Bisoprolol

Bisoprolol is a selective (cardioselective) beta-1 blocker with antihypertensive, antiarrhythmic and antianginal effects. The drug reduces the need for oxygen in the heart muscle, slows the heart rate, and “disarms” renin circulating in the blood plasma. Good tolerance by patients, high efficiency and the ability to prevent the development of a number of negative consequences of arterial hypertension have elevated beta blockers to the rank of permanent participants in the “battle” against cardiovascular diseases, which is waged today with varying success in modern cardiology. The discovery of subtypes of beta-1 and beta-2 adrenergic receptors at the end of the 60s of the last century prompted scientists to think about selective blockade of the former, because It is they, interacting with catecholamines, that create a favorable background for moving the tonometer needle beyond the WHO-recommended borderline readings of “140/90”. Selectivity (or cardioselectivity) has little effect on the hypotensive and antianginal effects of beta-blockers, while reducing the likelihood of a number of unpleasant side effects associated with stimulation of beta-2 adrenergic receptors (for example, bronchospasm or peripheral vasoconstriction).

Among all beta blockers known today, bisoprolol is endowed with the greatest selectivity and effectiveness. The antihypertensive effect of bisoprolol is comparable to that of calcium channel blockers and angiotensin-converting enzyme inhibitors. Distinctive features of this drug are also high (about 90%) bioavailability, long elimination period and “elusiveness” for proteins, with which no more than 30% of the active substance of the drug binds.

Moreover, these purely positive qualities of bisoprolol are characteristic of it regardless of the dose, which makes it possible to reduce the frequency of administration to a minimum - once a day. Having the advantages of both lipophilic (high absorption rate) and hydrophilic (long elimination time, insignificant biotransformations after the first passage through the liver) beta blockers, bisoprolol can be used in patients with liver and kidney diseases without changing the dose. As already mentioned, bisoprolol has the highest degree of cardioselectivity and only minimally affects beta-2 adrenergic receptors. This allows the drug to be prescribed to patients with chronic bronchial obstruction, bronchial asthma and atherosclerosis of peripheral vessels. Bisoprolol does not interfere with the processes of carbohydrate and lipid metabolism, and therefore does not cause increased insulin resistance. Regular and long-term use of bisoprolol for arterial hypertension, angina pectoris, chronic heart failure allows not only to curb “unleashed” blood pressure, reduce the frequency of angina manifestations, prevent or stop the progression of heart failure, but also significantly reduce the development of severe cardiovascular complications, thereby improving health prognosis patient and increasing his life expectancy.

BISOPROLOL-PRANA (tablets)

and with all this, the pressure drops sharply - to 90/40, and the pulse at the same time - 163 beats per minute, Oy!
And it has happened that after a minor load, for example playing volleyball, something similar happens. At first this happened once every six months and I did not pay attention to it, but after this phenomenon began to repeat almost every month, I was forced to see a doctor. The cardiologist wrote out a prescription and at the same time a referral for examination and treatment to the hospital, and that’s how I ended up in the cardiology department of the hospital. And after discharge, I discovered in the epicrisis, signed by the head of the department, that I needed to take Bisoprolol tablets for a year, half a tablet of 5 mg dosage once a day every day. The diagnosis is tachycardia, the pills seem to be suitable, but the annotation says that in addition to lowering the heart rate, they also reduce blood pressure, and my blood pressure has always been slightly below normal -110/70. Therefore, I was very surprised when I discovered this drug at home, in the discharge summary, and just in case, I went to the clinic, also to a cardiologist, for a consultation. The doctor firmly assured and confirmed that this medicine would suit me and there was no reason to worry. Although I laughed that Bisoprolol is somewhat outdated today and now there are more modern analogues, and indeed on the Internet I found information that Bisoprolol was discovered back in the sixties of the last century. But there are few side effects, “relatively” of course, and what worried me most was the situation with blood pressure. Probably in my eyes, after all, the doctor read the doubts and immediately offered to get this drug for free at the departmental pharmacy and wrote out a prescription for it. I had to agree, there is only one life. This box contained 3 plates of ten tablets each. I cut the tablets in half every morning with a knife along the line marked on them. In principle, it’s convenient, and I put the remaining half of the tablet back into the blister for storage. Well, I washed them down with water from this cooler. The package lasted me exactly two months. Our medicine’s manufacturer is the pharmaceutical company Pranafarm LLC, Samara. I can’t describe the taste of the tablets, since I swallowed them without chewing. This is what the doctor prescribed, and I had no desire to chew them. Probably bitter, like all pills. And now about health. The pills helped. My heart calmed down, my blood pressure did not drop two months after I started taking Bisoprolol, and my health improved. True, I just can’t forget the words of the head of the cardiology department upon discharge from the hospital: “We will meet again.” Now I decided to take a short break from taking Bisoprolol, let my tummy rest a little from the chemicals. The bottom line is clear to me: the medicine is good, but I will not recommend it, do not self-medicate, go to the doctor if you find similar symptoms as mine, although it helped me. Don't get sick, take care of yourself, have a good mood.

