USMLE
*
Step 1
Pharmacology
Notes
KAPLAN
"
medical
*USMLE is ajoint program of the Federation of State Medical Boards
of
the Unted States. Inc. and
the
National Board of
Medical
Examiners.
02002
Kaplan, Inc.
All
rights reserved. No part of this book may be reproduced in any form, by photostat,
microfilm, xerography or any other means, or incorporated into any information
retrieval system, electronic or mechanical, without the written permission of Kaplan, Inc.
Executive Editor and Contributing Author
Anthony Trevor, Ph.D.
Professor Emeritus
Department of Cellular and Molecular Pharmacology
University of California
San Francisco, CA
Contributing Authors
Maris Victor Nora, Pharm.D., Ph.D.
Associate Professor
Rush Medical College
Chicago, IL
Lionel
P.
Raymon, Pharm.D., Ph.D.
Department of Pathology
Forensic Toxicology Laboratory
University of Miami School of Medicine
Miami,
FL
Craig Davis, Ph.D.
Associate Professor
University of South Carolina School of Medicine
Department of Pharmacology and Physiology
Columbia, SC
Contributor
Kenneth
H.
Ibsen, Ph.D.
Director of Academic Development
Kaplan Medical
Professor Emeritus Biochemistry
University of California
-
Irvine
Irvine, CA
Executive Director of Curriculum
Richard Friedland, M.D.
Director of Publishing and Media
Michelle Covello
Director of Medical Illustration
Christine Schaar
Managing Editor
Kathlyn McGreevy
Production Editor
Ruthie Nussbaum
Production Artist
Michael Wolff
Cover Design
Joanna Myllo
Cover Art
Christine Schaar
Table of Contents
.......................................................
Preface vii
Section
I:
General Principles
......................................
Chapter
1:
Pharmacokinetics 3
....................................
Chapter
2:
Pharmacodynamics 19
Section
11:
Autonomic Pharmacology
....................
Chapter
I:
The Autonomic Nervous System (ANS)
39
..............................
Chapter
2:
Cholinergic Pharmacology 45
.......................
Chapter
3:
Adrenergic Neuroeffector Junctions
53
Chapter
4:
Autonomic Drugs: The Eye and Cardiovascular System
........
63
..............................
Chapter
5:
Autonomic Drug Summary
71
Section
Ill:
Cardiac and Renal Pharmacology
.................................
Chapter
1:
Fundamental Concepts 85
..................................
Chapter
2:
Antiarrhythmic Drugs 91
.................................
Chapter
3:
Antihypertensive Drugs 95
................................
Chapter
4:
Drugs for Heart Failure 103
....................................
Chapter
5:
Antianginal Drugs 109
............................................
Chapter
6:
Diuretics 115
...................................
Chapter
7:
Antihyperlipidemics 123
KAPLAN'
medical
v
Section
IV:
CNS Pharmacology
...................................
Chapter
1:
CNS
Pharmacology
141
Section V: Antimicrobial Agents
..................................
Chapter
1:
Antibacterial Agents 189
....................................
Chapter
2:
Antifungal Agents 205
......................................
Chapter
3:
Antiviral Agents
209
........
Chapter
4:
Antiprotozoal Agents and the Antimicrobial Drug List
217
Sedion VI: Drugs for Inflammatory and Related Disorders
.............
Chapter
1:
Drugs for Inflammatory and Related Disorders
233
Section VII: Drugs Used in Blood and Endocrine Disorders
..................................
Chapter
1:
Blood Pharmacology 267
..............................
Chapter
2:
Endocrine Pharmacology 273
Section VIII: Anticancer Drugs
.
Immunopharmacology. and Toxicology
.....................................
Chapter
1:
Anticancer Drugs
289
................................
Chapter
2:
lmmunopharmacology
293
..........................................
Chapter
3:
Toxicology
295
KAPLAN'
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SECTION
I
General Principles
Pharmacokinetics
PERMEATION
Pharmacokinetic characteristics of drug molecules concern the processes of absorption, distri
-
bution, metabolism, and excretion. The biodisposition of a drug involves its permeation across
cellular membrane barriers.
Tissue
Storage
Administration
(IV, PO, etc.)
t
Absorption into Plasma
Plasma
n
Distribution to Tissues
\
Bound Drug
=[
11
)
>
Free Drug
J
Sites of
Action
Receptors
Drug Metabolism
Drug Excretion
I
>
i
(Renal, Biliary, Exhalation,
(Liver, Lung, Blood, etc.)
etc.)
Figure
1-1-1
.
Drug Biodisposition
KAPLAN'
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USMLE Step
1:
Pharmacology
Drug Permeation Is Dependent
On:
Solubility. Ability to diffuse through lipid bilayers (lipid solubility) is important for most drugs;
however, water solubility can influence permeation through aqueous phases.
