IMINOSTILBENE DERIVATIVE

Toxicology

Cabamazepne is an antiepileptic drug also used for treatment of trigeminal neuralgia, and bipolar affective disorder.
Its absorption is erratic with a peak plasma levels in 4-8 hours postingestion. The peak serum levels with controlled-release formulations of carbamazepine can result in peak for 96 hours postingetion. The onset of toxic effects are thus delayed.
Carbamazepine is metabolized by the cytochrome P450 system into active metabolites such as carbamazepine-10,11-epoxide which are conjugated with glucuronic acid before renal excretion. This active metabolite increases duration of the symptoms of toxicity.
The mechanism of action of carbamazepine reduces the propagation of abnormal impulses in the brain by blocking sodium channels. In this way,carbamazepine causes cardiac conduction disorder and central nervous system depression.
Because of its high lipid solubility it enters the brain rapidly.
Toxic effects after acute carbamazepine overdose are dose related and correlate well with serum levels. Ingestions of >20 mg/kg are associated with ataxia, nystagmus, mydriasis, movement disorders and the anticholinergic toxidrome. Ingestion of doses >50 mg/kg, plasma concentration >40 mg/l (170 mmol/l) is associated with more severe neurological effects such as coma, respiratory depression and seizures (Soderstrom et al., 2006).

Clinical manifestation

• Drowsiness
• Slurred speech
• A rapid heart rate (tachycardia)
• Low blood pressure (hypotension) or high blood pressure (hypertension
• Ataxia
• Hallucinations
• Nausea, vomiting
• Tremors
• Seizures
• Oliguria
• Nystagmus
• Hyperthermia
• Blurred vision or mydriasis
• Bullous skin formations
• Glucose disturbance

Clinical manifestation

• Patient who has had massive overdose should be observed for neurological deterioration in an intensive care area with ready availability of staff and equipment to carry out endotracheal intubation.
• Consider gastric lavage wiithin 1 hour of ingestion provided the airway can be protected by endotracheal intubation
• Administer intravenous fluids to counter hypotension
• Administer intravenous diazepam (5-10 mg, repeat q10-15min) to control seizures.
• The patient should be placed in left lateral decubitus position or by intubatedto protect the patient’s airway from aspirations.
• Administer activated charcoal as aqueous suspension or combined with a saline cathartic (eg sorbitol 70%) if the bowel sounds are present.
• Consider multiple doses of activated charcoal (1 g/kg) 4 hours to enhance total body clearance and elimination in the patient with significant toxicity
• Administe whole-bowel irrigation after ingestion of extended-release drug formulation at 1.5-2 L/h (20-30 mL/min) of polyethylene glycol electrolyte lavage solution or 0.5 L/h for young childen.
• Administer sodium bicarbonate Iv 1mEq/kg bwt for cardiotoxicity (QRS 100 msec)
• Haemoperfusion or hemodialysis can be carried out if there is persistently raised plasma carbamazepine levels and a potential for prolonged coma, seizures, cardiovascular instability or other adverse outcome not easily managed with supportive care exist

Note

Patients at risk for coma and aspiration of gastric contents may be intubated her pre‐emptively at the first sign of deterioration in level of consciousness. This would permit early and safe administration of activated charcoal via a nasogastric tube.
The drug’s relatively high molecular weight, high volume of distribution, and protein-binding aes a porcanidte for extracorporeal elimnations.

Soderstrom,J Murray,L Little,M and Daly,F F S (2006). Toxicology case of the month: carbamazepine overdose. Emerg Med J.; 23(11): 869–871. doi: 10.1136/emj.2006.034884.
Seymour, J.F. Drug-Safety (1993) 8: 81. https://doi.org/10.2165/00002018-199308010-00010.
Guneysel, O., Onur, O., Denizbasi, A. et al. J Med Case Reports (2008) 2: 242. https://doi.org/10.1186/1752-1947-2-242.
Yaylac S, Demir M V, Acar B, Sipahi S, and Ali Tamer (2012). Indian J Pharmacol. May-Jun; 44(3): 417–418. doi: 10.4103/0253-7613.96353

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