Carvedilol Explained

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.[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] It is on the World Health Organization's List of Essential Medicines.[9] It is available as a generic medication.[5] In 2021, it was the 26th most commonly prescribed medication in the United States, with more than 21million 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. 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.

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] 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.

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.[26] [27] 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.[28] [29] [30]

Side effects

The most common side effects (>10% incidence) of carvedilol include:[31]

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, 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.[32] Also, combination of carvedilol with non-dihydropyridine calcium channel blockers, including diltiazem and verapamil, enhances it cardiodepressant effects.

Pharmacology

Pharmacodynamics

Carvedilol! Site! K (nM)! Action
5-HT1A3.4Antagonist
5-HT2207Antagonist
D2213Antagonist
α13.4Antagonist
α22,168Antagonist
β10.24–0.43Antagonist
β20.19–0.25Antagonist
M2?Antagonist[33]

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. The affinity (Ki) of carvedilol for the β-adrenergic receptors is 0.32nM for the human β1-adrenergic receptor and 0.13 to 0.40nM for the β2-adrenergic receptor.[34]

Using rat proteins, carvedilol has shown affinity for a variety of targets including the β1-adrenergic receptor (Ki = 0.24–0.43nM), β2-adrenergic receptor (Ki = 0.19–0.25nM), α1-adrenergic receptor (Ki = 3.4nM), α2-adrenergic receptor (Ki = 2,168nM), 5-HT1A receptor (Ki = 3.4nM), 5-HT2 receptor (Ki = 207nM), H1 receptor (Ki = 3,034nM), D2 receptor (Ki = 213nM), μ-opioid receptor (Ki = 2,700nM), veratridine site of voltage-gated sodium channels (IC50 = 1,260nM), serotonin transporter (Ki = 528nM), norepinephrine transporter (Ki = 2,406nM), and dopamine transporter (Ki = 627nM).[35] It is an antagonist of the human 5-HT2A receptors with moderate affinity (Ki = 547nM), although it is unclear if this is significant for its pharmacological actions given its much stronger activity at adrenergic receptors.[36]

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.[37] 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.[38]

Pharmacokinetics

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.

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 115L. Plasma clearance ranges from 500 to 700mL/min. Carvedilol is highly lipophilic and easily crosses the blood–brain barrier in animals, and hence is not thought to be peripherally selective.[39] [40]

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.

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.

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.[41] [42] [43] [44] [45]

