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Chapter: Modern Medical Toxicology: Neurotoxic Poisons: Anticonvulsants and Antiparkinsonian Drugs

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Carbamazepine - Anticonvulsant (Anti-Epileptic) Drug

Carbamazepine (5H-dibenzazepine-5-carboxamide) is a carba- mylated derivative of iminostilbene and is chemically as well as stereospatially related to the tricyclic antidepressants. and tonic-clonic seizures.

Carbamazepine

Carbamazepine (5H-dibenzazepine-5-carboxamide) is a carba- mylated derivative of iminostilbene and is chemically as well as stereospatially related to the tricyclic antidepressants. and tonicclonic seizures.

Uses

·              Carbamazepine is very useful in the treatment of partial It is also employed in the management of trigeminal neuralgia and bipolar affective disorder (manic-depressive psychosis).

·              Other uses include unipolar depression, schizoaffective illness, resistant schizophrenia, dyscontrol syndrome associated with limbic system dysfunction, intermittent explosive disorder, post-traumatic stress disorder and atypical psychosis.

·              There are also reports of beneficial effects in the manage- ment of alcohol, cocaine and benzodiazepine withdrawal, restless legs syndrome, nonneuritic pain syndromes, neurogenic or central diabetes insipidus, and hereditary and nonhereditary chorea in children.

Toxicokinetics

■■Absorption following oral administration is erratic, and it may take upto 24 hours for peak levels to occur. Most of the absorbed carbamazepine is metabolised to an epoxide, conjugated with glucuronic acid and excreted in the urine.

■■Carbamazepine is 75% protein bound and its epoxide metabolite is approximately 50% protein bound.

■■Following an oral dose of carbamazepine, about 72% is excreted in urine; 1 to 2% is unmetabolised drug. Approximately 15 to 30% of an oral dose of carbamazepine is excreted in faeces.

Drug Interactions

■■Erythromycin interferes with carbamazepine metabolism; concurrent administration of the two drugs has caused carbamazepine toxicity.

■■Isoniazid will slow the metabolism of carbamazepine and increase serum levels.

■■Drugs expected to increase carbamazepine half-life and plasma concentration by inhibition of its metabo-lism include the following: cimetidine, clarithromycin, desipramine, dextropropoxyphene (propoxyphene), diltiazem, erythromycin, fluconazole, fluoxetine, fluvox-amine, isoniazid, ketorolac, lamotrigine, metronidazole, nefazodone, niacinamide, omeprazole, rifampicin, sertra-line, terfenadine, ticlopidine, trazodone, valproic acid, and verapamil.

■■   The combination of lithium and carbamazepine has been reported to result in an interaction consisting of neurotoxic manifestations of tiredness, tremors, abnormal gait, and unsteadiness.

Clinical (Toxic) Features

·      Acute carbamazepine toxicity manifests as nausea, vomiting, hypotension, tachycardia, cardiac conduc-tion anomalies (sinus tachycardia, bradyarrhythmia, a-v conduction delay), mydriasis, nystagmus, ataxia, dysarthria, dystonia, myoclonus, choreoathetosis, encephalopathy, hallucinations, drowsiness, respiratory depression, and coma which may be preceded by convulsions. Cyclic coma may occur, possibly due to delayed absorption. Delayed onset of coma may occur following overdose of controlled-release carbamazepine.

·              Bullous lesions resembling barbiturate-induced bullous eruption has been reported.

·              Urinary retention may occur as an anticholinergic effect.

·              Cardiovascular effects are inconsistent and may not be clinically significant. Severe hypotension has been reported following overdose; it is not common, but is indicative of severe poisoning.

·              Hypothermia may occur following acute overdose and last up to 10 hours. Hyperthermia is a less common occurrence.

·              Death may result from cardiovascular toxicity, aspira-tion pneumonitis, hepatitis, or aplastic anaemia.

 

Chronic poisoning is characterised by recurrent headache, diplopia, ataxia, vertigo, haematological disturbances (neutropenia, pancytopenia, thrombocytopenia, aplastic anaemia, agranulocytosis), and hypersensitivity reactions (dermatitis, eosinophilia, lymphadenopathy, splenomegaly).

·              Progressive ataxia, resulting in difficulty in walking, is common following carbamazepine toxicity.

·              Hepatitis has been reported after chronic therapy.

·              Short-term therapy with carbamazepine has been associated with Stevens Johnson Syndrome and toxic epidermal necrolysis in a case-control study and appears to be a risk factor. The risk is largely confined to the start of carbamazepine therapy.

·              Therapeutic doses of carbamazepine in men appears to decrease the bioactivity of androgens, thus possibly affecting reproduction.

·              Carbamazepine has been reported to cause an unusual idiosyncratic reaction of antiepileptic hypersensitivity syndrome in some patients. Manifestations include fever, rash, lymphadenopathy, eosinophilia, lymphocy-tosis, elevated ESR, coagulopathy and hepatotoxicity.

·              If unrecognised and untreated, this syndrome can be fatal.

·              There are indications that carbamazepine is teratogenic and can cause spina bifida, congenital heart disease, diaphragmatic hernia, digital hypoplasia, and hydro-nephrosis. Facial abnormalities and growth retardation have also been reported. Other reported abnormalities include anal atresia, meningomyelocele, ambiguous genitalia, hypertelorism, cleft lip, congenital hip dislo-cation, and inguinal hernia.

Diagnosis

·              Diagnosis of carbamazepine poisoning is based on blood levels of the drug. Therapeutic concentrations vary between 4 and 12 mcg/ml (17 and 51 micromol/L). Ataxia and nystagmus may occur at levels greater than 12 mcg/ml. Levels above 40 mcg/ml are potentially fatal. Children are susceptible at lower levels.

·              Seizures, coma, and severe respiratory depression following large ingestions independently predict a poor prognosis. Ingestion of greater than 24 grams is also a predictor of poor prognosis in adults.

·              Patients with rising serum levels have been reported to have a coagulum of undigested tablets, which may be visualised on abdominal X-ray with contrast media

Treatment

·            Multiple-dose activated charcoal.

·            Stomach wash.

·            Cardiac monitoring: hypertonic sodium bicarbonate may help in reversing some of the electrocardiographic anomalies.

·            Endotracheal intubation and assisted ventilation.

·            Correction of hypotension, electrolyte abnormalities, and oliguria. For hypotension, infuse 10 to 20 ml/kg of isotonic fluid and place in Trendelenburg position. If hypotension persists, administer dopamine or noradrena-line. Consider central venous pressure monitoring to guide further fluid therapy.

·            For rhabdomyolysis: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be needed to maintain urine output. Urinary alka-linisation is NOT routinely recommended.

·            Treatment of convulsions. Attempt initial control with a benzodiazepine (diazepam or lorazepam). If convulsions persist or recur administer phenobarbitone.

·            Hypothermia should be managed by gradual rewarming.

·            Charcoal haemoperfusion is said to be effective in elimi-nating the drug. However, forced diuresis, haemodialysis, and peritoneal dialysis are not benefiial.

·            Flumazenil may help in reversing the coma (temporarily).

Forensic Issues

·              Like many other drugs in its category, carbamazepine is not infrequently involved in deliberate suicidal overdose.

·              Munchausen syndrome by proxy has also been reported with this drug.

 

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