CLINICAL PHARMACOLOGY
Phenytoin is an antiepileptic drug which can be useful
in the treatment of epilepsy. The primary site of action
appears to be the motor cortex where spread of seizure
activity is inhibited. Possibly by promoting sodium efflux
from neurons, phenytoin tends to stabilize the threshold
against hyperexcitability caused by excessive stimulation
or environmental changes capable of reducing membrane
sodium gradient. This includes the reduction of posttetanic
potentiation at synapses. Loss of posttetanic potentiation
prevents cortical seizure foci from detonating adjacent
cortical areas. Phenytoin reduces the maximal activity
of brain stem centers responsible for the tonic phase
of tonic-clonic (grand mal) seizures.
The plasma half-life in man after oral administration
of phenytoin averages 22 hours, with a range of 7 to 42
hours. Steady-state therapeutic levels are achieved at
least 7 to 10 days (5-7 half-lives) after initiation of
therapy with recommended doses of 300 mg/day.
When serum level determinations are necessary, they should
be obtained at least 5-7 half-lives after treatment initiation,
dosage change, or addition or subtraction of another drug
to the regimen so that equilibrium or steady-state will
have been achieved. Trough levels provide information
about clinically effective serum level range and confirm
patient compliance and are obtained just prior to the
patient's next scheduled dose. Peak levels indicate an
individual's threshold for emergence of dose-related side
effects and are obtained at the time of expected peak
concentration. For phenytoin sodium capsules kapseals
peak serum levels occur 4-12 hours after administration.
Optimum control without clinical signs of toxicity occurs
more often with serum levels between 10 and 20 mg/ml,
although some mild cases of tonic-clonic (grand mal) epilepsy
may be controlled with lower serum levels of phenytoin.
In most patients maintained at a steady dosage, stable
phenytoin serum levels are achieved. There may be wide
interpatient variability in phenytoin serum levels with
equivalent dosages. Patients with unusually low levels
may be noncompliant or hypermetabolizers of phenytoin.
Unusually high levels result from liver disease, congenital
enzyme deficiency or drug interactions which result in
metabolic interference. The patient with large variations
in phenytoin plasma levels, despite standard doses, presents
a difficult clinical problem. Serum level determinations
in such patients may be particularly helpful. As phenytoin
is highly protein bound, free phenytoin levels may be
altered in patients whose protein binding characteristics
differ from normal.
Most of the drug is excreted in the bile as inactive
metabolites which are then reabsorbed from the intestinal
tract and excreted in the urine. Urinary excretion of
phenytoin and its metabolites occurs partly with glomerular
filtration but, more importantly, by tubular secretion.
Because phenytoin is hydroxylated in the liver by an enzyme
system which is saturable at high plasma levels small
incremental doses may increase the half-life and produce
very substantial increases in serum levels, when these
are in the upper range. The steady-state level may be
disproportionately increased, with resultant intoxication,
from an increase in dosage of 10% or more.
|
|
