Chemistry:Bisoprolol

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Short description: Beta-1 selective adrenenergic blocker medication used to treat cardiovascular diseases
Bisoprolol
Bisoprolol.svg
Bisoprolol ball-and-stick.png
Clinical data
Trade namesZebeta, Concor, others
AHFS/Drugs.comMonograph
MedlinePlusa693024
License data
Pregnancy
category
  • AU: C
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • CA: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability>90%
Protein binding30%[1]
Metabolism50% liver, CYP2D6, CYP3A4[3]
Elimination half-life10–12 hours[2]
ExcretionKidney, fecal (<2%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC18H31NO4
Molar mass325.449 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  (verify)

Bisoprolol, sold under the brand name Zebeta among others, is a beta blocker medication used for heart diseases.[4] This includes tachyarrhythmias, high blood pressure, chest pain from not enough blood flow to the heart, and heart failure.[4][5] It is taken by mouth.[4]

Common side effects include headache, feeling tired, diarrhea, and swelling in the legs.[4] More severe side effects include worsening asthma, blocking the ability to recognize low blood sugar, and worsening heart failure.[6] There are concerns that use during pregnancy may be harmful to the baby.[7] Bisoprolol is in the beta blocker family of medications and is of the β1 selective type.[4]

Bisoprolol is on the World Health Organization's List of Essential Medicines.[8] Bisoprolol is available as a generic medication.[4][9] In 2020, it was the 267th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[10][11]

Medical uses

Zebeta 5-mg oral tablet

Bisoprolol is currently used for prevention of cardiovascular events following a heart attack in patients with risk factors for disease progression,[12] in the management of congestive heart failure with reduced ejection fraction,[13] and as a second-line agent for hypertension.[14]

Bisoprolol may be beneficial in the treatment of high blood pressure, but it is not recommended as a first-line antihypertensive agent. It can be an adjunct to first-line antihypertensive agents in patients with accompanying comorbidities, for example, congestive heart failure, where selected beta blockers can be added in patients who remain mildly to moderately symptomatic despite appropriate doses of an angiotensin-converting-enzyme inhibitor. [15]

In cardiac ischemia, the drug is used to reduce the activity of the heart muscle, thereby reducing its oxygen and nutrient demands and allowing its reduced blood supply to still transport sufficient amounts of oxygen and nutrients to meet its needs.[16][17][18]

Side effects

An overdose of bisoprolol can lead to fatigue, hypotension,[17] hypoglycemia,[19][20] bronchospasms, and bradycardia.[17] Bronchospasms and hypoglycemia occur because at high doses, the drug can be an antagonist for β2 adrenergic receptors located in the lungs and liver. Bronchospasm occurs due to the blockage of β2 receptors in the lungs. Hypoglycemia occurs due to decreased stimulation of glycogenolysis and gluconeogenesis in the liver via β2 receptors.[16][17][21]

There have been no reported cases of clinically evident drug-induced liver injury associated with bisoprolol.[22]

Cautions

Non-selective beta-blockers should be avoided in people with asthma or bronchospasm as they may cause exacerbations and worsening of symptoms.[23][24][25] β1 selective beta-blockers like bisoprolol have not been shown to cause an increase in asthma exacerbations,[24] and may be cautiously tried in those with controlled, mild-to-moderate asthma with cardiac comorbidities. A 2014 meta-analysis found that unlike non-selective beta-blockers, β1 selective beta-blockers (bisoprolol) showed only a small impact on lung function, with patients remaining responsive to salbutamol (β2 -agonist) rescue therapy and endorses the use of bisoprolol in select patients with controlled asthma.[23][26] This was supported by a 2020 clinical trial where bisoprolol had no significant impact on bronchodilation post salbutamol administration. [27]

Pharmacology

Mechanism of action

Bisoprolol is cardioprotective because it selectively and competitively blocks catecholamine (adrenaline) stimulation of β1 adrenergic receptors (adrenoreceptors), which are mainly found in the heart muscle cells and heart conduction tissue (cardiospecific), but also found in juxtaglomerular cells in the kidney.[16] Normally, adrenaline and noradrenaline stimulation of the β1 adrenoreceptor activates a signalling cascade (Gs protein and cAMP) which ultimately leads to increased myocardial contractility and increased heart rate of the heart muscle and heart pacemaker, respectively.[28] Bisoprolol competitively blocks the activation of this cascade, so decreases the adrenergic tone/stimulation of the heart muscle and pacemaker cells. Decreased adrenergic tone shows less contractility of heart muscle and lowered heart rate of pacemakers.[19][20][29]

