Nebivolol

Nebivolol
Clinical data
Trade names Nebilet, Bystolic
AHFS/Drugs.com Monograph
MedlinePlus a608029
License data
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    administration    		 Oral
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Protein binding 98%
    Metabolism Hepatic (CYP2D6-mediated)
    Elimination half-life 10 hours
    Excretion Renal and fecal
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEMBL
    Chemical and physical data
    Formula C22H25F2NO4
    Molar mass 405.435 g/mol
    3D model (JSmol)
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    Nebivolol is a β1 receptor blocker with nitric oxide-potentiating vasodilatory effect used in treatment of hypertension and, in Europe, also for left ventricular failure.[1] It is highly cardioselective under certain circumstances.[1] Nebivolol has also been paired with another blood pressure lowering medication, the angiotensin receptor blocker valsartan.

    Pharmacology and biochemistry

    β1-selectivity

    Beta blockers help patients with cardiovascular disease by blocking β receptors, while many of the side-effects of these medications are caused by their blockade of β2 receptors.[2] For this reason, beta blockers that selectively block β1 adrenergic 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 the β-blockers tested, being approximately 3.5 times more β1-selective than bisoprolol.[3] 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.[4] The drug is highly cardioselective at 5 mg.[5] In addition, at doses above 10 mg, nebivolol loses its cardioselectivity and blocks both β1 and β2 receptors.[4] (While the recommended starting dose of nebivolol is 5 mg, sufficient control of blood pressure may require doses up to 40 mg).[4] 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.[4] As many as 1 in 10 whites and even more blacks are poor CYP2D6 metabolizers and therefore might benefit less from nebivolol's cardioselectivity although currently there are no directly comparable studies.

    Due to enzymatic inhibition, fluvoxamine increases the exposure to nebivolol and its active hydroxylated metabolite (4-OH-nebivolol) in healthy volunteers.[6]

    Vasodilator action

    Nebivolol is unique as a beta-blocker.[7] Unlike carvedilol, it has a nitric oxide (NO)-potentiating, vasodilatory effect via stimulation of β3 receptors.[8][9][10] Along with labetalol, celiprolol and carvedilol, it is one of four beta blockers to cause dilation of blood vessels in addition to effects on the heart.[10]

    Antihypertensive effect

    Nebivolol lowers blood pressure (BP) by reducing peripheral vascular resistance, and significantly increases stroke volume with preservation of cardiac output.[11] 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.[12] 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 patients, and in those receiving concurrent treatment with other antihypertensive drugs.[13]

    Pharmacology of side-effects

    Several studies have suggested that nebivolol has reduced typical beta-blocker-related side effects, such as fatigue, clinical depression, bradycardia, or impotence.[14][15][16] However, according to the FDA[17]

    FDA warning letter about advertising claims

    In late August 2008, the FDA issued a Warning Letter to Forest Laboratories citing exaggerated and misleading claims in their launch journal ad, in particular over claims of superiority and novelty of action.[17]

    Contraindications

    • Severe bradycardia
    • Heart block greater than first degree
    • Patients with cardiogenic shock
    • Decompensated cardiac failure
    • Sick sinus syndrome (unless a permanent pacemaker is in place)
    • Patients with severe hepatic impairment (Child-Pugh class B)
    • Patients who are hypersensitive to any component of this product.

    Adverse drug reactions

    History

    Mylan Laboratories licensed the U.S. and Canadian rights to nebivolol from Janssen 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 from Mylan Laboratories and Forest Laboratories. Nebivolol is manufactured by Forest Laboratories.

    In India, nebivolol is available as 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 by Menarini as Lobivon. In the Middle East, Russia and in Australia, it is marketed under the name Nebilet and in Pakistan it is marketed by The Searle Company Limited as Byscard.


