Nebivolol in the Management of Essential Hypertension

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Abstract
Nebivolol is a lipophilic β1-blocker. It is devoid of intrinsic sympathomimetic or membrane stabilising activity but appears to have nitric oxide-mediated vasodilatory effects. Nebivolol is administered as aracemic mixture of equal proportions of d- and l-enantiomers. The drug does not significantly influence glucose or plasma lipid metabolism and appears to have a protective effect on left ventricular function. At the recommended dosage (5mg once daily) nebivolol reduces resting diastolic blood pressure as effectively as standard therapeutic dosages of atenolol, metoprolol, lisinopril and nifedipine, as shown in comparative trials. Nebivolol reduced blood pressure significantly more than enalapril 10mg daily in the short but not the long term, although the enalapril dose may not have been optimal. Nebivolol has an additive effect in combination with hydrochlorothiazide. Standing blood pressure and/or mean 24-hour ambulatory blood pressure is significantly and similarly reduced with nebivolol, atenolol or nifedipine. Nebivolol tended to prevent increases in early morning blood pressure better than nifedipine. Overall response rates to nebivolol therapy (a decrease in sitting/supine diastolic blood pressure to ≤90mm Hg or a 10% or ≥10mm Hg fall in diastolic blood pressure) ranged from 58 to 81% after 4 to 52 weeks’ treatment. In comparative studies, response rates were greater in nebivolol than in enalapril or metoprolol recipients, but not significantly different from those in atenolol or nifedipine recipients. Nebivolol 5mg once daily is well tolerated in patients with hypertension. Adverse events are infrequent, transient and mild to moderate. Those reported most often include headache, fatigue, paraesthesias and dizziness. Several studies reported no signs of orthostatic hypotension with nebivolol. Comparative trials revealed no significant differences between the frequency and severity of adverse events in patients receiving nebivolol, atenolol, enalapril or placebo; however, the overall incidence of adverse events was greater with nifedipine or metoprolol. Some atenolol or enalapril, but not nebivolol, recipients reported impotence or decreased libido during therapy. Conclusion: Current evidence indicates that nebivolol 5mg once daily is a well tolerated β-blocker, which is as effective as once daily atenolol and other classes of antihypertensive agents. It may therefore be recommended as a useful alternative first-line treatment option for the management of patients with mild to moderate uncomplicated essential hypertension. Nebivolol is a lipophilic β1-blocker administered clinically as a racemic mixture of equal proportions of its d- and l-enantiomers. The drug is devoid of intrinsic sympathomimetic or membrane stabilising activity but appears to have a nitric oxide-mediated vasodilatory effect. Unlike atenolol, nebivolol causes dose-related endothelium-dependent vasodilation in human dorsal hand or forearm vessels. Available data suggest that nebivolol has a protective effect on left ventricular function. The drug appears to reduce preload and maintain or decrease afterload. Total peripheral vascular resistance did not increase in any study of nebivolol. Heart rate and left ventricular end-diastolic pressure are decreased, whereas stroke volume is increased and cardiac output is generally maintained, notably in patients with heart failure. Nebivolol reduced left ventricular mass in hypertensive patients with left ventricular hypertrophy. Decreases in the ratio of pre-ejection period to left ventricular ejection time (PEP/LVET) were the result of significant shortening of PEP and lengthening of LVET periods (p ≤ 0.05 for both) in patients with hypertension treated with nebivolol for 1 year. Resting heart rates were reduced similarly with nebivolol 5mg and atenolol 50mg once daily, but resting and 24-hour ambulatory heart rates were reduced to a significantly greater extent with nebivolol than with nifedipine 20mg twice daily (p < 0.05) or enalapril 10mg once daily (p < 0.001). Single or multiple doses of nebivolol reduced exercise-induced tachycardia and attenuated exercise-induced increases in blood pressure in patients and volunteers to a similar or lesser extent than atenolol, propranolol or pindolol. Submaximal endurance time decreased with atenolol but was unchanged with nebivolol. Nebivolol does not appear to significantly influence glucose or plasma lipid metabolism although there have been rare instances of increases in triglyceride levels. The drug was associated with reductions in plasma renin levels and increased plasma atrial natriuretic peptide levels but did not alter renal haemodynamics in hypertensive patients with or without renal artery stenosis when administered for 4 weeks. The metabolism of nebivolol is subject to genetic polymorphism; phenotypically, individuals may be characterised as ‘poor’ (slow) or ‘extensive’ (fast) metabolisers. After a single 5mg oral dose, peak plasma drug concentrations (Cmax) for unchanged d, l-nebivolol were 1.48 μg/L in fast metabolisers and for active fractions of d- and l-nebivolol plus their corresponding hydroxylated metabolites were 7.3 and 13.1 μg/L, respectively, in hypertensive patients. Repeated doses increased the Cmax values for the individual d- and l-enantiomers and their respective metabolites. Time to Cmax after oral administration of nebivolol is reported to be about 0.5 to 2.0 hours and is not significantly affected by the presence of food. Generally, steady-state plasma concentrations are achieved within 1 day for nebivolol and within a few days for the active metabolites. Obesity does not appear to affect the total distribution volumes and total body clearance rates (per kilogram body weight) of unchanged nebivolol (racemate...