FIGURE 24–1 Molecular targets for antiseizure drugs at the excitatory glutamatergic synapse (A) and the inhibitory GABAergic synapse (B). Presynaptic targets diminishing glutamate release include Nav1.6 voltage-gated sodium channels (carbamazepine, monohydroxy derivative [MHD], phenytoin, lamotrigine, and lacosamide), Kv7 voltage-gated potassium channels (retigabine [ezogabine]), and α2δ (gabapentin and pregabalin). Postsynaptic targets at excitatory synapses are AMPA receptors (perampanel), T-type Cav voltage-gated calcium channels (ethosuximide, dimethadione), and Kv7 voltage-gated potassium channels (retigabine [ezogabine]). At inhibitory synapses and in astrocytes, vigabatrin inhibits GABA-transaminase (GABA-T) and tiagabine blocks GABA transporter 1 (GAT-1). Phenobarbital, primidone (via metabolism to phenobarbital), and benzodiazepines are positive allosteric modulators of synaptic GABAA receptors; high GABA levels resulting from blockade of GABA-T may act on extrasynaptic GABAA receptors.
TABLE 24–2 Molecular targets of antiseizure drugs.
1Fosphenytoin is a prodrug for phenytoin. 2Oxcarbazepine serves largely as a prodrug for licarbazepine, mainly S-licarbazepine. 3Eslicarbazepine acetate is a prodrug for S-licarbazepine. 4Gabapentin enacarbil is a prodrug for gabapentin. 5There is no consensus as to the mechanism of valproate; felbamate, topiramate, zonisamide, and rufinamide may have actions on as yet unidentified targets in addition to those shown in the table. Modified from Rogawski MA, Löscher W, Rho JM: Mechanisms of action of antiseizure drugs and the ketogenic diet. Cold Spring Harb Perspect Med 2016;6:a022780.
Antiseizure drugs must have reasonable oral bioavailability and must enter the central nervous system. These drugs are predominantly distributed into total body water. Plasma clearance is relatively slow; many antiseizure drugs are therefore considered to be medium to long acting, such that they are administered twice or three times a day. Some have half-lives longer than 12 hours. A few, such as zonisamide and perampanel, can often be administered once daily. For some drugs with short half-lives, extended-release preparations are now available; as a result, compliance is better. In the remainder of the chapter, the most widely used anti-seizure drugs, as well as some that are used only in special circumstances, are reviewed. The focal (partial onset) seizure medications are described first, followed by medications for generalized onset seizures and certain epileptic syndromes.