Chemistry:Carvedilol

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Carvedilol, sold under the brand name Coreg among others, is a beta blocker medication, that may be prescribed for the treatment of high blood pressure (hypertension) and chronic heart failure with reduced ejection fraction (also known as HFrEF or systolic heart failure).[1][2] Beta-blockers as a collective medication class are not recommended as routine first-line treatment of high blood pressure for all patients, due to evidence demonstrating less effective cardiovascular protection and a less favourable safety profile when compared to other classes of blood pressure-lowering medications.[1][3][4]

Common side effects include dizziness, tiredness, joint pain, low blood pressure, nausea, and shortness of breath.[5] Severe side effects may include bronchospasm.[5] Safety during pregnancy or breastfeeding is unclear.[6] Use is not recommended in those with liver problems.[7] Carvedilol is a nonselective beta blocker and alpha-1 blocker.[5] How it improves outcomes is not entirely clear but may involve dilation of blood vessels.[5]

Carvedilol was patented in 1978 and approved for medical use in the United States in 1995.[5][8] Carvedilol is a therapeutic alternative on the World Health Organization's List of Essential Medicines.[9] It is available as a generic medication.[5] In 2023, it was the 35th most commonly prescribed medication in the United States, with more than 16 million prescriptions.[10][11]

Medical uses

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.[12] The mechanism of carvedilol in heart failure is due to its inhibition of receptors in the adrenergic nervous system, which releases noradrenaline to the body, including the heart.[13] Noradrenaline is a hormone that causes the heart to beat faster and work harder.[13] Blocking its binding to adrenergic receptors in the heart causes vasodilation, decreases heart rate and blood pressure, and improves myocardial contractility,[14] which ultimately decreases the heart's workload.[13]

Carvedilol reduces the risk of death, hospitalisations, and recurring heart attacks in patients with moderate to severe heart failure (with an ejection fraction <40%) following a heart attack [15][16][17] Carvedilol has also been proven to reduce death and hospitalization in patients with severe heart failure.[18]

Carvedilol is not considered a first-line treatment for hypertension; however, research has demonstrated that it exhibits an antihypertensive effect when compared to a placebo or other antihypertensive medications.[19][20]

Carvedilol has shown efficacy in preventing bleeding from oesophageal varices in patients with mild to moderate cirrhosis and may have benefit in avoiding successive bleeds.[21][22]

Carvedilol is used in the treatment of acute cardiovascular toxicity (e.g. overdose) with sympathomimetics, for instance caused by amphetamine, methamphetamine, cocaine, or ephedrine.[23][24] It has also specifically been found to block the sympathomimetic effects of MDMA.[25][23][26] Dual α1 and beta blockers like carvedilol and labetalol may be more favorable for such purposes due to the possibility of "unopposed α-stimulation" with selective beta blockers.[23]

Available forms

Carvedilol is available in the following forms:

Contraindications

Carvedilol should not be used in patients with bronchial asthma or bronchospastic conditions due to increased risk of bronchoconstriction.[29][30] It should not be used in people with second- or third-degree atrioventricular block, sick sinus syndrome, severe bradycardia (unless a permanent pacemaker is in place), or a decompensated heart condition. People with severe hepatic impairment should use carvedilol with caution.[31][32][33]

Side effects

The most common side effects (>10% incidence) of carvedilol include:[27]

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.[27]

Carvedilol may mask symptoms of low blood sugar,[27] resulting in hypoglycemia unawareness. This is termed beta blocker induced hypoglycemia unawareness.

Interactions

The risk of bradycardia is increased if used with amiodarone, digoxin, diltiazem, ivabradine, or verapamil.[34] Also, combination of carvedilol with non-dihydropyridine calcium channel blockers, including diltiazem and verapamil, enhances it cardiodepressant effects.[34]

Pharmacology

Pharmacodynamics

Carvedilol activities
Site Ki (nM) Action
5-HT1A 3.4 Antagonist
5-HT2 207 Antagonist
5-HT2A 547 Antagonist
D2 213 Antagonist
α1 3.4 Antagonist
α2 2,168 Antagonist
β1 0.24–0.43 Antagonist
β2 0.13–0.40 Antagonist
H1 3,034 ?
M2 ? Antagonist[35]
MOR 2,700 ?
SERT 528 ?
NET 2,406 ?
DAT 627 ?
VGSC 547 (IC50) Inhibitor

