III generation beta-blockers in the treatment of cardiovascular diseases

Beta-2-adrenergic stimulants, also beta-2-agonists, β-2-agonists, -adrenergic receptor stimulants β-2-adrenergic agonists are a group of drugs whose mechanism of action is to stimulate beta-2 adrenergic receptors, and which are used primarily for the treatment of chronic diseases of the respiratory system, accompanied by bronchospasm, as well as in obstetrics to reduce the tone and relaxation of the smooth muscles of the uterus when there is a threat of premature birth.

History of creation

The use of drugs that stimulate adrenergic receptors for the treatment of bronchial asthma and other obstructive pulmonary diseases began in 1900, when adrenaline, a non-selective α- and β-adrenergic stimulant, was first used to treat bronchial asthma. But when using adrenaline, side effects were often observed (tachycardia, arrhythmogenic effects, headache), when inhaling this drug, damage to the mucous membrane of the upper respiratory tract was often observed, the disadvantage of using adrenaline is also the short duration of action (1-1.5 hours). These factors have become an incentive for the further development of more effective and safe drugs for the treatment of bronchospasm.

In 1940, isoprenaline was first synthesized - a synthetic catecholamine, a derivative of adrenaline, which is non-selective of β 2 -adrenergic receptors, and also has the properties of β 1 -adrenergic agonists. Fewer side effects were observed with its use. But this drug also had a short period of action (1-1.5 hours), which is associated with the destruction of the drug by the enzyme pulmonary catechol-O-methyltransferase, and in addition, the biotransformation of isoprenaline led to the formation of metabolites with β-blocker properties. In 1963, orciprenaline was synthesized in the laboratory - non-selective β 2 -adrenergic receptors, which, although it has lower activity compared to isoprenaline, has a longer period of action and affinity for bronchial adrenergic receptors and less affinity for myocardial adrenergic receptors and blood vessels.

But the uncontrolled use of non-selective beta-agonists has led to an increase in mortality among patients with bronchial asthma, associated with the accumulation of their metabolites as a result of an overdose of these drugs, which have the properties of beta-blockers and contribute to bronchospasm, as well as an increase in the incidence of complications from the cardiovascular system and mortality of patients . Further scientific research in the field of pharmacology led to the synthesis in 1967 in the UK of the first selective short-acting β 2 -adrenergic receptors - salbutamol, which was developed in the laboratory of the structural unit. In the early 80s of the twentieth century, the first β 2 -adrenergic receptor with a long period of action, salmeterol, was also synthesized in the laboratory, and in 1986, another long-acting adrenergic stimulant, formoterol, was developed in Japan. In parallel with the development of long-acting β 2 -adrenergic receptors, work continues on the synthesis of β 2 agonists with ultra-trivial action (more than 24 hours), which led to the creation of the first ultra-trivial acting β 2 -adrenergic receptor in the laboratory in 2009 - indacaterol.

Features of treatment with β-adrenergic agonists

Salbutamol and fenoterol have a rapid (the effect develops within 1-3 minutes) but short-lived (3-6 hours) effect, so they are used to relieve (eliminate) attacks of bronchial asthma.

Salmeterol and formoterol have a long-lasting effect - more than 12 hours; in addition, the effect of these drugs does not develop immediately, but only 30 minutes after use. That is why salmeterol and formoterol are used to prevent the development of bronchospasms.

In the long-term treatment of bronchial asthma and chronic obstructive pulmonary disease, combination drugs are used, which include both β2-adrenergic agonists and M-cholinergic blockers (ipratropium bromide, tiotropium bromide, umeclidinium bromide, aclidinium bromide, glycopyrronium bromide), as well as hormonal drugs of the class glucocorticosteroids (fluticasone, budesonide).

Classification

All drugs of the beta-2-adrenergic receptor group can be divided according to the selectivity of their action into β 2-adrenergic receptors. Non-selective drugs that, in addition to β 2 -adrenergic receptors, also act on β 1 -adrenergic receptors (including adrenergic receptors located in the myocardium, blood vessels and other organs), and have a short period of action, include isoprenaline, orciprenaline and hexoprenaline . Selective β 2 -agonists are divided according to the duration of action into short-acting drugs, which include salbutamol (as well as the levorotatory isomer of salbutamol - levosalbutamol), fenoterol and terbutaline. Long-acting β 2 -adrenergic receptors include salmeterol, formoterol, clenbuterol and bambuterol. There are also β 2 -adrenergic stimulants with ultra-trival action, the first representative of which is indacaterol.

