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in dose can produce an unexpectedly large rise in the level with accompanying neurotoxicity.
Conversely, levels can fall precipitously when the dose is reduced modestly, resulting
sometimes in unexpected deterioration in seizure control. The dosage producing the same
levels, therefore, varies substantially among different individuals.

Phenytoin can produce a range of dose-related and idiosyncratic adverse effects including rash,
hepatotoxicity and blood dyscrasias. Reversible cosmetic changes (gum hyperplasia, acne,
hirsutism, facial coarsening), although often mild, can be troublesome. Phenytoin is an enzyme
inducer and as such may impact on bone health. Symptoms of neurotoxicity (drowsiness,
dysarthria, tremor, ataxia, cognitive difficulties) become increasingly likely with higher levels
but the diagnosis of phenytoin toxicity should be made on clinical grounds and not assumed
from a high level. The person may complain of mental slowing and unsteadiness, and
neurological examination may show cerebellar signs. Permanent cerebellar damage may be a
consequence of chronic toxicity, so it is important to examine regularly the person taking it. In
some of these people, cerebellar atrophy will be apparent on brain imaging, although hard
evidence for cause and effect is not readily available. A paradoxical increase in seizure
frequency may also occur with marked phenytoin toxicity.

It can accelerate the metabolism of a number of lipid-soluble drugs, including carbamazepine,
sodium valproate, ethosuximide, anticoagulants, steroids and cyclosporin. Due to its saturable
metabolism, phenytoin provides a target for drugs such as allopurinol, amiodarone, cimetidine,
imipramine and some sulphonamides. Protein binding displacement interactions with AEDs are
only clinically relevant when there is concomitant enzyme inhibition, as is the case with the
combination of phenytoin and sodium valproate.

Phenobarbital

Phenobarbital is an established treatment for focal and tonic-clonic seizures but is seldom
currently used in developed countries due to its potential to cause neurotoxicity.

Phenobarbital is an easy drug to use clinically. To minimise sedation, a low dose should be
started (30 mg in adolescents and adults), which can be increased gradually (1530 mg
incremental steps) according to clinical requirements. The value of measuring its levels is
limited, as concentration associated with seizure control varies considerably. In addition, the
development of tolerance to its CNS side effects makes the toxic threshold imprecise.

The major problem in the clinical use of phenobarbital is its effect on cognition, mood and
behaviour. It can produce fatigue, listlessness and tiredness in adults and insomnia,
hyperactivity and aggression in children (and sometimes in the elderly). Subtle impairment of
memory, mood and learning capacity can occur. Depression may be a consequence of long-
term use and arthritic changes, frozen shoulder, and Dupuytren’s contracture can be associated
problems. Tolerance develops to the deleterious cognitive effects of the drug but also to its
efficacy in some people. Phenobarbital is an enzyme inducer and can accelerate the metabolism
of many lipid-soluble drugs and has an impact on bone health.

Piracetam

Piracetam is only indicated as an adjunctive treatment in refractory myoclonus. It has no use in
other seizure types. The usual starting dose is 7.2 g daily in two or three divided doses, increased
weekly by 4.8 g/day according to clinical response. Effective doses are usually between 12 and
24 g/day and this bulk is one of the limiting factors of the use of this drug. Piracetam is generally
well tolerated. The commonest side effects are diarrhoea, weight gain, insomnia, and
depression. Hyperkinesia has been reported with very high doses. There are no known drug
interactions with piracetam.