Concentration gradient. Diffusion down a concentration gradient
-
only free drug forms con
-
tribute to the concentration gradient.
Surface area and vascularity. Important with regard to absorption of drugs into the systemic
circulation.
In
A
Nutshell
For
Weak Acids and Weak
Bases
lonized
=
Water soluble
Nomomzed
=
Lipid soluble
Ionization
Many drugs are weak acids or weak bases and can exist in either nonionized or ionized forms
in an equilibrium, depending on the pH of the environment and their
pKa (the pH at which the
molecule is
50%
ionized and
50%
nonionized). Only the nonionized (uncharged) form of a
drug crosses biomembranes.
Acidic media: pH
<
pKa Basic media: pH
>
pKa
L
Weak Acid R.COOH
7
R.COO
-
+
H+
(crosses membranes)
L
Weak Base
R.NH
3
+
7
R.NH
2
+
H
+
(crosses membranes)
The percentage of ionization is determined by the Henderson
-
Hasselbalch equation.
[ionized]
For weak acids: pH
-
pKa
=
log
[nonionized]
[nonionized]
For weak bases: pH
-
pKa
=
log
[ionized]
Figure 1
-
1
-
2. Degree of Ionization and Clearance
Versus pH Deviation from
pKa
KAPLAN'
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medical
Pharmacokinetics
Example: Morphine is a weak base (pKa
8.0).
What percentage will be in the ionized form in the
urine at a pH of
6.0?
Table
I-1-1.
Percentage Nonionized as a Function of pH
From Table
I-1-l,1%
of morphine is in the nonionized form; thus,
99%
is ionized.
Ionization Increases Renal Clearance of Drugs
Only free, unbound drug is filtered.
Both ionized and nonionized forms of
a
drug are filtered.
Only nonionized forms undergo active secretion and active or passive reabsorption.
Ionized forms of drugs are
"
trapped
"
in the filtrate.
Acidification of urine
+
increases ionization of weak bases
-+
increases renal elimination.
Alkalinization of urine
-+
increases ionization of weak acids
-+
increases renal elimination.
pH
-
pKa
Modes of Drug Transport Across a Membrane
I
I
I
I
I
-
1
-
2
Table
I
-1-2. The Three Basic Modes of Drug Transport Across a Membrane
Energy
Mechanism Required Carrier
0
Passive diffusion
(
No
I
Facilitated diffusion
1
No
I
yes
+
1
Active transport
1
yes
+2
Yes
ABSORPTION
Concerns the processes of entry of a drug into the systemic circulation from the site of its
administration.
The determinants of absorption are those described for drug permeation.
Clinical Correlate
To
Change Urinary
pH
Acidify: NH4CI, vitamin
C,
cranberry juice
Alkalinize: NaHCO3, aceta
-
zolamide
Ion and molecular transport
mechanisms are discussed in
greater detail in Section
I
of
Physiology.
Intravascular administration (e.g.,
IV)
does not involve absorption, and there is no loss of drug.
KAPLAN'
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USMLE
Step
1
:
Pharmacology
With extravascular administration (e.g., per os
[PO;
oral], intramuscular
[IM],
subcutaneous
[SC],
inhalation), less than
100%
of a dose may reach the systemic circulation because of vari
-
ations
in
bioavailability.
Plasma Level Curves
Cmax
=
maximal drug level obtained with the dose.
tmax
=
time at which Cmax occurs.
Lag time
=
time from administration to appearance in blood.
Onset of activity
=
time from administration to blood level
reaching minimal effective concentration (MEC).
Duration of action
=
time plasma concentration remains
greater than MEC.
Time to peak
=
time from administration to Cmax
Figure
1
-
1
-
3.
Plot of Plasma Concentration Versus Time
KAPLAH'
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medical
.
-
-
Pharmacokinetics
Bioavailability
(f)
intravascular dose
(e.g.,
IV
bolus)
0
2
0
xtravascular dose
k
%
a'
Time
Measure of the fraction
of
a
dose that reaches the systemic circulation.
By definition, intravascular doses have 100% bioavailability, f
=
1.
AUC
=
area under the curve; po
=
oral; iv
=
intravenous bolus.
Figure
1
-
1
-
4.
Area Under the Curve for an
IV
Bolus
and
Extravascular Doses
Bioequivalence
For bioequivalence to occur between two formulations of the same compound, they must have
the same bioavailability and the same rate of absorption. When this occurs, the plasma levels of
the
two
products will be superimposable, if they are given at same dose, by the same mode.
,
,
Rates of Absorption
Time
Figure
1-1-5.
