Principles of Pharmacology: Chapter 2 Pharmacodynamics

- Pharmacodynamics is the term used to describe the effects of a drug on the body.

L is ligand (drug), R is free receptor &
LR is the bound drug-receptor complex.
Kd is a constant for each drug-receptor
combination.
Can deduce (1) as ligand concentration is increased, the concentration of bound receptors increases, (2)
as free receptor concentration increases, bound receptor concentration also increases. Therefore, an
increase in the effect of a drug can result from an increase in the concentration of either the ligand or
receptor.
- B/c drug responses occur over a wide range of doses (concentrations), the semilog plot is used to display
drug-receptor binding data in a drug-receptor binding curve.
- Kd is defined as the concentration of ligand at which 50% of the available receptors are occupied.
- The response to a drug is proportional to the concentration of receptors that are bound (occupied) by the
drug. [D] is the
concentration of
free drug, [DR] is
the concentration of
drug-receptor complex, [R0] is the concentration of total receptors & Kd is the equilibrium dissociation
constant for the drug-receptor interaction.
- There are 2 major types of dose-response relationships: graded & quantal. The difference b/w the 2
methods is that graded dose-response relationships describe the effect of various doses of a drug on an
individual, whereas quantal relationships show the effect of various doses of a drug on population of
individuals.
- A lower Kd indicates a tighter drug-receptor interaction
(higher affinity). B/c of this relationship, Drug A, which
has a lower Kd, will bind a higher proportion of total
receptors than Drug B at any given drug concentration.
- Potency (EC50) of a drug is the concentration at which
the drug elicits 50% of its maximal response.
- Efficacy (Emax) is the maximal response produced by
the dug.
- The quantal dose-response relationship plots the
fraction of the population that responds to a given dose
of drug as a function of the drug dose.
o B/c of differences in biological response among
individuals, the effects of a drug are seen over a
range of doses.
o The doses that produce responses in 50% of a
population are known as the median effective dose
(ED50), median toxic dose (TD50) & median lethal
dose (LD50).
o Quantal dose-response curves demonstrate the
average effect of a drug, as a function of its
concentration, in a population of individuals.
- Many receptors for drugs can be modeled as having 2 conformational states that are in reversible
equilibrium w/ one another. These 2 states are called the active state & the inactive state.
o Agonist: a drug that favors the active receptor conformation.
o Antagonist: a drug that
prevents agonist-induced
activation of the receptor.
- An agonist is a molecule that binds to
a receptor & stabilizes the receptor in
a particular conformation (usually, the
active conformation).
- Antagonists can be categorized based
on whether they bind to a site on the
receptor for agonist (receptor antagonists) or interrupt agonist-receptor signaling by other means
(nonreceptor antagonists)
o Receptor antagonists can bind either to the agonist (active) site or to an allosteric site on
the receptor. They do not affect basal receptor activity (the activity of the receptor in the
absence of agonist).
o Agonist (active) site receptor antagonists prevent the agonist from binding to the receptor.
o If the antagonist competes w/ the ligand for agonist site binding, it is termed a competitive
antagonist; high concentrations of agonist are able to overcome competitive antagonism.
o Noncompetitive agonist site antagonists bind covalently or w/ very high affinity to the
agonist site, so that even high concentrations of agonist are unable to activate the receptor.
o Allosteric receptor antagonists bind to the receptor at a site other than the agonist site,
they do not compete directly w/ agonist for receptor binding, but rather alter the kd for
agonist binding or inhibit the receptor from responding to the agonist binding.
o Chemical antagonists sequester agonist & thus prevent the agonist from interacting w/ the
receptor.
o Physiologic antagonists induce a physiologic response opposite to that of an agonist, but by
a molecular mechanism that does not involve the receptor for agonist.
- An antagonists is a molecule that inhibits the action of an agonist but has no effect in the absence
of agonist.
o A receptor antagonist binds to either the active site (agonist binding site) or an allosteric
site on a receptor.
o A nonreceptor antagonist does not bind to the same receptor as an agonist, but it inhibits
the ability of an agonist to initiate a response.
