I.

II.
III.

IV.

Introduction:
a. Pharmacodynamics is the term used to describe the effets of a drug on the body.
DRUG RECEPTOR BINDING
DOSE-RESPONSE RELATIONSHIPS
a. Pharmacodynamics of a drug can be quantified by the relationship between the
dose( concentration of the rug) and the organisns response to that drug.
b. A usuful assumption is that the response to a drug is proportional to the
concentration of receptors that are bound (occupied by the drug)
c. GRADED DOSE-RESPONSE RELATIONSHIPS. (scalar) ie. Such as change in BP or HR.
i. Response is proportional to receptor occupancy
ii. Two important parameterspotency and efficacy-can be deduced from the
graded dose-response curve.
iii. THE POTENCY: of a drug is the concentration at which the drug elicits 50% of
its maximal response.
iv. The efficacy (Emax) is the maximal response produced by the drug.
1. Can be thought of as the state at which receptor-mediated signaling is
maximal and, therefore, additional drug will produce no additional
response. This occurs when all the receptors are occupied by the drug.
2. Spare receptors: are those left over receptors that are not used when
drugs are capable of eliciting a maximal response when less than
100% of the drugs receptors are occupied.
v. GRADED DOSE-RESPONSE CURVES: demonstrate the effect of a drug as a
function to its concentration .
vi. E is the quantifiable response to a drug
vii. EC50 is the potency of the drug, or the concentration at which the drug
elicits 50% of its maximal effect.
d. QUANTAL DOSE-RESPONSE RELATIONSHIPS: plots the fraction of the population
that response to a given dose of drug as a function of the drug dose.
i. Describe the concentrations of a drug that produce a given effect in a
population.
ii. ED 50 dose at which 50% of subjects exhibit a therapeutic response to a
drug. ED 50 is dose at which subjects respond to a drug.
iii. TD 50 dose at which 50% of subjects experience a toxic response.
iv. LD 50 dose at which 50% of the subjects die.
v. EC 50 dose at which a drug elicits a 1/2 maximal effect in an individual
subject.
vi. RESPONSES ARE DEFINED AS present or not present
1. Ex: sleep or no sleep
2. Ex: alive @ 12 months dead at 12 months
vii. The doses that produce these responses(therapeutic effect, lethal, toxicity) in
50% of a population are known as the median effective dose (ED 50), median
toxic dose (TD 50), and median lethal dose (LD50) respectively.
DRUG RECEPTOR INTERACTIONS: drugs have two conformational states called active and
inactive state.
a. A drug that upon binding, favors its active state is called an agonist.
b. Antagonist: is a drug that prevents agonist-induced activation of the receptor
c. Some drugs are partial agonists and inverse agonists
i. AGONISTS: is a molecule that binds to a receptor and stabilizes the receptor
in a particular conformation (usually active form).
1. D+R->DR this suggests that agonist binding is proportional to receptor
activation.

2. Potency is the agonist concentration required to elicit a maximal

effect, and efficacy is the maximal effect of the agonist.
ii. ANTAGONISTS: is a molecule that inhibits the action of an agonist but has
noeffect in the absence of the agonist.
1. Antagonists can be categorized based on whether they bind to a site
on the receptor for agonist or interrupt agonist-receptor signaling by
other means (nonreceptor atagonistst).
a. Receptor antagonists can be divided into receptor on non
receptor
b. Receptor antagonists can bind either to the agonist(active)site or
to an allosteric site on the receptor.
c. Agonist(active) site receptor atagonists prevent the agonist from
binding to the receptor.
i. If the antagonists competes with the ligand for agonist site
binding it is termed a competeitive antagonist. And DO
NOT ACTIVATE SITE. FORM OF INHIBITION.
d. Noncompetitive agonist site antagonists bind covalently to the
agonist site, so that even high conc of agonist are unable to
acrtivate the receptor.
i. NON COMPETITIVE ANTAGONISTS: bind to a different site
and thereby prevent receptor activation, even when the
agonist is bound to the receptor.
e. Allosteric binding: bind to the receptor at a site other than the
agonist site. They do not compete directly with agonist for
receptor binding, butr rather alter the Kd for agonist bidning or
inhibit the receptor from responding to agonist bidning.
i. KD is the drug conc. at which 50% of the available
receptors are in use
ii. Cannot be reversed
iii. When an antagonist binds to an allosteric site it will alter
Kd for agonist binding or will prevent the conformational
change required for receptor activation.
f. NONRECEPTOR ANTAGONISTS: have 2 categories
i. Chemical antagonists: seize agonist and prevent the
agonist from interacting with the receptor.
ii. Physiologic antagonists: induce a physiologic response
opposite to that of an agonist, but by a molecular
mechanism that doesnt involve the receptor for agonist.
d. COMPETITIVE RECEPTOR ANTAGONISTS: binds reversibl to the active site of a
receptor.
i. The antagonist will block an agonist from binding to its receptor, while
maintaining the receptor in the inactive conformation.
ii. Antagonists decrease potency. Efficacy is not affected. This is because the
agonist concentration can be increased to counteract the antagonist thereby
washing out or reversing the effect of the antagonist.
e. NONCOMPETITIVE RECEPTOR ANTAGONISTS: can bind to either the active site or an
allosteric site of a receptor. A noncompetitive receptor antagonist that binds to the
active site of a receptor can bind either covalently or with a very high affinity; in
either case, the binding is effectively irreversible.
i. A noncompetitive allosteric antagonist acts by preventing the receptor from
being activated, even when the agonist is bound to the active site.

