Alicia B. Minns
First-generation anticonvulsants such as phenytoin and phenobarbital have potential for serious toxicity, especially in overdose. The newer, second-generation anticonvulsants generally have fewer adverse effects in overdose.
PHENYTOIN AND FOSPHENYTOIN
EPIDEMIOLOGY
Most phenytoin-related deaths have been caused by rapid IV administration or hypersensitivity reactions.
CLINICAL FEATURES
Toxicity depends upon the duration of exposure, dosage taken, and most importantly, route of administration.
Life-threatening effects such as hypotension, bradycardia, conduction delays, ventricular dysrhythmias, and asystole can be seen with IV administration, and are secondary to the diluent propylene glycol. This morbidity can be avoided by slowing the rate of administration.
Clinical manifestations in oral overdose are dose related and present with central nervous system (CNS) toxicity. Symptoms include nystagmus, depressed level of consciousness, nausea, vomiting, ataxic gait, dysarthria, and confusion. Seizures, coma, and apnea may occur in large overdoses. Death from oral overdose alone is extremely rare.
Cardiovascular toxicity is usually associated with IV administration. In an otherwise healthy patient, cardiac toxicity has never been reported after an oral overdose of phenytoin; when observed, this requires assessment for other causes.
Phenytoin causes significant soft tissue toxicity. Intramuscular injection can result in localized crystallization of the drug, hematoma, sterile abscess, and myonecrosis.
Reported complications of extravasation after IV infusion have included skin and soft tissue necrosis, compartment syndrome, gangrene, and death.
Fosphenytoin, a prodrug of phenytoin, is more soluble and less irritating to tissues. Fosphenytoin is well tolerated intramuscularly or intravenously, although intravenous fosphenytoin can cause pruritus and hypotension. The toxic effects of propylene glycol are not present.
Hypersensitivity reactions usually occur within 1 to 6 weeks of initiating phenytoin therapy. Reactions can include systemic lupus erythematosus, erythema multiforme, toxic epidermal necrolysis, Stevens–Johnson syndrome, hepatitis, rhabdomyolysis, acute interstitial pneumonitis, lymphadenopathy, leukopenia, disseminated intravascular coagulation, and renal failure.
Gingival hyperplasia is a common side effect of phenytoin and its absence may suggest poor compliance.
Phenytoin is teratogenic and should never be initiated in a pregnant patient without consulting a neurologist and obstetrician.
DIAGNOSIS AND DIFFERENTIAL
Therapeutic levels are between 10 and 20 micrograms/mL (40-80 micromoles/L). Some patients require levels above 20 micrograms/mL for adequate seizure control. Patients with underlying brain disease are predisposed to toxicity and may become toxic at low levels.
Toxicity generally correlates with increasing plasma levels (Table 111-1). Due to erratic absorption, serial phenytoin levels should be obtained to identify peak levels.
Almost any CNS-active drug, such as ethanol, car-bamazepine, benzodiazepines, barbiturates, and lithium, can mimic phenytoin toxicity.
Disease states that resemble phenytoin toxicity include hypoglycemia, Wernicke’s encephalopathy, and posterior fossa hemorrhage or tumor.
Seizures from phenytoin toxicity are uncommon, and other causes should be investigated, such as trauma or alcohol withdrawal.
TABLE 111-1 Correlation of Plasma Phenytoin Level and Side Effects
EMERGENCY DEPARTMENT CARE AND DISPOSITION
Place patients on a cardiac monitor, noninvasive blood pressure device, and pulse oximeter. Establish vascular access.
Correct acidosis (respiratory or metabolic) to decrease the active free phenytoin fraction.
Treat hypotension from IV administration of phenytoin with isotonic crystalloids and discontinuation of the infusion.
For an acute oral overdose, give multiple doses of oral activated charcoal (1 gram/kg) initially and then every 4 hours for the first 24 hours.
Consider atropine or cardiac pacing for bradydysrhythmias.
Treat seizures with a benzodiazepine or phenobarbital.
Hemodialysis and hemoperfusion are of no benefit.
Admit patients following oral ingestion, if serious complications (eg, seizures, coma, altered mental status, and ataxia) are present.
Observe patients with mild symptoms in the ED and discharge home if serum levels are declining. Cardiac monitoring after isolated oral ingestion is unnecessary.
After IV administration of phenytoin, admit patients with significant or persistent complications for observation on a telemetry unit. Discharge those with transient effects.
Admit patients with symptomatic chronic intoxication for observation unless the toxic effects are minimal, adequate care can be obtained at home, drug levels are decreasing, and patients are 6 to 8 hours from their last dose. Phenytoin should be stopped and levels rechecked in 2 to 3 days.
CARBAMAZEPINE
CLINICAL FEATURES
In acute toxicity, delayed and erratic absorption due to carbamazepine’s anticholinergic properties and lower water solubility can cause delayed clinical deterioration.
