(B) Voltage and use dependence of block of human Nav1.2 voltage-activated sodium channels. Sodium currents elicited by depolarization from a holding potential of –90 mV (where there is little inactivation) are minimally affected by 100 μM of lamotrigine, whereas there is strong block of current elicited from –60 mV (where there is more substantial inactivation). Trains of 0.7-millisecond (ms) duration pulses from –90 mV (minimal inactivation) are minimally blocked in a use-dependent fashion by 100 μM of lamotrigine, whereas 20-ms pulses (marked inactivation) show substantial use dependence. (Adapted, with permission, from Xie X, Hagan RM: Cellular and molecular actions of lamotrigine: Possible mechanisms of efficacy in bipolar disorder. Neuropsychobiology 1998;38:119.) been shown to have antiseizure activity. This reaction is primarily catalyzed by CYP3A4, although CYP2C8 also plays a role and CYP3A5 may be involved. The contribution of this and other metabolites to the clinical activity of carbamazepine is unknown.
Carbamazepine is available in oral forms (tablets and suspensions), and an intravenous formulation is available for temporary replacement of oral therapy. The drug is effective in children, in whom a dosage of 15–25 mg/kg/d is appropriate. In adults, the typical daily maintenance dose is 800–1200 mg/d, and the maximum recommended dose is 1600 mg/d, but rarely patients have required doses up to 2400 mg/d. Higher dosage is achieved by giving multiple divided doses daily. Extended-release preparations permit twice-daily dosing for most patients. In patients in whom the blood is drawn just before the morning dose (trough level), therapeutic concentrations are usually 4–8 mcg/mL. Although many patients complain of diplopia at drug levels above 7 mcg/mL, others can tolerate levels above 10 mcg/mL, especially with monotherapy. Drug initiation should be slow, with gradual increases in dose.
Carbamazepine stimulates the transcriptional up-regulation of CYP3A4 and CYP2B6. This autoinduction leads not only to a reduction in steady-state carbamazepine concentrations but also to an increased rate of metabolism of concomitant antiseizure drugs including primidone, phenytoin, ethosuximide, valproic acid, and clonazepam. Some antiseizure drugs such as valproic acid may inhibit carbamazepine clearance and increase steady-state carbamazepine blood levels. Other antiseizure drugs, notably phenytoin and phenobarbital, may decrease steady-state concentrations of carbamazepine through enzyme induction. These interactions may require dosing changes. No clinically significant protein-binding interactions have been reported.
Carbamazepine may cause dose-dependent mild gastrointestinal discomfort, dizziness, blurred vision, diplopia, or ataxia; sedation occurs only at high doses, and rarely, weight gain can occur. The diplopia often occurs first and may last less than an hour during a particular time of day. Rearrangement of the divided daily dose can often remedy this complaint. A benign leukopenia occurs in many patients, but there is usually no need for intervention unless neutrophil count falls below 1000/mm3. Rash and hyponatremia are the most common reasons for discontinuation. Stevens-Johnson syndrome is rare, but the risk is significantly higher in patients with the HLA-B*1502 allele. It is recommended that Asians, who have a 10-fold higher incidence of carbamazepineinduced Stevens-Johnson syndrome compared to other ethnic groups, be tested before starting the drug.