Phenytoin is a primary anticonvulsant for partial and generalized tonic-clonic seizures. It is useful in the treatment of non–drug-induced status epilepticus in conjunction with rapidly acting anticonvulsants.1 Phenytoin has been used to prevent seizures due to head trauma (in the immediate post-traumatic period) and in the management of some chronic pain syndromes. Serious complications are extremely rare after intentional phenytoin overdose if supportive care is provided. Most phenytoin-related deaths have been caused by rapid IV administration or hypersensitivity reactions.
Phenytoin is available in oral and injectable forms. Phenytoin has poor solubility in water, so the vehicle for the parenteral formulation is 40% propylene glycol and 10% ethanol, adjusted to a pH of 12 with sodium hydroxide. The acute cardiovascular toxicity seen with IV phenytoin infusion has frequently been ascribed to the propylene glycol diluent. Other limitations with parenteral phenytoin are the irritating nature of the vehicle and a tendency to precipitate in IV solutions. Fosphenytoin (a disodium phosphate ester of phenytoin) is a prodrug that is converted to phenytoin by phosphatases in the body with a conversion half-life of 10 to 15 minutes. The advantage with parenteral fosphenytoin is that it is soluble in aqueous solutions, is buffered to a pH of 8.8, is nonirritating to the tissues, and can be given by IM injection.2
Phenytoin exerts its anticonvulsant effect by blocking voltage-sensitive and frequency-dependent sodium channels in the neurons, suppressing repetitive neuronal activity, and preventing the spread of a seizure focus.3 At higher concentrations, phenytoin delays activation of outward potassium currents in nerves and prolongs the neuronal refractory period. It also may exert an anticonvulsant effect by influencing calcium channels and γ-aminobutyric acid receptors or by inhibiting adenosine reuptake.
Phenytoin is a weak acid with a pKa of 8.3. In the acid milieu of the stomach and even at physiologic pH, more of the drug is nonionized, and its aqueous solubility is limited. Absorption after oral ingestion is slow, variable, and often incomplete, especially after an overdose. Different phenytoin preparations can possess major differences in bioavailability. Consequently, it may be necessary to obtain serial measurements of serum level in suspected overdose to determine peak levels. Peak levels typically occur between 3 and 12 hours after a single therapeutic oral dose.
After absorption, phenytoin is distributed throughout the body, with a volume of distribution of 0.6 to 0.8 L/kg. Brain tissue concentrations equal those in plasma within about 10 minutes of IV infusion and are correlated with therapeutic effects, whereas cerebrospinal fluid and myocardium equilibrate within 30 to 60 minutes.
Phenytoin is extensively (about 90%) 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 unbound fraction of the drug is greater in neonates, the elderly, pregnant women, renal failure, hypoalbuminemia (cirrhosis, nephrosis, malnutrition, burns, trauma, or cystic fibrosis), and hyperbilirubinemia. Drugs that displace phenytoin from binding sites (salicylate, valproate, phenylbutazone, tolbutamide, and sulfisoxazole) also result in an increased unbound fraction.
Patients with decreased protein binding have higher levels of free phenytoin and experience a greater biologic effect despite lower levels of total phenytoin. Free phenytoin concentrations are more useful in predicting toxicity. Corrected serum phenytoin levels (the concentration that would be present if a patient’s serum albumin level were normal) can be calculated as follows: corrected phenytoin concentration = (measured phenytoin concentration × 4.4)/(albumin concentration), with phenytoin concentration measured in micrograms/mL and the albumin concentration measured in grams/dL.
After absorption and distribution, only 4% to 5% of phenytoin is excreted unchanged in the urine. The remainder is metabolized by hepatic microsomal enzymes, primarily hydroxylated through a series of inactive compounds. The metabolism of phenytoin is capacity limited (dose dependent). At plasma concentrations of <10 micrograms/mL, elimination is first-order kinetics (a fixed percentage of drug metabolized per unit of time). At higher concentrations, including those in the therapeutic range of 10 to 20 micrograms/mL, the metabolic pathways may become saturated, and the elimination may change to zero-order kinetics (a fixed amount metabolized per unit of time). With zero-order kinetics, small increases in maintenance doses may saturate the enzyme systems, markedly prolonging the half-life of phenytoin, and result in a disproportionate increase in the plasma level. Thus incremental dose increases should be limited to 30 to 50 milligrams at a time, and levels should be carefully monitored when it is necessary to raise phenytoin doses above 300 milligrams (or above 5 milligrams/kg) per day.
Concomitant use of drugs that 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 191-2).
