Carbamazepine

CARBAMAZEPINE

Closely related to imipramine and other antidepressants, carbam-azepine is a tricyclic compound effective in treatment of bipolar depression. It was initially marketed for the treatment of trigemi-nal neuralgia but has proved useful for epilepsy as well.

Chemistry

Although not obvious from a two-dimensional representation of its structure, carbamazepine has many similarities to phenytoin. The ureide moiety (–N–CO–NH₂) in the heterocyclic ring of most antiseizure drugs is also present in carbamazepine. Three-dimensional structural studies indicate that its spatial conforma-tion is similar to that of phenytoin.

Mechanism of Action

The mechanism of action of carbamazepine appears to be similar to that of phenytoin. Like phenytoin, carbamazepine shows activity against maximal electroshock seizures. Carbamazepine, like phenytoin, blocks Na⁺ channels at therapeutic concentrations and inhibits high-frequency repetitive firing in neurons in culture (Figure 24–4). It also acts presynaptically to decrease synaptic transmission. Potentiation of a voltage-gated K⁺ current has also been described. These effects probably account for the anticonvul-sant action of carbamazepine. Binding studies show that carbam-azepine interacts with adenosine receptors, but the functional significance of this observation is not known.

Clinical Uses

Although carbamazepine has long been considered a drug of choice for both partial seizures and generalized tonic-clonic seizures, some of the newer antiseizure drugs are beginning to displace it from this role. Carbamazepine is not sedative in its usual therapeutic range. The drug is also very effective in some patients with trigeminal neuralgia, although older patients may tolerate higher doses poorly, with ataxia and unsteadiness. Carbamazepine is also useful for controlling mania in some patients with bipolar disorder.

Pharmacokinetics

The rate of absorption of carbamazepine varies widely among patients, although almost complete absorption apparently occurs in all. Peak levels are usually achieved 6–8 hours after administra-tion. Slowing absorption by giving the drug after meals helps the patient tolerate larger total daily doses.

Distribution is slow, and the volume of distribution is roughly 1 L/kg. The drug is approximately 70% bound to plasma proteins; no displacement of other drugs from protein binding sites has been observed.

Carbamazepine has a very low systemic clearance of approxi-mately 1 L/kg/d at the start of therapy. The drug has a notable ability to induce microsomal enzymes. Typically, the half-life of 36 hours observed in subjects after an initial single dose decreases to as little as 8–12 hours in subjects receiving continuous therapy. Considerable dosage adjustments are thus to be expected during the first weeks of therapy. Carbamazepine also alters the clearance of other drugs .

Carbamazepine is completely metabolized in humans to several derivatives. One of these, carbamazepine-10,11-epoxide, has been shown to have anticonvulsant activity. The contribution of this and other metabolites to the clinical activity of carbamazepine is unknown.

Therapeutic Levels & Dosage

Carbamazepine is available only in oral form. The drug is effective in children, in whom a dosage of 15–25 mg/kg/d is appropriate. In adults, daily doses of 1 g or even 2 g are tolerated. Higher dos-age 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), the therapeutic level is 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. Extended-release formulations that overcome some of these issues are now available.

Drug Interactions

Drug interactions involving carbamazepine are almost exclu-sively related to the drug’s enzyme-inducing properties. As noted previously, the increased metabolic capacity of the hepatic enzymes may cause a reduction in steady-state carbamazepine concentrations and an increased rate of metabolism of other drugs, eg, primidone, phenytoin, ethosuximide, valproic acid, and clonazepam. Other drugs such as valproic acid may inhibit carbamazepine clearance and increase steady-state carbam-azepine blood levels. Other anticonvulsants, however, such as phenytoin and phenobarbital, may decrease steady-state con-centrations of carbamazepine through enzyme induction. No clinically significant protein-binding interactions have been reported.

Toxicity

The most common dose-related adverse effects of carbamazepine are diplopia and ataxia. 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. Other dose-related complaints include mild gastrointestinal upsets, unsteadiness, and, at much higher doses, drowsiness. Hyponatremia and water intoxication have occasionally occurred and may be dose related.Considerable concern exists regarding the occurrence of idio-syncratic blood dyscrasias with carbamazepine, including fatal cases of aplastic anemia and agranulocytosis. Most of these have been in elderly patients with trigeminal neuralgia, and most have occurred within the first 4 months of treatment. The mild and persistent leukopenia seen in some patients is not necessarily an indication to stop treatment but requires careful monitoring. The most common idiosyncratic reaction is an erythematous skin rash; other responses such as hepatic dysfunction are unusual.