Bisoprolol - Drug Monograph

Introduction

Bisoprolol is a cardioselective beta-1 adrenergic receptor blocker widely used in cardiovascular medicine. As a second-generation beta-blocker, it offers improved selectivity for cardiac beta-1 receptors while minimizing effects on beta-2 receptors in the lungs and vascular smooth muscle. Bisoprolol has established itself as a cornerstone therapy in the management of hypertension, heart failure, and coronary artery disease due to its favorable pharmacokinetic profile and demonstrated mortality benefits in clinical trials.

Mechanism of Action

Bisoprolol competitively blocks beta-1 adrenergic receptors in the heart and juxtaglomerular apparatus. This inhibition results in:

• Reduced heart rate (negative chronotropy)
• Decreased myocardial contractility (negative inotropy)
• Slowed atrioventricular conduction
• Reduced renin secretion from renal juxtaglomerular cells
• Decreased myocardial oxygen demand

At therapeutic doses, bisoprolol demonstrates approximately 75:1 selectivity for beta-1 versus beta-2 receptors, making it one of the most cardioselective beta-blockers available.

Indications

• Hypertension (monotherapy or combination therapy)
• Chronic stable heart failure with reduced ejection fraction (NYHA Class II-III) in combination with other heart failure therapies

• Stable angina pectoris
• Supraventricular arrhythmias
• Post-myocardial infarction management
• Migraine prophylaxis
• Essential tremor

Dosage and Administration

• Initial dose: 2.5-5 mg once daily
• Maintenance dose: 5-10 mg once daily
• Maximum dose: 20 mg once daily

• Initial dose: 1.25 mg once daily
• Titrate gradually: Double dose every 2-4 weeks as tolerated
• Target maintenance dose: 10 mg once daily

• Renal impairment: CrCl <40 mL/min - start with 2.5 mg daily
• Hepatic impairment: Use with caution, consider lower starting dose
• Elderly: No specific dose adjustment required
• Pediatric: Safety and effectiveness not established

• Take with or without food
• Administer at the same time each day
• Do not abruptly discontinue (taper over 1-2 weeks)

Pharmacokinetics

• Oral bioavailability: >90%
• Tmax: 2-3 hours
• Food does not significantly affect absorption

• Protein binding: 30%
• Volume of distribution: 3.5 L/kg
• Crosses blood-brain barrier and placenta

• Hepatic metabolism via CYP3A4 and CYP2D6 (minor)
• Oxidative metabolism to inactive metabolites
• Limited first-pass effect

• Half-life: 9-12 hours
• Elimination: 50% renal, 50% hepatic
• Dialyzable: No

Contraindications

• Cardiogenic shock
• decompensated heart failure requiring IV inotropic therapy
• Sick sinus syndrome or second/third-degree AV block (without pacemaker)
• Severe bradycardia (<50 bpm)
• Hypersensitivity to bisoprolol or related compounds
• Severe bronchial asthma or severe COPD

Warnings and Precautions

• May precipitate heart failure in susceptible patients
• Can mask tachycardia in hypoglycemia
• Abrupt withdrawal may cause rebound hypertension or angina

• Beta-1 selectivity is dose-dependent; beta-2 blockade may occur at higher doses
• Use with caution in patients with asthma or COPD

• May mask signs of hypoglycemia in diabetics
• Can alter lipid metabolism (increases triglycerides, decreases HDL)

• May exacerbate symptoms of peripheral arterial disease

• Pregnancy Category C: Use only if potential benefit justifies risk
• Lactation: Excreted in breast milk; use caution
• Major surgery: Consider preoperative withdrawal

Drug Interactions

• Verapamil, diltiazem: Enhanced bradycardia and AV block
• Other antihypertensives: Additive hypotensive effects
• Insulin/oral hypoglycemics: Masked hypoglycemia symptoms
• Clonidine: Rebound hypertension with concurrent use

• CYP3A4 inhibitors (ketoconazole, erythromycin): May increase bisoprolol levels
• Rifampin: May decrease bisoprolol levels
• Antiarrhythmics (amiodarone, flecainide): Increased risk of bradycardia

• Digoxin: Additive bradycardia
• NSAIDs: May decrease antihypertensive effect
• MAO inhibitors: Risk of hypertension

Adverse Effects

• Fatigue (∼26%)
• Dizziness (∼13%)
• Bradycardia (∼8%)
• Headache (∼8%)
• Cold extremities (∼6%)
• Diarrhea (∼3%)

• AV block
• Bronchospasm
• Heart failure exacerbation
• Depression
• Sexual dysfunction
• Hypotension
• Worsening of peripheral vascular disease

Monitoring Parameters

• Blood pressure and heart rate
• ECG (assess conduction abnormalities)
• Renal and hepatic function
• Blood glucose and lipids in diabetics
• Assessment of heart failure symptoms

• Blood pressure at each dose adjustment
• Heart rate and rhythm regularly
• Weight monitoring in heart failure patients
• Assessment for signs of bronchospasm
• Periodic renal function assessment
• Evaluation for depression or fatigue

• Hypertension: BP <130/80 mmHg
• Heart failure: Resting heart rate 50-60 bpm
• Angina: Reduced frequency of attacks

Patient Education

• Take medication exactly as prescribed
• Do not stop abruptly without medical supervision
• Rise slowly from sitting/lying position to prevent dizziness
• Monitor pulse rate regularly
• Report unusual fatigue, shortness of breath, or weight gain
• Inform all healthcare providers about bisoprolol use

• Limit alcohol consumption
• Maintain regular physical activity as tolerated
• Follow heart-healthy diet
• Avoid excessive heat exposure

• Heart rate <50 bpm
• Dizziness or lightheadedness
• Worsening breathing problems
• Swelling of feet or ankles
• Depression or mood changes

References

1. FDA Prescribing Information: Bisoprolol Fumarate Tablets 2. 2018 ESC/ESH Guidelines for the management of arterial hypertension 3. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 4. Frishman WH. Bisoprolol: a new beta-adrenergic blocking agent. Am J Cardiol. 1991 5. Beta-Blocker Evaluation of Survival Trial (BEST) Investigators. N Engl J Med. 2001 6. McTavish D, et al. Bisoprolol: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs. 1991 7. Packer M, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001 8. Wiest FC, et al. Beta-blockers for hypertension. Cochrane Database Syst Rev. 2007