Nebivolol is a third generation beta-adrenergic receptor blocker with vasodilating properties. It has the highest affinity for beta-1 receptors when compared to other beta-blockers (BB). Due to the leverage effect on endothelial nitric oxide synthase (eNOS) and its antioxidant activity, nebivolol significantly improves the endothelial function.
Endothelial function and dysfunction
Endothelium modulates the function of blood vessels and provides structural integrity. Endothelial cells synthesize nitric oxide (NO), which has powerful anti sclerosis activity and, along with prostacyclin, inhibits platelet aggregation, the neutrophil adhesion to endothelial cells, and the expression of inflammatory molecules. At a higher concentration NO inhibits smooth muscle cell proliferation.
The endothelial dysfunction treatment should aim not only to increase the NO level, but also to reduce the free radicals which neutralize it – superoxide and peroxynitrite.
It has been established that medicaments which are limited to the delivery of NO – like organic nitrates – due to the stimulation of the production of peroxynitrite worsen rather than improve the endothelial function.
The ideal drug for endothelial dysfunction treatment should stimulate the NO synthesis and simultaneously reduce the oxidative stress in the vessel wall.
Nebivolol is a third generation BB with vasodilating properties, thanks to its direct stimulating effect on eNOS. The mechanisms of action include a negative chronotropic effect, the inhibition of sympathetic stimuli from the brain vasomotor centers, the inhibition of peripheral alpha-1 adrenoceptors, the inhibition of renin activity and a decrease in peripheral vascular resistance.
The high selectivity for β1- versus β2-adrenergic receptors explains the limited effects of nebivolol on airway reactivity and insulin sensitivity, as well as the lesser negative inotropic action of the drug in patients with heart failure (HF).
As in other BB, nebivolol has important electrophysiological properties, such as increasing the threshold of ventricular fibrillation, and reducing the dispersion of the QT interval and P wave, which is associated with risk reduction for ventricular arrhythmia and atrial fibrillation.
The indications for the application of nebivolol include arterial hypertension (AH), chronic heart failure (HF) and ischemic heart disease (IHD).
The efficacy and safety of nebivolol in doses of 5 and 10 mg in patients with hypertension grades I and ΙΙ have been demonstrated in numerous clinical studies. The response of systolic blood pressure (BP) to nebivolol is similar to the use of other BB and calcium channel blockers (CCBs), and is more pronounced than that of angiotensin-converting enzyme inhibitors.
The effect of the drug on diastolic blood pressure is not so pronounced, contributing to the safety of nebivolol.
Large randomized trials and meta-analyzes have demonstrated that BB reduce morbidity and mortality in patients with chronic heart failure by about 30%. This effect is due to the decrease of adrenergic stimulation, modulating the balance between sympathetic and parasympathetic activity, influencing the heart rate and variability, and improving the myocardial function.
It is important to note that while other BB act mainly by decreasing the stroke volume, nebivolol and carvedilol cause peripheral vasodilatation, maintain the stroke volume, the cardiac output, and the chronotropic response during exercise.
Moreover, compared with bisoprolol, nebivolol and carvedilol do not lead to an increase of the pulmonary capillary wedge pressure (but rather improve it).
The average age of the patients included in trials with the use of BB in heart failure was 60 years. In this respect, SENIORS was an exception, as it included patients over the age of 70. It established a 14% reduction in all-cause mortality and improvement of the cardiac dimensions and function when nebivolol was used, as compared to placebo.
Ischemic heart disease
There is evidence that in comparison with atenolol, nebivolol more effectively improves exercise tolerance and time to onset of chest pain during ECG stress tests.
Moreover, nebivolol and carvedilol increase the coronary flow reserve in patients with Ischemic heart disease and non-ischemic cardiomyopathy more effectively compared to other BB, which is probably associated with an increased ischemic threshold.
Nebivolol is contraindicated in patients with severe bradycardia, atrioventricular block above the second degree, cardiogenic shock, decompensated heart failure and severe liver diseases failure.
Tolerability and safety profile
In patients with bronchial asthma and chronic obstructive pulmonary disease, the higher selectivity of nebivolol to beta-1 receptors compared to other BB results in better tolerance.
For the same reason nebivolol has no adverse effects on the libido and the sexual function. On the contrary, there is evidence that the drug improved erectile dysfunction, which could significantly increase the compliance of patients. Due to its vasodilatory effect (and unlike older beta-1 selective BB), nebivolol does not lead to the deterioration of insulin sensitivity and an increased risk of type 2 diabetes (neutral metabolic profile). It has no adverse effects on lipid parameters.