r IIIli

ti I
I
EDITOR: Bernd Meibohm
 edicin I hemistry
8..1 Physicochemical Properties of
m
Drug Molecules in Relation to
Drug Absorption, Distribution,
Metabolism, and Excretion
!7,_iiRc~E'·c7.F'CC
Acid-Base Properties of Drug Molecules
Drugs can be grouped into weak acids and weak
bases when in solution. The acid-base properties of
drugs influence absorption, excretion, and compati-
bility with other drugs in solution. The functional
groups (Table 8-1) in a drug molecule determine the
acid-base character of the drug.
An acidic drug (e.g., aspirin) donates a proton on
ionization to generate a conjugate base, whereas a
basic drug (e.g., amphetamine) accepts a proton to
generate a conjugate acid (Figure 8-1).
Resonance stabilization of the conjugate base of
an acidic drug enhances acidity. Delocalization of
electrons from the nitrogen atom of a basic drug de-
creases its basicity; hence, arylamines (pK. =4-5) are
less basic than alkylamines (pKa = 9-11).
Amphoteric drugs contain both acidic and basic
functional groups.
Organic functional groups that cannot donate or
accept a proton are neutral (i.e., nonelectrolytes).
Several drugs have nitrogen-containing heterocycles
(panel c of Figure 8-1) as a part of their chemical
structure. Drugs with nitrogen-containing saturated
heterocycles (e.g., pyrrolidine and piperidine) are basic
because the lone pair of electrons on the nitrogen is
readily available to serve as a proton acceptor.
The nitrogen atom in pyrrole does not contribute
to basicity of drug molecules because the lone pair of
Isaac 0. Donkor, PhD
electrons on the nitrogen contributes to the aromatic
sextet and thus is not available to accept a proton.
Six-member nitrogen-containing heterocycles (such
as pyridine) are weak bases. In pyridine, unlike pyrrole,
only one of the nitrogen lone pairs of electrons con-
tributes to the aromatic sextet. Thus, an unshared pair
of electrons is available to serve as a proton acceptor.
Relative acid strength (pKa) indicates the relative
acid-base strength of organic functional groups. It
cannot be used to determine whether a given drug
molecule is acidic or basic. It is used to calculate the
percentage of ionized and un-ionized forms of drugs
at a given pH, thereby allowing the prediction of rel-
ative water solubility, which is an important deter-
minant of absorption and excretion of drugs.
Aqueous Solubility of Drugs
Availability of functional groups that facilitate hy-
drogen bond formation with water molecules as well
as those that promote ionization enhances dissolu-
tion of drugs in water. The aqueous solubility of a
drug influences its route of administration, absorp-
tion, distribution, and excretion.
Highly polar drugs of low lipophilicity (e.g., hep-
arin) are candidates for parenteral administration
because such drugs poorly penetrate biological mem-
branes through passive diffusion.
Partition Coefficient (log P)
The partition coefficient of a drug is the ratio be-
tween the fraction of the drug that dissolves in an or-
ganic phase and the fraction that distributes into an
aqueous phase. The ratio is typically expressed as the
log P value of the drug.
 The APhA Complete Review for the Foreign Pharmacy Graduate Equivalency Examination®

• Common Functional Groups of Drug Molecules

Acidic Neutral
functional Conjugate Basic functional functional
groups base groups Conjugate acid groups
R-CH 20H
Alkyl alcohol
0 0 NH ®
II II 8 NH2
R-8-0H R-8-0 0
II II R-NANH2
0 0 H R-NANH2 R)lO/R'
Sulfonic acid Sulfonate Guanidine H
Guanidinium Ester
(0-1) (12-13)
R-0-R
Ether
NH ®
R----<0 R----<0 NH 2
oe 0
OH R)lNH2
Carboxylic acid Carboxylate Amidine R)lNH 2 R)lNH2
(5-6) (10-11) Amidinium Amide
R-8-R
Thioether
0 t>e R-NH2 ®
II
R-8-NH 2 R-8-NH Alkylamines R-NH 3 0
II II
0 0 (2°, 10-11) Alkyl- R,O)lN/R'
Sulfonamide Sulfonamidate ammonium
(10, 9-10) H
(9-10) Carbamate

0
v~
®
v8H VNH2
VNH, R)lR'
.r::- .r::-
.r::- .r::- Aldehyde
Thiophenol Arylamine
(9-1 0) Thiophenolate (4-5) Arylammonium and ketone
'
/

dII
8

0
® R/ 'R'
VOH
vet' .r::- OH Sulfoxide
.r::- .r::- .r::-
Phenol Aromatic amine
Aromatic o,, ---:-0
(9-11) Phenolate (5-6) 8
ammonium R"' 'R'
Sulfone

Source: Author's representation.

Note: The conjugate bases and conjugate acids of acidic and basic functional groups are also displayed. The numbers in parentheses are the pKa values of
the acidic and basic functional groups. The neutral functional groups are not ionizable at physiological pH.
 Medicinal Chemistry

8·1. Examples of Organic Acids and Bases

a. Ionization of aspirin and resonance stabilization of its conjugate base

e0 0
'X~,QI(CH, + H
®

Aspirin Resonance stabilization of conjugate base

lJo
b. Ionization of amphetamine to its conjugate acid
®
~NH3 e
VH. CH3 + OH

Conjugate acid
c. PKa values of cycloalkylamines and the corresponding heterocycle

Q H
0 H
0 N
H
0 N

Pyrrolidine Piperidine Pyrrole Pyridine

(PKa~11) (PKa ~ 11) (PKa ~ -0.27) (PKa ~ 5)

Source: Author's representation.

Biological membranes are lipid bilayers with a
lipophilic interior. Thus, drugs with high log P values
cross biological membranes more easily and tend to
be rapidly absorbed through passive diffusion from
the gastrointestinal (GI) tract.
Nonetheless, drugs must have some degree of
aqueous solubility because the availability of the
drug molecule in solution form is necessary for drug
absorption. Furthermore, the biological fluids at the
absorption site are aqueous in nature. Therefore, the
chemical nature of the drug molecule must maintain
a desirable log P to facilitate drug absorption.
Polar functional groups (e.g., OH, NH 2 , and
COOH) increase the hydrophilic character of drugs,
whereas nonpolar groups (e.g., halogens, sulfur, and
aliphatic and aromatic hydrocarbons) increase their
lipophilicity.
pH=Partition Theory
The pH-partition theory is governed by factors such
as the dissociation constant, lipid solubility, and pH
Generally, if the pK. of a weakly acidic drug is
greater than the pH of its environment (e.g., gastric
fluid), the drug exists predominantly in the un-ionized
state, which facilitates absorption. In contrast, if the
pK. of the acidic drug is less than the pH of its envi-
ronment, the drug exists mostly in the ionized state,
which limits absorption. /
A similar relationship applies to basic drugs. Thus,
for weakly basic drugs, if the pK. of the drug is greater
than the pH of its environment (e.g., gastric fluid), the
drug will exist mostly in the ionized state, which lim-
its absorption. However, if the pK. of the weakly basic
drug is less than the pH of its environment (e.g., the
duodenum), the un-ionized form of the drug will
predominate, which promotes absorption.
3.. 2. Chemical Basis and
Pharmacology and
Therapeutics
~.sm.!~5.?,:-:::;:-::c-2l'~~--:_~~'":;-:::,;--- r

of the fluid at the site of absorption. It influences

drug absorption from the GI tract and drug trans-
port across biological membrane. The un-ionized
fraction of a drug in solution is influenced by the
pK. of the drug and the pH of the solution at the site
of absorption.
Drug-Receptor Interaction and Drug Action
The majority of drugs produce their effects by binding
to specific receptors. The affinity of a drug for its recep-
tor and the resulting pharmacological outcome may be
influenced by the type of chemical bonding the drug
 The APhA Complete Review tor the Foreign Pharmacy Graduate Equivalency Examination®
makes with the receptor, the conformation of the drug,
and the stereochemistry of the drug molecule.
Chemical bonding
A drug molecule binds to its receptor through the com-
plementarities of their molecular geometries (pharm-
acodynamics). During the pharmacodynamic process,
the functional groups of the drug molecule interact
with corresponding functional groups of the receptor
by a combination of the chemical bonding interactions
(Figure 8-2). The outcome of the drug-receptor inter-
action may be activation or antagonism of the receptor
to produce the desired therapeutic effect. Changes in
the drug molecule (caused by metabolism or degra-
dation) may eliminate a desired drug-receptor inter-
action, which may result in loss of therapeutic efficacy.
The chemical bonding interactions that may occur
between a drug and its receptor include the following:
A covalent bond (50-150 kcallmol) is the strongest
of these interactions. Sharing of electrons between
an atom from the drug and an atom from the
receptor results in the covalent bond formation.
Covalent bonding is irreversible and leads to de-
struction of the receptor. A new receptor must be
synthesized for full recovery of cellular function.
An ionic bond (5-10 kcallmol), also known as
electrostatic interaction, occurs between oppositely
charged functional groups on the drug and the
receptor.
A hydrogen bond (2-5 kcal/mol) is a bond in
which a hydrogen atom serves as a bridge between
two electronegative atoms, one from the drug
and the other from the receptor.
A hydrophobic interaction (0.5-1 kcallmol) is
also referred to as van der Waals forces or
8·2. Examples of Potential Multiple Drug-Receptor Interactions of Pindolol with Adrenergic Receptors
Hydrogen-..............
Hydrophobic
\
bond donor H,NS,
~
---------~
- I®
Hydrophobic Y
/; /
0
Hydrogen bond ·qH._·'\1'
a?ceptor_ or H drogen bond donor
d!pole-d!pole Y
Source: Author's representation.
London forces. The interaction occurs between
nonpolar regions of the drug and the receptor.
The drug must be close to the receptor for this
interaction to occur.
Conformation
Several theories have been formulated to explain the
observed effects of the binding of a drug molecule to
its receptor, including the following:
The occupancy theory states that the binding of a
drug (agonist) to its receptor results in a confor-
mational change in the receptor that initiates a
pharmacological response whose magnitude is
directly proportional to the number of receptors
bound by the drug.
m1 The rate theory states that the number of drug-
receptor interactions per unit time determines the
magnitude of the pharmacological response.
The induced fit theory states that a receptor
undergoes conformational change near a drug
molecule to allow effective binding of the drug
to the receptor. Unlike an agonist, an antagonist
does not induce the correct conformational
change to induce a response.
The macromolecular perturbation theory
combines the induced fit and rate theories.
It suggests that two types of conformational
changes occur and the rate of their existence
determines the observed pharmacological
response. Agonists produce the required confor-
mational change for pharmacolqgical response,
but antagonists produce a non,specific confor-
mational change, which fails to induce pharma-
cological response. This theory partly explains
the activity of partial agonists.
I
Hydrogen bond donor
/ . Ionic or ion-dipole
H
CH3
~~
H CH3 } - -
Hydrophobic
 Medicinal Chemistry

activation-aggregation theory states that
receptors are always in a state of dynamic equilib-
rium between active and inactive states. Agonists
shift the equilibrium in favor of the active state,
whereas antagonists prevent the activated state.
This theory explains the activity of inverse
agonists.
Stereochemistry
Receptors are chiral molecules. As such, for effec-
tive interaction of drugs with their target receptors,
the pharmacophore of the drug molecule must
be presented for binding to the receptor in a spe-
cific three-dimensional arrangement. Enantiomers
or diastereomers may therefore induce different
receptor perturbations. For example, labetalol has
two stereocenters (Figure 8-3 ).
The R,R-diastereomer of labetalol binds best to the
~-adrenergic receptor; the S,R-diastereomer binds best
to the a-adrenergic receptor; the S,S-diastereomer
has some a-adrenergic receptor blocking activity
but no activity at ~-adrenergic receptors; and the R,
S-diastereomer practically has no activity at the a- and
~-adrenergic receptors. These differences in pharma-
cological activities may be attributable to the spatial
orientation of the groups at the chiral centers of the
drug in relation to the receptor (Figure 8-3 ).
Drug Stability
Drugs may undergo chemical reactions that result in
loss of therapeutic efficacy, generation of toxicants,
or both. Drugs can undergo decomposition by several
chemical pathways, but the most common are oxida-
tion and hydrolysis.
Molecular oxygen promotes drug oxidation, which
may be catalyzed by light, heat, metal ions, and per-
oxides. Examples of drugs that are prone to oxidation
include phenolic drugs (e.g., morphine, acetamino-
phen, and salbutamol); catecholamines (e.g., epineph-
rine); and polyunsaturated oils (e.g., vitamins A and E).
These drugs undergo decomposition by free radical
chain reaction.
Decomposition of drugs through oxidation may
be prevented by the following:
m~ Packing the drug under an inert gas atmosphere
to exclude oxygen
tlil Packaging the drug in amber-colored containers
to exclude light
lEi Adding chelating agents to remove metal ions
fil Adding antioxidants
Several functional groups (especially esters and ami des)
in drug molecules are susceptible to hydrolysis. The
process is slow but is accelerated in the presence of
acids and bases. Examples of drugs prone to hydroly-
sis include aspirin, procaine, and the penicillins.
Pro drugs
Prodrugs are chemically modified drugs that are in-
active in the form in which they are administered but
are converted in vivo to the therapeutically active
drug. The prodrug concept has beyn used to improve
therapeutic outcome of drugs ,by improving their

8·3. Effect of Stereochemistry on the Interaction of Diastereomers of Labetalol with Adrenergic Receptors

~~ ~~
HO

~~
HO

H2N
}~ - OH
.,,H:J
H2N - H
.,,0~
H2N - H
.,,o~
H2N - OH
.,,H:J

Gc. NH @c NH CH. NH CH. NH

R,RH1e H~ H,c~ H3C~

S,R Ph S,S Ph R,S Ph

Source: Author's representation.