Further reading

Notes and References

  1. Mancia G, Kreutz R, Brunström M, Burnier M, Grassi G, Januszewicz A, Muiesan ML, Tsioufis K, Agabiti-Rosei E, Algharably EA, Azizi M, Benetos A, Borghi C, Hitij JB, Cifkova R, Coca A, Cornelissen V, Cruickshank JK, Cunha PG, Danser AH, Pinho RM, Delles C, Dominiczak AF, Dorobantu M, Doumas M, Fernández-Alfonso MS, Halimi JM, Járai Z, Jelaković B, Jordan J, Kuznetsova T, Laurent S, Lovic D, Lurbe E, Mahfoud F, Manolis A, Miglinas M, Narkiewicz K, Niiranen T, Palatini P, Parati G, Pathak A, Persu A, Polonia J, Redon J, Sarafidis P, Schmieder R, Spronck B, Stabouli S, Stergiou G, Taddei S, Thomopoulos C, Tomaszewski M, Van de Borne P, Wanner C, Weber T, Williams B, Zhang ZY, Kjeldsen SE . 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) . en-US . Journal of Hypertension . 41 . 12 . 1874–2071 . December 2023 . 37345492 . 10.1097/HJH.0000000000003480 . 11379/603005 . free .
  2. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, Burri H, Butler J, Čelutkienė J, Chioncel O, Cleland JG, Coats AJ, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CS, Lyon AR, McMurray JJ, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GM, Ruschitzka F, Kathrine Skibelund A . 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure . European Heart Journal . 42 . 36 . 3599–3726 . September 2021 . 34447992 . 10.1093/eurheartj/ehab368 .
  3. Wei J, Galaviz KI, Kowalski AJ, Magee MJ, Haw JS, Narayan KM, Ali MK . 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 . 32083689 . 7043193 . 10.1001/jamanetworkopen.2019.21618 .
  4. Bangalore S, Parkar S, Grossman E, Messerli FH . 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 . 17920367 . 10.1016/j.amjcard.2007.05.057 .
  5. Web site: Carvedilol Monograph for Professionals . 24 December 2018 . Drugs.com . AHFS.
  6. Web site: Carvedilol Use During Pregnancy . Drugs.com . 24 December 2018 .
  7. Book: British national formulary : BNF 76. 2018. Pharmaceutical Press. 9780857113382. 147. 76.
  8. Book: Fischer J, Ganellin CR . Analogue-based Drug Discovery. 2006. John Wiley & Sons. 9783527607495. 463.
  9. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 22nd list (2021) . 2021 . 10665/345533 . World Health Organization . World Health Organization . Geneva . WHO/MHP/HPS/EML/2021.02 . free .
  10. Web site: The Top 300 of 2021 . ClinCalc . 14 January 2024 . 15 January 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
  11. Web site: Carvedilol - Drug Usage Statistics . ClinCalc . 14 January 2024.
  12. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL, Wilkoff BL . American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines . 2013 AHA Guidelines for the Management of Heart Failure. Circulation. 15 October 2013. 128. 16. 10.1161/CIR.0b013e31829e8776 . e240-327. 23741058.
  13. Web site: Ogbru O . 4 November 2022 . Shiel Jr WC . carvedilol (Coreg): Heart Failure, Side Effects, Uses & Dosage . 2024-05-01 . MedicineNet . en.
  14. Kubon C, Mistry NB, Grundvold I, Halvorsen S, Kjeldsen SE, Westheim AS . The role of beta-blockers in the treatment of chronic heart failure . Trends in Pharmacological Sciences . 32 . 4 . 206–212 . April 2011 . 21376403 . 10.1016/j.tips.2011.01.006 .
  15. Dargie HJ . 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 . 11356434 . 10.1016/s0140-6736(00)04560-8 . 1840228 .
  16. Huang BT, Huang FY, Zuo ZL, Liao YB, Heng Y, Wang PJ, Gui YY, Xia TL, Xin ZM, Liu W, Zhang C, Chen SJ, Pu XB, Chen M, Huang DJ . 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 . 25862157 . 10.1016/j.amjcard.2015.02.057 .
  17. Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Staiger C, Holcslaw TL, Amann-Zalan I, DeMets DL . 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 . 12390947 . 10.1161/01.cir.0000035653.72855.bf .
  18. Cleland JG, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJ, Manzano L, McMurray JJ, Ruschitzka F, van Veldhuisen DJ, von Lueder TG, Böhm M, Andersson B, Kjekshus J, Packer M, Rigby AS, Rosano G, Wedel H, Hjalmarson Å, Wikstrand J, Kotecha D . 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 . 29040525 . 5837435 . 10.1093/eurheartj/ehx564 .
  19. Weber MA, Sica DA, Tarka EA, Iyengar M, Fleck R, Bakris GL . Controlled-release carvedilol in the treatment of essential hypertension . The American Journal of Cardiology . 98 . 7A . 32L-38L . October 2006 . 17023230 . 10.1016/j.amjcard.2006.07.017 .
  20. Saul SM, Duprez DA, Zhong W, Grandits GA, Cohn JN . 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 . 23190794 . 10.1038/jhh.2012.54 .
  21. Reiberger T, Ulbrich G, Ferlitsch A, Payer BA, Schwabl P, Pinter M, Heinisch BB, Trauner M, Kramer L, Peck-Radosavljevic M . Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol . Gut . 62 . 11 . 1634–1641 . November 2013 . 23250049 . 10.1136/gutjnl-2012-304038 . free .
