Carvedilol

Carvedilol

Systematic (IUPAC) name
(±)-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl][2-(2-methoxyphenoxy)ethyl]amine
Clinical data
Trade names	Coreg
AHFS/Drugs.com	monograph
MedlinePlus	a697042
Pregnancy category	C
Legal status	℞ (Prescription only)
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	25–35%
Protein binding	98%
Metabolism	Liver (CYP2D6, CYP2C9)
Biological half-life	7–10 hours
Excretion	Urine (16%), Feces (60%)
Identifiers
CAS Number	72956-09-3 Y
ATC code	C07AG02 (WHO)
PubChem	CID: 2585
IUPHAR/BPS	551
DrugBank	DB01136 Y
ChemSpider	2487 Y
UNII	0K47UL67F2 Y
KEGG	D00255 Y
ChEBI	CHEBI:3441 Y
ChEMBL	CHEMBL723 Y
PDB ligand ID	CVD (PDBe, RCSB PDB)
Chemical data
Formula	C24H26N2O4
Molecular mass	406.474
SMILES O(c4ccccc4OCCNCC(O)COc3cccc2c3c1c(cccc1)n2)C
InChI InChI=1S/C24H26N2O4/c1-28-21-10-4-5-11-22(21)29-14-13-25-15-17(27)16-30-23-12-6-9-20-24(23)18-7-2-3-8-19(18)26-20/h2-12,17,25-27H,13-16H2,1H3 Y Key:OGHNVEJMJSYVRP-UHFFFAOYSA-N Y
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Carvedilol, sold under the brand name Coreg among others, is a nonselective beta blocker/alpha-1 blocker. It is used in the treatment of mild to severe congestive heart failure (CHF), left ventricular dysfunction (LVD) following heart attack in clinically stable patients, and high blood pressure.

Carvedilol was discovered by Fritz Wiedemann at Boehringer Mannheim and was initially approved in the U.S. in 1995, marketed as Coreg. On October 20, 2006, the FDA approved an extended-release formulation of carvedilol; it is marketed as Coreg CR.

Medical use

Carvedilol is indicated in the management of congestive heart failure (CHF), commonly as an adjunct to angiotensin-converting-enzyme inhibitor (ACE inhibitors) and diuretics. It has been clinically shown to reduce mortality and hospitalizations in people with CHF. The mechanism behind its positive effect when used long-term in clinically stable CHF patients is not fully understood, but is thought to contribute to remodeling of the heart, improving upon its structure and function.

In addition, carvedilol is indicated in the treatment of hypertension. It can be used alone or with other anti-hypertensive agents. In the 2013 guideline, it is recommended as the drug of choice in people with histories of CHF and/or myocardial infarction.

Side effects

The most common side effects (>10% incidence) include:

• dizziness
• fatigue
• low blood pressure
• diarrhea
• weakness
• slowed heart rate
• weight gain

Carvedilol is not recommended for people with uncontrolled bronchospastic disease (e.g. current asthma symptoms) as it can block receptors that assist in opening the airways.

Carvedilol may mask symptoms of low blood sugar.

Contraindications

According to the FDA, carvedilol should not be used in people with bronchial asthma or bronchospastic conditions. It should not be used in people with second- or third-degree AV block, sick sinus syndrome, severe bradycardia (unless a permanent pacemaker is in place), or a decompensated heart condition. People with severe hepatic impairment are also not advised to take carvedilol.

Mechanism of action

Carvedilol is both a non-selective beta adrenergic receptor blocker (β1, β2) and an alpha adrenergic receptor blocker (α1). The S(-) enantiomer accounts for the beta blocking activity whereas the S(-) and R(+) enantiomer have alpha blocking activity.

Carvedilol reversibly binds to beta adrenergic receptors on cardiac myocytes. Inhibition of these receptors prevents a response to the sympathetic nervous system, leading to decreased heart rate and contractility. This action is beneficial in heart failure patients where the sympathetic nervous system is activated as a compensatory mechanism.

Carvedilol blockade of α1 receptors causes vasodilation of blood vessels. This inhibition leads to decreased peripheral vascular resistance and an antihypertensive effect. There is no reflex tachycardia response due to carvedilol blockade of β1 receptors on the heart.

Pharmacokinetics

Carvedilol is about 25% to 35% bioavailable following oral administration due to extensive first-pass metabolism. The compound is metabolized by liver enzymes, CYP2D6 and CYP2C9 via aromatic ring oxidation and glucuronidation, then further conjugated by glucuronidation and sulfation. Compared with the parent compound, the three active metabolites exhibits only one-tenth of the vasodilating effect of the parent compound. However, the 4’hydroxyphenyl metabolite is about 13-fold more potent in ß-blockade than the parent compound.

The mean half-life of carvedilol following oral administration ranges from 7 to 10 hours. Carvedilol has two enantiomers: R(+)-carvedilol and S(-)-carvedilol. R(+)-carvedilol undergoes preferential selection for metabolism, so the mean half-life of the enantiomer is about 5 to 9 hours compared with 7 to 11 hours for the S(-)-enantiomer.

Majority of carvedilol is bound to plasma proteins (98%), mainly to albumin. Carvedilol is a basic, hydrophobic compound with a steady-state volume of distribution of 115 L. Plasma clearance ranges from 500 to 700 mL/min.

Absorption is slowed when administered with food, however it does not show significant difference in bioavailability. Taking carvedilol with food decreases the risk of orthostatic hypotension.

Formulations

•Tablet, Oral

•Capsule Extended Release 24 Hour, Oral

See also

• Labetalol

External links

• Coreg CR official website
• Physicians Desk Reference Info on Carvedilol
• Info on carvedilol through rxlist.com