Carvedilol is both a non-selective β-adrenergic receptor antagonist (β1, β2) and an α-adrenergic receptor antagonist (α1). The S(–) enantiomer accounts for the beta-blocking activity whereas the S(–) and R(+) enantiomers have alpha-blocking activity.[27] The affinity (Ki) of carvedilol for the β-adrenergic receptors is 0.32 nM for the human β1-adrenergic receptor and 0.13 to 0.40 nM for the β2-adrenergic receptor.[36]

Using rat proteins, carvedilol has shown affinity for a variety of targets including the β1-adrenergic receptor, β2-adrenergic receptor, α1-adrenergic receptor, α2-adrenergic receptor, 5-HT1A receptor, 5-HT2 receptor, H1 receptor, D2 receptor, μ-opioid receptor, veratridine site of voltage-gated sodium channels, serotonin transporter, norepinephrine transporter, and dopamine transporter.[37] It is an antagonist of the human 5-HT2A receptors with moderate affinity, although it is unclear if this is significant for its pharmacological actions given its much stronger activity at adrenergic receptors.[38]

Carvedilol reversibly binds to β-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.[39] Carvedilol blockade of α1-adrenergic 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-adrenergic receptors on the heart.[40]

Pharmacokinetics

Absorption

Carvedilol is about 25% to 35% bioavailable following oral administration due to extensive first-pass metabolism. Absorption is slowed when administered with food, however, it does not show a significant difference in bioavailability. Taking carvedilol with food decreases the risk of orthostatic hypotension.[27]

Distribution

The 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.[27] Carvedilol is highly lipophilic and easily crosses the blood–brain barrier in animals, and hence is not thought to be peripherally selective.[41][42]

Metabolism

The compound is metabolized by liver enzymes, CYP2D6 and CYP2C9 via aromatic ring oxidation and glucuronidation, then further conjugated by glucuronidation and sulfation. The three active metabolites exhibit only one-tenth of the vasodilating effect of the parent compound. However, the 4'-hydroxyphenyl metabolite is about 13-fold more potent in β-blockade than the parent.[27]

Elimination

The mean elimination half-life of carvedilol following oral administration ranges from 7 to 10 hours. The pharmaceutical product is a mix of two enantiomorphs, R(+)-carvedilol and S(–)-carvedilol, with differing metabolic properties. R(+)-Carvedilol undergoes preferential selection for metabolism, which results in a fractional half-life of about 5 to 9 hours, compared with 7 to 11 hours for the S(-)-carvedilol fraction.[27]

Chemistry

Carvedilol is a highly lipophilic compound with an experimental log P of 3.8 to 4.19 and a predicted log P of 3.05 to 4.2.[43][44][45][46][47] It showed the third highest predicted lipophilicity of 30 clinically relevant beta blockers, with the second and third most lipophilic beta blockers predicted to be bopindolol and penbutolol, respectively.[48]

History

Carvedilol was patented in 1978 and was approved for medical use in the United States in 1995.[5][8]

