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Toxicity, Phenytoin

Charlene A Miller, MD, Consulting Staff, Department of Emergency Medicine, Oakwood Hospital Medical Center
Daniel M Joyce, MD, Consulting Staff, Department of Emergency Medicine, Saint Vincent's and Saint Mary's Medical

Updated: Jul 15, 2009

Introduction

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 dysrhythmias due to digoxin toxicity. It has recently fallen out of favor because of the advent of digoxin antibody fragments. Phenytoin is no longer considered appropriate for the management of toxin-induced or alcohol withdrawal seizures.

Pathophysiology

Mechanism of action

Phenytoin blocks voltage-sensitive sodium channels in neurons. This action leads to a delay in neuronal electrical recovery from inactivation. 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 (water-soluble phenytoin prodrug) 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, but absorption can be extended up to 2 weeks, especially in massive overdose. Oral exposures are associated predominantly with CNS symptoms.

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. However, cardiac toxicity was reported even after rapid administration of fosphenytoin that does not contain propylene glycol, suggesting intrinsic phenytoin cardiac toxicity. Orally administered phenytoin is rarely, if ever, associated with cardiac toxicity.

Phenytoin has a large 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. Because CNS tissue levels are higher than in serum, levels may underestimate CNS concentrations of phenytoin.1

Population groups that are predisposed to elevated free phenytoin levels include neonates, elderly persons, and individuals with uremia, hypoalbuminemia (due to pregnancy, nephrotic syndrome, malignancy, malnutrition), 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

In the 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System, 2395 single exposures to phenytoin were reported. Of these, 1216 were unintentional toxicities, 600 were intentional, and 485 were reported as an adverse reaction.2

Mortality/Morbidity

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

Of the 2395 reported toxic exposures in 2007, 1710 were treated in a health care facility. Of this subset of patients, 391 had no significant outcome, 590 had minor effects, 528 had moderate morbidity, 45 had major morbidity, and 4 resulted in fatality.2

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 2395 reported exposures in 2007, a total of 289 patients were younger than 6 years, 121 were aged 6-19 years, and 1811 were older than 19 years.2

Clinical

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 - Ataxia is very typical presentation for patients with elevated phenytoin levels.
    • 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 (usually 1-4 wk after exposure)
    • Fever, rash, and lymphadenopathy, commonly observed together
    • Hepatitis
    • Myocarditis
    • Systemic lupus erythematosus (SLE)
    • Polyarteritis
    • Polymyositis
    • Eosinophilia
    • Megaloblastic anemia
    • Pseudolymphoma
    • Lymphadenopathy
  • Cardiovascular
    • Hypotension, bradycardia3 , myocardial depression, ventricular fibrillation, asystole, and tissue necrosis4 all have been associated with the IV formulation.
    • Phlebitis, necrosis, even gangrene
    • "Purple glove syndrome"
      • Distal limb edema, discoloration, and pain after IV administration
      • Usually in elderly and after massive/multiple doses
  • 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).
    • Trauma - Patients suffer from ataxia and consequently falling.

Differential Diagnoses

Alcohol and Substance Abuse Evaluation
Toxicity, Barbiturate
Encephalitis
Toxicity, Benzodiazepine
Erythema Multiforme
Toxicity, Carbamazepine
Hepatitis
Toxicity, Isoniazid
Hypoglycemia
Toxicity, Sedative-Hypnotics
Shock, Cardiogenic
Toxicity, Valproate
Stevens-Johnson Syndrome
Systemic Lupus Erythematosus
Toxic Epidermal Necrolysis

Workup

Laboratory 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.
  • Evaluate patient with the history of ataxia and consequent fall(s) for any traumatic injury

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

Prehospital Care

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

Emergency Department Care

  • Support airway, breathing, and circulation.5
  • 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 charcoal6 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. Activated charcoal may precipitate vomiting, aspiration pneumonia, or electrolyte disturbances.
  • Hemodialysis or hemoperfusion are ineffective for enhancing elimination.
  • The treatment of 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 treatment.7
  • 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

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

GI decontaminant

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


Activated charcoal (Liqui-Char)

Preferred GI decontamination method when decontamination is desired. It may be administered with a cathartic (eg, 70% sorbitol), except in young pediatric patients in whom electrolyte disturbances may be of concern. Limited benefit if administered greater than 1 h after ingestion.

