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102 ESSENTIAL PHARMACOLOGY
When the agonist falls off the receptor, the receptor will eventually
return to its high affinity state. Phosphatases will dephosphorylate
the receptor, preventing the binding of beta- arrestin and changing
the flux of receptors in and out of the plasma membrane to favor an
increase in receptors exposed on the cell surface, ready to respond
to norepinephrine again.
Pharmacological importance of receptor homeostasis. It
is important to remember that the use of agonists as drugs may lead
to receptor loss and a subsequent temporary failure of the system to
respond to endogenous agonists. Conversely, the use of antagonists
as drugs may create a supersensitive or hyperreactive state leading
to a crisis if the antagonist is suddenly removed.
Because of their central role in regulation of physiology, there are
a number of diseases associated with receptor malfunction due to
mutations, autoimmunity, or specific toxins that act on signaling
pathways. Some examples are:
1. G- proteins are targets for cholera toxin (turns on Gs) and pertus-
sis toxin (turns off Gi).
2. Genetic deficiency of Gs – involved in multiple endocrine
failures, manifest clinically as pseudohypoparathyroidism
Type Ia.
3. Autoimmune deficiencies– involved in myasthenia gravis (anti-
bodies to the acetylcholine receptor) and some forms of insulin-
resistant diabetes mellitus (antibodies to the insulin receptor).
4. Certain oncogenes are aberrant receptor/effector systems for
growth factor receptors, leading to uncontrolled cell growth.
103
Chapter 11
Testing and Evaluation
of New Drugs
P
harmacology is a rapidly developing field due to the current
pace of advances in understanding biological signaling sys-
tems. You, and your patients if you practice medicine, will
always be interested in what is “around the corner” in new thera-
peutic approaches. Therefore, it is useful to be familiar with the pro-
cess and regulatory time course of drug development.
The Food and Drug Administration oversees drug evaluation in
the United States and grants approval for the marketing of new drug
products. As summarized in Figure 11.1, the process of drug evalu-
ation usually takes a number of years. After basic research stud-
ies have resulted in the introduction of a new “lead compound,”
this compound will be tested for efficacy and toxicity in animals,
the FDA will approve an IND (“Notice of Claimed Investigational
104 ESSENTIAL PHARMACOLOGY
exemption for a New Drug”) and testing in humans may begin,
progressing through several phases:
Phase I: Testing in small numbers of normal volunteers or patients
for the basic pharmacokinetics of the drug (absorption, half- life, vol-
ume of distribution, excretion) and possible unexpected toxicities.
Phase II: Testing in larger numbers of patients to determine if
the drug is in fact efficacious in treating the disease in question.
Phase III: Testing in large groups of patients in several settings
in double- blind format to establish that the efficacy is statistically
significant.
Success in these phases will result in the approval of an NDA
(“New Drug Application”) and the marketing of the drug may begin.
Post- marketing surveillance of the efficacy and side effects of the drug
is termed Phase IV evaluation. Side effects or toxicities seen at very
low frequency may only become evident during this phase. Exclusive
marketing of the drug by the developer is typically protected by pat-
enting for no more than 14 years after filing of the NDA; subsequently
generic formulations may be marketed by other companies.
In vitro
studies
Animal
testing
Clinical
testing
Marketing
Biologic
products
Phase 1
(Is it safe,
pharmacokinetics?)
Generics
become
available
Lead compound
Efficacy
selectivity
mechanism
Phase 2
(Does it work
in patients?)
Phase 3
(Does it work,
double blind?)
Phase 4
(Postmarketing
surveillance)
Chemical
synthesis
Drug metabolism, safety assessment
0
Years (average
)
24
IND
(Investigational
New Drug)
8−9
NDA
(New Drug
Application)
20
(Patent expires
20 years after filing
of application)
Figure11.1 Testing and evaluation of new drugs.
SOURCE: TW Vanderah, Katzung’s Basic and Clinical Pharmacology, 2023, Figure 1–6 / with
permission of McGraw Hill LLC.
105
Chapter 12
Further Study
in Pharmacology
T
his book has emphasized the general principles of the
actions of drugs and their use in therapeutic settings. How-
ever, the book does not include a comprehensive review of
the vast knowledge of drug classes and their specific actions. This
is some of the most interesting content of pharmacology, and it is
well worth the investment to read some of the excellent books that
cover this broad area of medical science. The following two books
are used for training medical students and graduate students at the
University of Virginia and are highly recommended. They also serve
well for lay persons with a background in basic sciences obtained in
high school and college courses and who have an abiding interest
in pharmacology and medicine.
Goodman and Gilman’s The Pharmacological Basis of
Therapeutics. First published in 1941, with revised editions
106 ESSENTIAL PHARMACOLOGY
appearing every 5– 10 years, this encyclopedic book is highly
respected as representing the state of the art in pharmacological
knowledge. It is a multi- author text written by experts in all areas of
pharmacology, emphasizing clinical practice in humans. The chap-
ters have extensive literature references that are a useful resource
for following the development of the field through the decades. In
addition to being foundational for students, the book is an impor-
tant reference for active basic researchers and practitioners of clini-
cal medicine.
