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A Pharmacology Primer
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A Pharmacology Primer, 6e
Terry Kenakin, Author
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ACADEMIC
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A Pharmacology Primer
Techniques for More Effective and Strategic
Drug Discovery
Sixth Edition

Terry P. Kenakin
Professor of Pharmacology
The University of North Carolina School of Medicine
Chapel Hill, NC, United States
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 Dedication

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This page intentionally left blank
Contents
Preface to sixth edition xiii
2.6.3 Differences in receptor density 35
2.6.4 Target-mediated trafficking of
stimulus 37
1. What is pharmacology? 2.7 Receptor desensitization and
1.1 About this book 1 tachyphylaxis 37
1.2 What is pharmacology? 1 2.8 The measurement of drug activity 40
1.3 The receptor concept 3 2.9 Advantages and disadvantages of
1.4 Pharmacological test systems 4 different assay formats 40
1.5 The nature of drug receptors 7 2.10 Drug concentration as an independent
1.6 From the snapshot to the movie 7 variable 41
1.7 Pharmacological intervention and the 2.10.1 Dissimulation in drug
therapeutic landscape 8 concentration 41
1.8 System-independent drug parameters: 2.10.2 Free concentration of drug 43
affinity and efficacy 11 2.11 Chapter summary and conclusions 43
1.9 What is affinity? 13 2.12 Derivations 43
1.10 The Langmuir adsorption isotherm 14 2.12.1 Series hyperbolae can be
1.11 What is efficacy? 15 modeled by a single
1.12 Doseeresponse curves 17 hyperbolic function 44
1.12.1 Potency and maximal response 18 2.12.2 Successive rectangular hyper-
1.12.2 P-scales and the representation bolic equations necessarily
of potency 18 lead to amplification 44
1.13 Chapter summary and conclusions 20 2.12.3 Saturation of any step in a
1.14 Derivations: conformational selection stimulus cascade by two
as a mechanism of efficacy 20 agonists leads to identical
References 21 maximal final responses for
the two agonists 44
2. How different tissues process drug 2.12.4 Procedure to measure free
response drug concentration in the
receptor compartment 45
2.1 The ‘eyes to see’: pharmacologic assays 23 References 45
2.2 The biochemical nature of stimuluse
response cascades 25 3. Drugereceptor theory
2.3 The mathematical approximation of
stimuluseresponse mechanisms 27 3.1 About this chapter 47
2.4 Influence of stimuluseresponse 3.2 Drugereceptor theory 47
cascades on doseeresponse curve 3.3 The use of mathematical models in
slopes 29 pharmacology 48
2.5 System effects on agonist response: 3.4 Some specific uses of models in
full and partial agonists 30 pharmacology 49
2.6 Differential cellular response to 3.5 Mass action building blocks 55
receptor stimulus 33 3.6 Classical model of receptor
2.6.1 Choice of response pathway 33 function 56
2.6.2 Augmentation or modulation of 3.7 The operational model of receptor
stimulus pathway 34 function 57

vii
viii Contents

3.8 Two-state theory 58 4.7.3 Displacement of a radioligand

3.9 The ternary complex model 59 by an allosteric antagonist 92
3.10 The extended ternary complex model 59 4.7.4 Relationship between IC50 and
3.11 Constitutive receptor activity and KI for competitive antagonists 93
inverse agonism 60 4.7.5 Maximal inhibition of binding
3.12 The cubic ternary complex model 62 by an allosteric antagonist 94
3.13 Multistate receptor models and 4.7.6 Relationship between IC50 and
probabilistic theory 63 KI for allosteric antagonists 94
3.14 Chapter summary and conclusions 65 4.7.7 Two-stage binding reactions 94
3.15 Derivations 65 4.7.8 Effect of G-Protein coupling on
3.15.1 Radioligand binding to observed agonist affinity 94
receptor dimers demonstrating 4.7.9 Effect of excess receptor in
cooperative behavior 65 binding experiments: saturation
3.15.2 Effect of variation in an HIV-1 binding curve 94
binding model 66 4.7.10 Effect of excess receptor in
3.15.3 Derivation of the operational binding experiments: displace-
model 67 ment experiments 95
3.15.4 Operational model forcing 4.7.11 Derivation of an allosteric bind-
function for variable slope 67 ing model 95
3.15.5 Derivation of two-state theory 68 References 96
3.15.6 Derivation of the extended
ternary complex model 68 5. Drug targets and drug-target
3.15.7 Dependence of constitutive molecules
activity on receptor density 69
3.15.8 Derivation of the cubic ternary 5.1 Defining biological targets 97
complex model 69 5.2 Specific types of drug targets 100
References 69 5.2.1 G-protein-coupled receptors 100
5.2.2 Ion channels 102
5.2.3 Enzymes 103
4. Pharmacological assay formats:
5.2.4 Nuclear receptors 111
binding
5.2.5 Nucleotide-based drug targets 112
4.1 The structure of this chapter 71 5.3 Small drug-like molecules 114
4.2 Binding theory and experiment 71 5.3.1 Hybrid molecules 116
4.2.1 Saturation binding 74 5.3.2 Chemical sources for potential
4.2.2 Displacement binding 76 drugs 121
4.2.3 Kinetic binding studies 79 5.4 Biologics 126
4.3 Complex binding phenomena: agonist 5.4.1 Replacement proteins 127
affinity from binding curves 80 5.4.2 Eliminating ‘undruggable’ pro-
4.4 Experimental prerequisites for correct teins through PROTACs 130
application of binding techniques 84 5.4.3 Peptides 131
4.4.1 The effect of protein concentra- 5.4.4 Antibodies 135
tion on binding curves 84 5.4.5 Immunotherapy 141
4.4.2 The importance of equilibration 5.4.6 Vaccines 141
time for equilibrium between 5.4.7 Nucleic acidebased drug species 142
two ligands 85 5.5 Summary and conclusions 147
4.5 Binding in allosteric systems 87 References 147
4.6 Chapter summary and conclusions 91 Further reading 149
4.7 Derivations 92
4.7.1 Displacement binding: 6. Agonists: the measurement of affinity
competitive interaction 92 and efficacy in functional assays
4.7.2 Displacement binding:
noncompetitive interaction 92 6.1 Functional pharmacological
experiments 151
 Contents ix

6.2 The choice of functional assays 152 7.3.5 Analyses for partial agonists 201
6.3 Recombinant functional systems 156 7.3.6 The method of Lew and Angus:
6.4 Functional experiments: dissimulation nonlinear regression analysis 203
in time 159 7.4 Noncompetitive antagonism 204
6.5 Experiments in real time versus 7.5 Agonisteantagonist hemiequilibria 208
stop-time 160 7.6 Resultant analysis 210
6.6 Quantifying agonism: the BlackeLeff 7.7 Antagonism in vivo 210
operational model of agonism 162 7.7.1 Antagonists with efficacy in
6.6.1 Affinity-dependent versus vivo 212
efficacy-dependent agonist 7.7.2 Kinetics of target coverage 214
potency 166 7.7.3 Kinetics of dissociation 216
6.6.2 Secondary and tertiary testing 7.7.4 Estimating antagonist
of agonists 168 dissociation with hemiequilibria 219
6.7 Biased signaling 169 7.8 Blockade of indirectly acting agonists 219
6.7.1 Receptor selectivity 175 7.9 Irreversible antagonism 220
6.8 Null analyses of agonism 175 7.10 Chemical antagonism 222
6.8.1 Partial agonists 175 7.11 Chapter summary and conclusions 226
6.8.2 Full agonists 179 7.12 Derivations 227
6.9 Comparing full and partial agonist 7.12.1 Derivation of the Gaddum
activities: Log(max/EC50) 182 equation for competitive
6.10 Chapter summary and conclusions 183 antagonism 227
6.11 Derivations 183 7.12.2 Derivation of the Gaddum
6.11.1 Relationship between the EC50 equation for noncompetitive
and affinity of agonists 183 antagonism 227
6.11.2 Method of Barlow, Scott, and 7.12.3 Derivation of the schild
Stephenson for affinity of equation 228
partial agonists 184 7.12.4 Functional effects of an
6.11.3 Maximal response of a partial inverse agonist with the
agonist is dependent on operational model 228
efficacy 184 7.12.5 pA2 measurement for inverse
6.11.4 System independence of full agonists 228
agonist potency ratios 184 7.12.6 Functional effects of a partial
6.11.5 Measurement of agonist agonist with the operational
affinity: method of Furchgott 184 model 229
6.11.6 Agonism as a positive 7.12.7 pA2 measurements for partial
allosteric modulation of agonists 229
receptoresignaling protein 7.12.8 Method of Stephenson for
interaction to derive partial agonist affinity
DLog(max/EC50) ratios 185 measurement 229
References 187 7.12.9 Derivation of the Method of
Gaddum for noncompetitive
7. Orthosteric drug antagonism antagonism 230
7.12.10 Relationship of pA2 and pKB
7.1 Introduction 189
for insurmountable
7.2 Kinetics of drugereceptor interaction 189
orthosteric antagonism 230
7.3 Surmountable competitive antagonism 192
7.12.11 Resultant analysis 230
7.3.1 Schild analysis 192
7.12.12 Blockade of indirectly acting
7.3.2 Patterns of DoseeResponse
agonists 231
curves that preclude schild
7.12.13 Chemical antagonism:
analysis 197
abstraction of agonist
7.3.3 Best practice for the use of
concentration 231
schild analysis 198
7.12.14 Chemical antagonism:
7.3.4 Analyses for inverse agonists in
abstraction of antagonist
constitutively active receptor
concentration 231
systems 199
References 232
x Contents

