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 in the practice of a therapist

For citation. Kirichenko A.A. Bisoprolol in the practice of a therapist // RMJ. 2015. No. 27. pp. 1594–1597.

In the mid-1950s. D.W. Black theoretically developed a way to reduce the frequency of angina attacks. He suggested that it would be possible to invent a drug to effectively protect the b-receptors of the heart muscle from the effects of adrenaline. After all, this hormone stimulates the muscle cells of the heart, causing them to contract too intensely and causing heart attacks. The first such medicine was propranolol, the clinical use of which began in 1964. For the development of propranolol and the “theory” of b-blockers in 1988, D.W. Black was awarded the Nobel Prize in Physiology or Medicine (Figure 1). Today, every therapist has β-blockers (BABs) in their arsenal of treatments. Over 50 years of clinical use, they have proven their effectiveness in treating coronary heart disease (CHD), arterial hypertension (AH), cardiac arrhythmias, chronic heart failure (CHF), hypertrophic cardiomyopathy, etc. Over the years of widespread clinical use, drugs that block adrenergic receptors , have changed significantly, becoming safer and easier to use. The most widely used are selective β1-adrenergic receptor blockers, one of which is bisoprolol.

In therapeutic doses, bisoprolol is more selective than betaxolol, atenolol, metoprolol, its affinity for β1-adrenergic receptors is 100 times higher than for β2-adrenergic receptors [1, 2]. Since bisoprolol in therapeutic doses almost does not block the effects of endogenous catecholamines on β2-adrenergic receptors, it affects blood flow in the skin, liver, kidneys to a lesser extent than non-selective blockers, and does not have a significant effect on the tone of the bronchial muscles, blood flow and glycolytic processes in the skeletal muscles, as a result of which it does not reduce exercise tolerance. Bisoprolol is devoid of such adverse metabolic effects of non-selective blockers as hypoglycemia, hypokalemia, increased levels of very low density lipoproteins and plasma triglycerides [3]. Depending on their ability to dissolve in fats, biologically active substances are divided into fat-soluble and water-soluble. Fat-soluble drugs penetrate well through biological membranes, which determines rapid and almost complete absorption in the gastrointestinal tract, the ability to penetrate the blood-brain barrier and bind to central β1-adrenergic receptors. Bisoprolol has the property of amphiphilicity - the ability to dissolve in both lipids and water. After oral administration, bisoprolol is almost completely absorbed from the gastrointestinal tract. The absolute bioavailability of the drug is 88–90% [4]. The dependence of the pharmacokinetics of bisoprolol on the dose is linear, its individual and interindividual fluctuations are small, which ensures a constant and predictable therapeutic effect of the drug [4, 5]. Bisoprolol clearance is carried out in equal parts by the liver and kidneys. The peculiarities of the metabolism of bisoprolol determine its clinical advantages: the possibility of taking it once a day, high safety of treatment for patients with concomitant diseases, such as diabetes mellitus (DM), pathology of peripheral arteries, chronic obstructive pulmonary disease. According to the concept of D.W. Black, beta-blockers immediately found wide use as antianginal and anti-ischemic agents and maintain a leading position in the treatment of angina to this day. Thus, in accordance with the 2013 recommendations for the treatment of stable angina [6], beta blockers should be prescribed to all patients diagnosed with angina in the absence of contraindications. Numerous studies have shown that beta blockers significantly reduce the likelihood of sudden cardiac death (SCD), recurrent myocardial infarction (MI) and increase the overall life expectancy of patients who have had an MI. BBs significantly improve the prognosis of patients' lives if coronary artery disease is complicated by heart failure. According to the results of the study The β-Blockers Pooling Project (combined data for all drugs in this group), a significant reduction in mortality was found in the group of patients receiving beta blockers. For