Note: The OH and CH 3 groups at the chiral centers may make bonding interactions with the different adrenergic receptors depending on their
stereochemical orientation. These interactions may influence the pharmacological activities of the diastereomers.
 The APhA Complete Review for the Foreign Pharmacy Graduate Equivalency Examination®
~~):'~~:,~-,-~--~,
~;01,~~gure
~~b:{,;;-"~- "c
8·4. Examples of Prod rugs
H, NH2 ~ lj lj
: : S CH3
O
n.xCH3
y.,,COOR
H
Ampicillin, R = H
Pivampicillin, R=CH 20COC(CH 3)3
Source: Author's representation.
pharmacokinetic properties or improving patient
compliance (Figure 8-4 ), as in the following examples:
Pivampicillin is the hydroxymethyl ester prodrug
derivative of ampicillin with improved oral
bioa vaila bility.
Enalapril is an ester prodrug of enalaprilate with
enhanced bioavailability because of its higher
affinity for the peptide carrier.
Depot prodrugs of neuroleptics such as
fluphenazine have significantly improved the
therapy of schizophrenia because drugs can be
administered only once or twice a month.
The bad smell and taste of chloral hydrate has
been masked by making a phosphate ester pro-
drug to improve patient compliance.
9.. 3u Fundamental Pharmacophores
for Drugs Used to
Treat Disease
A pharmacophore may be defined as a set of struc-
tural features in a molecule that is recognized at a
receptor site and is responsible for the molecule's bi-
ological activity. Table 8-2lists the pharmacophores
of selected drugs used to treat disease.
8..4. Structure-Activity
Relationships in Relation
to Drug-Target Interactions
Drugs are generally discovered after structural mod-
ification of a lead compound. The lead compound
may be discovered serendipitously (e.g., the benzo-
diazepines) or from endogenous sources (e.g., insulin);
r(Ys~
~N~CF3
~Nl
Enalaprilate, R = H ~N~OR
Enalapril, R =CH2CH 3 Fluphenazine, R = H
Decanoate ester, R = C9H19 co-
exogenous sources (e.g., opium alkaloids); rational
drug design (e.g., HIV protease inhibitors); clinical
observation (e.g., sildenafil); high-throughput screen-
ing programs; and genomics and proteomics. The
lead is a prototype compound with a desired phar-
macological activity, but it may also have undesirable
features such as toxicity, limited in vivo metabolic
stability, and other pharmacokinetic or pharmaco-
dynamic problems.
To address these problems, structure-activity
relationship (SAR) studies are usually undertaken.
These studies involve the synthesis and biological
evaluation of several analogues of the lead com-
pound with the goal of enhancing the desirable prop-
erties of the compound while minimizing or eliminat-
ing undesirable characteristics.
The SAR study may include homologation, chain
branching, ring-chain transformations, and bio-
isosterism. Selected examples are ,discussed in the
following sections to illustrate SAR studies in rela-
tion to drug-target interactions.
Sulfonamides
Discovery that the antibacterial activity of the first
sulfonamide, Prontosil, is due to its reduction prod-
uct, sulfanilamide, initiated the first SAR studies.
The studies led to the observation that compounds of
the general sulfonamide structure displayed diuretic
and antidiabetic activities as well as antimicrobial
activity.
SAR for antimicrobial activity of sulfonamides
Sulfonamides with antimicrobial activity have struc-
ture 1 (Figure 8-5) and must satisfy the following
requirements:
cill The amino group must be para to the sulfamoyl
group.
 Medicinal Chemist1Jl"2IJI

.8·2. Pharmacophores of Selected Drugs in Clinical Use

8 EB
0 CH3 EB Br (H 3 C)sN~OI( N(CH 3h NHz H H H

H3C
A 0~N(CHsb Cl
8
Vo Ph~Ni----t--s ,,,CHs
Bethanecol Neostigmine 0 OJ-N-{<cHs
Ampicillin COOH

Selective muscarinic agonist Reversible acetylcholine esterase Penicillin antibacterial agent

used to treat postoperative inhibitor used to treat
urinary retention and postoperative abdominal
abdominal distention distention, urinary retention, and
myasthenia gravis

o~~(CH 3)s c1 8 Ph~~+f-~s

0

¢ 0
EB
O~N(CHsb Cl 8
o _j-N,
0
Cephalexm
.
_r::;

COOH

Succinylcholine Chloride
Thiazide diuretics Nicotine antagonist used as a Cephalosporin antibiotic
depolarizing neuromuscular
blocking agent
OH H yHs
OH
HOrN-y-CHs
HO¢NHCH
I s I CHs
_r::; HO _r::;
Albuterol
Phenylephrine

Selective a 1-adrenergic ~ 2 -adrenergic ,agonist used to treat

agonist used as a nasal asthma
decongestant
CH 3

O~N)___CH3
~OHH F

~ CH 3
Propranolol
Warfarin
Fluvastatin

Nonselective ~ 2 -adrenergic 4-hydroxycoumarin oral Statin used to treat primary

antagonist used to treat anticoag uIant hypercholesterolemia
hypertension and arrhythmias
(continued)
 The APhA Complete Review for the Foreign Pharmacy Graduate Equivalency Examination®

' .8·2. Pharmacophores of Selected Drugs in Clinical Use (Continued)

0 0 0 R'
0, 11 )l
'S,N N~ HN R"

Cl
H H
O~NH 0
Chlorpropamide
Barbiturates
Sulfonylurea hypoglycemic Local anesthetic agent Agents used as sedative-hypnotics,
agent used to treat diabetes antiepileptics, or anesthetics
0
HN--f
cf)o
t;; :~s H,c)
lN~O~ I
Pioglitazone CH 3
1,4-Benzodiazepines Imipramine
Member of the glitazone Agents used as anxiolytics, Tricyclic antidepressant
antidiabetic agents antiepileptics, or muscle
relaxants

~s~
~N~CI

HC)
3
I
OH 0
Doxycycline
0

CH 3
/
Chlorpromazine
Phenothiazine antipsychotic Tetracycline antimicrobial agent Antiviral agent and HIV protease
agent inhibitor
H3C,
~NH2 ~N

~ Qb
R~ CH 3
Phenylisopropylamines

HO O OH HO O OH
Morphine Naltrexone

Central nervous system ~-opioid receptor agonist ~-opioid receptor antagonist

stimulants (e.g.,
amphetamine)
 Medicinal Chemistry

Pharmacophores of Selected Drugs in Clinical Use (Continued)

Hydrocortisone 0~
0
H OH OH CHs
--}:( ~ oqoH
CHs 0--"b'~ OH
CHs
Digoxin
Member of the Selective COX-2 inhibitor Cardiac glycoside
adrenocorticoids

O~N_.CH3

-..;::: H
I
CH 3 N~ Cl Cl
~ ~> N ?"\
:::::......
Diphenhydramine
Cl
Miconazofe
First-generation First-generation tricyclic Imidazole antifungal agent
ethanolamine ether antihistamine, H1 antagonist
antihistamine

Cl
~ HOOC'-.,

OcH-N,__l~o
\_) 1\ I

H3C CH3

~ § Getirizine Nitedipine

Second-generation 1,4-dihydropyridine calcium H2 receptor antagonist used to treat

nonsedating H1 antihistamine channel blockers used to treat peptic ulcers
angina pectoris and hypertension

I
"
FroCOOH N-o-8-N--\--Z
0

I H2
- 0
H
N
-0
. o'():N o
H,c I -"' ~;>-:lycH,
("N ~ N CH3
HN_J ~ Sultamethoxazole
YocH3
Giprof/oxacin Omeprazole CH 3

Quinolone antimicrobial Sulfonamide antimicrobial agent H+fK+-ATPase proton pump inhibitor

agent used to treat peptic ulcers
Source: Author's compilation.
 The APhA Complete Review tor the Foreign Pharmacy Graduate Equivalency Examination®
8·5. General Structures of Drugs Derived from SAR of Sulfonamides
i 2
Source: Author's representation.
An unsubstituted anilino amino group is pre-
ferred, but if a substituent is present, it must be
removable in vivo.
The benzene ring must not have additional
substituents or be replaced with other ring
systems.
Monosubstitution on the sulfamoyl nitrogen
enhances activity, especially if the substituent is a
heteroaromatic group, but disubstitution results
in loss of activity.
SAR for antidiabetic activity of sulfonamides
Compounds with structure 2 (Figure 8-5), where X=
0, S, or N and forms a part of a heteroaromatic sys-
tem (e.g., thiadiazole or pyrimidine) or an acyclic
structure (e.g., urea or thiourea), demonstrate anti-
diabetic activity.
SAR for diuretic activity of sulfonamides
Two classes of diuretics were discovered because of
SAR studies of sulfonamides. They are the thiazide
diuretics of general structure 3 (Figure 8-5) (e.g.,
hydrochlorothiazide) and the high-ceiling diuretics
of general structure 4 (e.g., furosemide).
Barbiturates
SAR studies of the barbiturates did not identify clear
correlations between structure and activity, but it is
generally accepted that clinically useful barbiturates
must be weak acids and must have acceptable parti-
tion coefficients.
Barbiturates that meet these requirements include
5,5-disubstituted barbituric acids (e.g., phenobarbital);
5,5-disubstituted thiobarbituric acids (e.g., thiopental);
and 1,5,5-trisubstituted barbituric acids (e.g., metho-
hexital). Barbiturates with such substitution patterns
are used as sedative-hypnotics, antiepileptics, or anes-
thetics. All other substitution patterns are inactive or
produce convulsions.
1,4-Benzodiazepines
The serendipitous discovery of chlordiazepoxide
(Librium) initiated SAR studies, which led to the dis-
covery of several1,4-benzodiazepines that are used
as anxiolytics, hypnotics, antiepileptics, and muscle
relaxants.
After a large number of benzodiazepines were
synthesized and studied for biological activity, sev-
eral SAR conclusions were made. These conclusions
are summarized in Figure 8-6, which is an example
of a molecular activity map (structural drawing of
a lead compound annotated to show where in the
molecule specific structural changes affect activity
or potency).
8'"5m Chemical Pathways
of Drug Metabolism
Generally, drugs are metabolized po pharmacologi-
cally inactive metabolites, but iii some cases, the
metabolic process may generate a toxic metabolite
or, in a process called bioactivation, may convert an
inactive compound (prodrug) into a pharmacologically
active agent.
factors Affecting Drug Metabolism
Genetic factors
Racial and ethnic differences as well as interindivid-
ual differences in drug metabolism and disposition
may be due to genetic polymorphisms (mutations)
in drug-metabolizing enzymes. For example, cyto-
chrome P450 (CYP) 2D6 is involved in the meta-
bolism of more than 30 cardiovascular and central
nervous system drugs. Mutations in the gene encoding
for CYP2D6 generate three phenotypic subgroups
of metabolizers (i.e., poor, extensive, or ultra-rapid
metabolizers). Thus, patients on drugs that use the
CYP2D6 pathway as the major metabolic route will

8·6. SAR of the 1,4-Benzodiazepines
Substitution at
C-6, C-8, or C-9
reduces activit .
Small electron
withdrawing group
(e.g., Cl) at C-7
increases activity.
Substitution at 3',
4', or 5' positions
decreases activity.
Source: Author's representation.
experience different responses ranging from severe
toxicity to complete lack of efficacy.
Physiological factors
Age, gender, pregnancy, nutritional status, and dis-
ease (especially liver disease) can affect drug metab-
olism. The livers of very young patients, such as
newborns, are not fully developed, so these pa-
tients, as well as geriatric patients whose liver func-
tion has declined, metabolize drugs more slowly
than the normal adult population. Differences in
drug metabolism between men and women and be-
tween pregnant and nonpregnant women have also
been observed.
Pharmaceutical factors
Dose amount, dose frequency, dosage form, and
route of administration may affect the rate and ex-
tent of drug metabolism.
Environmental factors
Inhibition of drug-metabolizing enzymes by environ-
mental toxicants and competition with other xeno-
biotics for these enzymes may affect the rate of drug
metabolism. Coadministration with other drugs that
are inducers or inhibitors of CYP enzymes also influ-
ences metabolism.
Medicinal Chemistry
C-2 carbon must be Sp 2
hybridized. X= 0, NH, or S.
Usually unsubstituted. Drugs
with OH here are very active
and have short duration of action.
Halogens at the 2' or 6'
positions enhance activity.
Any other substituent
decreases actvity.
Phase 1 and Phase 2 Drug
Metabolism Reactions
Many enzymes are involved in drug metabolism,
but the various isoforms of the CYP450 mixed-
function monooxygenases located in the liver are
the most important enzymes involved in drug meta-
bolism. The two major groups of metabolic reac-
tions in the body are termed phase 1 and phase 2
reactions. I
,
Phase 1 reactions include oxidation, hydroxyla-
tion, reduction, and hydrolysis (see Table 8-3 for
examples). The reactions generally introduce a nucle-
ophile (e.g., OH, NH2 , and COO-) into the drug
molecule.
In phase 2 reactions, a nucleophile in the drug mol-
ecule reacts with a masking group (e.g., glucuronic
acid, sulfate, and acetyl and certain amino acids) to
give a conjugate with enhanced water solubility. In
glucuronic acid conjugation, the drug (or its phase
1 metabolite) is appended to an activated glucuronic
acid (uridine diphosphate glucuronic acid) to give
the glucuronide metabolite (Figure 8-7, panel a).
Sulfate conjugation involves the transfer of a sulfate
group from 3'-phosphoadenosine-5'-phosphosulfate
(PAPS) to the drug (Figure 8-7, panel b). Compounds
that contain an amino group may undergo acetyla-
tion as the phase 2 reaction (Figure 8-7, panel c).
Drugs containing carboxylic acid functional groups
(e.g., nonsteroidal anti-inflammatory drugs) undergo
 The APhA Complete Review tor the Foreign Pharmacy Graduate Equivalency Examination®

