Lamotrigine is almost completely absorbed and has a volume of distribution of 1–1.4 L/kg. Protein binding is only about 55%. The drug has linear kinetics and is metabolized primarily by glucuronidation in the liver to the inactive 2-N-glucuronide, which is excreted in the urine. Lamotrigine has a half-life of approximately 24 hours in normal volunteers; this decreases to 13–15 hours in patients taking enzyme-inducing drugs. Lamotrigine is effective in the treatment of focal seizures in adults at dosages typically between 100 and 300 mg/d. The initial dose is 25 mg/d, increasing to 50 mg/d after 2 weeks; thereafter, titration can proceed by 50 mg/d every 1–2 weeks to a usual maintenance dose of 225–375 mg/d (in two divided doses). Therapeutic serum levels have not been established, but toxicity is infrequent with levels < 10 mcg/mL. The combination of lamotrigine and valproate is believed to be particularly efficacious. However, valproate causes a two-fold increase in the half-life of lamotrigine and can increase blood levels correspondingly, leading to a risk of skin rash if valproate is added to a stable regimen of lamotrigine. In patients receiving valproate, the initial dose of lamotrigine must be reduced to 12.5–25 mg every other day, with increases of 25–50 mg/d every 2 weeks as needed to a usual maintenance dose of 100–200 mg/d.
Levetiracetam is a broad-spectrum antiseizure agent and one of the most commonly prescribed drugs for epilepsy, primarily because of its perceived favorable adverse effect profile, broad therapeutic window, favorable pharmacokinetic properties, and lack of drug-drug interactions.
Mechanism of Action
Levetiracetam is an analog of piracetam, which is purported to be a cognition enhancer. In animal testing, levetiracetam is not active in the MES or PTZ tests, but it does have activity against seizures in the 6-Hz and kindling models. Levetiracetam binds selectively to SV2A, a ubiquitous synaptic vesicle integral membrane protein, which may function as a positive effector of synaptic vesicle exocytosis. The drug accesses the luminal side of recycling synaptic vesicles by vesicular endocytosis. Binding to SV2A in the vesicle reduces the release of the excitatory neurotransmitter glutamate during trains of high-frequency activity.
Levetiracetam is effective in the treatment of focal seizures in adults and children, primary generalized tonic-clonic seizures, and the myoclonic seizures of juvenile myoclonic epilepsy. Adult dosing can begin with 500 or 1000 mg/d. The dosage can be increased every 2–4 weeks by 1000 mg to a maximum dosage of 3000 mg/d. The drug is dosed twice daily. Adverse effects include somnolence, asthenia, ataxia, infection (colds), and dizziness. Less common but more serious are behavioral and mood changes, such as irritability, aggression, agitation, anger, anxiety, apathy, depression, and emotional lability. Oral formulations include extended-release tablets; an intravenous preparation is also available.