Effect of Rate of Absorption
on Plasma Concentration
USMLE Step
1:
Pharmacology
Figure
1-1-5
illustrates an example of bio
-
inequivalence. The two formulations differ in rate of
absorption
-
brand
B
is more slowly absorbed than brand
A.
Cmax and tnlax are rate dependent. The faster the rate of absorption, the smaller the tma and the
larger the
Cma, and vice versa.
First
-
Pass Effect
With oral administration, drugs are absorbed into the portal circulation and initially distributed
to the liver. For some drugs, their rapid hepatic metabolism decreases bioavailability
-
the
"
first
-
pass
"
effect.
DISTRIBUTION
The processes of distribution of a drug from the systemic circulation to organs and tissue
involve its permeation through membrane barriers and are dependent on its solubility (recall
that only nonionized drugs cross biomembranes), the rate of blood flow to the tissues, and the
binding of drug molecules to plasma proteins.
Plasma Protein Binding
Many drugs bind to plasma proteins, including albumin, with an equilibrium between bound
and free molecules (recall that only unbound drugs cross biomembranes).
L
Drug
+
Protein
-
Drug
-
Protein Complex
Competition between drugs for plasma protein binding sites may increase the
"
free fraction,
"
possibly enhancing the effects of the drug displaced.
Special Barriers to Distribution
Placental: most small molecular weight drugs cross the placental barrier, although fetal
blood levels are usually lower than maternal
Blood
-
brain: permeable only to lipid
-
soluble drugs or those of very low molecular
weight
Apparent Volume of Distribution (Vd)
A
kinetic parameter of a drug that correlates dose with plasma level at zero time.
Bridge to Physiology
Points to remember:
Approximate Vd Values
(weight
70
kg)
plasma volume
(3
L), blood
volume
(5
L),
extracellular fluid
(ECF
12
-
14
L),
total body water
(TBW
40-42
L)
Dose
Vd
=
--
where
CO
=
[plasma] at zero time
c0
The higher the
Vd,
the lower the plasma concentration and vice versa.
Vd
is low when a high percentage of a drug is bound to plasma proteins.
This relationship can be used for calculating
Vd
by using the
dose
only if one knows or
can calculate
c'.
Tissue binding and accumulation of drugs with high
Vd
values raise the possibility of
displacement by other agents
+
changes in pharmacologic activity.
KAPLAN'
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USMLE Step
1:
Pharmacology
Clinical Correlate
Grapefruit Juice
Actwe components In
grapefru~t ju~ce dude
furanocoumarins capable of
lnh~blt~ng the
metabolism
of
many drugs,
lncludlng
alprazolam, atorvastatln,
clsaprlde, cyclosponne, and
mldazolam. Such compounds
may also enhance oral
bioava~lability
by
lnhibitmg
drug transporters in the
GI
tract
responsible
for Intestinal
efflux of drugs.
Genotypic variations in hydroxylation (fast and slow); substrates include codeine, debrisoquin,
and metoprolol; inhibited by haloperidol and quinidine; not inducible.
CYP3A4
Most abundant isoform; wide substrate range; inhibited by cimetidine, macrolides, azoles, and
ethanol (acute); induced by general
P450 inducers such as carbamazepine, griseofillvin, pheno
-
barbital, phenytoin, and rifampin and by ethanol (chronic).
Hydrolysis
Phase I reactions involving addition of a water molecule with subsequent bond breakage.
Include pseudocholinesterases responsible for metabolism of the slteletal muscle relaxant,
suc-
cinylcholine. Genetically determined defects in plasma esterases may result in prolonged actions
of succinylcholine in some persons.
Nonmicrosomal Oxidations
Include monoanline oxidases that metabolize both endogenous ainines (e.g., dopamine, sero
-
tonin) and exogenous compounds (e.g., tyramine).
Alcohols are metabolized by alcohol dehydrogenase (ADH) to aldehydes, which are then sub
-
strates for aldehyde dehydrogenase, which can be inhibited by disulfiram. The enhanced sensi
-
tivity of some persons to acetaldehyde formed from low doses of ethanol can result from geno
-
typic variations in aldehyde dehydrogenase activity.
Conjugation
Phase I1 reactions via transferases that usually inactivate drugs but occasionally activate (for
example, morphine and minoxidil). May follow a phase
I
hydroxylation but also occur directly.
Types
of Conjugation
Glucuronidation: inducible; conjugates may undergo enterohepatic cycling; reduced activity in
neonate.
Acetylation: genotypic variations (fast and slow)
Sulfation: minoxidil, steroids.
Glutathione (GSH) conjugation: depletion of GSH in the liver is associated with aceta
-
minophen hepatotoxicity.
Drug
-
induced systemic lupus erythematosus (SLE) by slow acetylators such as hydralazine, pro
-
cainamide, isoniazid (INH).
