Carbamazepine and Oxcarbazepine

General Principles

• Carbamazepine is an anticonvulsant that is structurally related to the tricyclic antidepressants (TCAs). It is also prescribed for trigeminal neuralgia and mood disorders.

• Oxcarbazepine is a prodrug that is converted to the active agent monohydroxy carbamazepine in vivo. The mechanism of action and toxicity of oxcarbazepine are generally similar to those of carbamazepine.

Pathophysiology

• Carbamazepine and oxcarbazepine exert their anticonvulsant effects via neuronal sodium channel blockade.

• Carbamazepine is structurally related to the TCAs.

• Carbamazepine is associated with the syndrome of inappropriate antidiuretic hormone release (SIADH).

Risk Factors

Coadministration of xenobiotics that inhibit the cytochrome P450 system (especially CYP 1A2, 2C8, 2C9, and 3A4) impairs the metabolism of carbamazepine and may lead to toxicity.

DIAGNOSIS

Clinical Presentation

• Patients with carbamazepine or oxcarbazepine poisoning present with tremor, nystagmus, ataxia, sedation, altered sensorium, or coma.

• Carbamazepine or oxcarbazepine poisoning may produce seizures in overdose.

• Carbamazepine produces antimuscarinic effects, including tachycardia, mydriasis, urinary retention, and delirium.

• The antimuscarinic effects of carbamazepine slow GI transit. Carbamazepine undergoes enterohepatic recirculation. This combined with active metabolites may create a “cyclical coma.”

In severe cases, bradycardia and hypotension may occur, due to direct myocardial toxicity.

Differential Diagnosis

• Carbamazepine poisoning is similar to poisoning by other anticonvulsants, including phenytoin, valproate, and lamotrigine.

The antimuscarinic and cardiotoxic effects of carbamazepine are generally not seen in poisoning by other antidepressants.

• Other antimuscarinic xenobiotics (e.g., TCAs, first-generation antihistamines, and botanical toxins) generally do not produce cerebellar signs, which may help distinguish carbamazepine poisoning from other causes of the antimuscarinic toxidrome.

• The nontoxicologic differential diagnosis for carbamazepine poisoning should include Wernicke encephalopathy, meningoencephalitis, posterior circulation ischemic stroke, and intracranial hemorrhage and mass lesion.

Diagnostic Testing

LABORATORIES

• Obtain a carbamazepine concentration.

๎ The therapeutic range is 4-12 mg/L.

๎ Concentrations above 40 mg/L are associated with cardiotoxicity. ¹³

๎ The carbamazepine concentration should be trended over time, as delayed absorption and delayed excretion are common in poisoning.

• Obtain a BMP to evaluate for evidence of SIADH.

ELECTROCARDIOGRAPHY

Obtain an ECG in all cases of known or suspected carbamazepine poisoning. In severe poisoning, carbamazepine prolongs the QRS complex and may cause atrioventricular conduction delays.

TREATMENT

• Treat seizures with benzodiazepines or other directly GABAergic agents.

• Patients with QRS prolongation should be treated with sodium bicarbonate as recommended in the discussion of TCAs below.

• MDAC enhances carbamazepine elimination and should be considered in patients without contraindication to AC. ¹⁴

• Hemodialysis effectively clears carbamazepine.

๎ Recommended: multiple seizures refractory to treatment or life-threatening dysrhythmias occur.

๎ Suggested: prolonged coma or respiratory depression requiring mechanical ventilation is expected or failure of other therapies.