Pediatric Carbamazepine Toxicity

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Carbamazepine (Tegretol) has been used for the treatment of trigeminal neuralgias since 1960. Since carbamazepine received approval for use as an antiepileptic agent in the United States in 1974, it became widely used for the management of partial or tonic-clonic epilepsy. Carbamazepine is also used as a treatment for patients with manic-depressive illness, 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.

The therapeutic plasma concentration is 4-12 mg/L. A peak plasma level is achieved in 6-24 hours. Controlled-release formulation could result in peak levels as late as 4 days after administration. [1] The volume of distribution is 1-2 L/kg. Carbamazepine is approximately 75-80% protein bound, and approximately 2-3% is excreted unchanged in the urine. Carbamazepine is oxidized by hepatic microsomal enzymes to produce its active metabolite, carbamazepine 10,11-epoxide. The serum concentration of the epoxide metabolite is approximately 20% in children and 10-15% in adults.

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. [2]

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 under treated. 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. [2]

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 woman who are taking both medications. [3]

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. [4]

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. [5]

Carbamazepine is a complex drug that has both anticonvulsant properties in therapeutic doses and a proconvulsant property in overdose situations with supratherapeutic serum levels. Carbamazepine is chemically and stereospatially related to the tricyclic antidepressant (TCA) imipramine; it is spatially similar to phenytoin. The therapeutic anticonvulsant mechanism of carbamazepine is similar to phenytoin and is believed to be primarily related to the blockade of presynaptic voltage-gated sodium channels.

Blockage of sodium channels is believed to inhibit the release of synaptic glutamate and possibly other neurotransmitters. It also inhibits N -methyl-D-aspartate (NMDA) receptors and CNS adenosine receptors. Carbamazepine also has powerful anticholinergic properties through inhibition of the muscarinic and nicotinic acetylcholine receptors. The seizures that occur with carbamazepine toxicity are largely secondary to a central anticholinergic syndrome. The coma and respiratory depression associated with overdose may be related to sodium channel suppression of neurotransmission.

Carbamazepine causes antagonism at the adenosine subtype A1 receptor and agonism at the adenosine subtype A2 receptor. In lower therapeutic doses, this may be partially responsible for the anticonvulsant effect, whereas, in overdose situations, it may increase sedation or precipitate coma.

Cardiac arrhythmias due to carbamazepine are related to its sodium channel and anticholinergic effects. In therapeutic doses, the cardiovascular sodium channels are only minimally affected, and carbamazepine does not appear to be proarrhythmic. However, in overdose situations, carbamazepine produces sodium channel blockade effects similar to those of TCAs.

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. [6]

The incidence of carbamazepine toxicity has decreased over the course of the 21st century. The American Association of Poison Control Centers reported 6096 cases of carbamazepine exposure in 2000, [7] 4255 case mentions and 2352 single exposures in 2007, [8] and 3734 case mentions and 1880 single exposures in 2014. [1]

From 2000 to 2012, there were 18,867cases, with a mean of 1451 exposures/year. The patients were predominantly adults, with 5,464 exposures in children younger than 6 years (29%). The most commonly reported clinical effects were drowsiness (N = 4703, 25%), vomiting (N = 1559, 8%), tachycardia (N = 590, 3%), agitation (N = 342, 1.8%), hypotension (N = 178, 0.9%), electrolyte disturbance (N = 153, 0.8%), coma (N = 156, 0.8%), and seizures (n = 121, 0.6%). Fifty-three percent of adults and 38% of children were managed in a health-care facility. [9]

In 2014, among 1880 single exposures to carbamazepine, 62 patients experienced major toxicity,  but no deaths were reported. [1] Complications of severe poisoning include coma, respiratory depression, seizures, hypotension, and GI hypomotility. Cardiac toxicity is uncommon in children, especially in those who have a structurally normal heart.

No specific sex predilection has been noted. Most pediatric patients are younger than 6 years. Of the 1880 cases of carbamazepine toxicity reported by the American Association of Poison Control Centers in 2014, 253 were in children younger than 6 years, 66 were in children aged 6-12, and 151 in patients 13-19 years old; 1331 were in individuals older than 19 years. [1]

A discussion regarding the prevention of unintentional ingestion is an important component of the routine care of the child.

The patient’s parents should be taught how to safely store medications.

For patient education resources, see the Drug Overdose Center and Poisoning – First Aid and Emergency Center, as well as Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

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Muhammad Waseem, MBBS, MS, FAAP, FACEP, FAHA Professor of Emergency Medicine in Clinical Pediatrics, Weill Cornell Medical College; Attending Physician, Departments of Emergency Medicine and Pediatrics, Lincoln Medical and Mental Health Center; Adjunct Professor of Emergency Medicine, Adjunct Professor of Pediatrics, St George’s University School of Medicine, Grenada

Muhammad Waseem, MBBS, MS, FAAP, FACEP, FAHA is a member of the following medical societies: American Academy of Pediatrics, American Academy of Urgent Care Medicine, American College of Emergency Physicians, American Heart Association, American Medical Association, Association of Clinical Research Professionals, Public Responsibility in Medicine and Research, Society for Academic Emergency Medicine, Society for Simulation in Healthcare

Disclosure: Nothing to disclose.

Joel R Gernsheimer, MD, FACEP Visiting Associate Professor, Department of Emergency Medicine, Attending Physician and Director of Geriatric Emergency Medicine, State University of New York Downstate Medical Center

Joel R Gernsheimer, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians, American Geriatrics Society

Disclosure: Nothing to disclose.

Nicholas D Caputo, MD House Staff, Department of Emergency Medicine, Lincoln Medical and Mental Health Center/Weill Cornell Medical College

Nicholas D Caputo, MD is a member of the following medical societies: American College of Emergency Physicians, Emergency Medicine Residents’ Association

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Jeffrey R Tucker, MD Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut School of Medicine, Connecticut Children’s Medical Center

Disclosure: Received salary from Merck for employment.

Timothy E Corden, MD Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children’s Hospital of Wisconsin

Timothy E Corden, MD is a member of the following medical societies: American Academy of Pediatrics, Phi Beta Kappa, Society of Critical Care Medicine, Wisconsin Medical Society

Disclosure: Nothing to disclose.

William T Zempsky, MD Associate Director, Assistant Professor, Department of Pediatrics, Division of Pediatric Emergency Medicine, University of Connecticut and Connecticut Children’s Medical Center

William T Zempsky, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Girish G Deshpande, MD, to the original writing and development of this article.

Pediatric Carbamazepine Toxicity

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