Carbamazepine Toxicity in Emergency Medicine
- Author: Nidhi Kapoor, MD; Chief Editor: Asim Tarabar, MD more...
Background
Carbamazepine (5H-dibenzazepine-5-carboxamide) is an iminostilbene derivative with a tricyclic structure. It is an antiepileptic drug widely used for treatment of simple partial seizures and complex partial seizures, trigeminal neuralgia, and bipolar affective disorder.
Carbamazepine selectively inhibits high frequency epileptic foci while normal neuronal activity remains undisturbed. Carbamazepine is absorbed erratically after oral administration because of its lipophilic nature. It has a large volume of distribution; peak plasma levels occur 4-8 hours postingestion but may take up to 24 hours to peak. The primary site of metabolism is the liver; its metabolite also is active, which may increase duration of the symptoms of toxicity.
Pathophysiology
Carbamazepine reduces the propagation of abnormal impulses in the brain by blocking sodium channels, thereby inhibiting the generation of repetitive action potentials in the epileptic focus. Carbamazepine is absorbed slowly and distributed erratically following oral administration. It enters the brain rapidly because of its high lipid solubility.
Carbamazepine is metabolized primarily in the liver by oxidative enzymes, then is conjugated with glucuronic acid, and finally is excreted in the urine. Its metabolite, carbamazepine-10,11-epoxide, is active and may achieve up to 50% concentration of the parent compound.
The elimination of carbamazepine increases over the first few weeks because of autoinduction. Carbamazepine also enhances the metabolism of phenytoin, causing its levels to fall. Erythromycin, isoniazid, and propoxyphene (withdrawn from US market) inhibit the hepatic metabolism of carbamazepine; therefore, the dose of carbamazepine may need to be adjusted in patients taking multiple medications.
Carbamazepine induces the hepatic cytochrome P-450 system and its half-life decreases with chronic administration. The enhanced cytochrome P-450 system increases metabolism of other antiepileptic drugs.
Epidemiology
Frequency
United States
According to the Annual Report of the American Association of Poison Control Centers' National Poison Data System, 2330 carbamazepine single exposures were reported in 2008. Of these, 1517 patients sought treatment in a health care facility.[1]
Mortality/Morbidity
Of the exposures to carbamazepine reported to the American Association of Poison Control Centers in 2008, 389 resulted in no significant outcome and 69 had a significant consequence. No deaths were reported.[1]
- Montgomery et al reports that severity of symptoms at the time of initial contact with the poison control center correlates with outcome severity for children and adults.[2] However, the amount of time between ingestion and poison control center contact did not alter the correlation between initial severity of symptoms and final outcome severity.
- Far more exposures to the drug are unintentional (57.2%) than intentional (37.6%). A small number of people experienced the effects of toxicity secondary to adverse reactions rather than true poisonings (4%). Montgomery et al found that the reason for ingestion was correlated significantly with outcome. Carbamazepine levels greater than 85 mg/L were associated with severe toxicity.[2]
- The new drug oxcarbazepine is structural derivative of carbamazepine. It is metabolized to a product called 10-monohydrate derivate (MHD); this is the pharmacologically effective compound. van Optstal et al reported a case when a patient ingested more than 100 tablets of oxcarbazepine.[3] The serum level of the parent compound was 10-fold higher than the therapeutic dosage of 31.6 mg/L. However, the concentration of MHD was only 2-fold higher. MHD levels peaked 7 hours after intake. The patient survived without an adverse outcome. The authors concluded that since oxcarbazepine is a prodrug, formation of the active MHD metabolite is a rate-limiting process contributing to low overall toxicity of this drug.
Age
Roughly one third of carbamazepine exposures occur in children younger than 6 years. Pediatric patients with carbamazepine ingestion are at higher risk for dystonic reactions, coma, and apnea if serum levels exceed 28 mg/L. Children eliminate the drug more rapidly than adults.
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