Mechanism of action

The mechanism of action of all beta-2-adrenergic receptors is to stimulate β 2-adrenergic receptors, which are mainly located in the smooth muscles of the bronchi, as well as the myometrium and blood vessels, by activating intracellular adenylate cyclase, which forms a complex with G-protein, under the influence of which the formation of cyclic AMP and stimulation of protein kinase type A, which leads to relaxation of the smooth muscles of internal organs. Selective β 2 agonists are not destroyed by the pulmonary catechol-O-methyltransferase enzyme, therefore they have a longer period of action, and can be used both inhalation and orally and parenterally. Fenoterol and formoterol are competitive antagonists of β 2 -adrenergic receptors, which ensures a rapid onset of action of the drugs, but also a greater likelihood of side effects (including “rebound syndrome” - increased bronchospasm when the recommended doses of the drug are exceeded, and increased tolerance to these drugs ). Salbutamol and salmeterol are non-competitive β 2 -adrenergic receptor antagonists, therefore, when used, there is a slow onset of action compared to competitive beta-adrenergic receptor antagonists, but also fewer side effects even with long-term use. The long period of action of salmeterol and formoterol is due to the high lipophilicity of these drugs. Formoterol, unlike salmeterol, has insignificant lipophilicity, therefore, after penetration into the cells of the respiratory tract, the drug quickly diffuses into the plasma membrane, in which a kind of formoterol depot is created, from which the drug passes into the intercellular space and simultaneously binds to smooth muscle adrenergic receptors and lipids, providing both the rapid onset of action (1-3 minutes after inhalation) and the duration (up to 12:00) of the effect of formoterol. The intracellular mechanism of action of salmeterol is somewhat different from the mechanism of action of other β 2 agonists. Salmeterol, due to the presence of a long lipophilic saliginine chain (the “tail” of the molecule), has a very high lipophilicity (10,000 times higher than the lipophilicity of salbutamol). During its passage into the cells of the respiratory tract, salmeterol quickly penetrates the cell membranes and is fixed at structures adjacent to β 2 -adrenergic receptors, and the long lipophilic part of the drug molecule binds to the inactive part of the receptor, providing a long-lasting effect of salmeterol. The membranes of the cells of the respiratory system become a kind of “depot” for the drug, from which salmeterol slowly diffuses into the smooth muscle cells of the respiratory tract. Under the influence of β 2 -adrenergic receptors, the release of inflammatory mediators from mast cells decreases (including the release of histamine and leukotrienes), capillary permeability decreases (which helps prevent the development of edema of the bronchial mucosa) and modulates the production of mucus in the bronchial glands, which leads to optimization of mucociliary clearance. But a decrease in the release of inflammatory mediators and a decrease in capillary permeability when using β 2 -adrenergic receptors is not accompanied by a decrease in the number of inflammatory cells in the bronchial mucosa (including activated macrophages, eosinophils and lymphocytes), which theoretically can lead to an increase in the inflammatory process in the respiratory tract ( for example, when, after using adrenergic stimulants, it becomes possible to breathe freely and at the same time inhale a large amount of exogenous allergens). When administered inhaled, drugs of this group act almost exclusively on β 2 -adrenergic receptors of the bronchi and only slightly affect adrenergic receptors in other organs. An increase in the effectiveness of beta-2-adrenergic receptors during inhalation is observed when used together with inhaled corticosteroids and anticholinergics. Some of the drugs in the group (non-selective adrenergic stimulants, as well as salbutamol and fenoterol) have a tocolytic effect, which leads to a decrease in tone and relaxation of the smooth muscles of the uterus, and are used when there is a threat of premature birth and isthmic-cervical insufficiency. Clenbuterol, in addition to its bronchodilator properties, has anabolic properties, and is used to quickly build muscle mass by bodybuilders or to maintain body shape in conjunction with visiting gyms.

III generation beta-blockers in the treatment of cardiovascular diseases

Modern cardiology cannot be imagined without drugs from the beta-blocker group, of which more than 30 names are currently known. The need to include beta-blockers in the treatment program for cardiovascular diseases (CVD) is obvious: over the past 50 years of cardiac clinical practice, beta-blockers have taken a strong position in the prevention of complications and in the pharmacotherapy of arterial hypertension (AH), coronary heart disease (CHD), chronic heart failure (CHF), metabolic syndrome (MS), as well as some forms of tachyarrhythmias. Traditionally, in uncomplicated cases, drug treatment of hypertension begins with beta-blockers and diuretics, which reduce the risk of myocardial infarction (MI), cerebrovascular accident and sudden cardiogenic death.

The concept of the indirect action of drugs through tissue receptors of various organs was proposed by N. Langly in 1905, and in 1906 H. Dale confirmed it in practice.

