Drug-Receptor

Interactions and
Pharmacodynamics
Joanna Peris

I. OVERVIEW
D Unoccupied receptor does not
lnfluenceintri!UIIular proc-s.

Pharmacodynamics describes the actions of a drug on the body. Most

drugs exert effects, both beneficial and harmful, by interacting with spe-
cialized target macromolecules called receptors, which are present on or
in the cell. The drug-receptor complex initiates alterations in biochemical
and/or molecular activity of a cell by a process called signal transduction
(Figure 2.1 ).
Receptor with bound 11gonist is

II. SIGNAL TRANSDUCTION

EJ acdvllted. It hu altered physical
and chemical properties, which
leads ta Interaction with cellular
molecules to c:au• a biologic
response.
Drugs act as signals, and receptors act as signal detectors. A drug is
termed an "agonisf' if it binds to a site on a receptor protein and activates
it to initiate a series of reactions that ultimately result in a specific intracel-
~D~

@
lular response. "Second messenger'' or effector molecules are part of the
cascade of events that translates agonist binding into a cellular response.

A. The drug-receptor complex

Cells have many different types of receptors, each of which is specific
for a particular agonist and produces a unique response. Cardiac cell 0 t
membranes, for example, contain p-adrenergic receptors that bind
and respond to epinephrine or norepinephrine. Cardiac cells also ~ ~~ Biologic

~~
contain muscarinic receptors that bind and respond to acetylcholine. respon•
These two receptor populations dynamically interact to control the
heart's vital functions. Signal
transduction
The magnitude of the cellular response is proportional to the num-
ber of drug-receptor complexes. This concept is conceptually similar
Figure 2.1
to the formation of complexes between enzyme and substrate and The recognition of a drug by a receptor
shares many common features, such as specificity of the receptor for triggers a biologic response.
a given agonist. Although much of this chapter centers on the inter-
action of drugs with specific receptors, it is important to know that
not all drugs exert effects by interacting with a receptor. Antacids, for
instance, chemically neutralize excess gastric acid, thereby reducing
stomach upset.

23
24 2. Drug-Receptor Interactions and Pharmacodynamics

B. Receptor states
Receptors exist in at least two states, inactive (R) and active (R*),
that are in reversible equilibrium with one another, usually favoring the
inactive state. Binding of agonists causes the equilibrium to shift from
R to R* to produce a biologic effect. Antagonists are drugs that bind to
the receptor but do not increase the fraction of R*, instead stabilizing
the fraction of R. Some drugs (partial agonists) shift the equilibrium
from R to R*, but the fraction of R* is less than that caused by an
agonist. The magnitude of biological effect is directly related to the
fraction of R*. In summary, agonists, antagonists, and partial agonists
are examples of molecules or ligands that bind to the activation site
on the receptor and can affect the fraction of R*.

C. Major receptor families

A receptor is defined as any biologic molecule to which a drug binds
and produces a measurable response. Thus, enzymes, nucleic acids,
and structural proteins can act as receptors for drugs or endogenous
agonists. However, the richest sources of receptors are membrane-
bound proteins that transduce extracellular signals into intracel-
lular responses. These receptors may be divided into four families:
1) ligand-gated ion channels, 2) G protein-coupled receptors, 3)
enzyme-linked receptors, and 4) intracellular receptors (Figure 2.2).
Generally, hydrophilic ligands interact with receptors that are found on
the cell surface (Figure 2.2A, B, C). In contrast, hydrophobic ligands
enter cells through the lipid bilayers of the cell membrane to interact
with receptors found inside cells (Figure 2.20).

f t Ligand-gated ion r.tl G protein-coupled IP!I Enzyme-linked ~ Intracellular

W channels 1.:11 receptors .:I receptors 1:.1 receptors
Example: Example: Example: Example:
Cholinergic nicotinic a and IS adrenoceptors Insulin receptors Steroid receptors
receptors

~
Changes In membrane Protein phosphorJiatlon Protein phosphorylation
potential or lonk
concentration within cell
h and altered
~ gene expression

INTRACELLULAR EFFECTS

Figure 2.2
Transmembrane signaling mechanisms. A. Ligand binds to the extracellular domain of a ligand-gated channel. B. Ligand
binds to a domain of a transmembrane receptor, which is coupled to a G protein. C. Ligand binds to the extracellular
domain of a receptor that activates a kinase enzyme. D. Lipid-soluble ligand diffuses across the membrane to interact with
its intracellular receptor. R = inactive protein.
II. Signal Transduction 25

1. Transmembrane ligand-gated ion channels: The extracellular

portion of ligand-gated ion channels contains the drug-binding site.
This site regulates the opening of the pore through which ions can
0
Extra-
Unoccupied receptor does
not Interact with G. prohlln.

