Phenytoin is used orally for the prevention of generalized (grand mal) and partial complex seizures. Intravenous phenytoin is used to treat status epilepticus and occasionally as an antiarrhythmic agent. Oral formulations include suspensions, capsules, extended-release capsules, and tablet preparations. The brand Dilantin Kapseals exhibits delayed absorption characteristics not usually shared by generic products.
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.)
Phenytoin suppresses high-frequency neuronal firing, primarily by increasing the refractory period of voltage-dependent sodium channels. Toxic levels usually cause CNS depression.
The propylene glycol diluent in parenteral preparations may cause myocardial depression and cardiac arrest when infused rapidly (>40–50 mg/min [0.5–1 mg/kg/min]). The mechanism is not known. The injectable form of phenytoin also is highly alkaline and can cause tissue necrosis if it infiltrates ("purple glove syndrome").
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.
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 (see also Table II–66).
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.
Mild-to-moderate intoxication commonly causes nystagmus, ataxia, and dysarthria. Nausea, vomiting, diplopia, hyperglycemia, agitation, and irritability have also been reported.
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.
Rapid intravenous injection, usually at rates exceeding 50 mg/min, can cause profound hypotension, bradycardia, arrhythmias, ...