this reason, it is generally accepted that blockers can reduce mortality, especially through the prevention of SCD and MI, even among patients without a history of MI [7]. The TIBBS study [8] assessed the effect of bisoprolol on transient myocardial ischemia in patients with stable angina with myocardial ischemia verified by a treadmill test and 24-hour ECG monitoring in comparison with treatment with nifedipine. After 4 weeks therapy in the bisoprolol group, the number of episodes of myocardial ischemia decreased from 8.1±0.6 to 3.2±0.4, the total duration of myocardial ischemia decreased from 99.3±10.1 to 31.2±5.5 minutes, significantly (by 135) the number of ischemic attacks in the early morning hours decreased. In addition, the TIBBS study provided very important data on the impact of immediate treatment results on the prognosis of patients with angina pectoris. It turned out that the risk of death, nonfatal myocardial infarction, unstable angina, and the need for revascularization operations directly correlated with the initial number and duration of myocardial ischemia episodes. IHD outcomes depended even more closely on the effectiveness of pharmacotherapy: patients in whom transient myocardial ischemia was completely eliminated had a significantly lower risk of death compared with patients in whom ischemic episodes persisted. Thus, the TIBBS study demonstrated not only the anti-ischemic effectiveness of bisoprolol, but also the positive effect of this drug on the prognosis of patients with angina pectoris. Since the main effect of beta blockers, with which its antianginal effectiveness is associated, was considered to be a decrease in heart rate (a decrease in heart rate leads to a decrease in myocardial oxygen consumption, an increase in diastolic perfusion time and an improvement in blood supply to the subendocardial sections), attempts were made to find a more advanced alternative. A new class of antianginal drugs—inhibitors of If channels in sinus node cells that selectively reduce sinus rhythm (ivabradine)—showed a pronounced antianginal effect comparable to the effect of beta blockers [9, 10]. However, in patients with stable coronary artery disease who do not have clinical symptoms of heart failure, reducing heart rate with ivabradine, despite improving the well-being of patients, did not lead to a reduction in mortality and the incidence of cardiovascular events [11]. Thus, limiting heart rate during angina may improve the well-being of patients, but does not have a significant effect on their prognosis. It would be an excessive simplification to reduce the anti-ischemic effects of beta blockers only to a decrease in heart rate. During beta blocker therapy, heart rate is an indicator of the adequacy of the blockade of β-adrenergic receptors and limiting the damaging effects of hyperactivation of the sympathetic system (hypercatecholaminemia). An improvement in the prognosis may be associated with other effects caused by the use of beta blockers, in addition to a decrease in heart rate: 1. Antihypertensive effect due to the weakening of central adrenergic effects, a decrease in cardiac output, and inhibition of the production of renin and angiotensin II. After all, hypertension is one of the main risk factors for the development of cardiovascular accidents. Hypertension has a direct effect on the arterial wall: disrupting the vasodilating and antithrombotic functions of the endothelium, causing remodeling of the vascular wall with increased arterial stiffness, promoting the progression of atherosclerosis, and increasing the risk of rupture of atherosclerotic plaques. Taken together, these factors increase the risk of adverse clinical outcomes in CAD. 2. Beta blockers prevent the development of stress-induced hyperglycemia (SH) and block the release of free fatty acids from adipose tissue caused by catecholamines. An increase in oxidative stress is considered as an explanation for the established unfavorable effect of FH on the course of IHD. It is believed that relative insulin deficiency and insulin resistance are accompanied by disturbances in glucose oxidation both in ischemic areas and in normally perfused areas of the heart with an increase in fatty acid metabolism. This metabolic inversion contributes to the progression of ischemia, a decrease in myocardial contractility and the development of arrhythmias [12]. 