flow across cell membranes (Figure 2.2A). The channel is usually cellular /? 0 Hormone or neuro-
space (..( tr.nsmltter
closed until the receptor is activated by an agonist, which opens
the channel for a few milliseconds. Depending on the ion con-
ducted through these channels, these receptors mediate diverse
functions, including neurotransmission and muscle contraction.
For example, stimulation of the nicotinic receptor by acetylcho-
line opens a channel that allows sodium influx and potassium
outflux across the cell membranes of neurons or muscle cells.
This change in ionic concentrations across the membrane gener-
ates an action potential in a neuron and contraction in skeletal Occupied receptor changes
and cardiac muscle. On the other hand, agonist stimulation of the
A subtype of the y-aminobutyric acid (GABA) receptor increases
EJ shape and Interacts with
G. proUiln. G. protein rel-s
GDP and binds GYP.
chloride influx, resulting in hyperpolarization of neurons and less
chance of generating an action potential. Drug-binding sites are
also found on many voltage-gated ion channels where they can
regulate channel function. For example, local anesthetics bind to
the voltage-gated sodium channel, inhibiting sodium influx and
decreasing neuronal conduction.

2. Transmembrane G protein-coupled receptors: The extracel-

lular portion of this receptor contains the ligand-binding site, and GYP GDP
the intracellular portion interacts (when activated) with a G protein.
There are many kinds of G proteins (for example, G., G1, and Gq),
but all types are composed of three protein subunits. The a subunit 0 a Subunit of G.. protaln
dlssoclatu and actlvatu
adenylyl cyclase.
binds guanosine triphosphate (GTP), and the ~ and y subunits
anchor the G protein in the cell membrane (Figure 2.3). Binding of
an agonist to the receptor increases GTP binding to the a subunit,
causing dissociation of the a-GTP complex from the Itt complex.
The a and Itt subunits are then free to interact with specific cellular
effectors, usually an enzyme or an ion channel, that cause further
actions within the cell. These responses usually last several sec-
onds to minutes. Often, the activated effectors produce "second
messenger" molecules that further activate other effectors in the
cell, causing a signal cascade effect.
. . When hormone Is no longar
A common effector, activated by G. and inhibited by G1, is ade- li.ll pnsant,. the recaptor reverts
nylyl cyclase, which produces the second messenger cyclic to Its rutlng state. GYP on the
a subunit Is hydrolyzed to GDP.
adenosine monophosphate (cAMP). The effector phospholipase and adenylyl cyclase Is dHCtlvlltad.
C, when activated by Gq, generates two second messengers:
inositol1 ,4,5-trisphosphate (IP3 ) and diacylglycerol (DAG). DAG
and cAMP activate specific protein kinases within the cell, lead-
ing to a myriad of physiological effects. IP3 increases intracel-
lular calcium concentration, which in turn activates other protein
kinases.
Inactive
3. Enzyme-linked receptors: This family of receptors undergoes adenylyl
cyclase
conformational changes when activated by a ligand, resulting in

Figure2.3
The recognition of chemical signals by
G protein-coupled membrane receptors
affects the activity of adenylyl cyclase.
PP1 = inorganic pyrophosphate.
26 2. Drug-Receptor Interactions and Pharmacodynamics

increased intracellular enzyme activity (Figure 2.4). This response

lasts for minutes to hours. The most common enzyme-linked
receptors (for example, growth factors and insulin) possess tyro-
Insulin sine kinase activity. When activated, the receptor phosphorylates
receptor tyrosine residues on itself and other specific proteins (Figure 2.4).
(inactive) Phosphorylation can substantially modify the structure of the tar-
get protein, thereby acting as a molecular switch. For example,
the phosphorylated insulin receptor in turn phosphorylates other
proteins that now become active. Thus, enzyme-linked receptors
often cause a signal cascade effect like that caused by G protein-
- Insulin
coupled receptors.

