| Antiepileptic drugs: carbamazepine |
Carbamazepine is an anticonvulsant. It prevents rapid, repetitive, action potential firing, through voltage- and use-dependent blockade of sodium channels, thus limiting the propagation of seizure activity. It is also used in other neurological conditions—it has established efficacy in patients with trigeminal neuralgia, but clinical experience has been varied in other neuropathic pain states. It is also used in the treatment of bipolar disorder.
Precautions and interactions: Carbamazepine may cause worsening of absence and myoclonic seizures.
Carbamazepine has a marked ability to induce its own metabolism (autoinduction), which begins after 3 to 5 days of therapy and is usually complete after 3 to 4 weeks. Carbamazepine dosage must be titrated upwards slowly over a few weeks to avoid adverse effects. The eventual maintenance dose depends partly on the extent of autoinduction.
Carbamazepine can also accelerate the hepatic oxidation and conjugation of other lipid-soluble drugs (eg corticosteroids, cyclosporin, oral contraceptives, other antiepileptic drugs, warfarin). Carbamazepine undergoes hepatic metabolism by the cytochrome P450 isoform CYP3A4 and toxicity may result if drugs that inhibit CYP3A4 are also used (eg dextropropoxyphene, diltiazem, erythromycin, verapamil). For further information on drug interactions with carbamazepine,
Adverse effects: Dose-related adverse effects include sedation, headache, ataxia, dizziness, nausea and visual symptoms such as diplopia. A mild elevation of gamma-glutamyltransferase, reflecting drug-induced enzyme induction, is common. A persistent rise in liver enzymes, however, should lead to cessation of carbamazepine because of the rare possibility of developing significant hepatic toxicity. Reversible mild leucopenia is common, but does not require discontinuation of therapy unless there is evidence of infection or the white cell count falls below 2000/mm3. At high plasma concentrations, carbamazepine has an antidiuretic hormone–like action, but the resulting hyponatraemia is usually mild and asymptomatic. If the plasma sodium concentration falls below 125 mmol/L, there may be confusion, peripheral oedema and decreasing control of seizures. Other idiosyncratic reactions include skin rash (usually mild erythematous, but may progress to Stevens-Johnson syndrome), diarrhoea and hepatitis. Carbamazepine is associated with the anticonvulsant hypersensitivity syndrome.
Formulations: Controlled-release carbamazepine may give a lower maximal concentration than an equivalent dose of the regular preparation. When switching between regular and controlled-release carbamazepine, the same initial daily dose is used. This dose may require adjustment depending upon individual patient response. There may be some benefit in preferentially using controlled-release carbamazepine in terms of patient compliance and greater stability of blood levels.
Monitoring: Assessment of haematological, renal, electrolyte and hepatic function before commencing carbamazepine could prove a useful baseline; however, there is no consensus on the value of subsequent routine haematological and biochemical monitoring. For further information on monitoring, see Monitoring antiepileptic drug therapy (Appendix 7.1).
There is no evidence for the utility of designated therapeutic plasma concentrations when carbamazepine is used to treat bipolar disorder. Although antiepileptic plasma concentration ranges (20 to 50 micromol/L or 5 to 12 mg/L) are used as a guideline, dose increases should be titrated against the appearance of adverse effects and clinical response. In general terms, concentrations of at least the order of the published antiepileptic range are required to achieve efficacy in bipolar disorder. At concentrations above the antiepileptic range the risk of toxicity is high.
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