Bisoprolol in real cardiology

The key to all science is the question mark.

Honore de Balzac

More than twenty years have passed since the English pharmacologist James Black received the Nobel Prize for his work on the creation of drugs that affect the receptor apparatus. Propranolol, which he created in the late 50s, turned out to be the world's first drug that demonstrated a reduction in mortality. This is a key indicator that has brought beta-blockers (BABs) success.

For many years, the basis of therapy for arterial hypertension (AH) was the Birmingham Square: a) angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists, b) beta-blockers, c) calcium antagonists and d) thiazide diuretics. A sensation occurred in 2006 in the British guidelines for the treatment of hypertension, beta-blockers were excluded from the list of main drugs for the treatment of hypertension. They started talking about the end of their era. Is it so?

Currently, many drugs related to beta blockers are known. They are divided into subgroups depending on their pharmacodynamic characteristics and pharmacokinetic properties. These are selectivity to receptor subtypes (beta1 and beta2), internal sympathomimetic activity (action as a partial agonist), duration of action, combined effect on alpha adrenergic receptors.

BBs are divided into selective and non-selective depending on the ability to block only beta1 or beta1 and beta2 adrenergic receptors. Propranolol is a typical non-selective beta blocker, the ratio of the effect on beta1- and beta2-adrenergic receptors is 1. For metoprolol this ratio is 6, for bisoprolol - 12. Selectivity is dose-dependent. It is not for nothing that the statement is well known: “What is the selectivity, so is the efficiency.” With increasing dose, undesirable effects increase [1, 2].

The most important is the division according to pharmacokinetic properties: lipophilicity and hydrophilicity.

Hydrophilic biologically active substances (atenolol, nadolol, sotalol):

excreted by the kidneys, therefore, dose adjustment is necessary in patients with kidney disease;
do not have a beneficial effect on the functional activity of the vagus nerve, since they do not penetrate the blood-brain barrier;
are not completely and unevenly absorbed in the gastrointestinal tract;
do not reduce the risk of overall mortality in patients after myocardial infarction.

Lipophilic beta blockers (propranolol, betaxolol, carvedilol, metoprolol, nebivolol):

metabolized in the liver, their dosage or frequency of administration should be reduced in patients with impaired liver function, with heart failure, in elderly patients, when taken together with drugs that affect the enzymatic system of the liver, and also in smokers;
penetrate the blood-brain barrier, causing a number of side effects from the central nervous system.

Bisoprolol is an amphophilic biologically active substance, as it dissolves in both fats and water. As a result, it slightly penetrates the blood-brain barrier and has two equivalent elimination routes.

Thus, only bisoprolol among all biologically active substances has these unique properties.

You can compare the pharmacological parameters of bisoprolol and another popular biologically active substance, metoprolol (table).

The main cardiovascular effects of beta blockers:

Antihypertensive effect:

decreased cardiac output;
blockade of presynaptic alpha-adrenergic receptors;
suppression of renin secretion, the formation of angiotensin II and aldosterone;
decreased vasomotor activity of the central nervous system;
restructuring of the baroreceptor mechanisms of the aortic arch and carotid sinus.

Anti-ischemic effect:

decreased myocardial oxygen demand due to decreased heart rate;
decreased myocardial contractility and systolic blood pressure;
improvement of blood supply to the myocardium against the background of lengthening diastole and reducing intracardial tension.

Improvement of myocardial functions:

anti-ischemic effect;
blockade of the toxic effects of high concentrations of catecholamines;
inhibition of the release of free fatty acids that disrupt the metabolism of cardiomyocytes.

Antiarrhythmic action:

decreased heart rate;
slowing of conduction and prolongation of the refractory period in the atrioventricular connection;
decrease in spontaneous activation of ectopic pacemakers.

The beta-blocker must be a drug with proven effectiveness. Bisoprolol fully possesses these qualities [3, 4].

