Nebivolol was patented in 1983 and came into medical use in 1997.[10] It is available as ageneric medication in the United Kingdom.[6] In 2023, it was the 191st most commonly prescribed medication in the United States, with more than 2million prescriptions.[11][12]
It is used to treathigh blood pressure andheart failure.[6] Nebivolol is used in the treatment of angina, to decrease the heart rate and contractile force. This is relevant in patients who need to decrease the oxygen demand of the heart so that the blood supplied from stenosed or constricted arteries is adequate.
Due to enzymatic inhibition,fluvoxamine increases the exposure to nebivolol and its active hydroxylated metabolite (4-OH-nebivolol) in healthy volunteers.[18]
Beta blockers help patients with cardiovascular disease by blocking β1 receptors, while many of the side-effects of these medications are caused by their blockade of β2 receptors.[19] For this reason, beta blockers that selectively block β1adrenergic receptors (termed cardioselective or β1-selective beta blockers) produce fewer adverse effects (for instance, bronchoconstriction) than those drugs that non-selectively block both β1 and β2 receptors.
In a laboratory experiment conducted on biopsied heart tissue, nebivolol proved to be the most β1-selective of theβ-blockers tested, being approximately 3.5 times more β1-selective thanbisoprolol.[20] However, the drug's receptor selectivity in humans is more complex and depends on the drug dose and the genetic profile of the patient taking the medication.[21] The drug is highly cardioselective at 5 mg.[22] In addition, at doses above 10 mg, nebivolol loses its cardioselectivity and blocks both β1 and β2 receptors,[21] while the recommended starting dose of nebivolol is 5 mg, sufficient control of blood pressure may require doses up to 40 mg.[21] Furthermore, nebivolol is also not cardioselective when taken by patients with a genetic makeup that makes them "poor metabolizers" of nebivolol (and other drugs) or with CYP2D6 inhibitors.[21] As many as 1 in 10 Caucasian people and even more black people arepoor CYP2D6 metabolizers and therefore might benefit less from nebivolol's cardioselectivity although currently there are no directly comparable studies.[citation needed]
Nebivolol[23] while selectively blocking beta(1) receptor acts as abeta(3)-agonist. β3 receptors are found in thegallbladder,urinary bladder, and inbrown adipose tissue. Their role in gallbladder physiology is unknown, but they are thought to play a role in lipolysis and thermogenesis in brown fat. In the urinary bladder it is thought to cause relaxation of the bladder and prevention of urination.[24][25][26]
Nebivolol is unique as a beta-blocker.[27] Unlikecarvedilol, it has anitric oxide (NO)-potentiating, vasodilatory effect via stimulation of β3 receptors.[28][29][30]
Nebivolol induces vasodilation by stimulating the production of nitric oxide, a natural blood vessel relaxant. This effect is achieved by activating the endothelial isoform ofNO synthase (eNOS) in the cells lining the blood vessels. Unlike traditional β-blockers, nebivolol's unique mechanism of action improves arterial flexibility and reducesperipheral resistance, making it beneficial for hypertensive patients withendothelial dysfunction. The drug's ability to increase NO production persists even aftermetabolism, offering long-lasting benefits. Nebivolol's distinct approach to promoting NO release has shown promising results in improving endothelial function and managing hypertension in clinical trials.[31]
Along withlabetalol,celiprolol andcarvedilol, it is one of four beta blockers to cause dilation of blood vessels in addition to effects on the heart.[30]
Nebivolol lowers blood pressure (BP) by reducingperipheral vascular resistance, and significantly increasesstroke volume with preservation of cardiac output.[32] The net hemodynamic effect of nebivolol is the result of a balance between the depressant effects of beta-blockade and an action that maintains cardiac output.[33] Antihypertensive responses were significantly higher with nebivolol than with placebo in trials enrolling patient groups considered representative of the U.S. hypertensive population, in black people, and in those receiving concurrent treatment with other antihypertensive drugs.[34]
The experimentallog P of nebivolol is 4.18 and its predicted log P ranges from 2.44 to 4.21.[38][39][40][41] It is a highly lipophilic beta blocker.[36][41] The drug showed the fourth highest predicted lipophilicity of 30clinically relevant beta blockers, with the most lipophilic beta blockers predicted to bebopindolol,penbutolol, andcarvedilol.[41]
Mylan Laboratories licensed the US and Canadian rights to nebivolol fromJanssen Pharmaceutica N.V. in 2001. Nebivolol is already registered and successfully marketed in more than 50 countries, including the United States where it is marketed under the brand name Bystolic fromMylan Laboratories andForest Laboratories. Nebivolol is manufactured by Forest Laboratories.
In India, nebivolol is available as Nebula (Zydus Healthcare Ltd), Nebizok (Eris life-sciences), Nebicip (Cipla ltd), Nebilong (Micro Labs), Nebistar (Lupin ltd), Nebicard (Torrent), Nubeta (Abbott Healthcare Pvt Ltd – India), and Nodon (Cadila Pharmaceuticals).
In Greece and Italy, nebivolol is marketed byMenarini as Lobivon.
In Germany it is marketed as Nebilet byBerlin Chemie.
In the Middle East, Russia and Australia, it is marketed under the name Nebilet and in Pakistan it is marketed by The Searle Company Limited as Byscard.
