Beta-agonists - Drug Directory

Adrenergic stimulants (adrenergic agonists) are medications that stimulate different types of adrenergic receptors in organs and tissues, thereby imitating the effects of natural biologically active substances - the mediator norepinephrine and the adrenal hormone adrenaline.

Norepinephrine is a transmitter of impulses in the peripheral nervous system, regulating the functioning of many internal organs and systems (in particular, the heart, blood vessels, bronchi, uterus, pancreas, urinary system, etc.). Adrenaline is similar in structure and function to norepinephrine and is a hormone of the inner (brain) layer of the adrenal cortex.

Norepinephrine and adrenaline realize their effects through interaction with special structural components of cells - receptors, namely adrenergic receptors. Depending on their location and functions, adrenergic receptors are classified into alpha (α)- and beta (β)-adrenergic receptors.

α-Adrenergic receptors are located mainly in blood vessels, the iris of the eye, and the urinary tract. The effects of α-adrenergic receptor stimulation include constriction of blood vessels (and consequently increased blood pressure), pupil dilation, and urinary retention.

β-Adrenergic receptors are localized primarily in the heart (β1-adrenergic receptors), as well as in the bronchi and uterus (β2-adrenergic receptors). When they are stimulated, an increase in the strength and frequency of heart contractions, dilation of the bronchi and relaxation of the uterus are observed.

There is a separate class of drugs that can stimulate adrenergic receptors (adrenergic agonists, adrenergic stimulants), and a group of drugs that can block adrenergic receptors (adrenergic blockers, adrenergic steroids).

Depending on the degree of selectivity, adrenergic stimulants are divided into α-adrenergic agonists, β-adrenergic agonists, as well as α- and β-adrenergic agonists. Let us consider in detail drugs that stimulate β-adrenergic receptors.

Indications for use

β1-adrenergic agonists are used for acute heart failure associated with low cardiac output - against the background of myocardial infarction, cardiomyopathies, cardiogenic shock, and during heart surgery.

β2-adrenergic agonists are used for diseases associated with bronchospasm - bronchial asthma, chronic obstructive pulmonary disease.

Also, β2-adrenergic agonists are prescribed when there is a threat of premature birth.

β3-adrenergic agonists are used for diseases associated with increased bladder tone - overactive bladder syndrome: urinary incontinence, frequent urination.

pharmachologic effect

β1-Adrenergic agonists stimulate β1-adrenergic receptors in the myocardium, which leads to an increase in the strength and frequency of heart contractions (and, as a consequence, cardiac output and blood pressure).

β2-Adrenergic agonists stimulate β2-adrenergic receptors in the bronchi, providing a bronchodilator (bronchodilator) effect, and also, due to stimulation of β2-adrenergic receptors of the uterus, have a tocolytic effect (relax the muscles of the uterus).

β3-Adrenergic agonists stimulate β3-adrenergic receptors in the bladder, relaxing its muscles and preventing urinary incontinence.

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.

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

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).

Journal "Diseases and Antibiotics" 2 (2) 2009

Bronchial asthma (BA) is a chronic inflammatory disease of the airways (AD), in which many cells and cellular elements play a role. Chronic inflammation causes the development of bronchial hyperreactivity, leading to repeated episodes of generalized bronchial obstruction of varying severity, reversible spontaneously or with treatment. According to WHO, about 300 million people worldwide suffer from asthma.

Therapy of asthma involves the predominant use of inhaled forms of medications, which are divided into drugs for stopping an attack and drugs for long-term control. β-adrenergic receptor agonists, available on the pharmaceutical market in various dosage forms, have properties to stop an asthma attack and control the course of the disease.

All processes occurring in the body, starting from the cellular level, are strictly coordinated with each other in time, speed and place of occurrence. This consistency is achieved due to the presence of complex regulatory mechanisms, which is carried out through the secretion of certain substances by some cells and their reception by others. The vast majority of such substances (neurotransmitters, hormones, prostaglandins) act on the cell without penetrating into it, but by interacting with special protein macromolecules - receptors built into the outer surface of the cell (surface membrane) [1].