The anti-ischemic activity of bisoprolol was proven in the TIBBS study (Total Ischemic Burden Bisoprolol Study) [5].

In patients with stable angina who received bisoprolol (at a dose of 10–20 mg per day), the incidence of coronary complications was significantly lower than in patients who received nifedipine (21.1% versus 33.5%), with better tolerability.

BBs, in particular bisoprolol, are the drugs of choice for the treatment of coronary heart disease (CHD) with episodes of silent ischemia, acute coronary syndrome (ACS), and post-infarction cardiosclerosis.

BBs are also the drugs of choice for many heart rhythm disorders. For a long time it was believed that they are more effective for supraventricular than for ventricular arrhythmias. However, it has now been established that beta blockers are effective for ventricular arrhythmias in patients with myocardial ischemia, mitral valve prolapse and a number of other cardiovascular diseases. BABs effectively control the heart rate (HR) with a permanent form of atrial fibrillation. In terms of clinical effectiveness for this arrhythmia, beta blockers are not inferior to cardiac glycosides, and, if necessary, can be used in combination with them.

Since 2001, beta blockers have been used as standard pharmacotherapy for chronic heart failure (CHF). Bisoprolol is included in domestic and international classifications for the treatment of this syndrome.

The CIBIS study (1994) was the first to show a 20% reduction in the risk of overall mortality in patients receiving bisoprolol.

With the continuation of the CIBIS II study (1999), a reduction in the risk of overall mortality by 32% and a reduction in the risk of sudden death by 45% were achieved.

The study was stopped prematurely for ethical reasons due to the significantly greater effectiveness of bisoprolol compared to placebo.

CIBIS III demonstrated that the use of bisoprolol at the beginning of the treatment of CHF is at least equivalent to the use of an ACE inhibitor (enalapril), and possibly has a number of advantages.

CIBIS III was a multicenter randomized controlled trial that included 1010 patients (mean age 72 years) with mild to moderate CHF who had not previously taken either beta blockers or ACE inhibitors. In the first six months, participants were randomized into two parallel groups receiving either bisoprolol or enalapril monotherapy. Over the next 6–24 months, all participants received combination therapy with both drugs. At the end of the study, cases of death or hospitalization of patients were taken into account.

By the end of the study (average follow-up period 1.2 years), it was not possible to identify differences in the effectiveness and tolerability of the prescribed treatment regimens. However, within a year after the study, the result clearly shifted in favor of bisoprolol. Additional analysis showed that in the first 6 months of monotherapy, 8 of 23 deaths were sudden in the bisoprolol group and 16 of 32 in the enalapril group (hazard ratio (HR) = 0.5, p = 0.107). During the first year, these were 16 of 42 deaths in the group of patients who started treatment with bisoprolol, and 29 of 60 with enalapril. Thus, in the bisoprolol group, sudden deaths were observed 46% less often (HR = 0.54, p = 0.049) [6].

Until recently, practicing doctors retained myths about the dangers of benzoic blockers. But the high degree of selectivity of bisoprolol for beta1-adrenergic receptors determines the high safety of the drug in a wide range of patients. So, for example, such complications. such as bradycardia, atrioventricular block, decompensation of heart failure, orthostatic hypotension, were observed only in 0.1–1% of patients.

Given its high selectivity, bisoprolol in therapeutic dosages does not impair bronchial conduction and respiratory function in patients with chronic obstructive pulmonary disease. The Chatterjee SS study, which examined the effects of bisoprolol in patients with bronchial asthma, showed that bisoprolol caused a non-significant decrease in forced expiratory volume in the first second (FEV1) and airway resistance comparable to placebo. Also, taking bisoprolol is not associated with the development of sexual dysfunction, which was confirmed in the study by Prisant LM et al., where the incidence of sexual dysfunction when taking bisoprolol did not differ from that when taking placebo. Consequently, bisoprolol is the only beta blocker for which no effect on sexual function in men has been convincingly proven.

There was no effect of bisoprolol on carbohydrate metabolism either in patients without metabolic disorders or in patients with diabetes mellitus. Bisoprolol also does not affect the content of cholesterol and lipoproteins in the blood plasma.

Therefore, bisoprolol is one of the most prescribed beta blockers among our doctors. High selectivity ensures the safety of its use in patients with diabetes mellitus, peripheral circulatory disorders, lipid metabolism disorders, and smokers. Safe in patients with impaired liver and kidney function.

