Pharmacodynamics (part II)

 Graded Dose-response Relationships:

 Agonist drugs mimic the action of the original endogenous ligand for the
receptor (for example, isoproterenol mimics norepinephrine on β1 receptors
of the heart).

 The magnitude of the drug effect depends on the drug concentration at

the receptor site, which is determined by both the dose of drug
administered and by the drug‟s pharmacokinetic profile, such as rate of
absorption, distribution, metabolism, and elimination.

 As the concentration of a drug increases, its pharmacologic effect also

gradually increases until all the receptors are occupied (the maximum
effect).
 Graded dose-response curve: it represent the graph of a particular
receptor response versus the drug concentration or dose.

 The curve can be described as a rectangular hyperbola.

 Two important properties of drugs, can be determined by graded dose–

response curves:

1. Potency

2. Efficacy
1. Potency:
 Potency is a measure of the amount of drug necessary to produce an effect
of a given magnitude.
 The concentration of drug producing 50% of the maximum effect (EC50)
is usually used to determine potency.
 Potency is determined mainly by the affinity of the receptor for the drug
and the number of receptors.
 In the following figure Drug A is more potent than Drug B, because a
lesser amount of Drug A is needed when compared to Drug B to obtain 50-
percent effect.
 Therapeutic preparations of drugs reflect their potency.
 For example, candesartan and irbesartan are angiotensin receptor blockers
that are used to treat hypertension. The therapeutic dose range for
candesartan is 4 to 32 mg, as compared to 75 to 300 mg for irbesartan.
Therefore, candesartan is more potent than is irbesartan (it has a lower
EC50 value, similar to Drug A).
 Since the range of drug concentrations (from 1% to 99% of the maximal
response) usually spans several orders of magnitude, semilogarithmic plots
are used so that the complete range of doses can be graphed. As shown in
Figure B, the curves become sigmoidal in shape, which simplifies the
interpretation of the dose– response curve.
 2. Efficacy:
It is the magnitude of response to the drug 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 all receptors are occupied
by the drug, and no increase in response is observed if a higher concentration
of drug is obtained.
 Therefore, the maximal response differs between full and partial agonists,
even when 100% of the receptors are occupied by the drug.
 Similarly, even though an antagonist occupies 100% of the receptor sites, no
receptor activation results and Emax is zero.
 Drug efficacy is of greater clinical importance than potency because a
greater therapeutic benefit may be obtained with a more efficacious drug,
while a more potent drug may merely allow a smaller dose to be given for
the same clinical benefit.

 In turn, efficacy and potency need to be balanced against drug toxicity to

produce the best balance of benefit and risk for the patient.

 Amiloride diuretic causes 5% excretion of Na+ (low efficacy).

 Frusemide causes 25% excretion of Na+ (high efficacy).
 Graded Dose-binding Relationship & Binding Affinity:

 dose-binding graph is similar to the dose-response curve, it measures the

percentage of receptors bound by a drug, against the log of the concentration
of the drug.

 The concentration of drug required to bind 50% of the receptor sites is

denoted by the dissociation constant (Kd) and is a useful measure of the
affinity of a drug molecule for its binding site on the receptor molecule.

 The smaller the Kd, the greater the affinity of the drug for its receptor.

 If the number of binding sites on each receptor molecule is known, it is

possible to determine the total number of receptors in the system from the
Bmax.
 Selectivity:
 drugs may act preferentially on particular receptor types or subtypes, such
as β1- and β2-adrenoceptors, it is important to be able to quantify the
degree of selectivity of a drug.
 For example, it is important in understanding the therapeutic efficacy and
unwanted effects of the bronchodilator drug salbutamol to recognize that it
is approximately 10 times more effective in stimulating the β2-
adrenoceptors in the airway smooth muscle than the β1-adrenoceptors in
the heart.
 Selectivity is likely to be investigated by measuring the effects of the
drug in vitro on different cells or tissues, each expressing only one of
the receptors of interest.
 Comparison of the two log dose–response curves in the following Fig.
shows that for a given response, smaller doses of the drug are required to
stimulate the β1- receptor compared with those required to stimulate the
β2-receptor; the drug is therefore said to have selectivity of action at the
β1-reoceptor.
 E.g., dobutamine, which is used to selectively stimulate β1-adrenoceptors
on the heart in heart failure.
 The degree of receptor selectivity is given by the ratio of the doses of the
drug required to produce a given level of response.
 It is clear from the Fig. that the ratio is highly dose-dependent and that the
selectivity disappears at extremely high drug doses, because the dose then
produces the maximal response of which the biological tissue is capable.
 Note: many drugs and most neurotransmitters can bind to more than one
type of receptor, thereby causing both desired therapeutic effects and
undesired side effects.
 Intrinsic Activity:
 It is the ability of the bound drug to induce the conformational changes in
the receptor that induce receptor signaling or response.
 It determines drug ability to fully or partially activate the receptors (agonist)
 Although affinity is a essential for binding to a receptor, a drug may bind
with high affinity but have low intrinsic activity.
 A drug with zero intrinsic activity is an antagonist.

