Bisoprolol

Bisoprolol is a cardioselective beta-1 adrenergic blocking agent belonging to the beta-blocker class. Bisoprolol is approved to treat myocardial infarction, heart failure, and mild to moderate hypertension.

Due to its nearly full absorption (more than 90%) and minimal first-pass impact, bisoprolol has a high absolute bioavailability (90%) in clinical trials. Intake of food has little impact on bioavailability. A once-daily dosing schedule is possible because of a lengthy plasma-elimination half-life (10–11h). Kinetics are insensitive to protein-binding interactions because of the low plasma protein-binding (30%).

The common side effects associated with Bisoprolol include slower heart rate, diarrhea, weakness, tiredness, dizziness, anxiety, nausea, dry or burning eyes, headache, cold or flu symptoms, etc.

Bisoprolol is available in the form of Tablets.

The molecule is available in Sweden, Germany, Spain, the US, India.

Bisoprolol is available in form of tablets.

Bisoprolol Comes as a tablet. As directed by a physician, the regular tablet is often taken once or twice a day.

Bisoprolol is used in the treatment of Hypertension,Angina, Arrhythmia, recent myocardial infarction and Migraine.

Bisoprolol works on specific receptors located in the heart (called beta1 receptors) to slow the heart rate. It decreases cardiac output, inhibits renin release from the kidneys, and reduces the activity of the sympathetic nervous system.Bisoprolol causes a reduction in heart rate both at rest and during exercise.Bisoprolol also lowers blood pressure and is used for the treatment of high blood pressure.

Bisoprolol is approved for use in the following clinical indications.

• High Blood Pressure: Beta-blocking medications' antihypertensive effects still lack a precise mechanism of action. However, several potential methods have been put forth: reduced cardiac output due to competing antagonistic interactions between catecholamines at peripheral adrenergic neuron locations, decreased sympathetic outflow to the periphery due to a significant influence; and suppression of renin activity.

Although not approved, there have been certain Off-label uses documented for Bisoprolol. These include:

• Angina Pectoris: Bisoprolol is helpful in the treatment of angina pectoris because it lowers the oxygen demands of the heart at any given amount of effort.
• Migraine: Beta-blockers alleviate that pain by making the blood vessels relax so that the blood can flow normally.
• Myocardial Infarction: Beta-blockers reduce myocardial workload, and thus oxygen demand, via a reduction in heart rate and blood pressure. They reduce catecholamine levels, decrease myocardial ischemia and limit infarct size, and may prevent the development of definite infarction in acute coronary syndrome (ACS) patients.
• Atrial fibrillation: Beta-blockers reduce the heart rate by limiting the effects of adrenaline and other related hormones on the heart. In the treatment of arrhythmia, beta-blockers are mainly used to regulate the heart rate. However, beta-blockers are also known as drugs with an antiarrhythmic effect due to the suppression of sympathetic activity. Regardless of whether a rhythm or rate control method is used, beta blockers are typically the first line of treatment for AF.

Bisoprolol is available in the form of tablets.

High Blood Pressure: Bisoprolol is administered only orally as 5 or 10 mg tablets once daily. Bisoprolol has low lipophilicity, so it does not cross the blood-brain barrier with a high amount. Bisoprolol has a long half-life that extends from 9 to 12 hours. It also has high bioavailability, reaching 80 % compared to most beta-blockers with lower bioavailability since they have high first-pass metabolism in the liver.

Bisoprolol are available with the dosage strength of 2.5 mg ,3.75 mg, 5 mg, 7.5 mg and 10 mg.

Bisoprolol is available in the form of tablets which is taken orally by mouth.

Bisoprolol should be used in the treatment of high blood pressure, angina pectoris, migraine, and acute myocardial infraction along with appropriate dietary restrictions.

• High Blood Pressure: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.
• Angina Pectoris: Avoid foods that are high in saturated fat and hydrogenated or partially hydrogenated fats. Reduce your intake of dairy products including cheese, cream, and eggs.
• Migraine: Some commonly triggered diets include: Baked food with yeast, such as sourdough bread, bagels, doughnuts, coffee cake, Chocolate, Cultured dairy products (like yogurt and kefir), Tomatoes, Vegetables like onions, pea pods, some beans, corn, and sauerkraut, Vinegar and Alcohol must be avoided.
• Myocardial infarction: No more than 25 to 35 percent of your daily calories should come from total fat (including saturated fat).

Less than 7 %of your daily calories should come from saturated fat. Avoid trans fats and Consume less than 200 milligrams a day of dietary cholesterol.

