B 2 short-acting antagonists. Long-acting beta2-agonists in the treatment of chronic obstructive pathology. Diagnostic criteria for AD

Peculiarities: Typically, these medicines come in the form of metered-dose aerosols. They are divided into short-acting drugs, which are usually used during an attack, and long-acting drugs, which prevent the development of bronchospasm.

Most Common Side Effects: palpitations, headache, anxiety, with too frequent use - a decrease in efficiency, up to aggravation of asthma attacks.
Main contraindications: individual intolerance.

Important information for the patient:

• Short-acting preparations are not recommended to be used more than 4 times a day. If seizures occur more frequently, you should consult a doctor to review the treatment regimen.
• In order for the drug to have the desired effect, it is very important to follow the rules for using the inhaler.

Remember, self-medication is life-threatening, consult a doctor for advice on the use of any medications.

These drugs, having a bronchospasmolytic effect, are first-line drugs in the treatment of asthma attacks.

Salbutamol(ventolin, salben, ventolin nebules and 0.1% salgim solution for nebulizer therapy) is a selective beta-2 adrenoreceptor agonist.

The bronchodilatory effect of salbutamol occurs after 4-5 minutes. The effect of the drug gradually increases to its maximum by 40-60 minutes. The half-life is 3-4 hours, and the duration of action is 4-5 hours.

Mode of application: Using a nebulizer, 2.5 ml nebules containing 2.5 mg salbutamol sulfate in saline. 1-2 nebules (2.5 - 5.0 mg) are prescribed for inhalation in undiluted form. If there is no improvement, repeated inhalations of salbutamol 2.5 mg every 20 minutes for an hour are carried out. In addition, the drug is used in the form of PDI (spacer), spacer or dischaler (100 mcg per inhalation of 1-2 breaths) or cyclohaler (200 mcg per inhalation of 1 breath).

FENOTEROL(BerotekN) and Berotek solution for nebulizer therapy is a short-acting selective beta-2 agonist. The bronchodilator effect occurs in 3-4 minutes and reaches its maximum effect by 45 minutes. The half-life is 3-4 hours, and the duration of action of fenoterol is 5-6 hours.

Mode of application: Using a nebulizer - 0.5-1.5 ml of a solution of fenoterol in saline for 5-10 minutes. If there is no improvement, repeat inhalations of the same dose of the drug every 20 minutes. Children 0.5-1.0 ml (10-20 drops) for 1 inhalation. BerotekN is also used in the form of PAI (100 mcg for 1-2 breaths).

Side effects. When using beta-2-agonists, hand tremor, agitation, headache, compensatory increase in heart rate, heart rhythm disturbances, arterial hypertension are possible. Side effects are more expected in patients with diseases of the cardiovascular system, in older age groups and in children; with repeated use of a bronchospasmolytic, depend on the dose and route of administration of the drug.

Relative contraindications to the use of inhaled beta-2-agonists - thyrotoxicosis, heart defects, tachyarrhythmia and severe tachycardia, acute coronary pathology, decompensated diabetes mellitus, hypersensitivity to beta-agonists.

Anticholinergics

Ipratropium bromide(atrovent) - anticholinergic agent with very low (less than 10%) bioavailability, which leads to good tolerability of the drug. Ipratropium bromide is used in case of ineffectiveness of beta-2-agonists, as an additional agent to enhance their bronchodilator action, with individual intolerance to beta-2-agonists, in patients with chronic bronchitis.

Mode of application: Inhalation - using a nebulizer - 1.0 - 2.0 ml (0.25 - 0.5 mg). If necessary, repeat after 30-40 minutes. With the help of PDI or spacer 40-80 mcg.

Combined drugs

BERODUAL - combined bronchospasmolytic drug containing two bronchodilators fenoterol and ipratropium bromide. One dose of berodual contains 0.05 mg of fenoterol and 0.02 mg of ipratropium bromide.

Mode of application: With the help of a nebulizer to stop an attack, a solution of berodual 1-4 ml in saline is inhaled for 5-10 minutes. If improvement does not occur, repeat inhalation after 20 minutes. The dose of the drug is diluted in physiological solution. With the help of PDI - 1-2 breaths, if necessary after 5 minutes - 2 more doses, the subsequent inhalation should be carried out no earlier than after 2 hours.

Systemic glucocorticoids

severe and life-threatening exacerbation of asthma

relief of an asthma attack in a patient with a hormone-dependent form of asthma

anamnestic indications of the need for the use of glucocorticoids to relieve exacerbation of asthma in the past.

Side effects: arterial hypertension, agitation, arrhythmia, ulcer bleeding

Contraindications: Peptic ulcer of the stomach and duodenum, severe arterial hypertension, renal failure.