In the 90s, it was established that beta-adrenergic receptors are divided into three subtypes:

• beta1-adrenergic receptors, which are located in the heart and through which the stimulating effects of catecholamines on the activity of the heart - pump are mediated: increased sinus rhythm, improved intracardiac conduction, increased myocardial excitability, increased myocardial contractility (positive chrono-, dromo-, batmo-, inotropic effects) ;
• beta2-adrenergic receptors, which are located mainly in the bronchi, smooth muscle cells of the vascular wall, skeletal muscles, and in the pancreas; when they are stimulated, broncho- and vasodilatory effects, relaxation of smooth muscles and insulin secretion are realized;
• beta3-adrenergic receptors, localized primarily on adipocyte membranes, are involved in thermogenesis and lipolysis. The idea of ​​using beta-blockers as cardioprotectors belongs to the Englishman J.?W.?Black, who in 1988, together with his collaborators, the creators of beta-blockers, was awarded the Nobel Prize. The Nobel Committee considered the clinical significance of these drugs to be “the greatest breakthrough in the fight against heart disease since the discovery of digitalis 200 years ago.”

The ability to block the effect of mediators on beta1-adrenergic receptors of the myocardium and the weakening of the effect of catecholamines on membrane adenylate cyclase of cardiomyocytes with a decrease in the formation of cyclic adenosine monophosphate (cAMP) determine the main cardiotherapeutic effects of beta-blockers.

The anti-ischemic effect of beta-blockers is explained by a decrease in myocardial oxygen demand due to a decrease in heart rate (HR) and the force of heart contractions that occur when beta-adrenergic receptors of the myocardium are blocked.

Beta blockers simultaneously improve myocardial perfusion by reducing left ventricular (LV) end-diastolic pressure and increasing the pressure gradient that determines coronary perfusion during diastole, the duration of which increases as a result of a slower cardiac rhythm.

Antiarrhythmic action of beta-blockers , based on their ability to reduce the adrenergic effect on the heart, leads to:

• decrease in heart rate (negative chronotropic effect);
• decreased automaticity of the sinus node, AV connection and the His–Purkinje system (negative bathmotropic effect);
• reducing the duration of the action potential and the refractory period in the His–Purkinje system (the QT interval is shortened);
• slowing down conduction in the AV junction and increasing the duration of the effective refractory period of the AV junction, lengthening the PQ interval (negative dromotropic effect).

Beta-blockers increase the threshold for the occurrence of ventricular fibrillation in patients with acute MI and can be considered as a means of preventing fatal arrhythmias in the acute period of MI.

The hypotensive effect of beta-blockers is due to:

• a decrease in the frequency and strength of heart contractions (negative chrono- and inotropic effects), which overall leads to a decrease in cardiac output (MCO);
• decreased secretion and decreased concentration of renin in plasma;
• restructuring of the baroreceptor mechanisms of the aortic arch and carotid sinus;
• central depression of sympathetic tone;
• blockade of postsynaptic peripheral beta-adrenergic receptors in the venous vascular bed, with a decrease in blood flow to the right side of the heart and a decrease in MOS;
• competitive antagonism with catecholamines for receptor binding;
• increased levels of prostaglandins in the blood.

Drugs from the group of beta-blockers differ in the presence or absence of cardioselectivity, intrinsic sympathetic activity, membrane-stabilizing, vasodilating properties, solubility in lipids and water, effect on platelet aggregation, and also in duration of action.

The effect on beta2-adrenergic receptors determines a significant part of the side effects and contraindications to their use (bronchospasm, constriction of peripheral vessels). A feature of cardioselective beta-blockers compared to non-selective ones is their greater affinity for beta1-receptors of the heart than for beta2-adrenergic receptors. Therefore, when used in small and medium doses, these drugs have a less pronounced effect on the smooth muscles of the bronchi and peripheral arteries. It should be taken into account that the degree of cardioselectivity varies among different drugs. The index ci/beta1 to ci/beta2, characterizing the degree of cardioselectivity, is 1.8:1 for non-selective propranolol, 1:35 for atenolol and betaxolol, 1:20 for metoprolol, 1:75 for bisoprolol (Bisogamma). However, it should be remembered that selectivity is dose-dependent; it decreases with increasing drug dose (Fig. 1).

Currently, clinicians identify three generations of drugs with a beta-blocking effect.

I generation - non-selective beta1- and beta2-adrenergic blockers (propranolol, nadolol), which, along with negative ino-, chrono- and dromotropic effects, have the ability to increase the tone of the smooth muscles of the bronchi, vascular wall, and myometrium, which significantly limits their use in clinical practice.

II generation - cardioselective beta1-adrenergic blockers (metoprolol, bisoprolol), due to their high selectivity for myocardial beta1-adrenergic receptors, have more favorable tolerability with long-term use and a convincing evidence base for long-term life prognosis in the treatment of hypertension, coronary artery disease and heart failure.