Table 191-2 Phenytoin Drug Interactions (Partial List) |Favorite Table|Download (.pdf)
Table 191-2 Phenytoin Drug Interactions (Partial List)
|Phenytoin increases serum levels of|
Phenytoin increases toxicity of
- Oral contraceptives
Phenytoin decreases serum levels of
- Oral anticoagulants
- Ethanol (chronic use)
|Phenytoin levels are increased by|
Phenytoin levels are decreased by
- Oral anticoagulants
- Salicylate (high dose)*
Propylene Glycol and Ethanol Diluents
Propylene glycol is a potent myocardial depressant and vasodilator and also enhances vagal tone. This chemical can cause coma, seizures, circulatory collapse, ventricular dysrhythmias, atrioventricular node depression, and hypotension in experimental animals.4 Other toxic effects from propylene glycol include hyperosmolality, hemolysis, and lactic acidosis.5 The ethanol diluent fraction of parenteral phenytoin may precipitate a reaction in patients taking disulfiram.
Central Nervous System Toxicity
As toxic phenytoin levels are reached, inhibitory cortical and excitatory cerebellar and vestibular effects begin to occur. The initial sign of toxicity is usually nystagmus, which is seen first on forced lateral gaze and later becomes spontaneous (Table 191-3).6 Vertical, bidirectional, or alternating nystagmus may occur with severe intoxication. A decreased level of consciousness is common, with initial sedation, lethargy, ataxic gait, and dysarthria.6 This may progress to confusion, coma, and even apnea in a large overdose. Nystagmus may disappear as the level of consciousness decreases, and complete ophthalmoplegia and loss of corneal reflexes may occur. Therefore, absence of nystagmus does not exclude severe phenytoin toxicity. Nystagmus returns as serum drug levels decrease and coma lightens.
Table 191-3 Clinical Features of Phenytoin Toxicity |Favorite Table|Download (.pdf)
Table 191-3 Clinical Features of Phenytoin Toxicity
|Central nervous system||Dizziness, tremor (intention), visual disturbance, horizontal and vertical nystagmus, diplopia, miosis or mydriasis, ophthalmoplegia, abnormal gait (bradykinesia, truncal ataxia), choreoathetoid movements, irritability, agitation, confusion, hallucinations, fatigue, coma, encephalopathy, dysarthria, meningeal irritation with pleocytosis, seizures (rare)|
|Peripheral nervous system||Peripheral neuropathy, urinary incontinence|
|Hypersensitivity (anticonvulsant hypersensitivity syndrome)||Eosinophilia, rash, pseudolymphoma (diffuse lymphadenopathy), systemic lupus erythematosus, pancytopenia, hepatitis, pneumonitis|
|Gastrointestinal||Nausea, vomiting, hepatotoxicity|
|Dermatologic||Hirsutism, acne, rashes (including Stevens-Johnson syndrome)|
|Other organs||Fetal hydantoin syndrome, gingival hyperplasia, coarsening of facial features, hemorrhagic disease of the newborn, hyperglycemia, hypocalcemia|
|Parenteral toxicity||May cause hypotension, bradycardia, conduction disturbances, myocardial depression, ventricular fibrillation, asystole, and tissue necrosis from infiltration|
Paradoxically, very high levels of phenytoin may be associated with seizures, although this is a rare occurrence, and such phenytoin-induced seizures are usually brief and generalized and almost always are preceded by other signs of toxicity, especially in acute overdose.7
Cerebellar stimulation and alterations in dopaminergic and serotonergic activities may cause acute dystonias and movement disorders, such as opisthotonos and choreoathetosis. Hyperactive deep tendon reflexes, clonus, and extensor toe responses also may be elicited. Chronic neurologic toxicity includes peripheral neuropathy and cerebellar degeneration with ataxia.
Cardiovascular complications have been almost entirely limited to cases of IV administration, in large part due to the constituents of the parenteral vehicle, or in rare cases of chronic oral toxicity.8 Cardiac toxicity after oral phenytoin overdose in an otherwise healthy patient has not been reported and, if observed, is due to other causes (e.g., hypoxia and other drugs).8
Reported cardiovascular complications include hypotension with decreased peripheral vascular resistance, bradycardia, conduction delays progressing to complete AV nodal block, ventricular tachycardia, primary ventricular fibrillation, and asystole. ECG changes include increased PR interval, widened QRS interval, and altered ST segments and T waves. Cardiovascular toxicity is more common in the elderly, those with underlying cardiac disease, and the critically ill. Guidelines for parenteral phenytoin administration stress a slow rate of infusion and constant monitoring (Table 191-4).
Table 191-4 Guidelines for Phenytoin or Fosphenytoin Loading |Favorite Table|Download (.pdf)
Table 191-4 Guidelines for Phenytoin or Fosphenytoin Loading
Loading dose is 18 milligrams/kg as phenytoin or fosphenytoin PE.*
Mix total dose in 150–200 mL of normal saline.
Keep phenytoin concentration <6 milligrams/mL or fosphenytoin PE concentration <25 milligrams/mL.