PREDNISOLONE is a dehydrated analog of hydrocortisone and belongs to synthetic glucocorticosteroid hormones. The half-life is 2-4 hours, the duration of action is 18-36 hours. It is administered parenterally to adults at a dose of at least 60 mg, to children - parenterally or orally 1-2 mg / kg.

METHYLPREDNISOLONE(solumedrol, metipred) Non-halogenated derivative of prednisolone, which has a greater anti-inflammatory (5 mg of prednisolone is equivalent to 4 mg of methylprednisolone) and significantly less mineralocorticoid activity.

The drug is characterized by a short, like prednisolone, half-life, weaker stimulation of the psyche and appetite. For the treatment of exacerbations of bronchial asthma, it is used like prednisolone, but in smaller doses (based on methylprednisolone-prednisolone as 4: 5).

Inhaled glucocorticoids (budesonide) may be effective. It is advisable to use inhaled glucocorticoids through a nebulizer.

Inhaled glucocorticoids

Budesonide(pulmicort) - suspension for a nebulizer in plastic containers 0.25-0.5 mg (2 ml).

During biotransformation of budesonide in the liver, it forms metabolites with low glucocorticosteroid activity.

Pulmicort suspension for nebulizer can be diluted with saline, as well as mixed with solutions of salbutamol and ipratropium bromide. The dose for adults is 0.5 mg (2 ml), for children - 0.5 mg (1 ml) twice every 30 minutes.

Methylxanthines

EUFILLIN is a combination of theophylline (80%), which determines the pharmacodynamics of the drug, and ethylenediamine (20%), which determines its solubility. The mechanisms of the bronchodilator action of theophylline are well known.

When providing emergency care, the drug is administered intravenously, while the action begins immediately and lasts up to 6-7 hours. Theophylline is characterized by a narrow therapeutic latitude, i.e. Even with a small overdose of the drug, side effects may develop. The half-life in adults is 5-10 hours. About 90% of the administered drug is metabolized in the liver, metabolites and unchanged drug (7-13%) are excreted in the urine through the kidneys. In adolescents and smokers, theophylline metabolism is accelerated, which may require an increase in the dose of the drug and infusion rate. Liver dysfunction, congestive heart failure and old age, on the contrary, slow down the metabolism of the drug, increase the risk of side effects and necessitate a dose reduction and a decrease in the rate of intravenous infusion of aminophylline.

Indications for use in BA:

relief of an asthma attack in the absence of inhalation agents or as an additional therapy for severe or life-threatening exacerbation of asthma.

Side effects:

on the part of the cardiovascular system - lowering blood pressure, palpitations, heart rhythm disturbances, cardialgia

from the gastrointestinal tract - nausea, vomiting, diarrhea;

from the side of the central nervous system - headache, dizziness, tremor, convulsions.

Interaction (see Table 3)

the drug is incompatible with glucose solution.

Dose in children: 4.5-5 mg/kg intravenously (given over 20-30 minutes) in 10-15 ml saline.

Bronchial asthma (BA) is a chronic inflammatory disease of the airways (AID) 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 under the influence of treatment. According to WHO, about 300 million people worldwide suffer from AD.

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. Properties to stop an asthma attack and a controlling effect on the course of the disease have β-adrenergic receptor agonists available on the pharmaceutical market in various dosage forms.

All processes occurring in the body, starting from the cellular level, are strictly coordinated with each other in terms of time, speed and place of occurrence. This consistency is achieved due to the presence of complex mechanisms of regulation, which is carried out due to 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 it, but interacting with special protein macromolecules - receptors built into the outer surface of the cell (surface membrane).

cell membrane is a bimolecular layer of phospholipids enclosed between two layers of adsorbed proteins. The nonpolar hydrophobic ends of the phospholipid molecules are directed towards the middle of the membrane, while the polar hydrophilic ends are directed towards the edges separating it from the aqueous phase. Large protein molecules are included in the bilayer lipid matrix. Some proteins penetrate the entire thickness of the membrane, while others are embedded only in 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 the cholesterol content, the fluidity decreases, and with an increase in the content of unsaturated or branching hydrophobic tails of phospholipid molecules, it increases.

The influence of circulating catecholamines is carried out by interaction with adrenoreceptors (AR). By definition, B.N. Manukhin, adrenoreceptors are functional formations of a cell that perceive the effect of a neurotransmitter and a 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 - units per square micron of the surface. This causes another feature of regulation - the effective number of regulators is negligible. 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 molecules of the regulator to the cell membrane is apparently sufficient. In the entire chain from the receptor to the considered cellular reaction, the signal is amplified by 10-100 million times.