References

  1. ↑ 1.0 1.1 "2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA)" (in en-US). Journal of Hypertension 41 (12): 1874–2071. December 2023. doi:10.1097/HJH.0000000000003480. PMID 37345492. 
  2. ↑ "2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure". European Heart Journal 42 (36): 3599–3726. September 2021. doi:10.1093/eurheartj/ehab368. PMID 34447992. 
  3. ↑ "Comparison of Cardiovascular Events Among Users of Different Classes of Antihypertension Medications: A Systematic Review and Network Meta-analysis". JAMA Network Open 3 (2): e1921618. February 2020. doi:10.1001/jamanetworkopen.2019.21618. PMID 32083689. 
  4. ↑ "A meta-analysis of 94,492 patients with hypertension treated with beta blockers to determine the risk of new-onset diabetes mellitus". The American Journal of Cardiology 100 (8): 1254–1262. October 2007. doi:10.1016/j.amjcard.2007.05.057. PMID 17920367. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 "Carvedilol Monograph for Professionals". AHFS. https://www.drugs.com/monograph/carvedilol.html. 
  6. ↑ "Carvedilol Use During Pregnancy". https://www.drugs.com/pregnancy/carvedilol.html. 
  7. ↑ British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 147. ISBN 978-0-85711-338-2. 
  8. ↑ 8.0 8.1 Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 463. ISBN 978-3-527-60749-5. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA463. 
  9. ↑ The selection and use of essential medicines, 2025: WHO Model List of Essential Medicines, 24th list. Geneva: World Health Organization. 2025. 
  10. ↑ "Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  11. ↑ "Carvedilol Drug Usage Statistics, United States, 2014 - 2023". https://clincalc.com/DrugStats/Drugs/Carvedilol. 
  12. ↑ "2013 AHA Guidelines for the Management of Heart Failure". Circulation 128 (16): e240-327. 15 October 2013. doi:10.1161/CIR.0b013e31829e8776. PMID 23741058. http://circ.ahajournals.org/content/early/2013/06/03/CIR.0b013e31829e8776.full.pdf. 
  13. ↑ 13.0 13.1 13.2 "carvedilol (Coreg): Heart Failure, Side Effects, Uses & Dosage" (in en). 4 November 2022. https://www.medicinenet.com/carvedilol/article.htm. 
  14. ↑ "The role of beta-blockers in the treatment of chronic heart failure". Trends in Pharmacological Sciences 32 (4): 206–212. April 2011. doi:10.1016/j.tips.2011.01.006. PMID 21376403. 
  15. ↑ "Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial". Lancet 357 (9266): 1385–1390. May 2001. doi:10.1016/s0140-6736(00)04560-8. PMID 11356434. 
  16. ↑ "Meta-Analysis of Relation Between Oral β-Blocker Therapy and Outcomes in Patients With Acute Myocardial Infarction Who Underwent Percutaneous Coronary Intervention". The American Journal of Cardiology 115 (11): 1529–1538. June 2015. doi:10.1016/j.amjcard.2015.02.057. PMID 25862157. 
  17. ↑ "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. October 2002. doi:10.1161/01.cir.0000035653.72855.bf. PMID 12390947. 
  18. ↑ "Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials". European Heart Journal 39 (1): 26–35. January 2018. doi:10.1093/eurheartj/ehx564. PMID 29040525. 
  19. ↑ "Controlled-release carvedilol in the treatment of essential hypertension". The American Journal of Cardiology 98 (7A): 32L–38L. October 2006. doi:10.1016/j.amjcard.2006.07.017. PMID 17023230. 
  20. ↑ "Effect of carvedilol, lisinopril and their combination on vascular and cardiac health in patients with borderline blood pressure: the DETECT Study". Journal of Human Hypertension 27 (6): 362–367. June 2013. doi:10.1038/jhh.2012.54. PMID 23190794. 
  21. ↑ "Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol". Gut 62 (11): 1634–1641. November 2013. doi:10.1136/gutjnl-2012-304038. PMID 23250049. 
  22. ↑ "Carvedilol Achieves Higher Hemodynamic Response and Lower Rebleeding Rates Than Propranolol in Secondary Prophylaxis". Clinical Gastroenterology and Hepatology 21 (9): 2318–2326.e7. August 2023. doi:10.1016/j.cgh.2022.06.007. PMID 35842118. 
  23. ↑ 23.0 23.1 23.2 "Treatment of toxicity from amphetamines, related derivatives, and analogues: a systematic clinical review". Drug Alcohol Depend 150: 1–13. May 2015. doi:10.1016/j.drugalcdep.2015.01.040. PMID 25724076. 
  24. ↑ "β-Blockers, Cocaine, and the Unopposed α-Stimulation Phenomenon". J Cardiovasc Pharmacol Ther 22 (3): 239–249. May 2017. doi:10.1177/1074248416681644. PMID 28399647. 
  25. ↑ "Ecstasy (3,4-methylenedioxymethamphetamine): Cardiovascular effects and mechanisms". Eur J Pharmacol 903. July 2021. doi:10.1016/j.ejphar.2021.174156. PMID 33971177. 