KAPLAN'
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Pharmacokinetics
ELIMINATION
Concerns the processes involved in the elimination of drugs from the body (andlor plasma) and
their kinetic characteristics. The major modes of drug elimination are:
Biotransforrnation to inactive metabolites
Excretion via the kidney
Excretion via other modes including the bile duct, lungs, and sweat
Zero
-
Order Elimination Rate
Rate of elimination is independent of plasma concentration (or amount in the body).
A
constant amount of drug is eliminated per unit time; for example, if
80
mg is administered
and
10
mg is eliminated every
4
h, the time course of drug elimination is:
Drugs with zero
-
order elimination have no fixed half
-
life. Graphically, zero
-
order elimination
follows a straight
-
line decay versus time.
Drugs with zero
-
order elimination include ethanol (except low blood levels), phenytoin (high
therapeutic doses), and salicylates (toxic doses).
Zero Order First Order
Time Time
Figure
1
-
1
-
6.
Plots of Zero
-
and First
-
Order
Drug Elimination versus Time
First
-
Order Elimination Rate
Rate of elimination is directly proportional to plasma level (or the amount present)
-
the high
-
er the amount, the more rapid the elimination.
A
constant fraction of the drug is eliminated per unit time. Graphically, first
-
order elimination
follows an exponential decay versus time.
In
A
Nutshell
Elimination Kinetics
Most drugs are first order
-
rate
falls as plasma level falls
Zero order
1s due to saturation
of
ellmination mechanisms;
e.g., drug-metabolizing
reactions have reached
V,,,.
KAPLAN'
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USMLE
Step
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Pharmacology
--
Time to eliminate 50% of a given amount (or to decrease plasma level to 50% of a former level)
is called the elimination half
-
life (tII2). For example, if 80 mg of a drug
is
administered and its
elimination half
-
life
=
4 h, the time course of its elimination is:
4h 4h 4h 4h
80
mg
+
40 mg
+
20
mg
+
10 mg
+
5
mg
Most drugs follow first
-
order elimination rates.
Graphic Analysis
1
2
3
4
5
6
Time
(h)
C0
=
plasma concentration at zero time
Figure 1
-
1
-
7. Plasma Decay Curve
-
First
-
Order Elimination
The figure shows a plasma decay curve of a drug with first
-
order elimination plotted on
semilog graph paper. The elimination half
-
life (tIl2) and the theoretical plasma concentration
at zero time
(C
O
)
can be estimated from the graphic relationship between plasma concentra
-
tions and time.
C0
is estimated
by
extrapolation of the linear plasma decay curve to intercept
with the vertical axis.
Useful relationships:
Dose
=
Vd
x
CO
tLI2
=
0.7/k, where
k
=
first order rate constant of elimination
Renal Elimination
Rate of elimination
=
glomerular filtration rate (GFR)
+
active secretion
-
reabsorption (active
or passive).
Filtration is a nonsaturable linear function. Ionized and nonionized forms of drugs are filtered,
but protein
-
bound drug molecules are not.
Pharmacokinetics
Clearance
Clearance is defined as the volume of blood cleared of the drug in unit time. It represents the
relationship between the rate of drug elimination and its plasma level. For drugs with
first-
order elimination, clearance is constant because rate of elimination is directly proportional to
plasma level.
Total body clearance (CL) may
itlvolve several processes, depending on different routes of drug
elimination.
CL
=
CL,
+
CL,,
where
CLR
=
renal clearance
and
CLNR
=
nonrenal clearance
With no active secretion or reabsorption, the renal clearance is the same as glomerular filtra
-
tion rate (CLR
=
GFR); if the drug is protein bound, then CLR
=
GFR
x
free fraction.
PHARMACOKINETICS CALCULATIONS
The following relationships are important for calculations:
Loading Dose (LD)
LD
=
Vd
x
C
SS
Where C
SS
=
plasma at steady state, the desired plasma concentration of drug required for opti
-
mum activity. Adjustment may be needed in calculations with bioavailability
<
f
=
1;
for exam
-
ple, iff
=
0.5, the LD must be doubled.
Clearance
CL=kxV,
Where
k
=
elimination rate constant.
Infusion Rate
(ko)
=
CL
x
C
SS
Where CL
=
total body clearance, and CSS is the desired plasma concentration.
Maintenance Dose (MD)
Infusion rate
x
dosing interval (a)
=
CL
x
CSb 7
Elimination Half
-
Life
0.7
X
V,
0.7
-
tIl2
=
-
-
-
CL
k
In the above relationships, having any two parameters enables one
to
calculate the third!