4. Intracellular receptors: The fourth family of receptors differs

0 Insulin binding activates receptor
tyrosine kinase activity in the
intracellular domain of the 13
considerably from the other three in that the receptor is entirely
intracellular, and, therefore, the ligand (for example, steroid hor-
subunit of the insulin receptor.
mones) must have sufficient lipid solubility to diffuse into the cell
to interact with the receptor (Figure 2.5). The primary targets
of activated intracellular receptors are transcription factors in
Insulin the cell nucleus that regulate gene expression. The activation
receptor
(active) or inactivation of transcription factors alters the transcription of
DNA into RNA and subsequently translation of RNA into pro-
teins. The effect of drugs or endogenous ligands that activate
intracellular receptors takes hours to days to occur. Other targets
of intracellular ligands are structural proteins, enzymes, RNA,
and ribosomes. For example, tubulin is the target of antineo-
plastic agents such as paclitaxel (see Chapter 35), the enzyme
dihydrofolate reductase is the target of antimicrobials such as
trimethoprim (see Chapter 31 ), and the 50S subunit of the bacte-
rial ribosome is the target of macrolide antibiotics such as eryth-
~ Tyrosine residues of
~ the 13 subunit are auto-
romycin (see Chapter 30).
phosphorylated.
D. Characteristics of signal transduction
11:111 Receptor tyrosine kinase Signal transduction has two important features: 1) the ability to amplify
1:.111 phosphorylates other small signals and 2) mechanisms to protect the cell from excessive
proteins, for example,
insulin receptor
stimulation.
substrates (IRSs).
1. Signal amplification: A characteristic of G protein-linked and
enzyme-linked receptors is the ability to amplify signal intensity
and duration via the signal cascade effect. Additionally, activated
G proteins persist for a longer duration than does the original ago-
nist-receptor complex. The binding of albuterol, for example, may
only exist for a few milliseconds, but the subsequent activated G
. , _ Phosphorylated IRSs promote proteins may last for hundreds of milliseconds. Further prolon-
laJII activation of other protein gation and amplification of the initial signal are mediated by the
kinases and phosphatases,
leading to biologic actions interaction between G proteins and their respective intracellular
of insulin. targets. Because of this amplification, only a fraction of the total
receptors for a specific ligand may need to be occupied to elicit a
maximal response. Systems that exhibit this behavior are said to
Biologic effects have spare receptors. About 99% of insulin receptors are "spare;•
of insulin providing an immense functional reserve that ensures that ade-
quate amounts of glucose enter the cell. On the other hand, only
Figure 2.4
Insulin receptor.
Ill. Dose-Response Relationships 27

about 5% to 10% of the total j3-adrenoceptors in the heart are

A lipid-soluble drug diffuses across
spare. Therefore, little functional reserve exists in the failing heart, the cell membrane and moves to the
because most receptors must be occupied to obtain maximum nucleus of the cell.
contractility.

2. Desensitization and down-regulation of receptors: Repeated

or continuous administration of an agonist or antagonist often
leads to changes in the responsiveness of the receptor. The
receptor may become desensitized due to too much agonist
stimulation (Figure 2.6), resulting in a diminished response. This
phenomenon, called tachyphylaxis, is often due to phosphoryla-
tion that renders receptors unresponsive to the agonist. In addi-
tion, receptors may be internalized within the cell, making them
unavailable for further agonist interaction (down-regulation).
Some receptors, particularly ion channels, require a finite time fol-
lowing stimulation before they can be activated again. During this
recovery phase, unresponsive receptors are said to be "refrac-
tory." Repeated exposure of a receptor to an antagonist, on the
other hand, results in up-regulation of receptors, in which recep-
tor reserves are inserted into the membrane, increasing the num-
ber of receptors available. Up-regulation of receptors can make
cells more sensitive to agonists and/or more resistant to effects
of the antagonist.

Ill. DOSE-RESPONSE RELATIONSHIPS

CYTOSOL

Agonist drugs mimic the action of the endogenous ligand for the receptor
(for example, isoproterenol mimics norepinephrine on f3 1 receptors of the
heart). The magnitude of the drug effect depends on receptor sensitivity
to the drug and the drug concentration at the receptor site, which, in turn,
is determined by both the dose of drug administered and by the drug's
pharmacokinetic profile, such as rate of absorption, distribution, metabo-
lism, and elimination.

A. Graded dose-response relationship

As the concentration of a drug increases, its pharmacologic effect
also gradually increases until all the receptors are occupied (the max- The drug-receptor
imum effect). Plotting the magnitude of response against increasing complex binds to
chromatin, activating
doses of a drug produces a graded dose-response curve that has the transcription
the general shape depicted in Figure 2.7A. Two important drug char- of specific genes. mRNA
1'---....:....___ __J ~
acteristics, potency and efficacy, can be determined by graded dose-
response curves. Specific proteins

1. Potency: Potency is a measure of the amount of drug necessary ~

Biologic effects
to produce an effect. The concentration of drug producing 50%
of the maximum effect (EC50 ) is often used to determine potency.
In Figure 2.7, the EC50 for Drugs A and 8 indicate that Drug A is
more potent than Drug 8, because a lesser amount of Drug A is Figure 2.5
needed to obtain 50% effect. Therapeutic preparations of drugs Mechanism of intracellular receptors.
mRNA = messenger RNA.
reflect their potency. For example, candesartan and irbesartan
28 2. Drug-Receptor Interactions and Pharmacodynamics

are angiotensin receptor blockers used to treat hypertension.

Repeated administration of an
agonist (such as epinephrine) The therapeutic dose range for candesartan is 4 to 32 mg, as
over a short time period compared to 75 to 300 mg for irbesartan. Therefore, candesartan
results in diminished response is more potent than irbesartan (it has a lower EC 50 value). Since
of the cell.
the range of drug concentrations that cause from 1% to 99% of
maximal response usually spans several orders of magnitude,
semilogarithmic plots are used to graph the complete range of
doses. As shown in Figure 2.78, the curves become sigmoidal in
shape, which simplifies the interpretation of the dose-response
curve.