In the mid-1980s, third-generation beta-blockers with low selectivity to beta1, 2-adrenergic receptors, but with combined blockade of alpha-adrenergic receptors, appeared on the global pharmaceutical market.

III generation drugs - celiprolol, bucindolol, carvedilol (its generic analogue with the brand name Carvedigamma®) have additional vasodilating properties due to the blockade of alpha-adrenergic receptors, without internal sympathomimetic activity.

In 1982–1983, the first reports of clinical experience with the use of carvedilol in the treatment of CVD appeared in the scientific medical literature.

A number of authors have revealed the protective effect of third-generation beta-blockers on cell membranes. This is explained, firstly, by inhibition of the processes of lipid peroxidation (LPO) of membranes and the antioxidant effect of beta blockers and, secondly, by a decrease in the effect of catecholamines on beta receptors. Some authors associate the membrane-stabilizing effect of beta-blockers with a change in sodium conductivity through them and inhibition of lipid peroxidation.

These additional properties expand the prospects for the use of these drugs, since they neutralize the negative effect on myocardial contractile function, carbohydrate and lipid metabolism characteristic of the first two generations, and at the same time provide improved tissue perfusion, a positive effect on hemostasis and the level of oxidative processes in the body.

Carvedilol is metabolized in the liver (glucuronidation and sulfation) by the cytochrome P450 enzyme system, using the CYP2D6 and CYP2C9 enzyme families. The antioxidant effect of carvedilol and its metabolites is due to the presence of a carbazole group in the molecules (Fig. 2).

Metabolites of carvedilol - SB 211475, SB 209995 inhibit LPO 40-100 times more actively than the drug itself, and vitamin E - about 1000 times.

Use of carvedilol (Carvedigamma®) in the treatment of coronary artery disease

According to the results of a number of completed multicenter studies, beta-blockers have a pronounced anti-ischemic effect. It should be noted that the anti-ischemic activity of beta-blockers is comparable to the activity of calcium antagonists and nitrates, but, unlike these groups, beta-blockers not only improve the quality of life, but also increase the life expectancy of patients with coronary artery disease. According to the results of a meta-analysis of 27 multicenter studies, which involved more than 27 thousand people, selective beta-blockers without intrinsic sympathomimetic activity in patients with a history of acute coronary syndrome reduce the risk of recurrent myocardial infarction and mortality from heart attack by 20% [1].

However, not only selective beta-blockers have a positive effect on the course and prognosis of patients with coronary artery disease. The non-selective beta blocker carvedilol has also demonstrated very good efficacy in patients with stable angina. The high anti-ischemic effectiveness of this drug is explained by the presence of additional alpha1-blocking activity, which promotes dilatation of coronary vessels and collaterals of the poststenotic region, and therefore improves myocardial perfusion. In addition, carvedilol has a proven antioxidant effect associated with the capture of free radicals released during ischemia, which determines its additional cardioprotective effect. At the same time, carvedilol blocks apoptosis (programmed death) of cardiomyocytes in the ischemic zone, maintaining the volume of functioning myocardium. The metabolite of carvedilol (BM 910228) has been shown to have less beta-blocking effect, but is an active antioxidant, blocking lipid peroxidation by “scavenging” active free radicals OH–. This derivative preserves the inotropic response of cardiomyocytes to Ca++, the intracellular concentration of which in the cardiomyocyte is regulated by the Ca++ pump of the sarcoplasmic reticulum. Therefore, carvedilol appears to be more effective in the treatment of myocardial ischemia through inhibition of the damaging effects of free radicals on the membrane lipids of the subcellular structures of cardiomyocytes [2].

Due to these unique pharmacological properties, carvedilol may be superior to traditional beta1-selective blockers in improving myocardial perfusion and helping to preserve systolic function in patients with coronary artery disease. As shown by Das Gupta et al., in patients with LV dysfunction and heart failure resulting from coronary artery disease, monotherapy with carvedilol reduced filling pressure and also increased LV ejection fraction (EF) and improved hemodynamic parameters, without being accompanied by the development of bradycardia [3] .

According to the results of clinical studies in patients with chronic stable angina, carvedilol reduces heart rate at rest and during exercise, and also increases EF at rest. A comparative study of carvedilol and verapamil, which involved 313 patients, showed that, compared with verapamil, carvedilol reduced heart rate, systolic blood pressure and the heart rate ´ blood pressure product to a greater extent at maximum tolerated physical activity. Moreover, carvedilol has a more favorable tolerability profile [4]. Importantly, carvedilol appears to be more effective in treating angina than conventional beta1-blockers. Thus, in a 3-month randomized, multicenter, double-blind study, carvedilol was directly compared with metoprolol in 364 patients with stable chronic angina. They took carvedilol 25–50 mg twice daily or metoprolol 50–100 mg twice daily [5]. While both drugs demonstrated good antianginal and antiischemic effects, carvedilol more significantly increased the time to 1 mm ST segment depression during exercise than metoprolol. Carvedilol was very well tolerated and, importantly, there was no noticeable change in the types of adverse events with increasing doses of carvedilol.

