Phenytoin Toxicity 

Updated: Dec 31, 2020
Author: Charlene Miller, MD; Chief Editor: David Vearrier, MD, MPH 

Overview

Practice Essentials

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 was used as an antidysrhythmic agent, especially in the treatment of dysrhythmias due to digoxin toxicity. It has fallen out of favor for that use because of the advent of digoxin antibody fragments. Phenytoin is no longer considered appropriate for the management of toxin-induced or alcohol withdrawal seizures.

Signs and symptoms of phenytoin toxicity typically correspond to the serum level, and progress from occasional mild nystagmus at 10-20 mcg/mL (the therapeutic range) to coma and seizures at levels above 50 mcg/mL (see Presentation and Workup). Treatment is supportive (see Treatment and Medication).

For patient education information, see Drug Overdose and Poison Proofing Your Home.

Pathophysiology

Mechanism of action

Phenytoin blocks voltage-sensitive sodium channels in neurons. This action leads to a delay in neuronal electrical recovery from inactivation.[1] 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 small 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.[2]

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. Genetic polymorphism in the cytochrome enzymes that metabolize phenytoin may be responsible for variable rates of metabolism and thus susceptibility to toxicity, even in individuals taking appropriate doses.[3, 4]

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.

Epidemiology

In the 2019 Annual Report of the American Association of Poison Control Centers' National Poison Data System, 1262 single exposures to phenytoin were reported. Of these, 527 were unintentional toxicities, 243 were intentional, and 522 were reported as an adverse reaction. In addition, 10 single exposures to fosphenytoin were reported, five as adverse reactionsand five as unintentional.[5]

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.

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 total phenytoin blood levels (see Lab Studies).

Of the 1262 reported exposures to phenytoin in 2019, a total of 42 were in children younger than 6 years, 25 in patients 6-19 years of age, and 1168 in those 20 years and older.[5]

Prognosis

Death or severe morbidity rarely occurs with an intentional overdose as long as the patient receives good supportive care. Of the 1262 reported toxic exposures to phenytoin in 2019, 1088 were treated in a health care facility. Of this subset of patients, 161 had no significant outcome, 356 had minor effects, 407 had moderate morbidity, and 41 had major morbidity; two deaths were reported.[5]

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

 

Presentation

History

Establish whether the toxicity is acute or chronic. Important historical elements in acute toxicity are as follows:

  • Time of ingestion
  • Co-ingestants
  • Motivation for ingestion (intentional versus accidental)
  • Medications available in the household

Paramedics or family members may be able to provide additional information (eg, medications, past medical history)

In chronic toxicity, important historical elements are as follows:

  • Duration of phenytoin use
  • Dosing
  • Frequency
  • Compliance (last dose and missed dose)
  • Recent changes in pharmacotherapy

Important elements for patient query are as follows:

  • When symptoms began
  • Severity of symptoms
  • Exacerbating factors
  • Associated problems
  • Relieving factors

Physical Examination

Gingival hyperplasia is the most common adverse effect (20%) seen with chronically elevated serum phenytoin concentrations but is not associated with acute toxicity.

Neurologic findings in phenytoin toxicity may include the following:

  • Hyperreflexia or hyporeflexia
  • Abnormal gait (bradykinesia, truncal ataxia - Ataxia is very typical with elevated phenytoin levels, and may lead to falls and consequent trauma
  • 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 (long-term use)
  • Priapism
  • Urinary incontinence
  • Choreoathetoid movements
  • Dysarthria
  • Dysphagia
  • Seizures (rare)
  • Death (rare)

Eye examination may reveal the following:

  • Nystagmus (horizontal, vertical)
  • Ophthalmoplegia
  • Diplopia
  • Miosis or mydriasis

Phentyoin has been reported to cause DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms), a potentially fatal hypersensitivity reaction. Hypersensitivity reactions, including DRESS syndrome, typically manifest after a delay of 2 - 6 wk after exposure and may include the following:

Cardiovascular findings may include the following:

Skin findings may include the following:

Gastrointestinal/abdomen findings may include the following:

  • Right upper quadrant tenderness
  • Hepatomegaly
  • Splenomegaly
  • Nausea
  • Vomiting

Metabolic findings in patients with chronic phenytoin toxicity include osteomalacia and hypothyroidism.

