Intentional phenytoin overdose rarely leads to death, provided adequate supportive care is administered. Most phenytoin-related deaths have been caused by rapid IV administration and hypersensitivity reactions.
The toxic effects of phenytoin depend on the duration of exposure, dosage taken, and route of administration. Life-threatening effects such as hypotension, bradycardia, and asystole are seen with IV administration and are secondary to the diluent, propylene glycol. Morbidity can be avoided by slowing the rate of administration. Fosphenytoin is well tolerated intramuscularly or intravenously; adverse and toxic effects are the same as those of phenytoin, except the toxic effects of propylene glycol are not present.
Clinical manifestations in overdose are typically dose related and are listed in Table 109-1. The primary clinical features of overdose are related to acute CNS effects while cardiovascular toxicity is almost entirely seen in cases of IV administration. Skin and soft tissue injury may be seen with IM injection of phenytoin or after extravasation from IV infusion, but are rarely seen with fosphenytoin. Therapeutic use has been associated with hypersensitivity reactions and gingival hyperplasia. Phenytoin is teratogenic.
Table 109-1 Clinical Features of Phenytoin Toxicity ||Download (.pdf)
Table 109-1 Clinical Features of Phenytoin Toxicity
|Central nervous system effects||Dizziness, tremor (intention), visual disturbance, horizontal and vertical nystagmus, diplopia, miosis or mydriasis, ophthalmoplegia, abnormal gait (bradykinesia, truncal ataxia), choreoathetoid movements, vomiting, dysphagia, irritability, agitation, confusion, hallucinations, fatigue, coma, encephalopathy, pseudodegenerative disease, dysarthria, meningeal irritation with pleocytosis, seizures (rare)|
|Peripheral nervous system effects||Peripheral neuropathy, urinary incontinence|
|Hypersensitivity reactions (anticonvulsant hypersensitivity syndrome)||Eosinophilia, rash, pseudolymphoma (diffuse lymphadenopathy), systemic lupus erythematosus, pancytopenia, hepatitis, pneumonitis|
|GI effects||Nausea and vomiting, hepatotoxicity|
|Dermatologic effects||Hirsutism, acne, rashes (including Stevens-Johnson syndrome)|
|Other effects||Fetal hydantoin syndrome, gingival hyperplasia, coarsening of facial features, hemorrhagic disease of the newborn, hyperglycemia, hypocalcemia|
|Parenteral toxicity||May cause hypotension, bradycardia, conduction disturbances, myocardial depression, ventricular fibrillation, asystole, and tissue necrosis from infiltration|
Diagnosis and Differential
Diagnosis is made by history and serum drug levels. The therapeutic range is 10 to 20 micrograms/mL and toxicity generally correlates with increasing plasma levels (Table 109-2). Absorption is erratic, and serial levels should be obtained. Electrocardiographic changes in toxicity include increased PR interval, widened QRS interval, and altered ST-wave and T-wave segments.
Table 109-2 Correlation of Plasma Phenytoin Level and Side Effects ||Download (.pdf)
Table 109-2 Correlation of Plasma Phenytoin Level and Side Effects
|Plasma Level (micrograms/mL)||Side Effects|
|10 to 20||Occasional mild nystagmus|
|20 to 30||Nystagmus|
|30 to 40||Ataxia, slurred speech, nausea and vomiting|
|40 to 50||Lethargy, confusion|
Almost any CNS-active drug can mimic phenytoin toxicity. Disease states that resemble phenytoin toxicity include hypoglycemia, Wernicke encephalopathy, and posterior fossa hemorrhage or tumor.