8·3. Selected Examples of Phase 1 Reactions Catalyzed by CYP450 Enzymes

Drug Metabolite Drug Metabolite

Side-chain oxidation Ring oxidation

Ht~ H
Primadone
Sulfoxidation Deamination

(YYCH3 ~CH 3
~ NH2
Amphetamine

Aromatic
N-dealkylation hydroxylation

HN~ 0
~
~N~ oA:X: H
~N"CH3 Phenobarbital
Desiparmine H

0-dealkylation Desulfuration
Jl~
~N i:x?~
0 H 0

(O~N~N'j HN,.,~ HN
~
0
CF3 lAOJlCF
3
H H
Flecainide Thiopental Pentobarbital
Source: Author's compilation.

conjugation with amino acids (e.g., glycine and
glutamine).
Metabolism of some drugs (e.g., acetaminophen)
generates reactive intermediates that are detoxified by
conjugation with glutathione. Several oxygen-, sulfur-,
and nitrogen-containing drugs are metabolized by
methylation under the catalysis of methyltransferases
(e.g., catechol-0-methyltransferase). Acetylation and
methylation reactions generate lipophilic compounds
that are generally not pharmacologically active because
of decreased affinity for the target receptor. Most drugs
undergo phase 1 and phase 2 reactions sequentially,
but drugs that are highly polar or resistant to drug-
metabolizing enzymes are excreted mostly unchanged.
 Medicinal Chemistry

• Examples of Phase 2 Reactions

a. Glucuronic acid conjugation

UDP-glucuronyl
transferase

b. Sulfate conjugation

t5:~N~y0-~-Ql-'-d3/:¢C: ¢o,oe
~~
0 0
Sulfotransferase
N + PAP
O I II
OH 0 HNI(CH 3
HN I(CH 3
OH OP03 H2 0
0
PAPS Acetaminophen Sulfate conjugate

c. N-acetylation
0
~N/NH2 __N_-_ac_e_,ty_lt_ra_n_sf_e_ra_s_e_
~~ H
lsoniazide
Source: Author's representation.

a. &u Application for Making Drug
Therapy Decisions
~""'''"'''"'''"''''
The pharmacist's role as a member of the health care
profession is to help improve patients' quality of life
by ensuring the responsible use of pharmaceuticals.
To adequately meet this responsibility, the pharma-
cist must be able to amalgamate concepts in the
basic sciences, including the medicinal chemistry of
drug molecules with the clinical sciences. This sec-
tion presents examples of situations in which chem-
ical knowledge of drugs aids in making drug therapy
decisions.
Dwg=Drug interactions
A common clinical problem is one in which the effi-
cacy or toxicity of a drug is affected as a result of
coadministration of two or more drugs.
Drugs that are potent inducets or inhibitors of the
CYP enzymes may influence the metabolism and elim-
ination of other drugs on coadministration. Cimetidine
is a potent inhibitor of several CYP isozymes and,
therefore, can increase the risk of toxicity when co-
administered with drugs metabolized by the CYP
isozymes such as CYP1A2 (e.g., clozapine); CYP2C9
(e.g., phenytoin); CYP2D6 (e.g., antidepressants); and
CYP3A4/5/7 (e.g., lovastatin).
Phenytoin and rifampin are examples of CYP
isozyme inducers. Drugs that are substrates of
CYP3A4 and CYP2C9 are generally very susceptible
to enzyme induction, which leads to rapid elimina-
tion of such drugs, resulting in decreased pharmaco-
dynamic activity.
Coadministration of drugs with opposing mecha-
nisms of action should be avoided because it will make
one or both drugs ineffective. For example, vitamin K
stimulates the synthesis of clotting factors, and
warfarin inhibits the synthesis of clotting factors.
 The APhA Complete Review for the Foreign Pharmacy Graduate Equivalency Examination®
Coadministration of these drugs may diminish the
effectiveness of warfarin.
Drug Metabolism
Drugs with amino groups generally undergo
N-acetylation (Figure 8-7, panel c). Because of a muta-
tion in the gene encoding for one of the major enzymes
involved in N-acetylation, N-acetyl transferase-2
(NAT2), some individuals have a reduced activity of
NAT2. They are termed slow acetylators, compared to
the fast acetylators with normal NAT2 activity.
Fast acetylators terminate the activity of amine-
containing drugs (e.g., procainamide and isoniazid)
much faster than slow acetylators, who cannot me-
tabolize such drugs quickly and so tend to accumu-
late the drug, which can lead to toxicity (e.g., liver
damage with isoniazid).
Tylenol is a popular over-the-counter analgesic that
is safe if taken in recommended doses. The drug is me-
tabolized in the liver to the highly reactive N-acetyl-
p-benzoquinoneimine (Figure 8-8). At therapeutic
concentrations, this metabolite is rapidly detoxified
by cellular glutathione. However, in cases of overdose,
the cellular glutathione pool is overwhelmed so the
excess N-acetyl-p-benzoquinoneimine arylates essen-
tial cellular proteins, leading to toxicity that, if not
treated with N-acetylcysteine, can cause liver failure.
Physicochemical Properties of Drug Molecules
The chemical nature of drugs influences their absorp-
tion, distribution, metabolism, and excretion.
The pH partition hypothesis predicts that weakly
acidic drugs (e.g., nonsteroidal anti-inflammatory
drugs) will be mostly absorbed from the stomach
rather than from the more basic small intestine, where
····lire 8·8. Metabolism of Acetaminophen
¢ GYP 450 ¢ 0
Glutathione
HNI(CH 3 NI(CH3
0 0
Acetaminophen N-acetyl-p-
benzoquinoneimine
I r
Source: Author's representation.
such drugs will be mostly ionized. On the contrary,
basic drugs (e.g., morphine) will be mostly absorbed
from the small intestine rather than from the stom-
ach, where the drug exists mainly as the ionized con-
jugate acid.
This fact is of practical importance to a patient,
because a delay in the onset of action will occur if a
basic drug is taken orally. The drug has to pass
through the stomach (where it will be mostly ionized
and, therefore, will be minimally absorbed) before
the stomach empties and the drug enters the small
intestine (where it will exist predominantly as the
unionized form and, therefore, will be mostly ab-
sorbed). Hence, if patients take a basic drug such as
an antihistamine for motion sickness, they should be
advised to take their medication at least an hour be-
fore they travel to allow the drug time to reach the
site of absorption and to be taken up into the sys-
temic circulation.
Rapid clearance of a drug molecule is desired in
cases of drug overdose. Manipulation of urinary pH to
maintain the drug in the ionized state in the urine will
enhance its excretion. If the drug taken in overdose is
a weak base (e.g., flurazepam), excretion should be en-
hanced by acidification of the urine with administra-
tion of~Cl or vitamin C (forced acid diuresis). If the
drug is a weak acid (e.g., phenobarbital), excretion
should be enhanced by making the urine basic with
administration of NaHC0 3 (forced alkaline diuresis).
Antacids such as TUMS will neutralize stomach pH
to approximately 3.5. Patients must therefore be coun-
seled on the effect of combining acidic or basic drugs
with antacids because the presence oflthe antacid may
enhance or diminish the rate of absorption of the drug.
Antacids also should not be taken with tetra-
cyclines, because the antibiotic will form a chelate with
metal ions in the antacid, which will diminish the ex-
q OH
8
'Giutathione
OH
?~'Protein
HNI(CH3 HN I(CH 3
0 0
Detoxified Arylated protein (toxicity)
metabolite
 Medicinal Chemistry

8·9. Oxidation of Epinephrine

0~0H
Oxidation
Several steps 0~/ \
CH 3
Adrenochrome
Source: Adapted with modification from Cairns 2003:186.

tent of absorption of the tetracycline. Tetracyclines
should not be taken concomitantly with foods that
are rich in calcium for this same reason. The drug
will form a complex with calcium ions and may be
deposited in developing teeth, leading to discoloration
of the teeth. For this reason, tetracyclines should not
be given to children (6-12 years old) who are forming
their permanent set of teeth.
Drug Stability
Drug decomposition can result in loss of efficacy,
generation of toxic products, or both. Therefore,
drugs administered to patients must meet standards
of desirable purity.
Oxidation
Drugs with phenolic groups, such as epinephrine,
norepinephrine, and isoproterenol, are very suscep-
tible to oxidation. These drugs are white crystalline
solids, which change color (darken) on exposure to
air. As shown in Figure 8-9, epinephrine is, on oxi-
dation, converted to adrenochrome (red-colored com-
pound), which can polymerize to give black-colored
compounds. Therefore, injections of epinephrine that
develop a pink color or contain crystals of black com-
pound must be discarded.
Hydrolysis
A large number of functional groups in drug mole-
cules (especially esters and amides) are susceptible to
hydrolysis during storage. For example, aspirin is
very susceptible to hydrolysis (Figure 8-10). There-
action produces salicylic acid and acetic acid, which
are responsible for the smell of vinegar when a bottle
of aspirin is opened.
The lactam ring of penicillin and cephalosporin
antibiotics is also prone to hydrolysis (Figure 8-10).
For this reason, these drugs are supplied as dry powder
for reconstitution by the pharmacist before dispensing.
The reconstituted drug must be stored in a refrigerator
to limit hydrolysis.
When exposed to light, some dr~gs undergo decom-
position and so must be packaged in amber-colored

~l!re 8·10. Hydrolysis of Aspirin and Ampicillin

'"'-'..0:.'";.-

COOH

CrOH + H3c-f
OH
0

Aspirin Salicylic acid Acetic acid

~HHH
U q,:{isx~~:
OH /''COOH

Penicilloic acid derivative

Source: Author's representation.
 The APhA Complete Review for the Foreign Pharmacy Graduate Equivalency Examination®
tH1. Light-Catalyzed Decomposition of Chlordiazepoxide
Cl
Chlordiazepoxide (Librium)
Source: Adapted with modification from Cornelissen, Beijersbergen Van Henegouwen, Gerritsma 1979.
containers. For example, chlordiazepoxide undergoes
a light-catalyzed cyclization reaction to generate an
inactive compound (Figure 8-11).
8"'7. Key Points
r?Z"TI'!il~"'l.:\\:..:':::::'.C_':-;.·._-.-,,- ..
The functional groups in a drug molecule deter-
mine its acid-base character, which may influence
the absorption, excretion, and compatibility of the
drug with other drugs in solution.
An acidic drug will donate a proton on ionization
to give a conjugate base, but a basic drug will
accept a proton on ionization to give a conju-
gate acid.
D Organic functional groups in drug molecules that
cannot accept a proton or donate a proton are
neutral (nonelectrolytes).
pK. is a measure of the relative acid-base
strength of organic functional groups.
E'l The aqueous solubility of a drug is influenced by
its ionizability and its ability to form hydrogen
bonding with water molecules.
Polar functional groups decrease the log P values
of drugs, whereas nonpolar functional groups
increase log P values.
I'] Drugs must have appropriate log P values to facili-
tate passive diffusion across biological membranes.
The pH-partition theory influences drug absorp-
tion from the GI tract and drug transport across
biological membranes.
Weakly acidic drugs are generally best absorbed
from the stomach, compared to the more basic
small intestine, where such drugs are predomi-
nantly ionized.
Manipulation of urinary pH to maintain a drug
in its ionized state will enhance its excretion by
preventing reabsorption.
Cl
Inactive oxaziridine derivative
EJ The conformation, stereochemistry, and type of
chemical bonding a drug makes with its receptor
may influence the affinity of the drug for the re-
ceptor and the resulting pharmacological activity.
l11l Drugs may bind to receptors through chemical
interactions such as ionic bonding, hydrogen
bonding, covalent bonding, and hydrophobic
interactions.
1.11 Theories that have been postulated to explain the
observed effects of drug-receptor interactions in-
clude (1) occupancy theory, (2) rate theory, (3) in-
duced fit theory, (4) macromolecular perturbation
theory, and (5) activation-aggregation theory.
l£l Drug instability may be due to chemical reactions
such as oxidation and hydrolysis. Phenolic drugs
are prone to oxidation, whereas drugs with ester
and amide groups are susceptible to hydrolysis.
EB Prodrugs are chemically modified drugs that are
inactive in the administered f¢rm but undergo
bioactivation to the active drug in vivo.
@1 Pharmacophore is the set of minimal structural
features of a drug molecule that is recognized by
a receptor and is required for the molecule to be
biologically active.
c:J Structure-activity relationship study is an
approach used to enhance the desired biological
activity of a compound while minimizing or
eliminating the undesirable properties of the
compound.
Ell Factors that may influence drug metabolism
include (1) genetic factors, (2) physiological fac-
tors, (3) pharmaceutical factors, and (4) environ-
mental factors.
I'D The CYP isoforms are the most important group
of enzymes involved in drug metabolism.
m The two major groups of metabolic reactions in the
body are termed phase 1 and phase 2 reactions.
Phase 1 metabolic reactions typically involve in-
troduction of a nucleophile into the drug mole-
 Medicinal Chemistry

cule, whereas phase 2 reactions usually increase A. covalent bonding.

the aqueous solubility of the drug through glu- B. ionic bonding.
curonidation or sulfation. C. hydrogen bonding.
i1!li Drugs that are potent inducers or inhibitors of the D. hydrophobic interaction.
CYP isoforms may influence the metabolism and
elimination of other drugs on coadministration. 4. The tertiary amine group of drug 1 may form
ELl Fast acetylators have normal NAT2 activity, so an ionic bond with which amino acid at the
they terminate the activity of amine-containing drug's target receptor?
drugs much faster than slow acetylators in
A. Arginine
whom the gene encoding for NAT2 is mutated.
B. Lysine
lR1 Factors that should be considered when making
C. Glycine
drug therapy decisions include (1) drug-drug
D. Glutamic acid
interactions, (2) drug metabolism, (3) physico-
chemical properties of the drug, and (4) drug
5. The best way to promote urinary clearance of
stability.
drug 1 is to
A. administer water for injection.
a.. am Questions B. administer a solution of NaHC0 3 •
C. administer 5% dextrose.
Answer Questions 1-5 using the illustration of drug 1. D. administer a solution of NH4 Cl.

