Introduction
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 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.
Frequency
United States
According to the annual report of the American Association of Poison Control Centers' National Poison Data System, 2352 carbamazepine single exposures were reported in 2007. Of these, 1482 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 2007, 471 resulted in no significant outcome and 78 had a significant consequence. One death was reported.1
- Montgomery et al reports that severity 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 and final 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 (4.0%). 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 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.
Clinical
History
Query about whether the patient has been taking carbamazepine on an acute or chronic basis, the time of ingestion, and the approximate dose ingested.
- Drowsiness
- Slurred speech
- Ataxia
- Hallucinations
- Nausea, vomiting
- Tremors
- Seizures
- Oliguria
- Blurred vision
- Bullous skin formations
Physical
- Ocular
- Mydriasis
- Nystagmus
- Ophthalmoplegia
- Hypotension
- Neurologic
- Ataxia
- Slurred speech
- Dystonia, myoclonic activity
- Varying degrees of CNS depression progressing to coma
- Seizures, headache, confusion, and athetosis
- Increased or decreased deep tendon reflexes
- Respiratory depression, apnea
- Delayed gastric emptying, abdominal pain
- Oliguria, urinary retention
- Skin
- Bullous skin eruptions: Toxic epidermal necrolysis (TEN) has been reported with use of this drug. Severe drug eruptions are rare, and life-threatening events occur in 4 per million persons a year. TEN can trigger a life-threatening systemic inflammatory reaction leading to respiratory failure.4
- Rash, dermatitis: Drug rash with eosinophilia and systemic symptoms, also known as DRESS syndrome, reflects a serious hypersensitivity reaction to drugs. Clinically, a diffuse maculopapular rash, exfoliative dermatitis, facial edema, lymphadenopathy, fever, and multivisceral involvement may be observed. All of these symptoms are associated with a high mortality rate.5 A cross-reactivity between carbamazepine and phenytoin occurs, which may lead to or worsen DRESS syndrome. Discontinuation of the anticonvulsants and topical steroids should ameliorate the rash.
- Stevens-Johnson syndrome
- Blood dyscrasias
- Pancytopenia
- Splenomegaly
- Lymphadenopathy
- Vasculitis
- Aplastic anemia
- Agranulocytosis
Causes
- Carbamazepine toxicity may result from acute overdose or chronic therapy.
- Therapeutic levels are 4-12 mg/L, but individual variation exists.
- Patients on multiple anticonvulsants may not tolerate high levels and can be maintained at 4-8 mg/L, while others can achieve levels of 8-12 mg/L without adverse effects.
- Ataxia and nystagmus may occur at levels greater than 10 mg/L.
- Cardiovascular effects are usually seen at levels greater than 12 mg/L. The drug interferes with action potentials in Purkinje fibers and the His bundle, which may lead to atrioventricular blocks and arrhythmias.
- Peak serum levels with controlled release formulations of carbamazepine can result in delayed presentations of toxicity. Levels may not peak for 96 hours from the time of ingestion. Continuing repeat dosing of activated charcoal and whole bowel irrigation is important. Hemoperfusion may be necessary if end-organ toxicity becomes evident.
- Drug-drug interactions are known to occur. Vander et al reported a case of carbamazepine toxicity that occurred after administration of oxybutynin and an increase in the dose of dantrolene.6 The combination of these drugs elevated the level of carbamazepine leading to toxicity.
More on Toxicity, Carbamazepine |
 Overview: Toxicity, Carbamazepine |
| Differential Diagnoses & Workup: Toxicity, Carbamazepine |
| Treatment & Medication: Toxicity, Carbamazepine |
| Follow-up: Toxicity, Carbamazepine |
| References |
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References
Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Heard SE. 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 25th Annual Report. Clin Toxicol (Phila). Dec 2008;46(10):927-1057. [Medline]. [Full Text].
