Link to [[:wikitox:3.4.2.3_carbamazepine_teaching_resources|3.4.2.3 Carbamazepine Teaching Resources]]\\ Link to [[:wikitox:problems_for_discussion_2_anticonvulsants_carbamazepine|Problems for Discussion]] ---- ====== 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 [[:wikitox:3.4.3.1_cardiac_arrhythmias_and_cardiac_arrest|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 [[:wikitox:2.1.11.9.2.1_tricyclic_antidepressants|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 ==== 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 but there is considerable variation rangeing from 84% to 50% in one series. These factors mean it is possible to significantly increase elimination with [[:wikitox:3.2.3.1.2_charcoal_haemoperfusion|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 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). ===== 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 ([[:wikitox:gcs|GCS]] < 9; high pCO2; for decontamination, etc.) * abnormal ECG (QRS > 100 ms, PR > 200 ms or heart block, arrhythmias) ==== GI Decontamination ==== Oral [[:wikitox:3.2.2.2.3_activated_charcoal|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 ([[:wikitox:3.2.2.2.4_whole_bowel_irrigation_lavage|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 [[:wikitox:3.2.2.2.2_gastric_lavage|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 === [[:wikitox:status_epilepticus_and_treatment_of_seizures|Seizures]] should be treated with intravenous [[:wikitox:benzodiazepines|]] (in adults: diazepam 5 to 10 mg, repeated if necessary every 15 to 20 minutes). [[:wikitox:barbiturates|Phenobarbitone]] (15 mg/kg) can be used if seizures are refractory to benzodiazepines. The use of other anticonvulsants, such as [[:wikitox:2.1.11.2.1_phenytoin|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 [[:wikitox:3.4.3.4_antiarrhythmics|class I antiarrhythmic drugs]], [[:wikitox:magnesium_treatment|magnesium]] and [[:wikitox:3.4.3.4.2_beta_blockers|beta-blockers]] are likely to exacerbate cardiac toxicity (convert ventricular arrhythmias into asystole). [[:wikitox:3.4.3.4.3_amiodarone|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 ==== [[:wikitox:3.2.2.2.3.1_repeated_doses_of_activated_charcoal|Multiple doses of activated charcoal]] moderately increase the clearance of carbamazepine (Bradbury & Vale, 1995). [[:wikitox:3.2.3.1.2_charcoal_haemoperfusion|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. ===== REFERENCES ===== [[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7741340&dopt=Abstract|Apfelbaum JD, Caravati EM, Kerns WP, Bossart PJ, Larsen G.]] Cardiovascular effects of carbamazepine toxicity. 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