A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

136 ANTI-EPILEPTICS
PHENYTOIN
Use
Phenytoin is effective in the treatment of tonic–clonic and partial
seizures, including complex partial seizures. Dose individualization
is essential. Plasma concentration is measured after
two weeks. According to clinical response and plasma concentration,
adjustments should be small and no more frequent than
every four to six weeks. Phenytoin illustrates the usefulness of
therapeutic drug monitoring (see Chapter 8), but not all
patients require a plasma phenytoin concentration within the
therapeutic range of 10–20 mg/L for optimum control of their
seizures. In status epilepticus, phenytoin may be given by slow
intravenous infusion diluted in sodium chloride. Fosphenytoin
is a more convenient parenteral preparation. It can cause dysrhythmia
and/or hypotension, so continuous monitoring (see
below) is needed throughout the infusion.
Adverse effects
These include the following:
• effects on nervous system – high concentrations produce a
cerebellar syndrome (ataxia, nystagmus, intention tremor,
dysarthria), involuntary movements and sedation.
Seizures may paradoxically increase with phenytoin
intoxication. High concentrations cause psychological
disturbances;
• ‘allergic’ effects – rashes, drug fever and hepatitis may
occur. Oddly, but importantly, such patients can show
cross-sensitivity to carbamazepine;
• skin and collagen changes – coarse facial features, gum
hypertrophy, acne and hirsutism may appear;
• haematological effects – macrocytic anaemia which
responds to folate is common; rarely there is aplastic
anaemia, or lymphadenopathy (‘pseudolymphoma’,
which rarely progresses to true lymphoma);
• effects on fetus – (these are difficult to distinguish from
effects of epilepsy). There is increased perinatal mortality,
raised frequency of cleft palate, hare lip, microcephaly and
congenital heart disease;
• effects on heart – too rapid intravenous injection causes
dysrhythmia and it is contraindicated in heart block
unless paced;
• exacerbation of porphyria.
Pharmacokinetics
Intestinal absorption is variable. There is wide variation in the
handling of phenytoin and in patients taking the same dose,
there is 50-fold variation in steady-state plasma concentrations
(see Figure 22.2). Phenytoin metabolism is under polygenic
control and varies widely between patients, accounting
for most of the inter-individual variation in steady-state
plasma concentration.
Phenytoin is extensively metabolized by the liver and less
than 5% is excreted unchanged. The enzyme responsible for
elimination becomes saturated at concentrations within the
therapeutic range, and phenytoin exhibits dose-dependent
kinetics (see Chapter 3) which, because of its low therapeutic
index, makes clinical use of phenytoin difficult. The clinical
implications include:
• Dosage increments should be small (50 mg or less) once the
plasma concentration approaches the therapeutic range.
• Fluctuations above and below the therapeutic range occur
relatively easily due to changes in the amount of drug
absorbed, or as a result of forgetting to take a tablet.
• Clinically important interactions are common with drugs
that inhibit or induce phenytoin metabolism (see Table 22.2).
The saturation kinetics of phenytoin make it invalid to calculate
t 1/2 , as the rate of elimination varies with the plasma
150
A B C D E
Serum phenytoin concentration (mol/L)
125
100
75
50
25
0 100 200 300 400 500 600
Phenytoin dose (mg/day)
Figure 22.2: Relationship between daily dose of
phenytoin and resulting steady-state serum level in
five patients on several different doses of the drug.
The curves were fitted by computer assuming
Michaelis–Menten kinetics (Redrawn with permission
from Richens A, Dunlop A. Lancet 1975; ii: 247.
© The Lancet Ltd.)