The cell membrane is a bimolecular layer of phospholipids sandwiched between two layers of adsorbed proteins. The non-polar hydrophobic ends of the phospholipid molecules are directed towards the middle of the membrane, and the polar hydrophilic ends are directed towards the edges separating it from the aqueous phase. Large protein molecules are included in the lipid bilayer matrix. Some proteins penetrate the entire thickness of the membrane, while others are embedded in only one of the layers (neurotransmitter receptors, adenylate cyclase). The membrane has some fluidity, and proteins and lipid molecules can move along its plane. The fluidity of a membrane is determined by its molecular composition and electrical properties: with an increase in cholesterol content, fluidity decreases, and with an increase in the content of unsaturated or branching hydrophobic tails of phospholipid molecules, it increases [2–6].

The influence of circulating catecholamines occurs through interaction with adrenergic receptors (AR). According to the definition of B.N. Manukhin, adrenergic receptors are functional cell formations that perceive the influence of a neurotransmitter and hormone of the adrenergic system and transform it into a specific quantitatively and qualitatively adequate reaction of the effector cell. The number of such receptors is small—a few per square micron of surface. This determines another feature of regulation - the effective quantities of regulators are negligibly small. In order to change the metabolism and functional activity of the entire cell, which includes hundreds of millions of different molecules, binding of 2–5 regulator molecules to the cell membrane is apparently sufficient. In the entire chain from the receptor to the cellular reaction in question, the signal is amplified by 10–100 million times [7].

Adrenergic receptors were initially characterized according to their functional response to stimulation when inhibited by various pharmacological agents [8]. They were subsequently qualified according to their affinity similarity when bound by labeled ligands. aadrenergic receptors are defined as oligomeric proteins localized on the surface of cell membranes; β-adrenergic receptors have been identified as proteolipids and nucleoproteins [9]. In 1948, R. Ahlquist established that adrenergic receptors are divided into two types - α and β. A. Lands in 1967 determined that there are subtypes of βAP. The use of molecular biology methods has confirmed the heterogeneity of adrenergic receptor subtypes as products of different genes. This made it possible to further identify at least nine subtypes of adrenergic receptors: α1A, α1B, α1C, α2A, α2B, α2C, β1, β2, β3 [10].

β-adrenergic receptors, identified as proteolipids and nucleoproteins, are located on the sarcolemma of cells, which makes them easily accessible to the neurotransmitter and hormone of the sympathoadrenal system. β-adrenergic receptors are not stable formations, but rather a dynamic structure, the properties of which can vary in response to physiological stress, diseases, and drug intake. The role of receptor modulators capable of transforming α and β adrenergic receptors can be played by endorphins, adenyl nucleotides, prostaglandins and other substances of endogenous and exogenous origin, including cations. The entire complex of receptors must be considered as a single system that ensures the interaction of cells with the environment, since almost all studied receptor populations are functionally interconnected through systems of second messengers and the cytoskeleton.

The hormone-sensitive adenylate cyclase signaling system (ACS) plays a key role in the regulation of the most important growth and metabolic processes of the cell [10, 11]. The molecular mechanisms of functional coupling of proteins—components of the ACS, despite the large number of works devoted to this problem, have not been sufficiently studied; however, individual determinants responsible for the process of transmitting a hormonal signal from the receptor to the effector systems of the cell have now already been identified. In this aspect, the adrenoreactive complex has been most fully studied. According to modern views, it is a complex system localized in the plasma membrane and consisting of at least three molecular components: receptor, regulatory and catalytic. The latter is adenylate cyclase, an enzyme that catalyzes the synthesis of cyclic adenosine monophosphate (cAMP). The regulatory component by its nature is a protein that is involved in the implementation of regulatory influences on the catalytic function of adenylate cyclase by agents of non-hormonal nature - nucleotides, anions, etc. [11–15].

Along with this, guanyl nucleotides are credited with the function of hormone-induced coupling of the receptor and catalytic components. There is evidence indicating the participation of membrane lipids in this process. The heterogeneity of the participants in the interface indicates its complexity. These and a number of other facts served as the basis for the assumption of the existence of an independent (fourth) component in the hormone-sensitive system, which has a coupling function. In the absence of a hormonal signal, these components exist independently of each other; in its presence, they interact, forming a temporary short-lived complex [16, 17].