8. Allosteric modulation 9.5.1 Predicting agonism 299

9.5.2 Predicting binding 301
8.1 Introduction 233 9.5.3 Drug combinations in vivo 302
8.2 The nature of receptor allosterism 233 9.6 Summary and conclusions 303
8.3 Unique effects of allosteric modulators 235 9.7 Derivations 304
8.4 Functional study of allosteric modulators 240 9.7.1 IC50 Correction Factors:
8.4.1 Phenotypic allosteric modulation competitive antagonists 304
profiles 242 9.7.2 Relationship of pA2 and pKB for
8.4.2 Allosteric agonism 243 Insurmountable Orthosteric
8.4.3 Affinity of allosteric modulators 243 antagonism 304
8.4.4 Negative allosteric modulators 246 9.7.3 Relationship of pA2 and pKB for
8.4.5 Positive allosteric modulators 250 Insurmountable Allosteric
8.4.6 Quantifying PAM activity in vivo 254 Antagonism 305
8.4.7 NAM/PAM induced agonist bias 255 References 305
8.4.8 Optimal assays for allosteric
function 255
10. Pharmacokinetics
8.5 Functional allosteric model with
constitutive activity 256 10.1 Introduction 307
8.6 Internal checks for adherence to the 10.2 Biopharmaceutics 307
allosteric model 257 10.3 The chemistry of “drug-like”
8.7 Methods for detecting allosterism 260 character 308
8.8 Chapter summary and conclusions 262 10.4 Pharmacokinetics 313
8.9 Derivations 262 10.4.1 Drug absorption 313
8.9.1 Allosteric model of receptor 10.4.2 Route of drug
activity 262 administration 319
8.9.2 Effects of allosteric ligands on 10.4.3 General pharmacokinetics 322
response: changing efficacy 263 10.4.4 Metabolism 325
8.9.3 Schild analysis for allosteric 10.4.5 Clearance 330
antagonists 263 10.4.6 Volume of distribution and
8.9.4 Application of Log(Max/R50) half-life 332
values from R50 curves to 10.4.7 Renal clearance 338
quantify the effects of PAMs 264 10.4.8 Bioavailability 340
8.9.5 Quantifying allosterically 10.5 Nonlinear pharmacokinetics 342
mediated induced bias in 10.6 Multiple dosing 343
agonism 264 10.7 Modifying pharmacokinetics through
8.9.6 Functional allosteric model with medicinal chemistry 345
constitutive receptor activity 265 10.8 Practical pharmacokinetics 347
References 266 10.8.1 Allometric scaling 349
10.9 Placement of pharmacokinetic assays
9. The optimal design of in discovery and development 350
pharmacological experiments 10.10 The pharmacokinetics of biologics 352
10.10.1 Absorption 353
9.1 Introduction 269 10.10.2 Duration of action 354
9.2 The optimal design of pharmacological 10.10.3 Antibody PK 355
experiments 269 10.10.4 mRNA PK 355
9.2.1 Drug efficacy 270 10.11 Summary and conclusions 355
9.2.2 Affinity 283 References 356
9.2.3 Orthosteric versus allosteric
mechanisms 292 11. Safety pharmacology
9.3 Null experiments and fitting data to
models 293 11.1 Safety pharmacology 359
9.4 Interpretation of experimental data 296 11.2 Hepatotoxicity 365
9.5 Predicting therapeutic activity in all 11.2.1 Drugedrug interactions 365
systems 299 11.2.2 Direct hepatotoxicity 370
 Contents xi

