Introduction
Zebeta (bisoprolol fumarate) is a cardioselective beta-1 adrenergic receptor blocking agent used primarily in the management of hypertension and heart failure. As a second-generation beta-blocker, it offers improved selectivity for cardiac beta-1 receptors compared to non-selective beta-blockers, potentially resulting in fewer pulmonary and metabolic side effects.
Mechanism of Action
Bisoprolol competitively blocks beta-1 adrenergic receptors in the heart and vascular smooth muscle. This inhibition results in:
- Decreased heart rate (negative chronotropy)
- Reduced myocardial contractility (negative inotropy)
- Slowed atrioventricular conduction
- Decreased cardiac output
- Reduced renin secretion from the kidneys
The drug's high beta-1 selectivity (approximately 75:1 ratio of beta-1 to beta-2 affinity) distinguishes it from non-selective beta-blockers, though this selectivity diminishes at higher doses.
Indications
FDA-approved indications:
- Management of hypertension (alone or in combination with other antihypertensive agents)
- Chronic stable heart failure (NYHA Class II-III) with reduced ejection fraction, in combination with ACE inhibitors, diuretics, and optionally digitalis
Off-label uses may include:
- Stable angina pectoris
- Supraventricular arrhythmias
- Migraine prophylaxis
Dosage and Administration
Hypertension:
- Initial dose: 2.5-5 mg once daily
- Maintenance dose: 2.5-10 mg once daily
- Maximum dose: 20 mg daily (though doses >10 mg provide little additional benefit)
Heart Failure:
- Initial dose: 1.25 mg once daily
- Titration: Double dose every 2-4 weeks as tolerated
- Target maintenance dose: 10 mg once daily
Special Populations:
- Renal impairment: CrCl <40 mL/min - start with 2.5 mg daily
- Hepatic impairment: Use with caution; consider lower starting dose
- Geriatric patients: Initiate at lower end of dosing range
- Pediatric patients: Safety and effectiveness not established
Pharmacokinetics
Absorption: Well-absorbed from GI tract (>80% bioavailability), unaffected by food
Distribution: Protein binding approximately 30%, volume of distribution 3.5 L/kg
Metabolism: Hepatic metabolism via CYP3A4 (minor pathway) and non-CYP pathways; minimal first-pass effect
Elimination: Half-life 9-12 hours; 50% excreted unchanged in urine, 50% as inactive metabolites
Onset of action: 1-2 hours for blood pressure reduction
Duration of action: 24 hours allowing once-daily dosing
Contraindications
- Severe bradycardia (heart rate <50 bpm)
- Heart block greater than first degree (without permanent pacemaker)
- Cardiogenic shock
- Decompensated cardiac failure
- Sick sinus syndrome
- Severe bronchial asthma or severe COPD
- Hypersensitivity to bisoprolol or any component of the formulation
Warnings and Precautions
Cardiac:
- May precipitate heart failure in patients with compensated cardiac function
- Abrupt withdrawal may cause exacerbation of angina or myocardial infarction
- Can mask signs of hypoglycemia in diabetics
- May reduce effectiveness of glucagon in treating hypoglycemia
Pulmonary:
- Although cardioselective, caution required in patients with bronchospastic disease
- Beta-1 selectivity is dose-dependent and may be lost at higher doses
Peripheral Vascular Disease:
- Can exacerbate symptoms of peripheral arterial insufficiency
Surgical Patients:
- Chronic beta-blocker therapy should generally be continued perioperatively
- Consideration for anesthetic agents that depress myocardial function
Other:
- May mask signs of hyperthyroidism
- Can cause depression or sleep disturbances
- Use with caution in patients with psoriasis
Drug Interactions
Major interactions:
- Verapamil, diltiazem: Additive bradycardia and AV block
- Digoxin: Enhanced bradycardic effect
- Clonidine: Exaggerated rebound hypertension upon withdrawal
- Antiarrhythmics (Class I): Increased risk of arrhythmias
- Insulin and oral hypoglycemics: Masked hypoglycemic symptoms, altered glucose metabolism
Moderate interactions:
- CYP3A4 inhibitors (ketoconazole, macrolides): May increase bisoprolol levels
- NSAIDs: May decrease antihypertensive effect
- Sympathomimetics: Mutual antagonism of effects
Adverse Effects
Common (≥5%):
- Fatigue (3-11%)
- Dizziness (6-10%)
- Headache (6-9%)
- Bradycardia (3-7%)
- Diarrhea (3-6%)
- Cold extremities (2-5%)
Less common but serious:
- Heart failure exacerbation
- Bronchospasm
- Depression
- Sexual dysfunction
- Worsening of peripheral vascular disease
- Hypoglycemia
- Vision disturbances
Monitoring Parameters
Baseline:
- Blood pressure and heart rate
- ECG (assess for conduction abnormalities)
- Renal and hepatic function
- Blood glucose in diabetics
- Signs/symptoms of heart failure
Ongoing:
- Blood pressure at each visit until controlled, then periodically
- Heart rate (ensure >50 bpm)
- Signs of fluid retention or heart failure exacerbation
- Respiratory status in patients with pulmonary disease
- Mental status changes
- Peripheral circulation
Therapeutic goals:
- Hypertension: BP <140/90 mmHg (individualized based on patient factors)
- Heart failure: Improved functional status, reduced hospitalizations
Patient Education
Key points to communicate:
- Take medication at the same time each day, with or without food
- Do not abruptly discontinue medication without physician guidance
- Rise slowly from sitting/lying position to minimize dizziness
- Monitor weight regularly and report sudden increases
- Report any shortness of breath, excessive fatigue, or swelling
- Inform all healthcare providers about bisoprolol use
- Use caution with alcohol and other sedating medications
- Diabetic patients should monitor blood glucose regularly
- Be aware that medication may affect ability to drive or operate machinery
- Store at room temperature away from moisture and heat
Missed dose:
- Take as soon as remembered unless close to next dose
- Do not double doses
References
1. Frishman WH. Bisoprolol: a new beta-adrenoceptor blocking agent. Am J Cardiol. 1991;67(16):43D-46D.
2. FDA Prescribing Information: Zebeta (bisoprolol fumarate). 2021.
3. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II). Lancet. 1999;353(9146):9-13.
4. Williams B, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021-3104.
5. Yancy CW, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2017;70(6):776-803.
6. McDonagh TA, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599-3726.
7. Lexicomp Online, Lexi-Drugs. Bisoprolol. Wolters Kluwer Clinical Drug Information, Inc. 2023.
8. Micromedex Solutions. Bisoprolol. Truven Health Analytics, Inc. 2023.
