0071643192.pdf

TOXICOLOGY

ANTICONVULSANTS

Anticonvulsant medications were developed for the treatment of seizures, but

they are also used for treatment of pain (carbamazepine, gabapentin), mood

disorders (carbamazepine, valproic acid, lamotragine), and migraines (valproic

acid, toperamide).

MECHANISM/TOXICITY

■ Slow conduction through Na+channels (phenytoin, carbamazepine, top-

eramide) orincrease activity in the GABA system (gabapentin, valproic

acid, phenobarbital)

■ All→CNS depression in overdose.

■ Some→slowed intracardiac conduction in overdose (carbamazepine, top-

eramide).

■ Rapid infusion of phenytoin →myocardial depression and cardiac arrest

frompropylene glycol diluent(not present in fosphenytoin).

DIAGNOSIS

■ Clinical laboratories can measure serum levels for many antiepileptics.

However, there is substantial intrasubject sensitivity to the effects of these

drugs, so levels are not accurate predictors of toxicity.

■ An elevated ammonia level is one of the most sensitive indicators of val-

proic acid toxicity. Results from depletion of carnitine and interference

with the urea cycle.

SYMPTOMS/EXAM

■ Carbamazepine

■ Mild/moderate toxicity is characterized by ataxia and nystagmus.

■ Serious ingestions (levels >40 mg/L) present with seizures, respira-

tory and CNS depression, and dysrhythmias (AV blocks, QRS/QT

prolongation).

■ Phenytoin

■ Mild to moderate toxicity: nystagmus, ataxia, and dysarthria

■ Severe toxicity (level >40 mg/L): stupor, coma, and respiratory arrest

■ Rapid IV injection →hypotension, bradycardia, and cardiac arrest.

■ Tissue infiltration →“purple glove syndrome”: edema, pain, ischemia,

tissue necrosis, compartment syndrome

■ Valproic acid

■ N/V, CNS depression

■ Severe toxicity (levels >850 mg/L): coma, respiratory depression, seizures,

metabolic disturbances, cardiac arrest

TREATMENT

■ Supportive therapy

■ Observe asymptomatic patients for at least 6 hours (depending on formu-

lation).

■ Activated charcoal

■ Hemodialysis is not effective in most overdoses; may be considered in

massive valproic acid ingestion.

■ Charcoal hemoperfusion has been used for carbamazepine and phenytoin

poisoning, but it is rarely available and of unproven value.

■ Multiple-dose activated charcoal increases the clearance of carbamazepine

and phenobarbital.

Cardiac toxicity with

intravenous phenytoin

administration is due to its

propylene glycol diluent.

Carbamazepine has a

structural similarity to TCA →

at high levels can cause

similar CNS and cardiac

toxicity.

Valproic acid toxicity (as

compared to phenytoin and

carbamazepine) can be

treated with hemodialysis.