Agonists are mainly of 3 types:

1. Full agonists
2. Partial agonists
3. Inverse agonists
1. Full agonist:
 a drug binds to a receptor and produces a maximal biologic response that
mimics the response to the endogenous ligand
 Full agonists have an intrinsic activity of one.
 All full agonists for a receptor population should produce the same Emax.
 For example, phenylephrine is a full agonist at α1-adrenoceptors, because it
produces the same Emax as does the endogenous ligand, norepinephrine.
 Upon binding to α1-adrenoceptors on vascular smooth muscle, phenylephrine
stabilizes the receptor in its active state. This leads to the mobilization of
intracellular Ca2+, causing interaction of actin and myosin filaments and
shortening of the muscle cells. The diameter of the arteriole
decreases(vasoconstriction), causing an increase in resistance to blood flow
through the vessel and an increase in blood pressure
2. Partial agonists:
 Even if all the receptors are occupied, partial agonists cannot produce the
same Emax as a full agonist.
 Partial agonists have intrinsic activities greater than zero but less than one.

 Partial agonist may have an affinity that is greater than, less than, or
equivalent to that of a full agonist.

 When a receptor is exposed to both a partial agonist and a full agonist, the
partial agonist may act as a weak antagonist of the full agonist because it
prevents access to the receptor of a molecule with higher intrinsic ability to
initiate receptor signaling; this results in a reduced response.
 This potential of partial agonists to act as both an agonist and antagonist
may be therapeutically utilized.
 For example, aripiprazole, an atypical antipsychotic, is a partial agonist at
selected dopamine receptors. Dopaminergic pathways that are overactive
tend to be inhibited by aripiprazole, whereas pathways that are underactive
are stimulated. This might explain the ability of aripiprazole to improve
symptoms of schizophrenia, with a small risk of causing extrapyramidal
adverse effects.
 So, partial agonists can act as stabilizers of the variable activity of the
natural ligand, as they enhance receptor activity when the endogenous
ligand levels are low or zero, but block receptor activity when endogenous
ligand levels are high
3. Inverse agonists
 Many receptor exhibit some activity in the absence of ligand, suggesting
that some fraction of the receptor is always in the activated state.
 Activity in the absence of ligand is called constitutive activity.
 Inverse agonists, unlike full agonists, stabilize the inactive R form and
cause Ra to convert to Ri. This decreases the number of activated receptors.
 Thus, inverse agonists have an intrinsic activity less than zero, reverse the
activity of receptors, and exert the opposite pharmacological effect of
agonists.
 An inverse agonist can be distinguished from the typical antagonists,
which, on their own, bind to the receptor without affecting receptor
signaling, as they have zero intrinsic activity („neutral‟ or „silent‟
antagonists). The action of a neutral antagonist depends on depriving the
access of agonists to the receptor
Antagonists (blockers or inhibitors):
 Antagonists bind to a receptor with high affinity but possess
zero intrinsic activity.
 An antagonist has no effect 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 ability
to bind to the receptor or by blocking its ability to activate the
receptor.
1. Competitive antagonists:
 If both the antagonist and the agonist bind to the same site on the
receptor in a reversible manner, they are said to be “competitive.”
 The competitive antagonist prevents an agonist from binding to its
receptor and maintains the receptor in its inactive state.
 For example, the antihypertensive drug terazosin competes with the
endogenous ligand norepinephrine at α1-adrenoceptors, thus decreasing
vascular smooth muscle tone(vasodilation) and reducing blood pressure.
 However, this inhibition can be overcome by increasing the concentration
of agonist relative to antagonist.
 Competitive antagonists characteristically shift the agonist dose–response
curve to the right (increased EC50) without affecting Emax
2- Irreversible antagonists:
 Irreversible antagonists bind covalently to the active site of the receptor,
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 (unless spare receptors are present).
 In contrast to competitive antagonists, the effect of irreversible antagonists
cannot be overcome by adding more agonist. Thus, irreversible antagonists
and allosteric antagonists are both considered noncompetitive antagonists
 The difference between competitive and noncompetitive antagonists is that
competitive agonists reduce agonist potency (increase EC50) and
noncompetitive antagonists reduce agonist efficacy (decrease Emax).
3-Allosteric antagonists:
 This type of antagonist binds to a site (“allosteric site”) other than the
agonist-binding site and prevents the receptor from being activated by the
agonist.
 An allosteric antagonist also causes a downward shift of the Emax, with no
change in the EC50 value of an agonist.
 An example is picrotoxin, which binds to the inside of the GABA- chloride
channel, prevent chloride influx through the channel, even when the
receptor is fully activated by GABA.
4. Functional antagonism:
 An antagonist may act at a completely separate receptor, initiating effects
that are functionally opposite those of the agonist.
 A classic example is the functional antagonism by epinephrine to
histamine-induced bronchoconstriction. Histamine binds to H1 histamine
receptors on bronchial smooth muscle, causing bronchoconstriction of the
bronchial tree.
 Epinephrine is a β2-adrenoceptors agonist on bronchial smooth muscle,
which causes bronchodilation .
 This functional antagonism is also known as “physiologic antagonism.”
5. Chemical Antagonists:
 A chemical antagonist interacts directly with the agonist to remove it or
prevent it from binding to its target.