Activation of adenylate cyclase requires binding of the agonist to the receptor and subsequent formation of the hormone-receptor-Nsprotein complex. During the activation process, the ACS proteins move in the membrane, the efficiency of which depends on the proportion of liquid crystalline lipids. Changes in the macrostructure of the cell membrane significantly alter the effectiveness of the effects of hormonal substances [18, 19]. Disturbances in the cyclic nucleotide system cause changes in the sensitivity of cells to nervous and humoral influences, which, in turn, can underlie or aggravate the course of many pathological processes.

β-adrenergic receptors form complexes with a heterotrimetric guanosine triphosphate (GTP) cluster consisting of α, β and γ protein subunits. The formation of this complex changes the properties of both the receptor and the Gprotein. Subsequently, the GsαGTP subunit can activate adenylate cyclase. This stimulation is carried out with the participation of guanosine triphosphatase, GTP hydrolysis and the formation of guanosine diphosphate (GDP). GsαGDP binds to βγ subunits, which allows for a repeated cycle of activation of the complex [20]. During stress and exercise, the production of catecholamines, which stimulate β-adrenergic receptors, increases significantly. This causes the formation of cAMP, which activates phosphorylase, which causes the breakdown of intramuscular glycogen and the formation of glucose and is involved in the activation of calcium ions. In addition, catecholamines increase membrane permeability for calcium ions and mobilize Ca2+ from intracellular stores [21].

A brief history of β-agonists. The history of the use of β-agonists is the consistent development and introduction into clinical practice of drugs with increasingly increasing β2-adrenergic selectivity and increasing duration of action.

The sympathomimetic adrenaline (epinephrine) was first used in the treatment of patients with bronchial asthma in 1900 [22]. The short duration of action and a large number of side effects stimulated the search for more attractive drugs.

In 1940, isoproterenol appeared. It was destroyed in the liver as quickly as adrenaline (with the participation of catecholomethyltransferase), and therefore was characterized by a short duration of action, and the resulting metabolites (methoxyprenaline) had a β-blocking effect.

The first selective β2-agonist was salbutamol in 1970. Then terbutaline and fenoterol appeared. The new drugs retained their speed of action (onset after 35 minutes) with a noticeable increase in duration (46 hours). This improved the ability to control asthma symptoms during the day, but did not prevent night attacks [23, 24].

The new possibility of taking individual β2-agonists orally (salbutamol, terbutaline, formoterol, bambuterol) to some extent solved the problem of nocturnal asthma attacks. However, the need to take higher doses (>20-fold) contributed to the occurrence of adverse events associated with stimulation of α and β1 adrenergic receptors. In addition, lower therapeutic efficacy of these drugs was also revealed [24].

The advent of long-acting inhaled β2-agonists salmeterol and formoterol significantly changed the possibilities of asthma therapy. The first to appear on the market was salmeterol, which lasted for 12 hours but had a slow onset [23]. Soon it was joined by formoterol, with a rate of onset of effect similar to salbutamol. Already in the first years of use of long-acting β2-agonists, it was noted that they help reduce asthma exacerbations, reduce the number of hospitalizations, and also reduce the need for inhaled corticosteroids.

The most effective route of administration of drugs for asthma, including β2-agonists, is inhalation. The important advantages of this path are:

— the possibility of direct delivery of drugs to the target organ;

— minimization of undesirable effects.

Of the currently known delivery vehicles, metered-dose aerosol inhalers are the most commonly used, and metered-dose inhalers and nebulizers are less commonly used. Oral β2-agonists in the form of tablets or syrups are used extremely rarely, mainly as an additional treatment for frequent nocturnal asthma symptoms or a high need for inhaled short-acting β2-agonists in patients receiving high doses of inhaled glucocorticosteroids (ICS) (> 1000 μg beclomethasone/day) [25– 27].

