Drug-Receptor Interaction IX

Time Course of Plasma Concentration
and Effect
After the administration of a drug, its
concentration in plasma rises, reaches a
peak, and then declines gradually to the
starting level, due to the processes of
distribution and elimination.
Plasma concentration at a given point in
time depends on the dose administered.
Many drugs exhibit a linear relationship
between plasma concentration and
dose within the therapeutic range
(dose-linear kinetic ; note different
scales on ordinate). However, the
same does not apply to drugs whose
elimination processes are already sufficiently
activated at therapeutic plasma
levels so as to preclude further proportional
increases in the rate of elimination
when the concentration is increased
further. Under these conditions,
a smaller proportion of the dose administered
is eliminated per unit of time.
The time course of the effect and of
the concentration in plasma are not
identical, because the concentrationeffect
relationships obeys a hyperbolic
function. This means
that the time course of the effect exhibits
dose dependence also in the presence
of dose-linear kinetics .
In the lower dose range (example
1), the plasma level passes through a
concentration range (0 ! 0.9) in which
the concentration effect relationship is
quasi-linear. The respective time courses
of plasma concentration and effect
are very similar.
However, if a high dose (100) is applied,
there is an extended period of time during
which the plasma level will remain
in a concentration range (between 90
and 20) in which a change in concentration
does not cause a change in the size
of the effect. Thus, at high doses (100),
the time-effect curve exhibits a kind of
plateau. The effect declines only when
the plasma level has returned (below
20) into the range where a change in
plasma level causes a change in the intensity
of the effect.
The dose dependence of the time
course of the drug effect is exploited
when the duration of the effect is to be
prolonged by administration of a dose
in excess of that required for the effect.
This is done in the case of penicillin G
, when a dosing interval of 8 h is
being recommended, although the drug
is eliminated with a half-life of 30 min.
This procedure is, of course, feasible only
if supramaximal dosing is not associated
with toxic effects.
Futhermore it follows that a nearly
constant effect can be achieved, although
the plasma level may fluctuate
greatly during the interval between
doses.
The hyperbolic relationship be
tween plasma concentration and effect
explains why the time course of the effect,
unlike that of the plasma concentration,
cannot be described in terms of
a simple exponential function. A halflife
can be given for the processes of
drug absorption and elimination, hence
for the change in plasma levels, but generally
not for the onset or decline of
the effect.