    References

    1. 1 2 de Boer RA, Voors AA, van Veldhuisen DJ (July 2007). "Nebivolol: third-generation beta-blockade". Expert Opin Pharmacother. 8 (10): 1539–50. doi:10.1517/14656566.8.10.1539. PMID 17661735.
    2. ↑ Tafreshi MJ, Weinacker AB (August 1999). "Beta-adrenergic-blocking agents in bronchospastic diseases: a therapeutic dilemma". Pharmacotherapy. 19 (8): 974–8. doi:10.1592/phco.19.11.974.31575. PMID 10453968.
    3. ↑ 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". Eur. J. Pharmacol. 460 (1): 19–26. doi:10.1016/S0014-2999(02)02875-3. PMID 12535855.
    4. 1 2 3 4 "Prescribing information for Bystolic" (PDF). Retrieved 2009-06-11.
    5. ↑ Nuttall SL, Routledge HC, Kendall MJ (June 2003). "A comparison of the beta1-selectivity of three beta1-selective beta-blockers". J Clin Pharm Ther. 28 (3): 179–86. doi:10.1046/j.1365-2710.2003.00477.x. PMID 12795776.
    6. ↑ Gheldiu, Ana-Maria; Vlase, Laurian; Popa, Adina; Briciu, Corina; Muntean, Dana; Bocsan, Corina; Buzoianu, Anca; Achim, Marcela; Tomuta, Ioan (2017). "Investigation of a Potential Pharmacokinetic Interaction Between Nebivolol and Fluvoxamine in Healthy Volunteers". Journal of Pharmacy & Pharmaceutical Sciences: A Publication of the Canadian Society for Pharmaceutical Sciences, Societe Canadienne des Sciences Pharmaceutiques. 20: 68–80. ISSN 1482-1826. PMID 28459657.
    7. ↑ Agabiti Rosei E, Rizzoni D (2007). "Metabolic profile of nebivolol, a beta-adrenoceptor antagonist with unique characteristics". Drugs. 67 (8): 1097–107. doi:10.2165/00003495-200767080-00001. PMID 17521213.
    8. ↑ Galougahi, Keyvan (February 19, 2016). "β3 Adrenergic Stimulation Restores Nitric Oxide/Redox Balance and Enhances Endothelial Function in Hyperglycemia". JAHA. 5 (2): e002824. doi:10.1161/JAHA.115.002824. PMC 4802476. PMID 26896479.
    9. ↑ Weiss R (2006). "Nebivolol: a novel beta-blocker with nitric oxide-induced vasodilatation". Vasc Health Risk Manag. 2 (3): 303–8. doi:10.2147/vhrm.2006.2.3.303. PMC 1993984. PMID 17326335.
    10. 1 2 Bakris G (May 2009). "An in-depth analysis of vasodilation in the management of hypertension: focus on adrenergic blockade". J. Cardiovasc. Pharmacol. 53 (5): 379–87. doi:10.1097/FJC.0b013e31819fd501. PMID 19454898.
    11. ↑ 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". Am. J. Cardiol. 92 (3): 344–8. doi:10.1016/S0002-9149(03)00645-3. PMID 12888152.
    12. ↑ Gielen W, Cleophas TJ, Agrawal R (August 2006). "Nebivolol: a review of its clinical and pharmacological characteristics". Int J Clin Pharmacol Ther. 44 (8): 344–57. doi:10.5414/cpp44344. PMID 16961165.
    13. ↑ Baldwin CM, Keam SJ. Nebivolol: In the Treatment of Hypertension in the US. Am J Cardiovasc Drugs 2009; 9 (4): 253-260. Link text
    14. ↑ Pessina AC (December 2001). "Metabolic effects and safety profile of nebivolol". J. Cardiovasc. Pharmacol. 38. Suppl 3: S33–5. PMID 11811391.
    15. ↑ Weber MA (December 2005). "The role of the new beta-blockers in treating cardiovascular disease". Am. J. Hypertens. 18 (12 Pt 2): 169S–176S. doi:10.1016/j.amjhyper.2005.09.009. PMID 16373195.
    16. ↑ Poirier L, Cléroux J, Nadeau A, Lacourcière Y (August 2001). "Effects of nebivolol and atenolol on insulin sensitivity and haemodynamics in hypertensive patients". J. Hypertens. 19 (8): 1429–35. doi:10.1097/00004872-200108000-00011. PMID 11518851.
    17. 1 2 Thomas Abrams (2008-08-28). "Warning Letter" (PDF). Food and Drug Administration. Retrieved 2008. 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.' Check date values in: |accessdate= (help)

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