It is noteworthy that carvedilol, which, unlike other beta-blockers, does not have a cardiodepressive effect, improves the quality and life expectancy of patients with acute myocardial infarction (CHAPS) [6] and post-infarction ischemic dysfunction of the LV (CAPRICORN) [7]. Promising data were obtained from the Carvedilol Heart Attack Pilot Study (CHAPS), a pilot study examining the effects of carvedilol on the development of myocardial infarction. This was the first randomized trial to compare carvedilol with placebo in 151 patients following acute MI. Treatment was started within 24 hours of the onset of chest pain, and the dose was increased to 25 mg twice daily. The primary endpoints of the study were LV function and drug safety. Patients were observed for 6 months from the onset of the disease. According to the data obtained, the incidence of serious cardiac events decreased by 49%.

Sonographic data from 49 patients with reduced LVEF (<45%) from the CHAPS study showed that carvedilol significantly improved recovery of LV function after acute MI, both at 7 days and at 3 months. When treated with carvedilol, LV mass significantly decreased, while in patients taking placebo it increased (p = 0.02). LV wall thickness also decreased significantly (p = 0.01). Carvedilol contributed to the preservation of LV geometry, preventing changes in the sphericity index, echographic global remodeling index and LV size. It should be emphasized that these results were obtained with carvedilol monotherapy. In addition, studies with thallium-201 in the same group of patients showed that only carvedilol significantly reduced the incidence of events in the presence of signs of reversible ischemia. The data collected during the studies described above convincingly prove the presence of clear advantages of carvedilol over traditional beta-blockers, which is due to its pharmacological properties.

The good tolerability and anti-remodeling effect of carvedilol indicate that this drug can reduce the risk of death in patients who have had a myocardial infarction. The large-scale CAPRICORN (CArvedilol Post InfaRct Survival CONtRol in Left Ventricular DysfunctionN) trial was designed to study the effect of carvedilol on survival in LV dysfunction after myocardial infarction. The CAPRICORN trial demonstrates for the first time that carvedilol in combination with ACE inhibitors is able to reduce all-cause and cardiovascular mortality, as well as the incidence of recurrent non-fatal myocardial infarction in this group of patients. New evidence that carvedilol is at least as effective, if not more effective, in reversing remodeling in patients with heart failure and coronary artery disease supports the need for earlier administration of carvedilol for myocardial ischemia. In addition, the effect of the drug on the “sleeping” (hibernating) myocardium deserves special attention [8].

Thus, all these data allow us to recommend the use of carvedilol for the treatment of patients with coronary artery disease.

Carvedilol in the treatment of hypertension

The leading role of impaired neurohumoral regulation in the pathogenesis of hypertension today is beyond doubt. Both main pathogenetic mechanisms of hypertension - increased cardiac output and increased peripheral vascular resistance - are controlled by the sympathetic nervous system. Therefore, beta blockers and diuretics have been the standard of care for antihypertensive therapy for many years.

In the JNC-VI recommendations, beta-blockers were considered as first-line drugs for uncomplicated forms of hypertension, since only beta-blockers and diuretics were proven in controlled clinical trials to reduce cardiovascular morbidity and mortality [9, 10]. According to the results of a meta-analysis of previous multicenter studies, beta-blockers did not live up to expectations regarding the effectiveness of reducing the risk of stroke. Negative metabolic effects and peculiarities of influence on hemodynamics did not allow them to take a leading place in the process of reducing myocardial and vascular remodeling [11]. However, it should be noted that the studies included in the meta-analysis concerned only representatives of the second generation of beta-blockers - atenolol, metoprolol and did not include data on new drugs of the class. With the advent of new representatives of this group, the danger of their use in patients with cardiac conduction disorders, diabetes mellitus, lipid metabolism disorders, and renal pathology was largely neutralized. The use of these drugs allows us to expand the scope of beta-blockers for hypertension.

Among all representatives of the class of beta-blockers, the most promising in the treatment of patients with hypertension are drugs with vasodilating properties, one of which is carvedilol.

Carvedilol has a long-term hypotensive effect. According to the results of a meta-analysis of the hypotensive effect of carvedilol in more than 2.5 thousand patients with hypertension, blood pressure decreases after a single dose of the drug, but the maximum hypotensive effect develops after 1–2 weeks [12]. The same study provides data on the effectiveness of the drug in different age groups: no significant differences in blood pressure levels were found during a 4-week intake of carvedilol at a dose of 25 or 50 mg in people under or over 60 years of age.