Bystolic is associated with a number of serious risks. Bystolic is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh > B) and in patients who are hypersensitive to any component of the product. Bystolic therapy is also associated with warnings regarding abrupt cessation of therapy, cardiac failure, angina and acute myocardial infarction, bronchospastic diseases, anesthesia and major surgery, diabetes and hypoglycemia, thyrotoxicosis, peripheral vascular disease, non-dihydropyridine calcium channel blockers use, as well as precautions regarding use with CYP2D6 inhibitors, impaired renal and hepatic function, and anaphylactic reactions. Finally, Bystolic is associated with other risks as described in the Adverse Reactions section of its PI. For example, a number of treatment-emergent adverse events with an incidence greater than or equal to 1 percent in Bystolic-treated patients and at a higher frequency than placebo-treated patients were identified in clinical studies, including headache, fatigue, and dizziness.
In August 2008, the FDA issued aWarning Letter to Forest Laboratories citing exaggerated and misleading claims in their launch journal ad, in particular over claims of superiority and novelty of action.[45]
^Seleme VB, Marques GL, Mendes AE, Rotta I, Pereira M, Júnior EL, da Cunha CL (March 2021). "Nebivolol for the Treatment of Essential Systemic Arterial Hypertension: A Systematic Review and Meta-Analysis".American Journal of Cardiovascular Drugs.21 (2):165–180.doi:10.1007/s40256-020-00422-0.PMID32710438.S2CID220732879.
^National Heart Foundation of Australia. National Blood Pressure and Vascular DiseaseAdvisory Committee (2016).Guideline for the diagnosis and management of hypertension in adults. Melbourne, Vic.ISBN978-1-74345-110-6.OCLC970693159.{{cite book}}: CS1 maint: location missing publisher (link)
^Bundkirchen A, Brixius K, Bölck B, Nguyen Q, Schwinger RH (January 2003). "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.doi:10.1016/S0014-2999(02)02875-3.PMID12535855.
^Nuttall SL, Routledge HC, Kendall MJ (June 2003). "A comparison of the beta1-selectivity of three beta1-selective beta-blockers".Journal of Clinical Pharmacy and Therapeutics.28 (3):179–186.doi:10.1046/j.1365-2710.2003.00477.x.PMID12795776.S2CID58760796.
^Rozec B, Erfanian M, Laurent K, Trochu JN, Gauthier C (April 2009). "Nebivolol, a vasodilating selective beta(1)-blocker, is a beta(3)-adrenoceptor agonist in the nonfailing transplanted human heart".Journal of the American College of Cardiology.53 (17):1532–1538.doi:10.1016/j.jacc.2008.11.057.PMID19389564.
^Sawa M, Harada H (2006). "Recent developments in the design of orally bioavailable beta3-adrenergic receptor agonists".Current Medicinal Chemistry.13 (1):25–37.doi:10.2174/092986706775198006.PMID16457637.
^abBakris G (May 2009). "An in-depth analysis of vasodilation in the management of hypertension: focus on adrenergic blockade".Journal of Cardiovascular Pharmacology.53 (5):379–387.doi:10.1097/FJC.0b013e31819fd501.PMID19454898.S2CID205598744.
^Kamp O, Sieswerda GT, Visser CA (August 2003). "Comparison of effects on systolic and diastolic left ventricular function of nebivolol versus atenolol in patients with uncomplicated essential hypertension".The American Journal of Cardiology.92 (3):344–348.doi:10.1016/S0002-9149(03)00645-3.PMID12888152.
^Gielen W, Cleophas TJ, Agrawal R (August 2006). "Nebivolol: a review of its clinical and pharmacological characteristics".International Journal of Clinical Pharmacology and Therapeutics.44 (8):344–357.doi:10.5414/cpp44344.PMID16961165.
^abcHanif N, Zamir A, Imran I, Saeed H, Majeed A, Rehman AU, Ashraf W, Alqahtani F, Rasool MF (November 2023). "Clinical pharmacokinetics of nebivolol: a systematic review".Drug Metab Rev.55 (4):428–440.doi:10.1080/03602532.2023.2271195.PMID37849071.
^abOlawi N, Krüger M, Grimm D, Infanger M, Wehland M (September 2019). "Nebivolol in the treatment of arterial hypertension".Basic Clin Pharmacol Toxicol.125 (3):189–201.doi:10.1111/bcpt.13248.PMID31066991.
^abcMannhold R (February 2005). "The impact of lipophilicity in drug research: a case report on beta-blockers".Mini Rev Med Chem.5 (2):197–205.doi:10.2174/1389557053402701.PMID15720289.
^Poirier L, Cléroux J, Nadeau A, Lacourcière Y (August 2001). "Effects of nebivolol and atenolol on insulin sensitivity and haemodynamics in hypertensive patients".Journal of Hypertension.19 (8):1429–1435.doi:10.1097/00004872-200108000-00011.PMID11518851.S2CID35105142.
^abThomas Abrams (28 August 2008)."Warning Letter"(PDF). Food and Drug Administration. Archived fromthe original(PDF) on 28 April 2017. Retrieved16 December 2019.FDA is not aware of any substantial evidence or substantial clinical experience that demonstrates that Bystolic represents a 'novel' or 'next generation' beta blocker for the treatment of hypertension. Indeed, we are not aware of any well-designed trials comparing Bystolic to other β-blockers. Furthermore, FDA is not aware of any data that would render Bystolic's mechanism of action 'unique.'
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