Fetal hydantoin syndrome

Intrauterine exposure to phenytoin may result in the following physical features:

  • Broad nasal bridge
  • Wide fontanelle
  • Low hairline
  • Cleft lip/palate
  • Epicanthal folds
  • Short neck
  • Microcephaly
  • Low-set ears
  • Small or absent nails
  • Hip dislocation
  • Hypoplasia of distal phalanges
  • Impaired growth
  • Congenital heart defects
 

DDx

Diagnostic Considerations

Drug interactions are an important consideration in patients who are taking other medications in combination with phenytoin. Numerous interactions between phenytoin and other medications are known to exist, and can result in inadvertent toxicity or decreased efficacy.

Phenytoin increases serum levels of toxic metabolites of the following:

  • Acetaminophen
  • Oral anticoagulants
  • Primidone (eg, phenobarbital)

Phenytoin decreases serum levels of the following:

  • Amiodarone
  • Carbamazepine
  • Oral contraceptives
  • Corticosteroids
  • Cyclosporine
  • Disopyramide
  • Doxycycline
  • Furosemide
  • Levodopa
  • Methadone
  • Mexiletine
  • Quinidine
  • Theophylline
  • Valproic acid

Serum levels of phenytoin are increased by the following:

  • Amiodarone
  • Chloramphenicol
  • Cimetidine
  • Disulfiram
  • Ethosuximide
  • Fluconazole
  • Isoniazid
  • Oral anticoagulants
  • Phenylbutazone (long banned in the United States and other countries, but still available in some Latin American countries)
  • Sulfonamides
  • Trimethoprim
  • Valproic acid

Serum levels of phenytoin are decreased by the following:

  • Antineoplastic drugs
  • Calcium
  • Diazepam
  • Diazoxide
  • Ethanol (long-term use),
  • Folic acid
  • Phenobarbital
  • Rifampin
  • Sucralfate
  • Theophylline

Differential Diagnoses

 

Workup

Laboratory Studies

Obtain a serum phenytoin level. The therapeutic range is 10-20 mcg/mL. Total phenytoin levels (mcg/mL) and typical corresponding signs and symptoms are as follows:

  • 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

Following an acute overdose, serial serum phenytoin concentrations should be obtained due to unpredictable absorption patterns. Zero-order pharmacokinetics at elevated serum phenytoin concentrations may result in prolonged elevated concentrations lasting days to weeks.

Normally, approximately 90% of circulating phenytoin is bound to albumin. Therapeutic free phenytoin levels are 1 - 2 mcg/mL. Individuals with decreased protein binding may have clincial toxicity despite a normal total phenytoin level; however, their free phenytoin level is elevated. Free phenytoin levels thus may be more accurate than total levels in patients with hypoalbuminemia; alternatively, in such cases the total phenytoin level can be corrected, using the Sheiner-Tozer formula (see Phenytoin level).[8] However, the predictive performance of such formulas has been called into question.[9]

In the intentional overdose setting, immediately perform a dextrose fingerstick test in any patient with altered mental status.

Obtain aspirin and acetaminophen levels in cases of self-injurious or exploratory ingestions when there is a possibility for co-ingestion of those medications. Consider measurement of other drugs the patient is taking, in view of the possibility of drug interactions with phenytoin (see Diagnostic Considerations).

Perform pregnancy tests in women of childbearing age.

For acute toxicity, do the following:

  • 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

For patients with hypersensitivity reactions, including possible DRESS syndrome, do the following:

  • Obtain a complete blood count (CBC) to rule out anemia, eosinophilia, atypical lymphocytosis, and pancytopenia
  • Perform liver function tests (LFTs) to rule out hepatotoxicity

Imaging Studies

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

Evaluate patients with a history of ataxia and consequent fall(s) for any traumatic injury.

Electrocardiography

Oral phenytoin overdose rarely causes cardiac toxicity. Check for evidence of dysrhythmia, severe clinical presentation, or multiple medication ingestion. 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

Management is as follows:

  • Support airway, breathing, and circulation [10]
  • Obtain IV access, provide supplemental oxygen, and institute cardiac monitoring
  • Consider gastric decontamination

The American Academy of Clinical Toxicology advises that no evidence supports the routine use of gastric lavage in the management of poisonings.[11] Orogastric lavage rarely offers any advantage over activated charcoal, and can result in serious complications.