6. Drugs such as aspirin should not be stored in

the bathroom because of the likelihood of
decomposition through
A. hydrolysis.
B. hydrogenolysis.
C. dehydration.
Cl D. reduction.

Drug i (PKa =8.2)

1. At what site of the GI tract will drug 1 be
least absorbed?
A. Stomach (pH 2)
B. Duodenum (pH 6) 7. 5,5-disubstituted barbituric acids are clinically
C. Colon (pH 8) used as
D. Absorption of drug from the GI tract is pH
independent A. anticoagulants.
B. antihistamines.
2. Drug 1 and others of similar pharmacophore C. sedative-hypnotics.
are used as D. coagulants.
A. diuretics.
B. anticancer agents. 0

HN~R'
C. anxiolytic agents.
D. anticoagulants.

3. The chemical bonding interaction that is un-

OAN~O
H
likely to occur between drug 1 and its target 5 ,5-disubstituted
receptor is barbituric acid
 The APhA Complete Review for the Foreign Pharmacy Graduate Equivalency Examination®

Answer Questions 8-13 using the structures in the 16. How would you treat an overdose of
following figure: acetaminophen?
A. Use forced alkaline diuresis.
B. Use forced acid diuresis.
A B C. Administer an osmotic diuretic.
oOf H o iHoH
0.::-SI )l f · N_H
D. Administer N-acetylcysteine.

'N N I '-'::: 'CH3 Answer Questions 17-20 using the following figure:
H H 0
Cl HO

c D A B
F Br
I I
F-C-C-CI
I I
F H

c D
8. Which drug is most likely to undergo decom-
position via oxidation?

9. Which drug contains a sulfonylurea functional

group?

10. Which drug will undergo N-demethylation 17. Patient J. B. is a slow acetylator. Which drug
in vivo? is potentially toxic to this patient?

11. Which drug has a primary amine functional 18. Which drug must be reconstituted just before
group? use to prevent decomposition?

12. Which drug is not ionizable? 19. Which drug must not be c6administered with
antacids?

13. Which drug will be predicted to have the

highest log P value? 20. Which drug has a pair of enantiomers?

14. Which of the following is a phase 2 reaction?

A. Acetylation a. .g n Answers
B. Oxidation
C. Demethylation 1. A. Most drugs are absorbed from the GI tract
D. Deamination as the un-ionized form by passive diffusion.
Drug 1 (flurazepam) is a basic drug, so its ion-
15. The drug that is a potent inhibitor of several ization will be greatest in the stomach, which
CYP isoforms and therefore must be used will limit absorption.
with caution in combination therapy is 2. C. Drug 1 belongs to the group of drugs
known as 1,4-benzodiazepines. Drugs in this
A. aspirin. class may be used as anxiolytics, hypnotics,
B. cimetidine (Tagamet). antiepileptics, or muscle relaxants.
C. gabapentin (Neurontin). 3. A. Covalent bonding involves the sharing of
D.levetiracetam (Keppra). electrons between an electrophilic center (usu-

ally in the drug molecule) and a nucleophilic
center (usually in the receptor). Drug 1 does
not possess an electrophilic center capable of
such an interaction with its receptor.
D. The tertiary amine of drug 1 will be proto-
nated at physiologic pH and so can form an
ionic bond with a glutamate of the receptor if
it is close to the protonated amine.
D. Administration of NH4 Cl will decrease uri-
nary pH to about 6, which will promote ioniza-
tion of drug 1. The ionized form of the drug
will not undergo passive diffusion back into
systemic circulation but will readily dissolve
and be excreted in the urine.
A. Aspirin is the acetyl ester derivative of sali-
cylic acid. In the presence of moisture, the ester
group can be hydrolyzed.
C. Drugs that are 5,5'-disubstituted derivatives of
barbituric acid may be used as sedatives, hyp-
notics, antiepileptics, or preanesthetic agents.
B. Phenolic drugs and drugs with the catechol
group (e.g., epinephrine) are prone to decompo-
sition through oxidation when exposed to air.
A. Drug A is chlorpropamide, which is a first-
generation sulfonylurea antidiabetic agent.
B. Drug B has an N-methyl group, so it is a
candidate for N-demethylation.
D. Drug D has a primary amine functional group.
Drug B has a secondary amine group. Drugs A
and C do not contain amine functional groups.
C. Drug C cannot donate a proton or accept a
proton. It is therefore not ionizable. Drug A is
an acidic drug because of the presence of the
sulfonylurea group in its structure. Drugs B and
D are basic drugs because of the amine group
in them.
13. C. Halogens are lipophilic in character and so
will increase the log P values of drugs, whereas
polar groups are hydrophilic in character and
so will decrease log P values of drugs. Drug C
is the only drug in the illustration without polar
residues; hence, it should have the highest log
P value.
14. A. Acetylation is a phase 2 reaction that occurs
in drugs with amine groups. All of the other re-
actions are phase 1 reactions.
15. B. Cimetidine is an anti peptic ulcer agent that
inhibits several CYP450 isoforms. For example,
it inhibits CYP1A2, CYP2C9, CYP2D6, and
CYP3A4.
Medicinal
16. D. Acetaminophen is metabolized in the liver
to a reactive quinoneimine intermediate, which
is detoxified by glutathione. In overdose, the
body's supply of glutathione is overwhelmed,
which could result in hepatotoxicity. N-acetyl-
cysteine reacts with the quinoneimine just like
glutathione to detoxify it.
17. C. Slow acetylators are prone to having high
plasma levels of drugs, such as drug C (isoni-
azid), that possess an amine group, because such
drugs are metabolized by acetylation. Drug D
has a basic group (the hydrazine), but it can
also be metabolized by glucuronide conjuga-
tion or methylation. Because of the multiple
routes of metabolism, drug D is unlikely to be
toxic to]. B.
18. A. Drug A is a cephalosporin. The cephalosporin
and the penicillin antibiotics have a beta-lactam
ring, which may undergo ring opening in aque-
ous media. These drugs must be reconstituted
just before dispensing and must be stored in the
refrigerator.
19. B. The tetracyclines will chelate metal ions,
which will lower their bioavailability.
20. D. Drug D (carbidopa) has one chiral center,
so it has a pair of enantiomers. Drugs A and
B have multiple chiral centers, so they have
diastereomers. Drug C does not have a chiral
center.
9..10. References
Cairns D, ed. Essentials of Pharmaceutical Chemistry.
2nd ed. Chicago: Pharmaceutical Press; 2003.
Cornelissen PJG, Beijersbergen Van Henegouwen
GMJ, Gerritsma KW. Photochemical decomposi-
tion of 1,4-benzodiazepines: Chlordiazepoxide.
Int] Pharm. 1979;3(4-5):205-20.
Lemke TL, ed. Review of Organic Functional Groups:
Introduction to Organic Medicinal Chemistry.
3rd ed. Philadelphia: Lea & Febiger; 1992.
Lemke TL, Williams DA, eds. Faye's Principles of
Medicinal Chemistry. 6th ed. New York:
Lippincott, Williams & Wilkins; 2008.
Nogrady T, Weaver DF. Medicinal Chemistry:
A Molecular and Biochemical Approach. 3rd ed.
New York: Oxford University Press; 2005:108-28.
 har acol
9..1. Mechanism of Action of Drugs
of Various Categories
~:~::z::~t_;':,_:c
The effects of drugs can be described on four differ-
ent levels:
II The system level. An effect occurs on an inte-
grated body system, such as the cardiovascular
or the respiratory system.
II The tissue level. An effect occurs on tissue
function, such as secretion, proliferation, or
metabolic activity.
II The cellular level. Signal transduction occurs
within a cell, such as the cascade of a biochemi-
cal signaling pathway such as the Raf kinase
pathway.
II The receptor level. Interaction takes place with a
drug's molecular target, such as the Pradrenergic
receptor.
Knowledge about a drug's effect at all four levels is
necessary to assess the drug's potential effective-
ness, synergistic or antagonistic effect with other
medications, and potential interactions with other
drugs.
Molecular Targets of Drugs
To exert an effect, either desired or undesired (side
effect or adverse event), drugs need to interact with
molecular targets. Depending on the availability of
its molecular targets in tissues and cells, a drug may
profoundly affect one type of tissue but not affect
other types of tissues. Examples of frequent molecu-
lar targets of drugs follow.
y
Bernd Meibohm, PhD, FCP
Receptors of endogenous hormones
or neurotransmitters
Drugs can act either as an agonist or as an antago-
nist on a receptor system. An agonist at a receptor
system triggers the action, which is also produced by
the receptor's natural, endogenous ligand. An antag-
onist blocks the effect of the natural endogenous
agonist on the receptor system. Examples include
loperamide, which is an agonist for the l-1-opioid
receptor, and propranolol, which is an antagonist for
p-adrenergic receptors.
Enzymes
Enzyme activity can be modulat~d by blocking the
normal enzymatic reaction either through direct bind-
ing to the enzyme or through competitive inhibition
by serving as a false substrate, thereby inhibiting the
enzymatic processing of the natural substrate. For
example, atorvastatin inhibits the enzyme HMG-CoA
(3-hydroxy-3-methylglutaryl-coenzyme A) reductase
in the endogenous synthesis pathway of cholesterol.
Transporters
Exchange of ions or other molecules across biomem-
branes can be stimulated or inhibited, for example, for
antiporters (exchange of ions across biomembranes)
or symporters (cotransport of ions across biomem-
branes). For example, cardiac glycosides such as
digoxin inhibit the Na+/1(+-ATPase.
lon channels
Transmembrane ion channels can be blocked, or
their probability of opening can be increased or
 The APhA Complete Review tor the Foreign Pharmacy Graduate Equivalency Examination®
decreased. The former is usually the case for voltage-
operated ion channels; the latter is the case for
receptor-operated ion channels. For examples, voltage-
operated sodium channels are blocked by lidocaine,
and the GABA (y-aminobutyric acid)-gated chloride
channel (a receptor-operated ion channel) is modu-
lated by benzodiazepines.
Nucleic acids
Drugs can inhibit the expression of genes (1) by
directly binding to DNA (deoxyribonucleic acid) and
thus modulating their transcription or (2) by bind-
ing to mRNA (messenger ribonucleic acid) and, thus,
modulating the translation of the gene. For example,
fomivirsen binds to viral mRNA, thereby inhibiting
viral replication in case of cytomegalovirus infection
in the eye.
Drugs that act without specific molecular targets
Although most drugs require a molecular target to
exert their effects, a few drugs act without interaction
with specific molecular targets:
Buffers, used as antacids
BJ Gaseous and volatile general anesthetics
Osmotic diuretics or laxatives
Receptor Theory
Types of receptors
The majority of drugs exert their effects by interaction
with receptors. Four major classes of receptor super-
families exist: receptor-operated channels, receptor-
operated enzymes, G-protein-coupled receptors, and
DNA-linked receptors.
Receptor-operated channels
An extracellular binding domain is coupled with mul-
tiple transmembrane domains that form an ion chan-
nel. An example is the nicotinic acetylcholine receptor.
Receptor-operated enzymes
The receptor has an extracellular ligand-binding
domain that is linked by a transmembrane region
to an intracellular catalytic domain that has either a
tyro~ine kinase or guanylyl kinase activity when the
binding site is activated. An example is the epidermal
growth factor receptor.
G-protein-coupled receptors
These receptors have a transmembrane protein with
extracellular and intracellular domain. The intra-
cellular domain is coupled with G-proteins, which
facilitate signal transduction after stimulation of the
receptor by second-messenger pathways. The drug-
binding domain lies within one of the transmembrane
domains. An example is the a 1-adrenergic receptor.
DNA-linked receptors
DNA-linked receptors are intracellular receptors, in
contrast to the other three receptor types discussed,
which are transmembrane receptors. The ligand-
binding domain is linked to a DNA-binding domain.
An example is the androgen receptor.
Prerequisites for receptor-mediated drug effects
Binding
For receptor-mediated drug effects, binding of the
drug to a specific region in the three-dimensional
structure of the receptor is a prerequisite to exert a
biological response.
Recognition
The receptor protein must exist in a conformational
state that allows recognition and binding of a com-
pound. It must satisfy the following criteria:
l'il Saturability. Receptors exists in finite numbers.
flJl Reversibility. Binding must occur noncovalently
because of weak intermolecular forces (H-bonding,
van der Waals forces).
Stereoselectivity. Receptors should recognize
only one of the naturally occurring optical
isomers of a drug.
Agonist specificity. Structurany related drugs
should bind well, whereas dissimilar compounds
should bind poorly.
Tissue specificity. Binding should occur in tis-
sues known to be sensitive to the endogenous
ligand. Binding should occur at physiologically
relevant concentrations.
Transduction. Binding of an agonist must be
translated into some kind of functional response
(biological or physiological).
Receptor interaction
Receptors are large proteins that contain a site that
"recognizes" drugs and binds them similarly to the
way a key fits a lock. Most cells harbor many differ-
ent receptor types and many receptor molecules of
each type.
Binding of a ligand (e.g., a drug) results in a confor-
mational (allosteric) change in the three-dimensional
structure of the receptor, creating an active agonist-
 Pharmacology

