SUMMARY

The Authors examined phenytoin toxicity

INTRODUCTION

Phenytoin is a primary anticonvulsant for all types of epilepsy except absence. It is useful in the treatment of status epilepticus in conjunction with other more rapidly acting anticonvulsants. Phenytoin has been used prophylactically in a variety of settings (head trauma, alcohol withdrawal, drug overdose), but has so far only proven useful in the setting of head trauma. Phenytoin is probably the most widely used anticonvulsant in the world and has been more thoroughly studied and evaluated than any other.

Phenytoin has been employed in the management of chronic pain syndromes. Historically, it has also been used as an antidysrhythmic agent, especially in the setting of digoxin toxicity, but it is no longer considered a first-line agent.

Death or severe morbidity is unusual following intentional phenytoin overdose, and an intact outcome is typical if good supportive care is provided. Most phenytoin-related deaths have been caused by rapid intravenous administration or hypersensitivity reactions. The acute life- and limb-threatening manifestations of phenytoin intoxication may be readily treated using conventional therapies immediately available to any acute care facility and can be prevented by adhering to the correct methods of administration.

MECHANISM OF ACTION

Phenytoin exerts its anticonvulsant effect by blocking voltage-sensitive sodium channels in the neurons. Phenytoin stabilizes sodium channels in an inactive state, and this inhibitory effect, similar to the action of local anesthetics, is dependent on the voltage and frequency of firing of the neuron. Phenytoin has no effect on the amplitude or duration of the action potential. Rather, it limits the ability of the neuron to fire trains of action potentials at high frequency by delaying recovery. In this fashion it suppresses repetitive neuronal activity and prevents the spread of a seizure focus. At higher concentrations, phenytoin delays activation of outward potassium currents in nerves and prolongs the neuronal refractory period. It may also exert its anticonvulsant effect by influencing calcium channels or g-aminobutyric acid (GABA) receptors, although this is not yet fully established.

PATHOPHYSIOLOGY

The toxic effects of phenytoin depend on the route of administration, the duration of exposure, and the dosage used. Of these determinants of toxicity, the most important is the route of administration. The intravenous administration of phenytoin carries the greatest risk, primarily due to the other constituents of the parenteral vehicle The most serious reactions following intravenous administration are cardiovascular (bradycardia, hypotension, asystole), although tissue necrosis and sloughing following extravasation have been described. Major cardiac toxicity only occurs following parenteral administration. It is more common in the elderly and those with underlying cardiac disease, but has been described in young healthy patients as well.

Many of the side effects of the oral preparation are dose-related and are predictable at higher plasma concentrations. Early toxicity is manifested by vestibular/ocular/cerebellar signs: nystagmus, dysdiadochokinesia, and ataxia. At higher levels, central nervous system (CNS) depression and other cognitive effects (confusion, dizziness, loss of concentration and memory) are seen. Only two areas of the brain normally exhibit spontaneous neuronal burst discharge: the hippocampus and the cerebellum. Phenytoin's ability to suppress these areas may result in impaired memory and balance, respectively. Paradoxically, very high levels of phenytoin may be associated with seizures. Acute oral overdose is usually manifested by nystagmus, nausea and vomiting, ataxia, and CNS depression. Deaths from oral ingestion of phenytoin are extremely rare.

The chronic administration of phenytoin is associated with numerous side effects that involve a variety of organ systems. Many of these are dose- and duration-dependent but some are idiosyncratic. Hypersensitivity reactions to phenytoin usually occur early (in the first few months of therapy) and include fever, skin rashes, blood dyscrasias, and, rarely, hepatitis. Deaths due to Stevens-Johnson syndrome have occurred and anyone exhibiting this syndrome should never receive phenytoin again.

