The New Antiepileptic Drugs Pharmacological and Clinical Aspects

Abstract

In recent years several new drugs (oxcarbazepine, lamotrigine, topiramate, gabapentin, zonisamide, tiagabine, fosphenytoin, vigabatrin and felbamate) have been added to the therapeutic armamentarium against epilepsy. Some of these represent structural modifications of pre-existing compounds, others were developed with the specific objective of modifying neurotransmitter function, and many more were found to be clinically useful even though their mode of action is unclear or differs from that originally planned. The pharmacokinetics of these drugs differ widely from one agent to another. Some (gabapentin and vigabatrin) are eliminated unchanged in urine and have little or no interaction potential; others (tiagabine, lamotrigine, topiramate, oxcarbazepine, zonisamide, felbamate) are subject to induction of metabolism by concomitant anticonvulsants; lamotrigine is vulnerable to metabolic inhibition by valproate, and felbamate is a powerful enzyme inhibitor in addition to being an inducer of the metabolism of carbamazepine and steroid oral contraceptives. All new antiepileptic drugs have been found to be effective in improving seizure control in patients with partial and secondarily generalized seizures. However, lamotrigine, topiramate, zonisamide and felbamate appear to have broader efficacy against both partial and many generalized seizure types, while vigabatrin is also valuable in the management of infantile spasms. In monotherapy studies, new drugs have not been found to be more efficacious than older agents, but some may offer limited advantages in terms of improved tolerability. On the other hand, serious toxicity restricts considerably the use of vigabatrin and felbamate. Overall, new drugs represent valuable tools in the fight against epilepsy, but because of limited experience and cost considerations their first-line use cannot be recommended in most situations.

Glutamate and the glutamate receptor system: a target for drug action

“…The better understanding of the meaning of glutamatergic neurotransmission in epilepsy has led to a prolonged systematic search for new anticonvulsants from the group of glutamate receptor antagonists. The inhibitory influence of anticonvulsants such as topiramate (AMPA receptor antagonist) and lamotrigine (glutamate release inhibitor) on glutamatergic transmission has been clinically exploited for some time (Gatti et al, 2000). Experimental studies have shown that more specific antagonists that act on the relevant receptor subunits firstly have a good clinical effect and secondly do not show the known and often limiting side effects (Boyce et al, 1999).…”

Newer antiepileptic drugs: Possible uses in the treatment of neuropathic pain and migraine

“…For that reason, it is recommended that patients taking either of these AEDs not use oral contraceptives. 141,142 Oxcarbazepine also inhibits CYP2C19, which alters levels of commonly used calcium channel antagonists. 129 Phenytoin, phenobarbital, and carbamazepine are all potent inducers of CYP isozymes and will lower serum levels of all AEDs mentioned in this article (except for gabapentin).…”

Innovations in Epilepsy Management – An Overview

“…The National Institute of Neurological Disorders and Stroke Anticonvulsant Screening Program (ASP) had provided direct preclinical support for these drugs in various stages of their development. They are oxcarbazepine, gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, zonisamide, vigabatrin, and felbamate, in addition to the water-soluble phenytoin prodrug fosphenytoin (4,5). These drugs produce a significant improvement in seizure control in many patients who had been refractory to the classical older drugs.…”