complex that activates a signal transduc- is produced by denying endogenous agonists

tion system. Drug-receptor complexes are repeat- access to the receptor.
edly and randomly created by collision of drug !!'1 Partial agonists bind to receptors and produce
molecules with unoccupied receptors. The formed a molecular response, but even at high con-
drug-receptor complexes also dissociate into their centrations the maximum cellular response
components, so a dynamic equilibrium exists between is not achieved. Thus, the maximum tissue
the two states. response for a partial agonist is less than that
Agonist-receptor complexes fluctuate between for a full agonist. Because partial agonists can
inactive and active conformations. The active confor- compete with full agonists in binding to the
mation results in signal transduction and subsequent receptor, they can act as antagonists to full
cellular response. agonists.
The number of drug receptors on a cell is not neces- !iiil Inverse agonists bind to receptor molecules that
sarily constant but can change under prolonged stimu- are in an activated state in the absence of ali-
lation or lack thereof by receptor up- or downregula- gand (basal activation). Thus, inverse agonists
tion, which is frequently observed during chronic drug decrease the basal activation level of a receptor
therapy. by stabilizing its inactive form.
Ligands for receptors can be differentiated accord-
Tissue responses are not necessarily directly propor-
ing to their ability to trigger the signal transduction
tional to molecular responses resulting from agonist-
(Figure 9-1):
ligand interactions. In most cells, the maximum cel-
Full agonists bind to receptors and produce a lular response to an agonist is already reached when
molecular response (conformational change and only a small fraction of receptors is occupied. Thus the
subsequent cellular responses) that results in number of receptors is much higher than necessary
maximum tissue response. for achieving the maximum response. This so-called
KA Competitive antagonists bind to receptors with- receptor reserve (spare receptors) increases the sensi-
out initiating a molecular response. Their effect tivity toward small changes in agonist concentration.

9·1. Concentration-Activity Relationships for Agonists and Antagonists

100% intrinsic
activity
A
"
/B
I

---:~-------

/
/
/
I c
I
/
I
I
I
I
/
/
/
/ E
Basal activation -~--...:--:::;;...""-~·-""···~--·~·-
...............,, ..···~··t..:;... ~..::.. ~.................................................. .
,,
'',,,
,,,, D
0 J_________________-=-,~--~-~--~-~--~-~--~-~--~-~--~-~--~-~--~-~--~-=--~-~--~-~--~-~-0

Concentration (log)

Source: Author's representation.

Note: The figure shows concentration-activity relationships for full agonists (A and B), a partial agonist (C), an inverse agonist (D), and a competitive
antagonist (f). A and Breach the full intrinsic activity but have different potency (EC50 ). C has a lower intrinsic activity (and in this example also a lower
potency). Dreduces basal activation. Einhibits competitive ligand binding to the receptor and results in no intrinsic activity.
 The APhA Complete Review for the Foreign Pharmacy Graduate Equivalency Examination®
For example, the skeletal neuromuscular junction has
30 million nicotinic acetylcholine receptors. Activation
of 40,000 of these receptors already elicits an action
potential followed by full twitch of the muscle fiber.
Partial agonism results from an inefficient activa-
tion of the receptor by a drug. The subsequent cellu-
lar response depends on the presence or absence of
spare receptors:
II!! If there are no spare receptors, the maximum
cellular response is less for a partial agonist than
for a full agonist, and the partial agonist does
not achieve the same maximum cellular response
as the full agonist.
llli If there are spare receptors (as in most cells), the
partial agonist needs to interact with more recep-
tors of the receptor pool to achieve the maximum
cellular response; thus, a higher dose is required
to achieve this response. If the dose is high
enough, the partial agonist may achieve the same
maximum cellular response as the full agonist.
For antagonism, two main mechanisms can be
distinguished:
IDl Competitive antagonists bind to the site normally
occupied by the agonist, thereby reducing the
number of receptors available for agonist binding.
Noncompetitive antagonists bind to a different
ligand-binding site on the receptor (allosteric
site). This binding to the allosteric site results in
a conformational change of the receptor, which
leads to reduced or no agonist binding and, thus,
no signal transduction.
Antagonism at the molecular level-that is, at the
receptor interaction level-has to be distinguished
from physiologic antagonism. In physiologic antago-
nism, the effects of two drugs are opposite on the level
of the organ system or whole body but are mediated
through different receptor systems and signaling path-
ways. The opposing effect of acetylcholine and nor-
adrenalin on arterioles is an example of physiologic
antagonism.
9..20 Role of Pharmacology
in Drug Choice and the
Treatment of Disease
Pharmacology is the discipline that studies the bio-
logic effects of drugs and the ways they produce such
effects. Pharmacokinetics and pharmacodynamics
are subdisciplines of pharmacology:
!ill Pharmacodynamics describes the desired and
undesired actions of drugs in a qualitative as
well as a quantitative manner. Pharmacodynamics
thus describes what the drug does to the body.
[\1! Pharmacokinetics describes the uptake, distribu-
tion, metabolism, and excretion of drugs in the
body-that is, their disposition. Pharmacokinetics
thus describes what the body does to the drug.
The rational use of drugs and the design of effec-
tive dosage regimens are facilitated by an appreci-
ation of the relationships between the administered
dose of a drug, the resulting drug concentrations in
various body fluids and tissues, and the intensity of
pharmacologic effects caused by these concentra-
tions. These relationships-and thus the dose of a
drug required to achieve a certain effect-are deter-
mined by the drug's pharmacokinetic and pharmaco-
dynamic properties.
By interacting with target structures in different
tissues and by interacting with more than one molec-
ular target, drugs may have not only desired thera-
peutic effects, but also undesired effects, which may
lead to adverse events and toxicity.
Selectivity
Selectivity describes the drug's property to interact
with one molecular target as opposed to others.
Selectivity depends on the chemical structure of the
drug, the drug dose, the route of drug administration,
and patient factors such as physiologic or patho-
physiologic conditions and genetically determined
susceptibility. /
An ideal drug has a high selectivity toward the
desired therapeutic effect rather than toward undesired
side effects at the therapeutically used dose level and
administration pathway. The latest generations of
inhaled corticosteroids, such as fluticasone propionate,
have a high selectivity toward anti-inflammatory activ-
ity in the lung (e.g., for the treatment of asthma) as
compared to undesired systemic effects such as growth
retardation. This selectivity of fluticasone propionate
is accomplished by its high metabolic instability after
being absorbed into the systemic circulation.
The benefit-to-risk ratio is a formal approach to com-
paring the therapeutically desired effect of a drug
with its health risks related to adverse events and
toxicity. The therapeutic acceptance of a benefit-to-
risk ratio depends on the nature and severity of the
treated disorder. In a life-threatening condition, a
 Pharmacology

risk may be tolerable for therapeutic benefit trations are either ineffective or toxic, but rather as
than would be acceptable, for example, in prophy- a therapeutic guidance. Because pharmacodynamic
·. lactic drug treatment. parameters and, thus, concentration-effect relation-
In cancer chemotherapy, potent drugs with lim- ships are variable among differe-nt patients, the
ited selectivity and high adverse event potential are therapeutic range can only indicate a high proba-
often administered at the maximum tolerable dose to bility of therapeutic response in a patient popula-
achieve high efficacy of tumor kill. In contrast, the tion; it cannot predict the response in an individual
same benefit-to-risk ratio would not be tolerable for patient.
the chronic pharmacotherapy of a not acutely life- Drugs with a wide therapeutic range have a large
threatening condition such as hypercholesterolemia. margin between concentrations necessary to achieve
therapeutic activity and concentrations that will result
in toxicity. ~-lactam antibiotics are an example of
Therapeutic Range drugs with a wide therapeutic range.
For many drugs, a therapeutic range of concentrations Drugs with a narrow therapeutic range have only a
can be defined in which a high likelihood of efficacy small margin between drug concentrations necessary
exists (that is, desired therapeutic response), but only for efficacy and drug concentrations that have a high
limited toxicity. The therapeutic range is a range of likelihood of toxicity. Digoxin is a narrow therapeu-
drug plasma concentrations within which the proba- tic range drug, with the upper limit of 2.0 ng/mL,
bility of desired clinical response is relatively high and only less than threefold higher than the lower limit of
the probability of unacceptable toxicity is relatively 0.8 ng/mL.
low (Figure 9-2). As such, the therapeutic range tries Narrow therapeutic range drugs often require
to leverage the selectivity of a drug between therapeu- individualization of dosing to keep plasma concen-
tic and toxic activity. trations in the therapeutic range despite differences
A therapeutic range should never be used as an in pharmacokinetic parameter between different
absolute concentration outside of which drug concen- patients. Therapeutic drug monitoring is an approach

9·2. Therapeutic Range

a b
40
100

Response
~
.§_
1: 30
0

Toxicity/
, "" ~
Q)
I g 20
I 0
,
I' (,)
tn
I 2
I
I
I' ~ 10
/ E
"'
"'
0::
0
0 10 20 30 0 24 48 72 96
Drug concentration (mg/L) Time(h)

Source: Author's representation.

Note: Panel a shows a drug concentration-probability of effect relationship. The probability of achieving the desired response is very low when drug
concentrations are less than 5 mg/L (as is the chance of observing toxicity). As drug concentrations increase from 5 to 20 mg/L, the probability of desired
effect (response) increases significantly, while the probability of toxicity increases more slowly. One could select a therapeutic range of 10 to 20 mg/L,
where the minimum probability of a therapeutic response is at least 50% and the probability of therapeutic failure (in this case, toxicity) is less than 10%.
Panel b demonstrates an optimal dosage regimen that maintains the plasma concentration of the drug within the therapeutic range. The dosing interval
(time between doses) is the same, but the dose given in regimen 2 (bold line) is twice as large as that given in regimen 1 (dotted line). As shown, drug
accumulates in the body during multiple dosing. Regimen 1 results in plasma concentrations within the therapeutic range. For regimen 2, the therapeutic
range is reached quickly, but the dosage regimen ultimately results in a high likelihood of toxicity.
 The APhA Complete Review for the Foreign Pharmacy Graduate Equivalency Examination®
that measures drug plasma concentrations of a
patient receiving narrow therapeutic range drugs
and adjusts their dose and dosing interval in such
a manner that concentrations remain in the thera-
peutic range throughout the whole therapy.
Combination Pharmacotherapy
Drugs that achieve a similar pharmacologic effect on
the whole body or system level through interaction
with different molecular targets are often given in
combination to further enhance the therapeutic effect
on the whole body or organ level.
For the treatment of hypertension, for exam-
ple, combinations may consist of thiazide diuretics,
angiotensin-converting enzyme (ACE inhibitors), and
Pcadrenoceptor blockers. Thiazide diuretics inhibit
the Na+/CL- cotransporter in the distal tubules of
the kidneys. ACE inhibitors reduce the catalytic
activity of angiotensin-converting enzyme, thereby
reducing the endogenous synthesis of angiotensin
II. P1-adrenoceptor blockers competitively inhibit
P1- and to a certain degree Pradrenoceptors and pro-
duce a decrease in vascular resistance. Therapy with
all three drugs results in a decrease in diastolic blood
pressure.
g.. a. Pharmacodynamics of Drug
Action and Relationship to
Drug Disposition
'':.',--::',\_, ____ ,___ ,
For most drugs, therapeutic response and toxicity
are related to their free concentration at the site of
action. However, drug concentrations at the site of
action (e.g., brain tissue for benzodiazepines) often
cannot be practically measured. Thus, drug con-
centrations in accessible body fluids such as plasma
are often related to the observed effect under the
assumption that the drug concentrations in the
measured body fluid and at the site of action are in
a constant relationship.
Pharmacodynamic Models
Pharmacodynamic models characterize the concen-
tration-effect relationship of a drug. Whereas the phar-
macokinetics of most drugs exhibits linear behavior
(i.e., doubling the dosing rate results in doubling the
systemic exposure), the pharmacodynamics is usually
characterized by nonlinearity (i.e., the relationship
between plasma concentration and effect is nonlin-
ear and levels off at a maximum effect being reached
with a specific dosing regimen).
For many drugs with reversible drug effects, the
concentration-effect relationship can be described
by an Emax model, which is characterized by an
S-shaped curve when depicted in a semilogarithmic
plot of effect intensity E versus drug concentration
C (Figure 9-3):
E= EmaxxC
EC 50 +C
where Emax = maximum effect possible with the spe-
cific drug and EC50 =concentration that causes 50%
of Emax' the half-maximum effect.
Emax refers to the intrinsic activity (IA) of a drug.
The intrinsic activity is the relative maximal drug
effect in a particular tissue. If compared to a natural
endogenous ligand, the IA can be used to differenti-
ate agonists from antagonists:
l'4 Full agonist: IA = 1 (i.e., equal to endogenous
ligand)
Antagonist: IA = 0
m1 Partial agonist: 0 < IA < 1 (produces less than
the maximal response of the natural, endoge-
nous ligand, despite maximal binding to the
receptors)
EJ Inverse agonist: IA = -1 (i.e., reduction below
baseline level)
EC 50 refers to the potency of a drug. The potency is
the ability to cause a functional'change at a certain
concentration. It is related to the affinity of the drug
for its target structure (e.g., a receptor). A more
potent drug needs a lower concentration to cause
the same functional change in a target structure (i.e.,
it has a smaller EC50 ).
Although the Emax model is an empirical relation-
ship, its value lies in the fact that it can be related to
the receptor theory of drug action. Under the assump-
tion that the observed effect E is directly proportional
to the number of occupied receptors, Emax is equiva-
lent to the number of receptors available and EC50 is
equivalent to the affinity constant of the drug to the
receptor (i.e., the concentration at which half the
receptor sites are occupied).
The Emax model describes the concentration-
effect relationship over a wide range of concentra-
tions, from zero effect in the absence of drug to
maximum effect at concentrations much higher
than EC50 (C » EC5 o).
 Pharmacology