The dietary restriction should be individualized as per patient requirements

Bisoprolol is contraindicated in patients with the following disease:

• Acute heart failure
• Cardiogenic shock
• Second or third-degree AV block
• Sick sinus syndrome
• Sinoatrial block
• Symptomatic bradycardia
• Symptomatic hypotension
• Severe bronchial asthma or severe chronic obstructive pulmonary disease
• Severe forms of peripheral arterial occlusive disease or severe forms of Raynaud's syndrome
• Untreated pheochromocytoma
• Metabolic acidosis

Cardiac Failure

Sympathetic stimulation is an important component supporting circulatory function in the setting of congestive heart failure, and beta blockade may result in further depression of myocardial contractility and precipitate more severe failure. In general, beta-blocking agents should be avoided in patients with overt congestive failure. However, in some patients with compensated cardiac failure it may be necessary to utilize them. In such a situation, they must be used cautiously.

• In Patients Without a History of Cardiac Failure:

Continued depression of the myocardium with beta-blockers can, in some patients, precipitate cardiac failure. At first signs or symptoms of heart failure, discontinuation of Bisoprolol should be considered. In some cases, beta-blocker therapy can be continued while heart failure is treated with the other drugs.

• Abrupt Cessation of Therapy :

Exacerbation of angina pectoris and, in some instances, myocardial infarction or ventricular arrhythmia, have been observed in the patients with coronary artery disease following abrupt cessation of therapy with beta-blockers. Such patients should, therefore, be cautioned against the interruption or discontinuation of therapy without the physician's advice. Even in patients without overt coronary artery disease, it may be advisable to taper therapy with Bisoprolol over approximately one week with the patient under careful observation. If withdrawal symptoms occur, Bisoprolol therapy should be reinstituted, at least temporarily.

• Peripheral Vascular Disease :

Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.

• Bronchospastic Disease

Patients with bronchospastic disease should, in general, not receive beta-blockers. Because of its relative beta1-selectivity, however, bisoprolol may be used with caution in patients with bronchospastic disease who do not respond to or who cannot tolerate other antihypertensive treatment. Since beta1-selectivity is not absolute, the lowest possible dose of Bisoprolol should be used, with therapy starting at 2.5 mg. A beta2 agonist (bronchodilator) should be made available.

• Anesthesia and Major Surgery

If Bisoprolol treatment is to be continued perioperatively, particular care should be taken when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used.

• Diabetes and Hypoglycemia

Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective beta-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Because of its beta1-selectivity, this is less likely with BISOPROLOL. However, patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, must be cautioned about these possibilities, and bisoprolol fumarate should be used with caution.

• Thyrotoxicosis

Beta-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

PRECAUTION:

• Applies only to hypertension or angina pectoris:

Bisoprolol must be used with caution patients with hypertension or angina pectoris and accompanying heart failure.

• Applies only to chronic heart failure:

There is no therapeutic experience of bisoprolol in treating heart failure in patients with the following diseases and conditions:

• Insulin dependent diabetes mellitus (type I)
• Severely impaired renal function
• Severely impaired hepatic function
• Restrictive cardiomyopathy
• Congenital heart disease
• Hemodynamically significant organic valvular disease
• Myocardial infarction within 3 months.

Alcohol lowers the blood pressure. Drinking alcohol while taking bisoprolol may lower the blood pressure to dangerously low levels.

It is unknown whether Bisoprolol is excreted in human milk. Therefore, breastfeeding is not recommended during the administration of bisoprolol.

The pharmacological actions of bisoprolol may have negative consequences on the fetus or baby during pregnancy. Beta-adrenoceptor blockers typically decrease placental perfusion, which has been linked to premature labor, intrauterine death, growth retardation, and abortion. The fetus and newborn infant may experience negative effects, such as hypoglycemia and bradycardia. If beta-adrenoceptor blockers are required for treatment, beta1-selective adrenoceptor blockers are preferred. When plainly essential, bisoprolol should not be administered during pregnancy. Monitoring the uteroplacental blood flow and fetal growth is advised if bisoprolol medication is considered necessary. Alternative treatments should be taken into consideration if there are negative effects on pregnancy or the fetus. The newborn infant needs to be watched carefully. Within the first three days, bradycardia and hypoglycemia symptoms are typically anticipated.

The food warning while consuming Bisoprolol that should be taken in concentrations while consumptions:

• Salt Substitutes: The combination of bisoprolol with foods rich in salts like sodium, calcium, and magnesium may reduce or negate the blood pressure-lowering effect of bisoprolol. It is better to avoid the intake of bisoprolol with salt-rich foods.

• Potassium Rich Foods: Bisoprolol may increase the potassium levels in the blood. Avoid taking potassium-rich foods with bisoprolol.

• Pleurisy Root: Pleurisy root is not recommended with most heart medications due to the cardiac glycoside content of the root.

