Carbamazepine

DRUGS INCLUDED IN THIS CATEGORY

Carbamazepine is available in both standard and sustained release forms.

OVERVIEW

Carbamazepine overdose most commonly leads to prolonged coma but is occasionally complicated by arrhythmias. Absorption is

often delayed and pharmacobezoar formation is common even with standard release preparations. The treatment is with

aggressive gastrointestinal decontamination, even in late presenters, and respiratory support. Cardiac complications should

be treated similarly to those associated with TCA poisoning. Clearance of carbamazepine may be enhanced with repeated doses

of activated charcoal or charcoal haemoperfusion but the clinical benefit from this is doubtful.

MECHANISM OF TOXIC EFFECTS

Carbamazepine blocks voltage-gated sodium channels in a rate dependent manner. It has numerous other pharmacological actions

at both therapeutic and overdose concentrations which are of unclear significance (Hardman et al, 1996). The CNS and

cardiovascular effects observed in overdose may be related to the sodium channel blocking effect, although the toxicity of

carbamazepine is different from other drugs whose toxicity is attributed to such effects.

KINETICS IN OVERDOSE

Absorption

Absorption is slow and erratic after the standard release preparation even in therapeutic doses with peak concentrations

occurring between 4 to 8 hours. The kinetics of the sustained release formulation are much the same in therapeutic doses. In

overdose, clumping of tablets into a pharmacobezoar is common and peak concentrations after both preparations may occur after

24 hours or more, with peaks as late as 72 hours seen in very large overdoses of the sustained release preparation.

Distribution

Carbamazepine distributes widely with a volume of distribution of 1.4 L/kg. It is about 75% bound to serum proteins. These

factors mean it is possible to significantly increase elimination with haemoperfusion.

Metabolism - Elimination

The elimination half-life of carbamazepine is 10 to 20 hours in chronic therapeutic doses. However, as there is considerable

enzyme induction with chronic use, the half-life may be much longer in naive individuals. Carbamazepine is metabolised in the

liver, primarily by the enzyme epoxide reductase to carbamazepine 10-11 epoxide (Hardman et al, 1996). This metabolite is

active as an anticonvulsant and accounts for many of the adverse effects in therapeutic use.

CLINICAL EFFECTS

Central nervous system effects

The most common effects are related to disturbance of neuronal transmission. At concentrations just above the therapeutic

range, nystagmus, ataxia, and sedation occur. As concentrations increase horizontal and vertical nystagmus, dysarthria,

delirium, and profound ataxia progress to deep coma often requiring ventilation. Paradoxical seizures may occur at high

carbamazepine concentrations (Spiller & Carlisle, 2002).

Cardiac effects

Hypotension is common but is likely to be due to CNS effects and dehydration rather than direct cardiac effects in most

cases. ECG changes, heart block and ventricular arrhythmias may occur, and indicate a severe overdose (Apfelbaum et al, 1995;

Hojer et al, 1993).

INVESTIGATIONS

Blood concentrations

Conversion factor

• mg/L x 4.23 = micromol/L
• micromol/L x 0.236 = mg/L

Carbamazepine concentrations should be monitored in patients who are symptomatic. concentrations may rise for many days and

correlate reasonably well with the clinical effects. The concentration of other anticonvulsants the patient is on should be

monitored.

The therapeutic range is usually quoted as 4 to 10 microg/mL (15 to 40 micromol/L). At concentrations just above the

therapeutic range (10 to 20 microg/mL; 40 to 85 micromol/L) nystagmus, ataxia and sedation occur. Concentrations of 20 to 40

microg/mL (85 to 170 micromol/L) are associated with horizontal and vertical nystagmus, dysarthria, and the patient is

generally unable to walk unaided, Some patients may have delirium, coma, require ventilation or have (paradoxical) seizures.

Coma and profound respiratory depression are usual with concentrations greater than 40 microg/mL (170 micromol/L) and

life-threatening arrhythmias are much more common above such concentrations (Hojer et al, 1993; Spiller et al, 1990).