KAPLAN'
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13
USMLE Step
1:
Pharmacology
Classic Clues
Time and Steady State
50010
=
1
x
half
-
life
90%
=
3.3
x
half
-
life
95%
=
4-5
x
half
-
life
"100"olo
=
>7
x
half
-
life
STEADY STATE
Steady state is reached either when rate in
=
rate out or when values associated with a dosing
interval are the same as those in the succeeding interval.
The time to reach steady state is dependent only on the elimination half
-
life of a drug and is
independent of dose size and frequency of administration.
Plateau Principle
Figure
1-1-8
shows plasma levels (solid lines) achieved following the IV bolus administration of
100 units of a drug at intervals equivalent to every half
-
life tl,,
=
4
h
(7).
With such intermit
-
tent dosing, plasma levels oscillate through peaks and troughs, with averages shown in the dia
-
gram by the dashed line.
I
ss
Cmax
(peak)
Time
(h)
Figure 1
-
1
-
8. Oscillations in Plasma Levels
Following
IV
Bolus Administration at Intervals
Equal
to
Drug Half
-
Life
In other words, plasma levels zigzag up and down, because at the end of each half
-
life the plas
-
ma level has decreased to 50% of its level immediately following the last dose:
Note the following:
Although it takes
>7
tllz to reach mathematical steady state, by convention clinical steady state
is accepted to be reached at 4
-
5 t,/,.
KAPLAN'
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Pharmacokinetics
Rate of Infusion
The graph in Figure I
-
1
-
9
shows the increases in plasma levels of the same drug infused at five
different rates. Irrespective of the rate of infusion, it takes the same amount of
time to reach
steady state.
All
have the same time to plateau
Time
Figure 1
-
1
-
9. Effect of Rate of Infusion on Plasma Level
Rate of infusion does determine plasma level at steady state. If the rate of infusion is doubled,
then the plasma level of the drug at steady state is doubled.
Linear
kinetics
refers to this direct
relationship between infusion rate and steady
-
state plasma level.
A
similar relationship can exist
for other forms of drug administration
(e.g., per oral)
-
doubling oral doses can double the
average plasma levels of a drug.
Effect
of Loading Dose
It takes
4-5
half
-
lives to achieve steady state.
In some situations,
it
may be necessary to give a higher dose (loading dose) to more rapidly
achieve effective blood levels.
USMLE
Step
1:
Pharmacology
doses
Time
Figure 1
-
1
-
1
0.
Effect of a Loading Dose on the Time
Required to Achieve the Minimal Effective
Plasma Concentration
Such loading doses are often one time only and (as shown in Figure
1
-
1
-
10)
are estimated to
achieve a plasma level equivalent to that of the level at steady state.
If doses are to be administered at each half
-
life of the drug, then the loading dose is twice the
amount of the dose used for maintenance.
pter
The pharmacokinetic characteristics of a drug are dependent upon the processes of absorption,
distribution, metabolism, and excretion. An important element concerning drug biodistribution is
permeation, which is the ability to cross membranes, cellular and otherwise.
A drug's ability to permeate is dependent on its solubility, the concentration gradient, and the available
surface area, which is influenced by the degree of vascularity. Ionization affects permeation because
unionized molecules are minimally water soluble but do cross biomembranes, a feat beyond the
capacity of ionized molecules. Figure
1-1-2 illustrates the principles associated with ionization, and Table
1-1-2 summarizes the three basic modes of transport across a membrane: passwe, facll~tated, and
actlve.
Absorpt~on concerns the processes of entry Into the system~c c~rculation. Except for the mtravascular
route, some absorpt~ve process
a
always ~nvolved. These have the same determmants as those of
perrneatlon Because absorpt~on may not be
lOOO/o
effluent, less than the ent~re dose adm~nrstered
may get into the c~rculatlon. Salient aspects of these principles and how they lead to b~oava~labrl~ty and
relate to
b~oequ~valence are illustrated In F~gures 1-1-3,
4,
and
5.
Any orally admmtered hydroph~l~: drug w~ll be absorbed f~rst into the portal veln and sent d~rectly to
the
her, where ~t may be part~ally
deactivated
Thls
IS
the f~rst-pass effect
(Continued)
Pharmacokinetics
The distribution of a drug into the various compartments of the body is dependent upon its
permeation properties and its tendency to bind to plasma proteins. The placental and blood
-
brain
barriers are of particular importance in considering distribution. The
Vd
is a kinetic parameter that
correlates the dose given to the plasma level obtained: the greater the
Vd
value, the less the plasma
concentration.
As well as having the ability to cross the blood
-
brain barrier, lipophilic drugs have a tendency to be
deposited in fat tissue. As blood concentrations fall, some of this stored drug is released. This is called
redistribution. Because with each administration more lipophilic drug is absorbed into the fat, the
duration of action of such a drug increases with the length of administration until the lipid stores are
saturated.