An important fact is that, unlike non-selective and some beta1-selective adrenergic blockers, beta blockers with vasodilating activity not only do not reduce tissue sensitivity to insulin, but even slightly enhance it [13]. Carvedilol's ability to reduce insulin resistance is an effect that is largely due to beta1-adrenergic blocking activity, which increases lipoprotein lipase activity in muscle, which in turn increases lipid clearance and improves peripheral perfusion, which promotes more active glucose uptake into tissues. Comparison of the effects of different beta blockers supports this concept. Thus, in a randomized study, carvedilol and atenolol were prescribed to patients with type 2 diabetes mellitus and hypertension [14]. It was shown that after 24 weeks of therapy, fasting blood glucose and insulin levels decreased with carvedilol treatment and increased with atenolol treatment. In addition, carvedilol had a greater positive effect on insulin sensitivity (p = 0.02), high-density lipoprotein (HDL) levels (p = 0.04), triglycerides (p = 0.01) and lipid peroxidation (p = 0.04).

As is known, dyslipidemia is one of the four main risk factors for the development of CVD. Its combination with hypertension is especially unfavorable. However, taking some beta-blockers can also lead to undesirable changes in blood lipid levels [15]. As already mentioned, carvedilol does not have a negative effect on serum lipid levels [14]. A multicenter, blinded, randomized study examined the effect of carvedilol on the lipid profile in patients with mild to moderate hypertension and dyslipoproteinemia [16]. The study included 250 patients who were randomized to treatment groups with carvedilol at a dose of 25–50 mg/day or the ACE inhibitor captopril at a dose of 25–50 mg/day. The choice of captopril for comparison was determined by the fact that it either has no effect or has a positive effect on lipid metabolism. The duration of treatment was 6 months. In both compared groups, positive dynamics were noted: both drugs comparablely improved the lipid profile. The beneficial effect of carvedilol on lipid metabolism is most likely related to its alpha-adrenergic blocking activity, since beta1-adrenergic receptor blockade has been shown to cause vasodilation, thereby improving hemodynamics and also reducing the severity of dyslipidemia [17].

In addition to blocking beta1, beta2 and alpha1 receptors, carvedilol also has additional antioxidant and antiproliferative properties [18, 19], which is important to consider in terms of influencing CVD risk factors and providing target organ protection in patients with hypertension.

Thus, the metabolic neutrality of the drug allows its widespread use in patients with hypertension and diabetes mellitus, as well as in patients with MS, which is especially important in the treatment of elderly people [20].

The alpha-blocking and antioxidant effects of carvedilol, which provide peripheral and coronary vasodilation, contribute to the effect of the drug on the parameters of central and peripheral hemodynamics; the positive effect of the drug on the ejection fraction and stroke volume of the left ventricle has been proven, which is especially important in the treatment of hypertensive patients with ischemic and non-ischemic heart failure [ 21].

As is known, hypertension is often combined with kidney damage, and when choosing antihypertensive therapy, it is necessary to take into account the possible adverse effects of the drug on the functional state of the kidneys. The use of beta-blockers in most cases can be associated with a decrease in renal blood flow and glomerular filtration rate. Carvedilol's beta-blocking effect and vasodilation have been shown to have a positive effect on renal function [22, 23].

Thus, carvedilol combines beta-blocking and vasodilatory properties, which ensures its effectiveness in the treatment of hypertension.

Beta-blockers in the treatment of CHF

CHF is one of the most unfavorable pathological conditions that significantly worsens the quality and life expectancy of patients. The prevalence of heart failure is very high, it is the most common diagnosis in patients over 65 years of age. Currently, there is a steady upward trend in the number of patients with CHF, which is associated with increased survival in other CVDs, primarily in acute forms of IHD. According to WHO, the 5-year survival rate of patients with CHF does not exceed 30–50%. In the group of patients who have had a myocardial infarction, up to 50% die within the first year after the development of circulatory failure associated with a coronary event. Therefore, the most important task of optimizing therapy for CHF is the search for drugs that increase the life expectancy of patients with CHF.

Beta-blockers are recognized as one of the most promising classes of drugs effective both for preventing the development and for treating CHF [6, 24], since activation of the sympathoadrenal system is one of the leading pathogenetic mechanisms for the development of CHF. Compensatory, at the initial stages of the disease, hypersympathicotonia subsequently becomes the main cause of myocardial remodeling, increased trigger activity of cardiomyocytes, increased peripheral vascular resistance and impaired perfusion of target organs.

