Table of Contents
DRUGS INCLUDED IN THIS CATEGORY
Carbamazepine is available in both standard and sustained release forms.
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. At high concentrations carabamazepine decrease presynaptic Acetylcholine release.
KINETICS IN OVERDOSE
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.
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 rangeing from 84% to 50% in one series. 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.
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).
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).
- 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)
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 abnormalities are unusual but comatose patients should have a 12 lead ECG and have cardiac monitoring while ventilated. 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).
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.
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)
Oral activated charcoal should be given to all patients, almost irrespective of how long it is since ingestion, since 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 may 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 thatlead to hypotension.
Treatment of specific complications
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).
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.
Atropine should be tried, followed by electrical pacing or pharmacological pacing with isoprenaline (isoproterenol).
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). High flux haemodialysis produces comparable clearance to charcoal haemoperfusion (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.
Apfelbaum JD, Caravati EM, Kerns WP, Bossart PJ, Larsen G. Cardiovascular effects of carbamazepine toxicity. Ann Emerg Med 1995; 25:631-635.
J J MacKichan, P K Duffner, and M E Cohen Salivary concentrations and plasma protein binding of carbamazepine and carbamazepine 10,11-epoxide in epileptic patients.Br J Clin Pharmacol. 1981 July; 12(1): 31–37 (full text)
Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol 1999; 37(6):731-751 (full text)
Buckley NA, Dawson AH, Reith DA. Controlled release drugs in overdose. Clinical considerations. Drug Safety 1995;12:73-84
Buckley NA, Newby DA, Dawson AH, Whyte IM. The effect of repackaging of carbamazepine on adult self-poisoning. Pharmacoepidemiology & Drug Safety 1995;4(6):351-354.
De Zeeuw RA, Westenberg HGM, Van der Kleijn E, Gimbrere JSF. An unusual case of carbamazepine poisoning with a near fatal relapse after two days. J Toxicol Clin Toxicol 1979; 14: 263-269.
Durelli L, Massazza U, Cavallo R. Carbamazepine toxicity and poisoning: Incidence, clinical features and management. Med Toxicol Adv Drug Exp 1989; 4:95-107.
Hardman JG, Gilman AG, Limbird LE. Gooodman and Gilman's The pharmacological basis of therapeutics 9th ed. 1996. McGraw Hill, New York.
Hojer J, Malmlund H-A, Berg A. Clinical features in 28 consecutive cases of laboratory confirmed massive poisoning with carbamazepine abuse. J Toxicol Clin Toxicol 1993;25:449-458.
Low CL, Haqqie SS, Desai R, Bailie GR. Treatment of acute carbamazepine poisoning by haemoperfusion. Am J Emerg Med 1996; 14: 540-1.
Morrow JI, Routledge PA. Poisoning by anticonvulsants. Adverse Drug Reactions & Acute Poisoning Reviews 1989;8:97-109
Seymour JF. Carbamazepine overdose. Features of 33 cases. Drug Safety 1993; 8:81-88.
Spiller HA, Carlisle RD. Status epilepticus after massive carbamazepine overdose. J Toxicol Clin Toxicol 2002;40(1):81-90
Spiller HA, Krenzelok EP. Carbamazepine overdose: Serum concentration less predictive in children. J Toxicol Clin Toxicol 1993;31:459-460.
Spiller HA, Krenzelok EP. Carbamazepine overdose: A prospective study of serum concentrations and toxicity. J Toxicol Clin Toxicol 1990;28:445-458.
Tibballs J. Acute toxic reaction to carbamazepine: clinical effects and serum concentrations. Journal of Pediatrics 1992;121:295-299.