Phenytoin Toxicity

Etiology

The different risk factors for phenytoin toxicity are as follows:

Change in Medications

Phenytoin toxicity can occur from an increase in the daily dose of phenytoin, changes in the formulations or brands, as well as changes in the frequency of administration. It can also occur when patients are started on new medications that interact with the metabolism or binding capacity of phenytoin to plasma proteins. Due to its metabolism by CYP450 liver enzymes, multiple drug interactions can occur.

Change in Physiology

New disease states can lead to changes in the phenytoin plasma concentration. Liver cirrhosis can lead to a decrease in serum albumin as well as a decreased metabolism of phenytoin by the CYP450 pathway, both leading to increased amounts of free phenytoin in the serum. Kidney disease can also lead to hypoalbuminemia as well as uremia, which decreases the percentage of bound phenytoin in the plasma. Malnutrition, malignancy, and pregnancy are other causes of phenytoin toxicity in a patient on chronic therapy without any changes in dose.

Acute Ingestion

Acute ingestion leading to overdose can be intentional or unintentional. There have also been reports of crack cocaine being adultered with phenytoin, which can lead to an unintentional overdose. 

Chronic Toxicity

One of the more common manifestations of chronic phenytoin ingestion is gingival hyperplasia. The etiology of phenytoin-induced gingival enlargement (PIGE) is likely due to the direct effects of the drug and its metabolites on the gingival fibroblasts. Other factors that can contribute to PIGE include adrenocortical axis suppression, alterations in the metabolism of calcium, low serum folic acid levels, and suppression of the immune system.

DRESS Syndrome

Drug reaction with eosinophilia and systemic symptoms, or DRESS syndrome, has been associated with chronic phenytoin use. This rare syndrome may occur in one out of 1000 to 10,000 users of any of the aromatic anticonvulsants, including phenytoin, carbamazepine, and lamotrigine. Onset is typically within two months of initiation of therapy and is triggered by metabolites of each agent inducing a type-IV hypersensitivity. Symptoms typically include high fever, a macular rash, and pharyngitis, and it is often mistaken early in the course for streptococcal pharyngitis. Multi-organ system involvement lymphadenopathy, liver injury, acute kidney injury (AKI), and occasional encephalitis may occur. A peripheral blood smear shows eosinophilia and atypical lymphocytosis, often confusing the diagnosis with acute mononucleosis. Fatalities in the unrecognized case can be as high as 10%. Immediately discontinuation of phenytoin and the initiation of steroid treatment is key to preventing progression. A skin biopsy may be needed to confirm the diagnosis. A substitute anticonvulsant from a non-aromatic class should be used in place of phenytoin.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Phenytoin has been associated with both Stevens-Johnson syndrome (SJS) and its more severe manifestation, toxic epidermal necrolysis (TEN). Once thought to be idiopathic, these life-threatening dermopathies have been linked to genetic variants of the human lymphocyte antigen system and in CYP genetic variants. Mostly in Asia, patients who carry the HLAB*1502 and CYP2C9*3 genes are at high risk. If a skin and mucosal rash is present, immediate discontinuation of phenytoin is mandatory. Genetic testing may be advised before switching to another aromatic anticonvulsant.

Epidemiology

According to the 2011 Annual Report of the American Association of Poison Control Centers (AAPCC) National Poison Data System, 1971 single-substance phenytoin exposures resulted in 46 major outcomes and 1 death.[4]

Pathophysiology

Like all toxicologic exposures, the nature of the toxicity depends on fundamental pharmacologic principles: the route of exposure (oral versus parenteral), duration of exposure (acute overdose versus chronic), dosage, and the nature of metabolism (or deficiency thereof). Phenytoin displays its main signs of toxicity on the nervous and cardiovascular systems. Overdose of oral phenytoin causes mainly neurotoxicity and only very rarely causes cardiovascular toxicity. On the other hand, cardiovascular toxicity is the main side effect of parenteral administration.[5][6]

Neurotoxicity

The neurotoxic effects are concentration-dependent and can range from mild nystagmus to ataxia, slurred speech, vomiting, lethargy, and eventually coma and death. Paradoxically, at very high concentrations, phenytoin can lead to seizures. Symptoms correlate well with the unbound plasma phenytoin concentration. However, this laboratory value is seldom obtained. The following is a loose correlation of side effects with total plasma phenytoin concentrations (the value obtained in most laboratories):

• Less than 10 mg/L: Rare side effects
• Ten to 20 mg/L: Occasional mild horizontal nystagmus on lateral gaze
• Twenty to 30 mg/L: Nystagmus
• Thirty to 40 mg/L: Ataxia, slurred speech, tremors, nausea, and vomiting
• Forty to 50 mg/L: Lethargy, confusion, hyperactivity
• Greater than 50 mg/L: Coma and seizures

Seizures are very rare and usually occur at very high serum concentrations. The presence of seizures in a patient with suspected phenytoin overdose should prompt the search for other coingestants.

