Absorption of retigabine is not affected by food, and kinetics are linear; drug interactions are minimal. The major metabolic pathways in humans are N-glucuronidation and N-acetylation. The drug neither inhibits nor induces the major CYP enzymes involved in drug metabolism.
Correct diagnosis is critical to antiseizure drug selection. The agents described in the previous section are effective for the treatment of focal onset seizures, including focal-to-bilateral tonicclonic seizures (secondarily generalized tonic-clonic seizures), but some can worsen certain seizure types in generalized epilepsy syndromes. A variety of drugs were shown initially to be effective in the treatment of focal onset seizures and are primarily used to treat these types of seizures; in addition, these drugs have also found uses in the treatment of certain generalized onset seizure types. These drugs are described below.
Lamotrigine is considered a sodium channel-blocking antiseizure drug; it is effective for the treatment of focal seizures, as are other drugs in this category. In addition, clinical trials of lamotrigine have demonstrated effectiveness in the treatment of generalized tonicclonic seizures (in idiopathic generalized epilepsy) and in the treatment of generalized absence epilepsy. In the latter, lamotrigine is not as effective as ethosuximide or valproate. The drug is generally well tolerated; however, it can produce a potentially fatal rash (Stevens-Johnson syndrome). Although adverse effects are similar to those of other sodium channel-blocking antiseizure drugs, lamotrigine paradoxically may cause insomnia instead of sedation. Lamotrigine causes fewer adverse cognitive effects than carbamazepine or topiramate. It can also improve depression in patients with epilepsy and reduces the risk of relapse in bipolar disorder.
Lamotrigine was developed when investigators thought that the antifolate effects of certain antiseizure drugs such as phenytoin might contribute to their effectiveness. Several phenyltriazines were developed; although their antifolate properties were weak, some were active in seizure screening tests. The antifolate activity of lamotrigine is not believed to contribute to its therapeutic activity in epilepsy.
Mechanism of Action
The action of lamotrigine on voltage-gated sodium channels is similar to that of carbamazepine. The mechanism by which lamotrigine is effective against absence seizures is not known.
Although most controlled studies have evaluated lamotrigine as add-on therapy, the drug is effective as monotherapy for focal seizures, and lamotrigine is now widely prescribed for this indication because of its excellent tolerability. Despite being less effective than ethosuximide and valproate for absence epilepsy, lamotrigine may be prescribed because of its tolerability or in females of childbearing age because it has fewer fetal risks than valproate. Lamotrigine is also approved for primary generalized tonic-clonic seizures and generalized seizures of the Lennox-Gastaut syndrome. Adverse effects include dizziness, headache, diplopia, nausea, insomnia, somnolence, and skin rash. The rash is a typical hypersensitivity reaction. Although the risk of rash may be diminished by introducing the drug slowly, pediatric patients are at greater risk. Serious rash occurs in approximately 0.3–0.8% of children age 2–17 years, whereas in adults, the rate is 0.08–0.3%.