20.01.2 Treatment of Partial Seizures

The drugs used to treat partial seizures include carbamazepine, phenytoin and valproate. These drugs all interact with Na⁺ channels in the nerves in the central nervous system. Normally, the Na⁺ channels alternate between the active state, where the channel is open and the Na⁺ flows through the channel to produce nerve activity, and the inactive state (Figure 20.1). Carbamazepine, phenytoin and valproate all bind to the inactivated gate of the Na⁺ channels to prolong the inactivation, which prolongs the quiescent state of the nerve.

Figure 20.1 Na⁺ channel (Copyright QUT, Sheila Doggrell)

Carbamazepine is an important drug for treatment of partial seizures and tonic-clonic seizures associated with partial or generalised seizures. It reduces nerve activity by binding to the inactivation gate of the Na⁺ channel and prolonging the time it is inactive. Carbamazepine is absorbed slowly and erratically after oral administration.

Carbamazepine is metabolised to carbamazepine 10,11-epoxide, which is an active metabolite. Carbamazepine also produces autoinduction of its own metabolism by the liver enzyme CYP3A4. Thus, with constant doses of carbamazepine, the plasma concentrations will decrease. Therapeutic drug monitoring of plasma levels of carbamazepine is done on a regular basis to ensure that it remains within the therapeutic range.

Also, by inducing CYP3A4, carbamazepine induces the metabolism off all the drugs metabolised by this enzyme, and this can lead to drug interactions. This includes induction of the metabolism of oral contraceptives, and the levels can fall below those needed for contraception.

The most common untoward effects of carbamazepine are drowsiness, vertigo, ataxia (unsteady and clumsy motion of the limbs), diplopia (double vision), and blurred vision.

Phenytoin is also effective in treatment of partial and tonic-clonic seizures. It also reduces nerve activity by binding to the Na⁺ channel, and prolonging the time it is inactive. Phenytoin is widely used in absence seizures but not particularly effective against these seizures.

Phenytoin is suitable for oral administration. Phenytoin is principally metabolised by CYP2C9/10. The metabolism of phenytoin is saturable, which is quite rare, and leads to zero order kinetics. Having zero order kinetics leads to phenytoin having a variable half-life. The half-life can range from 6 to 24 hours, as it increases with dose. Therapeutic drug monitoring is often required with phenytoin use.

Phenytoin induces CYPs including CYP3A4, which means it interacts with all the drugs that are metabolised by CYP3A4. This includes the oral contraceptives.

Gingival hyperplasia (enlargement of the gums) occurs in about 20% of patients during chronic use of phenytoin.

Valproate, also known as valproic acid, is effective in the treatment of both partial and generalised seizures, and is discussed in the next section.

When partial complex seizures are resistant to other medicines (e.g. carbamazepine, phenytoin and valproate), vigabatrin may be added. Vigabatrin inhibits the enzyme GABA aminotransferase, and this leads to a build-up of GABA in the synapse, and an increased effect of GABA, the inhibitory transmitter (Figure 20.2).

Figure 20.2 Mechanism of action of vigabatrin (Copyright QUT, Sheila Doggrell)

Vigabatrin can reduce the visual field, and this effect can be irreversible. Thus, the visual field needs testing before vigabatrin treatment is started and during treatment to avoid this adverse effect. Vigabatrin is excreted by the kidney and a dose reduction is necessary in renal impairment.