β1-selectivity

Bisoprolol β1-selectivity is especially important in comparison to other nonselective beta blockers. The effects of the drug are limited to areas containing β1 adrenoreceptors, which is mainly the heart and part of the kidney.[19][29] Bisoprolol, whilst β1 adrenoceptor selective can help patients to avoid certain side-effects associated with non-selective beta-blocker activity[2] at additional adrenoceptors (α1 and β2), it does not signify its superiority in treating beta-blocker indicated cardiac conditions such as heart failure but could prove beneficial to patients with specific comorbidities.[30][31]

Bisoprolol has a higher degree of β1-selectivity compared to atenolol, metoprolol and betaxolol.[32] With a selectivity ranging from being 11 to 15 times more selective for β1 over β2.[29][33][34][35][36][37][38][39][40][41] However, nebivolol is approximately 3.5 times more β1-selective.[42][43]

Renin-angiotensin system

Bisoprolol inhibits renin secretion by about 65% and tachycardia by about 30%.[33]

Pharmacokinetics

After ingestion, bisoprolol is absorbed and has a high bioavailability of approximately 90% with plasma half-life of 10-12 hours.[19][20] When being eliminated, the body evenly distributes it (50–50) between kidney excretion and liver biotransformation (then excreted).[19][20][29]

Bisoprolol has both lipid- and water-soluble properties.[19][29] It is classified as a beta blocker with moderate lipophilicity and hence intermediate potential for crossing the blood–brain barrier.[44] This in turn may result in fewer effects in the central nervous system as well as a lower risk of neuropsychiatric side effects than highly lipophilic beta blockers like propranolol but greater such effects than beta blockers with low lipophilicity like atenolol.[44]

The plasma protein binding of bisoprolol is approximately 35%, the volume of distribution is 3.5 L/kg and the total clearance is approximately 15 L/h. Bisoprolol is eliminated from the body in two ways - 50% of the substance is converted in the liver to inactive metabolites, which are then excreted in the kidneys. The remaining 50% is eliminated unchanged via the kidneys.[45] Since elimination is equal in liver and kidney, no dose adjustment is required in patients with hepatic or renal impairment.

The pharmacokinetics of bisoprolol are linear and independent of age.[2]

In patients with chronic heart failure, the plasma level of bisoprolol is higher and the half-life is longer than in healthy subjects when compared across studies. Currently, there is a lack of evidence directly comparing bisoprolol pharmacokinetics between healthy subjects and chronic heart failure subjects.[46][47]

History

Bisoprolol was patented in 1976 and approved for medical use in 1986.[48] It was approved for medical use in the United States in 1992.[4]

Brand names

In India, it is sold under trade name Bisotab and is available in 2 strengths of 2.5 mg and 5 mg.[49]

In Italy, it is sold under trade name Congescor and is available in 6 strengths of 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg.

In Germany and Eastern Europe bisoprolol is marketed as Bisoprolol-ratiopharm by Ratiopharm (Teva) and Concor COR.

