Karbamezepin (Tegretol)

Clinical Effects:

CARBAMAZEPINE
  • USES: Carbamazepine is used as an antiepileptic and for pain disorders and a range of psychiatric diagnoses. PHARMACOLOGY: Carbamazepine and its metabolite decrease repetitive action potential firing in the CNS via sodium channel inactivation. TOXICOLOGY: Toxic effects are due to the drug’s anticholinergic activity, sodium channel blockade, CNS depression, and myocardial depressant properties. EPIDEMIOLOGY: Poisoning is common and there are several deaths each year from carbamazepine poisoning. MILD TO MODERATE TOXICITY: Common initial signs of toxicity are nystagmus, ataxia, hyperreflexia, CNS depression, dystonia, sinus tachycardia, and mild anticholinergic symptoms such as mydriasis, delirium/encephalopathy, and decreased bowel sounds. These symptoms may occur with chronic supratherapeutic serum concentrations or acute overdoses. Patients will commonly experience nausea and vomiting after acute overdose. Less common effects include hepatotoxicity and hyponatremia secondary to syndrome of inappropriate ADH secretion due to vasopressin secretion. These effects are more common with chronic therapy. The onset of symptoms may be delayed 1 to 3 hours following the ingestion of extended release carbamazepine. SEVERE TOXICITY: Manifestations of severe toxicity include coma, seizures, and respiratory depression. Rhabdomyolysis and renal failure may occur rarely following large overdoses. Severe cardiac toxicity generally occurs at doses greater than 60 g and may include decreased myocardial contractility, pulmonary edema, hypotension, dysrhythmias and conduction delays including PR, QRS and QTc prolongation. ADVERSE EFFECTS: Patients may develop hypersensitivity reactions, dystonic reactions, rashes, exacerbation and development of cardiac dysrhythmias, cytopenias, transaminitis, pancreatitis, and the manifestations of mild toxicity with chronic therapy when levels are therapeutic or when above the therapeutic range. Adverse reactions are common.

Range of Toxicity:

CARBAMAZEPINE
  • TOXICITY: Patients may develop mild signs of toxicity at therapeutic doses and serum drug concentrations should be monitored when symptoms are consistent with toxicity. Lowest reported fatal ingestions in an adult was 3.2 g, and in a toddler was 1.6 g. Adults have survived ingestions of 40 g with intensive supportive care. Peak serum levels less than 30 mcg/mL are generally associated with mild to moderate toxicity, while peak levels above 40 mcg/mL may be associated with coma, seizures, and hypotension. Children may have more severe effects at lower serum levels. A 7-year-old boy became comatose after ingesting 2000 mg (100 mg/kg). THERAPEUTIC DOSE: Adult: 400 to 1600 mg/day depending on indication. Pediatric: Up to 6 years of age: 10 to 35 mg/kg day. Age 6 to 12 years: 200 to 1000 mg/day depending on indication. Therapeutic concentrations are in the range of 4 to 12 mg/L.

Treatment:

CARBAMAZEPINE
  • Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Treatment of mild to moderate toxicity is largely supportive. Sinus tachycardia should be treated with fluid resuscitation and benzodiazepines for anticholinergic symptoms. Dystonic reactions can be treated with anticholinergic medications, such as diphenhydramine 25 mg, or benzodiazepines if the patient is also exhibiting signs of anticholinergic toxicity (ie, mydriasis, delirium, flushing, dry mucous membranes, decreased bowel sounds, and urinary retention). Adverse reactions to chronic therapy such as transaminitis or cytopenia should be treated by discontinuation of the medication. MANAGEMENT OF SEVERE TOXICITY: Supportive care is the mainstay of treatment. Specific interventions based on the system of toxicity are as follows: CNS: Mental status depression may require airway protection. Coma should be treated with airway management and supportive care. Seizures should be treated with benzodiazepines as first-line therapy followed by barbiturates or propofol. Agitated patients should be treated with benzodiazepines, large doses may be required. CARDIOVASCULAR: Hypotension should be treated with isotonic fluids. If unresponsive to 2 or more liters of fluid, vasopressor agents, such as norepinephrine or phenylephrine, should be administered. In rare cases, cardiopulmonary bypass or aortic balloon pump may be used to maintain perfusion while carbamazepine is metabolized. QRS widening (progressive widening on serial ECGs or a single ECG with a QRS duration longer than 140 msec) should be treated with sodium bicarbonate boluses of 50 mEq (CHILD: 1 to 2 mEq/kg of sodium bicarbonate) until the QRS narrows. The serum pH should be maintained between 7.4 and 7.55. RESPIRATORY: Intubation and mechanical ventilation should be considered for respiratory depression. GASTROINTESTINAL: Severe nausea and vomiting should be treated with antiemetics, preferably agents without additional anticholinergic activity (eg, ondansetron). RENAL: Urinary retention is due to anticholinergic effects and should be treated with catheterization. Urine output should be maintained above 30 mL/hr because the metabolites are primarily renally cleared. Acute renal failure is due to hypotension or rhabdomyolysis and should be treated with liberal fluid administration.
  • Decontamination: PREHOSPITAL: Because of the risk of CNS depression and subsequent aspiration, prehospital decontamination should generally be avoided. HOSPITAL: Activated charcoal should be considered in asymptomatic patients who are likely to have medication remaining in their GI tract, or in symptomatic patients who have a secure airway. Whole bowel irrigation may be considered for patients with severe toxicity involving ingestion of a large amount of a sustained release formulation. Gastric lavage may be considered for very large overdoses (on the order of 40 g or more) presenting early, though airway protection should be considered prior to the procedure.
  • Airway management: May be necessary for airway protection in cases of prominent CNS depression, seizures or significant respiratory depression.
  • Antidote: There is no specific antidote for carbamazepine toxicity.
  • Monitoring of patient: Monitor mental status, pulse oximetry, and initiate continuous cardiac monitoring. Obtain an initial carbamazepine serum concentration every 4 hours until the concentration has peaked and is clearly declining. An ECG should be obtained upon initial evaluation and repeated every hour initially following a significant overdose. A basic metabolic panel should be obtained to evaluate serum sodium, potassium, and creatinine. Blood dyscrasias can be monitored with a CBC. An ABG should be obtained in patients with significant respiratory depression. Creatinine kinase should be measured in patients with prolonged coma or seizures. Carbamazepine will cause a false positive for tricyclic antidepressant on many urine drug screens.
  • Enhanced elimination procedure: MULTIPLE DOSE ACTIVATED CHARCOAL (MDAC) increases clearance of carbamazepine, but it has not been shown to improve clinical outcomes. If MDAC is initiated, 50 g of activated charcoal without sorbitol should be administered every 4 to 6 hours for a total of 24 hours; MDAC should NOT be continued in a patient who develops an ileus. HEMOPERFUSION or HIGH FLUX HEMODIALYSIS may be useful in acutely decreasing serum concentrations in a severe, life-threatening overdose.
  • Patient disposition: HOME CRITERIA: All suicide attempts should be referred to a health care facility. Asymptomatic patients with inadvertent ingestion of therapeutic doses may be observed at home. OBSERVATION CRITERIA: Patients with deliberate or large ingestions should be observed for at least 6 to 8 hours (OR 12 to 24 hours if a sustained release formulation is ingested), until serial carbamazepine concentrations have clearly peaked and are declining due to erratic absorption of the drug. Patients who develop significant symptoms should be admitted. ADMISSION CRITERIA: Patients with severe toxicity or those that are not able to ambulate safely should be admitted until symptoms resolve. CONSULT CRITERIA: A toxicologist should be consulted for patients with severe toxicity.