Use of activated charcoal may be considered, provided that the patient's airway is intact or protected; it is most likely to be beneficial if given within 1 hour after the ingestion took place. Case reports describe effective use of multiple-dose activated charcoal (MDAC) in both acute and chronic phenytoin toxicity.[12, 13]  In one randomized, controlled study, subjects with supratherapeutic phenytoin concentrations who were randomized to receive MDAC more rapidly reached a subtoxic levels than controls.[14] However, in a retrospective study of electronic poison center data on 132 hospitalized patients with phenytoin concentrations >20 mg/L, the use of activated charcoal (single or multiple dose) was associated with increased time to reach the composite end point of clinical improvement.[15]

If multiple-dose activated charcoal is used, it is administered 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 and hemoperfusion have traditionally been thought of as ineffective for phenytoin toxicity, given the protein binding of phenytoin. However, case reports and studies have suggested that hemodialysis or charcoal hemoperfusion may have a limited role in phenytoin toxicity.[16, 17]

The treatment of hypotension secondary to IV infusion includes decreasing the rate of infusion and, possibly, administering intravenous fluids or vasopressors.

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. Adequate IV hydration should be maintained. These patients should be out of bed only with assistance because they are at high risk of falling and sustaining serious injuries.

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

In chronic nonintentional overdoses, pay specific attention to the patient's pharmacopeia to determine if the toxicity was iatrogenic.

For nonintentional overdoses, individuals with mild toxicity may be treated as outpatients, provided that serial serum phenytoin concentrations are decreasing, they are not so ataxic that risk of self-injury is a concern, and 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.

Consultations

Consult neurology department personnel for moderate-to-severe hypersensitivity reactions, such as DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome, caused by long-term 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.[18]

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 medical toxicologist for additional information and patient care recommendations.

 

Medication

Medication Summary

Treatment of phenytoin toxicity is primarily focused on limiting the systemic burden of phenytoin by gastrointestinal decontamination and administration of benzodiazepines to manage any seizures that may occur.

GI decontaminant

Class Summary

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.

Benzodiazepines

Class Summary

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.

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.

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.

 

Questions & Answers

Overview

What is phenytoin toxicity?

What is the pathophysiology of phenytoin toxicity?

What are the pharmacokinetics of phenytoin toxicity?

What is the prevalence of phenytoin toxicity in the US?

What are the sexual predilections of phenytoin toxicity?

Which age groups have the highest prevalence of phenytoin toxicity?

What is the mortality and morbidity associated with phenytoin toxicity?

Presentation

Which clinical history findings are characteristic of acute phenytoin toxicity?

Which clinical history findings are characteristic of chronic phenytoin toxicity?

What is the focus of clinical history to evaluate phenytoin toxicity?

What is the most common adverse effect of phenytoin toxicity?

Which neurological findings suggest phenytoin toxicity?

Which eye exam findings suggest phenytoin toxicity?

What are the signs and symptoms of hypersensitivity reactions to phenytoin toxicity?

Which cardiovascular findings suggest phenytoin toxicity?

Which skin findings suggest phenytoin toxicity?

Which GI findings suggest phenytoin toxicity?

Which physical findings are characteristic of intrauterine exposure to phenytoin?

DDX

How do drug interactions affect phenytoin toxicity?

Serum levels of which medications are increased by phenytoin?

Serum levels of which medications are decreased by phenytoin?

Which medications increase serum levels of phenytoin?

Which medications decrease serum levels of phenytoin?

What are the differential diagnoses for Phenytoin Toxicity?

Workup

What is the role of lab testing in the workup of phenytoin toxicity?

Which lab tests are performed in the workup of acute phenytoin toxicity?

Which lab tests are performed in the workup of hypersensitivity reaction in phenytoin toxicity?

What is the role of imaging studies in the workup of phenytoin toxicity?

What is the role of electrocardiography in the workup of phenytoin toxicity?

Treatment

What is included in prehospital care for phenytoin toxicity?

How is phenytoin toxicity treated?

When is inpatient care indicated in the treatment of phenytoin toxicity?

What is included in the long-term monitoring of phenytoin toxicity?

Which specialist consultations are beneficial to patients with phenytoin toxicity?

Medications

What is the role of medications in the treatment of phenytoin toxicity?

Which medications in the drug class Benzodiazepines are used in the treatment of Phenytoin Toxicity?

Which medications in the drug class GI decontaminant are used in the treatment of Phenytoin Toxicity?