Hydantoins

Hydantoins exert their antiseizure action primarily by impairing the ability of neuronal sodium channels to repolarize during abnormally rapid firing. The two agents in this class that are of value in the critically ill patient are phenytoin and fosphenytoin. The important differences between them are confined to the pharmacokinetics of their administration. Because of the long excretion half-time of phenytoin, these drugs require loading doses at the beginning of treatment and whenever an increase in serum concentration is desired.

One advantage of hydantoins over most of the other antiseizure agents is their lack of sedation at the relevant plasma concentrations. Phenytoin

Phenytoin can be administered enterally or parenterally. The enteral formulations should be given twice daily (except for the extended-release form, which can be given once daily). If the patient is receiving tube feedings, these should be discontinued for 1 h before and after the phenytoin dose to allow absorption of the drug. The parenteral formulation of phenytoin consists of sodium hydroxide (at pH 12) and propylene glycol to keep the otherwise insoluble phenytoin in solution. Extravasation of this material can severely damage the skin and surrounding tissue. The maximum rate of administration is 50 mg/min, but many patients experience hypotension at this rate, mandating slower delivery. Phenytoin can increase atrioventricular block; if it is necessary in a patient with conduction abnormalities, it should be given with an external pacemaker available.

Under normal circumstances, about 90 per cent of phenytoin is bound to plasma proteins, yielding a 'free' phenytoin concentration of 1 to 2 pg/ml as the 'therapeutic range'. In uremic patients, phenytoin is displaced from proteins and the free fraction rises. If necessary, the free phenytoin concentration can be measured directly. Since only the free fraction of phenytoin is metabolized, the maintenance dose is unchanged in renal failure. Patients with liver disease or other causes of hypoproteinemia should receive a smaller loading dose. Those with altered synthetic function will usually need a smaller maintenance dose as well.

Near the upper end of the 'therapeutic range', the clearance mechanisms for phenytoin become saturated and drug metabolism shifts from first-order to zero-order kinetics. As a consequence, small increases in the maintenance dose may translate over time into large increases in the plasma phenytoin concentration.

Fosphenytoin

The major advantages of fosphenytoin, which is a phosphate prodrug of phenytoin, stem from its solubility in water. It can be administered at up to 150 mg/min. However, because of its conversion half-time, the free phenytoin levels produced rise only marginally faster than those produced by phenytoin at 50 mg/min. Extravasation does not damage tissue, but would result in a slower rise in plasma concentrations.

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