Bystolic - Drug Monograph

Introduction

Bystolic (nebivolol) is a third-generation beta-adrenergic receptor blocking agent approved by the FDA in 2007 for the treatment of hypertension. It belongs to the class of cardiovascular drugs known as beta-blockers and is distinguished by its unique pharmacological profile that includes vasodilatory properties mediated through endothelial nitric oxide release.

Mechanism of Action

Nebivolol is a highly selective beta-1 adrenergic receptor antagonist with approximately 3,200-fold greater affinity for beta-1 receptors than beta-2 receptors. Its mechanism involves:

• Competitive inhibition of catecholamine binding at beta-1 receptors in the heart
• Reduction of heart rate, myocardial contractility, and cardiac output
• Stimulation of beta-3 receptors leading to endothelial nitric oxide synthase activation
• Subsequent nitric oxide-mediated vasodilation (primarily with the d-isomer)

This dual mechanism provides both beta-blockade and vasodilation, distinguishing it from traditional beta-blockers.

Indications

FDA-approved indications:

• Treatment of hypertension (as monotherapy or in combination with other antihypertensive agents)

Off-label uses (based on clinical evidence):

• Stable chronic heart failure (NYHA Class II-III)
• Stable coronary artery disease
• Management of tachyarrhythmias

Dosage and Administration

• Initial dose: 5 mg once daily
• Maintenance dose: 5-40 mg once daily
• Titration: May increase at 2-week intervals

• Hepatic impairment: Maximum dose 10 mg daily
• Renal impairment (CrCl <30 mL/min): Initial dose 2.5 mg daily
• Geriatric patients: Consider starting with 2.5 mg daily
• CYP2D6 poor metabolizers: Maximum dose 10 mg daily

• Take with or without food
• Administer at the same time each day
• Do not crush or chew tablets

Pharmacokinetics

• Oral bioavailability: 12% in extensive metabolizers, 96% in poor metabolizers
• Tmax: 1.5-4 hours
• Food does not significantly affect absorption

• Protein binding: 98% (primarily to albumin)
• Volume of distribution: 673 L
• Crosses blood-brain barrier and placenta

• Extensive first-pass metabolism via CYP2D6 (aromatic hydroxylation) and CYP2C9 (aliphatic oxidation)
• Active metabolites: 4-OH-nebivolol and glucuronide conjugates
• Significant genetic polymorphism in metabolism

• Half-life: 12-19 hours in extensive metabolizers, up to 30 hours in poor metabolizers
• Excretion: Primarily feces (38-67%) and urine (13-50%)
• Clearance: Hepatic metabolism predominates

Contraindications

• Severe bradycardia
• Heart block greater than first degree
• Cardiogenic shock
• Decompensated cardiac failure
• Sick sinus syndrome (unless pacemaker present)
• Severe hepatic impairment (Child-Pugh Class C)
• Hypersensitivity to nebivolol or any component

Warnings and Precautions

• Abrupt discontinuation may cause angina exacerbation or myocardial infarction
• May mask signs of hypoglycemia and hyperthyroidism
• Can precipitate heart failure in susceptible patients

• Although highly beta-1 selective, caution in patients with bronchospastic disease

• May cause hypoglycemia or mask hypoglycemic symptoms
• Can alter lipid metabolism (increases triglycerides, decreases HDL)

• Peripheral vasoconstriction and Raynaud's phenomenon
• May exacerbate myasthenic symptoms
• Psoriasis exacerbation reported with beta-blockers

Drug Interactions

• CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine): Increase nebivolol concentrations
• Other beta-blockers: Additive effects
• Calcium channel blockers (verapamil, diltiazem): Additive bradycardia and AV block
• Digoxin: Additive bradycardia
• Insulin and oral hypoglycemics: Masked hypoglycemia symptoms

• Clonidine: Rebound hypertension with concurrent use
• NSAIDs: May reduce antihypertensive effect
• Antiarrhythmics (amiodarone, propafenone): Additive cardiac effects

Adverse Effects

• Headache (6-9%)
• Fatigue (5-6%)
• Dizziness (4-5%)
• Diarrhea (3-4%)
• Nausea (3-4%)

• Bradycardia
• Insomnia
• Dyspnea
• Rash
• Edema

• AV block
• Heart failure exacerbation
• Bronchospasm
• Depression
• Sexual dysfunction

Monitoring Parameters

• Blood pressure and heart rate
• ECG (especially heart rate and PR interval)
• Renal and hepatic function
• Blood glucose (in diabetics)

• Blood pressure at regular intervals
• Heart rate at each visit
• Signs of heart failure (weight, edema, dyspnea)
• Mental status changes
• Periodic metabolic panel

• Diabetics: Frequent blood glucose monitoring
• Pulmonary disease: Respiratory status
• Elderly: Fall risk assessment

Patient Education

• Take medication exactly as prescribed at the same time daily
• Do not stop abruptly without medical supervision
• Regular blood pressure monitoring is essential
• Report any dizziness, shortness of breath, or excessive fatigue
• Inform all healthcare providers about Bystolic use

• Maintain regular physical activity as tolerated
• Follow prescribed dietary recommendations
• Limit alcohol consumption
• Be cautious when rising from sitting/lying position

• Heart rate <50 bpm
• Significant weight gain or swelling
• Worsening breathing problems
• Depression or mood changes
• Sexual dysfunction

References

1. FDA Prescribing Information: Bystolic (nebivolol) tablets. 2022 2. Weiss RJ, et al. Nebivolol: a novel beta-blocker with nitric oxide-induced vasodilation. Vasc Health Risk Manag. 2006;2(3):303-8 3. Cockcroft JR, et al. Nebivolol: endothelium-mediated vasodilation and endothelial nitric oxide release. Eur Heart J. 2006;27(19):2283-4 4. Chrysant SG. Effectiveness and safety of nebivolol in the treatment of hypertension. Ther Clin Risk Manag. 2009;5:253-63 5. McNeely W, et al. Nebivolol in the management of essential hypertension: a systematic review and meta-analysis. Curr Ther Res. 2008;69(4):322-45 6. UpToDate: Nebivolol drug information. 2023 7. Clinical Pharmacology [database online]. Tampa, FL: Elsevier; 2023