Pharmacokinetics VII

Accumulation: Dose, Dose Interval, and
Plasma Level Fluctuation
Successful drug therapy in many illnesses
is accomplished only if drug concentration
is maintained at a steady high
level. This requirement necessitates
regular drug intake and a dosage schedule
that ensures that the plasma concentration
neither falls below the therapeutically
effective range nor exceeds
the minimal toxic concentration. A constant
plasma level would, however, be
undesirable if it accelerated a loss of effectiveness
(development of tolerance),
or if the drug were required to be
present at specified times only.
A steady plasma level can be
achieved by giving the drug in a constant
intravenous infusion, the steadystate
plasma level being determined by
the infusion rate, dose D per unit of time
and the clearance
This procedure is routinely used in
intensive care hospital settings, but is
otherwise impracticable. With oral administration,
dividing the total daily
dose into several individual ones, e.g.,
four, three, or two, offers a practical
compromise.
When the daily dose is given in several
divided doses, the mean plasma
level shows little fluctuation. In practice,
it is found that a regimen of frequent
regular drug ingestion is not well
adhered to by patients. The degree of
fluctuation in plasma level over a given
dosing interval can be reduced by use of
a dosage form permitting slow (sustained)
release .
The time required to reach steadystate
accumulation during multiple
constant dosing depends on the rate of
elimination. As a rule of thumb, a plateau
is reached after approximately
three elimination half-lives (t1/2).
For slowly eliminated drugs, which
tend to accumulate extensively (phenprocoumon,
digitoxin, methadone), the
optimal plasma level is attained only after
a long period. Here, increasing the
initial doses (loading dose) will speed
up the attainment of equilibrium, which
is subsequently maintained with a lower
dose (maintenance dose).