[
Show Section Outline]
DESCRIPTION
Phenytoin is a commonly used anticonvulsant medication.
FORMS AND USES
- Pharmaceutical preparations include phenytoin (Dilantin) and fosphenytoin (Cerebyx).
- These drugs have antiseizure and antidysrhythmic properties.
- They are also used for chronic pain and several other conditions.
- Typical dosages for adults and children are as follows:
- Phenytoin. 15 to 20 mg/kg loading, not to exceed 50 mg/min intravenous infusion rate; 3 to 5 mg/kg/day maintenance (dosage may vary).
- Fosphenytoin. 15 to 20 phenytoin equivalents intravenously or intramuscularly, not to exceed 150 mg/min intravenous (dosing based on phenytoin delivered).
TOXIC DOSE
- Acute ingestion above 20 mg/kg may cause ataxia; death is rare regardless of dose.
- Cardiac toxicity may develop if intravenous rate of administration exceeds 35 to 50 mg/min.
PATHOPHYSIOLOGY
- Phenytoin stabilizes neuronal membranes by decreasing resting membrane sodium flux and by decreasing sodium flow during action potentials; impaired cerebellar function is the initial manifestation, followed at higher levels by cortical function.
- The diluent for intravenous phenytoin contains propylene glycol.
- Rapid injection of propylene glycol may cause cardiac dysrhythmias and hypotension.
- Cardiac effects are extremely rare with oral administration.
- Fosphenytoin is a water-soluble prodrug of phenytoin. It is rapidly metabolized to phenytoin in the blood. It does not contain propylene glycol and causes fewer cardiovascular effects than phenytoin during intravenous administration.
EPIDEMIOLOGY
- Phenytoin toxicity is common.
- Toxic effects following exposure are typically mild.
- Death is rare and usually involves a coingestant.
CAUSES
- Toxicity usually involves unintentional drug accumulation during therapy.
- Child abuse must be considered if the patient is less than 1 year of age; suicide attempt if the patient is over 6 years of age.
RISK FACTORS
- Changes in dose and addition or cessation of medications that alter phenytoin metabolism can lead to toxicity.
- Dosing may require adjustment in the elderly because albumin levels may be decreased.
DRUG AND DISEASE INTERACTIONS
- Phenytoin levels are increased by dioumerol, disulfiram, cimetidine, isoniazid, and some sulfonamides.
- Phenytoin levels are decreased by concurrent use of carbamazepine.
- Interactions between phenobarbital and ethanol and phenytoin are variable.
PREGNANCY AND LACTATION
- US FDA Pregnancy Category D. Evidence of human fetal risk exists, but benefits in certain situations (e.g., life-threatening situations or serious diseases) may make use of the drug acceptable despite its risks.
- Phenytoin is generally contraindicated in pregnancy.
Section Outline:
[
Show Section Outline]
DIFFERENTIAL DIAGNOSIS
- Toxic causes of nystagmus and ataxia are ethanol, phenobarbital, sedative-hypnotics, and many others.
- Nontoxic causes include cerebellar disease, middle ear disease, hypoglycemia, and electrolyte disorder.
SIGNS AND SYMPTOMS
- Ataxia and lethargy are the predominant manifestations after acute ingestion.
- Cardiovascular complications have been reported only with intravenous administration.
Vital Signs
Hypotension is common with rapid intravenous infusion.
Dermatologic
Adverse drug reactions can include erythema multiforme; rarely, Stevens-Johnson may develop, with therapeutic dosing.
Cardiovascular
Myocardial depression occurs with rapid intravenous infusion but has not been reported with oral ingestion.
Neurologic
- Cerebellar impairment results in ataxia, dysarthria, and nystagmus; this may occur with therapeutic blood levels.
- Cortical depression occurs at very high serum levels and may lead to coma.
- Toxic levels are reported to increase seizures, but data are inconclusive.
PROCEDURES AND LABORATORY TESTS
Essential Tests
- Phenytoin level
- This is typically measured on total serum level; therapeutic levels are 10 to 20 mg/L (1 to 2 mg/dl, 10 to 20 µg/ml).
- Free (not protein-bound) phenytoin levels may be obtained at reference laboratories.
- Levels of other antiseizure medications should be obtained.
