Symptoms & Treatment Of Carbamazepine Toxicity

Carbamazepine is an orally administered, anticonvulsant used in the treatment of seizure disorders, as well as nonepileptic conditions related to neuropathic pain. Carbamazepine may also be used in the treatment of schizophrenia and bipolar disorder (Khalili and Murphy, 2018). The current therapeutic range of carbamazepine concentrations in plasma is 5-10 µg/mL in adults, when used for the treatment of seizures (Panday, D.R., et al. 2017).

The drug’s primary mechanism of action is thought to be through the inhibition of voltage-gated sodium channels in neuronal membranes, resulting in the channels being unsusceptible to depolarization and in turn neuronal firing (Gierbolini, et al. 2016). Carbamazepine overdose is not uncommon. In 2014, there were 1880 documented cases of carbamazepine toxicity, according to the American Association of Poison Control Centers report. Of the 1880 overdose cases, 57% were unintentional in nature (Khalili and Murphy, 2018). Because majority of overdoses are unintentional, studying carbamazepine from a toxicological perspective is meaningful and can aid clinicians at better determining a safe dose for individual patients.

Toxicokinetics

Absorption of carbamazepine by the body is slow (Pynnonen, S., 1979). In patients taking a therapeutic dose, peak concentrations in plasma can be observed 6-24 hours after ingestion, however in cases of overdose, peak levels may not be reached for up to 72 hours following ingestion (Mochizuki et al. 2016). As such the length of absorption time usually delays onset of acute overdose symptoms (Khalili and Murphy, 2018).

Carbamazepine is extensively metabolised in the liver by Cytochrome P4503A4 (Panday, D.R., et al. 2017). The main metabolite produced from oxidation of CBZ is carbamazepine-10,11-epoxide (3), which shares the same therapeutic and toxic effects as the parent drug (Ambrosio A.F., et al. 2001). Carbamazepine is an auto-inducer, meaning it induces the hepatic enzymes needed for its own metabolization (Panday, D.R., et al. 2017).

Clearance rates of carbamazepine increase with repetitive exposure to the drug due to autoinduction. As a result, the half-life of carbamazepine is initially about 30 hours after the first dose (Khalili and Murphy, 2018), but diminishes to 4 to 12 h following subsequent doses (Tolou-Ghamari, Z., et al. 2013). Because of autoinduction, the intended dose of the drug cannot be given initially, but rather gradually increased over time.

Mechanism of Toxicity

A study done in 2002, by Ambrosio A.F., et al, found that carbamazepine does not act by a single mechanism, but rather, is complex and exerts its effects on various levels (channels, receptors, signalling pathways). However, despite the degree to which these mechanisms contribute to a specific therapeutic or toxic effect is still largely unknown, multiple factors have been identified as potential contributors to carbamazepine toxicity. The active metabolite, carbamazepine-10,11-epoxide (3), is thought to contribute to toxic effects (Khalili and Murphy, 2018). One study found there to be a prolongation of CBZ half-life and elevated concentrations of the active metabolite, carbamazepine-10,11-epoxide (3), in five cases of overdose (Weaver D.F., et al, 1988).

Furthermore, studies in pharmacogenetics have identified an allele which carries an increased risk for developing carbamazepine induced, life-threatening, cutaneous disorders, Stevens-Johnson syndrome and toxic epidermal necrolysis (Ferrell P. B., and McLeod H. L., 2008) Patients with the HLA allele B*1502 who use carbamazepine are at a significant risk of developing either potentially fatal conditions. As such, the FDA recommends genotyping at risk populations (Asians) for the HLA allele B*1502 before administering carbamazepine (Farrell, P.B., et al. 2009).

Clinical Presentation of Acute Toxicity

There is some degree of correlation between plasma free carbamazepine levels and symptomatology, with higher concentrations often relating to an increase in symptom severity (Panday, D.R., et al, 2017). However, it is important to note that even doses within the therapeutic range can cause toxicity, and because of the drugs slow absorption, even severe signs may not occur immediately (Tolou-Ghamari, Z., et al. 2013). Symptoms of toxicity range from mild to life threatening. CNS effects are most common in cases of CBZ overdose and have been known to occur even at concentrations on the upper end of the therapeutic range (Tolou-Ghamari, Z., et al. 2013).

Common toxic neurologic effects include drowsiness, slurred speech, ataxia, vertigo, and tremor. Such CNS effects have been known to occur at concentrations greater than 9 µg/mL (Tolou-Ghamari, Z., et al. 2013), along with vomiting. In more severe cases of overdose, CNS effects may include agitation and hallucinations, followed by the potential for generalized seizures. Carbamazepine induced seizures during overdose are associated with increased mortality, and may occur in up to 34% of patients, including those without a history of seizures (Tolou-Ghamari, Z., et al. 2013). Life-threatening effects of acute CBZ toxicity include coma, which may occur with or without respiratory depression (Panday, D.R., et al, 2017).

Other symptoms may occur with acute intoxication. Cardiotoxicity is commonly observed in cases of carbamazepine overdose, and may present clinically as sinus tachycardia, bradycardia, and ventricular fibrillation. The risk for cardiotoxicity in carbamazepine overdose is higher in patients with a history of cardiovascular problems, however can be observed in patients with no prior abnormal cardiac history (Tolou-Ghamari, Z., et al. 2013). Anticholinergic effects are not uncommon with CBZ toxicity (Khalili and Murphy, 2018). Hepatic toxicity may include asymptomatic elevation of transaminases, and in severe cases hepatitis or pancreatitis may occur (Tolou-Ghamari, Z., et al. 2013). In cases of large ingestion, bezoars may remain in the gastrointestinal tract for prolonged periods of time (Ford M.D., et al. 2001).

Treatment

There is no antidote for carbamazepine toxicity (Ford M.D., et al. 2001). Following an initial assessment, treatment should be aimed at stabilization and decontamination. During this time, it is important to continue observing the patient for signs of neurological deterioration, as well as measure serial carbamazepine levels routinely (Khalili and Murphy, 2018). Carbamazepine is well absorbed to activated charcoal, administered at 1g/kg orally (Ford M.D., et al. 2001) causing an increase in rate of elimination of CBZ.

In addition, gastric lavage can be used in patients who are presumed to have ingested significant quantities of the drug, even hours after ingestion due to the drugs slow rate of absorption (Ford M.D., et al. 2001). Additional symptoms of CBZ toxicity must also be treated as presented. Intravenous benzodiazepines can be used in the treatment of seizures; however, this may increase the risk of additive respiratory depression, and as such clinicians should be prepared to treat possible respiratory depression (Ford M.D., et al. 2001).

Carbamazepine induces its own hepatic metabolism. After a single dose, concentrations in the blood according to base-line clearance and half-life. After multiple doses, clearance increases, and half-life decreases. Because of this change in pharmacokinetics, the ultimate desired dose cannot be given initially. Additional autoinduction occurs with subsequent increases in dose (Tolou-Ghamari, Z., et al. 2013). Carbamazepine concentrations in plasma following an acute overdose with seizures and treatment with 10g of activated charcoal. Treatment with activated charcoal is indicated by MDAC.

References:

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