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Chitika

5/7/09

PHENYTOIN

Phenytoin is the most important member of the hydantoin group of compounds, which are structurally related to the barbiturates. It is highly effective in reducing the intensity and duration of electrically induced convulsions in mice, although ineffective against PTZ-induced convulsions. Despite its many side effects and unpredictable pharmacokinetic behaviour, phenytoin is widely used, being effective against various forms of partial and generalised seizures, although not against absence seizures, which may even get worse.

Pharmacokinetic aspects

Phenytoin has certain pharmacokinetic peculiarities that need to be taken into account when it is used clinically. It is well absorbed when given orally, and about 80-90% of the plasma content is bound to albumin. Other drugs, such as salicylates, phenylbutazone and valproate, inhibit this binding competitively . This increases the free phenytoin concentration but also increases hepatic clearance of phenytoin , so may enhance or reduce the effect of the phenytoin in an unpredictable way. Phenytoin is metabolised by the hepatic mixed function oxidase system and excreted mainly as glucuronide. It causes enzyme induction, and thus increases the rate of metabolism of other drugs (e.g. oral anticoagulants). The metabolism of phenytoin itself can be either enhanced or competitively inhibited by various other drugs that share the same hepatic enzymes. Phenobarbital produces both effects, and because competitive inhibition is immediate whereas induction takes time, it initially enhances and later reduces the pharmacological activity of phenytoin . Ethanol has a similar dual effect.


The metabolism of phenytoin shows the characteristic of saturation , which means that over the therapeutic plasma concentration range the rate of inactivation does not increase in proportion to the plasma concentration. The consequences of this are as follow.

• The plasma half-life (approximately 20 hours) increases as the dose is increased.
• The steady-state mean plasma concentration, achieved when a patient is given a constant daily dose, varies disproportionately with the dose. shows that, in one patient, increasing the dose by 50% caused the steady-state plasma concentration to increase more than fourfold.

The range of plasma concentration over which phenytoin is effective without causing excessive unwanted effects is quite narrow (approximately 40-100μmol/l). The very steep relationship between dose and plasma concentration, and the many interacting factors, mean that there is considerable individual variation in the plasma concentration achieved with a given dose. A radioimmunoassay for phenytoin in plasma is available, and its use has helped considerably in achieving an optimal therapeutic effect. The past tendency was to add further drugs in cases where a single drug failed to give adequate control. It is now recognised that much of the unpredictability can be ascribed to pharmacokinetic variability, and regular monitoring of plasma concentration has reduced the use of polypharmacy.

Unwanted effects

Side effects of phenytoin begin to appear at plasma concentrations exceeding 100μmol/l and may be severe above about 150μmol/l. The milder side effects include vertigo, ataxia, headache and nystagmus, but not sedation. At higher plasma concentrations, marked confusion with intellectual deterioration occurs; a paradoxical increase in seizure frequency is a particular trap for the unwary prescriber. These effects occur acutely and are quickly reversible. Hyperplasia of the gums often develops gradually, as does hirsutism and coarsening of the features, which probably result from increased androgen secretion. Megaloblastic anaemia, associated with a disorder of folate metabolism, sometimes occurs, and can be corrected by giving folic acid (Ch. 22). Hypersensitivity reactions, mainly rashes, are quite common. Phenytoin has also been implicated as a cause of the increased incidence of fetal malformations in children born to epileptic mothers, particularly the occurrence of cleft palate, associated with the formation of an epoxide metabolite. Severe idiosyncratic reactions, including hepatitis, skin reactions and neoplastic lymphocyte disorders, occur in a small proportion of patients.