DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Some drugs cause low-dose stimulation and high-dose inhibition
of response. These U-shaped relationships for some receptor systems
are said to display hormesis. Several drug-receptor systems can
display this property (e.g., prostaglandins, endothelin, and purinergic
and serotonergic agonists, among others), which is likely to be at
the root of some drug toxicities (Calabrese and Baldwin, 2003).
Affinity, Efficacy, and Potency. In general, the drugreceptor
interaction is characterized by (1) binding of
drug to receptor and (2) generation of a response in a
biological system, as illustrated in Equation 3-1 where
the drug or ligand is denoted as L and the inactive
receptor as R. The first reaction, the reversible formation
of the ligand-receptor complex LR, is governed by
the chemical property of affinity.
k+
1
k+
2
L + R↽
⇀
LR ↽ ⇀LR
*
(Equation 3-1)
where LR* is produced in proportion to [LR] and leads
to a response. This simple relationship illustrates the
reliance of the affinity of the ligand (L) with receptor
(R) on both the forward or association rate (k +1
) and the
reverse or dissociation rate (k −1
). At any given time, the
concentration of ligand-receptor complex [LR] is equal
to the product of k +1
[L][R], the rate of formation of the
bi-molecular complex LR, minus the product k −1
[LR],
the rate dissociation of LR into L and R. At equilibrium
(i.e., when δ[LR]/δt = 0), k +1
[L][R] = k −1
[LR]. The equilibrium
dissociation constant (K D
) is then described by
ratio of the off and on rate constants (k −1
/k +1
).
Thus, at equilibrium,
K
D
k−1
k−2
= [ L][ R]
k
[ ]
= − LR k
+
(Equation 3-2)
The affinity constant or equilibrium association
constant (K A
) is the reciprocal of the equilibrium dissociation
constant (i.e., K A
= 1/K D
); thus a high-affinity
drug has a low K D
and will bind a greater number of a
particular receptor at a low concentration than a lowaffinity
drug. As a practical matter, the affinity of a drug
is influenced most often by changes in its off-rate (k −1
)
rather than its on-rate (k +1
).
Equation 3-2 permits us to write an expression of
the fractional occupancy (f ) of receptors by agonist:
f = [ ligand-receptor complexes ] [ LR]
=
[ total receptors]
[ R] + [ LR]
1
1
(Equation 3-3)
This can be expressed in terms of K A
(or K D
) and [L]:
K
A[ L]
[ L]
f = =
1 + K [ L]
[ L]
+ K
A
(Equation 3-4)
This relationship illustrates that when the concentration
of drug equals the K D
(or 1/K A
), f = 0.5, that is,
the drug will occupy 50% of the receptors. Note that
this relationship describes only receptor occupancy, not
the eventual response that is often amplified by the cell.
Many signaling systems reach a full biological response
with only a fraction of receptors occupied (described
later). Potency is defined by example in Figure 3–3.
Basically, when two drugs produce equivalent
responses, the drug whose dose-response curve (plotted
as in Figure 3-3A) lies to the left of the other (i.e.,
the concentration producing a half-maximal effect
[EC 50
] is smallest) is said to be the more potent.
Response to Drugs. The second reaction shown in
Equation 3-1 is the reversible formation of the active
% Maximal Effect
100
80
60
40
20
0
100
80
60
40
20
0
A
B
Relative potency
Drug X
EC 50
Relative efficacy
EC 50
Log [Agonist]
Log [Agonist]
D
Drug Y
Drug X
Drug Y
Figure 3–3. Two ways of quantifying agonism. A. The relative
potency of two agonists (Drug X, red line; Drug Y, purple line)
obtained in the same tissue is a function of their relative affinities
and intrinsic efficacies. The EC 50
of Drug X occurs at a concentration
that is one-tenth the EC 50
of Drug Y. Thus, Drug X is
more potent than Drug Y. B. In systems where the two drugs do
not both produce the maximal response characteristic of the tissue,
the observed maximal response is a nonlinear function of
their relative intrinsic efficacies. Drug X is more efficacious than
Drug Y; their asymptotic fractional responses are 100% (Drug
X) and 50% (Drug Y).
45
CHAPTER 3
PHARMACODYNAMICS: MOLECULAR MECHANISMS OF DRUG ACTION