Phenytoin and Fosphenytoin

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

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General Principles

Pathophysiology

  • Phenytoin exerts therapeutic activity by binding to neuronal sodium channels and inhibiting reactivation.
  • Phenytoin exhibits saturable kinetics, and at plasma levels >20 μg/mL, toxic effects become rapidly apparent.
  • Fosphenytoin is a prodrug that is converted to phenytoin after IV or IM injection.

Risk Factors

  • Patients with mutations of the cytochrome P450 system that impair phenytoin metabolism are at risk for toxicity even with therapeutic use.
  • Coadministration of xenobiotics that inhibit CYP 2C9, 2C19, or 3A4 impairs the metabolism of phenytoin and may lead to phenytoin toxicity.
  • Phenytoin is highly albumin bound; patients with hypoalbuminemia (e.g., those with malnutrition or cirrhosis) may have higher levels of free (active) drug and experience toxicity despite seemingly normal total phenytoin concentrations.

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General Principles

Pathophysiology

  • Phenytoin exerts therapeutic activity by binding to neuronal sodium channels and inhibiting reactivation.
  • Phenytoin exhibits saturable kinetics, and at plasma levels >20 μg/mL, toxic effects become rapidly apparent.
  • Fosphenytoin is a prodrug that is converted to phenytoin after IV or IM injection.

Risk Factors

  • Patients with mutations of the cytochrome P450 system that impair phenytoin metabolism are at risk for toxicity even with therapeutic use.
  • Coadministration of xenobiotics that inhibit CYP 2C9, 2C19, or 3A4 impairs the metabolism of phenytoin and may lead to phenytoin toxicity.
  • Phenytoin is highly albumin bound; patients with hypoalbuminemia (e.g., those with malnutrition or cirrhosis) may have higher levels of free (active) drug and experience toxicity despite seemingly normal total phenytoin concentrations.

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