Phenytoin Toxicity

Phenytoin has a narrow therapeutic range (total level 10 to 20 mg/L or 40 to 80 micromol/L, free level 1 to 2 mg/L) and zero-order (saturable) kinetics at therapeutic concentrations. Small increases in dose produce disproportionate rises in the serum level.

Causes of toxicity

• Oral overdose or dose escalation
• Drug interactions (inhibitors: amiodarone, fluconazole, isoniazid, metronidazole, valproate displacement, omeprazole, sertraline)
• Hypoalbuminemia, uremia and liver disease, which increase the free fraction
• Pregnancy and genetic variation in CYP2C9 and CYP2C19
• Too rapid intravenous loading (cardiovascular toxicity from the propylene glycol diluent)

Oral overdose rarely causes cardiac toxicity. Rapid intravenous administration at over 50 mg/min causes hypotension, bradycardia and asystole. Extravasation causes purple glove syndrome and tissue necrosis. Complications: cerebellar atrophy (chronic), paradoxical seizures at very high levels, gingival hyperplasia, hypersensitivity (Stevens-Johnson syndrome, DRESS) and teratogenicity (fetal hydantoin syndrome).

• Nystagmus (levels above 20 mg/L), blurred vision and diplopia
• Ataxia and slurred speech (above 30 mg/L)
• Lethargy, confusion, tremor, hyperreflexia (above 40 mg/L)
• Coma and, rarely, seizures (above 50 to 60 mg/L)
• Nausea, vomiting, hyperglycemia
• After intravenous infusion: hypotension, bradycardia, atrioventricular block, ventricular arrhythmia
• Red flags: coma, seizures, cardiac conduction abnormality and soft tissue swelling with distal discoloration

1. Serum phenytoin level (total, with albumin), repeated every 6 hours until falling. Measure the free level when albumin is low.
2. Adjusted level for low albumin: corrected total level equals the measured level divided by (0.2 × albumin in g/dL + 0.1). In renal failure use (0.1 × albumin + 0.1).
3. ECG and continuous monitoring for intravenous loading.
4. Blood tests: glucose, electrolytes, creatinine, liver tests and full blood count.
5. Medication review for interacting drugs.

Differentials: other anticonvulsant toxicity (carbamazepine, valproate), Wernicke encephalopathy, cerebellar stroke, alcohol intoxication, sedative overdose.

1. Stop phenytoin until the level is under 20 mg/L, and restart at a lower dose with a level after 5 to 7 days.
2. Activated charcoal 50 g orally (children 1 g/kg, maximum 50 g) within 1 to 2 hours for an acute ingestion, with repeated doses of 25 g every 4 hours (children 0.5 g/kg every 4 hours) for 24 hours if the airway is protected and there is no ileus.
3. Supportive care: IV crystalloid, airway protection and fall precautions.
4. Cardiovascular toxicity after rapid infusion: stop the infusion, give calcium chloride 10% 10 mL IV for hypotension, and atropine 0.5 to 1 mg IV for bradycardia.
5. Seizures (paradoxical, at very high levels): lorazepam 4 mg IV (children 0.1 mg/kg), and avoid more phenytoin.
6. Haemodialysis has little role. It may be considered only in very high levels with severe toxicity in renal failure.
7. Purple glove syndrome: elevation, avoid compression, and surgical review for fasciotomy or debridement if compartment syndrome or necrosis develops.
8. Safe intravenous loading: phenytoin 20 mg/kg IV (maximum rate 50 mg/min, or 25 mg/min in elderly patients and those with heart disease) in 0.9% saline with continuous ECG and blood pressure monitoring. Fosphenytoin 20 mg phenytoin equivalents/kg IV at up to 150 mg phenytoin equivalents/min is safer and can be given IM.
9. Chronic toxicity: adjust the dose by small steps (30 to 50 mg), check levels at 1 to 2 weeks, and review interacting drugs.

Follow-up: neurology review and consideration of an alternative anticonvulsant. Counsel on dental hygiene, bone health (vitamin D 800 to 1000 IU daily), pregnancy planning and the signs of rash.