Page 37 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 2 Drug Receptors & Pharmacodynamics 23

the total number of downstream signaling mediators present in agonist present at a concentration equal to the K will occupy 50%
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the cell, so that a maximal response occurs without occupancy of of the receptors, and half of the effectors will be activated, produc-
all receptors. In other cases, “spareness” of receptors appears to be ing a half-maximal response (ie, two receptors stimulate two effec-
temporal. For example, β-adrenoceptor activation by an agonist tors). Now imagine that the number of receptors increases tenfold
promotes binding of guanosine triphosphate (GTP) to a trimeric to 40 receptors but that the total number of effectors remains con-
G protein, producing an activated signaling intermediate whose stant. Most of the receptors are now spare in number. As a result,
lifetime may greatly outlast the agonist-receptor interaction (see a much lower concentration of agonist suffices to occupy 2 of the
also the following section on G Proteins & Second Messengers). 40 receptors (5% of the receptors), and this same low concentra-
Here, maximal response is elicited by activation of relatively few tion of agonist is able to elicit a half-maximal response (two of four
receptors because the response initiated by an individual ligand- effectors activated). Thus, it is possible to change the sensitivity of
receptor-binding event persists longer than the binding event tissues with spare receptors by changing receptor number.
itself. Irrespective of the biochemical basis of receptor reserve,
the sensitivity of a cell or tissue to a particular concentration of Competitive & Irreversible Antagonists
agonist depends not only on the affinity of the receptor for bind-
ing the agonist (characterized by the K ) but also on the degree of Receptor antagonists bind to receptors but do not activate them;
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spareness—the total number of receptors present compared with the primary action of antagonists is to reduce the effects of agonists
the number actually needed to elicit a maximal biologic response. (other drugs or endogenous regulatory molecules) that normally
The concept of spare receptors is very useful clinically because activate receptors. While antagonists are traditionally thought to
it allows one to think precisely about the effects of drug dosage have no functional effect in the absence of an agonist, some antago-
without having to consider (or even fully understand) biochemical nists exhibit “inverse agonist” activity (see Chapter 1) because they
details of the signaling response. The K of the agonist-receptor also reduce receptor activity below basal levels observed in the
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interaction determines what fraction (B/B max ) of total receptors absence of any agonist at all. Antagonist drugs are further divided
will be occupied at a given free concentration (C) of agonist into two classes depending on whether or not they act competitively
regardless of the receptor concentration: or noncompetitively relative to an agonist present at the same time.
In the presence of a fixed concentration of agonist, increasing
concentrations of a competitive antagonist progressively inhibit
the agonist response; high antagonist concentrations prevent the
response almost completely. Conversely, sufficiently high concen-
Imagine a responding cell with four receptors and four effectors. trations of agonist can surmount the effect of a given concentration
Here the number of effectors does not limit the maximal response, of the antagonist; that is, the E max for the agonist remains the same
and the receptors are not spare in number. Consequently, an for any fixed concentration of antagonist (Figure 2–3A). Because

A B

Agonist
Agonist alone
alone
Agonist effect (E) Agonist + Agonist effect (E)

competitive antagonist

Agonist +
noncompetitive antagonist

C C' = C (1 + [ l ] / K) EC 50

Agonist concentration Agonist concentration
FIGURE 2–3 Changes in agonist concentration-effect curves produced by a competitive antagonist (A) or by an irreversible antagonist
(B). In the presence of a competitive antagonist, higher concentrations of agonist are required to produce a given effect; thus the agonist
concentration (C′) required for a given effect in the presence of concentration [I] of an antagonist is shifted to the right, as shown. High
agonist concentrations can overcome inhibition by a competitive antagonist. This is not the case with an irreversible (or noncompetitive)
antagonist, which reduces the maximal effect the agonist can achieve, although it may not change its EC 50 .