Nebivolol

Structural formula
Mixture of stereoisomers - structural formula without stereochemistry
General
Non-proprietary name	Nebivolol
other names	α, α´- [Iminobis (methylene)] bis [6-fluoro-3,4-dihydro-2 H -1-benzo-pyran-2-methanol] α, α´- [Iminobis (methylene)] - bis [6-fluorochroman-2-methanol]
Molecular formula	C 22 H 25 F 2 NO 4
External identifiers / databases
CAS number 99200-09-6 (unspecified stereochemistry) 118457-14-0 [(α R *, α ′ R *, 2 R *, 2 ′ S *) - nebivolol] PubChem 71301 DrugBank DB04861 Wikidata Q418130
Drug information
ATC code	C07 AB12
Drug class	β-receptor blockers
Mechanism of action	highly selective blockade of β1 receptors and NO-dependent vascular vasodilation
properties
Molar mass	405.44 g mol −1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Caution H and P phrases H: 302 P: 264-270-301 + 312-330-501
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Nebivolol is a drug from the group of selective β ₁ -adrenoreceptor blockers ( beta blockers ) that is used to lower high blood pressure .

Stereoisomerism

Nebivolol is a 1: 1 mixture ( racemate ) of the two enantiomers (α R , α ' R , 2 R , 2' S ) - and (α S , α ' S , 2 S , 2' R ) -Nebivolol. Both enantiomers are involved in the effect. The active stereoisomer ( eutomer ) is the (α R , α ' R , 2 R , 2' S ) form of nebivolol.

Mode of action

As a representative of the 3rd generation of beta blockers, nebivolol has two mechanisms of action: in addition to the highly selective blockade of the β ₁ -adrenoceptors (which is characteristic of representatives of the 2nd generation) by D- nebivolol, L- nebivolol also acts on the endothelial cells of the vessels. In contrast to conventional beta blockers, it has a vasodilating effect due to the release of nitric oxide in the endothelial cells. As a result, there is a markedly improved endothelial function and an improvement in hemodynamics . Compared to conventional beta blockers, this active principle leads to improved circulation in the macro and micro vessels. The beta blockers Celiprolol and Carvedilol also have a vasodilating effect . Until 2012, however, studies could not prove whether this peculiarity has a positive influence on morbidity and mortality .

Application areas (indications)

Nebivolol is indicated for the treatment of high blood pressure and as an addition to standard therapies for the treatment of stable mild to moderate chronic heart failure ( heart failure ) in the elderly (over 70 years of age).

Contraindications (contraindications)

Nebivolol must not be taken in case of hepatic insufficiency or impaired liver function, acute heart failure , bronchospasm and bronchial asthma , bradycardia , severe peripheral circulatory disorders such as Raynaud's syndrome ("white fingers", white and numb toes) and hypotension .

Side effects

The following undesirable drug effects can occur: headache, dizziness, nausea, fatigue, edema and occasionally nightmares, visual disturbances, slowing of the heart rate ( bradycardia ).

Interactions

If paroxetine is taken at the same time, inhibition (enzyme inhibition) of the isoenzyme cytochrome P450 2D6 can lead to an increased nebivolol blood level and there is therefore a risk of cardiac arrhythmia with a slow pulse.

Development and marketing

Nebivolol was jointly developed by Menarini and Janssen Pharmaceutica as a 3rd generation beta blocker. In Germany, nebivolol was approved as a medicinal product for oral administration in the indication area high blood pressure in 1996 under the name Nebilet and came onto the market in 1997.

Janssen Pharmaceutica licensed the drug to Mylan Laboratories in 2001 for the US and Canadian markets .

At the beginning of 2008, the companies Hexal AG and Sandoz brought the first Nebivolol generics onto the market in Germany. Their legality was disputed because the originator Berlin-Chemie asserted patent protection until October 2010, against which some generic companies had brought nullity suits. The controversy was also explosive against the background that health insurance companies had concluded discount agreements with the generics companies , which on the one hand obliged the pharmacies to deliver, but on the other hand exposed them to possible claims for damages by Berlin-Chemie. The Federal Patent Court declared the patent for Nebilet null and void in June 2008 and the case went to the Federal Court of Justice , where it is still pending. Intermediaries (wholesalers) did not sell any nebivolol generics due to the ongoing legal uncertainty. After nebivolol was removed from the discount agreements, various generic companies withdrew their nebivolol drugs from the market in the course of 2009; In addition to the pending patent disputes, according to the companies, economic reasons played a role due to the pressure of the fixed price regulations . Since the patent expired at the end of October 2010, the generics market is now open to all competitors.

Trade names

Bystolic (USA), Hypoloc (A, DK, IS, IRE, NO, SE, UK), Lobivon (GR, ES), Nebilet (D, CH, PT), Nebilox (IT), Nobiten (LUX), Nomexor ( A), Temerit (FR), various generics (A, D)

Individual evidence

1. ↑ ^{a b} Registration dossier for 2H-1-Benzopyran-2-methanol, a, a '- [iminobis (methylene)] to [6-fluoro-3,4-dihydro-, (aR, a'R, 2R, 2'S) -rel- ( GHS section ) at the European Chemicals Agency (ECHA), accessed on July 8, 2020.
2. ↑ External identifiers of or database links to (αR *, α′R *, 2R *, 2′S *) - Nebivolol : CAS number: 118457-14-0, EC number: 601-527-4, ECHA InfoCard: 100.122.074 , Wikidata : Q64769175 .
3. ↑ Joni Agustiana, Azlina Harun Kamaruddina, Subhash Bhatiaa: Single enantiomeric β-blockers - The existing technologies . In: Process Biochemistry . tape 45 , no. 10 , 2010, p. 1587-1604 , doi : 10.1016 / j.procbio.2010.06.022 .
4. ↑ "BETTERBLOCKER" NEBIVOLOL (NEBILET). (25.6 kB; PDF) In: at 1997; No. 2: 17-8. ATI Arzneimittelformation Berlin GmbH, March 25, 2000, p. 18 , accessed on September 26, 2010 : “Speculations about a special position due to a“ dual point of attack ”due to vasodilating effects, which also have beta blockers such as Celiprolol (SELECTOL etc.), must go through Evidence of a positive influence on morbidity and mortality can be clinically confirmed ”  .
5. ↑ Torsten Kratz, Albert Diefenbacher: Psychopharmacotherapy in old age. Avoidance of drug interactions and polypharmacy. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f. (July 22) 2019, pp. 508-517, p. 510.
6. ^ S. Czajka: Nebivolol: a new beta blocker. In: Pharmaceutical newspaper . No. 17 (1997).
7. ↑ D. Kietzmann: Nebivolol manufacturers withdraw. In: Apotheke Adhoc. August 25, 2009. Retrieved October 7, 2017.

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