Bisoprolol, sold under the brand name Zebeta among others, is a

beta blocker Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack after a first heart attack ( secondary prevention). They are ...

medication used for heart diseases. This includes tachyarrhythmias, high blood pressure, chest pain from not enough blood flow to the heart, and heart failure. It is taken

by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...

. Common side effects include headache, feeling tired, diarrhea, and swelling in the legs. More severe side effects include worsening

asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...

, blocking the ability to recognize

low blood sugar Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose bel ...

, and worsening heart failure. There are concerns that use during

pregnancy Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...

may be harmful to the baby. Bisoprolol is in the

family of medications and is of the β₁ selective type. Bisoprolol is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. Bisoprolol is available as a generic medication. In 2020, it was the 267th most commonly prescribed medication in the United States, with more than 1million prescriptions.

Medical uses

Bisoprolol is currently used for prevention of cardiovascular events following a heart attack in patients with risk factors for disease progression, in the management of congestive heart failure with reduced ejection fraction, and as a second-line agent for hypertension. Bisoprolol may be beneficial in the treatment of high blood pressure, but it is not recommended as a first-line anti-hypertensive agent without an accompanying

comorbid In medicine, comorbidity - from Latin morbus ("sickness"), co ("together"), -ity (as if - several sicknesses together) - is the presence of one or more additional conditions often co-occurring (that is, concomitant or concurrent) with a primary ...

condition, for example, congestive heart failure. In cardiac ischemia, the drug is used to reduce the activity of the heart muscle, thereby reducing its oxygen and nutrient demands and allowing its reduced blood supply to still transport sufficient amounts of oxygen and nutrients to meet its needs.

Side effects

An overdose of bisoprolol can lead to fatigue,

hypotension Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dia ...

hypoglycemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose bel ...

bronchospasm Bronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release (degranulation) of substances from mast cells or basophils under the influence of anaphylatoxins. It causes di ...

s, and bradycardia. Bronchospasms and hypoglycemia occur because at high doses, the drug can be an antagonist for β₂ adrenergic receptors located in the lungs and liver. Bronchospasm occurs due to the blockage of β₂ receptors in the lungs. Hypoglycemia occurs due to decreased stimulation of glycogenolysis and gluconeogenesis in the liver via β₂ receptors.

Cautions

Non-selective beta-blockers should be avoided in people with asthma or bronchospasm as they may cause exacerbations and worsening of symptoms. A β₁ selective beta-blocker like bisoprolol may be cautiously tried in those with controlled, mild-to-moderate asthma with cardiac comorbidities. A 2014 meta-analysis found that cardioselective beta-blockers may cause detrimental changes in lung function and partially blunts β₂-agonist response. However, a 2017 control study found no significant association with asthma exacerbations by dose and exposure duration while a 2020 clinical trial found bisoprolol being non-inferior to

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. In general, placebos can af ...

in bronchodilator response to salbutamol.

Pharmacology

Mechanism of action

Bisoprolol is cardioprotective because it selectively and competitively blocks

catecholamine A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Catechol can be either a free molecule or a su ...

(

adrenaline Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands an ...

) stimulation of β₁ adrenergic receptors (adrenoreceptors), which are mainly found in the heart muscle cells and heart conduction tissue (cardiospecific), but also found in juxtaglomerular cells in the kidney. Normally, adrenaline and noradrenaline stimulation of the β₁ adrenoreceptor activates a

signalling cascade A biochemical cascade, also known as a signaling cascade or signaling pathway, is a series of chemical reactions that occur within a biological cell when initiated by a stimulus. This stimulus, known as a first messenger, acts on a receptor that ...

(

Gs protein The Gs alpha subunit (Gαs, Gsα) is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein. Gsα is the founding ...

and cAMP) which ultimately leads to increased

myocardial contractility Myocardial contractility represents the innate ability of the heart muscle (cardiac muscle or myocardium) to contract. The ability to produce changes in force during contraction result from incremental degrees of binding between different types of t ...

and increased heart rate of the heart muscle and heart pacemaker, respectively. Bisoprolol competitively blocks the activation of this cascade, so decreases the adrenergic tone/stimulation of the heart muscle and pacemaker cells. Decreased adrenergic tone shows less contractility of heart muscle and lowered heart rate of pacemakers.

β₁-selectivity

Bisoprolol β₁-selectivity is especially important in comparison to other nonselective beta blockers. The effects of the drug are limited to areas containing β₁ adrenoreceptors, which is mainly the heart and part of the kidney. Bisoprolol, whilst β₁ adrenoceptor selective can help patients to avoid certain side-effects associated with non-selective beta-blocker activity at additional adrenoceptors (α₁ and β₂), it does not signify its superiority in treating beta-blocker indicated cardiac conditions such as heart failure but could prove beneficial to patients with specific comorbidities. Bisoprolol has a higher degree of β₁-selectivity compared to

atenolol Atenolol is a beta blocker medication primarily used to treat high blood pressure and heart-associated chest pain. Atenolol, however, does not seem to improve mortality in those with high blood pressure. Other uses include the prevention of mi ...

metoprolol Metoprolol, sold under the brand name Lopressor, among others, is a selective β1 receptor blocker medication. It is used to treat high blood pressure, chest pain due to poor blood flow to the heart, and a number of conditions involving an a ...

and betaxolol. With a selectivity ranging from being 11-15 times more selective for β₁over β₂ However nebivolol is approximately 3.5 times more β₁-selective.

Renin-angiotensin system

Bisoprolol inhibits

renin Renin (etymology and pronunciation), also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin–angiotensin–aldosterone system (RAAS)—also known as the r ...

secretion by about 65% and

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ( ...

by about 30%.

Pharmacokinetics

After ingestion, bisoprolol is absorbed and has a high bioavailability of approximately 90% with plasma half-life of 10-12 hours. When being eliminated, the body evenly distributes it (50–50) between kidney excretion and liver biotransformation (then excreted). Bisoprolol has both lipid- and water-soluble properties. The plasma protein binding of bisoprolol is approximately 35%, the volume of distribution is 3.5 L/kg and the total clearance is approximately 15 L/h. Bisoprolol is eliminated from the body in two ways - 50% of the substance is converted in the liver to inactive metabolites, which are then excreted in the kidneys. The remaining 50% is eliminated unchanged via the kidneys. Since elimination is equal in liver and kidney, no dose adjustment is required in patients with hepatic or renal impairment. The pharmacokinetics of bisoprolol are linear and independent of age. In patients with chronic heart failure (NYHA stage III), the plasma level of bisoprolol is higher and the half-life is longer than in healthy subjects. At a daily dose of 10 mg, the steady-state peak plasma concentration is 64±21 ng/mL and the half-life is 17±5 hours.

History

Bisoprolol was

patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A ...

ed in 1976 and approved for medical use in 1986. It was approved for medical use in the United States in 1992.

Brand names

In India, it is sold under trade name Bisotab and is available in 2 strengths of 2.5 mg and 5 mg. In Italy, it is sold under trade name Congescor and is available in 6 strengths of 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg. In Germany and Eastern Europe bisoprolol is marketed as Bisoprolol-ratiopharm by Ratiopharm ( Teva).

References

External links

* {{Authority control Beta blockers N-isopropyl-phenoxypropanolamines Peripherally selective drugs Merck brands World Health Organization essential medicines Wikipedia medicine articles ready to translate