Cardiac Toxicity

Phenytoin is a Vaughn Williams Class IB antiarrhythmic, although it is almost never used as an antiarrhythmic anymore. Its effects on the cardiac voltage-gated sodium channels can lead to dysrhythmias as well as SA and AV nodal blocks although such effects have rarely been reported following ingestion of the oral form. In the intravenous form, the main toxicity is believed to be from its parenteral vehicle: propylene glycol. Propylene glycol is a cardiac depressant, and rapid infusions can lead to bradycardia, hypotension, and asystole. Care must be taken so that intravenous formulations of phenytoin are not administered at a rate faster than 50 mg per minute.

Other Toxicities

“Purple Glove syndrome” is a rare side effect that can occur with intravenous administration of phenytoin. It is characterized by worsening distal limb edema and discoloration, which can lead to extensive skin necrosis and limb ischemia. Phenytoin hypersensitivity has also been reported, generally occurring one week to 1 month after initiation of therapy. It is characterized by a fever, rash, and different internal organ involvement (hepatitis, myocarditis, pneumonitis). Chronic intake of phenytoin can lead to folate deficiency, peripheral neuropathy, or a lupus-like syndrome, although these effects have not been reported from acute overdoses.

Toxicokinetics

Phenytoin is available in oral and intravenous (IV) formulations. The oral form is completely absorbed after ingestion. Its absorption is rapid, with peak plasma concertation at 1.5 to 3 hours for the immediate-release formulation and 4 to 12 hours for the extended-release formulation. However, due to its effects of reducing gastrointestinal (GI) motility and its poor water solubility, absorption tends to be delayed in oral overdose, with peak concentrations occurring at up to 24 to 48 hours.[7]

Due to its poor water solubility, parenteral phenytoin is mixed with propylene glycol and alcohol and is only recommended for IV use. It needs to be administered slowly to prevent the adverse effects of rapid propylene glycol toxicity, usually over 45 minutes to an hour. Peak phenytoin concentrations occur 20 to 35 minutes after the completion of the infusion. Fosphenytoin is a water-soluble prodrug of phenytoin that can be administered intramuscularly (IM) or IV but needs to be converted enzymatically by phosphatase in the body to the active phenytoin compound. Intravenous fosphenytoin peaks within minutes, but the active phenytoin takes 34 to 42 minutes after completion of the IV infusion to reach peak plasma concentrations. If given by intramuscular route peak is delayed to 1.5 to 3.0 hours. Therefore, neither route results in rapid seizure control in status epilepticus. 

Phenytoin has a narrow therapeutic window, between 10-20 mg/L. Serum concentrations of phenytoin are monitored by measuring the total phenytoin concentration. However, phenytoin is generally 90% bound to plasma proteins (mostly albumin), and only its unbound form is pharmacologically active. A greater fraction of the drug is unbound in neonates and pregnant patients, a patient with hypoalbuminemia of any cause (renal failure, hepatic failure, malnutrition), and uremia. Patients with decreased protein binding capacity may display symptoms of toxicity despite normal total phenytoin levels. Phenytoin is distributed in all tissues and becomes firmly tissue-bound with a large volume of distribution. The level of unbound phenytoin may be calculated using the corrected Winter-Tozer formula:

• Corrected phenytoin levels (mg/dl):  serum phenytoin level (milligrams/Liter)
• (0.25 x albumin [grams/deciliter]) +0.1

Some literature may use 0.29 as the albumin coefficient to improve accuracy depending on whether the sample was run at room or body temperature.

Corrected Phenytoin Levels in patients with:

Hypoalbuminemia (mg/dl):

• Serum phenytoin level (milligrams/Liter)
• (0.20 x albumin [grams/deciliter]) +0.1

One to 5% of phenytoin is excreted unchanged in the urine. The remainder is metabolized by the hepatic P450 enzyme system, predominantly CYP2C9 and CYP 2C19, and induces CYP3A4, which accounts for many of its drug-drug interactions. All its metabolites are inactive. At plasma concentrations less than 10 mg/L, elimination follows first-order kinetics, and the rate of elimination is proportional to the drug concentration. With increasing plasma concentrations, the half-life increases as the kinetics approach zero-order. Following saturation of the system, elimination follows zero-order kinetics with the same amount of drug eliminated for a given amount of time, irrespective of plasma concentration. Subsequently, the normal average half-life of 22 hours can become significantly prolonged with marked overdose.

