Pharmacotherapeutic Group: Beta-blocking agent, selective.
Pharmacology: Pharmacodynamics: Nebivolol is a racemate of 2 enantiomers, SRRR-Nebivolol (or d-Nebivolol) and RSSS-Nebivolol (or l-Nebivolol). It combines 2 pharmacological activities: It is a competitive and selective β-receptor antagonist: This effect is attributed to the SRRR-enantiomer (d-enantiomer).
It has mild vasodilating properties due to an interaction with the L-arginine/nitric oxide pathway.
Single and repeated doses of nebivolol reduce heart rate and blood pressure at rest and during exercise, both in normotensive subjects and in hypertensive patients. The antihypertensive effect is maintained during chronic treatment. At therapeutic doses, nebivolol is devoid of α-adrenergic antagonism.
During acute and chronic treatment with nebivolol in hypertensive patients, systemic vascular resistance is decreased. Despite heart rate reduction, reduction in cardiac output during rest and exercise may be limited due to an increase in stroke volume. The clinical relevance of these hemodynamic differences as compared to other β1-receptor antagonists has not been fully established.
In hypertensive patients, nebivolol increases the nitric oxide-mediated vascular response to acetylcholine (ACh) which is reduced in patients with endothelial dysfunction.
In a mortality-morbidity, placebo-controlled trial performed in 2128 patients ≥70 years (median age 75.2 years) with stable chronic heart failure with or without impaired left ventricular ejection fraction (LVEF) (Mean LVEF: 36 ≥12.3%, with the following distribution: LVEF <35% in 56% of patients, LVEF between 35% and 45% in 25% of patients and LVEF >45% in 19% of patients) followed for a mean time of 20 months, nebivolol, on top of standard therapy, significantly prolonged the time to occurrence of deaths or hospitalizations for cardiovascular reasons (primary endpoint for efficacy) with a relative risk reduction of 14% (Absolute Reduction: 4.2%). This risk reduction developed after 6 months of treatment and was maintained for all treatment duration (Median Duration: 18 months). The effect of nebivolol was independent from age, gender or LVEF of the population on study. The benefit on all cause mortality did not reach statistical significance in comparison to placebo (Absolute Reduction: 2.3%). A decrease in sudden death was observed in nebivolol treated patients (4.1% vs 6.6%, relative reduction of 38%).
In vitro and in vivo experiments in animals showed that nebivolol has no intrinsic sympathicomimetic activity.
In vitro and in vivo experiments in animals showed that at pharmacological doses, nebivolol has no membrane stabilizing action.
In healthy volunteers, nebivolol has no significant effect on maximal exercise capacity or endurance.
Pharmacokinetics: Both nebivolol enantiomers are rapidly absorbed after oral administration. The absorption of nebivolol is not affected by food; nebivolol can be given with or without meals. Nebivolol is extensively metabolized, partly to active hydroxymetabolites. It is metabolized via alicyclic and aromatic hydroxylation, N-dealkylation and glucuronidation; in addition, glucuronides of the hydroxy-metabolites are formed. The metabolism of nebivolol by aromatic hydroxylation is subject to the CYP2D6 dependent genetic oxidative polymorphism. The oral bioavailability of nebivolol averages 12% in fast metabolizers and is virtually complete in slow metabolizers. At steady state and at the same dose level, the peak plasma concentration of unchanged nebivolol is about 23 times higher in poor metabolizers than in extensive metabolizers. When unchanged drug plus active metabolites are considered, the difference in peak plasma concentrations is 1.3- to 1.4-fold. Because of the variation in rates of metabolism, the dose of Nebilet should always be adjusted to the individual requirements of the patient. Poor metabolizers therefore may require lower doses.
In fast metabolizers, elimination t½ of the nebivolol enantiomers average 10 hrs. In slow metabolizers, they are 3-5 times longer. In fast metabolizers, plasma levels of the RSSS-enantiomer are slightly higher than for the SRRR-enantiomer. In slow metabolizers, this difference is larger. In fast metabolizers, elimination t½ of the hydroxymetabolites of both enantiomers average 24 hrs, and are about twice as long in slow metabolizers. Steady-state plasma levels in most subjects (fast metabolizers) are reached within 24 hrs for nebivolol and within a few days for the hydroxy-metabolites.
Plasma concentrations are dose-proportional between 1 and 30 mg. The pharmacokinetics of nebivolol are not affected by age. In plasma, both nebivolol enantiomers are predominantly bound to albumin. Plasma protein-binding is 98.1% for SRRR-Nebivolol and 97.9% for RSSS-Nebivolol.
One week after administration, 38% of the dose is excreted in the urine and 48% in the feces. Urinary excretion of unchanged nebivolol is <0.5% of the dose.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of genotoxicity and carcinogenic potential.