The Poison Control Center

Carbamazepine: Acute Ingestion and its Consequences

Case
Introduction
Pharmacology and pharmacokinetics
Clinical signs and symptoms
Treatment
Conclusion

Case

A four year old, 15 kilogram black male was admitted to the emergency room approximately 12 to 24 hours after ingesting an unknown quantity of 200 mg. carbamazepine tablets. The child had no seizure history or previous exposure to carbamazepine. On admission, the child was found to be obtunded with a rectal temperature of 95.8° F, and irregular pulse fluctuating from 42-84 beats per minute, respirations of 16 per minute, and a blood pressure of 72/40. Neurologic exam revealed nystagmus, but no seizure activity. Plasma level of carbamazepine upon admission was 29.8 mcg./ml. The child was placed on a warming blanket and treated with repeated doses of activated charcoal with a cathartic. Within 26-48 hours of the toxic ingestion, the patient's vital signs stabilized and the plasma level of carbamazepine decreased to 4.4 mcg./ml. The child was discharged approximately 48 hours after his admission.

Introduction

Carbamazepine (Tegretol®) was approved in the United States for use as an anti-epileptic agent in 1974. It is the drug of choice for the treatment of trigeminal neuralgia for which it has been used worldwide since the 1960s. Carbamazepine (CBZ) is a synthetic iminostilbene derivative that is chemically and structurally related to the tricyclic antidepressants and spatially related to phenytoin. In overdose, CBZ often exhibits toxicities shared by these compounds.1,2 The lethal dose of CBZ is not known, however, death has occurred with an ingestion of 20 grams.1,2 It is available in 100 mg. chewable tablets, 200 mg. tablets, and 100 mg./5 ml. syrup.1,2

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Pharmacology and Pharmacokinetics

Carbamazepine has been demonstrated to decrease seizure activity in animals with electrically and chemically induced seizures.5 It is believed to act by, "reducing polysynaptic responses and blocking the post-tetanic potentiation."5 It also reduces pain induced by nerve stimulation in animals, as well as depresses thalamic reflexes; however, its mechanism of action is unknown.1,5

CBZ is absorbed slowly and erratically, largely due to its limited aqueous solubility. Peak concentrations usually occur 4-8 hours after oral administration, but may be delayed up to 24 hours following ingestion of a large amount of the drug.1

CBZ has a dose-dependent volume of distribution in the body.1,2 The average volume of distribution in children is 1.94 L./kg., whereas in adults this value decreases to about 1 L./kg.1,2 CBZ is approximately 75 percent bound to plasma proteins. Levels of the drug in the CSF appear to correspond to free drug levels in the plasma (about 20-25 percent).1,2

CBZ follows first-order, nonsaturable kinetics.1,2 CBZ is metabolized in the liver to several metabolites, the primary metabolite being CBZ-10,11 epoxide (CBZ-E).1,2 CBZ-E possesses anticonvulsant activity similar to the parent drug. A large amount of carbamazepine undergoes enterohepatic recycling and is excreted in the bile.(1,2) Less than 3 percent of active drug (CBZ or CBZ-E) is excreted in the urine.1,2

Repeated administration of CBZ to an individual results in enhanced elimination of drug from the body.2,3,4 This is thought to be due to the induction of liver enzymes after prolonged exposure to CBZ.2,3,4 The elimination half-life in children and adults during chronic CBZ therapy may vary from 5-20 hours, whereas single dose administration of CBZ may result in an elimination half-life of about 36 hours.2,3,4 Concomitant drug administration may also influence the apparent half-life.2,3,4

Administration of phenytoin or phenobarbital may significantly shorten the half-life of CBZ, whereas erythromycin administration with CBZ may result in a longer half-life and toxic CBZ plasma levels.2,3,4 Many other drugs may also affect the disposition of CBZ.2,3,4

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Clinical Signs and Symptoms

Adverse reactions resulting from therapeutic doses of CBZ have been well described. These effects include: gastrointestinal complaints, blood dyscrasias, Stevens-Johnson syndrome, hypotension, hypertension, arrhythmias, AV block, abnormalities in LFT's, SIADH, and neurologic manifestations such as nystagmus, ataxia, chorea, and tremor.5

Toxic manifestations of acute and massive CBZ ingestion have recently been described by several authors6-10; however, a prospective analysis has not been performed to date. Table 1 provides a summary of the common presentation and clinical course of an acute CBZ ingestion as described by Weaver et al.8

Table 1
Stage I serum CBZ level is often > 25 ug./ml.
Profound stupor or coma, sometimes requiring assisted ventilation (usually lasts < 24 hours); hypothermia; seizure activity may be noted, though this is rarely seen in patients who do not have a previous seizure history.
Stage II serum CBZ level is 15-25 ug./ml.
Moderately stuporous, becoming irritable and combative when aroused; choreiform movements or hallucinations may occur.
Stage III serum CBZ level is 11-15 ug./ml.
Mild drowsiness, but readily arousable; nystagmus, ataxia, and cerebellar signs are noted.
Stage IV serum CBZ level < 11 ug./ml.
Mild ataxia; may have normal neurologic exam; sudden and potentially catastrophic relapse to either of the above stages may occur.

As stated previously, the absorption of CBZ from the gastrointestinal tract is often erratic and delayed, especially when a large amount of the drug is ingested at once. This may be due, in part, to the anticholinergic actions of CBZ, resulting in a decrease in gastrointestinal motility and absorption. As the CBZ level decreases and peristaltic activity resumes, and increase in the amount of drug absorbed may lead to a relapse into an earlier stage.6 This is the proposed reason for the "cyclic coma" pattern observed in some patients.6,8,10

Exacerbation of seizure activity in children with seizure histories, who have acutely ingested carbamazepine, has been documented in the literature.14 Cardiovascular abnormalities, such as heart block and sinus tachycardia have also been reported by several authors.4,6,7,8,12

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Treatment

The mainstay of treatment is supportive. If the patient is not able to maintain respirations, intubation may be required. If the patient is hypotensive, fluids must be administered cautiously and the patient should be placed in the Trendelenburg position. Patients should be admitted to an ICU if they are symptomatic or have ingested several grams of CBZ, and serial CBZ plasma levels should be performed.2

Emesis induced by syrup of ipecac may benefit the patient the patient up to several hours after CBZ ingestion since it is slowly absorbed. Caution must be exercised; however, because of the risk of aspiration in a patient that is not alert or who has a previous seizure history.2 If the patient is obtunded, comatose,seizing, or has lost the gag reflex, gastric lavage is indicated (with intubation).

Multiple doses of activated charcoal with a cathartic should be given through the lavage tube or nasogastric tube until plasma CBZ levels are within the therapeutic range or do not appear to be continually rising.2 In severe overdoses, charcoal hemoperfusion has been used with mixed results.11,12 Successful hemoperfusion depends on the intrinsic metabolic capacity of the patient as well as the length of the hemoperfusion period. Metoclopramide has been used to increase gut motility in anticholinergic and related poisonings; however, its efficacy has not been established.2

Zuber et al recently report the successful administration of flumazenil, a benzodiazepine antagonist that is not approved for use in the United States, in an acute CBZ ingestion.13 Zuber's case, which documents a positive carbamazepine, but negative benzodiazepine toxicology screen, is the only such report to date. Further investigation into the use of flumazenil must be done before its efficacy is established.

Conclusion

As previously stated, the mainstay of therapy in an acute CBZ ingestion is supportive. The stages described provide a general guideline for the health care provider when treating the patient. Presently, there is no antidote for CBZ ingestion.

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