The bronchi contain non-innervated β2-adrenergic receptors, the stimulation of which causes bronchodilation at all levels of the bronchial hierarchy. β2 receptors are widely present in the respiratory tract. Their density increases as the diameter of the bronchi decreases, and in patients with asthma, the density of β2 receptors in the airway is higher than in healthy people. This is due to an increase in the level of cAMP and a decrease in the content of intracellular Ca2+ in the smooth muscles of the respiratory tract. ARs are transmembrane receptors whose structure is based on a polypeptide chain of several hundred amino acids. β2AR forms a hydrophobic region in the cell membrane, consisting of 7 transmembrane domains; The Nterminal region is located outside the cell, the Terminal region is in the cytoplasm. The structure responsible for interaction with the β2 agonist is located on the outer surface of the cell. Inside the cell, β2ARs are associated with various types of regulatory Gproteins. G proteins interact with adenylate cyclase, which is responsible for the synthesis of cAMP. This substance activates a number of enzymes designated as cAMP-dependent protein kinases, one of which (protein kinase A) inhibits phosphorylation of myosin light chains, hydrolysis of phosphoinositide, activates the redistribution of calcium from inside to extracellular space, and the opening of large calcium-activated potassium channels. In addition, β2-agonists can bind to potassium channels and directly cause relaxation of smooth muscle cells, regardless of an increase in intracellular cAMP concentration [24, 28].

Numerous β2 receptors are found on the surface of mast cells, neutrophils, eosinophils, and lymphocytes.

Effects of respiratory β2-agonists. β2-agonists are considered as functional antagonists that cause the reverse development of bronchoconstriction, regardless of the constrictor effect that has taken place. This circumstance seems extremely important, since many inflammatory mediators and neurotransmitters have a bronchoconstrictor effect.

As a result of the effect on β-adrenergic receptors localized in various parts of the DP, additional effects of β2-agonists are revealed, which explain the possibility of their preventive use.

Stimulation of β2 adrenergic receptors of epithelial cells, glandular cells, vascular smooth muscles, macrophages, eosinophils, mast cells reduces the release of inflammatory mediators and endogenous spasmogens, helps restore mucociliary clearance and microvascular permeability. Blockade of the synthesis of leukotrienes, interleukins and tumor necrosis factor alpha by mast cells and eosinophils prevents the degranulation of mast cells and eosinophils, inhibiting the release of histamine, mucus secretion, and improves mucociliary clearance, suppresses the cough reflex, and reduces the permeability of blood vessels. Stimulation of β2-adrenergic receptors of cholinergic fibers reduces bronchoconstriction caused by hyperparasympathicotonia.

Microkinetic diffusion theory G. Andersen. The duration of action and the time of onset of the bronchodilator effect are determined by the different lipophilicity of β2 agonists. Formoterol occupies an intermediate position in terms of lipophilicity (420 ± 40 units) between salbutamol (11 ± 5 units) and salmeterol (12,450 ± 200 units). Salmeterol penetrates the lipophilic layer of the membrane and then slowly diffuses through the membrane to the receptor, leading to its prolonged activation (with a later onset of action). Salbutamol, entering the aqueous environment of the interstitial space, quickly interacts with the receptor and activates it without forming a depot. Formoterol forms a depot in the plasma membrane, from where it diffuses into the extracellular environment and then binds to β2AR [29].

Racemates. Selective β2-agonist preparations are racemic mixtures of two optical isomers R and S in a 50:50 ratio. It has been established that the pharmacological activity of R isomers is 20-100 times higher than that of S isomers. It has been shown that the R isomer of salbutamol exhibits bronchodilator properties [30]. At the same time, the S isomer has exactly the opposite properties: it has a pro-inflammatory effect, increases hyperreactivity, and enhances bronchospasm; in addition, it is metabolized much more slowly. Recently, a new drug for nebulizers was created containing only the R isomer, effective at a dose of 25% of the racemic mixture [31, 32].

Full and partial β2AR agonists. The completeness of β-agonism is determined in comparison with isoprenaline, which is able to activate the receptor in the same way as natural catecholamines. Salmeterol is called “salbutamol on a stalk”: its molecule consists of an active part (which directly interacts with the receptor and is actually salbutamol) and a long lipophilic part, which provides a prolonged effect by binding to the inactive part of the receptor. In this case, partial β2 agonists increase the concentration of cAMP by 2–2.5 times. The “hinge” mechanism of β2AR activation by salmeterol and the need to occupy 1 of its 30 possible spatial positions determine partial agonism. Formoterol is a full β2AR agonist: after its use, the intracellular concentration of cAMP increases 4 times. This circumstance is clinically most pronounced in patients who do not respond to salmeterol therapy (EFORA, 2003) [33, 34].