11.2.3 Hepatotoxicity in context in 13.2.3 Method of Furchgott for the

vivo 372 measurement of the affinity
11.3 Cytotoxicity 372 of a full agonist 428
11.4 Mutagenicity 374 13.2.4 Schild analysis for the
11.5 hERG activity and Torsades de measurement of competitive
Pointes 376 antagonist affinity 429
11.6 Autonomic receptor profiling and 13.2.5 Method of Stephenson for
off-target effects 376 measurement of partial
11.7 General pharmacology 377 agonist affinity 431
11.8 Clinical testing and drug toxicity 379 13.2.6 Method of Gaddum for
11.9 Summary and conclusions 381 measurement of noncom-
References 381 petitive antagonist affinity 433
13.2.7 Method for estimating affin-
12. The drug-discovery process ity of insurmountable antag-
onist (dextral displacement
12.1 Some challenges for modern drug
observed) 434
discovery 383
13.2.8 Resultant analysis for
12.2 The drug-discovery process 384
measurement of affinity of
12.3 Target-based drug discovery 384
competitive antagonists
12.3.1 Target validation and the
with multiple properties 436
use of chemical tools 385
13.2.9 Measurement of the affinity
12.3.2 Recombinant systems 388
and maximal allosteric
12.4 Systems-based drug discovery 390
constant for allosteric mod-
12.5 High-throughput screening 393
ulators producing surmount-
12.5.1 Structure-based drug design
able effects 436
and virtual screening 404
13.2.10 Method for estimating
12.5.2 Phenotypic screening 405
affinity of insurmountable
12.6 The lead optimization process 409
antagonist (no dextral
12.7 Drug effectiveness 413
displacement observed):
12.7.1 Clinical testing 414
detection of allosteric effect 438
12.7.2 Determining detailed profiles
13.2.11 Measurement of pKB for
of candidate efficacy 416
competitive antagonists
12.7.3 Assays in context 417
from a pIC50 441
12.7.4 Characterization of candidate
13.2.12 Statistical assessment of
efficacies 418
selectivity 442
12.8 Summary and conclusions 419
13.2.13 Measurement of surmount-
References 420
able allosteric antagonism 447
Further reading 422
13.2.14 Measurement of
insurmountable allosteric
13. Selected pharmacological methods antagonism (second
13.1 Binding experiments 423 method) 448
13.1.1 Saturation binding 423 13.2.15 Measurement of PAM
13.1.2 Displacement binding 423 activity 450
13.2 Functional assays 426 Reference 451
13.2.1 Determination of equiactive
concentrations on Dosee
Response curves 426
13.2.2 Method of Barlow, Scott,
Appendix 1: Statistics 453
and Stephenson for
measurement of the affinity Index 483
of a partial agonist 427
This page intentionally left blank
Preface to sixth edition
Pharmacologists almost always are working in systems
they do not fully understand. This has engendered a unique
“null system” of comparisons (before and after drug) that
has sustained the field. Our view of what is actually
happening in our experiment is obtained through our assay,
and as the Nobel Laureate Sir James Black wrote “.The
prismatic qualities of the assay distort our view in obscure
ways and degrees.” (1993; Nobel Lectures: Physiology
and Medicine). What this means to the discipline is that it is
uniquely dependent upon technology unveiling what we do
not understand about physiology and as technology ad-
vances the frontier of understanding, so too does the
perception of pharmacological mechanisms and the effect
of drugs on physiology. In essence, as the acuity of the
pharmacological prism improves, so too does our under-
standing of drug mechanisms. The practical outcome of this
is that a book on pharmacology must be updated every few
years to keep up with the new understanding gained from
technologies “new eyes to see.” This volume has been
updated and has added major chapters on biologics and the
drug discovery process that reflects the changing landscape
of drug therapy as well as views of historical findings
modified by new knowledge.
Terry P. Kenakin Ph.D.
Professor of Pharmacology,
The University of North Carolina School of Medicine,
Chapel Hill, NC, United States
xiii
This page intentionally left blank
Chapter 1
What is pharmacology?
I would in particular draw the attention to physiologists to
this type of physiological analysis of organic systems which
can be done with the aid of toxic agents ..
dClaude Bernard (1813e78).
1.1 About this book
Essentially this is a book about the methods and tools used in
pharmacology to quantify drug activity. Receptor pharma-
cology is based on the comparison of experimental data and
simple mathematical models, with a resulting inference of
drug behavior to the molecular properties of drugs. From this
standpoint, a certain level of understanding of the mathe-
matics involved in the models is useful but not imperative.
This book is structured such that each chapter begins with the
basic concepts and then moves on to the techniques used to
estimate drug parameters, and, finally, for those so inclined,
the mathematical derivations of the models used. Under-
standing the derivation is not a prerequisite for understanding
the application of the methods or the resulting conclusion;
these are included for completeness and are for readers who
wish to pursue exploration of the models. In general, facility
with mathematical equations is definitely not required for
pharmacology; the derivations can be ignored without any
detriment to the use of this book.
Second, the symbols used in the models and deriva-
tions, on occasion, duplicate each other (i.e., a is an
extremely popular symbol). However, the use of these
multiple symbols has been retained, since this preserves the
context of where these models were first described and
utilized. Also, changing these to make them unique would
cause confusion if these methods were to be used beyond
the framework of this book. Therefore, care should be taken
to consider the actual nomenclature of each chapter.
Third, an effort has been made to minimize the need to
cross-reference different parts of the book (i.e., when a
particular model is described, the basics are reiterated
somewhat to minimize the need to read the relevant but
different part of the book in which the model is initially
described). While this leads to a small amount of repeated
description, it is felt that this will allow for a more unin-
terrupted flow of reading and use of the book.
A Pharmacology Primer. https://doi.org/10.1016/B978-0-323-99289-3.00015-4
Copyright © 2022 Elsevier Inc. All rights reserved.
1.2 What is pharmacology?
Pharmacology (an amalgam of the Greek pharmakos,
medicine or drug, and logos, study) is a broad discipline
describing the use of chemicals to treat and cure diseases.
The Latin term pharmacologia was used in the late 1600s,
but the term pharmacum was used as early as the 4th
century to denote the term drug or medicine. In the Greek
translations “Pharmakeia” refers to Sorcery/Witchcraft
which no doubt was evident when particular herbal treat-
ments were effective. There are subdisciplines within
pharmacology representing specialty areas. Pharmacoki-
netics deals with the disposition of drugs in the human
body. To be useful, drugs must be absorbed and transported
to their site of therapeutic action. Drugs will be ineffective
in therapy if they do not reach the organs(s) to exert their
activity; this will be discussed specifically in Chapter 9,
Pharmacokinetics, of this book. Pharmaceutics is the study
of the chemical formulation of drugs to optimize absorption
and distribution within the body. Pharmacognosy is the
study of plant natural products and their use in the treat-
ment of disease. A very important discipline in the drug-
discovery process is medicinal chemistry, the study of the
production of molecules for therapeutic use. This couples
synthetic organic chemistry with an understanding of how
biological information can be quantified and used to guide
the synthetic chemistry to enhance therapeutic activity.
Pharmacodynamics is the study of the interaction of the
drug molecule with the biological target (referred to
generically as the “receptor,” vide infra). This discipline
lays the foundation of pharmacology since all therapeutic
application of drugs has a common root in pharmacody-
namics (i.e., as a prerequisite to exerting an effect, all drug
molecules must bind to and interact with receptors).
The history of pharmacology is tied to the history of
drug discoverydsee Chapter 9, The Optimal Design of
Pharmacological Experiments. As put by the Canadian
physician Sir William Osler (1849e919; the “father of
modern medicine”), “. the desire to take medicine is
perhaps the greatest feature which distinguishes man from
animals ..” Pharmacology as a separate science is
approximately 120e140 years old. The relationship be-
tween chemical structure and biological activity began to be
studied systematically in the 1860s [1]. It began when
1
2 A Pharmacology Primer
physiologists, using chemicals to probe physiological sys-
tems, became more interested in the chemical probes than
the systems they were probing. By the early 1800s, phys-
iologists were performing physiological studies with
chemicals that became pharmacological studies more aimed
at the definition of the biological activity of chemicals. The
first formalized chair of pharmacology, indicating a formal
university department, was founded in Estonia by Rudolf
Bucchiem in 1847. In North America, the first chair was
founded by John Jacob Abel at Johns Hopkins University
in 1890. A differentiation of physiology and pharmacology
was given by the pharmacologist Sir William Paton [2]:
If physiology is concerned with the function, anatomy with
the structure, and biochemistry with the chemistry of the
living body, then pharmacology is concerned with the
changes in function, structure, and chemical properties of
the body brought about by chemical substances
dW.D.M. Paton (1986).
Many works about pharmacology essentially deal in
therapeutics associated with different organ systems in the
body. Thus, in many pharmacology texts, chapters are
entitled drugs in the cardiovascular system, the effect of
drugs on the gastrointestinal (GI) system, the central ner-
vous system (CNS), and so on. However, the underlying
principles for all of these is the same, namely, the phar-
macodynamic interaction between the drug and the bio-
logical recognition system for that drug. Therefore, a
prerequisite to all of pharmacology is an understanding of
the basic concepts of doseeresponse and how living cells
process pharmacological information. This generally is
given the term pharmacodynamics or receptor pharma-
cology, where receptor is a term referring to any biological
recognition unit for drugs (membrane receptors, enzymes,
DNA, and so on). With such knowledge in hand, readers
will be able to apply these principles to any branch of
therapeutics effectively. This book treats doseeresponse data
generically and demonstrates methods by which drug ac-
tivity can be quantified across all biological systems irre-
spective of the nature of the biological target.
A great strength of pharmacology as a discipline is that
it contains the tools and methods to convert “descriptive
data,” i.e., data that serve to characterize the activity of a
given drug in a particular system, to “predictive data.” This
latter information can be used to predict that drug’s activity
in all organ systems, including the therapeutic one. This
defines the drug-discovery process which is the testing of
new potential drug molecules in surrogate systems (where a
potentially toxic chemical can do no lasting harm) before
progression to the next step, namely, testing in human
therapeutic systems. The models and tools contained in
pharmacology to convert drug behaviors in particular
organs to molecular properties (see Chapter 2: How
Different Tissues Process Drug Response) are the main
subject of this book, and the step-by-step design of phar-
macologic experiments to do this are described in detail in
Chapter 8, The Optimal Design of Pharmacological Ex-
periments (after the meaning of the particular parameters
and terms is described in previous chapters).
The human genome is now widely available for drug-
discovery research. Far from being a simple blueprint of
how drugs should be targeted, it has shown biologists that
receptor genotypes (i.e., properties of proteins resulting
from genetic transcription to their amino acid sequence) are
secondary to receptor phenotypes (how the protein interacts
with the myriad of cellular components and how cells tailor
the makeup and functions of these proteins to their indi-
vidual needs). Since the arrival of the human genome, re-
ceptor pharmacology as a science is more relevant than ever
in drug discovery. Current drug therapy is based on less
than 500 molecular targets, yet estimates utilizing the
number of genes involved in multifactorial diseases suggest
that the number of potential drug targets ranges from 2000
to 5000 [3]. Thus, current therapy is using only 5%e10%
of the potential trove of targets available in the human
genome.
A meaningful dialog between chemists and pharma-
cologists is the single most important element of the drug-
discovery process. The necessary link between medicinal
chemistry and pharmacology has been elucidated by
Paton [2]:
For pharmacology there results a particularly close rela-
tionship with chemistry, and the work may lead quite
naturally, with no special stress on practicality, to thera-
peutic application, or (in the case of adverse reactions) to
toxicology.
dW.D.M. Paton (1986).
Chemists and biologists reside in different worlds from
the standpoint of the type of data they deal with. Chemistry
is an exact science with physical scales that are not subject
to system variance. Thus, the scales of measurement are
transferable. Biology deals with the vagaries of complex
systems that are not completely understood. Within this
scenario, scales of measurement are much less constant and
much more subject to system conditions. Given this, a gap
can exist between chemists and biologists in terms of un-
derstanding and also in terms of the best method to progress
forward. In the worst circumstance, it is a gap of credibility
emanating from a failure of the biologist to make the
chemist understand the limits of the data. Usually, however,
credibility is not the issue, and the gap exists due to a lack
of common experience. This book was written in an
attempt to limit or, hopefully, eliminate this gap.
 What is pharmacology? Chapter | 1 3