Mechanism of Action

Phenytoin is a voltage-gated, sodium channel blocker, stabilizing the inactive state of the sodium channel and prolonging the neuronal refractory period. Phenytoin acts on the sodium channels in both neuronal and cardiac tissue. In the central nervous system, it targets neurons with high-frequency activity (as observed in seizures), with the majority of its actions on the motor cortex. This prevents the spread of a seizure’s focal point and reduces the activity of brain stem regions responsible for the tonic phase of a tonic-clonic seizure. In cardiac tissue, phenytoin shortens cardiac action potentials and prolongs the refractory period between them.

Evaluation

All patients suspected of possible phenytoin overdose should be evaluated with a broad differential in mind. Fingerstick glucose should be obtained on all patients as well as a pregnancy test on all female patients of child-bearing age. An ECG is recommended for all suspected phenytoin overdose patients, especially patients who have received parenteral phenytoin. Laboratory work should be obtained, including a complete blood count (CBC), basic metabolic panel (BMP), liver function test (LFT), total serum phenytoin concentration, and serum albumin. Urine toxicology, as well as acetaminophen, salicylic acid, and alcohol levels, should also be obtained to complete the toxicologic workup.[1][8]

Treatment / Management

There is no specific antidote for phenytoin toxicity, and the hallmark of treatment is supportive care. The management of phenytoin toxicity should initially proceed along the lines of accepted treatment of general overdoses. The airway should be assessed, and advanced airway management should be initiated in patients who cannot maintain their airway or respiratory drive. The circulation should be assessed and abnormalities in vital signs addressed. Hypotension can be treated with an initial bolus of isotonic solution. If unresponsive to fluid administration, vasopressors can be initiated with norepinephrine or dopamine being preferred. Bradycardia can also be managed according to standard ACLS protocols, including atropine, epinephrine, and if needed, transcutaneous or transvenous pacing. Consultation with a medical toxicologist is highly recommended.[9][10][11](A1)

Other symptoms of overdose can be managed according to standards of care. Antiemetics can be administered in cases of nausea and vomiting. Seizures can be controlled by following the normal seizure protocols with benzodiazepines as the first medications, followed by phenobarbital or levetiracetam for persistent or recurrent seizures.

Activated charcoal reliably binds phenytoin and prevents absorption. In acute ingestions, one dose of activated charcoal may be of benefit, especially in large acute overdoses, as phenytoin slows gastrointestinal motility and absorption is delayed. Activated charcoal is also of benefit in acute ingestions of extended-release tablets. Activated charcoal is not recommended if there is a depressed mental state. The role of multi-dose activated charcoal is controversial. Some studies have shown increased clearance rates, although no clinical benefit or improvement in patient outcomes could be demonstrated. Induced emesis, gastric lavage, and whole bowel irrigation are not recommended for phenytoin overdose.

Despite high-plasma protein binding by phenytoin, the drug can be removed by hemodialysis with moderate effectiveness. However, clinical benefits are controversial. Due to the high-risk nature of hemodialysis, the effectiveness of supportive treatment, and the self-limited nature of acute overdoses, hemodialysis is rarely recommended and should only be used in extreme situations after consultation with a medical toxicologist. One guideline by the EXTRIP group advises the consideration of hemodialysis in cases of coma and possibly in incapacitating ataxia; however, no specific serum concentration threshold can be used as a sole reason to perform dialysis.

Differential Diagnosis

• Barbiturate toxicity

• Benzodiazepine toxicity

• Carbamazepine toxicity

• Encephalitis

• Erythema multiforme

• Isoniazid toxicity

• Shock

• Stevens-johnson syndrome

• SLE

• Toxic epidermal necrolysis

Prognosis

Deaths are rare from phenytoin ingestion alone. Most reported cases involve ingestion of other substances along with phenytoin. Fatal cases of single phenytoin ingestions typically involve serum concentrations of greater than 125 mg/L.

Disposition of patients is made on an individual basis. Patients requiring ventilatory support, hemodynamically unstable patients, or patients with abnormal ECGs should be admitted to a monitored setting. Patients with mild to moderate overdoses, normal mentation, and normal ECGs without any hypotension, bradycardia, or arrhythmias can be safely admitted to a bed without cardiac monitoring.

Serum phenytoin levels should be repeated and trended. Decreasing levels of serum phenytoin in a patient who can ambulate without assistance and has someone at home who can assist with activities of daily living until all symptoms of toxicity have resolved may be safely discharged home. Adequate follow-up should be arranged. All patients with intentional overdoses should receive a psychiatric consultation while hospitalized.

Complications

• Confusion
• Hallucinations
• Neuropathy
• Falls
• Encephalopathy
• Urinary incontinence
• Movement disorders
• Priapism
• Rash
• Hyperglycemia
• Hypoglycemia