The abolition of
seizures using a single
antiepileptic agent can be expected in more than 80% of patients, although not necessarily with the first
drug tried. The remainder often receive
polypharmacy, and current evidence suggests that perhaps only around 10% of these benefit significantly in terms of improved seizure control. Many more experience complicated drug interactions.
Carbamazepine,
phenytoin,
phenobarbital, and
primidone (metabolized in part to
phenobarbital) all induce the synthesis of hepatic
monooxygenase and conjugating
enzymes. This will result in an acceleration in the metabolism of other
lipid-soluble drugs with likely attenuation of their pharmacological effects.
Valproate, on the other hand, is a minor
enzyme inhibitor. Pharmacokinetic interactions are almost invariable when more than one
antiepileptic drug is coprescribed. The extent and direction of interactions with combinations of these drugs are varied and unpredictable. Discontinuation of an
enzyme inducer or inhibitor will influence the concentrations of the remaining
drug(s). Pharmacodynamic interactions also cause problems in epileptic patients. A number of commonly prescribed
psychoactive drugs, such as
tricyclic antidepressants and
neuroleptics, can worsen seizure control by reducing the convulsion threshold. In addition, there seems little doubt that
ethanol abuse and withdrawal can precipitate
seizures in susceptible patients.
Antiepileptic polypharmacy is more likely to impair cognitive function than the same drugs used singly. In addition, the more
antiepileptic drugs received by a patient in the first trimester of pregnancy, the higher the risk of
teratogenesis in the exposed infant. Drug interactions prolong and complicate the process of new
drug assessment, particularly when introduced in treated patients with
refractory epilepsy. The candidate
antiepileptic drug may alter the concentration of concomitant
therapy, or its own breakdown may be influenced by coprescribed
enzyme inducers or inhibitors. Even if the new
drug is excreted unchanged by the kidney, unexpected interactions can be uncovered. Pharmacodynamic interactions need not always be detrimental. Currently, there is no rational approach to the treatment of
intractable epilepsy. As more new drugs with single mechanisms of action become available, the potential exists for combining these synergistically. This approach may revolutionize the pharmacological management of the epileptic patient in the 21st century.