Phenytoin is used orally for the prevention of generalized (grand mal) and partial complex seizures. Intravenous phenytoin is used to treat status epilepticus and rarely as an antiarrhythmic agent (Class 1B). Oral formulations include suspensions, capsules, extended-release capsules, and tablet preparations.

Toxicity may be caused by the phenytoin itself or by the propylene glycol diluent used in parenteral preparations. (To make it soluble for IV use, phenytoin must be dissolved in 40% propylene glycol and 10% ethanol at pH 12.)

1. Phenytoin suppresses high-frequency neuronal firing, primarily by increasing the refractory period of voltage-dependent sodium channels. Toxic levels usually cause CNS depression.
2. The propylene glycol diluent in parenteral preparations may cause myocardial depression and cardiac arrest when infused rapidly (>50 mg/min [0.5-1 mg/kg/min]). The mechanism is unknown. The injectable form of phenytoin is also highly alkaline and can cause tissue necrosis if it infiltrates.
3. Rarely, IV administration can also cause the “purple glove syndrome” characterized by delayed onset of pain, edema, and a purple-blue discoloration of the skin adjacent to the injection site. The syndrome may occur with or without extravasation of IV phenytoin.
4. Fosphenytoin, a water-soluble prodrug, does not contain the propylene glycol diluent and does not cause these toxic effects. As a result, it can be given at rates twice as fast as those for phenytoin. It does not appear to provide faster times to peak plasma phenytoin concentration or to result in fewer adverse effects compared with phenytoin.
5. Pharmacokinetics. Absorption may be slow and unpredictable. The time to peak plasma levels varies with the dosage. The volume of distribution is about 0.5-0.8 L/kg. Protein binding is about 90% at therapeutic levels. Since only free drug is pharmacologically active, the phenytoin level should be corrected for the serum albumin. Phenytoin is metabolized by hepatic microsomal enzymes (CYP2C9 and CYP2C19) to inactive metabolites. Hepatic elimination is saturable (zero-order kinetics) at levels near the therapeutic range, so the apparent “half-life” increases as levels rise: 26 hours at 10 mg/L, 40 hours at 20 mg/L, and 60 hours at 40 mg/L.

The minimum acute toxic oral overdose is approximately 20 mg/kg. Because phenytoin exhibits dose-dependent elimination kinetics, accidental intoxication can easily occur in patients on chronic therapy owing to drug interactions or slight dosage adjustments.

Toxicity caused by phenytoin may be associated with acute oral overdose or chronic accidental overmedication. In acute oral overdose, absorption and peak effects may be delayed.

1. Mild-to-moderate intoxication commonly causes nystagmus, ataxia, and dysarthria. Nausea, vomiting, diplopia, hyperglycemia, agitation, and irritability have also been reported.
2. Severe intoxication can cause stupor, coma, and respiratory arrest. Although seizures have been reported, seizures in a phenytoin-intoxicated patient should prompt a search for other causes (eg, anoxia, hyperthermia, or an overdose of another drug). Death from isolated oral phenytoin overdose is extremely rare.
3. Rapid intravenous injection, usually at rates exceeding 50 mg/min, can cause profound hypotension, bradycardia, arrhythmias, and cardiac arrest. These effects have previously been attributed to the propylene glycol diluent. However, serious arrhythmias have also been reported with rapid administration of fosphenytoin, which does not contain propylene glycol. In contrast, oral overdose does not produce cardiovascular toxicity.
4. Chronic phenytoin use may cause gingival hyperplasia. Stevens-Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS) have all been reported.

Is based on a history of ingestion or is suspected in any epileptic patient with altered mental status or ataxia.

1. Specific levels. Serum phenytoin concentrations are generally available in hospital clinical laboratories. Obtain repeated blood samples because slow absorption may result in delayed peak levels. The therapeutic concentration range is 10-20 mg/L.
   1. At levels above 20 mg/L, nystagmus is common. At levels above 30 mg/L, ataxia, slurred speech, and tremor are common. With levels higher than 40 mg/L, lethargy, confusion, and stupor ensue. Survival has been reported in three patients with levels above 100 mg/L.
   2. Because phenytoin is highly protein bound and most laboratories measure total (bound and free) drug levels, patients with hypoalbuminemia may experience toxicity at lower serum levels. A corrected phenytoin level can be obtained by using the following equation:
      where the adjustment = 0.2 (normal renal function) or the adjustment = 0.1 (for patients with creatinine clearance <20 mL/min). Free (unbound) serum phenytoin levels are available in some but not most clinical laboratories.
2. Other useful laboratory studies include electrolytes, glucose, BUN, creatinine, serum albumin, cardiac troponin, and ECG monitoring (during IV infusion).
3. Genetic polymorphisms. Individuals with the HLA-B*1502 genotype are at greater risk for developing Stevens-Johnson syndrome and toxic epidermal necrolysis. The prevalence rate of this mutation is highest among Asians, particularly Han Chinese and Thai. Testing is available through reference laboratories.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen.
   2. Treat stupor and coma if they occur. Protect the patient from self-injury caused by ataxia.
   3. If seizures occur, consider an alternative diagnosis and treat with other usual anticonvulsants.
   4. If hypotension occurs with intravenous phenytoin administration, immediately stop the infusion and administer IV fluids and vasopressors if necessary.
2. Specific drugs and antidotes. There is no specific antidote.
3. Decontamination . Administer activated charcoal orally if conditions are appropriate (see Table I-37,).
4. Enhanced elimination. Repeat-dose activated charcoal may enhance phenytoin elimination, but does not result in improved clinical outcomes, and may increase the risk for aspiration pneumonitis in drowsy patients. Despite its high degree of protein binding, high-efficiency hemodialysis effectively removes phenytoin. However, given the relatively benign course of most acute overdoses, management should focus on supportive care.