1.3 The receptor concept
One of the most important concepts emerging from early
pharmacological studies is the concept of the receptor.
Pharmacologists knew that minute amounts of certain
chemicals had profound effects on physiological systems.
They also knew that very small changes in the chemical
composition of these substances could lead to huge dif-
ferences in activity. This led to the notion that something
on or in the cell must specifically read the chemical infor-
mation contained in these substances and translate it into a
physiological effect. This something was conceptually
referred to as the “receptor” for that substance. Pioneers
such as Paul Ehrlich (1854e915, Fig. 1.1A) proposed the
existence of “chemoreceptors” (actually he proposed a
collection of amboreceptors, triceptors, and polyceptors) on
cells for dyes. He also postulated that the chemoreceptors
on parasites, cancer cells, and microorganisms were
different from healthy host and thus could be exploited
therapeutically. The physiologist turned pharmacologist
John Newport Langley (1852e926, Fig. 1.1B), during his
studies with the drugs jaborandi (which contains the alka-
loid pilocarpine) and atropine, introduced the concept that
receptors were switches that received and generated signals
and that these switches could be activated or blocked by
specific molecules. The originator of quantitative receptor
theory, the Edinburgh pharmacologist Alfred Joseph Clark
(1885e941, Fig. 1.1C), was the first to suggest that the
data, compiled from his studies of the interactions of
acetylcholine and atropine, resulted from the unimolecular
interaction of the drug and a substance on the cell surface.
He articulated these ideas in the classic work The Mode of
Action of Drugs on Cells [4], later revised as the Handbook
of Experimental Pharmacology [5]. As put by Clark
It appears to the writer that the most important fact shown
by a study of drug antagonisms is that it is impossible to
explain the remarkable effects observed except by assuming
that drugs unite with receptors of a highly specific pattern
.. No other explanation will, however, explain a tithe of
the facts observed.
dA.J. Clark (1937).
Clark’s next step formed the basis of receptor theory by
applying chemical laws to systems of “infinitely greater
complexity” [4]. It is interesting to note the scientific at-
mosphere in which Clark published these ideas. The
dominant ideas between 1895 and 1930 were based on
theories such as the law of phasic variation essentially
stating that “certain phenomena occur frequently.” Ho-
meopathic theories like the ArndteSchulz law and
WebereFechner law were based on loose ideas around
surface tension of the cell membrane, but there was little
physicochemical basis for these ideas [6]. In this vein,
prominent pharmacologists of the day, such as Walter
Straub (1874e944), suggested that a general theory of
chemical binding between drugs and cells utilizing re-
ceptors was “. going too far . and . not admissible”
[6]. The impact of Clark’s thinking against these concepts
cannot be overemphasized to modern pharmacology.

FIGURE 1.1 Pioneers of pharmacology. (A) Paul Ehrlich (1854e915). Born in Silesia, Ehrlich graduated from Leipzig University to go on to a
distinguished career as head of institutes in Berlin and Frankfurt. His studies with dyes and bacteria formed the basis of early ideas regarding recognition
of biological substances by chemicals. (B) John Newport Langley (1852e926). Though he began reading mathematics and history in Cambridge in 1871,
Langley soon took to physiology. He succeeded the great physiologist M. Foster to the chair of physiology in Cambridge in 1903 and branched out into
pharmacological studies of the autonomic nervous system. These pursuits led to germinal theories of receptors. (C) Alfred J. Clark (1885e941). Beginning
as a demonstrator in pharmacology in King’s College (London), Clark went on to become Professor of pharmacology at University College London. From
there he took the chair of pharmacology in Edinburgh. Known as the originator of modern receptor theory, Clark applied chemical laws to biological
phenomena. His books on receptor theory formed the basis of modern pharmacology.
4 A Pharmacology Primer
It is possible to underestimate the enormous signifi-
cance of the receptor concept in pharmacology until it is
realized how relatively chaotic the study of drug effect
was before it was introduced. Specifically, consider the
myriad of physiological and pharmacological effects of
the hormone epinephrine in the body. As shown in
Fig. 1.2, a host of responses are obtained from the CNS,
cardiovascular system, smooth muscle, and other organs.
It is impossible to see a thread which relates these very
different responses until it is realized that all of these are
mediated by the activation of a single protein receptor,
namely, in this case, the b-adrenoceptor. When this is
understood, a much better idea can be gained as to how to
manipulate these heterogeneous responses for therapeutic
benefit; the receptor concept introduced order into physi-
ology and pharmacology.
Drug receptors can exist in many forms, including cell
surface proteins, enzymes, ion channels, membrane trans-
porters, DNA, and cytosolic proteins (see Fig. 1.3). There
are examples of important drugs for all of these. This book
deals with general concepts which can be applied to a range
of receptor types, but most of the principles are illustrated
with the most tractable receptor class known in the human
genome, namely, seven transmembrane (7TM) receptors
(7TMRs). These receptors are named for their characteristic
structure that consists of a single protein chain that tra-
verses the cell membrane seven times to produce extra-
cellular and intracellular loops. These receptors activate
G-proteins to elicit response, thus they are also
commonly referred to as G-protein-coupled receptors
(GPCRs); this should now be considered a limiting moniker
as these proteins signal to a wide variety of signaling
molecules in the cell and are not confined to G-protein
FIGURE 1.2 A sampling of the heterogeneous physiological and pharmacological response to the hormone epinephrine. The concept of receptors links
these diverse effects to a single control point, namely, the b-adrenoceptor.
effects. There are between 800 and 1000 [7] of these in
the genome [the genome sequence predicts 650 GPCR
genes, of which approximately 190 (on the order of 1% of
the genome of superior organisms) are categorized as
known 7TMRs [8] activated by some 70 ligands]. In the
United States, in 2000, nearly half of all prescription drugs
were targeted toward 7TM receptors [3]. These receptors,
comprising between 1% and 5% of the total cell protein,
control a myriad of physiological activities. They are
tractable for drug discovery because they are on the cell
surface, and therefore drugs do not need to penetrate the
cell to produce effect. In the study of biological targets such
as 7TMRs and other receptors, a “system” must be
employed that accepts chemical input and returns biological
output. It is worth discussing such receptor systems in
general terms before their specific uses are considered.
1.4 Pharmacological test systems
Molecular biology has transformed pharmacology and the
drug-discovery process. As little as 20 years ago, screening
for new drug entities was carried out in surrogate animal
tissues. This necessitated a rather large extrapolation to
span the differences in genotype and phenotype. The belief
that the gap could be bridged came from the notion that the
chemicals recognized by these receptors in both humans
and animals were the same (vide infra). Receptors are
unique proteins with characteristic amino acid sequences.
While polymorphisms (spontaneous alterations in amino
acid sequence, vide infra) of receptors exist in the same
species, in general the amino acid sequence of a natural
ligand-binding domain for a given receptor type largely
may be conserved. There are obvious pitfalls of using

