title: [Antiepileptic drugs in North America].
abstract: In this review study, second-generation antiepileptic drugs (AEDs) (levetiracetam, gabapentin, topiramate, lamotrigine, zonisamide, oxcarbazepine, vigabatrin, pregabalin, rufinamide, tiagabine, lacosamide, and felbamate) and injectable AEDs (levetiracetam, lacosamide, fosphenytoin, lorazepam, and valproic acid) available in North America were compared with those available in Japan. Three second-generation AEDs (gabapentin, topiramate, and lamotrigine) were recently approved in Japan. Levetiracetam is currently under review for approval by the Japanese regulatory agency. An ideal AED would have a broad-spectrum activity to control multiple types of seizures, favorable safety profile, limited potential for drug-drug interaction, many bioequivalent formulations, long half life to allow infrequent administration, and antiepileptogenic effects that may provide a fundamental cure of epileptic patients by suppressing the development of epileptogenic network and neutralizing previously established epileptogenic foci in the brain. The second-generation AEDs have been developed to possess some of these ideal properties. All the second-generation AEDs are efficacious for the treatment of patients with partial seizures. In addition, levetiracetam, topiramate, lamotrigine, and zonisamide are effective for the treatment of patients with generalized tonic-clonic seizures, absences, myoclonic seizures, Lennox-Gastaut syndrome, and West syndrome; however, lamotrigine is not effective for the treatment of patients with myoclonic seizures. Rufinamide and felbamate are useful for the treatment of patients with Lennox-Gastaut syndrome; however owing to its serious adverse effects, including aplastic anemia and hepatic failure, felbamate is used as the last resort for the treatment of patients with intractable seizures. Vigabatrin is particularly effective for the treatment of patients with West syndrome; however, the patients need to be regularly monitored for the development of peripheral visual field defect. Gabapentin, oxcarbazepine, vigabatrin, and tiagabine are ineffective for the treatment of patients with absences and/or myoclonic seizures and may aggravate these conditions. Treatment with levetiracetam or topiramate (off-label use) is the new option for patients with refractory status epilepticus, which is characterized by downregulation of the inhibitory gamma-aminobutyric acid system, because these drugs act via different mechanisms and are rapidly titratable, especially intravenous levetiracetam. The pharmacokinetic profiles of levetiracetam, gabapentin, and pregabalin are favorable: these drugs exhibit minimal protein binding, do not undergo hepatic metabolism, are not involved in any clinically relevant drug interactions, and rarely lead to the development of serious adverse effects. In general, levetiracetam is probably the closest to being the ideal AED because of its broad-spectrum favorable pharmacokinetic profile and safety profile as well as because of the availability of its parenteral formulation. Among the injectable AEDs, fosphenytoin is a water-soluble prodrug and is used to treat patients with status epilepticus. Systemic and local side effects of this drug are fewer than those of phenytoin. Lorazepam, a benzodiazepine is used as the first-line AED for the treatment of patients with status epilepticus. The effects of this drug are more prolonged than those of diazepam. Intravenous administration of valproic acid is regarded as a new treatment option for patients with status epilepticus, because sedative and negative effects on the cardiorespiratory system of this drug are lesser than those of the traditional injectable AEDs. These novel medications will aid the improvement of the quality of life of epileptic patients through improved seizure control and reduced adverse effects.
authors.affiliation: Division of Neurology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Akiyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Otsubo
mesh_terms: D000927:Anticonvulsants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002220:Carbamazepine / Q000031:analogs & derivatives; D017277:Drug Approval; D005632:Fructose / Q000031:analogs & derivatives; D006801:Humans; D007564:Japan; D000077213:Lamotrigine; D000077287:Levetiracetam; D008140:Lorazepam; D009656:North America; D010672:Phenytoin / Q000031:analogs & derivatives; D010889:Piracetam / Q000031:analogs & derivatives; D000077236:Topiramate; D014227:Triazines
chemical_list: D000927:Anticonvulsants; D014227:Triazines; C476610:oxcarbamazepine; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D000077287:Levetiracetam; D010672:Phenytoin; C043114:fosphenytoin; D008140:Lorazepam; D000077213:Lamotrigine; D010889:Piracetam