A Textbook of Clinical Pharmacology and Therapeutics

GENERALPRINCIPLES OFTREATMENT OFEPILEPSY 135

absolute arbiter. The availability of plasma concentration moni-
toring of anticonvulsant drugs has allowed the more efficient
use of individual drugs, and is a crude guide to compliance. If a
drug proves to be ineffective, it should not be withdrawn sud-
denly, as this may provoke status epilepticus. Another drug
should be introduced in increasing dosage while the first is
gradually withdrawn.
Few studies have investigated combined drug therapy,
although empirically this is sometimes necessary. In most but
not all cases, effects are additive. Combinations of three or
more drugs probably do more harm than good by increasing
the likelihood of adverse drug reaction without improving
seizure control. Many anticonvulsant drugs are enzyme
inducers, so pharmacokinetic interactions are common (e.g.
carbamazepinereduces plasma concentrations of phenytoin).

occur only around peak drug concentrations, and in patients

who have difficulty in complying with three or more doses

per day.

Adverse effects

Adverse effects are common, but seldom severe. They are par-

ticularly troublesome early in treatment, before induction of

the enzyme responsible for carbamazepineelimination (see

above). Sedation, ataxia, giddiness, nystagmus, diplopia,

blurred vision and slurred speech occur in 50% of patients

with plasma levels over 8.5 mg/L. Other effects include rash

and (much more rarely) blood dyscrasia, cholestatic jaundice,

renal impairment and lymphadenopathy. Carbamazepine

can cause hyponatraemia and water intoxication due to an

antidiuretic action. It is contraindicated in patients with atrio-

ventricular (AV) conduction abnormalities and a history of

bone marrow depression or porphyria. Its use in pregnancy

has been associated with fetal neural-tube defects and

hypospadias.

Drug interactions

Carbamazepineshould not be combined with monoamine

oxidase inhibitors. It is a potent enzyme inducer and, in par-

ticular, it accelerates the metabolism of warfarin, theo-

phyllineand the oral contraceptive.

SODIUM VALPROATE

Use

Sodium valproate(dipropylacetate) is effective against many

forms of epilepsy, including tonic–clonic, absence, partial

seizures and myoclonic epilepsy. Dosage starts low and is

increased every three days until control is achieved.

Adverse effects

The adverse effects involve the following:

• tremor, ataxia and incoordination (dose related);


• nausea, vomiting and abdominal pain (reduced by using
  enteric-coated tablets);


• enhancement of sedatives (including alcohol);


• hair loss (temporary);


• thrombocytopenia: platelet count should be checked
  before surgery or with abnormal bruising;


• a false-positive ketone test in urine;


• teratogenic effects (neural-tube defects and hypospadias);


• hepatic necrosis, particularly in children taking high doses
  and suffering from congenital metabolic disorders;


• acute pancreatitis (another rare complication).

Pharmacokinetics

Valproate is well absorbed when given orally (95–100%

bioavailability). The plasma t1/2is seven to ten hours. Active

metabolites may explain its slow onset and long time-course

of action. The brain to plasma ratio is low (0.3). There is sub-

stantial inter-individual variation in metabolism. Plasma val-

proate concentrations do not correlate closely with efficacy.

Key points

Choice of anticonvulsant

• Use a single drug based on type of epilepsy.


• Generally increase the dose every two weeks until
  either the seizures cease or signs of toxicity appear
  and/or the plasma drug concentration is in the toxic
  range.


• If unsatisfactory, substitute another drug.


• Probably less than 10% of epileptic patients benefit
  from two or more concurrent anticonvulsants.

Beware drug interactions.

Beware pregnancy.

INDIVIDUAL ANTI-EPILEPTIC DRUGS

CARBAMAZEPINE

Use

Carbamazepineis structurally related to the tricyclic anti-
depressants. It is the drug of choice for simple and complex
partial seizures and for tonic–clonic seizures secondary to
a focal discharge seizure, and it is effective in trigeminal
neuralgia and in the prophylaxis of mood swings in manic-
depressive illness (see Chapter 20). A low starting dose
is given twice daily followed by a slow increase in dose
until seizures are controlled. Assays of serum concentration
are a useful guide to compliance, rapid metabolism or drug
failure if seizures continue. The therapeutic range is
4–12 mg/L.

Pharmacokinetics

Carbamazepineis slowly but well absorbed following oral
administration. Plasma t1/2after a single dose is 25–60 hours,
but on chronic dosing this decreases to 10 hours, because of
CYP450 enzyme induction. A controlled-release preparation
reduces peak plasma concentrations. It is indicated in patients
with adverse effects (dizziness, diplopia and drowsiness) that