Continuing Education Activity

Bisoprolol is a medication used to manage and treat hypertension and congestive heart failure. The drug belongs to the selective beta-blocker class of drugs and acts explicitly as a cardioselective beta1-blocker (B1-blocker). Bisoprolol mainly focuses on beta1 receptors in the heart to address several heart conditions, such as congestive heart failure. The drug does not affect the undesirable B2 receptors, which could affect different bodily systems. Selective B1-blockers, including bisoprolol, have adverse inotropic and chronotropic effects, decreasing heart contractions and heart rate. Consequently, bisoprolol reduces the oxygen consumption of myocardial cells, relieving the heart's workload. B1 receptors are also present in the juxtaglomerular cells of the kidneys. By blocking these receptors, bisoprolol reduces the release of renin, thereby blocking the activation of the renin-angiotensin system. This dual action on the heart and kidneys makes bisoprolol effective in managing hypertension and related conditions.

This activity discusses the indications, mechanism of action, and contraindications for bisoprolol in managing hypertension and other relevant disorders. This resource also covers the adverse event profile and other key factors, including the off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions of bisoprolol, pertinent to interprofessional healthcare teams when treating patients with hypertension and related conditions.

Objectives:

• Identify appropriate indications for bisoprolol therapy, including hypertension, heart failure, and certain arrhythmias.
• Screen patients for contraindications and risk factors before initiating bisoprolol treatment, such as bradycardia, heart block, asthma, or severe peripheral vascular disease.
• Assess patients' response to bisoprolol therapy, monitoring blood pressure, heart rate, and signs of adverse effects.
• Apply evidence-based guidelines and clinical recommendations to optimize bisoprolol therapy for individual patients.

Indications

Bisoprolol is a cardioselective beta1-blocker (B1-blocker). Selective B1-blockers are used to treat multiple heart diseases, such as congestive heart failure, without having the unwanted effect of the B2 receptor blocking, which can affect various systems in the body.[1]

• Bisoprolol is FDA-approved for the management of hypertension. Clinicians must recognize that according to ACC/AHA guidelines, bisoprolol or other beta blockers are not the first-line treatment for hypertension unless the patient has ischemic heart disease or HFrEF.[2]
• Bisoprolol is used in the treatment plan for compensated heart failure. According to 2022 AHA/ACC/HFSA guidelines, specific beta-blockers (bisoprolol, metoprolol succinate, and carvedilol) are included in guideline-directed medical therapy(GDMT) for heart failure with reduced ejection fraction(HFrEF). Bisoprolol is recommended to reduce mortality and hospitalizations in patients with HFrEF.[3]
• Selective B1- blockers are used as the first-line treatment for chronic stable angina.[4] According to the 2020 International Society of Hypertension practice guidelines, cardioselective beta-blockers such as bisoprolol should be used (with or without calcium channel blockers) in patients with coronary artery disease.[5]
• The use of bisoprolol correlates with decreased morbidity and mortality post-MI.[6] Bisoprolol reduces the risk of stroke and coronary artery disease in patients with heart disease.[7]
• Non-FDA-approved uses of bisoprolol include the treatment of migraine, arrhythmia, and tremors; as an anxiolytic for some athletes and musicians.[8][9]
• A fixed-dose combination of bisoprolol and hydrochlorothiazide is approved by FDA for managing hypertension.[10]

Mechanism of Action

Selective B1 blocker drugs have negative inotropic and chronotropic effects; they decrease heart contractions and heart rate. As a net result, bisoprolol reduces the oxygen consumption of myocardial cells. B1 receptors are also present in the juxtaglomerular cells. By blocking these receptors, bisoprolol leads to a decrease in the release of renin; as a result, this decrease in renin blocks the activation of the renin-angiotensin system.[11]

B1 adrenergic receptors are present in cardiac myocyte cells and juxtaglomerular cells. They couple with the G-stimulatory protein receptor (Gs receptor) and become stimulated by either norepinephrine or circulating catecholamine. Activation of B1 receptors in cardiac myocytes leads to positive chronotropic and inotropic effects; therefore, the net result will be increased heart rate, contraction, and the strength of myocyte contraction by activating Gs receptors (by the exchange of GTP to GDP). Eventually, this activity increases intracellular calcium concentration and promotes heart cell contraction.[12][13][14]

Activation of B1 receptors on juxtaglomerular cells leads to activating the renin-angiotensin system. Releasing renin increases the production of angiotensin I, which is eventually converted by an angiotensin-converting enzyme (ACE) to angiotensin II.