3. The antiarrhythmic effect is the result of both the direct electrophysiological action of beta blockers, which causes a decrease in heart rate and the threshold of spontaneous depolarization of ectopic pacemakers, prolongation of the refractory period of the AV node, and the ability of β-blockers with fat-soluble properties to penetrate the blood-brain barrier and weaken central adrenergic influences, increasing heart rate variability [12, 13]. Despite the fact that new classes of drugs have been introduced into clinical practice in recent decades, beta blockers, along with diuretics, still occupy a leading position among antihypertensive drugs. The antihypertensive effect of bisoprolol is based on a decrease in cardiac output, a decrease in the frequency and strength of heart contractions, a decrease in secretion and concentration of renin in plasma, and a depressant effect on vasomotor centers. The dose dependence of the antihypertensive effect of bisoprolol has been established. For 2–3 months of treatment of patients with mild and moderate hypertension with bisoprolol in doses of 5, 10 and 20 mg/day. systolic blood pressure decreased by 10–12%, 14% and 18–20%, respectively. As the dose increased, the number of patients with diastolic blood pressure levels below 90 mm Hg also increased. Art. [14–16]. The favorable pharmacokinetic properties of the drug allow it to be prescribed for hypertension 1 time per day. With long-term use, bisoprolol causes reverse development of left ventricular hypertrophy. In a comparative randomized study that lasted 6 months, while taking bisoprolol in doses of up to 20 mg/day. the left ventricular myocardial mass index significantly decreased [17]. A special study examined the effectiveness of the combined use of bisoprolol and hydrochlorothiazide in 512 patients with mild and moderate hypertension. Each of the drugs was prescribed in several doses (bisoprolol from 2.5 to 40 mg, hydrochlorothiazide from 6.25 to 25 mg). Combination therapy with these drugs in minimal doses is well tolerated by patients and leads to a decrease in diastolic blood pressure to 90 mm Hg. Art. and lower in 61% of patients [18]. When comparing the severity of the antihypertensive effect of bisoprolol in young (under 60 years of age) and elderly people (over 60 years of age), no significant differences were found, although the proportion of patients with a positive effect was slightly higher among the elderly (83.8% versus 76.1%). More elderly patients also responded to low doses of the drug (60% versus 53.7%). The frequency of side effects in the groups of young and elderly patients did not differ significantly [19]. In the randomized, double-blind, 4-week BISOMET trial, 87 patients with hypertension received either 10 mg of bisoprolol or 100 mg of metoprolol once a day. The effects of beta blockers on systolic blood pressure and heart rate during physical activity 3 and 24 hours after drug administration were compared with the corresponding baseline values. 24 hours after administration, the effect of bisoprolol was significantly superior to the effect of metoprolol, although after 3 hours no significant differences in the effect of the drugs were observed. The residual effect of bisoprolol after 24 hours in relation to its 3-hour level (86–93%) was higher than that of metoprolol (53–66%). Based on the results of the study, it was concluded that a single dose of 10 mg of bisoprolol guarantees a statistically significant decrease in average daytime and average nighttime blood pressure with a smooth decrease throughout the day and preservation of the circadian rhythm of blood pressure. This was accompanied by a reliable decrease in heart rate during physical activity throughout the entire 24-hour interval after taking the drug [20]. The antihypertensive effect of bisoprolol was also compared with the effect of dihydropyridine calcium antagonists. In a randomized, double-blind, 8-week study, patients with hypertension received bisoprolol at a dose of 10–20 mg/day. or long-acting nifedipine 20–40 mg 2 times a day. It was found that bisoprolol is not inferior to nifedipine in its antihypertensive effect and tolerability [21].

