Phenytoin and Fosphenytoin
GENERAL PRINCIPLES
Pathophysiology
Phenytoin exerts therapeutic activity by binding to neuronal sodium channels and inhibiting reactivation.
Phenytoin exhibits saturable kinetics, and at plasma levels gt;20 #956;g#8725;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.
DIAGNOSIS
Clinical Presentation
Patients with phenytoin poisoning will present with confusion, changes in mental status, and changes in gait and speech.
At plasma phenytoin concentrations of gt;15 #956;g#8725;mL, patients will exhibit nystagmus. Ataxia develops at concentrations of 30 #956;g#8725;mL. Confusion, encephalopathy, and frank movement disorders occur at concentrations above 50 #956;g#8725;mL.
Severe poisoning may actually produce seizures.
Rapid IV administration of phenytoin may produce bradycardia and hypotension due in part to propylene glycol and ethanol; these are not seen in chronic poisoning or acute oral overdose. 10
IV phenytoin may lead to severe tissue injury (typically with extravasation), purple glove syndrome, which may require surgical debridement. 11
Differential Diagnosis
Phenytoin poisoning may mimic other poisonings with mental status depression.
The nontoxicologic differential diagnosis for phenytoin poisoning should include Wernicke encephalopathy, meningoencephalitis, posterior circulation ischemic stroke, and intracranial hemorrhage and mass lesion.
Diagnostic Testing
LABORATORIES
Obtain a phenytoin concentration on any patient with a potential phenytoin exposure, even if acute overdose is not suspected.
๎ Most hospital laboratories report a total phenytoin concentration rather than free phenytoin. Correction for hypoalbuminemia is necessary.
๎ The phenytoin concentration should be trended over time, as delayed absorption and delayed excretion are common in poisoning.
Obtain a complete blood count, as phenytoin may cause agranulocytosis.
Obtain an HFP, as phenytoin may cause drug-induced liver injury (DILI).
ELECTROCARDIOGRAPHY
Electrocardiography and continuous cardiac monitoring are indicated only in cases of iatrogenic poisoning by intravenous phenytoin (see above).
TREATMENT
Most patients will do well with cessation of phenytoin therapy and supportive care.
MDAC is suggested by some experts to enhance phenytoin elimination.
Treat seizures with benzodiazepines or other directly GABAergic agents.
Hypotension and bradycardia in the setting of IV phenytoin administration are typically self-limiting, but may occasionally require treatment with fluids, atropine, and/or vasopressors.
Agranulocytosis should be treated with granulocyte colony-stimulating factor.
DILI typically resolves with drug discontinuation.
Hemodialysis effectively clears phenytoin and may be reasonable in cases of prolonged coma or prolonged and incapacitating ataxia.