Frank MC Besag, Philip N Patsalos

Although most people presenting with partial-onset seizures will achieve control with antiepileptic medication, a considerable minority will have difficult-to-treat epilepsy that is resistant to existing medication. Over the last few years, a large number of new antiepileptic drugs have been developed. Some of these have a novel mode of action. Many of the older antiepileptic drugs act through sodium channels or by enhancement of gamma amino butyric acid (GABA). Lamotrigine has sodium-channel blocking properties but also has other important modes of action, indicated by efficacy in treating not only partial-onset but also generalized seizures. Vigabatrin and tiagabine both increase GABA activity, by inhibiting GABA transaminase and limiting GABA reuptake, respectively. The main mode of action of gabapentin and pregabalin is not via GABA but through a selective inhibitory effect on voltage-gated calcium channels containing the α(2)δ-1 subunit. Levetiracetam inhibits the recycling of SV2A (synaptic vesicle protein 2A) neurotransmitter vesicles but also has other effects, including inhibition of voltage-dependent calcium channels. Some drugs, eg, felbamate, zonisamide, and topiramate, have multiple modes of action. In many cases, although the main mode of action may have been identified, other modes of action also play a role. Two recently developed antiepileptic drugs appear to have completely novel primary modes of action; retigabine (ezogabine) and perampanel act on the potassium channel and on AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, respectively. The hope is that antiepileptic drugs with a novel mode of action will be effective where previous drugs have failed and will not have unacceptable adverse effects. However, experience with these medications is too limited to allow any conclusions to be drawn at present.