PHARMACOKINETICS

Phenytoin is a weak acid with a pKa of 8.3. Thus, in the acid milieu of the stomach, and even at physiologic pH, its aqueous solubility is limited. The parenteral form is adjusted to a pH of 12 to keep the drug in solution, but it is very irritating to the tissues. Intramus-cular injection results in local precipitation of phenytoin with erratic absorption and is, therefore, not recommended. Absorption after oral ingestion is slow, variable, and often incomplete, especially following an overdose. Significant differences in bioavailability exist among different phenytoin preparations. Peak levels typically occur anywhere from 3 to 12 h after a single dose. Despite these limitations, single-dose oral loading with phenytoin has proven to be a safe and effective alternative to parenteral loading for many patients.

Following absorption, phenytoin is distributed throughout the body with a volume of distribution of 0.6 L/kg. Brain tissue concentrations equal those in plasma within about 10 min of intravenous infusion and correlate with therapeutic effects, while cerebrospinal fluid and myocardium equilibrate within 30 to 60 min. This slower distribution into tissue is further evidence that hypotension and arrhythmias occurring during phenytoin infusion are due to toxicity from propylene glycol, the most widely used diluent. At steady state, concentrations are higher in neural tissue than in the serum. Within the CNS, concentrations are higher in the brainstem and cerebellum that the cerebral cortex.

Protein Binding and Free Phenytoin Fractions

Phenytoin is extensively (90 percent) bound to plasma proteins, especially albumin. The free, unbound form is the biologically active moiety responsible for the drug's clinical effect and toxicity. The free phenytoin fraction normally constitutes 10 percent of the plasma level. The unbound fraction of the drug is greater in the following groups of patients: neonates; the elderly; pregnant women; patients with uremia, hypoalbuminemia (cirrhosis, nephrosis, ma-lnutrition, burns, trauma, cystic fibrosis), and hyperbilirubinemia; and in those taking drugs that displace phenytoin from binding sites (salicylates, valproate, phenylbutazone, tolbutamide, and sulfisoxazole).

Although patients with decreased protein binding may have higher levels of free phenytoin and a greater biological effect, they may have lower levels of total phenytoin since more of the drug is available for metabolism. These patients may become toxic with total phenytoin levels in the therapeutic range. Patients who exhibit toxic signs in the therapeutic range and those with decreased protein binding should have their free phenytoin levels measured. Recently, salivary levels of anticonvulsants have been found to correlate with the free fraction of drug in the plasma.

Metabolism

Following absorption and distribution, only 4 to 5 percent of phenytoin is excreted unchanged in the urine. The remainder is metabolized by hepatic microsomal enzymes. The drug is primarily hydroxylated to a series of inactive compounds.

The major (60 to 70 percent) metabolite is the parahydroxyphenyl derivative. It is glucuronidated, secreted in the bile, reabsorbed, and subsequently excreted in the urine. Phenytoin removal from the body is not appreciably influenced by hemodialysis or hemoperfusion.

Unlike the other anticonvulsant agents, the metabolism of phenytoin is capacity-limited (dose-dependent). At plasma concentrations below 10 mg/mL, elimination is first order (a fixed percentage of drug metabolized per unit of time). However, at higher concentrations of phenytoin, including those in the therapeutic range (10 to 20 mg/mL), the metabolic pathways may become saturated, and the elimination may change to zero-order kinetics (a fixed amount metabolized per unit of time). This change in kinetics can markedly prolong the half-life of phenytoin, which is normally 6 to 24 h. An understanding of capacity-limited kinetics is essential to the proper dosing of phenytoin, the avoidance of side effects with chronic therapy, and the management of overdoses. At higher levels in the therapeutic range, any increase in the daily dose will result in a disproportionate increase in the plasma level. Thus, at phenytoin doses above 300 mg (~5 mg/kg) per day, incremental doses should be limited to 30 mg. After each increase in dose, the patient should be maintained on the new dose for at least 2 weeks and the plasma level should be reassessed before any further increase.

Because phenytoin's half-life is 24 h or less, once-a-day regimens may result in erratic levels and become problematic for patients requiring tight control. However, one phenytoin preparation (Phenytoin Kapseals) has a delayed absorption and is the only preparation approved by the Food and Drug Administration (FDA) for once-a-day use. A once-a-day regimen is advisable since this facilitates compliance. Concomitant use of drugs that either inhibit or enhance hepatic microsomal activity may result in an increase or decrease of phenytoin level respectively. Phenytoin also affects the metabolism of various other agents (Table 1).