2. Efficacy: Efficacy is the magnitude of response a drug causes

when it interacts with a receptor. Efficacy is dependent on the
number of drug-receptor complexes formed and the intrinsic
activity of the drug (its ability to activate the receptor and cause a
cellular response). Maximal efficacy of a drug (Emax) assumes that
the drug occupies all receptors, and no increase in response is
observed in response to higher concentrations of drug. The maxi-
mal response differs between full and partial agonists, even when
the drug occupies 100% of the receptors. Similarly, even though
Repeated injection of drug an antagonist occupies 100% of the receptor sites, no receptor
activation results and Emax is zero. Efficacy is a more clinically use-
Following a period of rest, ful characteristic than potency, since a drug with greater efficacy
administration ofthe drug
results in a response of the is more therapeutically beneficial than one that is more potent.
original magnitude. Figure 2.8 shows the response to drugs of differing potency and
efficacy.

Figure 2.6
Desensitization of receptors.

i 100
Ill :a:
"
ii
E
]
...E
0

"at
:I
c:
."fl
II.
0

The ECso is the concentration of the

drug that produces a response equal The potency of drugs can be compared
to 50% of the maximal response. using the ECso: the smaller the ECso, the
more potent the drug.

Figure 2.7
The effect of dose on the magnitude of pharmacologic response. Panel A is a linear plot. Panel B is a semilogarithmic plot
of the same data. EC50 = drug dose causing 50% of maximal response.
Ill. Dose-Response Relationships 29

B. Effect of drug concentration on receptor binding

Drug A is more DrugCshows
The quantitative relationship between drug concentration and recep- potent than Drug lower potency
tor occupancy applies the law of mass action to the kinetics of the B, but both show and lower
the same efficacy. efficacy than
binding of drug and receptor molecules: Drugs A and B.

Drug+ Receptor p Drug- receptor complex ~ Biologic effect

100
By making the assumption that the binding of one drug molecule

~
does not alter the binding of subsequent molecules and applying the
law of mass action, we can mathematically express the relationship
.!:! 50----- Drug A--~ Drug B
between the percentage {or fraction) of bound receptors and the drug g'
concentration: 15 - - - - - - iI - - - - - Drug C
iii I I
I !
[DR] [D] Log drug concentration
=---=~--.,. {1) 0
EC~
[R1 ] Kd+[D]
EC!o EC!o
for for for
where [D] = the concentration of free drug, [DR] = the concentration Drug A Drug B Drug C
of bound drug, [R1] =the total number of receptors, and ~ = the equi-
librium dissociation constant for the drug from the receptor. The value Figure 2.8
of ~ can be used to determine the affinity of a drug for its receptor. Typical dose-response curve for drugs
Affinity describes the strength of the interaction {binding) between a showing differences in potency and
ligand and its receptor. The higher the ~ value, the weaker the inter- efficacy. EC50 = drug dose that shows
action and the lower the affinity, and vice versa. Equation {1) defines 50% of maximal response.
a curve that has the shapes shown in Figure 2.9 when plotted against
drug concentration {Panel A) or log drug concentration {Panel B). As
the concentration of free drug increases, the ratio of the concentra-
tions of bound receptors to total receptors approaches unity, thereby
producing the maximal effect. Thus, it is not surprising that the curves
shown in Figure 2.9 and those representing the relationship between
dose and effect {Figure 2.7) are similar. ~'iii'
0 ..
.. 0
D. ..
II D.

C. Relationship of drug binding to pharmacologic effect ! ¥0.5

-a.!:
c J!0
The law of mass action can be applied to drug concentration and :I

response providing the following assumptions are met: 1) The magni- ~t:.
tude of the response is proportional to the amount of receptors occu- Dose
pied by drug, 2) the Emax occurs when all receptors are bound, and 3)
one molecule of drug binds to only one molecule of receptor. In this
case,
~~
[E] [D] 0 ~
.. 0
D. ..
{2) II D.
[Emax] Kd+[D] u II
!!
'0-
! 0.5

where [E] = the effect of the drug at concentration [D] and [Emaxl = the §~
maximal effect of the drug. ~t:.

Thus, it follows that if a specific population of receptors is vital for Log dose
mediating a physiological effect, the affinity of an agonist for binding
to those receptors should be related to the potency of that drug for Figure 2.9
causing that physiological effect. Many drugs and most neurotrans- The effect of dose on the magnitude of
mitters can bind to more than one type of receptor, thereby causing drug binding.
30 2. Drug-Receptor Interactions and Pharmacodynamics

100,000 0 10,000 0
c: 10,000 Q ,,,,
_____ I!
1000 ,,
~ 1000 ,
.!!
=a0 -............____.............____ 0 :II

=
I!
100
0'
,ff,
.c:
..
"c:
0
100
10
- ......__
... ,
A.
"a
g 10 ,,"'"'
,,"'' ~
Ill
5: 1 cf) iii
0
1
,,"'
,,' 0
U' R.,= 1,,,,
lrl 0.1
R.y=O 1&.1 0.1

