pharmacodynamics

Lecture 7
Pharmacodynamics
DOSE–RESPONSE RELATIONSHIPS
Agonist drugs mimic the action of the original endogenous ligand for the
receptor (for example, isoproterenol mimics norepinephrine on ?1 receptors
of the heart). The magnitude of the drug effect depends on 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, metabolism, and elimination
Graded dose–response relations
As the concentration of a drug increases, its pharmacologic effect also
gradually increases until all the receptors are occupied (the maximum
effect). Plotting the magnitude of response against increasing doses of
a drug produces a graded dose–response curve that has the general
shape . The curve can be described as a rectangular
hyperbola, which is a familiar curve in biology because it can
be applied to diverse biological events, such as enzymatic activity, and
responses to pharmacologic agents. Two important properties of drugs,
potency and efficacy, can be determined by graded dose–response
curves
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. In Figure 2.7, the EC50 for
Drugs A and B indicate that 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
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. , the curves become sigmoidal
in shape, which simplifies the interpretation of the dose–
response curve.
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 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. Efficacy is a more clinically useful characteristic
than is drug potency, since a drug with greater efficacy is more
therapeutically beneficial than is one that is more potent.
Effect of drug concentration on receptor binding
The quantitative relationship between drug concentration and receptor
occupancy applies the law of mass action to the kinetics of the
binding of drug and receptor molecules:
Drug +Receptor ----------------Drug?receptor complex -----------Biologiceffect
Relationship of drug binding to pharmacologic effect
The mathematical model that describes drug concentration and receptor
binding can be applied to dose (drug concentration) and response (or
effect), providing the following assumptions are met: 1) The magnitude
of the response is proportional to the amount of receptors bound or
occupied, 2) the Emax occurs when all receptors are bound, and 3) binding
of the drug to the receptor exhibits no cooperativity. In this case,
INTRINSIC ACTIVITY
Full agonists
Partial agonists
Inverse agonists
Antagonists
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
Competitive antagonists
Irreversible antagonists
Allosteric antagonists
Functional antagonism
QUANTAL DOSE–RESPONSE RELATIONSHIPS
Another important dose–response relationship is that between the dose
of the drug and the proportion of a population that responds to it. These
responses are known as quantal responses, 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
The therapeutic index (TI) of a drug is the ratio of the dose that produces
toxicity in half the population (TD50) to the dose that produces
a clinically desired or effective response (ED50) in half the population:
TI = TD 50/ ED 50
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
Clinical usefulness of the therapeutic index
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
increase in the international normalized ratio [INR]) until, eventually,
all patients respond ( However, at higher doses
of warfarin, anticoagulation resulting in hemorrhage occurs in a
small percent of patients. Agents with a low TI (that is, drugs for
which dose is critically important) are those drugs for which bioavailability
critically alters the therapeutic effects
Penicillin (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. In
this case, bioavailability does not critically alter the therapeutic or
clinical effects