Phenytoin

Phenytoin (diphenylhydantoin, Epanutin, Dilantin) alters ionic fluxes but principally the voltage-dependent sodium ion channels in the neuronal membrane; this action is described as membrane stabilising, and discourages the spread (rather than the initiation) of seizure discharges.

Pharmacokinetics. Phenytoin provides a good example of the application of pharmacokinetics for successful prescribing. The important aspects are:

• Saturation (zero-order) kinetics

• Hepatic enzyme induction and enzyme inhibition

• Opportunities for clinically important unwanted interactions are extensive.

Saturation kinetics. Phenytoin is extensively hyd-roxylated in the liver and this process becomes saturated at about the doses needed for therapeutic effect. Thus phenytoin at low doses exhibits firstorder kinetics but saturation or zero-order kinetics develop as the therapeutic plasma concentration range (10-20 mg/1) is approached, i.e. the dose increments of equal size produce disproportional rise in steady-state plasma concentration.

A clinically meaningful single half-life can be quoted where a drug is subject only to first-order kinetics. At low doses, giving subtherapeutic plasma concentrations, the t'/2 of phenytoin is 6-24 h. But at doses giving therapeutic plasma concentrations, when metabolism is becoming saturated, elimination of the drug is relatively slower. This has signi ficant implications for patient care, e.g. the time taken to reach a steady-state plasma concentration after a dose increment (about 5 x tis 2-3 days at low dose and about 2 weeks at high doses. Thus dose increments should become smaller as the dose increases (which is why there is a 25-mg capsule). Plainly, monitoring serial plasma concentration measurement will help.

Enzyme induction and inhibition. Phenytoin is a potent inducer of hepatic metabolising enzymes affecting itself, other drugs and dietary and endogenous substances (including vitamin D and folate). The consequences of this are: a slight fall of steady state phenytoin level over the first few weeks of therapy, though this may not be noticeable if dose increments are being given; enhanced metabolism of other drugs, e.g. carbamazepine, warfarin, steroids (adrenal and gonadal), thyroxine, tricyclic antidepressants, doxycycline. Naturally this can also work in reverse, and other enzyme inducers, e.g. rifampicin, ethanol, may lower phenytoin concentrations when there is capacity for increase in enzyme induction.

Drugs that inhibit phenytoin metabolism (causing its plasma concentration to rise) include: sodium valproate, cimetidine, co-trimoxazole, isoniazid, chloramphenicol, some NSAIDs, disulfiram. There is a considerable body of mediocre and contradictory data, the lesson of which is that possible interaction should be borne in mind wherever other drugs are prescribed to a patient taking phenytoin.

Phenytoin is 90% bound to plasma albumin so that quite small changes in binding, e.g. a drop to 80%, will result in a higher concentration of free, active, drug. Since free drug is also available to be metabolised, the effect of such changes is probably short-lived. Phenytoin orally is well absorbed but there have been pharmaceutical bioavailability problems in relation to the nature of the diluent in the capsule; patients should always use the same formulation. Phenytoin should not be given i.m. since it precipitates and is poorly absorbed. It may be diluted and given by i.v. infusion over 1 hour but care should be taken to follow the manufacturer's instructions including the use of an in-line filter, because phenytoin may also precipitate in infusion fluids, particularly dextrose.

Uses. Phenytoin is used to prevent all types of partial epilepsy, whether or not the seizures thereafter become generalised, and to treat generalised seizures and status epiepticus. It is not used for absence attacks.

Other uses. The membrane-stabilising effect of phenytoin has been used in cardiac arrhythmias and, rarely, in cases of resistant pain, e.g. trigeminal neuralgia.

Adverse effects of phenytoin, many of which can be very slow to develop, include impairment of cognitive function, which has led many physicians to prefer carbamazepine and valproate. Other nervous system effects range from sedation to delirium to acute cerebellar disorder to convulsions. Peripheral neuropathy also occurs. Cutaneous reactions include rashes (dose related), coarsening of facial features and hirsutism. Gum hyperplasia (due to inhibition of collagen catabolism) may develop and is more marked in children and when there is poor gum hygiene.

Other effects include Dupuytren's contracture and pseudolymphoma. Some degree of macrocyto-sis is common but anaemia probably occurs only when dietary folate is inadequate. This responds to folate supplement (the requirement for folate is increased, as it is a cofactor in some hydroxylation reactions that are accelerated by enzyme induction by phenytoin). Osteomalacia due to increased metabolism of vitamin D occurs after years of therapy.

Overdose (causing cerebellar symptoms and signs, coma, apnoea) is treated according to general principles. The patient may remain unconscious for a long time because of saturation kinetics, but will recover if respiration and circulation are sustained.

Fosphenytoin, a prodrug of phenytoin, is soluble in water, easier and safer to administer; its conver-tion in the blood to phenytoin is rapid and it may be used as an alternative to phenytoin for status epilepticus (Table 20.1).

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