Comparative Anticonvulsant and Mechanistic Profile of the Established and Newer Antiepileptic Drugs

Abstract

Summary:Since 1993, several new antiepileptic drugs (AEDs) have been introduced for management of partial seizures. Like the established AEDs, the new drugs are believed to exert their anticonvulsant action through enhancement of inhibitory-mediated neurotransmission, or reduction of excitatory-mediated neurotransmission, or by a combination of both. Among the new drugs, vigabatrin (VGB) and tiagabine (TGB) are unique in that they were derived from mechanistic-based drug discovery programs designed to identify effective AEDs that inhibit the metabolism and reuptake of the inhibitory neurotransmitter GABA, respectively. For many of the newer AEDs, several molecular mechanisms of action have been identified. For example, felbamate (FBM), lamotrigine (LTG), zonisamide (ZNS), topiramate (TPM), oxcarbazepine (OCBZ), and possibly gabapentin (GBP) share a similar mechanism with that defined for phenytoin (PHT) athd carbamazepine (CBZ), i.e., a voltage-and use-dependent block of voltage-sensitive sodium (Na+) channels. In addition to their effects on Na+ currents, TPM, ZNS, and FBM also appear to act as allosteric modulators of the GABA, receptor, whereas GBP appears to increase brain GABA levels. GBP, ZNS, FBM, LTG, and OCBZ attenuate voltage-sensitive calcium (Ca2') channels, albeit through different mechanisms and with different classes of Ca2' channels. FBM and TPM differ from both the established and newer AEDs in their ability to modulate NMDA-and AMPAkainate-mediated excitatory neurotransmission, respectively. The multiple mechanisms of action associated with FBM, TPM, ZNS, GBP, and perhaps LTG, and the unique modulation of GABA levels by VGB and TGB, are likely to account for the anticonvulsant efficacy of these newer AEDs in patients with epilepsy. For each of the new drugs, their proposed mechanisms of action are discussed in relationship to their preclinical and clinical anticonvulsant profiles.

Tiagabine Synergistically Interacts with Gabapentin in the Electroconvulsive Threshold Test in Mice

“…The first oneFnonspecific, dose-dependent, and the second one (pharmacodynamic)Fclosely related with antiseizure mechanisms of action of AEDs. The proconvulsive mechanism of action of TGB, probably depends on the increase of GABA concentration within the synaptic clefts at the level of the thalamus, with subsequent potentialization of GABA B -mediated slow hyperpolarization of neurons, which finally leads to amplification of the thalamocortical rhythms necessary to support the spike-wave discharges (White, 1999). Experimental activation of GABA B receptors (with baclofenFa GABA B receptor agonist) increases the frequency of absence seizures in pharmacological and genetic models of seizures in animals (Hosford et al, 1992;Snead, 1992).…”

Tratamento de epilepsia: consenso dos especialistas brasileiros

“…É um sério problema de saúde acometendo indivíduos de todas as idades, raças e classes socioeconômicas. Na última década observamos um grande avanço no tratamento das epilepsias incluindo as novas drogas descobertas, novas formulações de antigas drogas, estimulação vagal, dieta cetogênica e o tratamento cirúrgico [3][4][5][6][7][8][9][10][11][12][13][14][15] . Apesar do crescente número de publicações cientí-ficas, algumas questões abrangendo o tratamento das epilepsias permanecem sem resposta ou controversas.…”

Interaction of the Novel Anticonvulsant, BIA 2‐093, with Voltage‐Gated Sodium Channels: Comparison with Carbamazepine

“…The voltage-gated sodium channels (VGSCs) that are responsible for actionpotential generation in central neurons are important targets for the actions of the most common used AEDs, such as carbamazepine (CBZ), phenytoin (PHT), lamotrigine (LTG), and possibly valproate (VPA). This effect is considered to contribute to the therapeutic actions of these agents (1)(2)(3)(4). Sodium channel inhibition has been a natural candidate for the mechanism of action of CBZ based on the reported interaction with receptor sites involved in the activation of sodium channels (5), and on the modulation of sodium entry (6) and sodium currents (7,8).…”