Phenytoin is a commonly prescribed anticonvulsant used to treat most types of seizure disorders and status epilepticus. It is not effective for treatment of absence seizures and it is no longer considered appropriate for the management of toxin-induced or alcohol withdrawal 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.
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).
Phenytoin blocks voltage-sensitive sodium channels in neurons.[1] This action leads to a delay in neuronal electrical recovery from inactivation.[2] Phenytoin's inhibitory effect is dependent on the voltage and frequency of neural cell firing; it selectively blocks 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 also be administered intramuscularly if intravenous access is unavailable.
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 extend for 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 have been attributed to the diluent, propylene glycol. However, cardiac toxicity was reported even after rapid administration of fosphenytoin, which does not contain propylene glycol, suggesting intrinsic phenytoin cardiac toxicity.[3] Orally administered phenytoin is rarely associated with cardiac toxicity.[4]
Phenytoin has a small volume of distribution of 0.6 L/kg and is extensively bound to plasma proteins (90%). Only the free unbound phenytoin has biological activity, but phenytoin assays report the total serum concentration of the drug. Because phenytoin levels are lower in serum than in CNS tissue, serum levels may underestimate CNS concentrations of the drug.[5]
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 Workup/Laboratory Studies). Certain medications can interfere with phenytoin levels.
Metabolism of phenyton is primarily by hepatic microsomal enzymes. 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.[6]
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.
In the 2023 Annual Report of the American Association of Poison Control Centers' National Poison Data System, 780 single exposures to phenytoin were reported. Of these, 269 were unintentional toxicities, 125 were intentional, and 322 were reported as an adverse reaction. In addition, three single exposures to fosphenytoin were reported, one as a major adverse reaction and two as unintentional.[7]
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 780 reported exposures to phenytoin in 2023, a total of 19 were in children younger than 6 years, 16 in patients 6-19 years of age, and 725 in those 20 years and older.[7]
Death or severe morbidity rarely occurs with an intentional overdose as long as the patient receives good supportive care. In 2023, 643 of the 780 reported toxic exposures to phenytoin were treated in a health care facility. Of this subset of patients, 70 had no significant outcome, 225 had minor effects, 266 had moderate morbidity, and 40 had major morbidity; no deaths were reported.[7]
The most common complications involve undiagnosed injuries sustained as a result of the phenytoin-induced ataxia.
Movement disorders have been associated with phenytoin use including dyskinesia, myoclonus -asterixis, dystonia, parkinsonism, tics, and restless leg syndrome.In almost all cases, these movement disorders resolve within 6 months after drug withdrawal.[8]
Establish whether the toxicity is acute or chronic. Important historical elements in acute toxicity are as follows:
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:
Important elements for patient query are as follows:
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:
Eye examination may reveal the following:
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:
Metabolic findings in patients with chronic phenytoin toxicity include osteomalacia and hypothyroidism.[11]
Intrauterine exposure to phenytoin may result in the following physical features:
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[1] :
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).[12] However, the predictive performance of such formulas has been called into question.[13]
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 DDx/Diagnostic Considerations).
Perform pregnancy tests in women of childbearing age.
For acute toxicity, do the following:
For patients with hypersensitivity reactions, including possible DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome, do the following:
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.
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.
Management is as follows:
The American Academy of Clinical Toxicology advises that no evidence supports the routine use of gastric lavage in the management of poisonings.[15] 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.[16, 17] In one randomized, controlled study, subjects with supratherapeutic phenytoin concentrations who were randomized to receive MDAC more rapidly reached a subtoxic levels than controls.[18] 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.[19]
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.[20, 21]
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 due to the severe ataxia or unable to eat due to the nausea. Adequate IV hydration should be maintained. These patients should be allowed 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.
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.[22]
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.
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.
Clinical Context: 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 longer than 1 h after ingestion.
Multiple-dose activated charcoal is thought to enhance the elimination of phenytoin that was administered orally or intravenously.
Clinical Context: Drug of choice for drug-induced seizures. Longer duration of action compared with other agents.
Clinical Context: IV/IM formulation with short duration of sedation. Used as alternative for termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak electroencephalographic effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose.
Clinical Context: 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.
Used for seizure control, although seizures in the presence of toxic levels of phenytoin are rare. Alternative formulations for patients without intravenous access include midazolam intranasal and, for pediatric patients, diazepam buccal.