Bisoprolol and chronic heart failure

Activation of the sympathetic nervous system in CHF is initially aimed at maintaining the normal functioning of the heart. However, prolonged and excessive increases in plasma norepinephrine levels are associated with cardiotoxic effects and worsening the prognosis of patients with CHF. Beta blockers protect the myocardium from the adverse damaging effects of excessive and prolonged activation of the sympathetic nervous system. The main mechanisms of action of bisoprolol in CHF include a decrease in heart rate, an antiarrhythmic effect, a decrease in the electrical instability of the myocardium, prevention of the death of cardiomyocytes (through necrosis and apoptosis), blockade of cardiac remodeling processes (reduction of myocardial hypertrophy and contraction of the cavities of the heart), normalization of diastolic function of the left ventricle, restoration of sensitivity receptors to external stimuli, reducing myocardial hypoxia, reducing the severity of congestion (through blockade of the renin-angiotensin-aldosterone system), increasing cardiac output [22–25]. A beneficial effect of bisoprolol on the so-called dormant (hibernating) myocardium in patients with heart failure of ischemic etiology was noted, even without the simultaneous use of angiotensin-converting enzyme inhibitors (ACEIs) [26].

The CIBIS (Cardiac Insufficiency Bisoprolol Stady) study included 641 patients with NYHA (New York Heart Association) functional classes III–IV CHF with a cardiac ejection fraction (EF) less than 40%. Bisoprolol was added to traditional vasodilator and diuretic therapy; The initial dose of 1.25 mg was increased over the course of a month to a maximum of 5 mg. During therapy with bisoprolol, the frequency of hospitalizations (relative risk reduction – 31%, p<0.01) due to cardiac decompensation significantly decreased, and NYHA FC decreased in 21% of patients with CHF. Bisoprolol did not have a statistically significant effect on overall mortality (16.6 versus 20.9% in the placebo group), but among patients with dilated cardiomyopathy, mortality significantly decreased [27]. The high effectiveness of the selective beta blocker bisoprolol in patients with CHF was also demonstrated by the CIBIS-II study [25]. The double-blind, placebo-controlled study CIBIS-II included 2647 patients with coronary artery disease, dilated cardiomyopathy with NYHA class III–IV CHF and EF <35%. Bisoprolol was prescribed against the background of constant use of diuretics and ACE inhibitors with a minimum dose of 1.25 mg. Then every 2 weeks. the dose of the drug was increased by 2 times until the maximum was reached (10 mg). After just 1 year, in the group of patients receiving bisoprolol, a reduction in mortality was achieved (Fig. 2) by 34% compared with placebo (11.8 and 17.3%; p <0.0001). The relative risk of sudden death with treatment decreased by 44% (3.6% in the bisoprolol group and 6.3% in the placebo group; p=0.0011), mainly due to the prevention of ventricular fibrillation. The total number of hospitalizations decreased by 20%, and hospitalizations due to decompensated heart failure by 36%. A meta-analysis of data from the CIBIS and CIBIS-II studies [28] demonstrated a significant (43%) reduction in the risk of sudden death at night during sleep (1.6% in the placebo group versus 0.6% during treatment with bisoprolol) . When analyzing in subgroups, there was no effect on the results of treatment of the etiology of CHF, gender, age, initial value of left ventricular EF and FC of CHF. The proportion of patients who refused to continue treatment due to the development of undesirable side effects (such as bradycardia, hypotension, dizziness and weakness) and intolerance to therapy was 15%. It should be noted that in 81% of cases, treatment discontinuation was not due to medical circumstances, but to the patient’s decision to discontinue participation in the study. The purpose of the CIBIS-III study was to question the effectiveness of bisoprolol monotherapy (target dose - 10 mg / day) compared with enalapril monotherapy (target dose - 10 mg 2 times / day) as the initial treatment of class II-III CHF during first 6 months followed by a combination of these drugs. The study included 1010 patients over 65 years of age (mean age 72.4 years) with EF <35% (mean 28.8%). For 62.4% of patients, the cause of CHF was ischemic heart disease, for 36.5% it was hypertension. The results of the study showed that both strategies for the initial treatment of CHF in the form of monotherapy with enalapril or bisoprolol are the same in terms of prognosis: complications of CHF (hospitalization, death) were observed in both subgroups of patients with the same frequency - 36.83 and 35.25%, respectively. However, in the group of patients who started treatment with bisoprolol, there was a slightly lower mortality rate after the first 6 months. and by the end of the first year of observation; Decompensation of CHF developed somewhat more often (and decompensation of heart failure, requiring emergency hospitalization, was observed significantly more often when taking bisoprolol). But, according to the authors, the use of bisoprolol before starting an ACE inhibitor is quite safe and may provide a certain benefit in terms of survival. With long-term therapy with bisoprolol, the severity of CHF symptoms decreases and quality of life improves, heart rate variability increases, and end-diastolic and systolic volumes decrease [29, 30]. When prescribing beta blockers to patients with CHF, the following rules must be adhered to: • Patients must be in a relatively stable condition without intravenous inotropic support or signs of severe congestion. • Treatment begins with small doses. If well tolerated, the dose of the drug is doubled no more than once every 2 weeks. (in the CIBIS-II study, a gradual increase in the dose of bisoprolol from 1.25 to 10.0 mg was carried out over 6 months). • At the beginning of therapy, hypotension, bradycardia, and increased signs of heart failure are possible (Fig. 3). Careful monitoring of the manifestations of heart failure, blood pressure and heart rate is necessary. With increasing symptoms of CHF, a temporary reduction in the dose of beta blockers, an increase in the dose of diuretics, and ACE inhibitors are necessary. If these rules were followed, the target dose of beta blockers in randomized clinical trials was achieved in only 1/3 of patients; 15% of patients had to stop taking the drug. Despite the fact that the addition of beta blockers improves the prognosis of patients with CHF, these drugs are prescribed to less than half of patients with CHF. According to a number of researchers, this is due to the deep-rooted idea of the frequent negative effects of beta blockers [31–33]. The main reasons limiting the use of beta blockers include old age, obstructive pulmonary diseases, and diabetes mellitus (DM) [32, 33].