Montgomery VL, Richman BJ, Goldsmith LJ, Rodgers GC Jr. Severity and carbamazepine level at time of initial poison center contact correlate with outcome in carbamazepine poisoning. J Toxicol Clin Toxicol. 1995;33(4):311-23. [Medline].
van Opstal JM, Janknegt R, Cilissen J, et al. Severe overdosage with the antiepileptic drug oxcarbazepine. Br J Clin Pharmacol. Sep 2004;58(3):329-31. [Medline].
Fischer M, Hamm H, Wirbelauer J. [Severe drug-related skin reaction: toxic epidermal necrolysis caused by carbamazepine]. Klin Padiatr. Sep-Oct 2004;216(5):288-93. [Medline].
Allam JP, Paus T, Reichel C, et al. DRESS syndrome associated with carbamazepine and phenytoin. Eur J Dermatol. Sep-Oct 2004;14(5):339-42. [Medline].
Vander T, Odi H, Bluvstein V, Ronen J, Catz A. Carbamazepine toxicity following Oxybutynin and Dantrolene administration: a case report. Spinal Cord. Apr 2005;43(4):252-5. [Medline].
Apfelbaum JD, Caravati EM, Kerns WP, et al. Cardiovascular effects of carbamazepine toxicity. Ann Emerg Med. May 1995;25(5):631-5. [Medline].
Bass J, Miles MV, Tennison MB, et al. Effects of enteral tube feeding on the absorption and pharmacokinetic profile of carbamazepine suspension. Epilepsia. May-Jun 1989;30(3):364-9. [Medline].
Goldfrank L, Flomenbaum NE, Lewin NA. Carbamazepine. In: Goldfrank's Toxicologic Emergencies. Appleton & Lange; 1994:594-5.
Graudins A, Peden G, Dowsett RP. Massive overdose with controlled-release carbamazepine resulting in delayed peak serum concentrations and life-threatening toxicity. Emerg Med (Fremantle). Mar 2002;14(1):89-94. [Medline].
Klimaszyk D, Lukasik-GLebocka M. [Cardiac toxicity of carbamazepine]. Przegl Lek. 2002;59(4-5):384-5. [Medline].
Micromedex. Toxicologic Managements of Carbamazepine. Healthcare Series Micromedex;95.
Miles MV, Lawless ST, Tennison MB, et al. Rapid loading of critically ill patients with carbamazepine suspension. Pediatrics. Aug 1990;86(2):263-6. [Medline].
Riva R, Contin M, Albani F, et al. Free and total plasma concentrations of carbamazepine and carbamazepine-10,11-epoxide in epileptic patients: diurnal fluctuations and relationship with side effects. Ther Drug Monit. 1984;6(4):408-13. [Medline].
Romero Maldonado N, Sendra Tello J, Raboso Garcia-Baquero E, Harto Castano A. Anticonvulsant hypersensitivity syndrome with fatal outcome. Eur J Dermatol. Sep-Oct 2002;12(5):503-5. [Medline].
Stremski ES, Brady WB, Prasad K, Hennes HA. Pediatric carbamazepine intoxication. Ann Emerg Med. May 1995;25(5):624-30. [Medline].
Van Der Meyden CH, Kruger AJ, Muller FO, et al. Acute oral loading of carbamazepine-CR and phenytoin in a double-blind randomized study of patients at risk of seizures. Epilepsia. Jan-Feb 1994;35(1):189-94. [Medline].
Wada JA, Troupin AS, Friel P, et al. Pharmacokinetic comparison of tablet and suspension dosage forms of carbamazepine. Epilepsia. Jun 1978;19(3):251-5. [Medline].
Further Reading
Keywords
toxicity carbamazepine, carbamazepine toxicity, carbamazepine poisoning symptoms, carbamazepine poisoning treatment, carbamazepine poisoning, 5H-dibenzazepine-5-carboxamide toxicity, antiepileptic drug toxicity, carbamazepine overdose, carbamazepine ingestion, carbamazepine exposure, antiepileptic drugs, AEDs, simple partial seizures treatment, complex partial seizures treatment, trigeminal neuralgia treatment, bipolar affective disorder treatment, iminostilbene derivative
