
there is in all a certain sort of fire which one cannot approach without
being warmed. It is the glorious spirit of Byron in music. There is the
facility of Byron, the posturing of Byron, the oratory of Byron; but
there is his superb self-confidence too, showing him tricking himself
as well as the public, yet at times a hero, and Byron’s unquenchable
enthusiasm and irrepressible passionateness.

Finally we come to the small group of big pieces in which we find the
sonata in B minor, the two concertos, several études, polonaises and
concert pieces. Among the études, the great twelve have been
already touched upon. Besides these the two best known are those
in D-flat major and in F minor. The former is wholly satisfactory. The
latter is at once more difficult and less spontaneous. The two
polonaises, one in C minor and one in E major, have the virtues
which belong to concert pieces in the style of Weber’s Polacca, the
chief of which is enormous brilliance. In addition to this that in C
minor is not lacking in a certain nobility; but that in E major is all of
outward show.

The two concertos are perfect works of their kind, unexcelled in

brilliancy of treatment of both the orchestra and the piano, and that in
E-flat major full of musical beauty. Both are free in form and
rhapsodical in character, effusions of music at once passionate and
poetical. That in A major loses by somewhat too free a looseness of
form. Even after careful study it cannot but seem rambling.

The sonata in B minor is perhaps Liszt’s boldest experiment in

original music for the pianoforte alone. One says experiment quite
intentionally, because the work shows as a whole more ingenuity
than inspiration, is rather an invention than a creation. There are
measures of great beauty, pages of factitious development. At times
one finds a nobility of utterance, at others a paucity of ideas.

As to the themes, most of them are cleverly devised from three

motives, given in the introduction. One of these is a heavy,
descending scale (lento assai); another a sort of volplane of
declamatory octaves which plunge downward the distance of a
diminished seventh, rise a third, and down a minor seventh again
through a triplet; the third a sort of drum figure (forte marcato). The
initial statement of these motives is impressive; but it is followed by a
sort of uninteresting music building which is, unhappily, to be found
in great quantity throughout the whole piece. This is no more than a
meaningless repetition of a short phrase or figure, on successive
degrees of the scale or on successive notes of harmonic importance.
Here in the introduction, for example, is a figure which consists of a
chord of the diminished seventh on an off beat of the measure,
followed by the downward arpeggio of a triad. This figure is repeated
five times without any change but one of pitch; and it is so short and
the repetitions so palpable that one feels something of the irritation
stirred by the reiterated boasting of the man who is always about to
do something.

The long work spins itself out page after page with the motives of the
introduction in various forms and this sort of sparring for time. There
is no division into separate movements, yet there are clear sections.
These may be briefly touched upon. Immediately after the
introduction there is a fine-sounding phrase in which one notices the
volplane motive (right hand) and the drum motive (left hand). It is
only two measures long, yet is at once repeated three times, once in
B minor, twice in E minor. Then follow measures of the most trite
music building. The phrases are short and without the slightest
distinction, and the ceaseless repetition is continued so inexorably
that one may almost hear in the music a desperate asthmatic
struggle for breath. One is relieved of it after two or three pages by a
page of the falling scale motive under repeated octaves and chords.

There is next a new theme, which seems to be handled like the

second theme in the classical sonata form, but leads into a long
section of recitative character, in which the second and third motives
carry the music along to a singing theme, literally an augmentation of
the drum motive. This is later hung with garlands of the ready-made
variety, and then gives way to a treatment of the volplane motive in
another passage of short breathing. The succeeding pages continue
with this motive, brilliantly but by no means unusually varied, and
there is a sort of stamping towards a climax, beginning incalzando.
But this growth of noise is coarse-grained, even though the admirer
may rightly say that it springs from one of the chief motives of the
piece. It leads to a passage made up of the pompous second theme
and a deal of recitative; but after this there comes a section in F-
sharp major of very great beauty, and the quasi adagio is hauntingly
tender and intimate. These two pages in the midst of all the noise
and so much that must be judged commonplace will surely seem to
many the only ones worthy of a great creative musician.

After them comes more grandiose material, with that pounding of

chords for noise one remembers at the end of Thalberg’s fantasia on
‘Moses,’ then a sort of dying away of the music which again has
beauty. A double fugue brings us back to a sort of restatement of the
first sections after the introduction, with a great deal of repetition,
scantness of breath, pompousness, and brilliant scoring. Just before
the end there is another mention of the lovely measures in F-sharp
major. There is a short epilogue, built on the three motives of the
introduction.

This sonata is a big work. It is broadly planned, sonorous and heavy.

It has the fire of Byron, too, and there is something indisputably
imposing about it. But like a big sailing vessel with little cargo it
carries a heavy ballast; and though this ballast is necessary to the
balance and safety of the ship, it is without intrinsic value.

