Pharmacokinetic aspects

Unlike most classes of psychotropic drugs where there is no direct correlation between the blood concentration and the therapeutic effect, for most of the commonly used anticonvulsants there is a high degree of correlation between the blood and brain concentrations and the therapeutic effect. A knowledge of the pharmacokinetic properties of the anticonvulsant drugs is therefore essential if their therapeutic efficacy is to be maximized and side effects minimized.

The anticonvulsants are metabolized in the liver by the microsomal oxidative pathway, although some drugs, such as phenobarbitone and ethosuximide, are partially eliminated unchanged. Most anticonvulsants act as inducers of the liver microsomal enzyme system and thereby enhance their own rate of destruction. In patients on a combination of anti-convulsants, this can result in shorter elimination half-lives for some of the drugs and a corresponding wide fluctuation in the plasma drug concentrations. Sodium valproate is an exception in that it does not act as a microsomal enzyme inducer.

Some anticonvulsants are metabolized in the liver to pharmacologically active metabolites which, if they have long half-lives, may accumulate and have neurotoxic effects. The following commonly used anticonvulsants are known to produce active metabolites:

Primidone - Phenobarbitone and phenylethylmalonamide

Carbamazepine - Carbamazepine 10,11-epoxide

Trimethadione - Dimethadione (long half-life)

Methsuximide - N-Desmethylmethsuximide (long half-life)

Most anticonvulsants have relatively long half-lives, which is clearly a major therapeutic advantage in achieving steady blood levels. Sodium valproate is exceptional in that it has a relatively short half-life, while phenobarbitone has the longest half-life of those drugs in general use. As with most psychotropic drugs, the half-life varies with the age of the patient; the older the patient, the longer the half-life. Slow absorption of a drug generally favours stable blood levels and to achieve this several anticonvulsants have been formulated into slowly absorbed formulations. Clearly it is important that the patient is treated with the same formulation of the drug. For patients being treated with diphenylhy-dantoin for example, changing formulations can lead to a sudden change in the steady-state drug concentration due to differences in the bioavailability of the preparations. This can lead to large fluctuations in the tissue drug concentrations with an increasing possibility of neurotoxicity and lack of seizure control despite similar peak blood concentrations being reached.

Most anticonvulsants have linear elimination kinetics, which means that an increase in the dose of drug administered leads to a proportional increase in the blood concentration and pharmacological activity. However, diphenylhydantoin and valproate are exceptions; the former does not follow linear kinetics so that the blood concentration is not directly related to the dose administered, while valproate is highly bound to serum proteins so that the total blood concentration may not directly reflect the quantity of drug available to the brain.


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