AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

Phenytoin is a commonly prescribed anticonvulsant used to treat most types of seizure disorders and status epilepticus, with the exception of absence seizures.

Historically, phenytoin has been used as an antidysrhythmic agent, especially in the treatment of digoxin toxicity. It has recently fallen out of favor because of the advent of digoxin antibody fragments. Similarly, phenytoin is no longer considered appropriate for the management of toxin-induced seizures or for the treatment of alcohol withdrawal syndrome.

Pathophysiology

Mechanism of action

Phenytoin blocks voltage-sensitive sodium channels in neurons. This action leads to a delay in neuronal electrical recovery. Phenytoin's inhibitory effect is dependent on the voltage and frequency of neural cell firing by selectively blocking the neurons that are firing at high frequency. Phenytoin prevents the electrical spread of a focus of irritable tissue from entering normal tissue.

Phenytoin administration has been associated with toxic effects. Phenytoin toxicity depends on the route of administration, duration, exposure, and dosage. The route of administration is the most important determinant of toxicity. Phenytoin may be administered orally or intravenously. In addition, fosphenytoin may be administered intramuscularly.

Pharmacokinetics

Phenytoin is a weak acid and has erratic GI absorption. Following ingestion, phenytoin precipitates in the stomach's acid environment; this characteristic is particularly important in the setting of an intentional overdose. Peak blood levels occur 3-12 hours following single dose ingestion.

The parenteral form of phenytoin is dissolved in 40% propylene glycol and 10% ethanol and adjusted to a pH of 12; sodium hydroxide is added to maintain solubility. Extravasation of the solution may cause skin irritation or phlebitis. Phenytoin administered intravenously at a rate higher than 50 mg/min may cause hypotension and arrhythmias. These complications are believed to be secondary to the diluent, propylene glycol.

Phenytoin has a volume of distribution of 0.6 L/kg and is extensively bound to plasma proteins (90%). Blood levels of phenytoin reflect only total serum concentration of the drug. Only the free unbound phenytoin has biological activity.

Population groups that are predisposed to elevated free phenytoin levels include neonates, elderly persons, and individuals with uremia, hypoalbuminemia, or hyperbilirubinemia. These patients may exhibit signs of toxicity when drug levels are within the therapeutic range (see Lab Studies). Certain medications can interfere with phenytoin levels.

Hepatic microsomal enzymes primarily metabolize phenytoin. Much of the drug is excreted in the bile as an inactive metabolite, which is then reabsorbed from the intestinal tract and ultimately excreted in the urine. Less than 5% of phenytoin is excreted unchanged in the urine. Individuals with impaired metabolic or excretory pathways may exhibit early signs of toxicity.

Phenytoin metabolism is dose dependent. Elimination follows first-order kinetics (fixed percentage of drug metabolized during a per unit time) at the low drug concentrations and zero-order kinetics (fixed amount of drug metabolized per unit time) at higher drug concentrations. This change in kinetics reflects the saturation of metabolic pathways. Thus, very small increments in dosage may result in adverse effects.

Frequency

United States

Of the 4145 toxic exposures reported in the 2003 Annual Report of the American Association of Poison Control Centers' Toxic Exposure Surveillance System (AAPCC TESS), 2173 were unintentional toxicities, 1398 were intentional, and 460 were reported as adverse reactions.¹

Mortality/Morbidity

Death or severe morbidity rarely occurs with an intentional overdose as long as the patient receives good supportive care.

Of the 4145 reported toxic exposures in 2003, 2756 were treated in a health care facility. Of this subset of patients, 850 had no significant outcome, 1035 had minor effects, 743 had moderate morbidity, 98 had major morbidity, and 10 resulted in fatality.¹

Race

No scientific evidence has demonstrated that outcomes of acute toxicity are based on race.

Sex

Phenytoin is a category D drug. Various congenital anomalies have been reported from usage during pregnancy (see Fetal hydantoin syndrome). No scientific data have demonstrated that effect or outcome of acute toxicity is based on sex.

Age

Neonates and elderly patients are at greater risk for toxicity because of impaired metabolism and decreased protein binding.

• Decreased protein binding contributes to higher levels of biologically active medication at therapeutic measured plasma levels (see Lab Studies).
• Of the 4145 reported exposures in 2003, a total of 600 patients were younger than 6 years, 283 were aged 6-19 years, and 3228 were older than 19 years.¹

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

Establish if the toxicity is acute or chronic.

