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Emergency And Acute Medicine – Phenytoin Poisoning
Phenytoin poisoning occurs because phenytoin follows zero-order (capacity-limited) pharmacokinetics, meaning small increases in dose can produce disproportionately large increases in serum concentration. In overdose, the half-life may be significantly prolonged, up to 70 hours. Cardiovascular toxicity associated with IV phenytoin is often related to its diluent, propylene glycol. Fosphenytoin, a parenteral prodrug converted to active phenytoin, does not contain propylene glycol and is less likely to cause hypotension or dysrhythmias.
Toxicity may result from acute overdose, chronic accumulation, or acute-on-chronic ingestion. In patients receiving long-term therapy, unexplained toxicity should prompt consideration of a change in brand, dosage formulation, drug interaction, or altered serum albumin affecting free drug levels.
Clinical manifestations correlate with serum concentration. At 20–40 µg/mL, patients commonly develop nystagmus, dizziness, ataxia, drowsiness, nausea, vomiting, diplopia, and slurred speech. At 40–90 µg/mL, confusion and disorientation occur. Levels above 90 µg/mL may lead to coma, respiratory depression, and paradoxical seizures. Rapid IV administration can produce hypotension and bradycardia, particularly with standard IV phenytoin formulations. Chronic exposure may also cause hypersensitivity reactions including rash, fever, neutropenia, agranulocytosis, hepatitis, and cholangitis.
Evaluation begins with determining the time, route, and amount of ingestion. After oral overdose, peak levels may not be reached for 24 hours or longer, and absorption varies between preparations. Serum phenytoin concentrations should be repeated every four hours until they peak and begin to decline; once declining, levels may be monitored every 24 hours until below 30 µg/mL. In hypoalbuminemic patients or those with altered protein binding, measurement of a free phenytoin level is recommended. Fosphenytoin concentrations are measured as phenytoin and should be checked after full conversion (approximately 2 hours after IV infusion or 4 hours after IM injection).
Additional laboratory evaluation includes electrolytes, BUN, creatinine, and glucose. An anion gap metabolic acidosis may suggest coingestants, seizure activity, or propylene glycol toxicity. Blood glucose should be assessed in any patient with altered mental status.
Management is primarily supportive. Airway, breathing, and circulation should be stabilized with IV access and cardiac monitoring, especially in IV overdoses. In altered mental status, bedside glucose testing is essential, with administration of naloxone, dextrose, and thiamine as indicated. Hypotension should be treated with IV fluids and positioning, with dopamine considered for refractory cases. Paradoxical seizures are treated with benzodiazepines such as diazepam. A single dose of activated charcoal may be administered in appropriate oral ingestions; multiple-dose charcoal can increase phenytoin clearance but has not consistently shown clinical benefit.
Patients require admission if they have altered mental status, severe ataxia, rising phenytoin levels, levels greater than 25 µg/mL, or toxicity from IV administration, which warrants ICU monitoring. Fall precautions are important due to marked ataxia. Patients may be discharged when levels are 25 µg/mL or less, symptoms are resolving, and they are ambulatory without ataxia. Intentional ingestions require psychiatric evaluation, and close outpatient follow-up is necessary to reassess phenytoin levels and adjust therapy, particularly after any change in manufacturer or dosage formulation.
Key clinical reminders include recognition that even small dose increases can precipitate toxicity due to zero-order kinetics, and that serial phenytoin levels should be obtained every four hours until a clear downward trend is established.
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