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Carvedilol: Wikis

  

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1 : 1 mixture (racemate)
Systematic (IUPAC) name
(±)-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl][2-(2-methoxyphenoxy)ethyl]amine
Identifiers
CAS number 72956-09-3
ATC code C07AG02
PubChem 2585
DrugBank APRD00091
ChemSpider 2487
Chemical data
Formula C24H26N2O4 
Mol. mass 406.474
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 25–35%
Protein binding 98%
Metabolism Liver (CYP2D6, CYP2C9)
Half life 7–10 hours
Excretion Urine (16%), Feces (60%)
Therapeutic considerations
Pregnancy cat. C
Legal status Prescription only
Routes Oral

Carvedilol is a non-selective beta blocker/alpha-1 blocker indicated in the treatment of mild to moderate congestive heart failure (CHF). It is marketed under various trade names including Coreg (GSK), Dilatrend (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).

Contents

Pharmacology

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 and reduces heart failure.
  • 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.

Side effects

The most common side effects include dizziness, fatigue, hypotension, diarrhea, hyperglycemia, asthenia, bradycardia, and weight gain.[5]

A case report of a patient with panic disorder associated sleep disturbances and nightmares with the improper usage of carvedilol.[6]

Enantiomers

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

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 CHF.[9] Carvedilol (Coreg) is available at the following doses 3.125 mg (smallest), followed by 6.25 mg, 12.5 mg, and 25 mg white tablets.

U.S. supply issues

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

Approval of controlled-release formulation

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

References

  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. 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. PMID 17614362. http://www.aapsj.org/view.asp?art=aapsj0902023. 
  4. ^ Vanderhoff BT, Ruppel HM, Amsterdam PB. Carvedilol: The new role of beta blockers in congestive heart failure. Am Fam Physician 1998;58(7):1627-34. PMID 9824960
  5. ^ Carvedilol Official FDA information, side effects and uses. Drugs.com, October 11, 2009.
  6. ^ Maebara C, Ohtani H, Sugahara H, Mine K, Kubo C, Sawada Y (November 2002). "Nightmares and panic disorder associated with carvedilol overdose". Ann Pharmacother 36 (11): 1736–40. PMID 12398570. http://www.theannals.com/cgi/pmidlookup?view=long&pmid=12398570. 
  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. PMID 18451529. http://joi.jlc.jst.go.jp/JST.JSTAGE/bpb/31.976?from=PubMed. 
  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. PMID 17978490. http://joi.jlc.jst.go.jp/JST.JSTAGE/bpb/30.2146?from=PubMed. 
  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. PMID 12390947. http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=12390947. 
  10. ^ http://www.fda.gov/cder/drug/shortages/Coreg_Pharmacist_Letter_27Apr06.pdf PDF at FDA.gov

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