In order to study the tolerability of beta blockers by patients of older age groups with CHF, a double-blind CIBIS-ELD study was conducted (n=883, 41 medical centers in Europe). This study compared bisoprolol (target dose 10 mg/day) and carvedilol (target dose 25–50 mg twice a day). The average age of patients included in the study was 73 years. 66% of patients had NYHA FC II CHF, 30% had FC III CHF. Most patients received ACE inhibitors or sartans (85%), diuretics (74%), and antiplatelet agents (66%). Cardiac glycosides were taken by 15% of patients. As a result of titration, 31% of patients managed to achieve the target dose of bisoprolol, and 32% of the target dose of carvedilol. The studied drugs were shown to be equally well tolerated, however, the spectrum of observed complications was different: against the background of bisoprolol, a dose-dependent decrease in pulse predominated, while carvedilol was characterized by a pronounced increase in bronchial resistance (a decrease in the forced expiratory volume in the first second by an average of 42 ml). The dynamics of blood pressure were almost the same (-9.3/-4.7 mm Hg for bisoprolol and -9.5/-4.2 mm Hg for carvedilol). Based on the results of the study, the following conclusion was drawn: in elderly patients with CHF, when selecting the dose of beta blockers, one should focus on achieving and maintaining the target heart rate level [34]. The CIBIS-ELD study confirmed that bisoprolol can be used if a patient with CHF has compensated type 2 diabetes, since the drug does not affect glycemia, the degree of albuminuria and lipid profile [35]. Thus, therapy with β-adrenergic receptor blockers leads to a reduction in the risk of death and severe vascular complications in patients with CHF. The effect of beta blocker treatment on the risk of fatal ventricular arrhythmias in groups of patients with a high risk of sudden death is especially significant. Bisoprolol ( Concor

) has good bioavailability, a long half-life, balanced clearance, and is metabolically neutral. The high efficiency and good tolerability of the drug allowed it to be included in the group of basic drugs recommended for use in patients with CHF.

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-Prana, 30 pcs., 10 mg, film-coated tablets

Monitoring of patients taking the drug BISOPROLOL-PRANA should include measuring heart rate and blood pressure (at the beginning of treatment - daily, then - once every 3-4 months), conducting an ECG, determining the concentration of glucose in the blood in patients with diabetes mellitus (once every 4 months). -5 months). In elderly patients, it is recommended to monitor renal function (once every 4–5 months).

The patient should be taught how to calculate heart rate and instructed about the need for medical consultation if the heart rate is less than 50 beats/min.

Before starting treatment, it is recommended to conduct a study of external respiratory function in patients with a burdened bronchopulmonary history.

In approximately 20% of patients with angina, β-blockers are ineffective. The main reasons: severe coronary atherosclerosis with a low ischemic threshold (heart rate less than 100 beats/min) and increased end-diastolic volume of the left ventricle, disrupting subendocardial blood flow.

In smokers, the effectiveness of β-blockers is lower.

Patients using contact lenses should take into account that during treatment the production of tear fluid may decrease.

When used in patients with pheochromocytoma, there is a risk of developing paradoxical arterial hypertension (if effective α-blockade is not previously achieved).

In thyrotoxicosis, bisoprolol may mask certain clinical signs of thyrotoxicosis (for example, tachycardia). Abrupt withdrawal in patients with thyrotoxicosis is contraindicated because it can increase symptoms.

In diabetes mellitus, it can mask tachycardia caused by hypoglycemia. Unlike non-selective beta-blockers, it practically does not enhance insulin-induced hypoglycemia and does not delay the restoration of blood glucose concentrations to normal levels.

When taking clonidine at the same time, it can be discontinued only a few days after discontinuation of the drug BISOPROLOL-PRANA.

It is possible that the severity of the hypersensitivity reaction may increase and there will be no effect from usual doses of epinephrine against the background of a burdened allergic history.

If planned surgical treatment is necessary, the drug should be discontinued 48 hours before the start of general anesthesia. If the patient took the drug before surgery, he should choose a drug for general anesthesia with minimal negative inotropic effect.

Reciprocal activation of the vagus nerve can be reversed by intravenous atropine (1–2 mg).

Medicines that reduce the supply of catecholamines (including reserpine) can enhance the effect of beta-blockers, so patients taking such combinations of drugs should be under constant medical supervision to detect a pronounced decrease in blood pressure or bradycardia.

Patients with bronchospastic diseases can be prescribed cardioselective β-blockers in case of intolerance and/or ineffectiveness of other antihypertensive drugs. Overdose is dangerous for the development of bronchospasm.

If increasing bradycardia (less than 50 beats/min), a pronounced decrease in blood pressure (systolic blood pressure below 100 mm Hg), or AV blockade is detected in elderly patients, it is necessary to reduce the dose or stop treatment.

