indication

For the treatment of mild or moderate (NYHA class II or III) heart failure of ischemic or cardiomyopathic origin.

pharmacology

Carvedilol is a nonselective beta-adrenergic blocking agent with alpha1-blocking activity and is indicated for the treatment of hypertension and mild or moderate (NYHA class II or III) heart failure of ischemic or cardiomyopathic origin. Carvedilol is a racemic mixture in which nonselective b-adrenoreceptor blocking activity is present in the S(-) enantiomer and a-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity. The effect of carvedilol's b-adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exercise-and/or isoproterenol-induced tachycardia and (3) reduces reflex orthostatic tachycardia.

mechanism of action

Carvedilol is a racemic mixture in which nonselective beta-adrenoreceptor blocking activity is present in the S(-) enantiomer and alpha-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol's beta-adrenergic receptor blocking ability decreases the heart rate, myocardial contractility, and myocardial oxygen demand. Carvedilol also decreases systemic vascular resistance via its alpha adrenergic receptor blocking properties. Carvedilol and its metabolite BM-910228 (a less potent beta blocker, but more potent antioxidant) have been shown to restore the inotropic responsiveness to Ca²⁺ in OH^- free radical-treated myocardium. Carvedilol and its metabolites also prevent OH^- radical-induced decrease in sarcoplasmic reticulum Ca²⁺-ATPase activity. Therefore, carvedilol and its metabolites may be beneficial in chronic heart failure by preventing free radical damage.

toxicity

Not expected to be toxic following ingestion.

biotransformation

Hepatic. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. Demethylation and hydroxylation at the phenol ring produce three active metabolites with b-receptor blocking activity. The 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for b-blockade.

absorption

Carvedilol is rapidly and extensively absorbed following oral administration, with an absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism.

half life

7-10 hours

route of elimination

Carvedilol is extensively metabolized. Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces.

drug interactions

Acetohexamide: The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.

Chlorpropamide: The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.

Citalopram: The SSRI, citalopram, may increase the bradycardic effect of the beta-blocker, carvedilol.

Clonidine: Increased hypertension when clonidine stopped

Cyclosporine: Carvedilol may increase the therapeutic and adverse effects of cyclosporine.

Digoxin: Carvedilol may increase the serum levels and effect of digoxin.

Dihydroergotamine: Ischemia with risk of gangrene

Dihydroergotoxine: Ischemia with risk of gangrene

Disopyramide: The beta-blocker, carvedilol, may increase the toxicity of disopyramide.

Epinephrine: Hypertension, then bradycardia

Ergonovine: Ischemia with risk of gangrene

Ergotamine: Ischemia with risk of gangrene

Escitalopram: The SSRI, escitalopram, may increase the bradycardic effect of the beta-blocker, carvedilol.

Fenoterol: Antagonism

Fluoxetine: The SSRI, fluoxetine, may increase the bradycardic effect of the beta-blocker, carvedilol.

Formoterol: Antagonism

Gliclazide: The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.

Glipizide: The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.

Glisoxepide: The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.

Glyburide: The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.

Glycodiazine: The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.

Ibuprofen: Risk of inhibition of renal prostaglandins

Indomethacin: Risk of inhibition of renal prostaglandins

Insulin Aspart: The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.

Insulin Detemir: The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.

Insulin Glargine: The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.

Insulin Glulisine: The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.

Insulin Lispro: The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.

Isoproterenol: Antagonism

Lidocaine: The beta-blocker, carvedilol, may increase the effect and toxicity of lidocaine.

Methysergide: Ischemia with risk of gangrene

Orciprenaline: Antagonism

Paroxetine: The SSRI, paroxetine, may increase the bradycardic effect of the beta-blocker, carvedilol.

Pipobroman: Antagonism

Pirbuterol: Antagonism

Piroxicam: Risk of inhibition of renal prostaglandins

Prazosin: Risk of hypotension at the beginning of therapy

Procaterol: Antagonism

Repaglinide: The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.

Salbutamol: Antagonism

Salmeterol: Antagonism

Sertraline: The SSRI, sertraline, may increase the bradycardic effect of the beta-blocker, carvedilol.

Terazosin: Increased risk of hypotension. Initiate concomitant therapy cautiously.

Terbinafine: Terbinafine may reduce the metabolism and clearance of Carvedilol. Consider alternate therapy or monitor for therapeutic/adverse effects of Carvedilol if Terbinafine is initiated, discontinued or dose changed.

Terbutaline: Antagonism

Tolazamide: The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.

Tolbutamide: The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.

Topotecan: The p-glycoprotein inhibitor, Carvedilol, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.

Treprostinil: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.

Verapamil: Increased effect of both drugs