Effects of Propylene Glycol and Ethanol Diluents

The acute cardiovascular toxicity seen with intravenous phenytoin infusion has frequently been ascribed to its diluent. The vehicle for the most widely used parenteral formulation of phenytoin is 40% propylene glycol and 10% ethanol, adjusted to a pH of 12 with sodium hydroxide. The glycol component has been shown to cause coma, seizures, circulatory collapse, ventricular arrhythmias, cardiac nodal depression, and hypotension in humans and animals. Propylene glycol is a strong myocardial depressant and vasodilator and increases vagal tone. Other toxic effects of propylene glycol include hyperosmolality, hemolysis, and lactate-associated metabolic acidosis. Louis et al. compared the acute toxicities of intravenous phenytoin and propylene glycol both alone and in combination. In a feline model, phenytoin alone did not cause significant cardiovascular effects, and instead partially reversed the toxic effects that occurred when propylene glycol was given. Acute toxic effects of propylene glycol are also strongly related to rate of infusion. This is further evidence for its etiologic role in intravenous phenytoin toxicity, a phenomenon which is almost always related to infusion rate. The ethanol intravenous diluent fraction may precipitate a reaction in patients taking disulfiram.

The limitations of the parenteral form of phenytoin (incomplete aqueous solubility, irritating nature of the vehicle, and tendency to precipitate in intravenous solutions) have prompted a search for a more suitable preparation. Recently, prodrugs of phenytoin have been synthesized that are more soluble and less irritating to the tissues. These agents are presently being field tested and may become standard in the future.

SERUM LEVELS AND RANGE OF TOXICITY

Therapeutic phenytoin levels are described as being 10 to 20 mg/mL (40 to 80 mmol/L)1 with a free phenytoin level of 1 to 2 mg/mL. Although 50 percent of seizure patients achieve reduction of seizure frequency with amounts below these levels, some patients require levels above 20 mg/mL for adequate seizure control.

The therapeutic range for phenytoin is rather narrow. However, some patients have a greater propensity to side effects than others. Individual variation in toxicity is a function of baseline neurologic status, individual response to the drug, and free drug fraction. Patients with underlying brain disease are predisposed to toxicity and may become toxic at much lower levels than usual. Long-term therapy must be individualized and based on the following parameters: clinical response, drug levels, and signs of toxicity. In general, toxicity correlates fairly well with increasing plasma levels (Table 2). Nystagmus usually appears first at phenytoin levels of 20 mg/mL but may occur at lower levels or not appear until much higher levels are attained. Ataxia usually begins at about 30 mg/mL, and lethargy at 40 mg/mL. Altered mental status and other motor signs may occur at levels below 20 mg/mL and are not necessarily preceded by nystagmus. Conversely, some patients may tolerate levels above 40 mg/mL and only demonstrate mild impairment on neuropsychologic testing. Almost all patients with phenytoin-induced seizures will have levels well above 30 mg/mL. Signs of toxicity occur at free phenytoin levels of 2.0 mg/mL and are consistently severe above 5.0 mg/mL.

CLINICAL PRESENTATIONS

Central Nervous System Toxicity

As toxic phenytoin levels are reached, both inhibitory cortical and excitatory cerebellar-vestibular effects begin to occur. The usual initial sign of toxicity is nystagmus, which is seen first on forced lateral gaze and then becomes spontaneous. Vertical, bidirectional, or alternating nystagmus may occur with severe intoxication.

Decreased level of consciousness is routine, with initial sedation, lethargy, ataxic gait, and dysarthria progressing to confusion, coma, and even apnea in large overdose. Chronically impaired cognitive function or acute encephalopathy may occur without other common signs of ataxia and nystagmus. This is usually seen at toxic levels but again may occur in the therapeutic range. Nystagmus will commonly disappear at levels sufficient to cause coma (above 35 to 55 mg/mL), and complete ophthalmoplegia and loss of corneal reflexes may occur. Therefore, absence of nystagmus does not exclude severe phenytoin toxicity. Nystagmus then returns as serum drug levels decrease and coma lightens.