It is recommended to discontinue therapy if depression develops.

Treatment should not be abruptly interrupted due to the risk of developing withdrawal syndrome (severe arrhythmias and myocardial infarction). Cancellation is carried out gradually, reducing the dose over 2 weeks or more (reduce the dose by 25% in 3-4 days). It should be discontinued before testing the content of catecholamines, normetanephrine and vanillylmandelic acid in the blood and urine, and titers of antinuclear antibodies.

Effect on the ability to drive a car and other mechanical means

The question of the possibility of engaging in potentially hazardous activities that require increased attention and speed of psychomotor reactions should be decided only after assessing the patient’s individual response to the drug (especially at the beginning of treatment, due to the possibility of developing dizziness).

Bisoprolol - Prana tablet p o film 5 mg x40

Bisoprolol-Prana tablet film 5, mg x40 ATX code: C07AB07 (Bisoprolol) Active substance: bisoprolol (bisoprolol) Rec.INN registered by WHO

Dosage form

BISOPROLOL-PRANA

tab., cover film-coated, 10 mg: 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 pcs.reg. No.: LSR-006031/10 from 06.28.10 - Indefinitely

Release form, composition and packaging

Film-coated tablets 1 tab.

bisoprolol fumarate 10 mg Clinical and pharmacological group: Beta1-adrenergic blocker Pharmaco-therapeutic group: Selective beta1-adrenergic blocker Open the description of the active components of the drug BISOPROLOL-PRANA

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 blood-brain barrier and the placental barrier and is 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. ICD-10 codes

ICD-10 code Indication

I10 Essential [primary] hypertension

I20 Angina pectoris

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 II and III degrees (without a pacemaker), SSSU, sinoatrial block, severe bradycardia (heart rate <.50 beats/min), Prinzmetal's angina, severe decreased blood pressure (systolic blood pressure <.90 mm Hg), severe forms of bronchial asthma and COPD in history, 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.

Bisoprolol-SZ

Monitoring of patients taking Bisoprolol-SZ should include measuring heart rate and blood pressure (at the beginning of treatment - daily, then once every 3-4 months), conducting an ECG, determining blood glucose levels in patients with diabetes mellitus (once every 4 months). -5 months). In elderly patients, it is recommended to monitor kidney function (once every 4-5 months).

The patient should be trained in the method of calculating heart rate and instructed about the need for medical consultation if the heart rate is less than 50 beats/min.

Before starting treatment, it is recommended to conduct a study of external respiratory function in patients with a burdened bronchopulmonary history.

In approximately 20% of patients with angina, beta blockers are ineffective. The main causes are severe coronary atherosclerosis with a low ischemic threshold (heart rate less than 100 beats/min) and increased end-diastolic volume of the left ventricle, which impairs subendocardial blood flow.

Bisoprolol-prana tablet p/o film 5mg 30 pcs

Monitoring of patients taking the drug BISOPROLOL-PRANA should include measuring heart rate and blood pressure (at the beginning of treatment - daily, then once every 3-4 months), conducting an ECG, determining the concentration of glucose in the blood in patients with diabetes mellitus (once every 4 months). -5 months). In elderly patients, it is recommended to monitor kidney function (once every 4-5 months). The patient should be taught how to calculate heart rate and instructed about the need for medical consultation if the heart rate is less than 50 beats/min.

Before starting treatment, it is recommended to conduct a study of external respiratory function in patients with a burdened bronchopulmonary history.

In approximately 20% of patients with angina, beta blockers are ineffective. The main reasons: severe coronary atherosclerosis with a low ischemic threshold (heart rate less than 100 beats per minute) and increased end-diastolic volume of the left ventricle, disrupting subendocardial blood flow.

Beta blockers are less effective in smokers.

Patients using contact lenses should take into account that during treatment the production of tear fluid may decrease.

When used in patients with pheochromocytoma, there is a risk of developing paradoxical arterial hypertension (if effective alpha-blockade is not previously achieved).

When taking clonidine at the same time, it can be discontinued only a few days after discontinuation of the drug BISOPROLOL-PRANA.

It is possible that the severity of the hypersensitivity reaction may increase and there will be no effect from usual doses of epinephrine against the background of a burdened allergic history.

Reciprocal activation of the vagus nerve can be eliminated by intravenous atropine (1-2 mg).