B2 receptors are present in multiple body organs and are activated by epinephrine, leading to different manifestations according to the location involved. In peripheral vessels, it causes vasodilation and decreases peripheral resistance, opposing the effect of alpha-1 receptors, which cause vasoconstriction in the peripheral vessels. On the bronchioles, it leads to extensive bronchodilation. In addition, B2 receptor activation in the liver and the muscles activates glycogenolysis and glucagon release, increasing blood sugar levels.

Non-selective beta-blocker drugs block both the B1 and B2 receptors, decreasing cardiac output and decreasing renin release from the kidney. And B2 receptor blockage leads to additional manifestations—vasoconstriction of the peripheral vessels. Blocking B2 receptors causes bronchial muscle contraction in the lung, leading to bronchospasm in patients with COPD or asthma. It also leads to decrease glycogenolysis and glucagon release, which may lead to hypoglycemia.[9][15]

Pharmacokinetics 

Absorption: Bisporolol is well absorbed, and the bioavailability of bisoprolol is approximately 80%. The time to peak plasma concentration is approximately 2 to 4 hours. Steady-state plasma concentration is achieved in 5 days.[16]

Distribution: Bisoprolol has low lipophilicity; penetration the through the blood-brain barrier is minimal. The volume of distribution of about 3.5 L/kg.[17]

Metabolism: Bisoprolol is primarily metabolized by the CYP3A4 and CYP2D6(minor). First-pass metabolism of bisoprolol is low.[18]

Excretion: Bisoprolol is eliminated by  50% renal excretion (unchanged drug) and 50% by hepatic metabolism to pharmacologically inactive metabolites excreted by the kidneys. Tubular secretion plays an important role in the renal elimination of bisoprolol. Excretion through feces is approximately 2%. Bisoprolol fumarate has a long half-life that extends from 9 to 12 hours.[19][20]

Administration

Cardioselective agents are either administered orally or intravenously. Bisoprolol fumarate is administered orally as 5 or 10 mg tablets once daily.

Hypertension: The dose of bisoprolol fumarate should be tailored to the patient's individualized needs. The usual starting dose is 5 mg once daily. If the 5 mg dose does not produce the desired antihypertensive effect,  the dose should be gradually increased to 10 mg and then, if needed, to 20 mg once daily.[21]

Heart Failure With Reduced Ejection Fraction: The initial dose is 1.25 mg once daily, while the target dose is 10 mg once daily. To optimize GDMT, the dose should be titrated every 1 to 2 weeks based on symptoms, vital signs, and volume status. Bisoprolol should be started once acute decompensated heart failure is stabilized, and the patient does not require vasopressors or inotropes.[3]

Atrial Fibrillation: According to AHA/ACC/HRS guidelines, the dose of bisoprolol for rate control is 2.5 mg to 10 mg PO once daily.[22][23]

Coronary Artery Disease: According to AHA/ACC/ASH guidelines, beta-blockers without intrinsic sympathomimetic activity, such as bisoprolol, should be used for CAD. The dose of bisoprolol is 5 to 10 mg once daily. The drug should not be used for variant angina (Prinzmetal angina).[24]

Specific Populations

Hepatic Impairment: According to the manufacturer's prescribing information in patients with hepatitis or cirrhosis, the initial daily dose should be 2.5 mg and, if needed, titrated upward slowly.

Renal Impairment: According to the manufacturer's prescribing information, in patients with creatinine clearance less than 40 ml/min starting dose should be 2.5 mg per day, and titrate upwards slowly. Since limited data suggest that bisoprolol fumarate is not dialyzable, dose adjustment is unnecessary for dialysis patients.