FIGURE 1.3 Schematic diagram of potential drug targets. Molecules can affect the function of numerous cellular components both in the cytosol and on
the membrane surface. There are many families of receptors that traverse the cellular membrane and allow chemicals to communicate with the interior of
the cell.
surrogate species receptors for predicting human drug ac-
tivity, and it never can be known for certain whether
agreement for estimates of activity for a given set of drugs
ensures accurate prediction for all drugs. The agreement is
very much drug and receptor dependent. For example, the
human and mouse a2-adrenoceptors are 89% homologous
and thus considered very similar from the standpoint of
amino acid sequence. Furthermore, the affinities of the a2-
adrenoceptor antagonists atipamezole and yohimbine are
nearly indistinguishable (atipamezole human a2-C10
Ki ¼ 2.9  0.4 nM, mouse a2-4H Ki ¼ 1.6  0.2 nM;
yohimbine human a2-C10 Ki ¼ 3.4  0.1 nM, mouse a2-
4H Ki ¼ 3.8  0.8 nM). However, there is a 20.9-fold
difference for the antagonist prazosin (human a2-C10
Ki ¼ 2034  350 nM, mouse a2-4H Ki ¼ 97.3  0.7 nM)
[9]. Such data highlight a general theme in pharmacological
research, namely, that a hypothesis, such as one proposing
that two receptors which are identical with respect to their
sensitivity to drugs are the same, cannot be proven, only
disproven. While a considerable number of drugs could be
tested on the two receptors (thus supporting the hypothesis
that their sensitivity to all drugs is the same), this hypoth-
esis is immediately disproven by the first drug that shows
differential potency on the two receptors. The fact that a
series of drugs tested show identical potencies may mean
only that the wrong sample of drugs has been chosen to
unveil the difference. Thus, no general statements can be
made that any one surrogate system is completely predic-
tive of activity on the target human receptor. This will al-
ways be a drug-specific phenomenon.
The link between animal and human receptors is the fact
that both proteins recognize the endogenous transmitter
(e.g., acetylcholine, norepinephrine), and therefore the hope
What is pharmacology? Chapter | 1 5
is that this link will carry over into other drugs that
recognize the animal receptor. This imperfect system
formed the basis of drug discovery until human cDNA for
human receptors could be used to make cells express hu-
man receptors. These engineered (recombinant) systems are
now used as surrogate human-receptor systems, and the
leap of faith from animal receptor sequences to human-
receptor sequences is not required (i.e., the problem of
differences in genotype has been overcome). However,
cellular signaling is an extremely complex process and cells
tailor their receipt of chemical signals in numerous ways.
Therefore, the way a given receptor gene behaves in a
particular cell can differ in response to the surroundings in
which that receptor finds itself. These differences in
phenotype (i.e., properties of a receptor produced by
interaction with its environment) can result in differences in
both the quantity and quality of a signal produced by a
concentration of a given drug in different cells. Therefore,
there is still a certain, although somewhat lesser, leap of
faith taken in predicting therapeutic effects in human tis-
sues under pathological control from surrogate recombinant
or even surrogate natural human-receptor systems. For this
reason, it is a primary requisite of pharmacology to derive
system-independent estimates of drug activity that can be
used to predict therapeutic effect in other systems.
A schematic diagram of the various systems used in
drug discovery, in order of how appropriate they are to
therapeutic drug treatment, is shown in Fig. 1.4. As dis-
cussed previously, early functional experiments in animal
tissue have now largely given way to testing in recombinant
cell systems engineered with human-receptor material. This
huge technological step greatly improved the predictability
of drug activity in humans, but it should be noted that there
6 A Pharmacology Primer
FIGURE 1.4 A history of the drug-discovery process. Originally, the only biological material available for drug research was animal tissue. With the
advent of molecular biological techniques to clone and express human receptors in cells, recombinant systems supplanted animal-isolated tissue work. It
should be noted that these recombinant systems still fall short of yielding drug response in the target human tissue under the influence of pathological
processes.
still are many factors that intervene between the genetically
engineered drug-testing system and the pathology of human
disease.
A frequently used strategy in drug discovery is to ex-
press human receptors (through transfection with human
cDNA) in convenient surrogate host cells (referred to as
“target-based” drug discovery; see Chapter 10: Safety
Pharmacology for further discussion). These host cells are
chosen mainly for their technical properties (i.e., robust-
ness, growth rate, stability) and not with any knowledge of
verisimilitude to the therapeutically targeted human cell
type. There are various factors relevant to the choice of
surrogate host cell, such as a very low-background activity
(i.e., a cell cannot be used that already contains a related
animal receptor for fear of cross-reactivity to molecules
targeted for the human receptor). Human receptors are often
expressed in animal surrogate cells. The main idea here is
that the cell is a receptacle for the receptor, allowing it to
produce physiological responses, and that activity can be
monitored in pharmacological experiments. In this sense,
human receptors expressed in animal cells are still a theo-
retical step distanced from the human receptor in a human
cell type. However, even if a human surrogate is used (and
there are such cells available), there is no definitive evi-
dence that a surrogate human cell is any more predictive of
a natural receptor activity than an animal cell when
compared to the complex receptor behavior in its natural
host cell type expressed under pathological conditions.
Receptor phenotype dominates in the end organ, and the
exact differences between the genotypic behavior of the
receptor (resulting from the genetic makeup of the receptor)
and the phenotypic behavior of the receptor (due to the
interaction of the genetic product with the rest of the cell)
may be cell specific. Therefore, there is still a possible gap
between the surrogate systems used in the drug-discovery
process and the therapeutic application. Moreover, most
drug-discovery systems utilize receptors as switching
mechanisms and quantify whether drugs turn on or turn off
the switch. The pathological processes that we strive to
modify may be more subtle. As put by pharmacologist Sir
James Black [10]:
. angiogenesis, apoptosis, inflammation, commitment of
marrow stem cells, and immune responses. The cellular
reactions subsumed in these processes are switch like in
their behavior . biochemically we are learning that in all
these processes many chemical regulators seem to be
involved. From the literature on synergistic interactions, a
control model can be built in which no single agent is
effective. If a number of chemical messengers each bring
information from a different source and each deliver only a
subthreshold stimulus but together mutually potentiate each
other, then the desired information-rich switching can be
achieved with minimum risk of miscuing.
dJ.W. Black (1986).
Such complex end points are difficult to predict from
any one of the component processes leading to yet another
leap of faith in the drug-discovery process. For these rea-
sons, an emerging strategy for drug discovery is the use of
natural cellular systems. This approach is discussed in some
detail in Chapter 11, The Drug Discovery Process.
Even when an active drug molecule is found and ac-
tivity is verified in the therapeutic arena, there are factors
that can lead to gaps in its therapeutic profile. When drugs
are exposed to huge populations, genetic variations in this
population can lead to discovery of alleles that code for
mutations of the target (isogenes), and these can lead to
variation in drug response. Such polymorphisms can lead to