Development of tolerance. Intense stimulation by β2 agonists β2AR leads to inhibition of signal transmission (desensitization of receptors), internalization of receptors (reduction in the number of receptors on the membrane surface), and subsequently to the cessation of the synthesis of new receptors (downregulation) [35]. Desensitization of β2AR is based on phosphorylation of the cytoplasmic regions of the receptor by cAMP-dependent protein kinases. It should be noted that the β receptors of the smooth muscles of the respiratory tract have a fairly significant reserve, and therefore they are more resistant to desensitization than the receptors of non-respiratory zones. Desensitization of β2AR causes a decrease in response by 40% after 2 weeks of formoterol and by 54% after a similar use of salmeterol. It has been established that healthy individuals quickly develop tolerance to high doses of salbutamol, but not to fenoterol and terbutaline. At the same time, in patients with asthma, tolerance to the bronchodilator effect of β2-agonists rarely appears; tolerance to their bronchoprotective effect develops much more often. H. J. van der Woude et al. (2001) found that against the background of regular use of formoterol and salmeterol by patients with asthma, their bronchodilator effect does not decrease; the bronchoprotective effect is higher for formoterol, but the bronchodilator effect of salbutamol is significantly less pronounced. Restoration of β2AR occurs within several hours during desensitization, and within several days during downregulation. ICS provide rapid (within 1 hour) recovery and high density of β2AR on target cell membranes, preventing the development of the downregulation phenomenon [36].

Pharmacogenetics. Many researchers associate individual variability in the response to β2-agonists and the development of tolerance to their bronchodilator effect with gene polymorphism. 9 variants of β2-adrenergic receptor gene polymorphism have been identified, 2 of which are particularly common. They are associated with the replacement of amino acids in the extracellular N fragment of the gene: β2-adrenergic receptors16 with the replacement of arginine (Arg16) with glycine (Gly16) and β2adrenergic receptors27 with the replacement of glutamine (Gln27) with glutamic acid (Glu27). The Gly16 variant is associated with the development of severe asthma with frequent nocturnal attacks and decreased effectiveness of salbutamol. The second option determines the high activity of methacholine in relation to bronchoconstriction. The β2AP polymorphism (replacement of threonine with isoleucine at position 164 in the IV transmembrane domain) alters the binding of salmeterol to the exosite, reducing the duration of action of salmeterol (but not formoterol) by 50% [33].

Safety and potential risk. Salmeterol and formoterol exhibit long-acting β2-agonist properties only in the form of inhaled drugs, which explains the low incidence of undesirable effects (the absorbed fraction is quickly inactivated). The higher bronchodilator activity of formoterol is not accompanied by an increase in the frequency of adverse effects. A feature of formoterol is the proven dose-dependent nature of the bronchodilator effect: with increasing dose, additional bronchodilation occurs.

The selectivity of β2-agonists is relative and dose-dependent. Minor activation of α and β1 adrenergic receptors, unnoticeable at usual average therapeutic doses, becomes clinically significant when the dose of the drug or the frequency of its administration during the day is increased. The dose-dependent effect of β2-agonists must be taken into account in the treatment of exacerbations of asthma, especially life-threatening conditions, when repeated inhalations for a short time are 5–10 times higher than the permissible daily dose [22, 24].

β2-adrenergic receptors are found in a variety of tissues and organs, especially in the left ventricle, where they make up 14% of all β-adrenergic receptors, and in the right atrium (26% of all β-adrenergic receptors). Stimulation of these receptors can lead to the development of adverse effects (> 100 mcg salbutamol):

- tachycardia;

- myocardial ischemia;

- arrhythmia;

- decrease in diastolic blood pressure upon stimulation of vascular ∆receptors;

- hypokalemia, prolongation of the QT interval and fatal arrhythmias (with activation of large potassium channels);

— hypoxemia and worsening respiratory failure as a result of dilatation of the vessels of the pulmonary circulation system in the hyperinflation zone in patients with chronic obstructive pulmonary diseases;

- skeletal muscle tremor (with stimulation of skeletal muscle β receptors).

