Chapter 126. Phenytoin

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, and tablet preparations. The brand Dilantin Kapseals exhibits delayed absorption characteristics not usually shared by generic products.

1. Mechanism of toxicity. 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 (>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”).

   3. 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.

   4. 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. The phenytoin level should be corrected for the serum albumin. 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–61).

2. Toxic dose. 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.

3. Clinical presentation. 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, and cardiac arrest. These effects are attributed to the propylene glycol diluent. Cardiac toxicity does not occur with an oral overdose or with fosphenytoin.

4. Diagnosis 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, and ECG monitoring (during IV infusion).

5. Treatment

   1. Emergency and supportive measures

      1. Maintain an open airway and assist ventilation if necessary (See Airway and Breathing). Administer supplemental oxygen.

      2. Treat stupor and coma (See Hypotension) 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 (See Seizures).

      4. If hypotension occurs with intravenous phenytoin administration, immediately stop the infusion and administer IV fluids and vasopressors (See Hypotension) if necessary.

   2. Specific drugs and antidotes. There is no specific antidote.

   3. Decontamination (See Decontamination). Administer activated charcoal orally if conditions are appropriate (see Table I–38). Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly.

   4. Enhanced elimination. Repeat-dose activated charcoal (See Repeat-dose activated charcoal) may enhance phenytoin elimination but is not necessary and may increase the risk for aspiration pneumonitis in drowsy patients. There is no role for diuresis, dialysis, or hemoperfusion.