 A chemical antagonist does not depend on interaction with the agonist‟s

receptor (although such interaction may occur).

 Common examples of chemical antagonists are:

1. Dimercaprol, a chelator of lead and some other toxic metals

2. Pralidoxime, which combines with the phosphorus in organophosphate

cholinesterase inhibitors.
 Quantal Dose-response Relationships
 It is a type of dose–response relationship, that between the dose of the
drug and the proportion of a population that responds to it, because, for
any individual, the effect either occurs or it does not.
 Graded responses can be transformed to quantal responses by designating
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 antihypertensive drug atenolol. A positive response is
defined as a fall of at least 5 mm Hg in diastolic blood pressure.
 Quantal dose–response curves are useful for determining doses to which
most of the population responds.
 They have similar shapes as log dose–response curves, and the ED50 is
the drug dose that causes a therapeutic response in half of the population.
Therapeutic index
 It is the ratio of the dose that produces toxicity in half the population (TD)
to the dose that produces a clinically desired or effective response (ED50)
in half the population: TI = TD50 / ED50
 Quantal relationships can be defined for both toxic and therapeutic drug
effects to allow calculation of the therapeutic index (TI).
 The TI is a measure of a drug‟s safety, because a larger value indicates a
wide margin between doses that are effective and doses that are toxic.
 The therapeutic window, a more clinically useful index of safety,
describes the dosage range between the minimum effective therapeutic
concentration or dose, and the minimum toxic concentration or dose.
 For example, if the average minimum therapeutic plasma concentration of
theophylline is 8 mg/L and toxic effects are observed at 18 mg/L, the
therapeutic window is 8–18 mg/L.
 Although high TI values are required for most drugs, some drugs
with low therapeutic indices are routinely used to treat serious
diseases. In these cases, the risk of experiencing side effects is not
as great as the risk of leaving the disease untreated.
 Warfarin ,oral anticoagulant (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 increase in the international normalized ratio
[INR] used to monitor warfarin) until, eventually, all patients
respond. However, at higher doses of warfarin, anticoagulation
results in hemorrhage.
 Penicillin, an antimicrobial (example of a drug with a large
therapeutic index): For drugs such as penicillin, it is safe and common
to give doses in excess of that which is minimally required to achieve a
desired response without the risk of adverse side effects.