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

48 agonist plus an effective concentration of the antagonist (Figure 3–4A).
As as more antagonist (I) is added, a higher concentration of the agonist
(A) is needed to produce an equivalent response (the half-maximal
or 50%, response is a convenient and accurately determined
level of response).
The extent of the rightward shift of the concentration-dependence
curve is a measure of the affinity of the inhibitor, and a higheraffinity
inhibitor will cause a greater rightward shift than a
lower-affinity inhibitor at the same inhibitor concentration. Using
Equations 3–3 and 3–4, one may write mathematical expressions of
fractional occupancy (f) of the receptor by agonist for the agonist
alone (control) and agonist in the presence of inhibitor.
For the agonist drug (L) alone,
SECTION I
GENERAL PRINCIPLES
For the case of agonist plus antagonist (I),
f
(Equation 3-5)
(Equation 3-6)
Assuming that equal responses result from equal fractional
receptor occupancies in both the absence and presence of antagonist,
one can set the fractional occupancies equal at agonist concentrations
(L and L′) that generate equivalent responses in
Figure 3–4A. Thus,
L
L + K
Simplifying, one gets:
D
f
+ I
=
control
[ L]
=
[ L]
+ K
L′
=
⎛ [] I ⎞
L′ + KD
+
⎝
⎜1
K ⎠
⎟
L′ [] I − 1 =
L K
(Equation 3-7)
(Equation 3-8)
where all values are known except K i
. Thus, one can determine the
K i
for a reversible, competitive antagonist without knowing the K D
for the agonist and without needing to define the precise relationship
between receptor and response.
PHARMACODYNAMIC VARIABILITY:
INDIVIDUAL AND POPULATION
PHARMACODYNAMICS
Individuals vary in the magnitude of their response to
the same concentration of a single drug or to similar
drugs, and a given individual may not always respond
in the same way to the same drug concentration.
Attempts have been made to define and measure individual
“sensitivity” (or “resistance”) to drugs in the clinical
setting, and progress has been made in understanding
D
[ L]
⎛ [] I ⎞
[ L]
+ KD
+
⎝
⎜1
K ⎠
⎟
i
i
i
some of the determinants of sensitivity to drugs that act
at specific receptors. Drug responsiveness may change
because of disease or because of previous drug administration.
Receptors are dynamic, and their concentration
and function may be up- or down-regulated by
endogenous and exogenous factors.
Data on the correlation of drug levels with efficacy
and toxicity must be interpreted in the context of
the pharmacodynamic variability in the population (e.g.,
genetics, age, disease, and the presence of co-administered
drugs). The variability in pharmacodynamic response in
the population may be analyzed by constructing a
quantal concentration-effect curve (Figure 3–5A).
The dose of a drug required to produce a specified effect
in 50% of the population is the median effective dose
(ED 50
, Figure 3–5A). In preclinical studies of drugs, the
median lethal dose (LD 50
) is determined in experimental
animals (Figure 3-5B). The LD 50
/ED 50
ratio is an
indication of the therapeutic index, which is a statement
of how selective the drug is in producing its desired
effects versus its adverse effects. A similar term, the
therapeutic window, is the range of steady-state concentrations
of drug that provides therapeutic efficacy with
minimal toxicity (Figure 3–6). In clinical studies, the
dose, or preferably the concentration, of a drug required
to produce toxic effects can be compared with the concentration
required for therapeutic effects in the population
to evaluate the clinical therapeutic index. Since
pharmacodynamic variation in the population may be
marked, the concentration or dose of drug required to
produce a therapeutic effect in most of the population
usually will overlap the concentration required to
produce toxicity in some of the population, even
though the drug’s therapeutic index in an individual
patient may be large. Also, the concentration-percent
curves for efficacy and toxicity need not be parallel,
adding yet another complexity to determination of the
therapeutic index in patients. Finally, no drug produces
a single effect, and the therapeutic index for a drug
will vary depending on the effect being measured.
A clear demonstration of the relation of plasma drug concentration
to efficacy or toxicity is not achievable for many drugs; even
when such a relationship can be determined, it usually predicts only
a probability of efficacy or toxicity. In trials of antidepressant drugs,
such a high proportion of patients respond to placebo that it is difficult
to determine the plasma drug level associated with efficacy.
There is a quantal concentration-response curve for efficacy and
adverse effects (Figure 3–5B); for many drugs, the concentration
that achieves efficacy in all the population may produce adverse
effects in some individuals. Thus, a population therapeutic window
expresses a range of concentrations at which the likelihood of