Chemical antagonists inactivate an agonist before it has the opportunity to act (e.g.
by chemical neutralization). It inactivates the agonist of interest by modifying or
sequestering it, so that the agonist is no longer capable of binding to & activating the
receptor.
Physiologic antagonists cause a physiologic effect opposite to that induced by the
agonist. It most commonly activates or blocks a receptor that mediates a response
physiologically opposite to that of the receptor for the agonist.
The presence of a competitive antagonist reduces the potency of an agonist.
- A competitive antagonist binds reversibly to the active site of a receptor. A competitive antagonist
blocks an agonist from binding to its
receptor, while maintaining the
receptor in the active conformation.
- Noncompetitive antagonists can
bind to either the active site or an
allosteric site of a receptor. A
noncompetititve antagonist that binds to the active site of a receptor can bind either covalently or
w/ very high affinity; in either case, the binding is effectively irreversible.
o A noncompetitive allosteric antagonist acts by preventing the receptor from being
activated, even when the agonist is bound to the active site.
o A receptor that is bound by a noncompetitive antagonist
can no longer be activated by the binding of an agonist.
Therefore, the maximal response (efficacy) of the agonist is
reduced. A characteristic difference b/w competitive &
noncompetitive antagonists is that competitive agonists
reduce against potency, whereas noncompetitive
antagonists reduce agonist efficacy.
- A partial agonist 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.
o B/c partial agonists & full agonists bind to the same site on
a receptor, a partial agonist can reduce the response
produced by a full agonist. Partial agonists can act as a
competitive antagonist, sometimes they are called partial
antagonists or mixed agonist-antagonists.
- Inverse agonists act by abrogating this intrinsic (constitutive) activity of the free (unoccupied)
receptor. Inverse agonists may function by binding to & stabilizing the receptor in the inactive
form. This has the effect of deactivating receptors that had existed in the active form in the
absence of a drug. An inverse agonist deactivates receptors that are constitutively active the
absence of an agonist.
- Full agonists stabilize the active complex, partial agonists stabilize both the active & inactive
complex, inverse agonists stabilize the inactive complex & competitive antagonists stabilize the
inactive complex by preventing full, partial, and inverse agonists from binding to the receptor.
- Spare receptors: the maximal response can be achieved w/ less than 100% receptor occupancy.
At least 2 molecular mechanisms are thought to be responsible for the spare receptor
phenomenon.
o First, the receptor could remain activated after the agonist departs, allowing one agonist
molecule to activate several receptors.
o Second, the cell signaling pathways could allow for significant amplification of a relatively
small signal & activation of only a few receptors could be sufficient to produce a maximal
response.
o The presence of spare receptors alters the effect of a noncompetitive antagonist on the
system. At low antagonist concentrations, the noncompetitive antagonist binds receptors
that are not required to produce a maximal response; therefore, the efficacy of the agonist
is not decreased. The potency of the agonist is affected, however, b/c potency is
proportional to the fraction of available receptors that must be occupied to produce a 50%
response. A noncompetitive antagonist reduces the # of available receptors, thereby
increasing the fraction of receptors that must be bound at any agonist concentration to
produce the same response. At high antagonist concentrations, the noncompetitive
antagonist binds not only the
spare receptors but also
receptors that are required to
produce a maximal response, &
the efficacy & potency of the
agonist are decreased.
- The therapeutic window is the range of
doses (concentrations) of a drug that
elicits a therapeutic response, without
unacceptable adverse effects (toxicity), in
a population of patients.
o The therapeutic window can be quantified by the
therapeutic index.
o TD50 = dose of drug that causes a toxic response in
50% of the population.
o ED50 = dose of drug that is therapeutically effective in 50% of the population.
- Pharmacodynamics is the quantitative study of the effects of drug on the body.
- In the study of pharmacodynamics, drugs can be divided into 2 broad classes agonists &
antagonists.
o Most agonists cause a receptor to maintain its conformation in the active state, whereas
antagonists prevent activation of the receptor by agonists.
o Antagonists are further divided according to the molecular location of their effect (i.e.
receptor or nonreceptor), the site at which they bind to the receptor (i.e. active site or
allosteric site), & the mode of their binding to the receptor (i.e. reversible & irreversible).