Page 294 - ILAE_Lectures_2015

Primidone

Primidone is metabolised to phenobarbital and its efficacy is similar to that of phenobarbital,
but it is not as well tolerated. There is therefore nothing to recommend it over phenobarbital
for people in whom treatment with a barbiturate is contemplated.

Sodium valproate (valproic acid)

Sodium valproate is a broad spectrum AED effective over the complete range of seizure types,
with particular value in the idiopathic generalised epilepsies. It use in women of childbearing
potential, however, is problematic in view of its potential teratogenicity.

The starting dose of sodium valproate for adults and adolescents should be 500 mg/day for one
or two weeks, increasing in most people to 500 mg twice daily. The controlled release
formulation can be given once daily. Alterations thereafter should be made according to clinical
need. Since the drug can take several weeks to become fully effective, frequent dosage
adjustments shortly after initiating therapy may be unwarranted. As valproate does not exhibit
a clear-cut concentration-effect-toxicity relationship and the daily variation in the level at a
given dose is wide, routine monitoring is not helpful unless used as a check of adherence to
therapy.

Side effects of sodium valproate include dose-related tremor, weight gain due to appetite
stimulation, thinning or loss of hair (usually temporary), and menstrual irregularities including
amenorrhoea. Polycystic ovarian syndrome has been reported in some women. Sedation is an
uncommon complaint, although stupor and encephalopathy can occur, albeit rarely, possibly as
a consequence of underlying carnitine deficiency. Hepatotoxicity, histologically a
microvesicular steatosis similar to that found in Reye’s syndrome, affects fewer than one in
20,000 exposed individuals. Children under three years of age receiving AED polypharmacy
are the highest risk group. Mild hyperammonaemia without hepatic damage is seen in up to
10% of people taking it. This is usually transient, but occasionally can present clinically with
confusion, nausea and vomiting and clouding of consciousness. Other sporadic problems
include thrombocytopenia and pancreatitis. Valproate is far more teratogenic than other
commonly used AEDs and this needs to be taken into account when treating women of
childbearing age.

Sodium valproate can inhibit a range of hepatic metabolic processes, including oxidation,
conjugation and epoxidation reactions. Targets include other AEDs, particularly phenytoin,
phenobarbital, carbamazepine epoxide, and lamotrigine. Aspirin displaces sodium valproate
from its binding sites on plasma protein and inhibits its metabolism. Sodium valproate,
however, does not interfere with the hormonal components of the oral contraceptive pill.

Tiagabine

Tiagabine is last resort drug for focal seizures with or without secondary generalisation. It has
no use in any other seizure type.

The recommended dose is between 30 and 45 mg/day, although higher doses (up to 80 mg/day)
have been used. Tiagabine should be started at 10 mg/day in two divided doses, and increased
by 510 mg/day each week up to 30 mg/day in the first instance. Doses above 30 mg/day should
be given in three divided doses.

Tiagabine does not affect levels of carbamazepine or phenytoin, but may reduce the plasma
concentration of valproate by about 10%, which is unlikely to be of clinical importance.