20.01.3 Treatment of Generalised Seizures

In addition to being effective in both partial and generalised seizures, valproate is the primary agent used in myoclonic seizures. Like carbamazepine and phenytoin, valproate reduces nerve activity by binding to the Na⁺ channel and prolonging the time it is inactive. Valproate also has an addition action; it interacts with the T-type Ca²⁺ channels. Ca²⁺ entry via the T-type Ca²⁺ channel underlies some of the currents observed in generalised seizures. Valproate inhibits the flow of Ca²⁺ through T-type Ca²⁺ channels (Figure 20.3).

Figure 20.3 Mechanism of valproate in generalized seizure (Copyright QUT, Sheila Doggrell)

Valproate is absorbed rapidly and completely after oral administration. It has a half-life of 15 hours, and undergoes metabolism by the liver.

Most common side effects with valproate are transient gastrointestinal symptoms, including anorexia, nausea, and vomiting in about 16% of patients.

Most barbiturates are active in seizures, but many of the barbiturates cause hypnosis, when the subject is in a trance and subject to manipulation. The only useful barbiturate in epilepsy is phenobarbital. This is because phenobarbital is active in seizures at lower concentrations than cause hypnosis. Phenobarbital is mainly used in myoclonic seizures.

Phenobarbital is very lipid soluble, and undergoes complete absorption after oral administration. Phenobarbital induces a range of liver metabolising enzymes incluing uridine diphosphate-glucuronesyltransferase (UGT) and CYP2C and CYP3A. Thus, the use of phenobarbital will lower the levels of many drugs.

Sedation is main adverse effect of phenobarbital, and this limits its use. Phenobarbital sometimes causes irritability and hyperactivity in children, and thus is not the primary agent for treating epilepsy in children. Phenobarbital causes agitation and confusion in the elderly, and thus it also not the primary agent in the elderly.

Ethosuximide has as its mechanism of action the ability to inhibit Ca²⁺ currents through T channels, which is one of the mechanisms of valproate. However, unlike valproate, ethosuximide has no effect on Na⁺ channels. This inhibition of Ca²⁺ currents through the T-type calcium channels includes inhibition of T channels in thalamus, which seem to have a major role in absence seizures.

Ethosuximide is primary agent for the treatment of absence seizures. Ethosuximide is not effective in tonic-clonic seizures.

The absorption of ethosuximide is complete. The most common side effects with ethosuximide are gastrointestinal (nausea, vomiting, and anorexia) and CNS (drowsiness, lethargy, euphoria, dizziness, headache and hiccough/hiccup).