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Mechanism Of Action
Phenytoin is an anticonvulsant which may be useful in the treatment of generalized tonicclonic status epilepticus. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of generalized tonic-clonic seizures.
Pharmacokinetics And Drug Metabolism
The plasma half-life in man after intravenous administration ranges from 10 to 15 hours. Optimum control without clinical signs of toxicity occurs most often with serum levels between 10 and 20 mcg/mL.
Phenytoin is metabolized by the cytochrome P450 enzymes CYP2C9 and CYP2C19.
A fall in plasma levels may occur when patients are changed from oral to intramuscular administration. The drop is caused by slower absorption, as compared to oral administration, due to the poor water solubility of phenytoin. Intravenous administration is the preferred route for producing rapid therapeutic serum levels.
When intramuscular administration may be required, a sufficient dose must be administered intramuscularly to maintain the plasma level within the therapeutic range. Where oral dosage is resumed following intramuscular usage, the oral dose should be properly adjusted to compensate for the slow, continuing IM absorption to avoid toxic symptoms.
Patients stabilized on a daily oral regimen of Dilantin experience a drop in peak blood levels to 50-60 percent of stable levels if crossed over to an equal dose administered intramuscularly. However, the intramuscular depot of poorly soluble material is eventually absorbed, as determined by urinary excretion of 5-(p-hydroxyphenyl)-5phenylhydantoin (HPPH), the principal metabolite, as well as the total amount of drug eventually appearing in the blood. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal.
A short-term (one week) study indicates that patients do not experience the expected drop in blood levels when crossed over to the intramuscular route if the Dilantin IM dose is increased by 50 percent over the previously established oral dose. To avoid drug cumulation due to absorption from the muscle depots, it is recommended that for the first week back on oral Dilantin, the dose be reduced to half of the original oral dose (onethird of the IM dose). Experience for periods greater than one week is lacking and blood level monitoring is recommended.
Patients with Renal or Hepatic Disease
Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations.
Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION).
Gender and Race
Gender and race have no significant impact on phenytoin pharmacokinetics.
A loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (1020 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 13 mg/kg/min or 50 mg per minute, whichever is slower.
Last reviewed on RxList: 2/7/2014
This monograph has been modified to include the generic and brand name in many instances.
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