  26. ↑ "Carvedilol inhibits the cardiostimulant and thermogenic effects of MDMA in humans". Br J Pharmacol 166 (8): 2277–2288. August 2012. doi:10.1111/j.1476-5381.2012.01936.x. PMID 22404145. 
  27. ↑ 27.0 27.1 27.2 27.3 27.4 27.5 27.6 27.7 27.8 "Coreg". GlaxoSmithKline. U.S. Food and Drug Administration. April 2008. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020297s029lbl.pdf. 
  28. ↑ "Drug Approval Package". U.S. Food and Drug Administration. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2006/022012s000TOC.cfm. 
  29. ↑ "Respiratory effect of beta-blockers in people with asthma and cardiovascular disease: population-based nested case control study". BMC Medicine 15 (1). January 2017. doi:10.1186/s12916-017-0781-0. PMID 28126029. 
  30. ↑ "Tolerability of carvedilol in patients with heart failure and concomitant chronic obstructive pulmonary disease or asthma". The Journal of Heart and Lung Transplantation 21 (12): 1290–5. December 2002. doi:10.1016/s1053-2498(02)00459-x. PMID 12490274. 
  31. ↑ "Carvedilol use is associated with improved survival in patients with liver cirrhosis and ascites". Journal of Hepatology 67 (1): 40–46. July 2017. doi:10.1016/j.jhep.2017.02.005. PMID 28213164. https://www.pure.ed.ac.uk/ws/files/33500796/Carvedilol_manuscript_RS_KALdocx.pdf. 
  32. ↑ "Carvedilol versus traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices". The Cochrane Database of Systematic Reviews 2018 (10). October 2018. doi:10.1002/14651858.CD011510.pub2. PMID 30372514. 
  33. ↑ "Randomized, controlled trial of carvedilol versus nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding". Journal of Gastroenterology and Hepatology 27 (11): 1681–7. November 2012. doi:10.1111/j.1440-1746.2012.07244.x. PMID 22849337. 
  34. ↑ 34.0 34.1 "Heart Failure". 15 March 2023. http://www.myrxtx.ca. 
  35. ↑ "Effects of carvedilol on M2 receptors and cholinesterase-positive nerves in adriamycin-induced rat failing heart". Autonomic Neuroscience 130 (1–2): 6–16. December 2006. doi:10.1016/j.autneu.2006.04.005. PMID 16798104. 
  36. ↑ "Carvedilol | Ligand page". IUPHAR/BPS Guide to PHARMACOLOGY. https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=551. 
  37. ↑ "The receptor binding profile of the new antihypertensive agent nebivolol and its stereoisomers compared with various beta-adrenergic blockers". Mol Pharmacol 34 (6): 843–51. December 1988. doi:10.1016/S0026-895X(25)10118-1. PMID 2462161. https://molpharm.aspetjournals.org/content/34/6/843.long. 
  38. ↑ "The adrenergic receptor antagonist carvedilol interacts with serotonin 2A receptors both in vitro and in vivo". Pharmacology, Biochemistry, and Behavior 181: 37–45. June 2019. doi:10.1016/j.pbb.2019.04.003. PMID 30998954. 
  39. ↑ "Beta blockers for congestive heart failure". Acta Medica Indonesiana 39 (1): 44–8. 2007. PMID 17297209. http://www.inaactamedica.org/archives/2007/17297209.pdf. Retrieved 12 November 2015. 
  40. ↑ "The pharmacology of carvedilol". European Journal of Clinical Pharmacology 38 (Suppl 2): S82–S88. 1990. doi:10.1007/BF01409471. PMID 1974511. 
  41. ↑ "Carvedilol as a potential novel agent for the treatment of Alzheimer's disease". Neurobiol Aging 32 (12): 2321.e1–12. December 2011. doi:10.1016/j.neurobiolaging.2010.05.004. PMID 20579773. 
  42. ↑ "New positron emission tomography tracer [(11)Ccarvedilol reveals P-glycoprotein modulation kinetics"]. Br J Pharmacol 145 (8): 1045–51. August 2005. doi:10.1038/sj.bjp.0706283. PMID 15951832. 
  43. ↑ "Carvedilol". https://pubchem.ncbi.nlm.nih.gov/compound/2585. 
  44. ↑ "Carvedilol: Uses, Interactions, Mechanism of Action". 14 September 1995. https://go.drugbank.com/drugs/DB01136. 
  45. ↑ "Carvedilol". 21 July 2022. https://www.chemspider.com/Chemical-Structure.2487.html. 
  46. ↑ "Human Metabolome Database: Showing metabocard for Carvedilol (HMDB0015267)". 6 September 2012. https://hmdb.ca/metabolites/HMDB0015267. 
  47. ↑ "Exploring the utility of the Chasing Principle: influence of drug-free SNEDDS composition on solubilization of carvedilol, cinnarizine and R3040 in aqueous suspension". Acta Pharm Sin B 9 (1): 194–201. January 2019. doi:10.1016/j.apsb.2018.07.004. PMID 30766791. 
  48. ↑ "The impact of lipophilicity in drug research: a case report on beta-blockers". Mini Rev Med Chem 5 (2): 197–205. February 2005. doi:10.2174/1389557053402701. PMID 15720289. 

Further reading



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