Mechanisms of action of currently used antiseizure drugs

Antiseizure drugs (ASDs) prevent the occurrence of seizures; there is no evidence that they have disease-modifying properties. In the more than 160 years that orally administered ASDs have been available for epilepsy therapy, most agents entering clinical practice were either discovered serendipitously or with the use of animal seizure models. The ASDs originating from these approaches act on brain excitability mechanisms to interfere with the generation and spread of epileptic hyperexcitability, but they do not address the specific defects that are pathogenic in the epilepsies for which they are prescribed, which in most cases are not well understood. There are four broad classes of such ASD mechanisms: (1) modulation of voltage-gated sodium channels (e.g. phenytoin, carbamazepine, lamotrigine), voltage-gated calcium channels (e.g. ethosuximide), and voltage-gated potassium channels [e.g. retigabine (ezogabine)]; (2) enhancement of GABA-mediated inhibitory neurotransmission (e.g. benzodiazepines, tiagabine, vigabatrin); (3) attenuation of glutamate-mediated excitatory neurotransmission (e.g. perampanel); and (4) modulation of neurotransmitter release via a presynaptic action (e.g. levetiracetam, brivaracetam, gabapentin, pregabalin). In the past two decades there has been great progress in identifying the pathophysiological mechanisms of many genetic epilepsies. Given this new understanding, attempts are being made to engineer specific small molecule, antisense and gene therapies that functionally reverse or structurally correct pathogenic defects in epilepsy syndromes. In the near future, these new therapies will begin a paradigm shift in the treatment of some rare genetic epilepsy syndromes, but targeted therapies will remain elusive for the vast majority of epilepsies until their causes are identified. This article is part of the special issue entitled ‘New Epilepsy Therapies for the 21st Century – From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy’.