|Systematic (IUPAC) name|
|Trade names||Nebilet, Bystolic|
|Licence data||US FDA:|
|Biological half-life||10 hours|
|Excretion||Renal and fecal|
|CAS Registry Number|
|Molecular mass||405.435 g/mol|
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. It is highly cardioselective under certain circumstances.
Pharmacology and biochemistry 1
- β1 Selectivity 1.1
- Vasodilator action 1.2
- Antihypertensive effect 1.3
- Pharmacology of side-effects 1.4
- FDA warning letter about advertising claims 1.5
- Contraindications 2
- Adverse drug reactions 3
- History 4
- Synthesis 5
- References 6
- External links 7
Pharmacology and biochemistry
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. 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. 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. The drug is highly cardioselective at 5 mg. In addition, at doses above 10 mg, nebivolol loses its cardioselectivity and blocks both β1 and β2 receptors. (While the recommended starting dose of nebivolol is 5 mg, sufficient control of blood pressure may require doses up to 40 mg). 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. 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.
Nebivolol is unique as a beta-blocker. Unlike carvedilol, it has a nitric oxide (NO)-potentiating, vasodilatory effect. 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. However, recent studies question the clinical relevance of this property to Nebivolol's efficacy.
Nebivolol lowers blood pressure (BP) by reducing peripheral vascular resistance, and significantly increases stroke volume with preservation of cardiac output. 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. 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.
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. However, according to the FDA
|“||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.||”|
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.
- Hepatic insufficiency
Adverse drug reactions
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 Nebistol (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.
Exhaustive hydrogenation of the chromone (1) leads to a reduction of both the olefin and the ketone group (cf. ablukast also). The carboxylic acid then undergoes partial reduction to an aldehyde (2) by means of DIBAL. Reaction of that intermediate with the ylide from trimethylsulfonium iodide gives the oxirane (3) via an addition-displacement process. Treatment of an excess of that epoxide with benzylamine leads to the addition of two equivalents of that compound with each basic nitrogen (4). The product is then debenzylated by catalytic reduction over palladium to afford nebivolol (5). The presence of four chiral centers in the product predicts existence of 16 chiral pairs.
- de Boer RA, Voors AA, van Veldhuisen DJ (July 2007). "Nebivolol: third-generation beta-blockade". Expert Opin Pharmacother 8 (10): 1539–50.
- Tafreshi MJ, Weinacker AB (August 1999). "Beta-adrenergic-blocking agents in bronchospastic diseases: a therapeutic dilemma". Pharmacotherapy 19 (8): 974–8.
- 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.
- "Prescribing information for Bystolic" (PDF). Retrieved 2009-06-11.
- 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.
- Agabiti Rosei E, Rizzoni D (2007). "Metabolic profile of nebivolol, a beta-adrenoceptor antagonist with unique characteristics". Drugs 67 (8): 1097–107.
- Weiss R (2006). "Nebivolol: a novel beta-blocker with nitric oxide-induced vasodilatation". Vasc Health Risk Manag 2 (3): 303–8.
- 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.
- National Prescribing Service (1 March 2010). "Nebivolol (Nebilet) for chronic heart failure". Retrieved 12 March 2010.
- 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.
- 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.
- Baldwin CM, Keam SJ. Nebivolol: In the Treatment of Hypertension in the US. Am J Cardiovasc Drugs 2009; 9 (4): 253-260. Link text
- Pessina AC (December 2001). "Metabolic effects and safety profile of nebivolol". J. Cardiovasc. Pharmacol. 38. Suppl 3: S33–5.
- Weber MA (December 2005). "The role of the new beta-blockers in treating cardiovascular disease". Am. J. Hypertens. 18 (12 Pt 2): 169S–176S.
- 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.
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.'
- Prescribing Information for BYSTOLIC