• Intentional overdose
• • Important historical elements
    • Time of ingestion
    • Co-ingestants
    • Motivation for ingestion
    • Medications available in the household
  • Paramedics or family members may be able to provide additional information (eg, medications, past medical history).
• Chronic toxicity
• • Important historical elements
    • Duration of administration
    • Dosing
    • Frequency
    • Compliance (last dose and missed dose)
    • Recent changes to their pharmacotherapy
  • Important elements for patient query
    • When symptoms began
    • Severity of symptoms
    • Exacerbating factors
    • Associated problems
    • Relieving factors

Physical

• Phenytoin may cause a febrile reaction, hypotension (during intravenous infusion), or bradycardia.
• Mouth - Gingival hyperplasia (chronic use), the most common adverse effect (20%)
• Neurologic
• • Hyperreflexia or hyporeflexia
  • Abnormal gait (bradykinesia, truncal ataxia)
  • Respiratory distress
  • Encephalopathy
  • Meningeal irritation with pleocytosis
  • Tremor (intention)
  • Irritability or agitation
  • Confusion
  • Hallucinations
  • Mental status varies from completely normal to the extremes of stupor and coma, particularly if co-ingestants are present
  • Peripheral neuropathy (chronic use)
  • Priapism
  • Urinary incontinence
  • Choreoathetoid movements
  • Dysarthria
  • Dysphagia
  • Seizures (rare)
  • Death (rare)
• Eyes
• • Nystagmus (horizontal, vertical)
  • Ophthalmoplegia
  • Diplopia
  • Miosis or mydriasis
• Hypersensitivity reactions
  
  
  • Fever, rash, and lymphadenopathy, commonly observed together
  • Systemic lupus erythematosus (SLE)
  • Polyarteritis
  • Polymyositis
  • Eosinophilia
  • Megaloblastic anemia
  • Pseudolymphoma
  • Lymphadenopathy
• Vascular - Phlebitis
• Skin
• • Hirsutism
  • Acne
  • Rashes, can be mild, morbilliform, scarlatinoid or as severe as Stevens-Johnson syndrome
  • Jaundice
  • Facial or periorbital edema
  • Erythema multiforme (EM)
  • Toxic epidermal necrolysis (TEN)
• GI/abdomen
• • Right upper quadrant tenderness
  • Hepatomegaly
  • Splenomegaly
  • Nausea
  • Vomiting
  • Hepatitis
• Other
• • Fetal hydantoin syndrome is manifested by broad nasal bridge, wide fontanelle, low hairline, cleft lip/palate, epicanthal folds, short neck, microcephaly, low-set ears, small or absent nails, dislocated hip, hypoplasia of distal phalanges, impaired growth, and congenital heart defects.
  • Metabolic symptoms may include osteomalacia and hypothyroidism (chronic toxicity).
  • Hypotension, bradycardia², myocardial depression, ventricular fibrillation, asystole, and tissue necrosis³ all have been associated with the IV formulation.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

• Serum phenytoin level
• • The therapeutic range is 10-20 mcg/mL. Plasma levels (mcg/mL) have an association with acute neurological symptoms. Free phenytoin levels range from 1-2 mcg/mL and correlate well with clinical evidence of toxicity (ie, individuals with decreased protein binding may have signs and symptoms of toxicity despite a normal total phenytoin level; however, their free phenytoin level is elevated).
  • Lower than 10 - Rare
  • Between 10 and 20 - Occasional mild nystagmus
  • Between 20 and 30 - Nystagmus
  • Between 30 and 40 - Ataxia, slurred speech, nausea, and vomiting
  • Between 40 and 50 - Lethargy and confusion
  • Higher than 50 - Coma and seizures
• In the intentional overdose setting, immediately perform a dextrose finger-stick test in any patient with altered mental status.
• Aspirin and acetaminophen levels
• Perform pregnancy tests in women of childbearing age.
• Acute toxicity
• • Measure ethanol level for multiple ingestions or altered mental status.
  • Measure electrolyte levels for questionable clinical presentation, elderly persons, or patients with multiple medical problems.
  • Perform liver function tests for suspected hepatotoxicity or to determine patient's baseline.
• Chronic toxicity
• • Obtain a complete blood count (CBC) to rule out anemia, eosinophilia, atypical lymphocytosis, and pancytopenia.
  • Perform liver function tests (LFTs) to rule out hepatotoxicity.
  • Measure electrolytes to rule out hyperglycemia and hyperosmolar nonketotic coma.
• Drug interactions: If prescribing other medications in combination with phenytoin, be very alert to the possibility of inadvertent toxicity or decreased efficacy of the antiepileptic medication. Numerous interactions between phenytoin and other medications are known to exist.
  • Phenytoin increases serum levels of toxic metabolites of acetaminophen, oral anticoagulants, and primidone (eg, phenobarbital).
  • Phenytoin decreases serum levels of amiodarone, carbamazepine, contraceptives, corticosteroids, cyclosporine, disopyramide, doxycycline, furosemide, levodopa, methadone, mexiletine, quinidine, theophylline, and valproic acid.
  • Serum levels are increased by amiodarone, chloramphenicol, cimetidine, disulfiram, ethosuximide, fluconazole, isoniazid, oral anticoagulants, phenylbutazone, sulfonamides, trimethoprim, and valproic acid.
  • Serum levels are decreased by antineoplastic drugs, calcium, diazepam, diazoxide, ethanol (chronic), folic acid, phenobarbital, rifampin, sucralfate, and theophylline.

