Drug interactions in epilepsy.
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.