Phenytoin-induced seizures are usually brief, and are usually generalized. They are quite rare and almost always preceded by other signs of toxicity, especially in acute overdose.

Cerebellar stimulation and alteration in dopaminergic and seroto-nergic activity may be responsible for acute dystonias and movement disorders seen in overdose, including opisthotonos and choreoathetosis. Either depressed or hyperactive deep tendon reflexes, clonus, and extensor toe responses may also be elicited. Some signs of neurologic toxicity may outlast the presence of drug by months, especially mild peripheral neuropathy or acute reversible cerebellar degeneration with ataxia.

Psychosis, toxic delirium, visual and auditory hallucinations, euphoria, irritability, agitation, and combativeness have all been reported with toxicity.

Cardiovascular Toxicity

Significant cardiac toxicity after oral phenytoin overdose in an otherwise healthy patient has never been reported and, if observed, should mandate a rapid assessment for other causes (e.g., hypoxia, other drugs). Cardiovascular complications have been almost entirely limited to cases of intravenous administration. These include hypotension with decreased peripheral vascular resistance, bradycardia, conduction delays progressing to complete AV nodal block, ventricular tachycardia, primary ventricular fibrillation, and asystole. Electrocardiographic changes include increased PR interval, widened QRS interval, and altered S-T and T-wave segments. Bradycardia, hypotension, and syncope in healthy volunteers have been reported even after small intravenous doses. Slowly administered (<25 mg/min) intravenous phenytoin has also been reported to cause precipitous, refractory hypotension and cardiac arrest in critically ill patients receiving dopamine infusions to support blood pressure. Most of these complications can be attributed to rapid intravenous administration of the propylene glycol diluent fraction and are avoidable with cautious administration (Table 3).

Vascular, Extravasation, and Soft Tissue Toxicity

An important but infrequently considered toxic effect is local vascular and tissue injury after injection. Although still recommended by the manufacturer, intramuscular injection results in localized crystallization of the drug, with erratic and unpredictable absorption, hematomas, sterile abscess, and myonecrosis at the injection site. Complications after intravenous infusion have included skin and soft tissue necrosis requiring skin grafting, compartment syndrome, gangrene, amputation, and death (at a fatality rate exceeding that from oral overdose). A syndrome of delayed bluish discoloration of the affected extremity, followed by erythema, edema, vesicles, bullae, and local tissue ischemia, has also been described. This has been reported after intravenous push administration of undiluted phenytoin even in the absence of extravasation, and has eventually necessitated amputation in some cases. The propylene glycol diluent, strong alkalinity of the intravenous solution, and crystallization of the drug contribute.

Hypersensitivity Reactions

Hypersensitivity reactions usually occur within 1 to 6 weeks of beginning phenytoin therapy and can include fever, systemic lupus erythematosus, erythma multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, hepatitis, rhabdomyolysis, acute interstitial pneumonitis, lymphadenopathy, leukopenia, disseminated intravascular coagulation, and renal failure. An erythematous morbilliform rash is common after initiation of phenytoin, occurring more frequently in the summer. One should always ask about a history of previous hypersensitivity reactions before making the decision to restart phenytoin in the emergency department setting.

MISCELLANEOUS EFFECTS

Other side effects from phenytoin include gingival hyperplasia, hirsutism, hypocalcemia, osteomalacia, megaloblastic anemia responsive to folate administration, lymphoma, and hemorrhagic disease of the newborn responsive to vitamin K (Table 4). Gingival hyperplasia is so common that its absence should suggest poor compliance.

Another clinically significant effect in some is hyperglycemia, felt to be secondary to inhibition of insulin release. This can lead to diabetic ketoacidosis or nonketotic hyperosmolar coma. The teratogenic fetal hydantoin syndrome is well described, so oral phenytoin therapy in a pregnant patient should never be initiated or continued by the emergency physician without consultation and close follow-up from the attending neurologist and obstetrician.

