Nebivolol in the Management of Essential Hypertension
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 or each enantiomer).
Extensive first-pass metabolism after oral administration of nebivolol produces active β-blocking hydroxy-metabolites. Elimination half-lives for the unchanged compound (racemate or each enantiomer) average about 10 hours, but are reported to increase by up to 5 times in poor metabolisers. Elimination half-lives for the hydroxy-metabolites of both enantiomers average about 24 hours in extensive metabolisers, but are almost doubled in poor metabolisers.
One week after administration, 38 and 48%, respectively, of the nebivolol dose is excreted in urine and faeces; unchanged nebivolol accounts for <0.05% of the amount recovered in the urine.
Plasma concentrations of nebivolol (both enantiomers) and its hydroxy metabolites are elevated in patients with renal disease.
Nebivolol 5mg once daily (the recommended dosage; see Dosage and Administration summary) significantly reduces mean sitting or supine diastolic blood pressure (DBP) [by about 10mm Hg]. Significant reductions are maintained during continued therapy with no sign of rebound hypertension or tolerance. In the following discussion the nebivolol dosage is 5mg once daily.
Nebivolol produced similar reductions in resting DBP to atenolol 50 or 100mg once daily for up to 24 weeks and metoprolol 100mg twice daily for 12 weeks in hypertensive patients with or without comorbidities (concomitant type 2 diabetes mellitus or left ventricular hypertrophy).
In addition, nebivolol reduced sitting DBP in patients with hypertension to a similar extent to nifedipine 20mg twice daily after 12 weeks or lisinopril 40mg once daily after 8 weeks. Nebivolol was more effective than enalapril 10mg once daily (usual dosage is 10 to 20mg once daily) after 4 or 12 weeks but not after 28 weeks of treatment. The drug had an additive effect when combined with hydrochlorothiazide 12.5 or 25mg once daily but not with enalapril.
Nebivolol significantly reduced sitting/supine systolic blood pressure (SBP) compared with baseline or placebo. Standing SBP/DBP was also significantly reduced compared with baseline or placebo and to a similar extent to reductions with atenolol, enalapril or nifedipine.
Nebivolol 5 mg/day and atenolol 100mg once daily, nifedipine 20mg twice daily or lisinopril ≤40mg once daily similarly and significantly reduced mean 24-hour ambulatory blood pressure. However, nebivolol tended to prevent increases in early morning blood pressure better than nifedipine. In addition, nebivolol reduced blood pressure loads by about 50% from baseline.
Trough to peak ratios of about 0.9 for supine or sitting DBP have been reported for nebivolol 5mg once daily, which is the same as that for nifedipine sustained release 20mg twice daily but higher than for enalapril 10mg once daily.
Overall response rates (a decrease in sitting/supine diastolic blood pressure to ≤90mm Hg or a 10% or ≥10mm Hg fall in diastolic blood pressure) to treatment with nebivolol 5mg once daily ranged from 58% after 4 weeks’ therapy to 81% after 52 weeks’ therapy. Response rates in nebivolol recipients were significantly greater than in those receiving enalapril early (≤12 weeks), but not later (7 months), or metoprolol but did not differ between patients receiving nebivolol, atenolol or nifedipine. More nebivolol than nifedipine recipients responded to treatment after 2 weeks.
Nebivolol 5mg once daily is well tolerated in patients with hypertension. Adverse events are typically transient and mild to moderate; the type, severity and frequency are not dose-related. Adverse events experienced most often include headache, fatigue, paraesthesias and dizziness. Importantly, several studies reported no signs of orthostatic hypotension with nebivolol.
In comparative trials the frequency and severity of adverse events reported in patients receiving once daily nebivolol 5mg or atenolol 50mg, enalapril 10mg or placebo were not significantly different. However, the overall incidence of adverse events was greater with nifedipine 20mg twice daily or metoprolol 100mg twice daily than with nebivolol. More atenolol or enalapril than nebivolol recipients reported impotence or decreased libido during therapy. In addition, the incidence of fatigue increased from baseline in atenolol recipients but remained constant in nebivolol recipients during a 4-week treatment period.
Dosage and Administration
The recommended dosage of nebivolol is 5mg once daily taken with or without food, preferably at the same time of day.
Use of the drug in children and patients with hepatic insufficiency is not recommended. A reduced starting dose of 2.5mg (with upward titration where necessary) is recommended in the elderly and in patients with renal insufficiency. Nebivolol may be used alone or in combination with other antihypertensive agents. To date, additive antihypertensive effects have been seen only during combination therapy with hydrochlorothiazide.
KeywordsDiastolic Blood Pressure Adis International Limited Nifedipine Enalapril Atenolol
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