Introduction
Nebivolol is a third-generation beta-adrenergic receptor blocker with unique pharmacologic properties that distinguish it from other beta-blockers. It is a racemic mixture of d- and l-nebivolol, with the d-enantiomer primarily responsible for its beta-blocking activity and the l-enantiomer contributing to its vasodilatory effects. Nebivolol is primarily indicated for the management of hypertension and heart failure with reduced ejection fraction.
Mechanism of Action
Nebivolol exhibits highly selective beta-1 adrenergic receptor blockade (approximately 320-fold greater affinity for β1 vs β2 receptors). Its unique mechanism involves endothelial-dependent vasodilation through stimulation of β3-adrenergic receptors, which increases nitric oxide (NO) bioavailability. This dual mechanism results in both reduced cardiac workload (through beta-blockade) and decreased peripheral vascular resistance (through vasodilation).
The drug does not demonstrate intrinsic sympathomimetic activity and has minimal membrane-stabilizing effects. Nebivolol's nitric oxide-mediated vasodilation contributes to its favorable hemodynamic profile, including maintained cardiac output and reduced afterload.
Indications
- Hypertension: First-line treatment for essential hypertension as monotherapy or in combination with other antihypertensive agents
- Heart Failure: Treatment of stable chronic heart failure with reduced ejection fraction (NYHA Class II or III) in addition to standard therapy (ACE inhibitors, diuretics)
Dosage and Administration
Hypertension:- Initial dose: 5 mg once daily
- Maintenance dose: 5-40 mg once daily
- Titration: May increase at 2-week intervals
- Initial dose: 1.25 mg once daily
- Titration: Double dose every 1-2 weeks as tolerated
- Target dose: 10 mg once daily
- Renal impairment: CrCl <30 mL/min - initial dose 2.5 mg daily
- Hepatic impairment: Initial dose 2.5 mg daily
- Geriatric patients: Consider starting with 2.5 mg daily
- CYP2D6 poor metabolizers: Reduced dose may be necessary
Pharmacokinetics
Absorption: Rapidly absorbed after oral administration with absolute bioavailability of 12% in fast metabolizers and 96% in slow metabolizers Distribution: Extensive tissue distribution with volume of distribution of 673 L; protein binding approximately 98% Metabolism: Extensive hepatic metabolism primarily via CYP2D6 (and to lesser extent CYP2C19 and CYP3A4) with significant first-pass metabolism Elimination: Primarily renal excretion (38% urine, 44% feces) with terminal half-life of 12-19 hours Active metabolites: 4-hydroxynebivolol and glucuronide conjugates contribute to pharmacological activityContraindications
- Severe bradycardia (heart rate <50 bpm)
- Heart block greater than first degree (without pacemaker)
- Cardiogenic shock
- Decompensated cardiac failure
- Severe hepatic impairment (Child-Pugh Class C)
- Hypersensitivity to nebivolol or any component of the formulation
- Sick sinus syndrome (unless pacemaker present)
- Severe bronchial asthma or severe COPD
Warnings and Precautions
Cardiac Effects: May cause bradycardia, heart block, or worsening heart failure during initiation. Gradually titrate dose and monitor closely. Abrupt Withdrawal: Avoid sudden discontinuation (risk of rebound hypertension, angina exacerbation, or myocardial infarction). Taper over 1-2 weeks. Peripheral Vascular Disease: May precipitate or aggravate symptoms of arterial insufficiency. Diabetes: May mask hypoglycemia symptoms and prolong hypoglycemia. Monitor blood glucose regularly. Thyrotoxicosis: May mask clinical signs of hyperthyroidism. Anesthesia/Surgery: Consider preoperative withdrawal due to impaired ability to respond to reflex stimuli. Bronchospastic Disease: Use caution in patients with chronic bronchitis, emphysema, or asthma.Drug Interactions
Strong CYP2D6 Inhibitors: Fluoxetine, paroxetine, quinidine - may increase nebivolol concentrations (reduce nebivolol dose) Other Antihypertensives: Additive hypotensive effects with calcium channel blockers, ACE inhibitors, ARBs, diuretics Antiarrhythmics: Increased risk of bradycardia and AV block with digoxin, diltiazem, verapamil Insulin/Oral Hypoglycemics: Enhanced hypoglycemic effects Sympathomimetics: Reduced effectiveness of beta-agonists MAO Inhibitors: Potential for hypertension (avoid concurrent use)Adverse Effects
Common (>10%):- Headache (6-9%)
- Fatigue (5-8%)
- Dizziness (2-4%)
- Bradycardia (2-3%)
- Nausea
- Diarrhea
- Dyspnea
- Insomnia
- Edema
- Rash
- AV block
- Heart failure exacerbation
- Bronchospasm
- Depression
- Sexual dysfunction
- Hepatotoxicity
Monitoring Parameters
- Blood pressure (standing and supine)
- Heart rate (especially during titration)
- ECG for signs of conduction abnormalities
- Renal function (BUN, creatinine)
- Hepatic function (baseline and periodically)
- Signs/symptoms of heart failure
- Blood glucose in diabetic patients
- Mental status changes
- Peripheral perfusion
Patient Education
- Take medication at the same time each day, with or without food
- Do not stop taking suddenly - consult provider before discontinuing
- Rise slowly from sitting/lying position to prevent dizziness
- Monitor pulse rate regularly and report rates below 50 bpm
- Report unusual fatigue, shortness of breath, weight gain, or swelling
- Inform all healthcare providers about nebivolol use before procedures
- Use caution when driving or operating machinery until effects are known
- Avoid alcohol as it may enhance hypotensive effects
- Diabetic patients should monitor blood glucose more frequently
- Notify provider if pregnancy is planned or occurs
References
1. FDA Prescribing Information: Bystolic (nebivolol) tablets 2. Weiss R. Nebivolol: a novel beta-blocker with nitric oxide-induced vasodilation. J Clin Hypertens. 2006;8(1):33-42. 3. Cockcroft JR, et al. Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO-dependent mechanism. J Pharmacol Exp Ther. 1995;274(3):1067-1071. 4. Mangrella M, et al. Nebivolol: a review of its pharmacological and clinical profile. Curr Med Chem. 2008;15(3):242-256. 5. McNeely W, et al. Nebivolol in the management of essential hypertension: a review. Drugs. 1999;57(4):633-651. 6. Cleophas TJ, et al. Nebivolol: a review of its clinical and pharmacological characteristics. Int J Clin Pharmacol Ther. 2006;44(7):344-357. 7. UpToDate: Nebivolol drug information 8. Lexicomp Online: Nebivolol monograph