9·3. Emax Model

a

100

80

.....
(.) t)
~Ol 60 ~ 60
E E
:::1 :::1
E
·xIll ·xEIll
....E0
-;R
0
40
-
0
~
E 40

20
ECso

I
0 20 40 60 80 100 -4-3-2-1 0 2 3 4 5 6 7 8 9 10
Concentration (ng/mL) In C(ng/ml)

Source: Adapted with modification from Meibohm, Derendort 1997:404.

Note: The figure depicts the effect versus concentration relationship defined by an Emax model, depicted in a linear (panel a) and a semilogarithmic (panel
b) plot. EC50 denotes the concentration that produces one-half the maximum effect. In the range between 20% and 80% of the maximum effect, the effect
is directly proportional to the logarithm of the concentration, with a slope of Em,/4.

Three characteristic phases can be distinguished: Pharmacokinetic-Pharmacodynamic

12'! Linear phase. For concentrations much smaller
than EC50 ( C « EC50 ), the Emax model simplifies
to a linear model:
E=mxC
with slope m = EmaxfECso
Ill Constant phase. For concentrations much larger
than EC50 ( C » EC50 ), the effect is essentially
constant:
Log-linear phase. ForE between 20% and 80%
of Emax, the Emax model follows a log-linear rela-
tionship, where the effect is proportional to the
logarithm of the concentration. Thus, in this
range, the Emax equation can be rewritten for a
log-linear model as
E = Emax X ln C + Emax X (ln EC + 2)
4 4
where Emaxl4 is the slope in the log-linear
relationship.
Relationships
Pharmacokinetic-pharmacodynamic (PK-PD) rela-
tionships integrate a pharmacokinetic model compo-
nent that describes the time course of drug in plasma
and a pharmacodynamic model component that
relates the plasma concentration to the drug effect.
Thus, PK-PD models allow the description of the
continuous profile of drug effect intensity over time in
response to a given dose or dosing regimen. The gen-
eral concept of PK-PD relationships is presented in
panel a of Figure 9-4.
A simple PK-PD model, a one-compartment phar-
macokinetic model combined with an Emax model, is
depicted in panel b of Figure 9-4. Figure 9-5 shows the
resulting time courses of plasma concentration (dotted)
and effect (solid) (in the depicted case, EC50 is 1/100
of C0 ). The insert shows the concentration-effect rela-
tionship and the corresponding phases characterizing
drug response:
50
In phase 3, when the plasma concentration is
always much higher than EC50 , effect intensity
remains almost maximal despite a large fall in
 The APhA Complete Review tor the Foreign Pharmacy Graduate Equivalency Examination®

a b

Pharmacokinetics Pharmacodynamics Pharmacokinetics Pharmacodynamics

Concentration vs. Effect D -k,Xt
E=
Emax xC
C =-xe
Vd
C Concentration
ECSO + c
t Time C Concentration
D Dose E Effect
Vd Volume of distribution Emax Maximum effect
Elimination rate constant EC50 Concentration at 50% of Emax

PK/PD
Effect vs. Time

Time

Source: Adapted with modification from Derendorf, Meibohm 1999:177.

Note: Panel a shows the general concept of integrated PK-PD modeling. Pharmacokinetics describes the time of drug concentration resulting from a
dosing regimen. Pharmacodynamics describes the relationship between drug concentration and effect intensity. The integrated PK-PD model describes
the time course of effect intensity resulting from a dosing regimen. Panel b depicts a simple, integrated PK-PD model where the pharmacokinetics is
described by a one-compartment model with instantaneous drug input and the pharmacodynamics is described by an fmax model. The integrated PK-PD
model describes the effect intensity over time based on the PK parameters elimination rate constant ke and volume of distribution Vd as well as the PD
parameters maximum achievable effect (fmaxl and concentration that produces the half maximal effect (fC50).

hl:i~figure 9·5.
\~.fl.';:'~~'',-
Time Courses of Concentration and Effect

100
100
80

tl 60
80 Q)

iii Phase
\Concentration ~ 40

1 3
60 .. 20

.. Phase 3
0
1o-• 10-1 100 10' 102
% Concentration
40

Phase 2
20

0 2 4 6 8 10 12
Time (h)

Source: Adapted with modification from Rowland, Tozer 1995.

Note: The decline in effect Intensity (bold line) in relation to the decline in plasma concentration (dotted line) is based on the model introduced in Figure
9-4. The insert depicts the corresponding concentration-effect relationship by an fmax model with fC50 =1 (arbitrary concentration unit). The phases
correspond to the relationship between the drug concentration and fC50 (see text for details).
 Pharmacology

the concentration. This phase is characterized by
a shallow relationship between concentration
and effect, and drug concentration appears to
have little influence on drug effect.
Ill In phase 2, when concentrations are in a similar
range to that of EC50 , the effect intensity declines
approximately linearly with time despite an
exponential decay in concentration; that is, drug
effect disappears in this phase with a zero-order
rate constant.
!lll In phase 1, when the concentrations are much
lower than EC50 , the effect is approximately
directly proportional to the concentration; that
is, it follows an exponential decline.
According to this model, the relationship between EC50
more potent drug (EC50 = 0.2 mg/L), effect intensity
diminishes rapidly, within a few hours, after dosing
for the less potent drug (EC50 = 20 mg/L) and would
require multiple additional daily doses to maintain an
efficacy level similar to that of the more potent drug.
As illustrated in the example, the relationship
between pharmacodynamic parameters (i.e., EC50 as
measure of potency) and pharmacokinetic parameters
(i.e., clearance and volume as determinants of initial
concentration Co and elimination half-life) determines
which doses or dosing regimens are required for ther-
apeutic efficacy.
g..4a Drug-Target Interactions
t.:-:£~::::::;::~,-;-{~;s:;.;z-;..ib s"t:.: :,:,_~ .-,

and drug concentration determines the effect-time pro-

When drugs interact with their molecular targets, the
file after a dose. Figure 9-6 shows concentration-
resulting drug-target binding can be reversible or
time and effect-time profiles for an intravenous bolus
irreversible:
dose of the same amount of two hypothetical drugs
with identical pharmacokinetic properties but differ- Reversible drug-target interaction is mediated by
ent potency. Although the dose is sufficient to main- ionic bonding, hydrogen bonding, or hydrophobic
tain nearly maximal drug effect for 24 hours for the interaction.

9·6. Concentration-Time and Effect-Time Profiles for an Intravenous Bolus of Two Drugs
lUU
a lUU
90
~ 80 80

.sc: 60 - 60
70

0
~ ~50
c
Q)
40 t1/2 4 h w 40
(.)
c: C0 100 mg/L 30
8 20 EC50 20 mg/L 20
EC5o Ratio C0 /EC50 5 10
0 0
0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48
Time(h) Time(h)

100 b 100
90
:J' 80 80
0,
.sc: 60 - 60
70

0
" 50
~ 4h
t1/2 ~
40 w 40
Q) C0 100 mg/L
(.)
c: 30
EC50 0.2 mg/L
8 20 20
Ratio C0 /EC50 500 10
EC5o
0
6 12 18 24 30 36 42 48 0 6 12 18 24 30 36 42 48
Tlme(h) Tlme(h)

Source: Author's representation.

Note: The figure shows the effect of EC50 relative to the plasma concentrations achieved in a dosing interval. If the ratio of C0 to EC50 Is relatively low (panel
a), the effect intensity can be maintained only for a short period of time at therapeutically effective levels as drug concentrations rapidly fall below EC50
because of typical first-order elimination. If the ratio of C0 to EC50 is relatively high (panel b), the effect intensity can be maintained for multiple elimination
half-lives above therapeutically effective levels despite the monoexponential decrease in drug plasma concentrations.
 The APhA Complete Review for the Foreign Pharmacy Graduate Equivalency Examination®
Irreversible drug-target interaction is mediated
by covalent bonding.
For reversible interaction with a molecular receptor,
binding of the ligand (drug) to the receptor occurs
when ligand and receptor collide with the proper ori-
entation and energy.
The binding process follows the law of mass action,
assuming that all receptors are equally accessible, no
partial binding occurs (receptors are either free of li-
gand or bound with ligand), and the ligand is not
altered by binding. The relationship can be described
as follows:
J
[drug + [receptor J kon >[drug e receptor
koff
where [drug], [receptor], and [drug e receptor] are the
concentrations of the free drug, the free receptor, and
the drug ., receptor complex. kon and koff are rate con-
stants for the association and dissociation process,
respectively.
The rate of association or number of binding
events per time is equal to
[ligand] X [receptor J X kon; [kon] = M-1 min-1
The rate of dissociation or number of dissociation
events per time is equal to
[ligand e receptor JX koff ; [ koff J= min- 1
Thus, the rates of association and dissociation depend
solely on the number of receptors, the concentration
of ligand, and the rate constants kon and koff·
At equilibrium, the rate of formation equals that
of dissociation:
[DR ]x koff = [D ]x[R ]x kon
_ koff _ [D]x[R]
Ko- koff- [DR]
The dissociation constant KD is an inverse measure
of receptor affinity. It is the drug concentration that
produces 50% of receptor occupancy.
Although EC50 is related to K0 , it is often not iden-
tical because KD solely characterizes the drug-receptor
interaction, whereas EC50 also represents the effi-
ciency of signal transduction pathways subsequent to
receptor interaction.
The drug-:target interaction can be time variant if,
for example, the potency or intrinsic activity of a drug
and its target structure are changing.
Functional tolerance development is a prime
example of a time-variant drug-target interaction.
Functional tolerance is characterized by a reduction
in effect intensity over time despite constant effect-
site concentration. This diminishing response with
rechallenging stimulus may be caused by
!03 A decrease in the number of receptors, called
receptor downregulation
1m A decrease in the signal transduction efficiency,
called receptor desensitization
J Functional tolerance results in a clockwise hysteresis
loop in the plot of effect intensity versus target-site
concentration.
Receptor downregulation entails internalization
or proteolytic degradation of receptors in response
to prolonged ligand-induced stimulation, result-
ing in a net loss of available receptors in the cell. In
this situation, intrinsic activity (Emax) of the drug
typically decreases while potency (EC 50 ) remains
unchanged.
Receptor desensitization entails loss of agonist sig-
nal transduction efficiency, for example, by the uncou-
pling of G-protein for G-protein-coupled receptors in
response to prolonged ligand-induced stimulation,
resulting in less efficient signal transduction by the
receptor. In this situation, intrinsic activity (Emax) of
the drug remains typically unchanged because the
receptor number remains unchanged, whereas ECso
increases because more receptot~ need to be stimu-
lated to produce the same drug response.
g.. s. Adverse Effects and
Side Effects of Drugs
Because any xenobiotic may interact not only with
the intended target structure (e.g., a receptor in spe-
cific tissues), but also with the same, similar, or
unrelated receptors or other target structures in
the same or other tissues, the intended or beneficial
effects of pharmacotherapy are usually also accompa-
nied by adverse drug reactions (ADRs). Investigation
of these potential off-target effects constitutes a major
effort during the drug development process.
ADRs are defined as any response to a drug that is
noxious and unintended and that occurs at doses used
in humans for prophylaxis, diagnosis, or treatment.