0.01 0 0.01 .a'

a a
" "~ "'"af"~f,f " "~ "' "af"~~ff
"a "a

K.. a, Binding "' K.. a, Binding

Jj
100,000
,, 10,000 0
c: 1000 ,Q' 1000
0
;:; ,, I! ,,,, 0
,,
:I
.!! 1000 VI ,,,,
, "' 100 ,,,,
=a0 ,, I! ,,,,
100
,, 0 A. ,,,, 0
,,
.c: "a 10 ,,,,
"c:
e 10 0
m ,,,,
Ill
0 1
,,
,,'li 0
iii
0
"'
1 0
,,,,

U'
1&.1 0.1
R.,= 1 ,, u
1&.1 0.1 R.y=O
,,' 0 Q
0.01 0.01
" "~ "' "af"~fffff " "~
"' "af"~f#~ff
"a "a

" "a
Kct ~ Binding Kct ~ Binclng "' "a

Figure 2.10
Correlation of drug affinity for receptor binding and potency for causing a physiological effect. A positive correlation should
exist between the affinity(~ value) of a drug for binding to a specific receptor subtype and the potency (EC50 value) of
that drug to cause physiological responses mediated by that receptor population. For example, many drugs have affinity
for both a, and 13:z adrenergic receptors. The circled letters in the figure represent agonists with varying affinities for a, and
13:z receptors. However, from the data provided, it becomes clear that a, receptors only mediate changes in blood pressure,
while l3:z receptors only mediate changes in bronchodilation.

both desired therapeutic effects and undesired adverse effects. In

order to establish a relationship between drug occupation of a par-
ticular receptor subtype and the corresponding biological response to
that drug, correlation curves of receptor affinity and drug potency are
often constructed (Figure 2.1 0).

IV. INTRINSIC ACTIVITY

As mentioned above, an agonist binds to a receptor and produces a bio-

logic response based on the concentration of the agonist, its affinity for
the receptor and, hence, the fraction of occupied receptors. However,
the intrinsic activity of a drug further determines its ability to fully or par-
tially activate the receptors. Drugs may be categorized according to their
intrinsic activity and resulting Emax values.
IV. Intrinsic Activity 31

A. Full agonists A full agonist produces

complete activation of a
If a drug binds to a receptor and produces a maximal biologic response receptor at high drug
that mimics the response to the endogenous ligand, it is a full agonist concentrations.
(Figure 2.11 ). Full agonists bind to a receptor, stabilizing the recep-
tor in its active state and are said to have an intrinsic activity of one. Partial agonist binding
All full agonists for a receptor population should produce the same results in less than 100%
activation, even at very
Emax· For example, phenylephrine is a full agonist at a 1-adrenoceptors, high concentrations.
because it produces the same Emax as the endogenous ligand, nor-
epinephrine. Upon binding to a 1-adrenoceptors on vascular smooth 100
muscle, both norepinephrine and phenylephrine stabilize the recep-
tor in its active state, thereby increasing Gq activation. Activation of
Gq increases intracellular Ca2+, causing interaction of actin and myo-
sin filaments and shortening of the muscle cells. The diameter of the
arteriole decreases, causing an increase in resistance to blood flow
through the vessel and an increase in blood pressure. Thus, effects
of agonists on intracellular molecules, cells, tissues, and intact organ-
isms are all attributable to interaction of the drug with the receptor.
For full agonists, the dose-response curves for receptor binding and
each of the biological responses should be comparable.

B. Partial agonists
Partial agonists have intrinsic activities greater than zero but less than
one (Figure 2.11 ). Even when all the receptors are occupied, partial Inverse agonists produce
a response below the base-
agonists cannot produce the same Emax as a full agonist. Even so, a line response measured
partial agonist may have an affinity that is greater than, less than, in the absence of drug.
or equivalent to that of a full agonist. A partial agonist may also act
as a partial antagonist of a full agonist (Figure 2.12). As the number In this example, a portion of the
receptors show constitutive
of receptors occupied by the partial agonist increases, the number activity (without stimulation),
of receptors that can be occupied by the full agonist decreases and such that 12% of maximal
response is seen.
therefore Emax would decrease until it reached the Emax of the partial
agonist. This potential of partial agonists to act as both an agonist
and antagonist may have therapeutic utility. For example, aripiprazole, Figure 2.11
an atypical antipsychotic, is a partial agonist at selected dopamine Effects of full agonists, partial agonists,
receptors. Overactive dopaminergic pathways tend to be inhibited and inverse agonists on receptor activity.
by aripiprazole, whereas underactive pathways are stimulated. This
might explain the ability of aripiprazole to improve symptoms of
schizophrenia, with a small risk of causing extrapyramidal adverse
effects (see Chapter 11 ).