resistant populations (i.e., resistance of some asthmatics to
the b-adrenoceptor bronchodilators [11]). In the absence of
genetic knowledge, these therapeutic failures for a drug
could not easily be averted since they in essence occurred
because of the presence of new biological targets not
originally considered in the drug-discovery process. How-
ever, as new epidemiological information becomes avail-
able, these polymorphisms can now be incorporated into
the drug-discovery process.
There are two theoretical and practical scales that can
be used to make system-independent measures of drug
activity on biological systems. The first is a measure of the
attraction of a drug for a biological target, namely, its
affinity for a receptor. Drugs must interact with receptors
to produce an effect, and the affinity is a chemical term
used to quantify the strength of that interaction. The sec-
ond is much less straightforward and is used to quantify
the degree of effect imparted to the biological system after
the drug binds to the receptor. This is termed efficacy. This
property was named by Stephenson [12] within classical
receptor theory as a proportionality factor for the tissue
response produced by a drug. There is no absolute scale
for efficacy, but rather it is dealt with in relative terms
(i.e., the ratio of the efficacy of two different drugs on a
particular biological system can be estimated and, under
ideal circumstances, will transcend the system and be
applicable to other systems as well). It is the foremost task
of pharmacology to use the translations of drug effect
obtained from cells to provide system-independent esti-
mates of affinity and efficacy. Before specific discussion
of affinity and efficacy, it is worth considering the mo-
lecular nature of biological targets.
1.5 The nature of drug receptors
While some biological targets such as DNA are not protein
in nature, most receptors are. It is useful to consider the
properties of receptor proteins to provide a context for the
interaction of small molecule drugs with them. An impor-
tant property of receptors is that they have a 3D structure.
Proteins are usually composed of one or more peptide
chains; the composition of these chains makes up the pri-
mary and secondary structure of the protein. Proteins also
are described in terms of a tertiary structure, which defines
their shape in 3D space, and a quaternary structure, which
defines the molecular interactions between the various
components of the protein chains (Fig. 1.5). It is this 3D
structure which allows the protein to function as a recog-
nition site and effector for drugs and other components of
the cell; in essence, the ability of the protein to function as a
messenger, shuttling information from the outside world to
the cytosol of the cell. For 7TMRs, the 3D nature of the
receptor forms binding domains for other proteins such as
What is pharmacology? Chapter | 1 7
G-proteins (these are activated by the receptor and then go
on to activate enzymes and ion channels within the cell; see
Chapter 2: How Different Tissues Process Drug Response)
and endogenous chemicals such as neurotransmitters, hor-
mones, and autacoids that carry physiological messages.
This important class of drug target is named for a charac-
teristic structure consisting of 7TM domains looping into
the extracellular and intracellular spacedsee Fig. 1.6.
These molecules are the main transfer points of information
from the outside to the inside of the cell, and such transfers
occur through changes in the conformation of the receptor
protein (vide infra). For other receptors, such as ion chan-
nels and single transmembrane enzyme receptors, the
conformational change per se leads to a response, either
through an opening of a channel to allow the flow of ionic
current or the initiation of enzymatic activity. Therapeutic
advantage can be taken by designing small molecules to
utilize these binding domains or other 3D binding domains
on the receptor protein in order to modify physiological and
pathological processes.
1.6 From the snapshot to the movie
Drugs interact with living physiology and the outcome of
the interaction is controlled by a combination of the
intrinsic properties of the drug and the sensitivity of the
system to intervention. This being the case, drugs can have
different profiles of activity in different tissues depending
on the tissue sensitivity and setpoint of physiology.
Through the mechanics of mathematical models of drug
activity and the system-independent scales of drug activity
(i.e., affinity, efficacy), pharmacological procedures are
uniquely able to convert a single observation of drug ac-
tivity in a test system (the ‘snapshot’) to a prediction of the
complete realm of activities for that same drug in a range of
tissues of varying setpoints of physiology (the ‘movie’).
This is an essential property of pharmacology in drug dis-
covery as all initial evaluations of new drug activity are
made in isolated systems and assessments of what the new
molecule will do in other systems must be made. In
essence, the cellular host system completely controls what
the experimenter observes regarding the events taking place
at the drug receptor. Drug activity is thus revealed through
a “cellular veil” that can, in many cases, obscure or sub-
stantially modify drugereceptor activity (Fig. 1.7). Minute
signals, initiated either at the cell surface or within the
cytoplasm of the cell, are interpreted, transformed, ampli-
fied, and otherwise altered by the cell to tailor that signal to
its own particular needs. The application of pharmacolog-
ical principles and modeling enable ‘snapshots’ of drug
activity obtained is experiments to guide the progress of
molecules toward drug candidate statusdsee Chapter 3 for
further details.
8 A Pharmacology Primer
FIGURE 1.5 Increasing levels of protein structure. A protein has a given amino acid sequence to make peptide chains. These adopt a 3D structure
according to the free energy of the system. Receptor function can change with changes in tertiary or quaternary structure.
1.7 Pharmacological intervention and
the therapeutic landscape
It is useful to consider the therapeutic landscape with
respect to the aims of pharmacology. As stated by Sir
William Ossler (1849e919) “. the prime distinction be-
tween man and other creatures is man’s yearning to take
medicine.” The notion that drugs can be used to cure dis-
ease is as old as history. One of the first written records of
actual “prescriptions” can be found in the Ebers Papyrus
(c.1550 BCE): “. for night blindness in the eyes . liver
of ox, roasted and crushed out . really excellent!“dsee
Fig. 1.8. Now it is known that liver is an excellent source of
vitamin A, a prime treatment for night blindness, but that
chemical detail was not known to the ancient Egyptians.
Disease can be considered under two broad categories:
those caused by invaders such as pathogens and those
caused by intrinsic breakdown of normal physiological
function. The first generally is approached through the
invader (i.e., the pathogen is destroyed, neutralized, or
removed from the body). The one exception of where the
host is treated when an invader is present is the treatment of
HIV-1 infection leading to AIDS. In this case, while there
are treatments to neutralize the pathogen, such as anti-
retrovirals to block viral replication, a major new approach
is the blockade of the interaction of the virus with the
protein that mediates viral entry into healthy cells, the
chemokine receptor CCR5. In this case, CCR5 antagonists
are used to prevent HIV fusion and subsequent infection.
The second approach to disease requires an understanding
of the pathological process and repair of the damage to
return to normal function.
The therapeutic landscape onto which drug discovery
and pharmacology in general combat disease can gener-
ally be described in terms of the major organ systems of
the body and how they may go awry. A healthy cardio-
vascular system consists of a heart able to pump deoxy-
genated blood through the lungs and to pump oxygenated
blood throughout a circulatory system that does not
unduly resist blood flow. Since the heart requires a high

FIGURE 1.6 Depiction of the structure of seven transmembrane domain
receptors, one of the most if not the most important therapeutic targets
available in the human genome. Chemicals access the receptor through the
extracellular space by binding to the extracellular domains of the protein.
This causes a conformational change in the protein that alters the inter-
action of signaling proteins in the cell cytosol. This latter process results in
the initiation of cellular signaling.
degree of oxygen itself to function, myocardial ischemia
can be devastating to its function. Similarly, an inability to
maintain rhythm (arrhythmia) or loss in strength with
concomitant inability to empty (congestive heart failure)
can be fatal. The latter disease is exacerbated by elevated
arterial resistance (hypertension). A wide range of drugs
are used to treat the cardiovascular system, including
coronary vasodilators (nitrates), diuretics, renine
angiotensin inhibitors, vasodilators, cardiac glycosides,
calcium antagonists, beta and alpha blockers, antiar-
rhythmics, and drugs for dyslipidemia. The lungs must
extract oxygen from the air, deliver it to the blood, and
release carbon dioxide from the blood into exhaled air.
Asthma, chronic obstructive pulmonary disease (COPD),
and emphysema are serious disorders of the lungs and
airways. Bronchodilators (beta agonists), antiin-
flammatory drugs, inhaled glucocorticoids, anticholiner-
gics, and theophylline analogs are used for treatment of
these diseases. The CNS controls all conscious thought
and many unconscious body functions. Numerous dis-
eases of the brain can occur, including depression, anxi-
ety, epilepsy, mania, degeneration, obsessive disorders,
and schizophrenia. Brain functions such as those
What is pharmacology? Chapter | 1 9
controlling sedation and pain also may require treatment.
A wide range of drugs is used for CNS disorders,
including serotonin partial agonists and uptake inhibitors,
dopamine agonists, benzodiazepines, barbiturates, opi-
oids, tricyclics, neuroleptics, and hydantoins. The GI tract
receives and processes food to extract nutrients and
removes waste from the body. Diseases such as stomach
ulcers, colitis, diarrhea, nausea, and irritable bowel syn-
drome can affect this system. Histamine antagonists,
proton pump blockers, opioid agonists, antacids, and se-
rotonin uptake blockers are used to treat diseases of the GI
tract.
The inflammatory system is designed to recognize self
from nonself, and to destroy nonself to protect the body. In
diseases of the inflammatory system, the self-recognition
can break down, leading to conditions in which the body
destroys healthy tissue in a misguided attempt at protection.
This can lead to rheumatoid arthritis, allergies, pain, COPD,
asthma, fever, gout, graft rejection, and problems with
chemotherapy. Nonsteroidal antiinflammatory drugs,
aspirin and salicylates, leukotriene antagonists, and hista-
mine receptor antagonists are used to treat inflammatory
disorders. The endocrine system produces and secretes
hormones crucial to the body for growth and function.
Diseases of this class of organs can lead to growth and
pituitary defectsddiabetes; abnormality in thyroid, pitui-
tary, adrenal cortex, and androgen function; osteoporosis;
and alterations in estrogeneprogesterone balance. The
general approach to treatment is through replacement or
augmentation of secretion. Drugs used are replacement
hormones, insulin, sulfonylureas, adrenocortical steroids,
and oxytocin. In addition to the major organ and physio-
logical systems, diseases involving neurotransmission and
neuromuscular function, ophthalmology, hemopoiesis and
hematology, dermatology, immunosuppression, and drug
addiction and abuse are amenable to pharmacological
intervention.
Cancer is a serious malfunction of normal cell growth.
In the years from 1950 to 1970, the major approach to
treating this disease was to target DNA and DNA pre-
cursors according to the hypothesis that rapidly dividing
cells (cancer cells) are more susceptible to DNA toxicity
than normal cells. Since that time, a wide range of new
therapies based on manipulation of the immune system,
induction of differentiation, inhibition of angiogenesis, and
increased killer T-lymphocytes to decrease cell prolifera-
tion has greatly augmented the armamentarium against
neoplastic disease. Previously, lethal malignancies such as
testicular cancer, some lymphomas, and leukemia are now
curable.
Three general treatments of disease are surgery, genetic
engineering (still an emerging discipline), and pharmaco-
logical intervention. While early medicine was subject to
the theories of Hippocrates (460e357 BCE), who saw
10 A Pharmacology Primer

FIGURE 1.7 The cellular veil. Drugs act on biological receptors in cells to change cellular activity. The initial receptor stimulus usually alters a
complicated system of interconnected metabolic biochemical reactions, and the outcome of the drug effect is modified by the extent of these in-
terconnections, the basal state of the cell, and the threshold sensitivity of the various processes involved. This can lead to a variety of apparently different
effects for the same drug in different cells. Receptor pharmacology strives to identify the basic mechanism initiating these complex events.