DIFFERENTIAL DIAGNOSIS

Intoxication with almost any CNS-active or sedative-hypnotic drug may mimic early phenytoin intoxication, especially ethanol, carbamazepine, benzodiazepines, barbiturates, and lithium. Disease states resembling phenytoin toxicity include hypoglycemia, Wernicke encephalopathy, and posterior fossa hemorrhage or tumor. Although seizures may be caused by phenytoin at toxic levels, other epileptogenic drug overdoses and seizures due to withdrawal from ethanol or other sedative-hypnotics must be considered in adults.

LABORATORY DIAGNOSIS AND ANCILLARY STUDIES

In oral overdose, the prolonged absorption phase mandates serial assessment to determine peak serum phenytoin levels. Phenytoin concentrations are most commonly measured by an enzyme-mediated immunoassay (EMIT) technique, which is specific and sensitive to &le:1 mg/mL. If available, free phenytoin concentrations are more useful to predict toxicity. Corrected serum phenytoin levels can be calculated in hypoproteinemia patients with a known serum albumin level. To calculate the phenytoin concentration (Cnormal) that would be present if the patient's serum albumin were normal, the following equation is used: [acj phenytoin concentration, phenytoin level]

where phenytoin concentrations are in micrograms per milliliter and albumin concentration is in grams per deciliter.

Similarly, the free phenytoin fraction (FPF) may be corrected for hypoalbuminemia with this equation: [ack free phenytoin fraction, FPF]

1+(2.1 x albumin)

TREATMENT

Initial treatment of oral phenytoin overdose, including airway management, is similar to that for other ingested drugs. Respiratory acidosis due to ventilatory insufficiency or metabolic acidosis should be corrected to decrease the active free phenytoin fraction. Multiple doses of oral activated charcoal (1 g/kg) in the first 24 h may be of benefit, given the known poor solubility and resultant extended absorptive phase of oral phenytoin in overdose. Hemodialysis and hemoperfusion are of no clinical benefit in phenytoin poisoning.

Seizures may be treated with intravenous benzodiazepines or phenobarbital, again with the caution that seizures are not common in phenytoin overdose and other causes must be ruled out. Cardiovascular toxicity is extremely rare in oral overdose and should suggest other etiologies. Prolonged cardiac monitoring after oral ingestion is unnecessary. Atropine and temporary cardiac pacing may be used for symptomatic bradyarrhythmias associated with intravenous phenytoin. Hypotension that occurs during intravenous administration usually responds to discontinuation of the infusion and the administration of isotonic crystalloid. Hospital admission and appropriate orthopedic or plastic surgery consultation should be obtained for patients with any significant extravasation of intravenous phenytoin or other signs of local vascular or tissue toxicity after infusion.

To minimize complications due to infusion, intravenous phenytoin should be administered only under close observation with constant cardiac and blood pressure monitoring. The infused solution should be given slowly (< 25 mg/min) through a large, well-positioned catheter.

ADMISSION INDICATIONS

Patients with serious complications following an oral ingestion (seizures, coma, altered mental status, ataxia, etc.) should be admitted for further evaluation and treatment. Others with only mild symptoms may be treated with charcoal in the emergency department and if an observation unit is available, discharged after their levels have returned to normal, provided they are not actively suicidal. Given the long and erratic absorption phase of phenytoin after oral overdose, the decision to discharge or medically clear a patient for psychiatric evaluation cannot be based on a single serum level. Patients with symptomatic chronic intoxication should be admitted for observation unless signs are minimal, adequate care can be obtained at home, and they are 8 to 12 h from their last therapeutic dose. Phenytoin therapy should be stopped in all cases, and if toxicity continues to resolve, a serum level may be reassessed in 2 to 3 days to guide resumption of therapy.

Patients with significant or persistent complications following the intravenous administration of phenytoin should be admitted. Those with transient effects need not be although, in practice, patients receiving intravenous phenytoin loading are admitted if the underlying condition warrants.