A type A ADR, also called a side effect, is a dose-
related, predictable reaction to a drug. Side effects
are expected on the basis of the pharmacologic activ-
ity of the drug, and depending on their severity, they
are accepted as occurring in a certain fraction of
treated individuals.
A type B ADR is a non-dose-related, unexpected
ADR, also called idiosyncratic reaction. Examples
for type B ADRs include allergic reactions as well as
carcinogenic and teratogenic effects.
Pharmacovigilance is a systematic approach to
collecting, monitoring, researching, assessing, and
evaluating ADR-related information from health care
providers and patients. The U.S. Food and Drug
Administration (FDA) has established a national ADR
reporting system, the MedWatch system.
The frequency and severity of type A ADRs is
directly related to a drug's therapeutic range and selec-
tivity (see Section 9-2). The more selective a drug is
with regard to its receptor interactions, the larger its
therapeutic range will be and the less likely is the
occurrence of type A ADRs.
The phosphodiesterase-S (PDE5) inhibitor sil-
denafil, for example, is approved for the treatment of
erectile dysfunction. Sildenafil has only limited selec-
tivity toward some other phosphodiesterase families,
particularly phosphodiesterase-6 (PDE6). PDE6 is
expressed only in the retina and is relevant for visual
transduction. Partial inhibition of PDE6 by therapeu-
tic sildenafil doses has been associated with the rela-
tively high frequency of visual disturbances under
sildenafil therapy. Tadalafil, another PDES inhibitor
with much higher selectivity for PDES than PDE6,
has a substantially lower frequency of visual side
effects than has sildenafil.
g.. &.. Drug Interactions with
Concomitant Drug, Food,
and Lab Tests
Dmg-Dmg Interactions
Drug-drug interactions can occur on the pharmaco-
kinet!c or the pharmacodynamic level, or on both
simultaneously.
Pharmacokinetic drug.:...drug interactions occur if a
drug interferes with the absorption, disposition, and
elimination of another drug. Most frequent sources of
pharmacokinetic drug-drug interactions are inhibi-
tion or induction of the activity of drug-metabolizing
Pharmacology
enzymes and drug transporters, such as the following
examples:
Ketoconazole is a strong inhibitor of the drug-
metabolizing enzyme cytochrome P450 (CYP)
3A4 and has the potential to substantially
increase the systemic exposure of drugs prima-
rily metabolized by CYP3A4, such as the
immunosuppressants cyclosporine or tacrolimus.
Rifampin is a strong inducer for the drug-
metabolizing enzymes CYP2D6 and CYP3A4
and results in reduced systemic exposure of
drugs that are predominantly metabolized by
these enzymes, such as tamoxifen.
Quinidine is a strong inhibitor of the drug efflux
transporter P-glycoprotein. Quinidine coadminis-
tration results in increased exposure to digoxin,
most likely through reduced renal elimination and
increased gastrointestinal uptake of digoxin.
The reader is referred to the constantly updated phar-
macokinetic drug-drug interaction database at Indiana
University (http://medicine.iupui.edu/clinpharm/ddis/)
for more examples and detailed information.
Although often cited in the pharmaceutical litera-
ture, pharmacokinetic drug-drug interactions based
on protein binding-site displacement have for most
drugs only limited or no clinical relevance.
Pharmacodynamic drug-drug interactions can
occur on the levels of the receptor or the organ or
functional system. Pharmacodynamic interactions
on the molecular level occur when drugs interact
with the same receptor system:
f!li Competitive interaction of twb agonists for a
receptor will enhance the response by resulting
in more occupied, activated receptors.
Competitive interaction of an agonist and an
antagonist will reduce the response as antagonist
molecules compete with agonist molecules for
the same binding sites. Competitive antagonism
can be overcome by increasing the agonist
concentration.
Noncompetitive interaction of an agonist and an
antagonist will reduce the response as the antag-
onist interacts with an allosteric binding site that
reduces the affinity of the agonist for the recep-
tor or reduces signal transduction efficiency.
Noncompetitive antagonism cannot be over-
come by increasing the agonist concentration.
For example, naloxone is a r-opioid receptor com-
petitive antagonist and antagonizes the effect of the
r-opioid receptor-ligand morphine. Buprenorphine
is a partial agonist for the r-opioid receptor.
 The APhA Complete Review tor the Foreign Pharmacy Graduate Equivalency Examination®
Buprenorphine acts as a competitive antagonist for
morphine if coadministered because it competes with
morphine for J.I-opioid receptors and has a lower IA
than morphine.
Pharmacodynamic drug-drug interactions occur
on the organ or system level if two drugs do not inter-
act with the same molecular structure but enhance or
diminish each other's effect through different molecu-
lar pathways that affect the same response system. For
example, the potentiating effect of coadministration of
aspirin (acetylsalicylic acid) and warfarin is likely the
consequence of an inhibition of blood coagulation by
two separate pathways.
Drug-Food Interactions
Mechanisms of drug-food interactions include
Delayed gastric emptying
Solubilization of drug by food and digestive fluids
Complexation of drug with food components
Alterations in hepatic blood flow and modula-
tion of drug-metabolizing enzymes or drug
transporters by constituents of food
Alterations of intestinal drug-metabolizing
enzyme and drug transporter activity
Clinically, most important drug-food interactions
are interactions with drug-metabolizing enzymes and
drug transporters. Some examples follow:
i!\l The grapefruit juice ingredient bergamottin and
other furanocoumarins have been identified as
strong inhibitors of intestinal CYP3A4. ADRs
have been reported for coadministration of
grapefruit juice and calcium channel blockers
(felodipine, nisoldipine, nicardipine, nimodipine:
hypotension, tachycardia); statins (simvastatin,
lovastatin, atorvastatin: rhabdomyolysis, acute
renal failure); and cyclosporine (nephrotoxicity,
hypertension, cerebral toxicity).
The food supplement St. John's wort has been
identified as a strong inducer for CYP3A4 and
P-glycoprotein. Because HIV-1 protease
inhibitors such as indinavir are cosubstrates for
both, St. John's wort coadministration has been
reported to result in reduced protease inhibitor
systemic exposure, resulting in antiretroviral
therapy failure.
Drug-lab Test Interactions
In vivo interferences between drugs and lab tests occur
if the drug changes the analyte concentration or activ-
ity prior to analysis. In vitro interferences occur if drug
molecules present in body fluids or tissue specimens
undergoing clinical diagnostic procedures affect the
results of the lab test by interfering with the chemical
or physicochemical process used to detect and quan-
tify the specific analyte.
For example, digoxin levels are frequently deter-
mined by fluorescence polarization immunoassays.
Many drugs with similar, steroid-like chemical
structures have been reported to cross-react with this
test, such as estrogen derivatives, corticosteroids,
and spironolactone.
g.. 7. Drug Discovery
and Development
~~JL).,-;~~-~1"C!~--~::·,_ "'"'"
The approval and marketing of drugs in the United
States is regulated by the Federal Food, Drug, and
Cosmetic Act of 1938 and its amendments, particularly
the Kefauver-Barris amendments of 1962, which
established requirements for drugs to be efficacious
and safe. The act gives FDA the dual missions of
f!li Protecting the public health by ensuring the safety,
efficacy, and security of human and veterinary
drugs, biological products, medical devices, foods,
cosmetics, and products that emit radiation
flil Advancing the public health by helping to speed
innovations that make medicines and foods
more effective, safer, and more affordable and
by helping the public get the accurate,
/
science-
based information it needs to1use medicines and
foods to improve health
The Federal Food, Drug, and Cosmetic Act provides
FDA with authority to regulate development, manu-
facturing, use, and marketing of drugs and medical
devices to ensure their safety and efficacy:
1m Permission for marketing a drug in the United
States requires prior submission and approval
of a new drug application (NDA) to FDA.
fEl Generic versions of a brand-name drug can be
approved by a process with reduced require-
ments. In such cases, an abbreviated new drug
application (ANDA) is submitted. At the core of
an ANDA is the requirement to show bioequiva-
lence between an approved reference drug and
the generic version of the drug.
!i!l The first use in humans of a drug that is a new
molecular entity or a biologic requires submission
of an investigational new drug (IND) application.

Drug Discovery and Preclinical Development
The drug discovery process is aimed at identifying a
lead compound and ideally several backup compounds
that target a specific biochemical pathway or receptor
that interferes with pathogenesis, disease progression,
or the symptoms of a disease. The process usually
entails understanding the molecular mechanism of the
disease, selecting a target, designing compounds that
interact with the target in the desired fashion (hits), and
then optimizing the initial hits to obtain leads for fur-
ther development.
Enabling techniques in this process include high-
throughput screening, combinatorial chemistry, quan-
titative structure-activity relationships, structure-based
design, and computer-based molecular modeling.
Preclinical drug development entails the evalua-
tion and optimization of chemical leads in in vitro
assays and in vivo animal models with regard to effi-
cacy and safety.
In vitro studies frequently include cell-line-based
assays as well as cell-free systems (for example, iso-
lated receptor systems). These studies are usually
aimed at identifying the mechanism of action of a
drug and assessing its potential for off-target effects,
such as interaction with pharmacologic targets or
mechanisms other than the one required to elicit the
desired effect.
In vivo preclinical studies in animal species are
aimed at
fill Establishing drug efficacy in animal models of
the targeted disease
llf5 Establishing pharmacokinetic and pharmaco-
dynamic relationships, including oral bioavailabil-
ity, penetration into different organs and tissues,
and the dose-concentration effect relationships
Tested species usually include rodent (rat, mouse, rab-
bit) and nonrodent species (dog, pig, monkey), includ-
ing nonhuman primates.
Drug manufacturing and formulation development
efforts at this stage of development are aimed at scal-
ing up drug substance and drug product manufactur-
ing for producing materials for further preclinical
testing, especially toxicology, as well as for clinical
testing. Manufacturing of pharmaceutical products
for clinical testing and use must be conducted under
current Good Manufacturing Practice guidelines that
have been established by FDA.
Toxicology studies performed during preclinical
development include acute toxicity, multidose (long-
term) toxicity, reproductive toxicity, mutagenicity, and
carcinogenicity. Acute and repeat-dose toxicology
Pharmacology
studies have to be performed in at least two species, one
of which has to be a nonrodent species.
All studies submitted to FDA for regulatory deci-
sions (e.g., IND, NDA decisions) have to be performed
under good laboratory practice conditions.
Animal scale-up is used to extrapolate results from
preclinical development to humans, thereby defining
the first-in-humans dose to be used initially in human
studies. Allometric approaches are frequently used to
scale pharmacokinetic and pharmacodynamic prop-
erties across animal species and humans.
PreclinicaHo~Ciinical Transition
Before a new drug can be studied in humans, an IND
application needs to be filed with FDA. The IND appli-
cation is intended to ensure that the product is reason-
ably safe for initial use in humans. The application
must contain information in three broad areas:
Animal pharmacology and toxicology studies. It
must include preclinical data to permit an assess-
ment about whether the product is reasonably
safe for initial testing in humans.
Manufacturing information. It must include
information pertaining to the composition, manu-
facturer, stability, and controls used for manufac-
turing the drug substance and the drug product.
Clinical protocols and investigator information.
It must include detailed protocols for proposed
clinical studies to assess whether the initial phase
trials will expose subjects to unnecessary risks.
FDA has 30 days to object to ,fin IND after it has
been filed.
Research in human subjects is regulated by fed-
eral laws, and each investigational study in humans
requires approval by an institutional review board
that ensures adequate protection of the human sub-
jects involved and ethical considerations in their use
for research purposes. Written informed consent has
to be obtained from all research subjects before enroll-
ment in clinical studies.
Clinical Drug Development
Clinical drug development usually comprises four
major phases:
Phase I studies usually comprise small numbers
of healthy subjects (< 100). Phase I studies are
intended solely to establish the tolerability and
safety of a new drug product. Secondary aims
include characterizing the pharmacokinetics in
 The APhA Complete Review for the Foreign Pharmacy Graduate Equivalency Examination®
humans. Efficacy is not an objective in phase I
studies. For drugs that have inherent toxicity,
such as cytotoxic anticancer medications,
phase I studies are performed in patients with
the targeted disease instead of healthy individ-
uals. Nevertheless, establishing tolerability and
safety remain the primary objectives in these
studies.
til Phase II studies are performed in patients with
the illness to be treated and usually comprise
between 24 and 300 subjects. Early phase II
(phase Ila} studies are proof-of-concept studies
that are intended to show that the hypothesized
therapeutic concept is working in vivo in
humans. Late-stage phase II (phase lib) studies
are focused on identifying the appropriate
patient populations in which the drug works
best and determining appropriate dosing regi-
mens for subsequent large-scale trials.
Phase III studies are conducted to confirm the
efficacy and safety of a new drug in a larger
patient population (250-1,000 or more patients}
and to detect and evaluate adverse drug events
that may be encountered during subsequent clin-
ical use. For submission of an NDA, the efficacy
and safety results of the phase III program usu-
ally need to be replicated with the same dosing
regimen in two independent, double-blind, ran-
domized, placebo-controlled clinical trials (piv-
otal trials). Depending on the indication, placebo
control might need to be replaced by the current
standard of care for ethical reasons.
Phase IV studies, or so-called postmarketing
studies, are conducted after drug approval to
further refine the use of the drug in different
patient populations, different indications, or
different formulations.
Although the traditional four phases are helpful in
broadly defining a clinical drug development pro-
gram, the use of these phases in strict chronological
order is misleading. Nowadays, drug development is
widely accepted as an iterative knowledge-building
process with learning phases in which information
about the drug's properties and effects are collected
and in which the previously established and inte-
grated knowledge and the derived hypotheses are
confirmed.
Pharmacovigilance and risk mitigation strategies
are growing efforts in postmarketing drug develop-
ment that are intended to identify new information
about side effects and adverse events associated with
medicines and to prevent harm to patients.
g.. a. Key Points
n:~~!<,':E~c::::.:,.~;_n:yc;~-~s~-~,-. ;:_ ~
Most drugs exert their effects by interacting with
molecular targets such as receptors, enzymes,
transporters, ion channels, and nucleic acids.
!¥:l The four major classes of receptors for drugs are
receptor-operated channels, receptor-operated
enzymes, G-protein-coupled receptors, and
DNA-linked receptors.
Ell Receptor theory is the underlying principle for
drug-receptor interactions. Drug-receptor inter-
actions entail the consecutive processes of bind-
ing, recognition, and signal transduction.
M Ligands, for receptors can be differentiated into
full agonists, partial agonists, antagonists, and
inverse agonists.
1:2 The rational use of drugs and the design of effec-
tive dosage regimens are determined by the two
pharmacological subdisciplines pharmacokinet-
ics and pharmacodynamics.
"" Selectivity of a drug toward the desired thera-
peutic effect rather than undesired side effects
largely determines a drug's therapeutic range
and benefit-to-risk ratio.
1'1?!1 The concentration-effect relationship of a drug
can be characterized by pharmacodynamic mod-
els such as the Emax model, which can be related
to receptor theory. The parameters Emax and
EC50 characterize the intrinsic activity and the
potency of the drug, respectively.
Integrated pharmacokinetic-pharmacodynamic
relationships allow the description of the contin-
uous profile of drug effect intensity over time in
response to a given dose or dosing regimen.
fhll Functional tolerance is the consequence of time-
dependent drug-target interactions such as recep-
tor desensitization or receptor downregulation.
I'K! Adverse drug reactions can be differentiated into
type A (dose-dependent, predictable ADRs) and
type B (non-dose-related, unpredictable ADRs).
The frequency and severity of type A ADRs is
directly related to a drug's therapeutic range and
selectivity.
f£1 Drug-drug interactions can originate from inter-
actions in pharmacokinetic as well as pharmaco-
dynamic processes. Inhibition or induction of
drug-metabolizing enzymes and drug trans-
porters are the most important pharmacokinetic
drug-drug interactions.
E2l Pharmacodynamic drug-drug interaction can
occur on the molecular level as well as on the
organ or system level.