ii.

V.

VI.

VII.

VIII.

A receptor that is bound by a noncompetitive antagonist can no longer be

activated by the binding of an agonist.
iii. There fore, the maximal response (efficacy of the agonist is reduced.
iv. ****the difference is that a competitive antagonist continuously competes for
receptor binding, effectively reducing the receptors affinity for an agonist
without limiting the number of available receptors.
v. In contrast, a noncompetitive antagonist removes functional receptors from
the system, thereby limiting the number of available receptors.
1. Aspiring is a noncomeptetitive antagonist
f. NONRECEPTOR ANTAGONIST: can be divided into chemical and physiologic
antagonists.
i. A chemical antagonist inactivates the agonist of interest by modifying or
sequestiering it, so that the agonist is no longer capable of binding to and
activating the receptor
1. Protamine is a chmical antagonist; this protein binds stoichiometrically
to the acidic heparin class of anticoagulants and thereby inactivates
these agents.
ii. Physiologic antagonist activates or blocks a receptor that mediates a
response physiologically opposite to that of the receptor for the agonist.
1. Ex: Beta-adrenergic antagonists are used as physiologic antagonists to
counteract the tachycardic effect of endogenous thyroid hormone.
!!!!!!PARTIAL AGONISTS: is a molecule that binds to a receptor at its active site but
produces only a partial response, even when all of the receptors are occupied (bound) by
the agonist.
a. Because Partial and full agonists bind to the same site on the receptor, a partial
agonist can reduce the response produced by a full agonist. In this way, the partial
agonist can act as a competitive antagonist.
Inverse agonists: acts by canceling this intrinsic activity of the free receptor.
a. Inverse agonists may function by inding to and stabilizing the receptor in the DR
(inactive form.
b. This can deactivate receptors that had existed in the R form in the absence of
drug.
c.
Spare receptor: there are 2 mechanisms that are thought to be responsible for the spare
receptor phenomenon.
a. First, the receptor could remain activated after the agonist departs, allowing one
agonist molecule to activate several receptors.
b. Sexond, the cell signaling pathways could allow for significant amplification of a
relatively small signal, and activation of only a few receptors could be sufficient to
produce a maximal response.
i. In a system without spare receptors, a noncompetitive antagonist causes
efficacy to decrease at all concentrations of the antagonists
ii. In a system with spare receptors, however, potency is decreased but efficacy
is unaffected at low concentrations of the antagonist, because a sufficient
number of unoccupied receptors are available to generate a maximal
response.
iii. As increasing concentrations of antagonist bind noncompetitively to more
and more receptors, the antagonist eventually occupies all of the spare
recepots, and efficacy is also reduced.
Concepts in therapeutics:

a. THERAPEUTIC INDEX AND THERAPEUTIC WINDOW: is the range of doses of a drug

that elicits a therapeutic response, without unacceptable adverse effects (toxicity),
in a population of patients.
i. TD 50 is the dose of drug that causes a toxic response in 50% of the
population.
ii.