Karvedilol

Clinical Effects:

CARVEDILOL
  • USES: Myocardial infarction, angina pectoris, heart failure, and hypertension. PHARMACOLOGY: Carvedilol is a non-selective beta-adrenergic blocking agent with alpha 1-adrenergic blocking activity and no intrinsic sympathomimetic activity. The beta-adrenergic blocking activity of carvedilol decreases cardiac output, exercise-induced tachycardia, and reflex orthostatic tachycardia. The alpha 1-adrenergic blocking activity of carvedilol causes vasodilation and reduces peripheral vascular resistance. The effect of alpha 1-adrenergic blockade is a reduction in standing blood pressure (more than supine). TOXICOLOGY: Bradycardia and hypotension are the most common effects in beta blocker overdose, and have been reported after carvedilol overdose. The additional component of alpha-1 blocking activity of carvedilol may predispose patients to more pronounced episodes of hypotension. EPIDEMIOLOGY: Poisoning is uncommon but can be severe. MILD TO MODERATE POISONING: Mild hypotension, orthostatic hypotension, dizziness, syncope, and bradycardia. SEVERE POISONING: More severe bradycardia and hypotension, AV dissociation and QRS widening. ADVERSE EFFECTS: Weakness, loss of appetite, profuse sweating, difficult or labored breathing, fever, dizziness, nausea, vomiting, and chest pain. Hepatotoxicity, apparently reversible and rare, has occurred during treatment with carvedilol.

Range of Toxicity:

CARVEDILOL
  • TOXICITY: An adult developed bradycardia, hypotension, and drowsiness following an overdose of 1,050 mg carvedilol in addition to 10 tablets of zopiclone. THERAPEUTIC DOSE: ADULTS: HEART FAILURE: The recommended starting dose is 3.125 mg orally twice daily for 2 weeks. If tolerated, the dose may then be increased at 2-week intervals to 6.25 mg and 12.5 mg twice daily, up to a maximum dose of 25 mg twice daily in patients weighing 85 kg or less, or up to a maximum of 50 mg twice daily in patients who weigh more than 85 kg. CHILDREN: Adjunctive treatment with twice-daily carvedilol at initial doses starting from 0.05 mg/kg to 0.09 mg/kg per dose, titrated every 2 weeks to a maximum of 25 mg per dose, led to improvements in ventricular function in children with ventricular dysfunction or heart failure in small, prospective and retrospective studies.

Treatment:

CARVEDILOL
  • Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: The vast majority of overdoses require only supportive care; activated charcoal is indicated if patients present shortly after ingestion. IV fluids should be administered to support blood pressure. Fall precautions should be ordered to prevent secondary injury due to dizziness or orthostatic hypotension. MANAGEMENT OF SEVERE TOXICITY: Perform early orotracheal intubation for airway protection if the patient has altered mental status. Initially, manage hypotension with IV fluids (500 mL boluses up to 2 liters) and atropine for symptomatic bradycardia. Glucagon should be considered if patient does not respond appropriately to IV fluids. Give catecholamines to those who do not respond to IV fluids and glucagon. No one catecholamine has been shown to be consistently effective; dopamine, norepinephrine, and epinephrine may be considered. High doses may be required. If catecholamines are required despite glucagon and IV fluids, high-dose insulin euglycemia therapy should be considered. Catecholamines should be titrated down when high-dose insulin euglycemia therapy starts to take effect. Intravenous lipid emulsion should be considered in patients with refractory hypotension. Other non-pharmacological therapies include: cardiac pacing, placement of an intra-aortic balloon pump, cardiopulmonary bypass, and extracorporeal membrane oxygenation (ECMO).
  • Decontamination: PREHOSPITAL: Activated charcoal should be given to those who are able to reliably protect their airway and IV fluids should be given for hypotension or tachycardia. HOSPITAL: Activated charcoal should be given to those who are able to reliably protect their airway. Gastric lavage is generally not indicated; however, in massive overdoses, this might be considered.
  • Airway management: Perform early in patients with severe intoxication (seizures, dysrhythmias, severe delirium, CNS or respiratory depression).
  • Hypotensive episode: Initially manage hypotension with intravenous fluids (500 mL boluses up to 2L) and atropine for symptomatic bradycardia.
  • Antidote: GLUCAGON: Patients who do not respond to intravenous fluids (500 mL boluses up to 2L) and atropine should be treated with glucagon. Initial dosing is 5 to 15 mg by slow IV push followed by an infusion rate of 5 to 15 mg/hour. Glucagon may also induce nausea/vomiting, as well as elevate blood glucose.
  • Insulin: High-dose insulin euglycemia (HIS) may be considered in patients who do not respond adequately to fluids and catecholamines. HIS is another potential therapy with some positive animal data and case-based human evidence. Administer a bolus of 1 unit/kilogram of insulin followed by an infusion of 0.1 to 1 units/kilogram/hour, titrated to a systolic blood pressure of greater than 90 to 100 mmHg (bradycardia may or may not respond). Reassess every 30 minutes to titrate insulin infusion. High-dose insulin euglycemia therapy may allow the practitioner to decrease the dose of catecholamines and avoid the adverse effects of prolonged high dose catecholamines. Before, during, and after the therapy, monitor for hypoglycemia and hypokalemia. Administer dextrose bolus to patients with an initial blood glucose of less than 250 mg/dL (Adult: 25 to 50 mL dextrose 50%; Children: 0.25 g/kg dextrose 25%). Begin a dextrose infusion of 0.5 g/kg/hour in all patients. Monitor blood glucose every 15 to 30 minutes until consistently 100 to 200 mg/dL for 4 hours, then monitor every hour. Titrate dextrose infusion to maintain blood glucose in the range of 100 to 200 mg/dL. As the patient improves, insulin resistance abates and dextrose requirements will increase. Supplemental dextrose will be needed for at least several hours after the insulin infusion is discontinued. Administer supplemental potassium initially if patient is hypokalemic (serum potassium less than 2.5 mEq/L). Monitor serum potassium every 4 hours and supplement as needed to maintain potassium of 2.5 to 2.8 mEq/L.
  • Fat Emulsion: Another potential pharmacological treatment is with lipid emulsion therapy, though at this point in time, there is only animal data supporting its use in beta-blocker toxicity; in theory it may be effective for lipid soluble beta blockers such as propranolol. The dose of 20% lipid emulsion is 1.5 mL/kg over 1 minute followed immediately with an infusion at a rate of 0.25 mL/kg/min, and to repeat the bolus dosing every 3 to 5 minutes up to 3 mL/kg total dose until circulation is restored. If BP declines, increase the infusion rate to 0.5 mL/kg/min. A maximum dose of 8 mL/kg is recommended. For example, the resuscitation of an adult weighing 70 kg is equivalent to taking a 500 mL bag of 20% lipid emulsion and drawing up 50 mL twice and giving it IV push, and then attaching the infusion bag to an IV and running it in over 15 minutes.
  • Inamrinone: A phosphodiesterase inhibitor which also has theoretical benefit via decreasing breakdown of myocardial cAMP. The dosing is 1 mg/kg bolus then 3 to 6 mcg/kg/minute. It is very rarely used because, although it increases inotropy, it may induce peripheral vasodilation and is difficult to titrate due to a relatively long half-life.
  • Calcium: Calcium chloride has been effective for some beta blocker overdoses that were refractory to conventional therapy. Administer calcium chloride 0.2 mL/kg or calcium gluconate 0.6 mL/kg intravenously.
  • Bradycardia: Atropine, glucagon (50 to 150 mcg/kg bolus followed by an infusion 1 to 5 mg/hr), and pacemaker.
  • Conduction disorder of the heart: QRS widening or ventricular tachycardia may respond to sodium bicarbonate. A reasonable starting dose is 1 to 2 mEq/kg bolus, repeat as needed; endpoints include resolution of dysrhythmias, narrowing of QRS complex and blood pH 7.45 to 7.55. Use lidocaine (1 mg/kg intravenous bolus followed by 20 to 50 mcg/kg/min intravenous infusion) if sodium bicarbonate is not successful.
  • Seizure: All symptomatic patients should be placed on seizure and fall precautions. Seizures should be treated with benzodiazepines; however, the typical cause of seizures in this population is either due to hypotension or low blood sugar if insulin treatment is ongoing.
  • Monitoring of patient: Monitor vital signs and mental status. Monitor electrolytes, renal function, troponin, and liver enzymes in patients with significant overdose. Glucose should be monitored hourly in patients receiving high doses insulin/dextrose therapy. Obtain an ECG and institute continuous cardiac monitoring. Carvedilol blood concentrations are not clinically useful or readily available.
  • Enhanced elimination procedure: Hemodialysis is not expected to be of benefit for removal of carvedilol after an overdose due to its high degree of plasma protein binding (greater than 98%) and large volume of distribution.
  • Patient disposition: HOME CRITERIA: Asymptomatic adults with unintentional ingestions of 50 mg or less and asymptomatic children with unintentional ingestions of 0.5 mg/kg or less can be monitored at home. OBSERVATION CRITERIA: Patients with deliberate ingestions, symptomatic patients, adults ingesting more than 50 mg, and children ingesting more than 0.5 mg/kg should be referred to a health care facility for observation for 6 to 8 hours. ADMISSION CRITERIA: Patients with significant persistent CNS depression (weakness, ataxia, vertigo, coma), or those with persistent abnormal vital signs, such as bradycardia and hypotension, should be admitted. Patients with dysrhythmias, severe hypotension, or end organ damage should be admitted to an intensive care setting. CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (dysrhythmias, severe hypotension, coma), or in whom the diagnosis is not clear.
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