With systemic administration of large doses, an increase in the levels of free fatty acids, insulin, glucose, pyruvate and lactate is possible. Therefore, additional glycemic control is recommended in patients with diabetes. Undesirable cardiac effects are especially pronounced in conditions of severe hypoxia during exacerbations of asthma: an increase in venous return (especially in the orthopneic position) can cause the development of Bezold-Jarisch syndrome with subsequent cardiac arrest [24, 30].

The anti-inflammatory effect of β2 agonists, which helps modify acute bronchial inflammation, can be considered to be inhibition of the release of inflammatory mediators from mast cells and a decrease in capillary permeability. At the same time, biopsies of the bronchial mucosa of BA patients regularly taking β2-agonists showed that the number of inflammatory cells, including activated ones (macrophages, eosinophils, lymphocytes), does not decrease [24, 37]. Regular use of β2-agonists can mask the development of exacerbations of asthma, including fatal ones.

For the first time, serious doubts about the safety of inhaled β-agonists arose in the 1960s, when an “epidemic of deaths” broke out among patients with asthma in a number of countries (England, Australia, New Zealand). From 5 to 34 years of age for the period 1961–1967. 3,500 people died (at a rate of 2 per 1,000,000). Then publications began to appear in the press about how asthma patients were found dead with an empty (or almost empty) aerosol inhaler in their hands. Mortality was hypothesized to be related to the development of fatal arrhythmias and β-receptor blockade by isoproterenol metabolites, although a causal relationship between β-agonist use and increased mortality has not been established [38, 39].

A connection has been identified between the use of fenoterol and an increase in mortality from asthma in New Zealand in the 80s of the last century. An epidemiological study conducted in Canada (WO Spitzer et al., 1992) [39] showed that an increase in the incidence of deaths is associated with high-dose therapy with inhaled β2-agonists. At the same time, patients with uncontrolled and severe asthma are less adherent to taking anti-inflammatory drugs - inhaled corticosteroids. Misconceptions about the ability of salmeterol to relieve acute asthma attacks led to at least 20 deaths from asthma being reported in the first 8 months after the drug was introduced on the pharmaceutical market in the United States. Based on the results of the SMART study, it was decided to use long-acting β2 agonists (LABA) only in combination with ICS. Moreover, the addition of LABA is equivalent to doubling the dose of ICS.

Dosage regimen for inhaled short-acting β2 agonists (SABA). They are the drugs of choice for situational symptomatic control of asthma [25], as well as for preventing the development of symptoms of exercise asthma (PAE). Their regular use can lead to loss of adequate control over the course of the disease. M. R. Sears et al. (1990) found in a group of asthma patients who consumed fenoterol regularly (4 times a day) poor control over asthma symptoms, more frequent and severe exacerbations. Patients who used fenoterol on demand showed an improvement in respiratory function, morning peak expiratory flow, and a decrease in response to a bronchoprovocation test with methacholine. There is evidence that regular use of salbutamol is accompanied by an increase in the frequency of episodes of AFU and an increase in the severity of inflammation in the DP [24].

Short-acting β-agonists should be used only when required. Patients receiving high (more than 1.4 aerosol cans per month) doses require effective anti-inflammatory therapy. The bronchoprotective effect of β-agonists is limited to 3–4 inhalations per day. Oral β-agonists help improve performance by increasing muscle mass, protein and lipid anabolism, and psychostimulation. Thus, 41 of the 67 athletes with AFU who regularly used SABA at the 1984 Olympic Games received medals of varying denominations.

Dosage regimen for long-acting inhaled β2-agonists. The differences between salmeterol and formoterol are that bronchodilation occurs quickly after using the latter, and there are significantly fewer adverse events than with salbutamol. These drugs can be prescribed as monotherapy in patients with mild asthma and as bronchoprotectors in AFU. When using formoterol more than 2 times a week, it is necessary to add ICS to the treatment.

To date, no studies have been conducted that comply with the principles of good clinical practice (GCP) in which the disease-modifying effect of LABA monotherapy has been proven.

Studies conducted to date indicate the possibility of earlier administration of long-acting inhaled β2-agonists. The addition of formoterol to 400–800 mcg/day of ICS (budesonide) provides more complete and adequate control compared to increasing the dose of ICS [24, 40].