Medicines that reduce catecholamine reserves (including reserpine) can enhance the effect of beta-blockers, so patients taking such combinations of drugs should be under constant medical supervision to detect a pronounced decrease in blood pressure or bradycardia.

Patients with bronchospastic diseases can be prescribed cardioselective beta-blockers in case of intolerance and/or ineffectiveness of other antihypertensive drugs. An overdose is dangerous due to the development of bronchospasm.

If increasing bradycardia (less than 50 beats per minute), a pronounced decrease in blood pressure (systolic blood pressure below 100 mm Hg), or AV blockade is detected in elderly patients, it is necessary to reduce the dose or stop treatment.

It is recommended to discontinue therapy if depression develops.

Treatment should not be abruptly interrupted due to the risk of developing withdrawal syndrome (severe arrhythmias and myocardial infarction). Cancellation is carried out gradually, reducing the dose over 2 weeks or more (reduce the dose by 25% in 3-4 days). It should be discontinued before testing the content of catecholamines, normetanephrine and vanillinmandelic acid in the blood and urine, and titers of antinuclear antibodies.

Impact on the ability to drive a car and other mechanical means: the question of the possibility of engaging in potentially hazardous activities that require increased attention and speed of psychomotor reactions should be decided only after assessing the patient’s individual response to the drug (especially at the beginning of treatment, due to the possibility of developing dizziness) .

Bisoprolol-Teva

The effectiveness and tolerability of drugs may be affected by concomitant use of other drugs. This interaction can also occur when two drugs are taken within a short period of time. The doctor must be informed about the use of other medications, even if used without a prescription.

Class I antiarrhythmic drugs (for example, quinidine, disopyramide, lidocaine, phenytoin; flecainide, propafenone), when used simultaneously with bisoprolol, can reduce AV conduction and myocardial contractility.

Class III antiarrhythmic drugs (eg, amiodarone) may worsen AV conduction disturbances.

The effect of beta-blockers for topical use (for example, eye drops for the treatment of glaucoma) may enhance the systemic effects of bisoprolol (lowering blood pressure, lowering heart rate).

Parasympathomimetics, when used simultaneously with bisoprolol, may enhance AV conduction disturbances and increase the risk of developing bradycardia.

The simultaneous use of Bisoprolol-Teva with beta-agonists (for example, isoprenaline, dobutamine) may lead to a decrease in the effect of both drugs.

The combination of bisoprolol with adrenergic agonists that affect beta and alpha adrenergic receptors (for example, norepinephrine, epinephrine) may enhance the vasoconstrictor effects of these drugs that occur with the participation of alpha adrenergic receptors, leading to an increase in blood pressure. Such interactions are more likely when using non-selective beta-blockers.

Mefloquine, when used simultaneously with bisoprolol, may increase the risk of bradycardia.

Allergens used for immunotherapy or allergen extracts for skin testing increase the risk of severe systemic allergic reactions or anaphylaxis in patients receiving bisoprolol.

Iodine-containing radiopaque diagnostic agents for intravenous administration increase the risk of developing anaphylactic reactions.

Phenytoin, when administered intravenously, and agents for inhalation anesthesia (hydrocarbon derivatives) increase the severity of the cardiodepressive effect and the likelihood of lowering blood pressure.

The effectiveness of insulin and hypoglycemic agents for oral administration may change during treatment with bisoprolol (masks the symptoms of developing hypoglycemia: tachycardia, increased blood pressure).

The clearance of lidocaine and xanthines (except theophylline) may be reduced due to a possible increase in their concentration in the blood plasma, especially in patients with an initially increased clearance of theophylline under the influence of smoking.

Bisoprolol-Vertex

Combinations not recommended

Treatment of chronic heart failure:

Class I antiarrhythmic drugs

Class I antiarrhythmic drugs (for example, quinidine, disopyramide, lidocaine, phenytoin, flecainide, propafenone), when used simultaneously with bisoprolol, can slow down atrioventricular conduction and reduce cardiac contractility.

All indications for the use of bisoprolol:

Verapamil and diltiazem

Non-dihydropyridine slow calcium channel blockers (SCBCs), such as verapamil and, to a lesser extent, diltiazem, when used simultaneously with bisoprolol, can lead to a decrease in myocardial contractility and impaired atrioventricular conduction, cardiac arrest and heart failure. In particular, intravenous administration of verapamil to patients taking beta-blockers can lead to severe arterial hypotension and atrioventricular block.

