Carvedilol

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Carvedilol
Carvedilol.svg
Carvedilol-I-3D-balls.png
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 cat. C
Legal status Prescription only
Routes Oral
Pharmacokinetic data
Bioavailability 25–35%
Protein binding 98%
Metabolism Liver (CYP2D6, CYP2C9)
Half-life 7–10 hours
Excretion Urine (16%), Feces (60%)
Identifiers
CAS number 72956-09-3 YesY
ATC code C07AG02
PubChem CID 2585
IUPHAR ligand 551
DrugBank DB01136
ChemSpider 2487 YesY
UNII 0K47UL67F2 YesY
KEGG D00255 YesY
ChEBI CHEBI:3441 YesY
ChEMBL CHEMBL723 YesY
Chemical data
Formula C24H26N2O4 
Mol. mass 406.474
 YesY (what is this?)  (verify)

Carvedilol is a nonselective beta blocker/alpha-1 blocker indicated in the treatment of mild to severe congestive heart failure (CHF) and high blood pressure. It is marketed under various trade names including Carvil (Zydus Cadila), Coreg (GSK), Dilatrend , Kredex (Roche), Eucardic (Roche), and Carloc (Cipla) as a generic drug (as of September 5, 2007 in the U.S.),[1] and as a controlled-release formulation, marketed in the US as Coreg CR (GSK). Carvedilol was discovered by Robert R. Ruffolo, Jr. It has had a significant role in the treatment of congestive heart failure.

Pharmacology[edit]

Carvedilol is both a beta blocker1, β2) and alpha blocker1):

  • Norepinephrine stimulates the nerves that control the muscles of the heart by binding to the β1- and β2-adrenergic receptors. Carvedilol blocks the binding to those receptors,[2] which both slows the heart rhythm and reduces the force of the heart's pumping. This lowers blood pressure thus reducing the workload of the heart, which is particularly beneficial in heart failure patients.
  • Norepinephrine also binds to the α1-adrenergic receptors on blood vessels, causing them to constrict and raise blood pressure. Carvedilol blocks this binding to the α1-adrenergic receptors too,[3] which also lowers blood pressure.

Relative to other beta blockers, carvedilol has minimal inverse agonist activity.[4] This suggests that carvedilol has a reduced negative chronotropic and inotropic effect compared to other beta blockers, which may decrease its potential to worsen symptoms of heart failure. However, to date this theoretical benefit has not been established in clinical trials, and the current version of the ACC/AHA guidelines on congestive heart failure management does not give preference to carvedilol over other beta-blockers.[citation needed]

Carvedilol does also act as FIASMA (functional inhibitor of acid sphingomyelinase).[5]

Side effects[edit]

The most common side effects include dizziness, fatigue, hypotension, diarrhea, asthenia, bradycardia, and weight gain.[6]

Enantiomers[edit]

Carvedilol has enantiomers with distinct pharmacodynamics.[7]

The term "racemic carvedilol" is sometimes used to explicitly denote that both enantiomers are applied.[8]

Clinical use[edit]

Carvedilol is indicated in the management of congestive heart failure (CHF), as an adjunct to conventional treatments (ACE inhibitors and diuretics). The use of carvedilol has been shown to provide additional morbidity and mortality benefits in severe CHF.[9] Carvedilol (Carvil) is available at the following doses 3.125 mg (smallest), followed by 6.25 mg,12.5 mg, and 25 mg white tablets. Coreg CR is available at the following doses: 10mg(white/green capsules), 20mg(white/yellow capsules), 40mg(yellow/green capsules), and 80mg(white capsules). [10]

U.S. supply issues[edit]

On January 10, 2006 carvedilol supply became limited in the United States, due to changes in documentation procedures at a plant. This was lifted on April 27, 2006 in a Dear Pharmacist letter.[11]

Approval of controlled-release formulation[edit]

On October 20, 2006, the FDA approved a controlled release formulation of carvedilol; it is marketed as Coreg CR.

References[edit]

  1. ^ Press Release, FDA Approves First Generic Versions of Coreg, U.S. Food and Drug Administration, Sep. 5, 2007
  2. ^ Stafylas PC, Sarafidis PA (2008). "Carvedilol in hypertension treatment". Vasc Health Risk Manag 4 (1): 23–30. doi:10.2147/vhrm.2008.04.01.23. PMC 2464772. PMID 18629377. 
  3. ^ Othman AA, Tenero DM, Boyle DA, Eddington ND, Fossler MJ (2007). "Population pharmacokinetics of S(-)-carvedilol in healthy volunteers after administration of the immediate-release (IR) and the new controlled-release (CR) dosage forms of the racemate". AAPS J 9 (2): E208–18. doi:10.1208/aapsj0902023. PMC 2751410. PMID 17614362. 
  4. ^ Vanderhoff BT, Ruppel HM, Amsterdam PB (November 1998). "Carvedilol: the new role of beta blockers in congestive heart failure". Am Fam Physician 58 (7): 1627–34, 1641–2. PMID 9824960. 
  5. ^ Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P (2011). "Identification of novel functional inhibitors of acid sphingomyelinase". PLoS ONE 6 (8): e23852. doi:10.1371/journal.pone.0023852. PMC 3166082. PMID 21909365. 
  6. ^ Carvedilol Official FDA information, side effects and uses. Drugs.com, October 11, 2009.
  7. ^ Horiuchi I, Nozawa T, Fujii N, et al. (May 2008). "Pharmacokinetics of R- and S-carvedilol in routinely treated Japanese patients with heart failure". Biol. Pharm. Bull. 31 (5): 976–80. doi:10.1248/bpb.31.976. PMID 18451529. [dead link]
  8. ^ Takekuma Y, Takenaka T, Yamazaki K, Ueno K, Sugawara M (November 2007). "Stereoselective metabolism of racemic carvedilol by UGT1A1 and UGT2B7, and effects of mutation of these enzymes on glucuronidation activity". Biol. Pharm. Bull. 30 (11): 2146–53. doi:10.1248/bpb.30.2146. PMID 17978490. [dead link]
  9. ^ Packer M, Fowler MB, Roecker EB, et al. (October 2002). "Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study". Circulation 106 (17): 2194–9. doi:10.1161/01.CIR.0000035653.72855.BF. PMID 12390947. 
  10. ^ http://online.factsandcomparisons.com/DetailTable.aspx?page=product&monoid=fandc-hcp12482&sort=2&route=Oral&quick=248977%7C5&search=248977%7C5&isstemmed=True&fromtop=true&hashCoregCR2_prodlist
  11. ^ http://www.fda.gov/cder/drug/shortages/Coreg_Pharmacist_Letter_27Apr06.pdf PDF at FDA.govdead link

11. Subhashis Chakraborty, Dali Shukla, Brahmeshwar Mishra & Sanjay Singh.Clinical updates on carvedilol: a first choice beta-blocker in the treatment of cardiovascular diseases. Expert Opin Drug Metab Toxicol. 2010 Feb;6(2):237-50. DOI 10.1517/17425250903540220, PMID 20073998

External links[edit]