C. Inverse agonists
Typically, unbound receptors are inactive and require interaction with
an agonist to assume an active conformation. However, some recep-
tors show a spontaneous conversion from R to R* in the absence of
an agonist. Inverse agonists, unlike full agonists, stabilize the inac-
tive R form and cause R* to convert to R. This decreases the num-
ber of activated receptors to below that observed in the absence of
drug (Figure 2.11 ). Thus, inverse agonists have an intrinsic activity
less than zero, reverse the activation state of receptors, and exert the
opposite pharmacological effect of agonists.
32 2. Drug-Receptor Interactions and Pharmacodynamics

Fullagonist • D. Antagonists
Key:
Partlalagonlst
Fully active receptor + + Antagonists bind to a receptor with high affinity but possess zero
intrinsic activity. An antagonist has no effect on biological function in
the absence of an agonist, but can decrease the effect of an agonist
when present. Antagonism may occur either by blocking the drug's
Partially active receptor ~
ability to bind to the receptor or by blocking its ability to activate the
receptor.

++++
High levels of agonist may activate
all rac:eptors and produce unwantad
1. Competitive antagonists: If the antagonist binds to the same site
on the receptor as the agonist in a reversible manner, it is "com-
petitive!' A competitive antagonist interferes with an agonist bind-
ing to its receptor and maintains the receptor in its inactive state.
overstlmulatlon.
For example, the antihypertensive drug terazosin competes with
the endogenous ligand norepinephrine at a1-adrenoceptors, thus
decreasing vascular smooth muscle tone and reducing blood pres-
sure. However, increasing the concentration of agonist relative to
The presence of partial antagonist can overcome this inhibition. Thus, competitive antago-
agonist displaces some nists characteristically shift the agonist dose-response curve to the
agonist. resulting In right (increased EC50) without affecting Emax (Figure 2.13).
diminished receptor
response.
2. Irreversible antagonists: Irreversible antagonists bind cova-
lently to the active site of the receptor, thereby permanently
reducing the number of receptors available to the agonist. An
irreversible antagonist causes a downward shift of the Emax.
with no shift of EC50 values (Figure 2.13). In contrast to com-
petitive antagonists, addition of more agonist does not over-
come the effect of irreversible antagonists. Thus, irreversible
antagonists and allosteric antagonists (see below) are both
considered noncompetitive antagonists. A fundamental differ-
ence between competitive and noncompetitive antagonists is
that competitive antagonists reduce agonist potency (increase
EC50) and noncompetitive antagonists reduce agonist efficacy
(decrease Emax).

3. Allosteric antagonists: An allosteric antagonist binds to a site

(allosteric site) other than the agonist-binding site and prevents
-10 -8 -6
receptor activation by the agonist. This type of antagonist also
Log [partial agonist)
causes a downward shift of the Emax of an agonist, with no change
Response provided in the EC50 value. An example of an allosteric agonist is picrotoxin,
bythe partial agonist which binds to the inside of the GABA-controlled chloride chan-
nel. When picrotoxin binds inside the channel, no chloride can
pass through the channel, even when GABA fully occupies the
receptor.
~~ 4. Functional antagonism: An antagonist may act at a completely
At high concentration of partial
agonist, the agonist is completely separate receptor, initiating effects that are functionally opposite
displaced, and receptor activity those of the agonist. A classic example is the functional antago-
Is determined by the Intrinsic
activity of the partial agonist. nism by epinephrine to histamine-induced bronchoconstriction.
Histamine binds to H1 histamine receptors on bronchial smooth
muscle, causing bronchoconstriction of the bronchial tree.
Epinephrine is an agonist at P2-adrenoceptors on bronchial smooth
Figure 2.12 muscle, which causes the muscles to relax. This functional antago-
Effects of partial agonists. nism is also known as "physiologic antagonism."
V. Quantal Dose-Response Relationships 33

V. QUANTAL DOSE-RESPONSE RELATIONSHIPS

Drug with
compatitiYtl
Another important dose-response relationship is that between the .magonlst
dose of the drug and the proportion of a population of patients that )
responds to it. These responses are known as quantal responses,
because, for any individual, either the effect occurs or it does not.
Graded responses can be transformed to quantal responses by des-
ignating a predetermined level of the graded response as the point
at which a response occurs or not. For example, a quantal dose-
response relationship can be determined in a population for the anti-
Drug concentr~~tion
hypertensive drug atenolol. A positive response is defined as a fall of
at least 5 mm Hg in diastolic blood pressure. Quantal dose-response t
EC50 EC
t
curves are useful for determining doses to which most of the popula- for drug for~
tion responds. They have similar shapes as log dose-response curves, alone or In tha pnsanc•
and the ED50 is the drug dose that causes a therapeutic response in In the presence crf a compatltiYtl
crf a noncomp.tltlv• antagonist
half of the population. antagonist

A. Therapeutic index Figure 2.13

The therapeutic index (TI) of a drug is the ratio of the dose that pro- Effects of drug antagonists. EC50 =
drug dose that shows 50% of maximal
duces toxicity in half the population {TD50) to the dose that produces response.
a clinically desired or effective response (ED50) in half the population:

Tl = TD50 I ED50
n Warfarin: Small
The Tl is a measure of a drug's safety, because a larger value indi-
W therapeutic index
cates a wide margin between doses that are effective and doses that
are toxic.

