Phenobarbital Introduced as an antiepileptic drug in 1912, it is as effective as phenytoin and carbamazepine, but because of its dose-related toxic effects—drowsiness and mental dullness, nystagmus, and staggering, as well as the availability of better alternatives—it is now infrequently used in adults. It inhibits sodium currents through the sodium channel and has been found to have some additional GABA-ergic effect. The drug strongly induces cytochrome P450 and therefore has interactions with many medications. There are infrequent disorders of connective tissue, such as frozen shoulder and Duyputren contractures that have been attributed to long-term use. The adverse effects of primidone are much the same. Both drugs may provoke behavioral problems in developmentally delayed children and they are still used to advantage as an adjunctive anticonvulsant and as primary therapy in infantile seizures. The rate of teratogenicity is increased (stated to be approximately 5.5 percent) and comparable to other main line drugs.
Lamotrigine This drug closely resembles phenytoin in having a broad spectrum of antiseizure activity but has different features relating to toxicity. It functions by selectively blocking the slow sodium channel, thereby preventing the release of the excitatory transmitters glutamate and aspartate. It is effective as a first-line and adjunctive drug for generalized and focal seizures, and may be an alternative to valproate in young women because it does not provoke weight gain and ovarian problems. The main limitation to its use has been a serious rash in approximately 1 percent of patients, requiring discontinuation of the drug, and lesser dermatologic eruptions in 12 percent. It should be pointed out that some registries have reported considerably lower rates of these complications and the slow introduction of the medication may reduce the incidence of drug eruptions (see below). Rare cases of reversible chorea have been reported, especially with the concurrent use of phenytoin. Combined use with valproate greatly increases the serum level of lamotrigine. It has been said to have a more favorable teratogenic profile than most other drugs. Dosing depends greatly on the concurrent use of other drugs, reducing its dose and rapidity of escalation if used with other enzyme-inducing AEDs such as phenytoin or carbamazepine and particularly with valproate.
Levetiracetam This novel drug with uncertain mechanism has been useful in the treatment of both partial and generalized seizures. The agent interacts with the SV2A synaptic vesicle protein, but how this relates to its antiepileptic properties is still being investigated. It is well tolerated if initiated slowly, but may produces considerable sleepiness and dizziness and if used at high doses. It also may produce irritability and depression or exaggerate underlying depression. A major advantage is that there are no important interactions with other antiepileptic drugs and it is renally excreted for which reason it is often chosen as a first-line agent in patients who have organ failure and require numerous medications, as well as those receiving hepatically metabolized chemotherapeutics. There are some data showing a favorable teratogenic profile.
Other antiepileptic drugs Two other drugs, gabapentin and vigabatrin, were synthesized specifically to enhance the intrinsic inhibitory system of GABA in the brain. Gabapentin is chemically similar to GABA, but its anticonvulsant mechanism is not known; it has an apparent effect on calcium channels. It is moderately effective in partial and secondary generalized seizures and has the advantage of not being metabolized by the liver. Vigabatrin inhibits GABA transaminase. Vigabatrin is no longer used in adults because of the side effect or retinal damage. Tiagabine is considered to be an inhibitor of GABA reuptake.