TABLE 1

Phenytoin-Drug Interactions

Phenytoin increases serum level of:

Phenytoin decreases serum level of

Phenytoin levels are increased by:

Phenytoin levels are decreased by:

*These drugs displace phenytoin from its protein-binding sites, thus increasing the free phenytoin fraction, although the total phenytoin level may decrease.

TABLE 2

Correlation of Plasma Phenytoin Level and Side Effects

TABLE 3

Guidelines for Safe Phenytoin Loading

Intravenous

• Loading dose is 18 mg/kg
• Mix total dose in 75-100 mL of normal saline
• Administer through a milipore filter using an infusion pump
• Rate of administration should not exceed 30 mg/min (less in patients with cardiovascular disease)
• Monitor the blood pressure and cardiac rhythm continually during the infusion
• In the event of complications, immediately stop the infusion and administer isotonic crystalloid and other treatment as indicated

Oral*

• Loading dose is 20 mg/kg
• Phenytoin tablets or suspension may be used
• Patient must be conscious with an intact gag reflex and not actively seizing or vomiting
• Administer the total amount in one dose
• Check phenytoin level 6-8 h after administration

*Unlike IV loading, not all patients orally loaded will reach a therapeutic level.

TABLE 4

Toxicity of Phenytoin

Central nervous system

- Dizziness, tremor (intention), visual disturbance (horizontal and vertical nystagmus), diplopia, miosis or mydriasis, ophthalmoplegia, abnormal gait (bradykinesia, truncal ataxia), choreoathetoid movements, vomiting, dysphagia, respiratory distress, irritability, agitation, confusion, hallucinations, fatigue, coma, death (rare), encephalopathy, pseudodegenerative disease, dysarthria, meningeal irritation with pleocytosis, rarely seizures

Peripheral nervous system

- Peripheral neuropathy, urinary incontinence

Hypersensitivity reactions

- Eosinophilia, rash, pseudolymphoma (diffuse lymphadenopathy), systemic lupus erythematosus, pancytopenia

Metabolic

- Osteomalacia (rickets-like metaphyseal abnormality in children), increased thyroid uptake, interference with folic acid metabolism, insulin secretion inhibition (hyperglycemia), pyridoxine deficiency

Hematologic

- Megaloblastic anemia, aplastic anemia, thrombocytopenia, hemorrhagic disease of the newborn

Gastrointestinal

- Nausea and vomiting, hepatotoxicity

Skin

- Hirsutism, acne, rashes (including Stevens-Johnson syndrome)

Other

- Fetal hydantoin syndrome, gingival hyperplasia, coarsening of facial features

Parenteral preparations

- May cause hypotension, bradycardia, conduction disturbances, myocardial depression, ventricular fibrillation, asystole, and sloughing of tissues

BIBLIOGRAPHY

1. Leppik JE, Patrick B, et al: Intravenous phenytoin: Clinical and pharmacokinetic aspects. Neurology. 28:874, 1978.
2. Howard CE, Roberts S, Ely DS, et al: Use of multiple-dose activated charcoal in phenytoin toxicity. Ann Pharmacother 28:201, 1994.
3. Louis S, Kutt H, McDowell F: The cardiocirculatory changes caused by intravenous dilantin and its solvent. Am Heart J 74:523, 1967.
4. MacDonald RL, Kelly KM: Mechanisms of action of currently prescribed and newly developed anti-epileptic drugs. Epilepsia 35(suppl 4):541, 1994.
5. Mellick LB, Morgan JA, Mellick GA: Presentations of acute phenytoin overdose. Am J Emerg Med 7:61, 1989.
6. Murphy JM, Motiwala R, Devinsky O: Phenytoin intoxication. So Med J 84:1199, 1991.
7. Osorio I, Burnstine TH, Pemler B, et al: Phenytoin-induced seizures: A paradoxical effect at toxic concentrations in epileptic patients. Epilepsia 30(2):230, 1989.
8. Wyte CD, Berk WA: Severe oral phenytoin overdose does not cause cardiovascular morbidity. Ann Emerg Med 20:508, 1991.
9. York RC, Coleridge ST: Cardiopulmonary arrest following intravenous phenytoin loading. Am J Emerg Med 6:255, 1988.