The high adherence of patients to treatment taking bisoprolol is due to the ease of use (once a day) regardless of food intake, the ability to divide the tablet and the lack of special storage conditions. Drug withdrawal syndrome is practically not observed.

Cardiologists prefer to use bisoprolol, since it is prescribed to patients with comorbid pathology, does not require dosage adjustment for the elderly, and is combined with most antihypertensive drugs.

Literature

Teplova N.V., Teplova N.N. Use of the β-blocker bisoprolol in cardiological practice // Russian Medical Journal. 2009. T. 17. No. 18. P. 1205–1208.
Oleynikova G.L. Some aspects of the use of bisoprolol in cardiovascular pathology // Russian Medical Journal. 2009. T. 17. No. 8. pp. 614–616.
Bragina A. E. Modern positions of beta blockers in cardiology: from recommendations to real practice // Attending Physician. 2010. No. 7. pp. 50–54.
Kuprina A. A., Belousov Yu. B., Sokolov A. V., Maneshina O. A. Clinical value of the selective beta-blocker bisoprolol in the treatment of cardiovascular diseases in medicine, based on evidence // Farmateka. 2007. No. 19. pp. 19–22.
Von Armin T. Prognostic significance of transient ischemic episodes: response to treatment shows improved prognosis. Results of Total Ischemic Burden Bisoprolol Study (TIBBS) follow-up // J Am Coll Cardiol. 1996; 28 (1): 20–24.
Wilenheimer R., van Veldhuisen DJ, Siike B. et al. Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence. Results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III // Circulation. 2005; 112:2426–2435.

T. V. Tkachenko, Candidate of Medical Sciences, Associate Professor N. I. Fisun, Candidate of Medical Sciences, Associate Professor S. F. Gunter

State Budgetary Educational Institution of Higher Professional Education "Omsk State Medical Academy of the Ministry of Health and Social Development" of Russia, Omsk

Contact information for authors for correspondence

Bisoprolol-Prana film-coated tablets 5 mg No. 30

pharmachologic effect

A selective beta1-blocker without internal sympathomimetic activity and does not have membrane stabilizing activity.
Reduces plasma renin activity, reduces myocardial oxygen demand, reduces heart rate (at rest and during exercise) and cardiac output, while stroke volume does not decrease significantly. Inhibits AV conduction. Has antianginal and hypotensive effects. In high doses (200 mg or more) it can cause blockade of β2-adrenergic receptors, mainly in the bronchi and vascular smooth muscles. The hypotensive effect is associated with a decrease in minute blood volume, sympathetic stimulation of peripheral vessels, a decrease in the activity of the renin-angiotensin system (of greater importance for patients with initial hypersecretion of renin), restoration of sensitivity in response to a decrease in blood pressure and an effect on the central nervous system.

The antianginal effect is due to a decrease in myocardial oxygen demand as a result of a decrease in heart rate and decreased contractility, prolongation of diastole, and improved myocardial perfusion.

The antiarrhythmic effect is due to the elimination of arrhythmogenic factors (tachycardia, increased activity of the sympathetic nervous system, increased cAMP content, arterial hypertension), a decrease in the rate of spontaneous excitation of sinus and ectopic pacemakers and a slowdown in AV conduction (mainly in the antegrade and, to a lesser extent, in the retrograde directions via the AV node) and along additional paths.

Pharmacokinetics

Absorption - 80-90%, food intake does not affect absorption.

Cmax in blood plasma is achieved after 2-4 hours. Plasma protein binding is 26-33%. Bisoprolol penetrates to a small extent through the BBB and the placental barrier; excreted in breast milk.

Metabolized in the liver.

T1/2 - 9-12 hours. Excreted by the kidneys - 50% unchanged, less than 2% - with bile.

Indications

Arterial hypertension, prevention of angina attacks, chronic heart failure.

Dosage regimen

Individual. For oral administration, the daily dose is 2.5-10 mg, the frequency of administration is 1 time / day. The maximum daily dose is 10 mg.

Side effect

From the nervous system: weakness, fatigue, dizziness, headache, sleep disorders, mental disorders (depression, rarely hallucinations), feeling of cold and paresthesia in the extremities.

From the cardiovascular system: orthostatic hypotension, bradycardia, impaired AV conduction, the appearance of symptoms of heart failure, worsening intermittent claudication and the main clinical symptoms of Raynaud's syndrome.

From the organ of vision: decreased secretion of tear fluid, conjunctivitis.

From the digestive system: diarrhea, constipation, nausea, abdominal pain.

From the musculoskeletal system: muscle weakness, muscle cramps.