B. Clinical usefulness of the therapeutic Index

The Tl of a drug is determined using drug trials and accumulated clin-
ical experience. These usually reveal a range of effective doses and a
different (sometimes overlapping) range of toxic doses. Although high
Tl values are required for most drugs, some drugs with low therapeu-
tic indices are routinely used to treat serious diseases. In these cases,
the risk of experiencing adverse effects is not as great as the risk of
leaving the disease untreated. Figure 2.14 shows the responses to
warfarin, an oral anticoagulant with a lowTI, and penicillin, an antimi- r.1l Penldllln: Large
crobial drug with a large Tl. ._. therapeutic Index
1. Warfarin (example of a drug with a small therapeutic index): As
the dose of warfarin is increased, a greater fraction of the patients
respond (for this drug, the desired response is a two- to threefold i1oo
increase in the international normalized ratio [INR]) until, eventu-
ally, all patients respond (Figure 2.14A). However, at higher doses i'0 so : D•slrad
of warfarin, anticoagulation resulting in hemorrhage occurs in a ; :therapeutic
small percent of patients. Agents with a low Tl (that is, drugs for :1 I efftld
which dose is critically important) are those drugs for which bio-
availability critically alters the therapeutic effects (see Chapter 1).
~ 0~-----7!~--~-----
11: Log conc..tration crf
drug In plasma
(.-bltrary units)
2. Penicillin (example of a drug with a large therapeutic index):
For drugs such as penicillin (Figure 2.148), it is safe and com-
mon to give doses in excess of that which is minimally required to
Figure 2.14
achieve a desired response without the risk of adverse effects. In Cumulative percentage of patients
this case, bioavailability does not critically alter the therapeutic or responding to plasma levels of
clinical effects. warfarin and penicillin.
34 2. Drug-Receptor Interactions and Pharmacodynamics

Study Questions

Choose the ONE best answer.

2.1 Which of the following best describes how a drug that

Correct answer= C. The GABA-A receptor is a ligand-gated
acts as an agonist at the A subtype of GABA receptors
ion channel selective for chloride. Agonlsts for the GABA-A
affects signal transduction in a neuron? receptor Increase opening of channels, resulting in chloride
A. Activation of this receptor subtype alters transcription entry Into the neuron, hyperpolarization, and decreased
of DNA in the nucleus of the neuron. action potential events.
B. Activation of this receptor subtype opens ion chan-
nels that allow sodium to enter cells and increases
the chance of generating an action potential.
C. Activation of this receptor subtype opens ion chan-
nels that allow chloride to enter cells and decreases
the chance of generating an action potential.
D. Activation of this receptor subtype results in G protein
activation and increased intracellular second mes-
senger levels.
2.2 If 1 mg of lorazepam produces the same anxiolytic
Correct answer = A. A drug that causes the same effect at
response as 10 mg of diazepam, which is correct?
a lower dose is more potent. B and C are incorrect because
A. Lorazepam is more potent than is diazepam. without information about the maximal effect of these
B. Lorazepam is more efficacious than is diazepam. drugs, no conclusions can be made about efficacy or Intrin-
C. Lorazepam is a full agonist, and diazepam is a partial sic activity. D Is Incorrect because the maximal response
obtained Is often more important than the amount of drug
agonist.
needed to achieve it.
D. Lorazepam is a better drug to take for anxiety than is
diazepam.
2.3 If 10 mg of oxycodone produces a greater analgesic
Correct answer = A. Drugs with greater response at maxi-
response than does aspirin at any dose, which is correct?
mally effective concentrations are more efficacious than
A. Oxycodone is more efficacious than is aspirin. drugs with a lower maximal response. Choice B is incorrect
B. Oxycodone is less potent than is aspirin. since no Information Is given about the half maximal con-
C. Aspirin is a full agonist, and oxycodone is a partial centrations of either drug. Choices C and Dare Incorrect
since It Is not known if both drugs bind to the same receptor
agonist. population.
D. Oxycodone and aspirin act on the same drug target.

2.4 In the presence of propranolol, a higher concentration of

Correct answer = C. Since propranolol decreases the effect
epinephrine is required to elicit full antiasthmatic activity.
of epinephrine but the inhibition can be overcome by giv-
Propranolol has no effect on asthma symptoms. Which is ing a higher dose of epinephrine, propranolol must be a
correct regarding these medications? competitive antagonist. If D were correct, even very high
A. Epinephrine is less efficacious than is propranolol. concentrations of epinephrine would not be able to elicit a
B. Epinephrine is a full agonist, and propranolol is a par- maximal effect in the presence of propranolol. Since pro-
pranolol has no effect by ltseH, A and B are Incorrect.
tial agonist.
C. Epinephrine is an agonist, and propranolol is a com-
petitive antagonist.
D. Epinephrine is an agonist, and propranolol is a non-
competitive antagonist.
2.5 In the presence of picrotoxin, diazepam is less efficacious
Correct answer = B. Since picrotoxin decreases the maxi-
at causing sedation, regardless of the dose. Picrotoxin
mal effect of diazepam regardless of the diazepam dose, it
has no sedative effect, even at the highest dose. Which is a noncompetitive antagonist. Picrotoxin has no efficacy
of the following is correct regarding these agents? alone, so C is incorrect. No information is provided about
A. Picrotoxin is a competitive antagonist. potency of either drug.
B. Picrotoxin is a noncompetitive antagonist.
C. Diazepam is less efficacious than is picrotoxin.
D. Diazepam is less potent than is picrotoxin.
Study Questions 35