References

  1. ↑ "Pharmacokinetics and metabolism of bisoprolol-14C in three animal species and in humans". Journal of Cardiovascular Pharmacology 8 (Suppl 11): S21–S28. 1986. doi:10.1097/00005344-198511001-00004. PMID 2439794. 
  2. ↑ 2.0 2.1 2.2 "Balanced pharmacokinetics and metabolism of bisoprolol". Journal of Cardiovascular Pharmacology 8 (Suppl 11): S16–S20. 1986. doi:10.1097/00005344-198511001-00003. PMID 2439789. 
  3. ↑ "Pharmacokinetics and metabolism of bisoprolol enantiomers in humans". Journal of Pharmaceutical Sciences 87 (3): 289–294. March 1998. doi:10.1021/js970316d. PMID 9523980. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 "Bisoprolol Fumarate". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/bisoprolol-fumarate.html. 
  5. ↑ "Bisoprolol 2.5mg/5mg/10mg film coated tablet - Summary of Product Characteristics (SPC) - (eMC)". 18 February 2014. https://www.medicines.org.uk/emc/medicine/25983. 
  6. ↑ "Bisoprolol - FDA prescribing information, side effects and uses". https://www.drugs.com/pro/bisoprolol.html. 
  7. ↑ "Bisoprolol (Zebeta) Use During Pregnancy". https://www.drugs.com/pregnancy/bisoprolol.html. 
  8. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  9. ↑ "Drugs@FDA: FDA Approved Drug Products". http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=BISOPROLOL%20FUMARATE. 
  10. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  11. ↑ "Bisoprolol - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Bisoprolol. 
  12. ↑ "Clinical outcomes with β-blockers for myocardial infarction: a meta-analysis of randomized trials". The American Journal of Medicine 127 (10): 939–953. October 2014. doi:10.1016/j.amjmed.2014.05.032. PMID 24927909. 
  13. ↑ CIBIS-II Investigators (January 1999). "The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomised trial.". The Lancet 353 (9146): 9–13. doi:10.1016/S0140-6736(98)11181-9. >
  14. ↑ "Beta-blockers for hypertension". The Cochrane Database of Systematic Reviews 1 (1): CD002003. January 2017. doi:10.1002/14651858.CD002003.pub5. PMID 28107561. 
  15. ↑ "Clinical information for Hypertension I Heart Foundation" (in en-au). https://heartfoundation-prod.azurewebsites.net/bundles/for-professionals/hypertension. 
  16. ↑ 16.0 16.1 16.2 CIBIS Investigators and Committees (October 1994). "A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS).". Circulation 90 (4): 1765–1773. doi:10.1161/01.cir.90.4.1765. PMID 7923660. 
  17. ↑ 17.0 17.1 17.2 17.3 "Comparative effects of carvedilol vs bisoprolol for severe congestive heart failure". Circulation Journal 74 (6): 1127–1134. June 2010. doi:10.1253/circj.cj-09-0989. PMID 20354334. 
  18. ↑ "Improved survival with bisoprolol in patients with heart failure and renal impairment: an analysis of the cardiac insufficiency bisoprolol study II (CIBIS-II) trial". European Journal of Heart Failure 12 (6): 607–616. June 2010. doi:10.1093/eurjhf/hfq038. PMID 20354032. 
  19. ↑ 19.0 19.1 19.2 19.3 19.4 19.5 "Basic pharmacokinetics of bisoprolol, a new highly beta 1-selective adrenoceptor antagonist". Journal of Clinical Pharmacology 26 (8): 616–621. 1986. doi:10.1002/j.1552-4604.1986.tb02959.x. PMID 2878941. 
  20. ↑ 20.0 20.1 20.2 20.3 "Pharmacodynamic profile of bisoprolol, a new beta 1-selective adrenoceptor antagonist". British Journal of Clinical Pharmacology 22 (3): 293–300. September 1986. doi:10.1111/j.1365-2125.1986.tb02890.x. PMID 2876722. 
  21. ↑ "Pharmacological actions of the selective and non-selective beta-adrenoceptor antagonists celiprolol, bisoprolol and propranolol on human bronchi". British Journal of Pharmacology 113 (3): 1043–1049. November 1994. doi:10.1111/j.1476-5381.1994.tb17098.x. PMID 7858847. 
  22. ↑ Bisoprolol. 2012. 
  23. ↑ 23.0 23.1 "Adverse respiratory effect of acute β-blocker exposure in asthma: a systematic review and meta-analysis of randomized controlled trials". Chest 145 (4): 779–786. April 2014. doi:10.1378/chest.13-1235. PMID 24202435. 
  24. ↑ 24.0 24.1 "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. doi:10.1186/s12916-017-0781-0. PMID 28126029. 
  25. ↑ "The safety of cardioselective β1-blockers in asthma: literature review and search of global pharmacovigilance safety reports". ERJ Open Research 7 (1). January 2021. doi:10.1183/23120541.00801-2020. PMID 33681344. 
  26. ↑ "β-Adrenoceptor blockers and pulmonary function in the general population: the Rotterdam Study". British Journal of Clinical Pharmacology 77 (1): 190–200. January 2014. doi:10.1111/bcp.12181. PMID 23772842. 
  27. ↑ "The impact of regular bisoprolol on the response to salbutamol in asthma: A double-blind randomized placebo-controlled crossover trial". Respirology 26 (3): 225–232. March 2021. doi:10.1111/resp.13955. PMID 33043552. 