Drug-food interactions are largely pharmaco-
kinetic interactions.
11 FDA has the authority to regulate development,
manufacturing, use, and marketing of drugs
and medical devices to ensure their safety and
efficacy.
Preclinical drug development is aimed at the
evaluation and optimization of new chemical
entities and biologics in in vitro and in vivo
animal models with regard to efficacy and
safety and at providing sufficient data for an
IND filing.
Studies in human subjects can be pursued only
after an IND filing with FDA and review by an
institutional review board to protect the health
of the involved study subjects.
I! Clinical drug development can be differentiated
in phase I, II, and III studies and is intended to
establish efficacy and safety in the intended
indication in humans.
I! Clinical research on a drug is continued after
approval of an NDA by phase IV postmarketing
studies.
g.. g. Questions
1. Which statement is correct regarding an
antagonist in a system without spare recep-
tors that is stimulated by an agonist?
A. The effect of an irreversible antagonist
can be overcome by increasing the agonist
concentration.
B. The effect of a competitive antagonist is
independent of the agonist concentration.
C. The effect of a noncompetitive antagonist
can be overcome by increasing the agonist
concentration.
D. The effect of a competitive antagonist can
be overcome by increasing the agonist
concentration.
2. Drug A is a full agonist for a specific receptor
system; drug B is a competitive antagonist for
the same receptor system. If increasing doses
of drug B are coadministered with drug A,
drug B will
A. increase the apparent Emax of drug A.
B. reduce the apparent Emax of drug A.
C. increase the apparent EC50 of drug A.
D. reduce the apparent EC50 of drug A.
Pharmacology
3. Which statement is correct for a receptor sys-
tem that exhibits a receptor reserve of 90%?
A. Partial agonists are not able to achieve
maximum cellular response.
B. Only 10% of the available receptors need
to be occupied by a full agonist to achieve
maximum cellular response.
C. More than 99% of the receptors need to
be occupied by a competitive antagonist
to have an effect on the dose-response
relationship of a full agonist.
D. Only the 90% in the receptor reserve is
available for interaction with competitive
antagonists.
E. The inhibitory effect of a noncompetitive
(allosteric) inhibitor can always be over-
come by increasing the dose of a full
agonist.
4. EC50 is a measure of
A. the intrinsic activity of a drug.
B. the lipophilicity of a drug.
C. the efficacy of a drug.
D. the potency of a drug.
E. the dissociation rate of a drug-receptor
complex.
5. Which of the following can act as an antago-
nist for a full agonist?
A. Inverse agonist
B. Partial agonist
C. Less potent agonist
6. An inverse agonist produces what kind of
response on its receptor system?
A. Reduction in the number of spare receptors
B. Increase in binding affinity for full agonists
C. Reversal of the effect of irreversible
antagonists
D. Reduction in basal receptor activation
7. Isosorbide dinitrate (ISDN) is used for the treat-
ment of coronary heart disease. Its major effect
is vasodilation of coronary arteries. ISDN is
known to exhibit functional tolerance. Which
of the following will be observed if three doses
of ISDN are administered every 8 hours?
A. The bioavailability of the third dose will be
substantially less than the bioavailability
of the first dose.
 The APhA Complete Review tor the Foreign Pharmacy Graduate Equivalency Examination®
B. The maximum plasma concentration Cmax
for ISDN will be smaller after the third
dose than after the first dose.
C. An ISDN plasma concentration of 10 ng/mL
obtained after administration of the third
dose results in a higher degree of vasodila-
tion than the same concentration after
administration of the first dose.
D. There is no difference in vasodilation and
ISDN plasma concentration between the
first and the third doses.
E. The degree of vasodilation is smaller after
the third dose than after the first dose.
8. For a drug that follows linear pharmacokinet-
ics (i.e., first-order elimination) and exhibits a
concentration-effect relationship character-
ized by a simple Emax model, the decline in
effect intensity over time after intravenous
bolus administration within the range of
20-80% of Emax will be
A. linear.
B. monoexponential.
C. biexponential.
D. cubic.
E. no different.
9. An ACE inhibitor has a short elimination
half-life of 3 hours and a wide therapeutic
range. Why can it be administered once daily
and still achieve therapeutic efficacy despite
its short elimination half-life?
A. The therapeutic efficacy of ACE inhibitors
is independent of the administered dose
and resulting drug concentration.
B. After five elimination half-lives (15 hours),
more than 90% of the administered drug
has been eliminated, and the drug will not
be effective any more. Hence, FDA made a
mistake in approving this dosing regimen.
C. Elimination half-life is irrelevant for
designing dosing regimens.
D. Because of the wide therapeutic range, the
daily dose can be so high that even at the
end of the 24-hour dosing interval, drug
concentrations are still above the EC50 to
maintain therapeutic efficacy.
E. Despite the short elimination half-life, the
drug is still effective after 24 hours because
only volume of distribution determines
drug concentrations so late after drug
administration.
10. Which of the following statements regarding
the concept of the therapeutic range is correct?
A. Drug plasma concentrations below the
lower limit of the therapeutic range are
ineffective in all treated patients.
B. If drug plasma concentrations are main-
tained within the therapeutic range, the
drug's desired therapeutic effect is
achieved in all treated patients.
C. The therapeutic range defines a range of
drug plasma concentration with high prob-
ability of desired clinical efficacy and low
probability of unacceptable toxicity.
D. If drug plasma concentrations always
remain below the upper limit of the thera-
peutic range, none of the treated patients
will experience drug-related toxicity.
11. Assume a class of drug substances with the
same pharmacokinetic characteristics and the
same mechanism of action but different EC50
values. To achieve the same therapeutic effect,
drugs with a higher EC50 need to be adminis-
tered at dose rate than drugs with
a lower ECso·
A. a higher
B. the same
C. a lower
12. In the United States, first-in-humans studies
can be initiated after
I. FDA has approved a res,pective NDA.
II. research subjects have teceived financial
compensation.
III. FDA has not objected to an IND filing.
IV. subjects have given written informed
consent.
V. studies have been approved by an institu-
tional review board.
A. Onlyl
B. I, II, and V
C. I and IV
D. III, IV, and V
13. Phase I studies in drug development are
usually performed
A. in healthy subjects.
B. in patients with the targeted disease.
C. in special populations such as elderly
patients or pediatric patients.
D. in patients who have been cured from the
targeted disease.
14. The primary objective of phase III studies is to
A. assess the pharmacokinetics of the drug in
healthy individuals.
B. determine the physicochemical stability of
the dosage form.
C. determine the pharmacoeconomic benefit
of a novel drug therapy.
D. determine the efficacy and safety of a novel
drug therapy.
E. explore the mechanism of action of a novel
therapy.
15. Pharmacovigilance is an approach
A. to increasing drug safety in the post-
marketing phase.
B. to preventing theft in the pharmacy.
C. to increasing drug efficacy by switching
nonresponders to different therapies.
D. to preventing the use of drugs after their
expiration date.
16. Why is selectivity of a drug an important
concept to minimize adverse drug reactions?
A. Selectivity determines the fraction of
patients who are nonresponders.
B. Selectivity determines in which organ a
drug accumulates.
C. Selectivity determines the extent of a drug's
interaction with off-target receptors.
17. Two concurrently administered drugs are
metabolized by the same hepatic enzyme sys-
tem, CYP2D6. What conclusions should the
pharmacist draw?
A. There will certainly be a drug-drug inter-
action because both drugs use the same
enzyme system.
B. There is the potential for a drug-drug
interaction, but it may not necessarily
occur, depending on the doses of the drugs
used and their affinities to CYP2D6.
C. There will certainly be no drug-drug inter-
actions because CYP2D6 is polymorphi-
cally expressed.
18. The drug-food interaction with grapefruit juice
A. is limited to intravenously administered
drugs that are substrates for CYP3A.
B. is limited to orally administered drugs that
are substrates for CYP3A.
C. affects all drugs that are substrates for
CYP3A.
19. Indicate the incorrect answer: The acceptance
of a specific benefit-to-risk ratio
A. depends on the treated disease.
B. depends on the dose level of the drug.
C. depends on the shelf life of the drug.
D. depends on the treated patient
population.
E. depends on the frequency and severity of
adverse drug reactions.
20. A clockwise hysteresis loop in the plot of
effect versus concentration indicates
A. an Emax relationship.
B. a development of functional tolerance.
C. an irreversible binding of the drug to the
receptor.
9..10. Answers
1. D. Competitive antagonism can be overcome
by increasing agonist concentrations.
2. C. Antagonists increase the apparent EC50 of a
drug by shifting the effect versus concentration
curve to the right.
3. B. In a system with spare receptors or receptor
reserve, only a fraction of available receptors
needs to be stimulated to achieve
I
the maximum
pharmacologic response. /
4. D. The concentration at half maximum effect,
ECso, is a measure of drug potency. The more
potent a drug is, the smaller is EC50 •
5. B. A partial agonist can act as an antagonist for
a full agonist because it occupies the receptors
but has a reduced intrinsic activity.
6. D. Inverse agonists decrease the basal activa-
tion level of a receptor by stabilizing its inactive
form.
7. E. Functional tolerance is characterized by a
decreasing response to a repeated stimulus.
8. A. In the range of 20-80% of Emax, the effect is
proportional to the logarithm of the concentra-
tion. As concentration decreases monoexpo-
nentially, effect intensity decreases linearly.
9. D. Initial concentrations multiple times higher
than the EC50 ensure therapeutically efficacious
concentrations throughout the dosing interval
despite the short half-life.
 The APhA Complete Review tor the Foreign Pharmacy Graduate Equivalency Examination®
10. C. The therapeutic range is a concentration
range with high probability for efficacy and
low probability for toxicity.
11. A. Drugs with a higher EC50 are less potent and
need higher drug concentrations to achieve the
same therapeutic effect.
12. D. First-in-human dosing requires an IND filing
with FDA that FDA is not objecting to, as well as
approval of the study protocol by an institutional
review board and written informed consent by
the participating subjects.
13. A. Phase I studies establish the safety and tol-
erability of a new drug in healthy subjects.
14. D. Phase III study programs are aimed at deter-
mining the efficacy and safety of a new drug
therapy.
15. A. Pharmacovigilance is a systematic approach
to collecting, monitoring, researching, assess-
ing, and evaluating ADR-related information
from health care providers and patients.
16. C. Selectivity is directly related to the frequency
and severity of adverse drug reactions.
17. B. The fact that two drugs are metabolized by
the same enzyme system indicates only that the
potential exists for a drug-drug interaction.
18. B. Grapefruit juice inhibits intestinal CYP3A
activity only.
19. C. The benefit-to-risk ratio balances the poten-
tial harm and the potential desired therapeutic
outcome of a drug therapy.
20. A. Hysteresis loops in the concentration-
. effect relationship are indicative of time-variant
changes in the pharmacodynamic parameters.
A clockwise loop is produced by tolerance
development.
I
.J
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