In view of Liszt’s great personal influence, of his service rendered to

the public both as player and conductor, of his vast musical
knowledge, his enthusiasms and his prodigious skill with the
keyboard, one must respect his compositions, especially those for
the pianoforte with which we have been dealing. Therefore, though
when measured by the standards of Bach, Mozart and Chopin they
cannot but fall grievously short, one must admit that such a standard
is only one of many, and furthermore that perhaps Liszt’s music may
have itself set a new standard. Certainly in many ways it is
superlative. It is in part the loudest and the fastest music that has
been written for the piano, and as such stands as an achievement in
virtuosity which was not before, and has not since been, paralleled.
Also it is in part the most fiery and the most overpowering of
pianoforte music. It is the most sensational, as well, with all the
virtues that sensationalism may hold.

These are, indeed, its proved greatness, and chief of them is a direct
and forceful appeal to the general public. It needs no training of the
ear to enjoy or to appreciate Liszt’s music. Merely to hear it is to
undergo its forceful attraction. Back of it there stands Liszt, the
pianist and the virtuoso, asserting his power in the world of men and
women. However much or little he may be an artist, he is ever the
hero of pianoforte music. So it seems fitting to regard him last as
composer of nineteen Hungarian Rhapsodies, veritably epics in
music from the life of a fiery, impetuous people. Rhythms, melodies,
and even harmonies are the growth of the soil of Hungary. They
belonged to the peasant before Liszt took them and made them
thunderous by his own power. What he added to them, like what he
added to airs from favorite operas, may well seem of stuff as
elemental as the old folk-songs themselves: torrents and hurricanes
of sound, phenomena of noise. The results are stupendous, and in a
way majestic.
As far as pianoforte music is concerned Liszt revealed a new power
of sound in the instrument by means of the free movement of the
arms, and created and exhausted effects due to the utmost possible
speed. These are the chief contributions of his many compositions to
the literature of the piano. His music is more distinguished by them
than by any other qualities. In melody he is inventive rather than
inspired. His rhythms lack subtlety and variety. Of this there can be
no better proof than the endless short-windedness already observed
in the sonata in B minor, which is to be observed, moreover, in the
Symphonic Poems for orchestra. As a harmonist he lacks not so
much originality as spontaneity. He is oftener bold than convincing.
One finds on nearly every page signs of the experimentalist of heroic
calibre. He is the inventor rather than the prophet, the man of action
rather than the inspired rhapsodist. He is a converter into music
oftener than a creator of music.

Hence we find him translating caprices of Paganini into caprices for

the pianoforte; and when by so doing he has, so to speak, enlarged
his vocabulary enormously, he gives us, in the Douze Études, a sort
of translation of the pianoforte itself into a cycle of actions. Again he
translates a great part of the literature of his day into terms of music:
Consolations, Harmonies poétiques et réligieuses, Légendes,
Eclogues and other things. Even Dante and Petrarch are so
converted, not to mention Sénancourt, Lamartine, Victor Hugo,
Byron, and Lenau, with other contemporaries. The Chapel of William
Tell, the Lake of Wallenstadt, the cypresses and fountains at the Villa
d’Este, even the very Alps themselves pass through his mind and
out his fingers. In this process details are necessarily obscured if not
obliterated, and the result is a sort of general reproduction in sound
that is not characterized by the detailed specialities of the art of
music, that is, of the art of Bach, Mozart, and Chopin. And even of
Schumann, it may be added, for Schumann’s music runs
independently beside poetry, not with it, so closely associated, as
Liszt’s runs.

The question arises as to how this generalization of music will

appear to the world fifty years hence. Is Liszt a radical or a
reactionary, after all? Did he open a new life to music, a further
development of the pianoforte, or did he, having mastered utterly all
the technical difficulties of the pianoforte, throw music back a stage?
Internally his music has far less independent and highly organized
life than Chopin’s. But by being less delicate is it perhaps more
robust, more procreative? At present such hardly seems to be the
case. A great part of the pianoforte music of Liszt is sinking out of
sight in company with that of Herz and Thalberg—evidently for the
same reason; namely, that it is sensationalist music. Its relations to
poetry, romanticism, nature or landscape will not preserve it in the
favor of a public whose ear little by little prefers rather to listen than
to be overpowered. Yet, be his music what it may, he himself will
always remain one of the great, outstanding figures in the history of
music, the revealer of great treasures long ignored. Whatever the
value of his compositions, he himself, the greatest of all pianoforte
virtuosi, set the standard of the new virtuosity which, thanks to his
abiding example, becomes less and less a skill of display, more and
more an art of revelation.
 FOOTNOTES:
[37] W. von Lenz: ‘The Great Piano Virtuosos of Our Time.’ Translated from the
German by Madeline R. Baker, New York, 1899.