The history of the use of beta-blockers in the treatment of patients with CHF goes back 25 years [25]. Large-scale international studies CIBIS-II, MERIT-HF, US Carvedilol Heart Failure Trials Program, COPERNICUS approved beta-blockers as first-line drugs for the treatment of patients with CHF [26, 27, 28], confirming their safety and effectiveness in the treatment of such patients (.). A meta-analysis of the results of major studies studying the effectiveness of beta-blockers in patients with CHF showed that the addition of beta-blockers to ACE inhibitors, along with improvement of hemodynamic parameters and well-being of patients, helps to improve the course of CHF, quality of life indicators, and reduces the frequency of hospitalization - by 41 % and the risk of death in patients with CHF by 37% [29].

According to the 2005 European guidelines, the use of beta-blockers is recommended in all patients with CHF in addition to therapy with ACE inhibitors and symptomatic treatment [30]. Moreover, according to the results of the multicenter COMET study, which was the first direct comparative test of the effect of carvedilol and the second-generation selective beta-blocker metoprolol in doses providing an equivalent antiadrenergic effect on survival with an average follow-up of 58 months, carvedilol was 17% more effective than metoprolol in reducing the risk of death [ 20].

This provided an average gain in life expectancy of 1.4 years in the carvedilol group with a maximum follow-up of 7 years. This advantage of carvedilol is due to the lack of cardioselectivity and the presence of an alpha-blocking effect, which helps to reduce the hypertrophic response of the myocardium to norepinephrine, reduce peripheral vascular resistance, and suppress the production of renin by the kidneys. In addition, in clinical trials in patients with CHF, the antioxidant, anti-inflammatory (decrease in the levels of TNF-alpha (tumor necrosis factor), interleukins 6–8, C-peptide), antiproliferative and antiapoptotic effects of the drug have been proven, which also determines its significant advantages in treatment of this contingent of patients not only among drugs from their own group, but also from other groups [27].

In Fig. Figure 3 shows a scheme for titrating doses of carvedilol for various pathologies of the cardiovascular system.

Thus, carvedilol, having a beta- and alpha-adrenergic blocking effect with antioxidant, anti-inflammatory, antapoptic activity, is among the most effective drugs from the class of beta-blockers currently used in the treatment of CVD and MS.

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A. M. Shilov *, Doctor of Medical Sciences, Professor M. V. Melnik *, Doctor of Medical Sciences, Professor A. Sh. Avshalumov **

* MMA named after. I. M. Sechenova, Moscow ** Clinic of the Moscow Institute of Cybernetic Medicine, Moscow

Contact information for authors for correspondence

Pharmacokinetics

Most β 2 -adrenergic receptor drugs are well absorbed when administered orally, but the oral bioavailability of adrenergic stimulants is low due to the presence of a first-pass effect through the liver in the metabolism of these drugs. The main route of use of the group’s drugs is inhalation, in which, for various forms of use (via a nebulizer, inhalation of a dry powder or aerosol), the bioavailability of the drugs ranges from 5 to 38%. The exception is the ultra-trivalent drug indacaterol, whose bioavailability when administered in inhalation is 43%. Some of the drugs in the group are also used parenterally, mainly intravenously, and the bioavailability of the drugs is 100%. Drugs of this group bind poorly to plasma proteins (on average 14-25%). Most drugs from the β 2 -adrenergic receptor group create high concentrations in most body tissues, penetrate the placental barrier and are excreted into breast milk. Drugs of the group are metabolized mainly in the liver, as well as in other tissues of the body under the action of MAO enzymes and catechol-O-methyltransferase. The half-life of the drugs in this group varies from 2 minutes for isoprenaline to 24 hours for indacaterol. β 2 -adrenergic stimulants are excreted from the body both in urine and feces, partly in the form of inactive metabolites, partly in unchanged form.

Indications for use

The main indications for the use of β 2 -adrenergic receptors are broncho-obstructive diseases of the respiratory system (bronchial asthma, chronic obstructive pulmonary diseases, emphysema), in which β 2 -adrenergic receptor agonists are used primarily by inhalation, often in combination with inhaled corticosteroids or anticholinergics. In the case of broncho-obstructive diseases, adrenostimulants can be used in a nebulizer, metered aerosols and in the form of metered dry powders. Salbutamol, fenoterol, orciprenaline, hexoprenaline and isoprenaline are also used in obstetric practice, mainly intravenously for isthmic-cervical insufficiency and the threat of premature birth. Clenbuterol is also used to quickly build muscle mass by bodybuilders or to maintain body shape and lose weight in conjunction with visiting gyms.

Basics of treatment with β-adrenergic agonists

β-Adrenergic stimulants are classified as prescription drugs - drugs are dispensed from pharmacies only with a doctor's prescription.

