Pharmacological management of epilepsy. Mechanism of action, pharmacokinetic drug interactions, and new drug discovery possibilities.

Despite recent advances in neurobiology and significant insight into the molecular dysfunction of epilepsy, about 25% of patients do not completely respond to current frontline therapeutic agents such as carbamazepine, phenytoin, valproic acid, ethosuximide, phenobarbital, and benzodiazepine. Recently, much effort has been made to discover new antiepileptic drugs effective in refractory seizures. Two major groups of drugs have emerged of which felbamate, gabapentin, lamotrigine, oxcarbazepine, and vigabatrin are among the most promising. The mechanism of action of the first group works by enhancing brain GABA activity (e.g. vigabatrin) while the second group inhibits excitatory amino acids (e.g. lamotrigine and felbamate). Oxcarbazepine acts in a similar manner to carbamazepine while gabapentin's mode of action is still unclear. The major clinical indications of these new antiepileptics are partial complex seizures. They exhibit limited drug interactions with few adverse effects. A rational approach to the drug discovery process is necessary in order to lead to novel effective therapy. Another line of research is the use of the structure-activity relationship to fine-tune the pharmacology of existing antiepileptics providing less adverse effects with the same or better efficacy. Clinical perspectives from the discovery of new drugs such as fosphenytoin and valproyl glycinamide look promising. Rapid development in molecular biologic techniques for the study of the neurophysiology of epilepsy and the neurotransmitters which are the target for the antiepileptic drugs may also provide better insight into the interactions of antiepileptics with either ion channels or brain receptors.