Katzung’s Basic and Clinical Pharmacology, Similar to
Goodman and Gilman, this is a multi- authored text that provides
a comprehensive overview of medical pharmacology. It is particu-
larly suited for medical students.
Pharmacology review books. Additionally, a number of books
are available for reviewing pharmacology, particularly in the context
of preparing for Medical Board Exams. These provide additional
examples of solutions to pharmacology problems introduced in this
book. Two representative books, which are frequently updated, are
listed below.
Katzung and Trevor’s Pharmacology Examination and Board
Review, McGraw Hill
Lippincott Illustrated Reviews: Pharmacology, Walters Kluwer
107
Index
A
absorption of drugs
oral administration, 13–14
parenteral (nonoral)
administration, 14
acetaminophen metabolites, 22
acetylcholine, 11
acid/base determination, 11, 12
active transport processes, 7
adrenergic receptors, 91
agonists see also antagonists
endogenous, 76
full, 89
inverse, 81
partial, 73–77, 89
allosteric model, drug–receptor
interaction, 77–81
amines, 11
amplification of signals,
Gproteins, 99
antagonists
competitive/surmountable,
68–71
definition, 63
irreversible, 73
noncompetitive/insurmountable,
71–73, 84–86, 88
partial, 73–78
AP2 see assembly protein (AP2)
aqueous pores, 7
108 INDEX
Area Under the Curve
(A.U.C), 54– 55
aspirin, 12
assembly protein (AP2), 100
atropine, 12
average drug concentration, 53
B
bacteriorhodopsin, 96
BBB see blood brain barrier (BBB)
Beta Adrenergic Receptor Kinase
(BARK), 100
biliary excretion, 27
bioavailability, 15
bioequivalent, 15
biological receptor effector
mechanisms
G protein coupled receptors, 96
G proteins
activation cycle, 96– 98
amplification of signal, 99
diffusion of signal, 99
integration of signal, 99
identification and
classification, 90– 91
location of receptors, 92
protein kinases and transcription
factors, 93
receptor malfunction,
diseases, 102
receptor structure and proximal
effector systems, 94– 95
second messengers, 92– 93
importance of, 94
signaling homeostasis and
receptor metabolism,
100– 102
biotransformation of drugs
drug metabolism
consequences, 20
enzymatic biotransformation
reactions, 20– 21
smooth endoplasmic reticulum,
21– 25
blood brain barrier (BBB), 15– 16
C
cancer chemotherapeutic
agents, 63
carcinogenic/teratogenic
compounds, 22, 23
carrier mediated transport, 7
cell membranes, 7, 33, 62, 92,
93, 96
clearance, 32– 34, 40, 44, 48, 55
of drugs and environmental
toxins, 20
of isradipine, 43
in kidney, 34, 35
in liver, 34, 35
plasma concentration, 32– 34, 36
clinical pharmacokinetics, 28
dose dependent (or non
linear) pharmacokinetic
model, 47– 52
dose independent
pharmacokinetic model, 36
dosing rate, 28
half time of elimination, 39
intermittent oral dosing, 52– 54
linear pharmacokinetic model,
36, 37, 43– 47
loading dose, 42
parameters and variables, 29
bioavailability, F
(dimensionless), 30
clearance CL ml/min
per kg, 32– 35
dose, D mg, or mg/kg,
29– 30
dosing rate or dosage, D.R. mg/
min per kg., 30
plasma drug concentration, C
μg/ml, mg/ml, 29
Index 109
volume of distribution, V
d
,
l/kg, 30– 32
plasma drug accumulation, 41
plasma drug concentration,
38, 40
recapitulation of equations, 55
single compartment model, 36
of single doses, 54– 55
steady state solution, 42
competitive antagonist, 68– 71
concentration axis, 58
constitutive metabolic
capacity, 24– 25
CYP1, CYP2, and CYP3, 22
cytochrome p450 systems, 22
D
diacylglycerol, 93
diffusion
drug characteristics, 15
hydrophobic substances, 7
passive, 6, 7, 10, 27
of signals, 99
digoxin, 15
distribution of drugs
antiparasitic drugs, 17
BBB, 15– 16
fractional binding, 17
local anesthetics distribution, 18
placental transfer, 18
plasma proteins binding, 17
protein binding, 17– 18
dose dependent model, 47– 52
dose (dosage) versus intensity of
effect, 56– 58
dose independent model, 36, 50
dose response curve, 56
dose response relationship, 70
dosing rate = rate of elimination, 42
drug absorption
oral administration, 13– 14
parenteral (non oral)
administration, 14
pH effect, 10
drug metabolism consequences, 20
drug tolerance, 58
E
ED50 (effective dose for 50%
activation), 57
Ehrlich, Paul, 61
endogenous agonists, 76
enterohepatic circulation, 27