2.6 Haloperidol, chlorpromazine, and clozapine are antipsy-

Correct answer = C. To conclude that the mechanism of
chotic medications that bind to the D2 subtype of dopa-
antipsychotic effect for these drugs is via binding to D2
mine receptors, with a binding affinity of haloperidol > receptors, there should be a positive correlation between
chlorpromazine > clozapine. Which statement would the affinity of the drugs for D2 receptors and their potency
have to be correct to conclude that the mechanism of for antipsychotic actions. Haloperidol should have the high-
antipsychotic effects for these drugs is via binding to D2 est antipsychotic potency and clozaplne the lowest. There
receptors? Is no guarantee the therapeutic effects and adverse effects
are mediated by the same receptor population; therefore, a
A. Haloperidol should have the lowest potency of the different correlation may exist for the adverse effects and
three antipsychotic drugs. D2 receptor affinity.
B. D2 receptor binding should also be related to the
potency of these drugs in causing Parkinson's-like
adverse effects.
C. A positive correlation should exist between the affin-
ity of these drugs to bind to D2 receptors and their
potency for antipsychotic actions.
D. Clozapine would have to be more potent than chlor-
promazine for decreasing psychosis.

2.7 If there were spare fl1-adrenergic receptors on cardiac

Correct answer = C. Only a fraction of the total receptors
muscle cells, which statement would be correct?
need to be bound to elicit a maximum cellular response
A. The number of spare fl 1-adrenergic receptors deter- when spare receptors are present. The other choices do not
mines the size of the maximum effect of the agonist accurately describe the effects of having spare receptors.
epinephrine.
B. Spare fl1 adrenergic receptors make the cardiac tis-
sue less sensitive to epinephrine.
C. A maximal effect of epinephrine is seen when only a
portion of fl1 adrenergic receptors are occupied.
D. Spare receptors are active even in the absence of
epinephrine.

2.8 Which of the following up-regulates postsynaptic a1-

Correct answer= D. Up-regulation of receptors occurs when
adrenergic receptors?
receptor activation is lower than normal, such as when the
A. Daily use of amphetamine that causes release of receptor Is continuously exposed to an antagonist for that
norepinephrine receptor. Down-regulation of receptors occurs when recep-
B. A disease that causes an increase in the activity of tor activation Is greater than normal because of continuous
exposure to an agonist, as described in A, B, and C.
norepinephrine neurons
C. Daily use of phenylephrine, an a1 receptor agonist
D. Daily use of prazosin, an a1 receptor antagonist

2.9 Methylphenidate helps patients with attention deficit

Correct answer = A. Therapeutic Index Is calculated by divid-
hyperactivity disorder (ADHD) maintain attention and
ing TD50 by ED50 (30/10), making B incorrect. Cis incorrect
perform better at school or work, with an EDso of 10 mg. because methylphenidate is more potent at treating ADHD
However, methylphenidate can also cause significant (it takes a lower dose) than causing nausea. D. No informa-
nausea at higher doses (TD50 "' 30 mg). Which is correct tion about efficacy is provided.
regarding methylphenidate?
A. The therapeutic index of methylphenidate is 3.
B. The therapeutic index of methylphenidate is 0.3.
C. Methylphenidate is more potent at causing nausea
than treating ADHD.
D. Methylphenidate is more efficacious at causing nau-
sea than treating ADHD.
36 2. Drug-Receptor Interactions and Pharmacodynamics

2.10 Which is correct concerning the safety of using warfarin

Correct answer = B. Agents with a low n (that is, drugs for
(with a small therapeutic index) versus penicillin (with a
which dose is critically important) are those drugs for which
large therapeutic index)? bioavailability critically alters the therapeutic and adverse
A. Warfarin is a safer drug because it has a low thera- effects. A is incorrect, because a drug with a low Tl is not
peutic index. generally considered to be safe. C Is Incorrect because a
high Tl does not ensure safety across the entire patient
B. Warfarin treatment has a high chance of resulting in
population. D Is Incorrect because the hi!1J Tl makes it
dangerous adverse effects if bioavailability is altered.
unlikely that bioavailability alters the incidence of therapeu-
C. The high therapeutic index makes penicillin a safe tic or adverse effects.
drug for all patients.
D. Penicillin treatment has a high chance of causing
dangerous adverse effects if bioavailability is altered.