Administer phenytoin through Millipore filter using an infusion pump.
Rate of administration should not exceed 25–50 milligrams/min of phenytoin or 150 milligrams/min of fosphenytoin PE.
Use a slower rate of infusion 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.
|IM||Administer 15 milligrams/kg fosphenytoin PE preparation in one or multiple IM sites.|
Loading dose is 20 milligrams/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.
Even though fosphenytoin does not contain the propylene glycol diluent, cardiovascular toxicity can occur with IV administration. Hypotension is seen in about 8%, and rare cases of bradycardia, AV nodal block, and asystole have been observed.2,10,11
Vascular and Soft Tissue Toxicity
IM injection of phenytoin may result in localized crystallization of the drug with hematoma, sterile abscess, and myonecrosis at the injection site. IV extravasation may produce skin and soft tissue necrosis, compartment syndrome, and limb gangrene. Delayed bluish discoloration of the affected extremity (“purple glove syndrome”) followed by erythema, edema, vesicles, bullae, and local tissue ischemia has been described.12
Hypersensitivity reactions usually occur within 1 to 6 weeks of beginning phenytoin therapy and can present as a febrile illness with skin changes (erythema multiforme, toxic epidermal necrolysis or Stevens-Johnson syndrome) and internal organ involvement (hepatitis, rhabdomyolysis, acute interstitial pneumonitis, renal failure, lymphadenopathy, leukopenia and/or disseminated intravascular coagulation). Patients with a history of previous hypersensitivity reactions should not receive phenytoin, and because of similar reactions to phenobarbital, lamotrigine, felbamate, and carbamazepine, these anticonvulsants should also be avoided.
Gingival hyperplasia is relatively common and is associated with poor dental hygiene (gingivitis and dental plaques). Because of the risk of fetal hydantoin syndrome, oral phenytoin therapy should never be initiated in a pregnant patient without consultation with and close follow-up by a neurologist and obstetrician.
The therapeutic phenytoin serum level is 10 to 20 micrograms/mL (40 to 80 micromoles/L), which generally corresponds to a free phenytoin level of 1 to 2 micrograms/mL.13 Although 50% of patients achieve reduction in seizure frequency below these levels, some patients require levels as high as 20 micrograms/mL for adequate control. The ratio of toxic dose to therapeutic dose for phenytoin is rather low, and there is wide individual variability in the levels required to cause adverse effects. In general, toxicity is correlated with increasing plasma levels (Table 191-5).
Table 191-5 Correlation of Plasma Phenytoin Level and Toxic Effects |Favorite Table|Download (.pdf)
Table 191-5 Correlation of Plasma Phenytoin Level and Toxic Effects
|Total Plasma Level (micrograms/mL)||Toxic Effects|
|10–20||Occasional mild nystagmus|
|30–40||Ataxia, slurred speech, nausea and vomiting|
The initial treatment of severe oral phenytoin overdose is similar to that for ingestion of other drugs. Correct acidosis (respiratory or metabolic) to decrease the active free phenytoin fraction. Multidose activated charcoal may decrease drug half-life but does not decrease time to recovery and does not change outcome in overdose patients.14 Seizures may be treated with IV benzodiazepines or phenobarbital, with the caution that seizures are uncommon in phenytoin overdose. For patients with severe and persistent toxicity, hemodialysis and hemoperfusion can produce substantial improvement in neurologic toxicity.15-17
Cardiac monitoring after isolated oral ingestion is unnecessary. Atropine and temporary cardiac pacing may be used for symptomatic bradyarrhythmias associated with IV phenytoin. Hypotension that occurs during IV administration of phenytoin or fosphenytoin usually responds to discontinuation of the infusion and administration of isotonic crystalloid.
Disposition and Follow-Up
Phenytoin has a long and erratic absorption phase after oral overdose, so the decision to discharge or medically clear a patient for psychiatric evaluation cannot be based on one serum level. After acute ingestions, serum level should be measured every few hours. Patients with serious complications after an oral ingestion (seizures, coma, altered mental status, or significant ataxia) should be admitted for further evaluation and treatment. Those with mild symptoms should be observed in the ED and discharged once their levels of phenytoin are declining and they are clinically well. Mental health or psychiatric evaluation should be obtained, as indicated, in cases of intentional overdose.
Patients with symptomatic chronic intoxication should be admitted for observation unless signs are minimal, adequate care can be obtained at home, drug levels are decreasing, and 6 to 8 hours have elapsed since the patient’s last therapeutic dose. Phenytoin therapy should be stopped in all cases, and if toxicity continues to resolve, serum level may be reassessed in 2 to 3 days to guide resumption of therapy. Surgical consultation should be obtained for patients with significant extravasation of IV phenytoin or with other signs of local vascular or tissue toxicity after infusion.