Carbamazepine is a prototype of the antiseizure drugs primarily used in the treatment of focal onset seizures. In addition to being effective in the treatment of focal seizures, carbamazepine is indicated for the treatment of tonic-clonic (grand mal) seizures. This indication derives from studies in patients whose focal onset seizures progressed to bilateral tonic-clonic seizures (previously called “secondarily generalized tonic-clonic seizures”). Drugs like carbamazepine exacerbate certain seizure types in idiopathic generalized epilepsies, including myoclonic and absence seizures, and are generally avoided in patients with such a diagnosis. There is evidence from anecdotal reports and small studies indicating that carbamazepine, phenytoin, and lacosamide may be effective and safe in the treatment of generalized tonic-clonic seizures in idiopathic generalized epilepsies. The most popular drugs for the treatment of focal seizures are carbamazepine, lamotrigine, phenytoin, and lacosamide; levetiracetam is also commonly used. Phenobarbital is useful if cost is an issue. Vigabatrin and felbamate are third-line drugs because of risk of toxicity.
Carbamazepine is one of the most widely used antiseizure drugs despite its limited range of activity as a treatment for focal (partial onset) and focal-to-bilateral tonic-clonic seizures. It was initially marketed for the treatment of trigeminal neuralgia, for which it is highly effective; it is usually the drug of first choice for this condition. In addition, carbamazepine is a mood stabilizer used to treat bipolar disorder.
Structurally, carbamazepine is an iminostilbene (dibenzazepine)— a tricyclic compound consisting of two benzene rings fused to an azepine group. The structure of carbamazepine is similar to that of tricyclic antidepressants such as imipramine, but unlike the tricyclic antidepressants, carbamazepine does not inhibit monoamine (serotonin and norepinephrine) transporters with high affinity; therefore, carbamazepine is not used as an antidepressant despite its ability to treat bipolar disorder.
Mechanism of Action
Carbamazepine is a prototypical sodium channel-blocking antiseizure drug that is thought to protect against seizures by interacting with the voltage-gated sodium channels (Nav1) responsible for the rising phase of neuronal action potentials (see Chapters 14 and 21). In the normal state, when neurons are depolarized to action potential threshold, the sodium channel protein senses the depolarization and, within a few hundred microseconds, undergoes a conformational change (gating) that converts the channel from its closed (resting) nonconducting state to the open conducting state that permits sodium flux (Figure 24–2). Then, within less than a millisecond, the channel enters the inactivated state, terminating the flow of sodium ions. The channel must then be repolarized before it can be activated again by a subsequent depolarization. Brain sodium channels can rapidly cycle through the resting, open, and inactivated states, allowing neurons to fire high-frequency trains of action potentials.