What is the role of carbamazepine (CBZ) in the treatment of epilepsy?

Updated: Jan 28, 2020
  • Author: Juan G Ochoa, MD; Chief Editor: Selim R Benbadis, MD  more...
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Carbamazepine (CBZ) is a major first-line AED for partial seizures and generalized tonic-clonic seizures. It is a tricyclic compound and initially was used primarily for the treatment of trigeminal neuralgia; its value in the treatment of epilepsy was discovered quite by chance. CBZ’s main mode of action is to block sodium channels during rapid, repetitive, sustained neuronal firing and to prevent posttetanic potentiation. It has been approved in the United States for the treatment of epilepsy since 1974; however, it has been used for epilepsy since 1968.

CBZ is a crystalline substance that is insoluble in water and thus is limited to oral administration. It is unstable and must be protected from hot or humid conditions, which decrease its bioavailability by 50%. Approximately 75-85% of the drug is plasma protein bound, and it has a free fraction of 20-24% of the total plasma concentration. Cerebrospinal fluid (CSF) levels range from 17% to 31%. It is metabolized extensively in the liver and induces its own metabolism. The major metabolic pathway is epoxidation to CBZ 10,11-epoxide and hydrolysis to CBZ 10,11-trans -dihydrodiol.

Because CBZ induces its own metabolism, causing an increase in clearance and a decrease in levels, the serum half-life decreases by 50% during the first few weeks of treatment. The elimination half-life ranges from 5 to 26 hours following repeated treatment in healthy volunteers and patients with epilepsy. In children, the half-life ranges from 3 to 32 hours. Its induction of hepatic cytochrome P-450 system activity also increases the metabolism of other AEDs. Peak levels of the drug are present in the blood for 4-8 hours.

Formulations that are available include suspension, syrup, tablets (100 mg, 200 mg, 400 mg), chewable tablets (100 mg, 200 mg), extended-release capsules (Tegretol XR; 100 mg, 200 mg, 400 mg), Carbatrol (200 mg, 300 mg), and rectal suppositories. The extended-release preparations, Tegretol XR (Novartis) and Carbatrol (Shire), are better tolerated than the immediate-release preparations.

CBZ is one of the most widely used AEDs in the world. It is highly effective for partial-onset seizures, including cryptogenic and symptomatic partial seizures. It also has demonstrated good efficacy in the treatment of generalized tonic-clonic seizures. The drug is highly effective and well tolerated. Its major disadvantages are transient adverse dose-related effects at initiation of therapy and occasional toxicity.

Potential dose-related adverse effects include dizziness, diplopia, nausea, ataxia, and blurred vision. Rare idiosyncratic adverse effects include aplastic anemia, agranulocytosis, thrombocytopenia, and Stevens-Johnson syndrome. Asymptomatic elevation of liver enzymes is observed commonly during the course of therapy in 5-10% of patients. Rarely, severe hepatotoxic effects can occur.

Several drugs, such as macrolide antibiotics (eg, erythromycin and clarithromycin), isoniazid, chloramphenicol, calcium channel blockers, cimetidine, and propoxyphene (withdrawn from the US market), inhibit the hepatic enzyme cytochrome P-4503A4 (CYP3A4), which is responsible for the metabolic breakdown of CBZ, thereby raising its levels.

Phenobarbital (PHB), phenytoin (PHT), felbamate, and primidone also lower CBZ levels through CYP3A4. Toxic symptoms or breakthrough seizures may occur if the dose of CBZ is not adjusted. Grapefruit juice and St. John’s wort are inducers of CYP3A4 and can decrease CBZ levels.

CBZ induces the metabolism of tricyclic antidepressants, oral contraceptives, cyclosporin A, and warfarin. Any drug that is metabolized by the hepatic enzyme CYP3A4 will have reduced levels because CBZ induces this enzyme.

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