Recommended Tests
- Serum albumin. In hypoalbuminemic patients the phenytoin level is corrected using the following formula: Corrected value = (concentration measured × 4.4) ÷ (albumin level).
- Serum electrolytes, glucose, BUN, creatinine, calcium, and magnesium should be determined in patients with altered mental status.
- ECG, serum acetaminophen and aspirin levels should be screened in an overdose setting to detect occult ingestion.
- Head CT, lumbar puncture, and cultures should be performed in patents with altered mental status.
Section Outline:
[
Show Section Outline]
- Treatment should focus on prevention of absorption, maintenance of airway, and prevention of falls due to ataxia.
- Dose and time of exposure should be determined for all substances involved.
DIRECTING PATIENT COURSE
The health-care professional should call the poison control center when:
- Coma or hypotension occur.
- Toxic effects are not consistent with phenytoin poisoning.
- Coingestant, drug interaction, or underlying disease presents an unusual problem.
The patient should be referred to a health-care facility when:
- Attempted suicide or homicide is possible.
- Patient or caregiver seems unreliable.
- Ataxia or other toxic effects develop.
- Toxic effects are not consistent with phenytoin poisoning.
- Coingestant, drug interaction, or underlying disease presents an unusual problem.
Admission Considerations
Inpatient management is warranted if the patient is unable to ambulate safely or perform activities of daily life.
DECONTAMINATION
Out of Hospital
Emesis should be induced with ipecac within 1 hour of ingestion for alert pediatric or adult patient if health-care evaluation will be delayed.
In Hospital
- Ipecac-induced emesis within 1 hour of ingestion is appropriate for the pediatric patient who is too small to have effective gastric lavage.
- Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients presenting within 1 hour of a large ingestion or if serious effects are present.
- One dose of activated charcoal (1-2 g/kg) should be administered without a cathartic if a substantial ingestion has occurred within the previous few hours.
- Multiple-dose charcoal decreases serum phenytoin levels more rapidly, but has not been shown to shorten clinical course.
ANTIDOTES
There is no specific antidote for phenytoin toxicity.
ADJUNCTIVE THERAPIES
- Ataxia. Bed rest with precautions for falling are needed until ataxia resolves.
- Apnea and ventricular dysrhythmias have occurred during rapid intravenous infusion.
- Immediate advanced cardiac life support (ACLS) usually produces rapid improvement.
- Infusion should be discontinued immediately; intubation may be needed.
- Normal saline should be infused for hypotension.
- Dysrhythmias should be treated according to ACLS protocols.
- Patients who become hypotensive or have dysrhythmias during intravenous infusion should have the infusion stopped immediately; endotracheal intubation and fluid resuscitation may be needed.
Section Outline:
[
Show Section Outline]
PATIENT MONITORING
- Phenytoin levels should be monitored; level should be decreasing before patient is discharged.
- Continuous respiratory and cardiac monitoring should be performed in patients receiving phenytoin intravenously.
EXPECTED COURSE AND PROGNOSIS
Ataxia may last several days, but usually sufficient recovery often occurs within 24 hours.
DISCHARGE CRITERIA/INSTRUCTIONS
Patients who can ambulate safely and have decreasing serum levels can be discharged following psychiatric evaluation, if needed.
Section Outline:
[
Show Section Outline]
DIAGNOSIS
- Patients with focal neurologic findings or CNS effects other than ataxia should be evaluated for CNS lesions.
- Hypoalbuminemic patients may be toxic at therapeutic levels of phenytoin due to reduced protein binding (e.g., high fraction of free drug).
TREATMENT
- Infusion rate greater than 50 mg/min may produce dysrhythmia or apnea.
- Failure to monitor intravenous infusion closely has resulted in death on rare occasions.
FOLLOW-UP
Patients who become toxic due to drug interactions should have the offending agent stopped.
Section Outline:
ICD-9-CM 966.1Poisoning by anticonvulsants and anti-parkinsonism drugs: hydantoin derivatives.
RECOMMENDED READING
Parke-Davis. Product information: Fosphenytoin. 1996.
Wyte CD, Berk WA. Severe oral phenytoin overdose does not cause cardiovascular morbidity. Ann Emerg Med 1991;20:508-512.
Author: Kennon Heard
Reviewer: Richard C. Dart