Continued...

New Derivatives or formulations of First line ASDs

Topiramate: It also has a broad spectrum of activity. It acts by promoting the inactivated state of voltage gated sodium channels. It appears to help balance electrical activity in the brain while blocking other substances that increase activity. Weight loss has been noted, which can be a desirable lateral side effect. It also inhibits enzyme carbonic anhydrase, which is believed to be the mechanism of developing some other side effects like paresthesia and nephrolithiasis. Topiramate is approved for adjunctive therapy for partial and generalized seizures in adult and pediatric patients older than 2 years of age. It has been found to be effective as adjunctive therapy for Lennox-Gastaut syndrome and infantile spasms (10,11).

Tiagabine: It is a GABA Transporter GAT1 inhibitor that reduces uptake of GABA and thus acts as anti seizure drug. It is rapidly absorbed, extensively bound to protein and metabolized in liver. Efficacy and tolerability in children have been encouraging. Tiagabine has no significant systemic or serious idiosyncratic adverse side effects, but it does have a relatively narrow spectrum of activity and must be titrated slowly. It is approved as adjunctive therapy for partial seizures in adults and adolescents. It has been found to be efficacious in refractory partial epilepsy. It should be used with caution in patients with generalized seizures, as they may be exacerbated (13,14).

Note: One limitation of Lamotrigine, Topiramate and Tiagabine, is that they need to be initiated at a low dosage and slowly increased in dosage over several weeks.

Vigabatrin: It is another second generation ASD working on GABA inhibitory neurons. It is an irreversible inhibitor of GABA transaminase which leads to increased levels of GABA. It is used as add-on treatment of patients with refractory partial epilepsy. Vigabatrin has been approved in many countries but not the United States. It is rapidly absorbed following oral administration and peak plasma concentrations are reached within 2 hours. It is only slightly metabolized and majority of the drug is eliminated unchanged through kidneys. In some studies, it has been attributed to cause irreversible visual field defects, hence it should be used with caution particularly in children having renal impairment (14). Its use has been limited to patients with refractory partial epilepsy when other appropriate drugs have failed, and to patients with infantile spasms. Many regard vigabatrin as the drug of choice for infantile spasms. Vigabatrin may exacerbate absence and myoclonic seizures (15).

Levetiracetam: It is another very exciting drug. It is unique among the SGASDs because it is effective starting with the initial dose and thus it has a role in treating ongoing seizure activities including status epilepticus. Its mechanism of action is not known. Neither inactivation of voltage gated sodium channel nor GABA activation is observed. Like Gabapentin, its tolerability and pharmacokinetics profiles are very attractive. Levetiracetam is not metabolized by the liver (about 65% is excreted by the kidneys unchanged), and less than 10 percent is protein bound. It is neither an inducer nor inhibitor of hepatic microsomal enzyme systems. As a result, drug interactions are minimal. Levetiracetam is approved for adjunctive treatment of partial seizures with or without generalization in adults and children. Various clinical trials has showed effective conversion to monotherapy in patients with refractory partial seizures (16-18).