What is carbamazepine toxicity?

Updated: Apr 29, 2020
  • Author: Muhammad Waseem, MBBS, MS, FAAP, FACEP, FAHA; Chief Editor: Stephen L Thornton, MD  more...
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Carbamazepine is an antiepileptic drug widely used for treatment of simple partial seizures and complex partial seizures, trigeminal neuralgia, and bipolar affective disorder. Carbamazepine is also used as a treatment for postherpetic neuralgia and phantom limb pain. Some of the available dosage forms for carbamazepine include 100-mg and 200-mg oral tablets and a 100 mg/5 mL oral suspension.

Carbamazepine (5H-dibenzazepine-5-carboxamide) is an iminostilbene derivative with a tricyclic structure. It 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. Controlled-release formulation could result in peak levels as late as 4 days after administration. The primary site of metabolism is the liver; its metabolite also is active, which may increase duration of the symptoms of toxicity.

Autoinduction of microsomal enzyme results in a shorter carbamazepine half-life (10-20 h) in patients who use the drug long-term compared with those with a short-term exposure (31-35 h). The autoinduction process takes about 4 weeks.

Carbamazepine stimulates the synthesis of many monooxygenase and conjugating enzymes, which leads to the metabolism of many medications. [1]  In terms of drug interactions, carbamazepine induces the metabolism of other anticonvulsant drugs such as phenytoin, clonazepam, primidone, valproic acid, and ethosuximide. This may lead to subtherapeutic levels of these drugs, especially phenytoin.

In addition, carbamazepine reduces the duration and action of many therapeutic agents, including anticoagulants, cytotoxic drugs, analgesics, antiretrovirals, glucocorticoids, statins, antihypertensives, oral contraceptives, psychoactive drugs, and immunosuppressants. This can lead to patients on these drugs and carbamazepine being undertreated. If carbamazepine is stopped while these drugs are continued, then the level of these drugs may rise, leading to toxicity. In addition, induction of enzymes can affect enzymes in endogenous metabolic pathways, which can subsequently affect bone, gonadal steroid, and lipid metabolism. This may lead to osteoporosis, sexual dysfunction, and vascular diseases. [1]

Inhibitors of hepatic microsomal enzymes, such as erythromycin, clarithromycin, and cimetidine, increase carbamazepine levels and may cause toxicity. Carbamazepine may increase the toxicity of adenosine and may increase the risk of heart block. Lower initial doses of adenosine should be used in patients who are taking carbamazepine.

Carbamazepine can interfere with the action of low-dose oral contraceptives and may lead to breakthrough vaginal bleeding, ovulation, and even pregnancy in women who are taking both medications. [2]

Armodafinil is a stimulant whose indications include obstructive sleep apnea, narcolepsy, and shift work sleep disorder, and like carbamazepine, it is an inducer of and substrate for cytochrome P450 (CYP3A4). A drug interaction study of the two agents found that systemic exposure to both carbamazepine and armodafinil was reduced after pretreatment with the other drug; A dose adjustment may be required when coadministering these compounds. [3]

On an interesting note, carbamazepine has been detected in the environment. Significant carbamazepine levels have been found in juvenile rainbow trout, probably due to pharmaceuticals that were discarded and contaminated the water. [4]

In 2004, HLA-B*1502 was found to be strongly associated with carbamazepine-induced Stevens-Johnson syndrome in people of Han-Chinese ethnicity, increasing the risk by about 100-fold. As a result, screening for HLA-B*1502 before carbamazepine prescription is routinely performed in the South-East Asian population. [5, 6]

Patients with carbamazepine toxicity may present with neurologic, ocular, cardiovascular, and cutaneous signs and symptoms (see Presentation). In addition to measurement of the serum carbamazepine level, the workup should include testing to detect organ system complications and rule out alternative diagnoses (see Workup). Treatment focuses on decontamination and supportive care (see Treatment and Medication).

Education and communication between the primary care physician and the patient is important for prevention of carbamazepine overdose.

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