Page 278 - ILAE_Lectures_2015

Chapter 28

Overview of established antiepileptic drugs

J.W. SANDER

UCL Institute of Neurology, University College London, National Hospital for Neurology
and Neurosurgery, Queen Square, London, and Epilepsy Society, Chalfont St Peter,
Buckinghamshire

Established antiepileptic drugs (AEDs) are those which were licensed before 2000. By now,
substantial data have accumulated on them. Their pharmacokinetic properties are listed in
Table 1, and indications and a guide to dosing in children, adults and adolescents are outlined
in Tables 2 and 3, respectively. These drugs are not without their hazards and their optimum
use must be governed by an appreciation of their potential for dose-related and idiosyncratic
toxicity (Table 4). The clinical use of each drug will be considered, highlighting the practical
problems likely to be encountered during every day clinical use.

Carbamazepine

Carbamazepine is indicated for focal seizures and generalised tonic-clonic seizures. It is not
effective, and may even be deleterious, for some people with absences and myoclonic
seizures.

Carbamazepine, as a strong auto-inducer, should be introduced in low dosage (100200 mg
daily) to allow tolerance to develop to its CNS side effects. The dose can then be increased
in 12 weekly increments of 100200 mg/day to a maintenance dose that completely controls
seizures.

Diplopia, headache, dizziness, nausea and vomiting are the commonest side effects of
carbamazepine, some of which may be due to its active epoxide metabolite. Peak levels often
result in intermittent side effects occurring around two hours after dosing, necessitating
administration three or four times daily in some. These problems can often be overcome by
prescribing the controlled-release formulation, which can be given twice daily.

Carbamazepine can cause a range of idiosyncratic reactions, the most common of which is a
skin rash, occurring in up to 10% of people exposed to it. Slow dosage titration reduces the
risk. Rarely, it may cause more severe skin eruptions including erythema multiforme and
Stevens-Johnson syndrome. Reversible mild leucopenia often occurs and has no clinical
significance. Discontinuation of therapy is not required unless accompanied by evidence of
infection or if the cell count is well below 2 x 109/L. Blood dyscrasias and toxic hepatitis
occur very rarely.

There are some long-term problems with carbamazepine. As a strong enzyme inducer it has
the potential to affect bone health in the long term and this needs to be taken into account
particularly if lifelong treatment is a consideration. At high levels, carbamazepine has an
antidiuretic hormone-like action that can result in fluid retention in people with cardiac failure
and in the elderly. Mild hyponatraemia is usually asymptomatic, but if serum sodium falls
below 125 mmol/L there might be confusion, peripheral oedema and worsening seizure
control. Cardiac arrhythmia is also an occasional complication.