What is Nebivolol (beta blocker)?

What is Nebivolol?

Nebivolol is a highly selective β1-adrenergic receptor blocker with unique nitric oxide-mediated vasodilatory properties that distinguish it from traditional beta-blockers, making it particularly advantageous for hypertension management in patients with metabolic syndrome, diabetes risk, or erectile dysfunction from other beta-blockers. 1, 2

Pharmacological Characteristics

Mechanism of Action

• Nebivolol is a racemic mixture of d-nebivolol and l-nebivolol enantiomers, where the d-isomer provides selective β1-adrenergic receptor blockade while the l-isomer primarily facilitates nitric oxide (NO) release 1, 3, 4
• The β1-selectivity is preferential at doses ≤10 mg in extensive metabolizers (most of the population), but at higher doses or in poor metabolizers, it inhibits both β1 and β2 receptors 1
• Nebivolol lacks intrinsic sympathomimetic activity and membrane-stabilizing effects, and does not demonstrate α1-adrenergic receptor blockade at clinically relevant doses 1, 5

Unique Vasodilatory Properties

• The nitric oxide-potentiating effect produces sustained vasodilation with decreased peripheral vascular resistance, an effect not shared by other beta-blockers like atenolol or metoprolol 3, 6, 4
• This NO-mediated mechanism may be particularly beneficial in hypertensive populations with reduced endothelial function, including diabetics, African-Americans, and those with vascular disease 3

Clinical Indications

FDA-Approved Use

• Nebivolol is FDA-approved for hypertension treatment at a recommended dosage of 5 mg once daily 1, 5

Guideline-Recommended Indications

The 2018 ESC/ESH and 2017 ACC/AHA guidelines recommend beta-blockers, including nebivolol, for hypertension with specific compelling indications: 7

• Symptomatic angina pectoris
• Post-myocardial infarction
• Heart failure with reduced ejection fraction (HFrEF)
• Heart rate control (target <80 beats/min)
• Atrial fibrillation (prevention, rhythm control, rate control)
• Women of childbearing potential or planning pregnancy

Heart Failure Evidence

• Nebivolol is one of four evidence-based beta-blockers proven to reduce mortality in HFrEF (along with carvedilol, metoprolol succinate, and bisoprolol) 8, 2
• The SENIORS trial demonstrated mortality reduction in elderly patients (≥70 years) with heart failure, including those with preserved ejection fraction 7, 8
• In heart failure with preserved ejection fraction (HFpEF), nebivolol showed a 19% reduction in the composite endpoint of mortality or cardiovascular hospitalization 9

Additional Clinical Uses

Beyond cardiovascular indications, nebivolol has documented efficacy for: 7

• Migraine prophylaxis (probable efficacy, though propranolol and metoprolol have stronger evidence)
• Panic disorder (off-label use for symptom relief)

Metabolic and Vascular Advantages

Superior Metabolic Profile

• Nebivolol does not worsen glucose tolerance or insulin sensitivity, even when combined with hydrochlorothiazide, whereas traditional beta-blockers increase diabetes risk by 15-29% 2, 8, 9
• The European Heart Journal recommends nebivolol for superior metabolic effects compared to atenolol and metoprolol, making it advantageous in patients with metabolic syndrome or diabetes risk 2
• Cholesterol and triglycerides decreased significantly during treatment (8% and 13% respectively), with diabetic patients showing the greatest benefit (9% cholesterol reduction, 18% triglyceride reduction, 16% glucose reduction) 10

Vascular Benefits

• Nebivolol reduces central pulse pressure and aortic stiffness better than atenolol or metoprolol, addressing a key limitation of traditional beta-blockers in stroke prevention 2, 9
• The vasodilatory properties may explain why nebivolol is useful in patients who experienced erectile dysfunction with other beta-blockers 2, 9

