Phenytoin and Fosphenytoin

Phenytoin and Fosphenytoin is a topic covered in the Washington Manual of Medical Therapeutics.

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General Principles


There are four major mechanisms by which anticonvulsants exert therapeutic activity—sodium channel blockade, GABA agonism, calcium channel antagonism, and inhibition of excitatory amino acids. In overdose, these features are enhanced.


  • Phenytoin has been a first-line treatment for seizures since its introduction. Fosphenytoin was developed as a response to some of the toxicity associated with IV phenytoin administration. Fosphenytoin is a prodrug that is converted to phenytoin after IV or IM injection and therefore will be referred to as phenytoin in the following text.
  • Neither of these drugs is indicated for the treatment of toxin-induced seizures,1 including ethanol withdrawal seizures.2
  • Phenytoin exerts therapeutic activity by binding to sodium channels and inhibiting reactivation.3 Phenytoin exhibits saturable kinetics, and at plasma levels >20 μg/mL, toxic effects become rapidly apparent.
  • Acute toxicity is associated with the development of a neurologic syndrome that appears to be cerebellar in origin. Cardiotoxicity is not associated with phenytoin ingestion4; however, it has been reported with IV administration of phenytoin. Rapid IV administration slows cardiac conduction and decreases systemic vascular resistance and myocardial contractility. The cardiac toxicity associated with IV phenytoin administration is due in part to the presence of propylene glycol and ethanol in the diluent, which are known myocardial depressants and vasodilators.5 The introduction of fosphenytoin has decreased the incidence of cardiac complications as it does not contain propylene glycol as a diluent.

Risk Factors

Other than overdose, risk factors for developing phenytoin toxicity are associated with the coadministration of drugs that affect the cytochrome P450 system.

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