  22. Jachs M, Hartl L, Simbrunner B, Bauer D, Paternostro R, Balcar L, Hofer B, Pfisterer N, Schwarz M, Scheiner B, Stättermayer AF, Pinter M, Trauner M, Mandorfer M, Reiberger T . 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 . 35842118 . 10.1016/j.cgh.2022.06.007 . free .
  23. Richards JR, Albertson TE, Derlet RW, Lange RA, Olson KR, Horowitz BZ . Treatment of toxicity from amphetamines, related derivatives, and analogues: a systematic clinical review . Drug Alcohol Depend . 150 . 1–13 . May 2015 . 25724076 . 10.1016/j.drugalcdep.2015.01.040 .
  24. Richards JR, Hollander JE, Ramoska EA, Fareed FN, Sand IC, Izquierdo Gómez MM, Lange RA . β-Blockers, Cocaine, and the Unopposed α-Stimulation Phenomenon . J Cardiovasc Pharmacol Ther . 22 . 3 . 239–249 . May 2017 . 28399647 . 10.1177/1074248416681644 .
  25. Web site: Drug Approval Package. U.S. Food and Drug Administration . 5 November 2015.
  26. Morales DR, Lipworth BJ, Donnan PT, Jackson C, Guthrie B . Respiratory effect of beta-blockers in people with asthma and cardiovascular disease: population-based nested case control study . BMC Medicine . 15 . 1 . 18 . January 2017 . 28126029 . 5270217 . 10.1186/s12916-017-0781-0 . free .
  27. Kotlyar E, Keogh AM, Macdonald PS, Arnold RH, McCaffrey DJ, Glanville AR . 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 . 12490274 . 10.1016/s1053-2498(02)00459-x .
  28. Sinha R, Lockman KA, Mallawaarachchi N, Robertson M, Plevris JN, Hayes PC . Carvedilol use is associated with improved survival in patients with liver cirrhosis and ascites . Journal of Hepatology . 67 . 1 . 40–46 . July 2017 . 28213164 . 10.1016/j.jhep.2017.02.005 . 20.500.11820/7afe3b88-1064-4da1-927e-4d4e867387eb .
  29. Zacharias AP, Jeyaraj R, Hobolth L, Bendtsen F, Gluud LL, Morgan MY . Carvedilol versus traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices . The Cochrane Database of Systematic Reviews . 2018 . 10 . CD011510 . October 2018 . 30372514 . 6517039 . 10.1002/14651858.CD011510.pub2 .
  30. Lo GH, Chen WC, Wang HM, Yu HC . 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 . 22849337 . 10.1111/j.1440-1746.2012.07244.x . 23494154 .
  31. Web site: Coreg . April 2008 . GlaxoSmithKline . U.S. Food and Drug Administration.
  32. Web site: Koshman SL, Paterson I . March 15, 2023 . Heart Failure . April 29, 2024 . Canadian Pharmacists Association (CPS).
  33. Xu XL, Zang WJ, Lu J, Kang XQ, Li M, Yu XJ . 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 . 16798104 . 10.1016/j.autneu.2006.04.005 . 22480332 .
  34. Web site: Carvedilol | Ligand page . IUPHAR/BPS Guide to PHARMACOLOGY.
  35. Pauwels PJ, Gommeren W, Van Lommen G, Janssen PA, Leysen JE . 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 . 2462161 .
  36. Murnane KS, Guner OF, Bowen JP, Rambacher KM, Moniri NH, Murphy TJ, Daphney CM, Oppong-Damoah A, Rice KC . 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 . 30998954 . 6570414 . 10.1016/j.pbb.2019.04.003 .
  37. Manurung D, Trisnohadi HB . Beta blockers for congestive heart failure . Acta Medica Indonesiana . 39 . 1 . 44–8 . 2007 . 17297209 . 12 November 2015 . https://web.archive.org/web/20160304103842/http://www.inaactamedica.org/archives/2007/17297209.pdf . 4 March 2016 . dead .
  38. Ruffolo RR, Gellai M, Hieble JP, Willette RN, Nichols AJ . The pharmacology of carvedilol . European Journal of Clinical Pharmacology . 38 . Suppl 2 . S82–S88 . 1990 . 1974511 . 10.1007/BF01409471 . 2901620 .
  39. Wang J, Ono K, Dickstein DL, Arrieta-Cruz I, Zhao W, Qian X, Lamparello A, Subnani R, Ferruzzi M, Pavlides C, Ho L, Hof PR, Teplow DB, Pasinetti GM . Carvedilol as a potential novel agent for the treatment of Alzheimer's disease . Neurobiol Aging . 32 . 12 . 2321.e1–12 . December 2011 . 20579773 . 2966505 . 10.1016/j.neurobiolaging.2010.05.004 .
  40. Bart J, Dijkers EC, Wegman TD, de Vries EG, van der Graaf WT, Groen HJ, Vaalburg W, Willemsen AT, Hendrikse NH . New positron emission tomography tracer [(11)C]carvedilol reveals P-glycoprotein modulation kinetics . Br J Pharmacol . 145 . 8 . 1045–51 . August 2005 . 15951832 . 1576233 . 10.1038/sj.bjp.0706283 .
  41. Web site: Carvedilol . PubChem . 1 August 2024.
  42. Web site: Carvedilol: Uses, Interactions, Mechanism of Action . DrugBank Online . 14 September 1995 . 1 August 2024.
  43. Web site: Carvedilol . ChemSpider . 21 July 2022 . 1 August 2024.
  44. Web site: Human Metabolome Database: Showing metabocard for Carvedilol (HMDB0015267) . Human Metabolome Database . 6 September 2012 . 1 August 2024.
  45. Siqueira Jørgensen S, Rades T, Mu H, Graeser K, Müllertz A . 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 . 30766791 . 6361727 . 10.1016/j.apsb.2018.07.004 .

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