Manifestations of acute toxicity include coma, respiratory failure, ataxia, nystagmus, miosis or mydriasis, ileus, bowel obstruction, hypertonicity, increased deep tendon reflexes, dystonic reactions, and anticholinergic toxidrome.
Seizures may occur at high concentrations.
Although cardiac arrhythmias are rare, carbamazepine is one of the few anticonvulsants that can cause a wide QRS and seizures.
DIAGNOSIS AND DIFFERENTIAL
Serum carbamazepine concentrations do not accurately correlate with the severity of the poisoning; however, concentrations of >40 micrograms/mL may be associated with an increased risk of serious complications and concentrations higher than 60 to 80 micrograms/mL may be fatal.
Obtain an ECG to evaluate the QRS interval in suspected carbamazepine toxicity.
A false-positive tricyclic antidepressant result on urine drug screen can occur due to structural similarity.
EMERGENCY DEPARTMENT CARE AND DISPOSITION
Consider activated charcoal if the patient is not obtunded and presents within 1 hour of ingestion.
Hemodialysis or hemodiafiltration are effective in life-threatening overdose.
Give sodium bicarbonate for widening of the QRS.
Asymptomatic patients may be medically cleared if at least two carbamazepine levels obtained a few hours apart are decreasing.
VALPROATE
CLINICAL FEATURES
In acute overdose, the most frequent sign is central nervous system depression. Other findings include respiratory depression, hypotension, hypoglycemia, hypernatremia, hypophosphatemia, and an anion gap metabolic acidosis that may persist for days.
Liver toxicity leads to elevated serum aminotransferases, ammonia, and lactate. Hepatic failure (microvesicular steatosis) occurs in about 1 in 20,000 patients on long-term therapy. Children <3 years of age on multiple antiepileptics with multiple medical problems are at increased risk of hepatotoxicity.
Hyperammonemia in the absence of liver failure has been reported following both overdose and long-term therapeutic use.
Pancreatitis and thrombocytopenia may occur.
Cerebral edema has been observed after acute overdose.
DIAGNOSIS AND DIFFERENTIAL
Therapeutic valproate concentrations are between 50 and 100 micrograms/mL. Adverse effects increase as concentrations rise above 150 micrograms/mL, and frank coma may occur with levels above 800 micrograms/mL.
Obtain serum ammonia and bedside glucose concentrations in patients with altered level of consciousness. Consider a CBC, electrolytes, liver function tests, and serum lactate.
EMERGENCY DEPARTMENT CARE AND DISPOSITION
Consider multidose activated charcoal after ingestion of enteric-coated delayed-release preparations. Consider whole-bowel irrigation in extended-release preparations.
Measure serial concentrations due to delayed peak serum concentration.
Administer L-carnitine, 50 milligrams/kg/d, to patients with lethargy, coma, hyperammonemia, and hepatic dysfunction.
Initiate hemoperfusion or hemodiafiltration for severe overdose.
A patient should be asymptomatic with a decline in levels before considered stable for discharge.
SECOND-GENERATION ANTICONVULSANTS
As a group, the second-generation anticonvulsants possess little toxicity in acute overdose.
Felbamate may cause aplastic anemia and hepatic failure with therapeutic use. In large overdose, it can crystallize in the kidney, causing acute renal failure.
Gabapentin produces little toxicity in overdose—usually drowsiness, ataxia, nausea, and vomiting that resolve in about 10 hours.
Lacosamide can cause dizziness, headache, nausea, and diplopia in therapeutic use. Clinical experience in overdose is limited.
Lamotrigine has been associated with autoimmune reactions, such as Stevens–Johnson syndrome during therapeutic use. The most common effects in overdose are drowsiness, vomiting, ataxia, and dizziness. Seizures, coma, cardiac toxicity (QRS and QT-interval prolongation), and acute pancreatitis have been reported with lamotrigine overdose. Treatments include sodium bicarbonate and IV lipid emulsion.
Levetiracetam can cause lethargy, coma, and respiratory depression.
Oxcarbazepine may cause hyponatremia and a drug rash with therapeutic use. There is little toxicity from isolated overdose.
Pregabalin can cause somnolence and dizziness in long-term therapeutic use. There is little experience with overdose.
Rufinamide may cause headache, dizziness, fatigue, and somnolence in long-term therapy. Clinical experience in overdose is limited.
Tiagabine overdose can cause rapid onset of neurologic toxicity, including lethargy, coma, and seizures (status epilepticus, even in patients without an underlying seizure disorder, may be seen). Other findings in overdose include myoclonus, muscular rigidity, and delirium.
Topiramate can promote renal stone formation and glaucoma in therapeutic use. In overdose, topiramate can cause somnolence, vertigo, agitation, and mydriasis. Seizures and status epilepticus have been reported. It can produce a metabolic acidosis, which can last up to 7 days due to the long half-life of the drug.
Zonisamide can promote renal stone formation and cause a drug rash in therapeutic use. Clinical experience in overdose is limited.
For further reading in Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 7th ed., see Chapter 191, “Anticonvulsants,” by Frank LoVecchio and Jennifer C. Smith.