FIGURE 1.8 The Ebers Papyrus is a 110-page scroll (20 m long) thought to have been written in 1550 BCE but containing information dating from
3400 BCE. It is a record of Egyptian medicine and contains numerous “prescriptions” some of which, though empirical, are valid therapeutic approaches
to diseases.

health and disease as a balance of four humors (i.e., black
and yellow bile, phlegm, and blood), by the 16th century
pharmacological concepts were being formulated. These
could be stated concisely as the following [13]:
l Every disease has a cause for which there is a specific
remedy.
l Each remedy has a unique essence that can be obtained
from nature by extraction (“doctrine of signatures”).
l The administration of the remedy is subject to a dosee
response relationship.
The basis for believing that pharmacological interven-
tion can be a major approach to the treatment of disease is
the fact that the body generally functions in response to
chemicals. Table 1.1 shows partial lists of hormones and
neurotransmitters in the body. Many more endogenous
chemicals are involved in normal physiological function.
 What is pharmacology? Chapter | 1 11

TABLE 1.1 Some endogenous chemicals controlling normal physiological function.

Neurotransmitters
Acetylcholine 2-Arachidonylglycerol Anandamide
ATP Corticotropin-releasing hormone Dopamine
Epinephrine Aspartate Gamma-aminobutyric acid
Galanin Glutamate Glycine
Histamine Norepinephrine Serotonin
Hormones
Thyroid-stimulating hormone Follicle-stimulating hormone Luteinizing hormone
Prolactin Adrenocorticotropin Antidiuretic hormone
Thyrotropin-releasing hormone Oxytocin Gonadotropin-releasing hormone
Growth-hormone-releasing hormone Corticotropin-releasing hormone Somatostatin
Melatonin Thyroxin Calcitonin
Parathyroid hormone Glucocorticoid(s) Mineralocorticoid(s)
Estrogen(s) Progesterone Chorionic gonadotropin
Androgens Insulin Glucagon
Amylin Erythropoietin Calcitriol
Calciferol Atrial-natriuretic peptide Gastrin
Secretin Cholecystokinin Neuropeptide Y
Insulin-like growth factor Angiotensinogen Ghrelin

Leptin

ATP, adenosine triphosphate.

The fact that so many physiological processes are
controlled by chemicals provides the opportunity for
chemical intervention. Thus, physiological signals medi-
ated by chemicals can be initiated, negated, augmented, or
modulated. The nature of this modification can take the
form of changes in the type, strength, duration, or location
of signal.
1.8 System-independent drug
parameters: affinity and efficacy
The process of drug discovery relies on the testing of mol-
ecules in systems to yield estimates of biological activity in
an iterative process of changing the structure of the molecule
until optimal activity is achieved. It will be seen in this book
that there are numerous systems available to do this, and that
each system may interpret the activity of molecules in
different ways. Some of these interpretations can appear to
be in conflict with each other, leading to apparent capricious
patterns. For this reason, the way forward in the drug
development process is to use only system-independent in-
formation. Ideally, scales of biological activity should be
used that transcend the actual biological system in which the
drug is tested. This is essential to avoid confusion and also
because it is quite rare to have access to the exact human
system under the control of the appropriate pathology
available for in vitro testing. Therefore, the drug-discovery
process necessarily relies on the testing of molecules in
surrogate systems and the extrapolation of the observed ac-
tivity to all systems. The only means to do this is to obtain
system-independent measures of drug activity, namely, af-
finity and efficacy.
If a molecule in solution associates closely with a re-
ceptor protein, it has affinity for that protein. The area where
it is bound is the binding domain or locus. If the same
molecule interferes with the binding of a physiologically
active molecule such as a hormone or a neurotransmitter
(i.e., if the binding of the molecule precludes activity of the
physiologically active hormone or neurotransmitter), the
molecule is referred to as an antagonist. Therefore, a phar-
macologically active molecule that blocks physiological ef-
fect is an antagonist. Similarly, if a molecule binds to a
receptor and produces its own effect, it is termed an agonist.
It also is assumed to have the property of efficacy. Efficacy is
12 A Pharmacology Primer

detected by observation of pharmacological response.
Therefore, agonists have both affinity and efficacy.
Classically, agonist response is described in two stages,
the first being the initial signal imparted to the immediate
biological target, namely, the receptor. This first stage is
composed of the formation, either through interaction with
an agonist or spontaneously, of an active state receptor
conformation. This initial signal is termed the stimulus
(Fig. 1.9). This stimulus is perceived by the cell and pro-
cessed in various ways through successions of biochemical
reactions to the end point, namely, the response. The sum
total of the subsequent reactions is referred to as the
stimuluseresponse mechanism or cascade (see Fig. 1.10).
Efficacy is a molecule-related property (i.e., different
molecules have different capabilities to induce a physio-
logical response). The actual term for the molecular aspect
of response-inducing capacity of a molecule is intrinsic
efficacy (see Chapter 3: DrugeReceptor Theory for how
this term evolved). Thus, every molecule has a unique
value for its intrinsic efficacy (in cases of antagonists this
could be zero). The different abilities of molecules to
induce response are illustrated in Fig. 1.10. This figure
shows doseeresponse curves for four 5-HT (hydroxytryp-
tamine) (serotonin) agonists in rat jugular vein. It can be
seen that if response is plotted as a function of the percent
receptor occupancy, different receptor occupancies for
the different agonists lead to different levels of response.
For example, while 0.6 g force can be generated by
5-HT by occupying 30% of the receptors, the agonist 5-
cyanotryptamine requires twice the receptor occupancy to
generate the same response (i.e., the capability of 5-
cyanotryptamine to induce response is half that of 5-HT
[14]). These agonists are then said to possess different
magnitudes of intrinsic efficacy.

FIGURE 1.9 Schematic diagram of response production by an agonist. An initial stimulus is produced at the receptor as a result of agonistereceptor
interaction. This stimulus is processed by the stimuluseresponse apparatus of the cell into observable cellular response.

FIGURE 1.10 Differences between agonists producing contraction of rat jugular vein through activation of 5-HT receptors. (A) Doseeresponse curves
to 5-HT receptor agonists, 5-HT (filled circles), 5-cyanotryptamine (filled squares), N,N-dimethyltryptamine (open circles), and N-benzyl-5-
methoxytryptamine (filled triangles). Abscissae: logarithms of molar concentrations of agonist. (B) Occupancy response curves for curves shown in
panel A. Abscissae: percent receptor occupancy by the agonist as calculated by mass action and the equilibrium dissociation constant of the agoniste
receptor complex. Ordinates: force of contraction in g. Data drawn from P. Leff, G.R. Martin, J.M. Morse, Differences in agonist dissociation constant
estimates for 5-HT at 5-HT2-receptors: a problem of acute desensitization? Br. J. Pharmacol. 89 (1986) 493e499.