The β1-adrenergic agonist dobutamine is administered intravenously in a hospital setting under the constant supervision of a physician. The effect of the drug develops after 1-2 minutes, the maximum effect is observed after 10 minutes.

For the treatment of bronchial asthma and chronic obstructive pulmonary disease, β2-adrenergic agonists are used by inhalation.

To prevent premature birth, β2-agonists are used as intravenous injections, infusions, or taken orally (orally) as tablets.

Mirabegron is used orally in tablet form once a day.

Side effect

When using selective beta-2 adrenergic receptors, hand tremors and tachycardia are most often observed (more often when using salbutamol). When using non-selective β 2 -adrenergic receptors, side effects from the cardiovascular system are more often observed, caused by stimulation of adrenergic receptors of the myocardium and blood vessels - arrhythmias (including atrial fibrillation, supraventricular tachycardia and extrasystole), arterial hypertension or hypotension, myocardial ischemia. With long-term uncontrolled use of β 2 -adrenergic receptors, “rebound syndrome” can be observed - paradoxical bronchospasm when the dose of the drug is increased, as well as increased tolerance to the drugs of the group. Among other side effects, allergic reactions in the form of urticaria or skin rashes, nausea, vomiting, stomatitis and pharyngitis (due to irritation of the mucous membranes during inhalation use), agitation, convulsions, metabolic disorders (hyperglycemia, hypokalemia, hyperlipidemia, lactic acidosis) are more often observed.

Contraindications

Beta-2-adrenergic stimulants are contraindicated in cases of hypersensitivity to drugs of this group, tachyarrhythmias, coronary heart disease, decompensated thyrotoxicosis and diabetes mellitus, severe heart failure, uncorrected arterial hypertension. Drugs from this group are used with caution in cases of liver and kidney failure, and epilepsy. B2-agonists are not used simultaneously with beta-blockers due to the antagonism of their action, as well as with other adrenostimulants due to the increased risk of side effects. The drugs of this group are not used with cardiac glycosides due to the increased risk of intoxication with glycosides, tricyclic antidepressants and MAO inhibitors due to the risk of developing hypotension.

Prohibited use by athletes

Some drugs from the group of beta-2 adrenergic receptors, namely salbutamol, salmeterol and formoterol, are prohibited for use by athletes during competitions by decision of the World Anti-Doping Agency as stimulants of the respiratory system, and clenbuterol also as a drug with an anabolic effect. And identification of these drugs in the body of athletes during competitions may cause their disqualification. But some athletes suffering from bronchial asthma have permission to use salbutamol, formoterol and salmeterol (but not clenbuterol) from the World Anti-Doping Agency.

The Center for Drug Safety Expertise draws the attention of specialists to the emergence of new information regarding the safety of long-acting beta-adrenergic agonists.

Long-acting beta-agonists (LABA) are a group of drugs intended for the treatment of bronchial asthma and chronic obstructive pulmonary disease (COPD).

During post-registration clinical studies conducted to determine the effectiveness and safety of long-acting beta-agonists in the treatment of lung diseases, information appeared about the worsening of bronchial asthma in children and adults, up to the development of death from complications of bronchial asthma.

In this regard, the US Food and Drug Administration (US FDA) decided on the need to include appropriate warnings in the instructions for medical use of all representatives of the pharmacotherapeutic group of long-acting beta-adrenergic agonists (INN Salmeterol, Formoterol, Arformoterol). Cautions and additions that affected the sections “Indications for use” and “Contraindications” included the following information:

• BAMDD monotherapy for long-term treatment of bronchial asthma is contraindicated;
• Long-acting beta-agonists are not recommended for use in patients whose asthma is controlled with low or moderate doses of corticosteroids;
• Long-acting beta-agonists are allowed as additional therapy when it is not possible to achieve the desired result with basic therapy (for example, corticosteroids). When the necessary control is achieved during combined therapy with BAMDD and inhaled corticosteroids, it is necessary to gradually reduce the dose of adrenergic agonists until they are completely discontinued.
• For more convenient controlled administration of drugs, it is recommended that children and adolescents be prescribed combination inhalation drugs containing BAMDD and corticosteroids.

In addition, doctors are not recommended to prescribe long-acting medications to patients with newly diagnosed bronchial asthma.

In order to prevent the development of asthmatic attacks in such patients, it is advisable to use short-acting adrenergic agonists (for example, Salbutamol). If the recommendations proposed above are followed, the benefits of treating bronchial asthma with long-acting beta-agonists are assessed higher than the possible risk of developing serious complications of this disease.

Table No. 1 provides a list of long-acting beta-adrenergic agonists (LABA) registered in the Russian Federation and their combinations with glucocorticosteroids (GCS).
Table No. 1