enzymatic biotransformation
reactions, 20– 21
Euler method, 49
excretion of drugs, 26– 27
excretory process, kidney, 27
F
Fick’s law, 6
fractional occupancy
threshold, 86– 87
full agonist, 89
G
GDP, 97, 98, 100
GFR see glomerular filtration
rate (GFR)
glomerular filtration rate (GFR), 27
glucuronide synthesis, UDP
glucuronate, 21
Goodman and Gilman’s The
Pharmacological Basis of
Therapeutics, 105– 106
G protein Receptor Kinase
(GRK), 100
G proteins
activation cycle, 96– 98
amplification of signal, 99
diffusion of signal, 99
integration of signal, 99
110 INDEX
G proteins coupled receptors, 96
GRK see G protein Receptor
Kinase (GRK)
GTP, 97– 100
GTPase activity, 98
H
half time of elimination, 39
Henderson– Hasselbalch equation, 8
heparin, 12
hepatic cytochrome P450 system, 22
histamine, 12
histamine H2 antagonist
cimetidine, 23– 24
humane end point, 59
hydrophilic character, 7
hyperreactivity, 58
hypersensitivity, 58
hyporeactive, 58
I
idiosyncratic dose response curves, 58
IND see Investigational exemption
for a New Drug (IND)
induction, 21
of microsomal enzymes, 23– 24
inhibitors of agonists, 63
inositol trisphosphate (IP3), 93
insulin receptor, 91
insurmountable antagonists, 71– 73
integration of signals, G proteins, 99
intracellular language, 92– 93
inverse agonists, 77– 81
Investigational exemption for a New
Drug (IND), 103– 104
irrelevant binding sites, 4, 5
irreversible antagonists, 73
K
“Kact” (K for activation), 57
Katzung’s Basic and Clinical
Pharmacology, 106
kidney tubules, 10, 11, 16, 26
L
lead compound, 103
linear pharmacokinetic model,
36, 37, 43– 47
loading dose, 42, 45, 51
M
magic bullet, 61
Maximal Effect, 66, 67
Michaelis– Menton equation, 66
Michaelis– Menton kinetics, 33,
48, 64, 65
Michaelis– Menton theory, 48
microsomal fraction of cell
homogenates, 21– 25
molecular fire, 22
morphine sulfate, 13
muscarinic cholinergic receptor, 91
N
negative agonists, 79
New Drug Application (NDA), 104
nicotinic acetylcholine receptor, 94
nicotinic cholinergic receptor, 91
noncompetitive antagonists,
71– 73, 84– 86, 89
nonlinear model, 48
non linear pharmacokinetic
model, 47– 52
non microsomal biotransformation, 25
non synthetic/Phase I
reactions, 20– 21
norepinephrine, 12
O
oral administration, 13– 14
orphan receptors, 91
P
parenteral (non oral)
administration, 14
parenteral drug preparations, 13
partial agonists, 73– 77, 89
Index 111
passive diffusion, 6, 7
Pasteur, Louis, 61
penicillin, 27
permeability, 7
pharmacodynamics, 4
pharmacodynamics I
dose (dosage) versus intensity of
effect, 56– 58
therapeutic index, 58– 59
therapeutic window, 59
pharmacodynamics II
drug receptors, 63
dyes, 60– 61
mechanisms, 61– 62
specificity of drugs, 62
pharmacodynamics III
allosteric model for drug– receptor
interaction, 77– 81
competitive/surmountable
antagonists, 68– 71
dose– response curve, 87– 89
fractional occupancy
threshold, 86– 87
irreversible antagonists, 73
noncompetitive/insurmountable
antagonists, 71– 73
partial agonists, 73– 77
simple occupancy model, 65– 68
spare receptors (see spare
receptors)
pharmacokinetics, 4
pharmacology
definition, 3
discipline of, 1
further study in, 105– 106
mechanisms of action, 2
pharmacodynamics, 4
pharmacokinetics, 4
Phase I reactions, 20– 21
Phase II reactions, 21
phenytoin, 12, 13
phenytoin sodium, 13
pH, influence of, 7– 13
phospholipids, 63
plasma concentration, 15, 38
A.U.C., 54
clearance, 32– 34, 36
loading dose, 42
rapid reduction of, 46– 47
renal excretion, 27
risk inherent, 48
steady state, 42, 44
plasma drug concentration, 29, 38,
48, 50, 55
propranolol, 62
protein kinase C, 93
pyridoxal phosphate, 12
R
rapid reduction, plasma
concentration, 46– 47
recapitulation of equations, 55
S
second messengers, 92– 93
importance of, 94
sildenafil (Viagra), 62
simple occupancy model, 65– 68, 81– 83
single compartment model, 36
smooth endoplasmic
reticulum, 21– 25
spare receptors, 89
noncompetitive antagonists, 84– 86
simple occupancy model, 81– 83
specificity of drugs, 62
steady state plasma
concentration, 42, 44
sulfanilamide, 12– 13
surmountable antagonist, 68– 71
synthetic dyes, 60
synthetic/Phase II reactions, 21
T
T
1/2
(or half life of elimination), 39
tachyphylaxis, 58
therapeutic index, 58– 59
therapeutic window, 59