Centrally acting antihypertensives

The simultaneous use of bisoprolol with centrally acting antihypertensive drugs (such as clonidine, methyldopa, moxonidine, rilmenidine) can lead to a worsening of heart failure due to a decrease in central sympathetic tone (decreased heart rate, decreased cardiac output, peripheral vasodilation).

Abrupt discontinuation of centrally acting antihypertensive drugs, especially before discontinuation of beta-blockers, may increase the risk of developing “rebound” arterial hypertension (slow calcium channel syndrome (SCCS) - dihydropyridine derivatives CMCA - dihydropyridine derivatives (for example, nifedipine, felodipine, amlodipine) with simultaneous use with bisoprolol may increase the risk of developing arterial hypotension.In patients with CHF, the risk of further deterioration in cardiac contractile function cannot be excluded.

Medicines that lower blood pressure

Antihypertensive drugs (diuretics, clonidine, etc.) as well as other drugs with a possible antihypertensive effect (for example, tricyclic antidepressants, barbiturates, phenothiazines) can enhance the antihypertensive effect of bisoprolol and lead to an excessive decrease in blood pressure.

Beta blockers for topical use

The effect of beta-blockers for topical use (for example, eye drops for the treatment of glaucoma) may enhance the systemic effects of bisoprolol (lowering blood pressure, lowering heart rate).

Cholinomimetics

Cholinomimetics (parasympathomimetics), when used simultaneously with bisoprolol, may increase atrioventricular conduction disturbances and increase the risk of developing bradycardia.

Hypoglycemic drugs

The hypoglycemic effect of insulin or oral hypoglycemic agents may be enhanced. Signs of hypoglycemia, in particular tachycardia, may be masked or suppressed. Such interactions are more likely when using non-selective beta-blockers.

General anesthesia products

Inhalational anesthetics may increase the risk of cardiodepressive effects. There is a decrease in reflex tachycardia, an increase in the risk of bradyarrhythmias and severe arterial hypotension.

Cardiac glycosides

Cardiac glycosides, when used simultaneously with bisoprolol, can lead to an increase in impulse conduction time, and thus to the development of bradycardia. Cardiac glycosides increase the risk of developing atrioventricular block, cardiac arrest and heart failure.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs may reduce the antihypertensive effect of bisoprolol (through sodium ion retention and blockade of prostaglandin synthesis by the kidneys).

Sympathomimetics

Concomitant use of bisoprolol with beta-agonists (such as isoprenaline or dobutamine) may lead to a decrease in the effect of both drugs. Concomitant use of bisoprolol with beta- and alpha-adrenergic agonists (such as epinephrine [adrenaline]) may enhance the vasoconstrictor effects resulting from alpha-adrenergic stimulation and lead to the development of hypertension or worsening intermittent claudication. Such interactions are more likely when using non-selective beta-blockers.

Cases of the development of severe arterial hypertension have been described with the simultaneous use of beta-blockers with alpha-agonists, including drugs for topical use (for example, decongestants in the form of nasal drops).

Combinations to Consider

Mefloquine

Mefloquine, when used simultaneously with bisoprolol, may increase the risk of bradycardia.

Monoamine oxidase inhibitors MAO

MAO inhibitors (except MAO B inhibitors) may enhance the antihypertensive effect of beta-blockers. Concomitant use may also lead to the development of a hypertensive crisis. The break in treatment between the discontinuation of MAO inhibitors and the prescription of bisoprolol should be at least 14 days.

Ergot alkaloids

Non-hydrogenated ergot alkaloids increase the risk of developing peripheral circulatory disorders when taking beta-blockers. Ergotamine increases the risk of developing peripheral circulatory disorders.

Pharmacokinetic interactions

Rifampicin increases metabolic clearance and shortens the half-life of bisoprolol. Usually no dose adjustment is required.

Caution should be exercised when using bisprolol simultaneously with inducers of isoenzymes of microsomal liver oxidation.

It is possible to increase the concentration of bisoprolol in the blood plasma when used simultaneously with inhibitors of the CYP3A4 isoenzyme and reduce it when used simultaneously with inducers of CYP3A4. Bisoprolol may increase the plasma concentration of drugs metabolized with the participation of the CYP3A4 isoenzyme and, possibly, CYP2D6.

Pharmacokinetic studies did not reveal interactions of bisoprolol with thiazide diuretics, digoxin and cimetidine.

Bisoprolol does not affect prothrombin time in patients receiving a stable dose of warfarin.