Older Patients: The dose needs to be adjusted in older patients only if there is significant hepatic or renal dysfunction.

Pediatric Patients: Product labeling has no information on pediatric experience with bisoprolol fumarate; there are no approved indications for pediatric patients.

Pregnancy Considerations: Bisoprolol is a former FDA category C medicine and should be used only if there are no other alternatives to its therapy. According to the ACOG (American College of Obstetricians and Gynecologists), labetalol might be preferred over bisoprolol to treat gestational hypertension.[25][26]

Breastfeeding Considerations: The excretion of beta blockers in breast milk is primarily determined by plasma protein binding (PPB). Low plasma protein binding is associated with increased excretion in breast milk. Bisoprolol has low PPB (30%), a long half-life, and a potential risk of accumulation in infants. In addition, there is minimal clinical experience in using bisoprolol during breastfeeding; consequently, other drugs are preferred, particularly if nursing a newborn or preterm infant.[27]

Adverse Effects

A common adverse effect of cardiovascular blockers is bradycardia, decreasing heart rate and strength of contraction due to its negative chronotropic and inotropic effects. Bisoprolol also decreases cardiac output; therefore, it decreases exercise capacity. Blocking beta receptors on the SA and AV node always carries a risk of heart block. It correlates less frequently with exacerbating peripheral diseases such as the Raynaud phenomenon, bronchoconstriction, and hypoglycemia than non-selective beta-blockers.[28]

Other commonly encountered adverse effects include nausea, vomiting, and constipation. Hypoglycemia is a dangerous adverse effect in people with diabetes using beta-blockers. The drug blocks the typical signs of hypoglycemia, such as tachycardia, delaying the body's normal response to hypoglycemia, possibly leading to fear of complications.[29] 

Bradycardia, fatigue, asthenia, diarrhea, and sinusitis are dose-related among all adverse events. Beta-blockers, including bisoprolol, are implicated in drug-induced psoriasis and the worsening of pre-existing psoriasis.[30][31][32] 

Neuropsychiatric adverse events such as insomnia may be caused by bisoprolol, but a recent study by AHA found no association between bisoprolol use and depression.[33]

Drug-Drug Interactions

• Abrupt discontinuation of clonidine while taking bisoprolol results in a catecholamine surge and can lead to rebound hypertension. Bisoprolol should be stopped several days before the discontinuation of clonidine.[34]
• Concomitant use of bisoprolol with calcium channel blockers such as verapamil and diltiazem may worsen the myocardial function and result in hypotension, bradycardia, and AV block.[35]
• Strong CYP3A4 induces, like rifampin, increases the clearance of bisoprolol, resulting in a short elimination half-life of bisoprolol.[36]
• Concomitant administration of cholinesterase inhibitors like donepezil with bisoprolol can increase the risk for bradycardia, falls, and syncope.[37]
• Concomitant use of bisoprolol with digoxin delays AV conduction and can increase the risk of bradycardia.[38]

Contraindications

Cardioselective beta-blockers are contraindicated in patients with marked sinus bradycardia, cardiogenic shock, and complete heart block (third-degree AV block).[39] Patients with second-degree AV block should be monitored carefully. In addition, patients with a history of recent fluid retention should not use beta-blockers without the concomitant use of diuretics.[40] 

New studies suggest that cardioselective beta-blockers are contraindicated in patients with severe asthma or COPD, while it is entirely safe in patients with mild to moderate diseases.[41] 

In patients with diabetes, beta blockers may mask hypoglycemia, so careful monitoring is necessary.[42] Bisoprolol should not be abruptly withdrawn as doing so can cause rebound hypertension and tachycardia. In addition, some patients have developed or exacerbated existing angina pectoris, myocardial infarction, or ventricular arrhythmia when cessed therapy abruptly. Gradual reduction of the dose is recommended.[43]

Monitoring

The essential components to monitor at every visit in patients on the cardioselective beta-blocker are blood pressure and heart rate to detect and prevent bradycardia and hypotension. The cardiac electricity level should be monitored to avoid any degree of heart block. Renal function tests and complete blood counts are not indicated for regular monitoring but are necessary when there is a suspicion of toxicity or if the physician is concerned about the therapeutic level of the medicine.[28] 

