WikiTox

Overview

Carbamazepine is a commonly prescribed anticonvulsant which acts via sodium channel blockade. It has further use for bipolar affective disorder and neuropathic pain.

Carbamazepine overdose is most commonly associated with neurotoxicity but is occasionally complicated by cardiovascular effects including arrhythmias in severe poisonings. Carbamazepine ingestion can result in ileus and pharmacobezoar formation, regardless of the preparation taken, which can lead to prolonged and even cyclical toxicity.

Supportive care and aggressive gastrointestinal decontamination are the mainstays of therapy. In more severe cases attempts at enhanced elimination with multi-dose charcoal or dialysis may be considered.

Oxcarbazepine, a related drug, has much lower toxicity, even when large ingestion are taken.

Mechanism of Toxic Effects

Carbamazepine is structurally similar to tricyclic antidepressants. In toxicity the most important effect is blockade of voltage-gated sodium channels, in a rate dependent manner. This has effects most prominently in the central nervous system and in more severe cases the cardiovascular system.

Carbamazepine toxicity results in anticholinergic effects, but unlike most other anticholinergic drugs, where this effect is mediated via competitive blockade of cholinergic receptors, carbamazepine has its effect by decreasing presynaptic acetylcholine release.

Risk Assessment

Carbamazepine toxicity is mediate both through the drug and its active metabolites. Carbamazepine induces it own metabolism and therefore carbamazepine naïve individuals tend to exhibit more toxic symptoms than those using it therapeutically.

Sedation is normally seen with doses >20mg/kg. The threshold for more severe toxicity, including need for intensive care admission, intubation and cardiac effects is classically reported as doses >50mg/kg. It is however unclear where this figure originated, and a more recent case series suggests that a dose of >100mg/kg is more predictive of these more severe manifestations.

Kinetics in Overdose

Absorption

Oral bioavailability of carbamazepine is high; however, it can clump easily in the stomach and has slow dissolution regardless of the formulation and thus peak concentrations can be significantly delayed.

In overdose, peak concentrations may occur after 24 hours or more, with peaks as late as 72 hours seen in very large overdoses of the sustained release preparation.

Carbamazepine can cause cyclical toxicity, due to its ability to induced ileus. When ileus is present, there is a temporary reduction in absorption of the drug from the gastrointestinal lumen. The drug concentration subsequently falls, with resultant improvement in gut motility and increased absorption of further drug from the gut. The resultant increase in drug concentration can again induce another period of ileus, until concentrations fall again.

Distribution

Carbamazepine distributes widely with a volume of distribution of 1.4 L/kg. It is about 75% bound to serum proteins but there is considerable variation ranging from 84% to 50% in one series.

Metabolism

Carbamazepine is primarily metabolised in the liver by CYP3A4. It is an inducer of many cytochrome P450 isoenzymes and therefore implicated in several drug interactions.

In chronic therapeutic use the half-life is between 10-20 hours, but is expected to be much longer in carbamazepine naïve patients as they lack the enzyme induction seen in chronic use

Carbamazepine is metabolised in the liver to carbamazepine-10, 11-epoxide. This metabolite is active as an anticonvulsant and contributes to many of the adverse effects observed in therapeutic use. Carbamazepine-10, 11-epoxide is 50% protein bound.

Elimination

Following hepatic metabolism, inactive metabolites of carbamazepine are excreted renally. Enterohepatic and enteroenteric recirculation can prolong elimination, particularly in overdose, contributing to delayed or multiple peaks in serum concentrations.

Clinical Effects

CNS: nystagmus, ataxia, dysarthria, delirium, agitation, respiratory depression, seizures and coma may all been seen with varying degrees of toxicity
CVS: tachycardia and hypotension due to peripheral vasodilatation are common. Arrhythmias including sodium channel blockade, heart block and ventricular fibrillation are rare
Gastrointestinal: Intermittent ileus, nausea, vomiting

Investigations

Serum carbamazepine concentrations: Measure serial concentrations every 6 -12 hours in those with sedation. Given slow absorption, early levels are usually expected to rise further. Clinical effects associated with specific levels are shown in the table below.

Serum Concentration	Clinical Effects
5-12 mg/L	Therapeutic range
12-20 mg/L	Sedation, ataxia, nystagmus
20-40 mg/L	Progressive worsening of CNS effects
>40 mg/L	Coma, seizures, respiratory depression, cardiovascular toxicity

Serum electrolytes and renal function
Bloods gas
ECG

Differential Diagnosis

The differential diagnosis is of any drug that causes profound sedation. Complications of epilepsy (e.g. status epilepticus, head injury) or carbamazepine therapy (e.g. hepatic coma, hyponatraemia) should also be considered.

Treatment

Supportive Care

Airway and breathing

In large overdoses, coma may lead to compromised airway or breathing and require intonation.

Circulation

Hypotension is common and mostly related to sedation induced vasodilatation and dehydration rather than direct cardiac effects. First line treatment for hypotension is IV fluids. If hypotension is unresponsive to fluid expansion initiate a vasopressor.

Sedated patients, and those ingesting >50mg/kg should remain on continuous cardiac monitoring.

If there is evidence of QRS widening (uncommon) then treat with sodium bicarbonate to achieve serum alkalinisation.

Seizures

Paradoxical seizures can happen with high carbamazepine levels. They are often short lived and self-terminating. If they are persistent or recurrent treat along standard lines, starting with an intravenous benzodiazepine.

Decontamination

Offer oral activated charcoal to all patients who have taken a carbamazepine overdose, if they are able to take it. This is somewhat irrespective of the time since since ingestion, due to carbamazepine’s delayed and prolonged absorption.

Give: 50g Activated Charcoal (Child: 1g/kg, max 50g)

Whole bowel irrigation can be considered when patients present early, in massive ingestion. However, impaired gastric motility/ileus risk can preclude this. Discuss with a clinical toxicologist.

Endoscopic retrieval can also be considered in those with a large tablet burden, presenting early.

Enhanced Elimination

MDAC

Multidose activated charcoal can enhance elimination, however due to the decreased gut motility associated with carbamazepine, MDAC tolerance may be limited. Neostigmine can be considered in those with ileus to improve tolerance. Consider in ingestions >50mg/kg who present early. Discuss with a clinical toxicologist

Dialysis

Extracorporeal treatments can increase clearance of carbamazepine, but this is likely comparable to the clearance achieved by MDAC.

Consider in patients with a level >60mg/L or those with severe cardiac toxicity.

Carbamazepine naïve patienst i.e. those who do not have enzyme induction would be expected to benefit greater than those on chronic carbamazepine therapy.

Antidote

There is not a specific antidote the carbamazepine toxicity

Observation and Disposition

Patients with significant neurotoxicity or cardiotoxicity will need care in a high dependency or intensive care environment.

Any patient who has ingested more than 50mg/kg, or children who ingest > 20mg/kg, should be observed with ECG monitoring, for a minimum of 12 hours. Ideally 2 serum carbamazepine concentrations would be measured over that time, to ensure the level is not rising. Timely serum concentrations are not always practicable, and in such case, clinical assessment is likely sufficient.

Carbamazepine

Table of Contents