Phenytoin Toxicity

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.

In the 2021 Annual Report of the American Association of Poison Control Centers' National Poison Data System, 872 single exposures to phenytoin were reported. Of these, 527 were unintentional toxicities, 284 were intentional, and 342 were reported as an adverse reaction. In addition, four single exposures to fosphenytoin were reported, two as major adverse reactions and two 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 872 reported exposures to phenytoin in 2021, a total of 24 were in children younger than 6 years, 20 in patients 6-19 years of age, and 804 in those 20 years and older.[5]

Death or severe morbidity rarely occurs with an intentional overdose as long as the patient receives good supportive care. Of the 872 reported toxic exposures to phenytoin in 2021, 735 were treated in a health care facility. Of this subset of patients, 77 had no significant outcome, 282 had minor effects, 274 had moderate morbidity, and 37 had major morbidity; two deaths were reported.[5]

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.[6]

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

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:

• Fever, rash, and lymphadenopathy, commonly observed together
• Hepatitis
• Myocarditis
• Systemic lupus erythematosus (SLE)
• Polyarteritis
• Polymyositis
• Eosinophilia
• Megaloblastic anemia
• Pseudolymphoma
• Lymphadenopathy

Cardiovascular findings may include the following:

• Hypotension, bradycardia ^[7] , myocardial depression,  ventricular fibrillation,  asystole, and tissue necrosis ^[8]  all have been associated with the IV formulation.
• Phlebitis, necrosis, even gangrene
• "Purple glove syndrome," comprising distal limb edema, discoloration, and pain after IV administration, usually occurs in elderly patients and after massive/multiple doses

Skin findings may include the following:

• 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)

Gastrointestinal/abdomen findings may include the following:

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

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

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).[9] However, the predictive performance of such formulas has been called into question.[10]

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

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.

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

Management is as follows:

• Support airway, breathing, and circulation ^[11]
• 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.[12] 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.[13, 14]  In one randomized, controlled study, subjects with supratherapeutic phenytoin concentrations who were randomized to receive MDAC more rapidly reached a subtoxic levels than controls.[15] 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.[16]

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.[17, 18]

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.

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.[19]

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.

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.

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.