Blotransformation is the metabolic conversron of drugs, generally to less active compounds but
somet~mes to iso-act~ve or more active forms. Phase
I
biotransformat~on occurs via oxidation,
reduction, or
hydrolys~s Phase II metabolism occurs via conjugat~on.
The cytochrome P,,, isozymes are a family of microsomal enzymes that collectively have the capacity
to transform thousands of different molecules. The transformations include hydroxylations and
alkylations, as well as the promotion of
oxidation/reduction reactions. These enzymes have an absolute
requirement for NADPH and
0,.
The various isozymes have different substrate and inhibitor
specificities.
Other enzymes involved in phase
I
reactions are hydrolases (e.g., esterases and amidases) and the
nonmicrosomal oxidases
(e.g., monoamine oxidase and alcohol and aldehyde dehydrogenase).
Phase
II react~ons involve conjugation, somet~mes after a phase I hydroxylation. The conjugation may
be a
glucuronidatron, an acetylation, a sulfation, or an addition of glutathione.
Modes of drug elmnation are blotransformation, renal excretion, and excret~on by other routes (e g.,
brle, sweat, lungs, etc). Most drugs follow first
-
order ehmination rates Figure 1-1-6 compares zero
-
and
first
-
order elimination, and F~gure 1
-
1
-
7 demonstrates how the t,/, and the
theoretical
zero tlme plasma
concentration (C
O
) can be graphrcally determmed. Two important relatlonsh~ps are dose
=
Vd
x
C0 and
tl/,
=
0.7k (k
=
the first
-
order rate constant of elimrnat~on).
Renal clearance
(CLR)
represents the volume of blood cleared by the kidney per unit time and is a
constant for drugs with first
-
order elirnrnation kinetics. Total body clearance equals renal plus nonrenal
clearance.
Equations
descr~b~ng relat~onships important for calculation are those used to determine the loading
dose, clearance, infusion rate, maintenance dose, and
ehminat~on half
-
life.
A steady state is achieved when the rate coming in equals the rate going out. The time to reach a
steady state is dependent only on the
elimmation half
-
life. It is independent of dose and frequency of
administration or rate of infusion (see Figures 1
-
1
-
8,
-
9,
and -10).
Pharmacodynamics
GRADED (QUANTITATIVE) DOSE
-
RESPONSE (D
-
R) CURVES
Plots of dose (or log dose) versus response for drugs (agonists) that activate receptors can
reveal the following characteristics of such drugs:
Affinity:
ability of drug to bind to receptor, shown by the proximity of the curve to the
y
axis
(if the curves are the nearer the
y
axis, the greater the affinity.
Potency: shows relative doses of two or more agonists to produce the same magnitude of effect,
again shown by the proximity of the respective curves to the
y
axis (if the curves do not cross).
Efficacy: a measure of how well a drug produces a response (effectiveness), shown by the max
-
imal height reached by the curve.
Parallel and Nonparallel
D
-
R
Curves
Log Dose of Drug
Log Dose of Drug
Figure 1
-
2
-
1. Comparison of D
-
R Curves for
Two
Drugs Acting
on the Same (left panel) and on Different
(right panel) Receptors
It may be seen from the log dose
-
response curves in Figure
1-2-1
that:
1.
When two drugs interact with the same receptor (same pharmacologic mechanism), the D
-
R
curves will have parallel slopes. Drugs
A
and
B
have the same mechanism; drugs
X
and
Y
do
not.
2.
Affinity can be compared only when two drugs bind to the same receptor. Drug
A
has
a
greater affinity than drug
R.
Bridge to Biochemistry
Definitions
Potency:
the quantity of drug
required to achieve a desired
effect. In
D
-
R
measurements,
the chosen effect is usually
50%
of the maximal effect.
The primary determinant is
the affinity of the drug for the
receptor. Notice the analogy to
the Km value used in enzyme
kinetic studies.
Efficacy:
the maximal effect an
agonist can achieve at the
highest practical concentration.
Notice the analogy with the
V,,!
used in enzyme kinetic
stud~es.
KAPLAN'
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19
USMLE
Step
1:
Pharmacology
--
--
-
-
3. In terms of potency, drug A has greater potency than drug
B,
and
X
is more potent than
Y.
4.
In terms of efficacy, drugs
A
and
B
are equivalent. Drug
X
has greater efficacy than drug
Y.
Full
and
Partial
Agonists
Full agonists produce a maximal response
-
they have maximal efficacy.
Partial agonists are incapable of eliciting a maximal response and are less effective than
full
agonists.
In Figure
1-2-2, drug
B
is a full agonist, and drugs
A
and
C
are partial agonists.
