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Phenytoin is an anticonvulsant whose main use is as a second line drug in treating generalised tonic-clonic seizures and sometimes other forms of epilepsy. It can be used either to treat patients in whom seizures have occurred or to prevent seizures in patients at risk (for example, after neurosurgery).

Because of large individual variation in the disposition of phenytoin patients taking the same dosage have up to a 50-fold difference in plasma phenytoin concentration.

The metabolism of phenytoin is non-linear within the therapeutic range. This is because the enzyme system responsible gradually becomes saturated at relatively low plasma phenytoin concentrations (within the therapeutic range), resulting in a progressive decrease in the rate of elimination of phenytoin as the dosage is increased. As saturation of the enzyme system is reached a small increase in dosage will result in a large increase in plasma phenytoin concentration. Thus, measuring the plasma phenytoin concentration will allow the dosage to be increased within safe limitsensuring, firstly, that an inadequate response to treatment is not missed because the dose is suboptimal and, secondly, that toxicity does not occur because the dose is too large, which is especially important as the saturation of phenytoin metabolism is approached.

Criteria for measurement

In this chapter we apply to phenytoin the criteria that must be fulfilled in part or in full before the measurement of its plasma concentration can be considered worth while.

Is there difficulty in interpreting clinical evidence of the therapeutic or toxic effects?

In patients who are having frequent regular epileptic seizures the total suppression or a measurable reduction in the frequency of seizures is a clearly defined end point by which to assess the therapeutic response to phenytoin. However, in patients in whom epileptic seizures occur infrequently and irregularly and in patients taking phenytoin prophylactically (for example, after neurosurgery) it can be difficult to assess the therapeutic response. In such cases a target plasma phenytoin concentration may provide the most rational means of assessing whether or not a therapeutic response is likely to be achieved.

In all cases the signs of phenytoin toxicity may be insidious and difficult to differentiate from those of associated neurological disease. Plasma phenytoin concentration measurements may therefore help.

Is there a good relation between the plasma concentration and its therapeutic or toxic effect?

Longitudinal studies in patients with epilepsy have clearly shown improved seizure control when plasma phenytoin concentrations are increased above 40 µmol/l. Most of the patients in these studies however, had relatively severe epilepsy, and a prospective study has shown that 35% of newly diagnosed epileptic patients could have their seizures completely controlled with concentrations below 40 µmol/l. There is also evidence that even very low plasma phenytoin concentrations (5-10 µmol/l) may be associated with effective seizure control in some patients.

Nevertheless, it is generally accepted that it is more likely that optimal suppression of seizures will be achieved without toxicity when the plasma phenytoin concentration is within the range 40-80 µmol/l. The upper limit has been so defined because the risk of toxicity increases at a concentration above 80 µmol/l and is almost invariable at concentrations greater than 100 µmol/l.

Dose dependent signs of toxicity become prominent at plasma phenytoin concentrations above 80-100 µmol/l. But sometimes the signs of phenytoin toxicity are difficult to detect, especially if the patient has underlying neurological disease which might confuse the diagnosis of toxicity-for example, pre-existing cerebellar dysfunction.

Some patients may tolerate a plasma phenytoin concentration in excess of 100 µmol/l, whereas others may show signs of toxicity with a concentration less than 80 µmol/l. A plasma concentration below 80 µmol/l does not therefore exclude the possibility of toxicity, and if there are good clinical reasons for suspecting toxicity then reducing the dosage should be tried.

There is a less clear relation between plasma concentrations of phenytoin and its long term adverse effects. Many of these effects are probably related to the duration of treatment as well as to the plasma concentration.

Is phenytoin metabolised to active metabolites?

Phenytoin is metabolised to 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH), which is clinically inactive. Less than 5% of phenytoin is excreted unchanged in the urine, so the interpretation of the plasma concentration is not complicated by the presence of pharmacologically active substances not measured by the assay.