• Interaction with caffeine: The interaction of caffeine-containing food items and beverages along with beta-blockers like bisoprolol may decrease the effectiveness of the drug. It is better to avoid tea or coffee while taking bisoprolol.

Most adverse effects have been mild and transient.

• Common Adverse effects:

Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by the disorientation of time and place; short-term memory loss; emotional lability with slightly clouded sensorium; and decreased performance on neuropsychometrist.

• Infrequent adverse effects:

Mesenteric arterial thrombosis, ischemic colitis, fever, combined with an aching and sore throat, laryngospasm, and respiratory distress.

• Rare adverse effect:

Erythematous rash.

• Miscellaneous:

There have been reports of skin rashes and dry eyes associated with the use of beta-adrenergic blocking drugs.

The clinically relevant drug interactions of Bisoprolol are briefly summarized as follows:-

• Bisoprolol should not be combined with the other beta-blocking agents. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored because added beta-adrenergic blocking action of Bisoprolol may produce an excessive reduction of the sympathetic activity.
• In patients receiving concurrent therapy with clonidine, if therapy is to be discontinued, it is suggested that Bisoprolol be discontinued for several days before the withdrawal of clonidine. Bisoprolol should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
• Concurrent use of rifampin increases the metabolic clearance of Bisoprolol, resulting in a shortened elimination half-life of Bisoprolol.
• However, initial dose modification is generally not necessary. Pharmacokinetic studies document no clinically relevant interactions with other agents given concomitantly, including thiazide diuretics and cimetidine. There was no effect of Bisoprolol on prothrombin time in patients on stable doses of warfarin.
• Risk of Anaphylactic Reaction: While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenges, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

The common side effects of Bisoprolol include headache, feeling tired, insomnia, joint pain, swelling, or cold symptoms such as stuffy nose, runny nose, cough, and sore throat.

Other side effects include: shortness of breath, slow heart rate, eye pain, vision problems, etc.

Pharmacodynamics

The most prominent effect of Bisoprolol is the negative chronotropic effect, resulting in a reduction in resting and exercise heart rate. There is a fall in resting and exercise cardiac output with little observed change in stroke volume, and only a small increase in right atrial pressure, or pulmonary capillary wedge pressure at rest or during exercise.

Findings in short-term clinical hemodynamics studies with Bisoprolol are similar to those observed with other beta-blocking agents.

The mechanism of action of its antihypertensive effects has not been completely established. Factors that may be involved include:

1. Decreased cardiac output,

2. Inhibition of renin release by the kidneys,

3. Diminution of tonic sympathetic outflow from the vasomotor centers in the brain.

The most prominent effect of bisoprolol fumarate is the negative chronotropic effect, resulting in a reduction in resting and exercise heart rate. There is a fall in resting and exercise cardiac output with little observed change in stroke volume and only a small increase in right atrial pressure, or pulmonary capillary wedge pressure at rest or during exercise.

Pharmacokinetics

• Absorption:

Bisoprolol is well absorbed in the gastrointestinal tract. The AUC is 642.87 g.hr/mL, and the bioavailability of bisoprolol is about 90% due to the minimal first pass effects. Absorption is unaffected by food intake. Peak plasma concentrations of bisoprolol are attained within 2-4 hours and steady-state concentrations are achieved within 5 days of administration. In a pharmacokinetic study, the mean peak concentration of bisoprolol was 52 micrograms/L. Cmax at steady-state concentrations of bisoprolol is 64±21 ng/ml administered at 10 mg daily.

• Distribution:

The volume of distribution of bisoprolol is 3.5 L/kg. The mean volume of distribution was found to be 230 L/kg in heart failure patients, which was similar to the volume of distribution in healthy patients. Bisoprolol is known to cross the placenta.

• Metabolism:

About 50% of a single bisoprolol dose is metabolized mainly by the enzyme CYP3A4 to inactive metabolites.

• Elimination:

Bisoprolol is eliminated equally by both renal and hepatic pathways. About 50% of an oral dose is excreted and remained unchanged in the urine, with the remainder of the dose excreted as inactive bisoprolol metabolites. Under 2% of the ingested dose is found to be excreted in the feces.

1. Leizorovicz A, Lechat P, et.al. Bisoprolol for the treatment of chronic heart failure: a meta-analysis on individual data of two placebo-controlled studies—CIBIS and CIBIS II. American Heart Journal. 2002 Feb 1;143(2):301-7. DOI: https://doi.org/10.1067/mhj.2002.120768
2. Sabidó M, Thilo H, et.al. Long-term effectiveness of bisoprolol in patients with angina: a real-world evidence study. Pharmacological research. 2019 Jan 1;139:106-12. DOI: https://doi.org/10.1016/j.phrs.2018.10.031
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