Dosing

Adult

1 g/kg (50-100 g) PO

Pediatric

1-2 g/kg (15-30 g) PO
<2 years: cathartic not recommended

Interactions

Effectiveness of other medications decreases with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases adsorptive properties)

Contraindications

Documented hypersensitivity; poisoning or overdose of mineral acids and alkalies; unprotected airway with absent gag reflex

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor for presence of bowel sounds to minimize risk of charcoal ileus; not very effective in poisonings of ethanol, methanol, and iron salts; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black

Benzodiazepines

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


Lorazepam (Ativan)

DOC for drug-induced seizures. Longer duration of action compared to the other agents.

Dosing

Adult

0.044 mg/kg (2-4 mg) IV, titrate to effect
Status epilepticus: 4 mg IV over 2-5 min; may repeat second dose in 10-15 min prn; not to exceed 8 mg/dose

Pediatric

Infants and children: 0.02-0.1 mg/kg IV slowly over 2-5 min; repeat in 10-15 min at 0.05 mg/kg prn; not to exceed 4 mg/dose
Adolescents: 0.07 mg/kg IV slowly over 2-5 min; repeat in 10-15 min prn; not to exceed 4 mg/dose

Interactions

Effects are potentiated by narcotics, barbiturates, MAOIs, and other antidepressants

Contraindications

Documented hypersensitivity; preexisting CNS depression, hypotension, and narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, or Parkinson disease; monitor for respiratory depression with high or repeated doses; contains benzyl alcohol, which may be toxic to infants in high doses


Midazolam (Versed)

IV/IM formulation with short duration of sedation. Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose.

Dosing

Adult

0.05 mg/kg IV; repeat prn

Pediatric

Administer as in adults

Interactions

Sedative effects of midazolam may be antagonized by theophyllines; narcotics and erythromycin may accentuate sedative effects of midazolam because of decreased clearance

Contraindications

Documented hypersensitivity; preexisting hypotension, narrow-angle glaucoma, and sensitivity to propylene glycol (diluent)

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in congestive heart failure, pulmonary disease, renal impairment, and hepatic failure; monitor for respiratory depression with high or repeated doses


Diazepam (Valium)

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Commonly available, also useful for treatment of seizures or agitation.

Dosing

Adult

0.1-0.2 mg/kg IV or 5-10 mg IV q10-15min until symptoms resolve; not to exceed 30 mg

Pediatric

30 days to 5 years: 0.2-0.5 mg IV (slowly) q2-5min until symptoms resolve; not to exceed 5 mg
>5 years: 1 mg IV (slowly) q2-5min until symptoms resolve; not to exceed 10 mg

Interactions

Increases toxicity of benzodiazepines in CNS with coadministration of phenothiazines, barbiturates, alcohols, and MAOIs

Contraindications

Documented hypersensitivity; hypotension or narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution with other CNS depressants, low albumin levels, or hepatic and renal disease (may increase toxicity); monitor for respiratory depression with high or repeated doses

Follow-up

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.
  • Patients with the evidence of cardiac toxicity and ECG changes should be admitted to monitored settings
  • 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

Medicolegal 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
  • Failure to diagnose traumatic injury in patients who are ataxic and suffer from fall
  • Aspiration pneumonia after administration of multiple doses of activated charcoal in patients with altered mental status

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.

References

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Keywords

phenytoin toxicity, phenytoin poisoning, phenytoin exposure, anticonvulsant drug, seizure disorder, phenytoin overdose, elevated phenytoin levels, status epilepticus, phenytoin ingestion, seizure treatment, treatment of seizure

Contributor Information and Disclosures

Author

Charlene A Miller, MD, Consulting Staff, Department of Emergency Medicine, Oakwood Hospital Medical Center
Charlene A Miller, MD is a member of the following medical societies: American College of Emergency Physicians
Disclosure: Nothing to disclose.

Coauthor(s)

Daniel M Joyce, MD, Consulting Staff, Department of Emergency Medicine, Saint Vincent's and Saint Mary's Medical
Daniel M Joyce, MD is a member of the following medical societies: American College of Emergency Physicians and American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Lance W Kreplick, MD, MMM, FAAEM, FACEP, Medical Director of Hyperbaric Medicine, Fawcett Wound Management and Hyperbaric Medicine; Consulting Staff in Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC
Lance W Kreplick, MD, MMM, FAAEM, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physician Executives
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

Fred Harchelroad, MD, FACMT, FAAEM, FACEP, Chair, Department of Emergency Medicine, Director of Medical Toxicology - Allegheny General Hospital, Associate Professor, Department of Emergency Medicine, Drexel University College of Medicine
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Department of Surgery, Section of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

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