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Chapter 109: Anticonvulsants

Robert J. Hoffman

PHENYTOIN

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. Phenytoin toxicity may occur after single acute exposure, and also may occur in patients chronically using phenytoin. In patients using phenytoin, toxicity occurs after lesser ingestions because a large quantity of phenytoin is already present in the body.

Clinical Features

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 likely secondary to the diluent, propylene glycol. Morbidity can be avoided by slowing the rate of administration during infusion. Extravasation of phenytoin, but not fosphenytoin, may result in catastrophic injury with significant loss of soft tissue or even loss of digits or the hand.

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 almost exclusively results from IV administration. Supratherapeutic phenytoin levels commonly result in cerebellar symptoms of dizziness, ataxia, and nystagmus. Skin and soft tissue injury may be seen with IM injection or after extravasation from IV infusion. Therapeutic use has been associated with hypersensitivity reactions and gingival hyperplasia. Phenytoin is teratogenic.

Table 109-1

Clinical Features of Phenytoin Toxicity

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Table 109-1

Clinical Features of Phenytoin Toxicity
Central nervous system Dizziness, tremor (intention), visual disturbance, horizontal and vertical nystagmus, diplopia, miosis or mydriasis, ophthalmoplegia, abnormal gait (bradykinesia, truncal ataxia), choreoathetoid movements, irritability, agitation, confusion, hallucinations, fatigue, coma, encephalopathy, dysarthria, meningeal irritation with pleocytosis, seizures (rare)
Peripheral nervous system Peripheral neuropathy, urinary incontinence
Hypersensitivity (anticonvulsant hypersensitivity syndrome) Eosinophilia, rash, pseudolymphoma (diffuse lymphadenopathy), systemic lupus erythematosus, pancytopenia, hepatitis, pneumonitis
Gastrointestinal Nausea, vomiting, hepatotoxicity
Dermatologic Hirsutism, acne, rashes (including Stevens–Johnson syndrome)
Other organs 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, clinical exam, and serum drug levels. The therapeutic range is 10 to 20 µg/mL and toxicity generally correlates with increasing plasma levels (Table 109-2). Absorption is erratic, and serial levels should be obtained in cases of suspected ingestion. 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

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Table 109-2

Correlation of Plasma Phenytoin Level and Side Effects
Total Plasma Level (µg/mL) Toxic Effects
<10 Usually none
10–20 Occasional mild nystagmus
20–30 Nystagmus
30–40 Ataxia, slurred speech, nausea ...

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