Log Dose of Drug
Figure 1
-
2
-
2. Efficacy and Potency of
Full and Partial Agonists
Drug A is more potent than drug
C
and appears to be more potent than drug
B.
However, no gen
-
eral comparisons can be made between drugs A and
C
and drug
B
in terms of potency because
the former are partial agonists and the latter is a full agonist.
At low responses
A is more potent than
B,
but at high responses the reverse is true, so no gen
-
eral comparison can be made between these two drugs that have different efficacy.
Duality
of
Partial
Agonists
In Figure 1-2-3, the lower curve represents effects of a partial agonist when used alone
-
its
ceil
-
ing. effect
=
50%
of maximal.
a dose of
full
agonist
'OOT
---
-
_
',
+
partial agonist
50
V)
8
a
'
I
Jpartial agonist alone
Log Dose of Partial Agonist
Figure 1
-
2
-
3. Duality of Partial Agonists
Pharmacodynamics
The upper curve shows the effect of increasing doses of the partial agonist on the maximal
response
(100%)
achieved in the presence of or by pretreatment with a full agonist.
As the partial agonist displaces the full agonist from the receptor, the response is reduced
-
the
partial agonist is acting as an
antagonist.
Antagonism and Potentiation
Graded dose
-
response curves also provide information about antagonists
-
drugs that interact
with receptors to interfere with their activation by agonists.
Antagonists displace
D
-
R
curves for agonists to the right.
control
noncompetitive
V)
a
a
Log Dose of Drug
Figure
1
-
2
-
4.
D
-
R
Curves of Antagonists and Potentiators
Competitive antagonists cause a parallel shift to the right and can be reversed completely by
increasing the dose of the agonist drug. In effect, such antagonists appear to decrease the potency
of the agonist drug.
Most receptor antagonists used in medicine are competitive. Examples include atropine block
of acetylcholine
(ACh) at
M
receptors and propranolol block of norepinephrine (NE) at beta
receptors.
Noncompetitive antagonists cause a nonparallel shift to the right and can be reversed only par
-
tially by increasing the dose of the agonist drug. Such antagonists appear to decrease both the
potency and the efficacy of agonists. One example is phenoxybenzamine, which irreversibly
blocks the effects of
NE
at alpha receptors by formation of a covalent bond.
Pharmacologic Antagonism (Same Receptor)
An agonist and antagonist compete for a single receptor type, as in the antagonisms described
above.
Physiologic Antagonism (Different Receptors)
Occurs when an agonist response mediated through activation of one receptor is antagonized
by an opposing agonist action at a different receptor;
e.g., acetylcholine (ACh) bradycardia
induced through
M
receptor activation may be antagonized by
NE
tachycardia induced via beta
receptor activation.
Parallels between Receptor
Antagonists and Enzyme
Inhibitors
Competitive antagonists are
analogous to competitive
inhibitors; they decrease
affinity (Km) but not maximal
response
(V,,,).
Noncompetitive antagonists
decrease
V,,,
but do not
change the Krn.
KAPLAN'
medical
USMLE
Step
1:
Pharmacology
--
-
-
-
--
Chemical
Antagonism
Occurs when a drug effect is antagonized by fdrmation of a complex between the effector drug
and another compound;
e.g., protamine binds to heparin to reverse its actions.
Potentiation
Potentiation of agonist action leads to displacement of D
-
R curves to the left. Examples incIude
the effect of benzodiazepines to enhance the activity of gamma
-
aminobutyric acid
(GABA)
and
the effect of amphetamine to enhance the activity of
NE.
QUANTA1 (CUMULATIVE) D
-
R CURVES
These curves plot the percentage of a population responding to a specified drug effect versus
dose or log dose. They permit estimations of the median effective dose, or effective dose in 50%
of a population
-
ED50.
Quantal curves can reveal the range of
intersubject variability in drug response. Steep D
-
R
curves reflect little variability; flat D
-
R curves indicate great variability in patient sensitivity to
the effects of a drug.
Toxicity and the Therapeutic Index (TI)
therapeutic toxic
I00
-
rn
c
E
2
4
6
8
10
Figure 1-2-5. Quantal D
-
R Curves of Therapeutic
and Toxic Effects of a Drug
As
shown in Figure 1-2-5, these D
-
R curves can also be used to show the relationship between
dose and toxic effects of a drug. The median toxic dose of a drug
(TD50) is the dose that causes
toxicity in 50% of a population.
Comparisons between ED50 and TD50 values permit evaluation of the relative safety of a drug
(the therapeutic index), as would comparison between ED50 and the lethal median dose
(LD50) if the latter is known.