Children may develop toxicity at lower concentrations than adults (Spiller et al, 1993)

Biochemistry

Electrolyte abnormalities may occur in carbamazepine overdose and these should be measured in patients with coma.

Hyponatraemia due to SIADH has been reported with chronic use, the clinical features of which could conceivably be mistaken

for carbamazepine intoxication.

ECG

ECG abnormalities are unusual but comatose patients should have a 12 lead ECG and have cardiac monitoring while they require

ventilation. Heart block, increased QRS width, and ventricular arrhythmias have been observed in carbamazepine overdose.

These have generally been observed in patients with profound sedation and concentrations greater than 40 microg/mL (170

micromol/L) (Hojer et al, 1993; Apfelbaum et al, 1995).

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

Maintenance of the airway and ventilation is the first priority in unconscious overdoses. IV access with IV fluids (normal

saline) should be secured as soon as possible in order to have access for the treatment of seizures or arrhythmias. The

following should indicate the need for intensive care admission:

• Large overdose (>3,000 mg)
• concentrations above 30 microg/mL (120 micromol/L) or rapidly rising concentrations
• Need for intubation or ventilation (GCS < 9; high pCO2; for decontamination, etc.)
• Abnormal ECG (QRS > 100 ms, PR > 200 ms or heart block, arrhythmias)

GI Decontamination

Oral activated charcoal should be given to all patients, almost irrespective of how long it is since ingestion, as

carbamazepine is very slowly absorbed and delays gastric emptying. Polyethylene glycol (whole bowel irrigation) should be

given to patients who ingest large overdoses (> 10 tablets) or who have ingested controlled release preparations. Repeat dose

activated charcoal should also be given. Patients may often require endotracheal intubation to safely administer such

treatments and gastric lavage mat be considered if this is the case. Generous fluid replacement (normal saline) to counteract

the volume depletion associated with gastrointestinal decontamination is particularly important in overdose with drugs that

lead to hypotension.

Treatment of specific complications

Seizures

Seizures should be treated with intravenous benzodiazepines (in adults: diazepam 5 to 10 mg, repeated if necessary every 15

to 20 minutes). Phenobarbitone (15 mg/kg) can be used if seizures are refractory to benzodiazepines. The use of other

anticonvulsants, such as phenytoin, is not recommended due to the similar toxic and pharmacological effects these drugs share

with carbamazepine. Seizures may be very resistant to therapy and may require multiple drug therapy (Spiller & Carlisle,

2002).
Arrhythmias

Ventricular arrhythmias and heart block are the usual cause of in-hospital deaths. Ventricular arrhythmias should be treated

with either overdrive pacing or lignocaine. Other class I antiarrhythmic drugs, magnesium and beta-blockers are likely to

exacerbate cardiac toxicity (convert ventricular arrhythmias into asystole). Amiodarone or bretylium could be considered on

theoretical grounds, although experience with both of these drugs in drug-induced arrhythmias is very limited.
Heart block

Atropine should be tried, followed by electrical pacing or pharmacological pacing with isoprenaline (isoproterenol).

Elimination enhancement

Multiple doses of activated charcoal moderately increase the clearance of carbamazepine (Bradbury & Vale, 1995). Charcoal

haemoperfusion may also increase clearance although by no more than repeated doses of charcoal (assuming these are tolerated)

(Low et al, 1996). Carbamazepine has a relatively short half-life in patients on regular carbamazepine and clearance is

unlikely to be significantly enhanced in such individuals. However, patients who have not had their enzymes induced by

carbamazepine (i.e. have not been on treatment or have been so for less than 2 to 3 weeks) may have their half-life roughly

halved with either of these methods. Repeated doses of charcoal (and perhaps polyethylene glycol) should be given to all

patients who have ingested a large overdose and can tolerate this therapy.

LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP

Long term sequelae have not been reported and no follow up is required after resolution of the clinical signs & ECG findings

unless the patient has been profoundly hypotensive.

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