It is important to consider affinity and efficacy as
separately manipulatable properties. Thus, there are chem-
ical features of agonists that pertain especially to affinity
and other features that pertain to efficacy. Fig. 1.11 shows a
series of key chemical compounds made en route to the
histamine H2 receptor antagonist cimetidine (used for
healing gastric ulcers). The starting point for this discovery
program was the knowledge that histamine, a naturally
occurring autacoid, activates histamine H2 receptors in the
stomach to cause acid secretion. This constant acid secre-
tion is what prevents the healing of lesions and ulcers. The
task was then to design a molecule that would antagonize
the histamine receptors mediating acid secretion and pre-
vent histamine H2 receptor activation to allow the ulcers to
heal. This task was approached with the knowledge that
molecules, theoretically, could be made that retained or
even enhanced affinity but decreased the efficacy of hista-
mine (i.e., these were separate properties). As can be seen
in Fig. 1.11, molecules were consecutively synthesized
with reduced values of efficacy and enhanced affinity until
the target histamine H2 antagonist cimetidine was made.
This was a clear demonstration of the power of medicinal
chemistry to separately manipulate affinity and efficacy for
which, in part, the Nobel Prize in Medicine was awarded in
1988.
1.9 What is affinity?
The affinity of a drug for a receptor defines the strength of
interaction between the two species. The forces control-
ling the affinity of a drug for the receptor are thermody-
namic (enthalpy as changes in heat and entropy as changes
FIGURE 1.11 Key compounds synthesized to eliminate the efficacy (burgundy red) and enhance the affinity (green) of histamine for histamine H2
receptors to make cimetidine, one of the first histamine H2 antagonists of use in the treatment of peptic ulcers. Quotation from J.W. Black, A personal view
of pharmacology, Ann. Rev. Pharmacol. Toxicol. 36 (1996) 1e33.
What is pharmacology? Chapter | 1 13
in the state of disorder). The chemical forces between the
components of the drug and the receptor vary in impor-
tance in relation to the distance of the drug from the re-
ceptor’s binding surface. Thus, the strength of
electrostatic forces (attraction due to positive and negative
charges and/or complex interactions between polar
groups) varies as a function of the reciprocal of the dis-
tance between the drug and the receptor. Hydrogen
bonding (the sharing of a hydrogen atom between an
acidic and basic group) varies in strength as a function of
the fourth power of the reciprocal of the distance. Also
involved are van der Waals’ forces (weak attraction be-
tween polar and nonpolar molecules) and hydrophobic
bonds (interaction of nonpolar surfaces to avoid interac-
tion with water). The combination of all of these forces
causes the drug to reside in a certain position within the
protein-binding pocket. This is a position of minimal free
energy. It is important to note that drugs do not statically
reside in one uniform position. As thermal energy varies
in the system, drugs approach and dissociate from the
protein surface. This is an important concept in pharma-
cology as it sets the stage for competition between two
drugs for a single binding domain on the receptor protein.
The probability that a given molecule will be at the point
of minimal free energy within the protein-binding pocket
thus depends on the concentration of the drug available to
fuel the binding process and also the strength of the in-
teractions for the complementary regions in the binding
pocket (affinity). Affinity can be thought of as a force of
attraction and can be quantified with a very simple tool,
first used to study the adsorption of molecules onto a
surface, namely, the Langmuir adsorption isotherm.
14 A Pharmacology Primer
1.10 The Langmuir adsorption isotherm
Defined by the chemist Irving Langmuir (1881e957,
Fig. 1.12), the model for affinity is referred to as the
Langmuir adsorption isotherm. Langmuir, a chemist at
General Electric, was interested in the adsorption of mol-
ecules onto metal surfaces for the improvement of lighting
filaments. He reasoned that molecules had a characteristic
rate of diffusion toward a surface (referred to as conden-
sation and denoted a in his nomenclature) and also a
characteristic rate of dissociation (referred to as evapora-
tion and denoted as V1; see Fig. 1.12). He assumed that the
amount of surface that already has a molecule bound is not
available to bind another molecule. The surface area bound
by molecule is denoted q1, expressed as a fraction of
the total area. The amount of free area open for the binding
of molecule, expressed as a fraction of the total area, is
denoted as 1  q1. The rate of adsorption toward the sur-
face therefore is controlled by the concentration of drug in
the medium (denoted m in Langmuir’s nomenclature)
multiplied by the rate of condensation on the surface and
the amount of free area available for binding:
Rate of diffusion toward surface ¼ amð1  q1 Þ. (1.1)
The rate of evaporation is given by the intrinsic rate of
dissociation of bound molecules from the surface multi-
plied by the amount already bound:
Rate of evaporation ¼ V1 q1 .
Once equilibrium has been reached, the rate of
adsorption equals the rate of evaporation. Equating (1.1)
and (1.2) and rearranging yields
FIGURE 1.12 The Langmuir adsorption isotherm representing the binding of a molecule to a surface. Photo shows Irving Langmuir (1881e957), a
chemist interested in the adsorption of molecules to metal filaments for the production of light. Langmuir devised the simple equation still in use today for
quantifying the binding of molecules to surfaces. The equilibrium is described by condensation and evaporation to yield the fraction of surface bound (q1)
by a concentration m.
am
q1 ¼ . (1.3)
am þ V1
This is the Langmuir adsorption isotherm in its original
form. In pharmacological nomenclature, it is rewritten ac-
cording to the convention
½AR ½A
r¼ ¼ ; (1.4)
½Rt  ½A þ KA
where [AR] is the amount of complex formed between the
ligand and the receptor, and [Rt] is the total number of re-
ceptor sites. The ratio r refers to the fraction of maximal
binding by a molar concentration of drug [A] with an equi-
librium dissociation constant of KA. This latter term is the
ratio of the rate of offset (in Langmuir’s terms V1 and
referred to as k2 in receptor pharmacology) divided by
the rate of onset (in Langmuir’s terms a denoted k1 in re-
ceptor pharmacology).
It is amazing to note that complex processes such as
drugs binding to protein, activation of cells, and observa-
tion of syncytial cellular response should apparently so
closely follow a model based on these simple concepts.
This was not lost on A.J. Clark in his treatise on druge
receptor theory The Mode of Action of Drugs on Cells [4]:
It is an interesting and significant fact that the author in
1926 found that the quantitative relations between the con-
centration of acetylcholine and its action on muscle cells, an
(1.2) action the nature of which is wholly unknown, could be most
accurately expressed by the formulae devised by Langmuir
to express the adsorption of gases on metal filaments.
dA.J. Clark (1937).

The term KA is a concentration, and it quantifies af-
finity. Specifically, it is the concentration that binds to 50%
of the total receptor population [see Eq. (1.4) when [A] ¼
KA]. Therefore, the smaller is the KA, the higher is the
affinity. Affinity is the reciprocal of KA. For example, if
KA ¼ 108 M, then 108 M binds to 50% of the receptors.
If KA ¼ 104 M, a 10,000-fold higher concentration of the
drug is needed to bind to 50% of the receptors (i.e., it is of
lower affinity).
It is instructive to discuss affinity in terms of the
adsorption isotherm in the context of measuring the amount
of receptor bound for given concentrations of drug. Assume
that values of fractional receptor occupancy can be visu-
alized for various drug concentrations. The kinetics of such
binding is shown in Fig. 1.13. It can be seen that initially
the binding is rapid, in accordance with the fact that there
are many unbound sites for the drug to choose. As the sites
become occupied, there is a temporal reduction in binding
until a maximal value for that concentration is attained.
Fig. 1.13 also shows that the binding of higher concentra-
tions of drug is correspondingly increased. In keeping with
the fact that this is first-order binding kinetics (where the
rate is dependent on a rate constant multiplied by the
concentration of reactant), the time to equilibrium is shorter
for higher concentrations than for lower concentrations.
The various values for receptor occupancy at different
concentrations constitute a concentration binding curve
(shown in Fig. 1.14A). There are two areas in this curve of
particular interest to pharmacologists. The first is the
maximal asymptote for binding. This defines the maximal
number of receptive binding sites in the preparation. The
binding isotherm [Eq. (1.4)] defines the ordinate axis as the
fraction of the maximal binding. Thus, by definition, the
maximal value is unity. However, in experimental studies,
real values of capacity are used since the maximum is not
FIGURE 1.13 Time course for increasing concentrations of a ligand with a KA of 2 nM. Initially, the binding is rapid but slows as the sites become
occupied. The maximal binding increases with increasing concentrations as does the rate of binding.
What is pharmacology? Chapter | 1 15
known. When the complete curve is defined, the maximal
value of binding can be used to define fractional binding at
various concentrations and thus define the concentration at
which half-maximal binding (binding to 50% of the re-
ceptor population) occurs. This is the equilibrium dissoci-
ation constant of the drugereceptor complex (KA), the
important measure of drug affinity. This comes from the
other important region of the curve, namely, the midpoint.
It can be seen from Fig. 1.14A that graphical estimation of
both the maximal asymptote and the midpoint is difficult to
perform with the graph in the form shown. A much easier
format to present binding, or any concentrationeresponse
data, is a semilogarithmic form of the isotherm. This allows
better estimation of the maximal asymptote and places the
midpoint in a linear portion of the graph where intra-
polation can be done (see Fig. 1.14B). Doseeresponse
curves for binding are not often visualized, as they require a
means to detect bound (over unbound) drug. However, for
drugs that produce a pharmacological response (i.e., ago-
nists), a signal proportional to bound drug can be observed.
The true definition of a doseeresponse curve is the
observed in vivo effect of a drug given as a dose to a whole
animal or human. However, it has entered into the common
pharmacological jargon as a general depiction of drug and
effect. Thus, a doseeresponse curve for binding is actually
a binding concentration curve, and an in vitro effect of an
agonist in a receptor system is a concentrationeresponse
curve.
1.11 What is efficacy?
The property that gives a molecule the ability to change a
receptor, such that it produces a cellular response, is termed
efficacy. Early concepts of receptors likened them to locks
and keys. As stated by Paul Ehrlich,
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