TD50 LD50
TI
=
-
--
or
-
ED50 ED50
From the data shown, TI
=
1012
=
5
Such indices are of most value when toxicity represents an extension of the pharmacologic
actions of a drug. They do not predict idiosyncratic reactions or drug hypersensitivity.
Pharmacodynamics
SIGNALING MECHANISMS:
TYPES OF DRUG
-
RESPONSIVE SIGNALING
MECHANISMS
Binding of an agonist drug to its receptor activates an effector or signaling mechanism.
Several different types of drug
-
responsive signaling mechanism are known.
lntracellular Receptors
These include receptors for steroids. Binding of hormones or drugs to such receptors releases
regulatory proteins that permit
dimerization of the hormone
-
receptor complex. Such com
-
plexes interact with response elements on nuclear DNA to modify gene expression. For exam
-
ple, drugs interacting with glucocorticoid receptors lead to gene expression of proteins that
inhibit the production of inflammatory mediators.
Other examples include intracellular receptors for thyroid hormones, gonadal steroids, and
vitamin
D.
Pharmacologic responses elicited via modification of gene expression are usually slower in
onset but longer in duration than
many other drugs.
Membrane Receptors Directly Coupled to Ion Channels
Many drugs act by mimicking or antagonizing the actions of endogenous ligands that regulate
flow of ions through excitable membranes via their activation of receptors that are directly cou
-
pled (no second messengers) to ion channels.
For example, the nicotine receptor for
ACh (present in autonomic nervous system [ANSI gan
-
glia, the skeletal myoneural junction, and the central nervous system [CNS]) is coupled to a
Na/K ion channel. The receptor is a target for many drugs, including nicotine, choline esters,
ganglion blockers, and skeletal muscle relaxants.
Similarly,
the GABAA receptor in the CNS, which is coupled to a chloride ion channel, can be
modulated by anticonvulsants, benzodiazepines, and barbiturates.
Receptors Linked
Via
Coupling Proteins to lntracellular Effectors
Many receptor systems are coupled via GTP
-
binding proteins (G
-
proteins) to adenylyl cyclase,
the enzyme that converts ATP to
CAMP, a second messenger that promotes protein phosphory
-
lation by activating protein ltinase A. These receptors are typically
"
serpentine,
"
with seven
transmembrane spanning domains, the third one of which is coupled to the G
-
protein effector
mechanism.
The protein kinase A serves to phosphorylate a set of tissue
-
specific substrate enzymes, thereby
affecting their activity.
C,
Proteins
Binding of agonists to receptors linked to
GS
proteins increases CAMP production. Such recep
-
tors include those for catecholamines (beta), dopamine (Dl), glucagon, histamine
(H2),
prosta
-
cyclin, and some serotonin subtypes.
KAPLAN'
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23
USMLE Step
1
:
Pharmacology
--
In
A
Nutshell
Key
ANS
Receptors
MI, M,,
a,:
Cq
actlvatlon
of
phosphohpase
C
M,,
a;
G,
mhlb~tlon of
adenylyl cyclase
p,
Dl:
G,
actlvatlon of adenylyl
cyclase
Receptors for
Gi
Proteins
Binding of agonists to receptors linked to Gi proteins decreases CAMP production. Such recep
-
tors include adrenoreceptors (alpha,), ACh
(M,),
dopamine
(D,
subtypes), and several opioid
and serotonin subtypes.
G,
Proteins
Other receptor systems are coupled via GTP
-
binding proteins
(G
),
which activate phospholi
-
q.
pase C. Activation of this enzyme releases the second messengers inositol triphosphate
(IP,)
and
diacylglycerol (DAG) from the membrane phospholipid phosphatidylinositol bisphosphate
(PIP,). The
IP3 induces release of Ca2+ from the sarcoplasmic reticulum (SR), which, together
with DAG, activates protein kinase C. The protein kinase C serves then to phosphorylate a set of
tissue
-
specific substrate enzymes, usually not phosphorylated by protein kinase A, and thereby
affects their activity.
These signaling mechanisms are invoked following activation of receptors for
ACh
(M1
and
M3), norepinephrine (alpha
l
), angiotensin 11, and several opiojd and serotonin subtypes.
NH2
I
CAMP
system
PIP2
NH2
system
1
Receptors for
Catecholamines
P
(G,) Catecholamines
a,
alphamethyldopa (Gi) acetylcholine
MI
Mg
acetylcholine
Ma
(Gi)
angiotensin II
glucagon (G,) vasopressin
C
enzymes
dephosphorylated
k
I
\
/
\
/
..
-__-*#
Protein Phosphatases
Figure 1
-
2
-
6. Receptors Using Cyclic
-
AMP and Phosphatidylinositol
Bisphosphate (PIP,) as Second Messengers
KAPLAN'
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