Pharmacokinetics

Absorption and Distribution

• Peak plasma concentrations occur approximately 1.5-4 hours post-dosing 1
• Absolute bioavailability is similar to oral solution, and food does not alter pharmacokinetics, so nebivolol may be administered without regard to meals 1
• Plasma protein binding is approximately 98%, mostly to albumin 1

Metabolism and Elimination

• Nebivolol is predominantly metabolized via direct glucuronidation and, to a lesser extent, via CYP2D6-mediated N-dealkylation and oxidation 1
• The active d-nebivolol has an effective half-life of approximately 12 hours in extensive metabolizers and 19 hours in poor metabolizers 1
• Poor metabolizers attain 5-fold higher Cmax and 10-fold higher AUC of d-nebivolol compared to extensive metabolizers 1
• Multiple oxidative metabolites and glucuronide conjugates contribute to β-blocking activity 1

Special Populations

• In patients with moderate hepatic impairment (Child-Pugh Class B), d-nebivolol peak concentration increased 3-fold, AUC increased 10-fold, and apparent clearance decreased by 86% 1

Clinical Efficacy

Blood Pressure Reduction

• At 5 mg once daily, nebivolol reduces resting diastolic blood pressure as effectively as standard therapeutic dosages of atenolol, metoprolol, lisinopril, and nifedipine 5
• In a large multicentric observational study of 6,376 patients, systolic blood pressure decreased by a mean of 29 mmHg (from 173 to 144 mmHg) and diastolic blood pressure decreased by 16 mmHg (from 101 to 85 mmHg) over 6 weeks 10
• Normalization of diastolic blood pressure (<90 mmHg) was achieved in 62.2% of patients 10
• Response rates (diastolic BP ≤90 mmHg or ≥10 mmHg reduction) ranged from 58-81% after 4-52 weeks of treatment 5

Heart Rate Effects

• Nebivolol is unique among beta-blockers in that, at doses <10 mg, it does not inhibit the increase in heart rate normally seen with exercise 3
• Mean heart rate decreased from 84 to 73 beats per minute in clinical studies 10

Safety and Tolerability

Adverse Event Profile

• Nebivolol has a side effect profile similar to placebo in controlled clinical trials, particularly regarding fatigue and sexual dysfunction 3
• The most commonly reported adverse events are headache, fatigue, paresthesias, and dizziness, which are infrequent, transient, and mild to moderate 5
• Physician assessment rated tolerability as "very good or good" in 97% of cases 10
• No signs of orthostatic hypotension have been reported in several studies 5

Comparative Tolerability

• The tolerability of nebivolol has been shown to be superior to that of atenolol and metoprolol 3
• Some atenolol or enalapril recipients reported impotence or decreased libido during therapy, but not nebivolol recipients 5
• The overall incidence of adverse events was greater with nifedipine or metoprolol compared to nebivolol 5

Clinical Algorithm for Beta-Blocker Selection

For Hypertension Without Heart Failure

Choose nebivolol as first-line beta-blocker if the patient has: 2, 8

• Metabolic syndrome or diabetes risk
• Erectile dysfunction on other beta-blockers
• Peripheral arterial disease
• Concerns about metabolic deterioration

For Heart Failure with Reduced Ejection Fraction

First choice should be carvedilol, metoprolol succinate, or bisoprolol for the strongest mortality reduction evidence 8

• Consider nebivolol specifically for elderly patients (≥70 years) or those with significant metabolic syndrome 8
• Nebivolol provides mortality benefit without metabolic deterioration in HFrEF patients with metabolic syndrome 2

Common Pitfalls to Avoid

• Do not combine nebivolol with other beta-blockers or drugs from the same class 7
• Avoid abrupt cessation of nebivolol, as with all beta-blockers 7
• Exercise caution in patients with reactive airways disease, though nebivolol does not significantly decrease airway conductance compared to atenolol and propranolol 6
• Dose adjustment is necessary in moderate hepatic impairment due to 10-fold increase in drug exposure 1