Drug/Small Molecule:

carvedilol

Overview

Generic Names:	Carvedilolum [Latin]; carvedilol
IUPAC Name:	1-(9H-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)ethylamino]propan-2-ol
Trade Names:	Coreg
PharmGKB Accession Id:	PA448817

Description

Carvedilol is a non-selective beta blocker indicated in the treatment of mild to moderate congestive heart failure (CHF). It blocks beta-1 and beta-2 adrenergic receptors as well as the alpha-1 adrenergic receptors.

Indication

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

ATC Therapeutic Category

• C07AG:Alpha and beta blocking agents

Pharmacology and Interactions

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.

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.

Food Interactions

Take with food, food slows the absorption rate and reduces the incidence of adverse effects (extent of absorption is not affected).

Absorption, Distribution, Metabolism, Elimination & Toxicity

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.

Protein Binding

98%

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

Toxicity

Not expected to be toxic following ingestion.

Chemical Properties

Chemical Formula:

C₂₄H₂₆N₂O₄

SMILES Code:

COC1=CC=CC=C1OCCNC[C@H](COC2=CC=CC3=C2C4=CC=CC=C4N3)O

(Format: OpenEye Isomeric)

Molecular Weight ( average / monoisotopic )

406.4742 / 406.1893

Curated Annotations ()

1. rs1042714 at chr5:148186666 in ADRB2
   Heart failure patients homozygous for Gln27 were less likely to have improved left ventricular ejection fraction after carvedilol treatment compared to Glu27 carriers. However, in another study of heart failure patients, Gln27Glu polymorphism was not associated with the improvement of left ventricular ejection fraction or decrease in heart rate to a beta blocker in stable congestive heart failure.

   Variant Name:

   ADRB2: Gln27Glu; 318C>G ; Gln27

   Related Drugs:

   carvedilol

   Related Diseases:

   Heart Failure

   Evidence:

   PMID:12835612
   PMID:15861037
   

Curated Information

The following genes are in curated knowledge about this drug.

	Gene	Relationship	Evidence
	ABCB1	FA	Publications
	ADRB1	CO          GN	Publications
	ADRB2	CO PD       GN	Publications, Variants
	CYP2D6	PK	Publications
	GRK5	CO          GN	Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other genes is available.

Metabolizing Enzymes

• CYP2D6
• CYP2C9
• XDH

Drug Targets

• KCNH2
• ADRB1
• VEGFA
• GJA1
• ABCB1
• NDUFC2
• ADRA1A
• ADRB2
• VCAM1
• NPPB

Non-Curated Information

A list of non-curated publications that mention this drug along with other drugs is available.

Drug Interactions

Curated Information

The following diseases are in curated knowledge about this drug.

	Disease	Relationship	Evidence
	Cardiomyopathies	PD	Publications
	Cardiomyopathy, Dilated	CO          GN	Publications
	Cardiomyopathy, Hypertrophic	CO          GN	Publications
	Diabetes Mellitus	PD	Publications
	Heart Failure	CO          GN	Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

1. Physicochemical determinants of human renal clearance

LinkOuts

Common Searches

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Non-Curated Publications

A list of non-curated publications that mention this drug is available.