Carvedilol

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
MedlinePlus
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 Registry Number  Y
ATC code C07
PubChem CID:
IUPHAR/BPS
DrugBank  Y
ChemSpider  Y
UNII  Y
KEGG  Y
ChEBI  Y
ChEMBL  Y
PDB ligand ID CVD (, )
Chemical data
Formula C24H26N2O4
Molecular mass 406.474
 Y   

Carvedilol is a nonselective beta blocker/alpha-1 blocker used 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 Fritz Wiedemann at Boehringer Mannheim.[2] It has had a significant role in the treatment of congestive heart failure.

Contents

  • Medical use 1
  • Side effects 2
  • Pharmacology 3
  • Enantiomers 4
  • Society and culture 5
    • U.S. supply issues 5.1
    • Approval of controlled-release formulation 5.2
  • See also 6
  • References 7
    • Further reading 7.1
  • External links 8

Medical 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 severe CHF.[3]

Side effects

The most common side effects include dizziness, fatigue, low blood pressure, diarrhea, weakness, slowed heart rate, and weight gain.[4]

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,[5] which 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,[6] which also lowers blood pressure.

Relative to other beta blockers, carvedilol has minimal inverse agonist activity.[7] 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.

Carvedilol also acts as a functional inhibitor of acid sphingomyelinase.[8]

Carvedilol is known to act as a calcium channel blocker at high doses.[9]

Carvedilol is lipid-soluble and is able to cross the blood-brain-barrier.[10][11][12]

Enantiomers

Carvedilol has enantiomers with distinct pharmacodynamics.[13]

The term "racemic carvedilol" is sometimes used to explicitly denote that both enantiomers are applied.[14]

Society and culture

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 on April 27, 2006 in a Dear Pharmacist letter.[15]

Approval of controlled-release formulation

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

See also

References

  1. ^ Press Release, FDA Approves First Generic Versions of Coreg, U.S. Food and Drug Administration, Sep. 5, 2007
  2. ^ U.S. Patent 4503067
  3. ^ 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.  
  4. ^ Carvedilol Official FDA information, side effects and uses. Drugs.com, October 11, 2009.
  5. ^ Stafylas PC, Sarafidis PA (2008). "Carvedilol in hypertension treatment". Vasc Health Risk Manag 4 (1): 23–30.  
  6. ^ 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.  
  7. ^ 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.  
  8. ^ 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.  
  9. ^ Stephen Brennan (2009). MRCP Cardiology MCQs. Radcliffe Publishing. pp. 10–.  
  10. ^ Manuchair Ebadi (29 December 1997). CRC Desk Reference of Clinical Pharmacology. CRC Press. pp. 121–.  
  11. ^ Stephen Jackson; Paul Jansen; Arduino Mangoni (22 April 2009). Prescribing for Elderly Patients. John Wiley & Sons. pp. 46–.  
  12. ^ Joseph Colombo; Rohit Arora; Nicholas L. DePace; Charlotte Ball (22 September 2014). Clinical Autonomic Dysfunction: Measurement, Indications, Therapies, and Outcomes. Springer. pp. 161–.  
  13. ^ 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.  
  14. ^ 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.  
  15. ^ [2]

Further reading

  • Chakraborty, Subhashis; Shukla, Dali; Mishra, Brahmeshwar; Singh, Sanjay (February 2010). "Clinical updates on carvedilol: a first choice β-blocker in the treatment of cardiovascular diseases". Expert Opinion on Drug Metabolism & Toxicology 6 (2): 237–250.  

External links

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