  28. ↑ "Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium". Molecular Pharmacology 35 (3): 295–303. March 1989. PMID 2564629. 
  29. ↑ 29.0 29.1 29.2 29.3 29.4 "High beta 1-selectivity and favourable pharmacokinetics as the outstanding properties of bisoprolol". Journal of Cardiovascular Pharmacology 8 (Suppl 11): S2-15. 1986. doi:10.1097/00005344-198511001-00002. PMID 2439793. 
  30. ↑ "Switching from carvedilol to bisoprolol ameliorates adverse effects in heart failure patients with dizziness or hypotension". Journal of Cardiology 61 (6): 417–422. June 2013. doi:10.1016/j.jjcc.2013.01.009. PMID 23548374. 
  31. ↑ "Titration to target dose of bisoprolol vs. carvedilol in elderly patients with heart failure: the CIBIS-ELD trial". European Journal of Heart Failure 13 (6): 670–680. June 2011. doi:10.1093/eurjhf/hfr020. PMID 21429992. 
  32. ↑ "Beta-blockers for the treatment of arrhythmias: Bisoprolol - a systematic review". Annales Pharmaceutiques Françaises 80 (5): 617–634. September 2022. doi:10.1016/j.pharma.2022.01.007. PMID 35093388. https://hal.archives-ouvertes.fr/hal-03719705/file/Muresan%20et%20al-2022-Beta%20blockers%20for%20the%20treatment%20of%20arrhythmias.pdf. 
  33. ↑ 33.0 33.1 "Pharmacodynamic profile of the selective beta 1-adrenoceptor antagonist bisoprolol". Arzneimittel-Forschung 36 (2): 200–208. February 1986. PMID 2870720. 
  34. ↑ "Direct labelling of myocardial beta 1-adrenoceptors. Comparison of binding affinity of 3H-(-)-bisoprolol with its blocking potency". Naunyn-Schmiedeberg's Archives of Pharmacology 331 (1): 27–39. October 1985. doi:10.1007/bf00498849. PMID 2866449. 
  35. ↑ "Studies on the receptor profile of bisoprolol". Arzneimittel-Forschung 36 (2): 197–200. February 1986. PMID 2870719. 
  36. ↑ "Characterization of [3H](+/-)carazolol binding to beta-adrenergic receptors. Application to study of beta-adrenergic receptor subtypes in canine ventricular myocardium and lung". Circulation Research 49 (2): 326–336. August 1981. doi:10.1161/01.res.49.2.326. PMID 6113900. 
  37. ↑ "Antagonistic effects of bisoprolol on several beta-adrenoceptor-mediated actions in anaesthetized cats". European Journal of Pharmacology 123 (2): 253–261. April 1986. doi:10.1016/0014-2999(86)90666-7. PMID 3011461. 
  38. ↑ "Beta 1-selectivity of bisoprolol, a new beta-adrenoceptor antagonist, in anesthetized dogs and guinea pigs". Journal of Cardiovascular Pharmacology 6 (6): 1156–1160. 1984. doi:10.1097/00005344-198406060-00024. PMID 6084774. 
  39. ↑ "Binding properties of beta-blockers at recombinant beta1-, beta2-, and beta3-adrenoceptors". Journal of Cardiovascular Pharmacology 36 (4): 466–471. October 2000. doi:10.1097/00005344-200010000-00008. PMID 11026647. 
  40. ↑ "Beta-blocker selectivity at cloned human beta 1- and beta 2-adrenergic receptors". Cardiovascular Drugs and Therapy 13 (2): 123–126. April 1999. doi:10.1023/A:1007784109255. PMID 10372227. 
  41. ↑ "Affinity and selectivity of beta-adrenoceptor antagonists in vitro". Journal of Cardiovascular Pharmacology 8 (Suppl 11): S36–S40. 1986. doi:10.1097/00005344-198511001-00006. PMID 2439796. 
  42. ↑ "Beta 1-adrenoceptor selectivity of nebivolol and bisoprolol. A comparison of [3H]CGP 12.177 and [125I]iodocyanopindolol binding studies". European Journal of Pharmacology 460 (1): 19–26. January 2003. doi:10.1016/S0014-2999(02)02875-3. PMID 12535855. 
  43. ↑ "A comparison of the beta1-selectivity of three beta1-selective beta-blockers". Journal of Clinical Pharmacy and Therapeutics 28 (3): 179–186. June 2003. doi:10.1046/j.1365-2710.2003.00477.x. PMID 12795776. 
  44. ↑ 44.0 44.1 "Neuropsychiatric Consequences of Lipophilic Beta-Blockers". Medicina (Kaunas) 57 (2): 155. February 2021. doi:10.3390/medicina57020155. PMID 33572109. 
  45. ↑ "Bisoprolol". https://go.drugbank.com/drugs/DB00612. 
  46. ↑ "Pharmacokinetics of bisoprolol during repeated oral administration to healthy volunteers and patients with kidney or liver disease". Clinical Pharmacokinetics 13 (2): 110–117. August 1987. doi:10.2165/00003088-198713020-00003. PMID 2887325. 
  47. ↑ "Bisoprolol pharmacokinetics and body composition in patients with chronic heart failure: a longitudinal study". European Journal of Clinical Pharmacology 72 (7): 813–822. July 2016. doi:10.1007/s00228-016-2041-1. PMID 26996442. 
  48. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 461. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA461. 
  49. ↑ "Bisotab-Physician Information Page". Medical Dialogues. 22 August 2020. https://medicaldialogues.in/partner/jbcpl/bisotab-bisoprolol-fumarate-tablets. 

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