From the skin and subcutaneous tissues: skin itching; in some cases - increased manifestations of psoriasis, the appearance of psoriasis-like rashes.

From the respiratory system: in predisposed patients, symptoms of bronchial obstruction may appear.

Other: sweating, hot flashes, impaired potency, decreased glucose tolerance in patients with diabetes, allergic reactions.

Contraindications for use

Acute heart failure, chronic heart failure in the stage of decompensation, cardiogenic shock, collapse, AV block of II and III degrees (without a pacemaker), SSSU; sinoatrial blockade, severe bradycardia (heart rate <50 beats/min), Prinzmetal's angina, marked decrease in blood pressure (systolic blood pressure <90 mm Hg), history of severe forms of bronchial asthma and COPD, late stages of peripheral circulatory disorders, Raynaud's disease , pheochromocytoma (without simultaneous use of alpha-blockers), metabolic acidosis, simultaneous use of MAO inhibitors (except for MAO type B inhibitors), children and adolescents under 18 years of age, hypersensitivity to bisoprolol and other beta-blockers.

Use during pregnancy and breastfeeding

Use during pregnancy and lactation is not recommended and is possible only in cases where the expected benefit to the mother outweighs the potential risk of side effects in the fetus and child.

In exceptional cases of use during pregnancy, bisoprolol should be discontinued 72 hours before the expected due date due to the possibility of bradycardia, arterial hypotension, hypoglycemia and respiratory depression in the newborn. If discontinuation is not possible, then the condition of the newborn must be carefully monitored for 72 hours after birth.

If it is necessary to use bisoprolol during lactation, breastfeeding should be stopped.

Use for liver dysfunction

The dose should not exceed 10 mg/day in case of severe liver dysfunction.

Use for renal impairment

The dose should not exceed 10 mg/day in case of renal failure (creatinine clearance less than 20 ml/min).

Use in children

Use in children is not recommended.

special instructions

Use with caution for psoriasis and when there is a family history of psoriasis, diabetes mellitus in the decompensation phase, or with a predisposition to allergic reactions. In case of pheochromocytoma, the use of bisoprolol is possible only after taking alpha-blockers. Avoid abrupt withdrawal of bisoprolol; the course of treatment should be completed slowly with a gradual reduction in dose. Before surgery, the anesthesiologist should be informed about treatment with bisoprolol.

Bisoprolol at a dose of more than 10 mg/day should be used only in exceptional cases.

This dose should not be exceeded in case of renal failure (creatinine clearance less than 20 ml/min) and severe liver dysfunction.

During the treatment period, avoid drinking alcohol.

Impact on the ability to drive vehicles and operate machinery

Use with caution in patients whose activities require concentration and high speed of psychomotor reactions.

Drug interactions

With the simultaneous use of antacids and antidiarrheals, the absorption of beta-blockers may be reduced.

With the simultaneous use of antiarrhythmic drugs, a sharp decrease in blood pressure, a decrease in heart rate, and the development of arrhythmia and/or heart failure are possible.

With the simultaneous use of antihypertensive drugs, the antihypertensive effect may be enhanced.

With the simultaneous use of cardiac glycosides, conduction disturbances are possible.

With the simultaneous use of sympathomimetics (including those included in cough suppressants, nasal drops, eye drops), the effectiveness of bisoprolol decreases.

With the simultaneous use of verapamil and diltiazem, a sharp decrease in blood pressure, a decrease in heart rate, and the development of arrhythmia and/or heart failure are possible.

With simultaneous use of guanfacine, severe bradycardia and conduction disturbances are possible.

With the simultaneous use of insulin and hypoglycemic agents for oral administration, the effect of insulin or other hypoglycemic agents is enhanced (regular monitoring of plasma glucose levels is necessary).

With simultaneous use of clonidine, severe bradycardia, arterial hypotension, and conduction disturbances are possible.

In case of sudden withdrawal of clonidine in patients receiving bisoprolol, a sharp increase in blood pressure is possible.

With the simultaneous use of nifedipine, other calcium channel blockers, dihydropyridine derivatives, the antihypertensive effect of bisoprolol is enhanced.

With the simultaneous use of reserpine and alpha-methyldopa, severe bradycardia is possible.

With simultaneous use of rifampicin, a slight decrease in T1/2 of bisoprolol is possible.

With the simultaneous use of ergotamine derivatives (including drugs for the treatment of migraines containing ergotamine), symptoms of peripheral circulatory disorders increase.