Chapter 109. Anticonvulsants

Intentional phenytoin overdose rarely leads to death, provided adequate supportive care is administered. Most phenytoin-related deaths have been caused by rapid IV administration and hypersensitivity reactions.

Clinical Features

The toxic effects of phenytoin depend on the duration of exposure, dosage taken, and route of administration. Life-threatening effects such as hypotension, bradycardia, and asystole are seen with IV administration and are secondary to the diluent, propylene glycol. Morbidity can be avoided by slowing the rate of administration. Fosphenytoin is well tolerated intramuscularly or intravenously; adverse and toxic effects are the same as those of phenytoin, except the toxic effects of propylene glycol are not present.

Clinical manifestations in overdose are typically dose related and are listed in Table 109-1. The primary clinical features of overdose are related to acute CNS effects while cardiovascular toxicity is almost entirely seen in cases of IV administration. Skin and soft tissue injury may be seen with IM injection of phenytoin or after extravasation from IV infusion, but are rarely seen with fosphenytoin. Therapeutic use has been associated with hypersensitivity reactions and gingival hyperplasia. Phenytoin is teratogenic.

Diagnosis and Differential

Diagnosis is made by history and serum drug levels. The therapeutic range is 10 to 20 micrograms/mL and toxicity generally correlates with increasing plasma levels (Table 109-2). Absorption is erratic, and serial levels should be obtained. Electrocardiographic changes in toxicity include increased PR interval, widened QRS interval, and altered ST-wave and T-wave segments.

Almost any CNS-active drug can mimic phenytoin toxicity. Disease states that resemble phenytoin toxicity include hypoglycemia, Wernicke encephalopathy, and posterior fossa hemorrhage or tumor.

Emergency Department Care and Disposition

1. Place patients on monitors and obtain IV or IO access.

2. Treat acute oral overdose with multi-dose of oral activated charcoal (1 gram/kilogram) every 4 hours for the first 24 hours. Correct acidosis to decrease free serum phenytoin. Hemodialysis and hemoperfusion are of no benefit.

3. Treat hypotension from IV administration of phenytoin with IV isotonic crystalloid and discontinuation of the infusion.

4. Treat bradydysrhythmias with atropine or cardiac pacing.

5. Treat seizures with a benzodiazepine or phenobarbital.

6. Obtain orthopedic or plastic surgery consultation for significant soft tissue injury.

7. Admit patients with serious complications (eg, seizures, coma, altered mental status, and ataxia). Observe patients with mild symptoms until serum levels are declining; cardiac monitoring after isolated oral ingestion is unnecessary. Discontinue phenytoin and recheck levels in 2 to 3 days.

Clinical Features

Carbamazepine's anticholinergic properties delay GI motility and 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 an anticholinergic toxidrome. Seizures can occur at high concentrations. Though rare, carbamazepine can widen the QRS interval and cause cardiac arrhythmias.

Diagnosis and Differential

Serum carbamazepine concentrations do not correlate with the severity of poisoning, though concentrations >40 micrograms/mL may be associated with an increased risk of complications, and those >60 to 80 micrograms/mL may be fatal. A false positive tricyclic antidepressant result on urine drug screen can occur. Obtain an ECG to evaluate for QRS interval widening.

Emergency Department Care and Disposition

1. Consider activated charcoal in the awake patient within 1 hour of ingestion.

2. Consider hemodialysis or hemodiafiltration for life-threatening overdose.

3. Treat QRS interval widening with sodium bicarbonate.

4. Patients can be discharged if asymptomatic, with declining serum levels (below 15 micrograms/mL), and a normal ECG.

Clinical Features

In acute overdose, valproate causes central nervous system depression. Other findings include respiratory depression, hypotension, hypoglycemia, hypernatremia, hypophosphatemia, and anion gap metabolic acidosis that may persist for days. Liver toxicity, cerebral edema, hyperammonemia, pancreatitis, and thrombocytopenia have been reported after acute overdose. Hepatic failure (microvesicular steatosis) occurs in about 1 in 20,000 patients on long-term therapy, with children <3 years of age on multiple antiepileptics at greatest risk.

Diagnosis and Differential

Obtain a serum valproate level. The therapeutic range is 50 to 100 micrograms/mL; adverse effects increase at concentrations >150 micrograms/mL and frank coma may occur with levels above 800 micrograms/mL. Check serum ammonia and bedside glucose in patients with altered level of consciousness. Consider liver function tests, electrolytes, and a CBC.

Emergency Department Care and Disposition

1. Consider multidose activated charcoal after ingestion of enteric-coated, delayed-release preparations and measure serial concentrations due to delayed peak serum concentration. Consider whole-bowel irrigation in extended-release preparations.

2. L-carnitine, 50 milligrams/kilogram/d, may hasten recovery in patients with acute intoxication and increase survival from hepatotoxicity.

3. Hemoperfusion and hemodiafiltration can be used to treat severe overdose.

4. All symptomatic patients require admission, while asymptomatic patients with declining serum levels can be discharged.

As a group, the second-generation anticonvulsants possess little toxicity in acute overdose.

• Felbamate may cause aplastic anemia and hepatic failure and can crystallize in the kidney, leading to acute renal failure in large overdose.
• Gabapentin may cause drowsiness, ataxia, nausea, and vomiting that generally resolve in about 10 hours.
• Lacosamide may cause dizziness, headache, nausea, and diplopia in therapeutic use.
• Lamotrigine has been associated with autoimmune reactions in therapeutic use and drowsiness, vomiting, ataxia, and dizziness in overdose. Seizures, coma, cardiac toxicity (QRS and QT-interval prolongation), and acute pancreatitis have been reported. Treatments include sodium bicarbonate and IV lipid.
• Levetiracetam may cause lethargy, coma, and respiratory depression.
• Oxcarbazepine may cause hyponatremia and a drug rash in therapeutic use.
• Pregabalin has been reported to cause somnolence and dizziness in long-term therapeutic use. Overdose may cause depressed level of consciousness.
• Rufinamide may cause headache, dizziness, fatigue and somnolence in long-term therapy.
• Tiagabine may cause the rapid neurologic toxicity, including lethargy, coma, seizures, myoclonus, muscular rigidity, and delirium.
• Topiramate may cause nephrolithiasis and glaucoma in therapeutic use. In overdose, somnolence, vertigo, agitation, mydriasis, and seizures 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 may promote renal stone formation and cause a drug rash in therapeutic use.