Imaging Studies

• Obtain a CT scan of the head for patients with unexplained altered mental status.

Other Tests

• Electrocardiogram
• • Check for evidence of dysrhythmia, severe clinical presentation, or multiple medication ingestion.
  • Oral phenytoin overdose rarely causes cardiac toxicity.
  • Most cardiovascular complications have occurred with rapid (>50 mg/min) intravenous administration.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Prehospital Care

• The usual measures of airway maintenance, breathing assessment, and circulatory support are indicated.

Emergency Department Care

• Support airway, breathing, and circulation.⁴
• Obtain IV access, provide supplemental oxygen, and place on a cardiac monitor.
• Consider the risks versus the benefits of orogastric lavage; it rarely offers any advantage over activated charcoal and cathartic use.
• Administer multiple dose activated charcoal⁵ every 2-6 hours until passage of charcoal stool, loss of bowel sounds, or improved clinical condition is observed. This may be difficult because nausea and emesis may complicate phenytoin toxicity.
• Hemodialysis or hemoperfusion are ineffective for enhancing elimination.
• The treatment for hypotension secondary to IV infusion includes decreasing the rate of infusion, intravenous fluids, and, possibly, vasopressors.

Consultations

• Consult neurology department personnel for moderate-to- severe reactions caused by chronic therapy. Patients require close follow-up and changes in anticonvulsant medication.
• Patients with serious complications (eg, dysrhythmias, hemodynamic instability, altered mental status, severe ataxia, coma, seizures) following a toxic exposure require hospital admission for further monitoring and treatment⁶.
• Consultation of psychiatry department personnel for intentional overdoses is mandatory.
• Consult a plastic surgeon for extravasation injuries.
• Consult the regional poison control center or a local medical toxicologist (certified by the American Board of Medical Toxicology or the American Board of Emergency Medicine) for additional information and patient care recommendations.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Treatment is primarily focused on limiting the systemic burden of phenytoin by GI decontamination and management of any seizures that may occur with benzodiazepines.

Drug Category: GI decontaminant

Multiple dose activated charcoal is thought to enhance the elimination of phenytoin that was administered orally or intravenously.

Drug Category: Benzodiazepines

Used for seizure control, although seizures in the presence of toxic levels of phenytoin are rare.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Further Inpatient Care

• Many patients with moderate toxicity require inpatient care because they are unable to ambulate from the severe ataxia or unable to eat secondary to the nausea.
• • Maintain adequate IV hydration.
  • These patients should be out of bed only with assistance because they are at high risk of falling and sustaining serious injuries.
• Numerous, repeat phenytoin levels are not required because symptoms and clinical signs allow determination of toxicity.
• In chronic nonintentional overdoses, pay specific attention to the patient's pharmacopeia to determine if the toxicity was iatrogenic.

Further Outpatient Care

• For nonintentional overdoses, individuals with mild toxicity may be treated as outpatients if they are not so ataxic that risk of self-injury is a concern and if they are capable of maintaining adequate hydration despite their nausea. In these instances, carefully review their medications and correct any wrong dosages or drug interactions.

Complications

• The most common complications involve undiagnosed injuries sustained as a result of the phenytoin-induced ataxia.

Patient Education

• For excellent patient education resources, visit eMedicine's Drug Overdose Center and Poisoning - First Aid and Emergency Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• Failure to diagnose a phenytoin hypersensitivity reaction, thus not stopping further phenytoin ingestion
• Failure to realize that signs and symptoms may progress as the free phenytoin penetrates the CNS, thereby discharging a patient with a deteriorating clinical picture
• Prescribing a new drug that causes adverse pharmacokinetic reaction with a stable dose of phenytoin, thus leading to signs and symptoms of toxicity

Special Concerns

• Phenytoin toxicity may manifest itself in a variety of clinical symptoms and syndromes.
• • Because many clinicians are unfamiliar with subtle presentations of these syndromes, many cases of chronic toxicity may go unrecognized, with resultant serious consequences.
  • Phenytoin hypersensitivity is not a typical hypersensitivity reaction.
  • It may present as one of many different syndromes, such as lymphoma, hepatitis, or Stevens-Johnson syndrome.
  • It may include a wide variety of symptoms, such as fever, rash, arthralgias, or lymphadenopathy.
• Because phenytoin toxicity may take many forms, consider the possibility of a phenytoin hypersensitivity reaction in any patient receiving phenytoin who has unusual symptoms. This is especially important if the patient presents with the triad of fever, rash, and lymphadenopathy.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the assistance of Lada Kokan, MD, with the literature review and referencing for this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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Article Last Updated: Dec 11, 2007