The blood sugar level is regularly monitored in diabetic patients to prevent beta blocker-masked hypoglycemic episodes. Monitoring of lactate level is mandatory in a patient suspected of ingesting a high dose of beta-blockers due to the chance of having mesenteric ischemia.[44] 

In case of maternal exposure to bisoprolol, monitor the newborn baby's HR, blood glucose, and respiratory rate for 48 hours after birth.[25] Beta-blockers can worsen myasthenia gravis. Monitor for worsening of ptosis, diplopia, and muscle weakness.[45]

Toxicity

The toxicity of cardio-selective beta-blockers occurs after ingesting a high dose of the drug, either intentionally or unintentionally. Toxicity can be asymptomatic in some patients, but treatment is always required. Patients in such cases usually present with bradycardia and hypotension. In addition, selective beta-blockers in high doses lose their selectivity, causing patients to demonstrate signs of respiratory distress, congestive heart failure, and neurological manifestations, such as confusion and mental retardation, hypoglycemia, and hyperkalemia.

The beta-blocker overdose treatment protocol includes several medicines based on the signs and symptoms of clinical toxicity.[46][47]

• Sympathomimetic agents (IV atropine or isoproterenol) are used in patients who experience bradycardia.
• To antagonize beta-blocker-induced hypotension, the clinician should administer intravenous glucagon and fluid. Epinephrine may be ineffective in anaphylaxis induced by beta blockers. Glucagon stimulates heart contraction by glucagon receptors, which are not blocked by beta-blockers.[48]
• To reverse the bronchospasm induced by beta-blockers, isoproterenol, and aminophylline can be used.
• Depending on the patient's hemodynamic stability, hypoglycemia can be addressed by administering glucose orally or IV.
• The patient needs to be monitored carefully in case of a heart block and should be treated with isoproterenol infusion or transvenous cardiac pacemaker insertion.[49]
• Congestion and impaired perfusion status should be accurately determined in acute decompensated heart failure due to severe overdose. Digitalis, diuretics, inotropic agents, and vasopressors should be used according to hemodynamic status.[50]

Enhancing Healthcare Team Outcomes

Clinicians prescribe bisoprolol for hypertension, Heart failure with reduced ejection fraction, and coronary artery disease. Bisoprolol can mask the symptoms of hypoglycemia in diabetes; drug interactions can lead to bradycardia and AV block. In addition, abrupt withdrawal of bisoprolol can be life-threatening as it can cause life-threatening tachycardia, rebound hypertension, and in some cases, angina.

With careful monitoring of the patient's heart rate, blood pressure, temperature, and renal function, the clinician must know the possible adverse drug reactions and their appropriate management. The cardiologist's role is crucial in managing coronary artery disease. Arrhythmias refractory to bisoprolol therapy may require EP consultation. Patient care delivered by heart failure specialists is associated with lower mortality rates.[51]

Pharmacists must be aware of the required doses of the drug for each patient and perform medication reconciliation. Nurses can counsel the patients regarding administration and, along with the pharmacist, counsel the patient on potential adverse effects. Pharmacists and nurses must report any issues with the therapy regimen to the prescribing clinician for corrective action. Bisoprolol toxicity from accidental overdose is also possible in a patient with hypertension, so it is essential to know how to antagonize the drug's effect using high-dose glucagon. A study demonstrated that inpatient services delivered by medical toxicologists are associated with reduced length of stay and mortality in poisoning and overdose.[52] 

A psychiatrist consultation is required if the overdose of bisoprolol is intentional. An interprofessional team approach delivered by physicians, advanced practice practitioners, cardiologists, pulmonologists (for patients with asthma), pharmacists, specialty-trained nursing staff, and toxicologists can achieve optimal patient outcomes related to bisoprolol therapy.

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Disclosure: Ali Bazroon declares no relevant financial relationships with ineligible companies.

Disclosure: Nada Alrashidi declares no relevant financial relationships with ineligible companies.