Adrenoreceptors were originally characterized according to their functional response to stimulation when inhibited by various pharmacological agents. Subsequently, they were qualified according to their affinity similarity when bound by labeled ligands. a-adrenergic receptors are defined as oligomeric proteins localized on the surface of cell membranes; β-adrenergic receptors have been identified as proteolipids and nucleoproteins. In 1948, R. Ahlquist found that adrenoreceptors are divided into two types - α and β. A. Lands in 1967 determined that there are subtypes of β-AR. The use of molecular biology methods confirmed the heterogeneity of adrenoreceptor subtypes as products of various genes. This made it possible to further identify at least nine subtypes of adrenergic receptors: α 1A, α 1B, α 1C, α 2A, α 2B, α 2C, β 1 , β 2 , β 3 .

β-adrenergic receptors , identified as proteolipids and nucleoproteins, are located on the cell sarcolemma, which makes them easily accessible to the neurotransmitter and hormone of the sympathetic-adrenal system. β-adrenergic receptors are not stable formations, but rather a dynamic structure, the properties of which can vary in response to physiological stress, disease, and drug intake. The role of receptor modulators capable of transforming α- and β-adrenergic receptors can be performed 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.

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. The molecular mechanisms of the functional conjugation of proteins that are ACS components, despite the large number of works devoted to this problem, have not been adequately studied; however, individual determinants responsible for the process of transmission of the hormonal signal from the receptor to the effector systems of the cell have 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 agents of a non-hormonal nature - nucleotides, anions, etc.

Along with this, the function of hormone-induced coupling of the receptor and catalytic components is attributed to guanyl nucleotides. There is evidence that membrane lipids are also involved in this process. The heterogeneity of the conjugation participants indicates its complexity. These and a number of other facts formed the basis for the assumption of the existence of an independent (fourth) component in the hormone-sensitive system, which has the function of conjugation. 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.

Activation of adenylate cyclase requires binding of the agonist to the receptor and subsequent formation of the hormone-receptor-Ns-protein complex. In the process of activation, 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 change the effectiveness of the action of hormonal substances. Disturbances in the cyclic nucleotide system cause a change in the sensitivity of cells to nervous and humoral influences, which, in turn, can underlie or exacerbate the course of many pathological processes.

β-adrenergic receptors form complexes with heterotrimetric guanosine triphosphate (GTP)-accumulation, consisting of α-, β- and γ-protein subunits. The formation of this complex alters the properties of both the receptor and the G-protein. Subsequently, the Gs α -GTP subunit can activate adenylate cyclase. This stimulation is carried out with the participation of guanosine triphosphatase, hydrolysis of GTP and the formation of guanosine diphosphate (GDP). Gs α -GDP binds to βγ subunits, which allows the repeated activation cycle of the complex. Under stress and physical exertion, 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 the permeability of the membrane for calcium ions and mobilize Ca 2+ from intracellular depots.

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 ever-increasing β 2 -adrenergic selectivity and increasing duration of action.

For the first time, the sympathomimetic adrenaline (epinephrine) was used in the treatment of patients with bronchial asthma in 1900. The short duration of action and a large number of side effects were an incentive to 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.

In 1970, salbutamol became the first selective β 2 -agonist. Then came terbutaline and fenoterol. The new drugs retained their rapid response (onset in 35 minutes) with a marked increase in duration (46 hours). This improved the ability to control asthma symptoms during the day, but did not prevent nighttime attacks.

The possibility of taking individual β 2 -agonists orally (salbutamol, terbutaline, formoterol, bambuterol) to some extent solved the problem of nocturnal asthma attacks. However, the need to take higher doses (> 20 times) contributed to the emergence of adverse events associated with stimulation of α- and β 1 -adrenergic receptors. In addition, a lower therapeutic efficacy of these drugs was also revealed.

The appearance of long-acting inhaled β 2 -agonists salmeterol and formoterol significantly changed the possibilities of AD therapy. The first to appear on the market was salmeterol, which lasted for 12 hours but had a slow onset. Soon, formoterol joined him, with a speed of development of effect similar to salbutamol. Already in the first years of the use of prolonged β 2 -agonists, it was noted that they contribute to a decrease in asthma exacerbations, a decrease in the number of hospitalizations, and a decrease in the need for inhaled corticosteroids.

The most effective way of administering drugs for AD, including β 2 -agonists, is recognized as inhalation. 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 means of delivery, metered-dose aerosol inhalers are the most commonly used, less often metered-dose inhalers and nebulizers. Oral β 2 -agonists in the form of tablets or syrups are used very rarely, mainly as an adjunct for frequent nocturnal symptoms of asthma or a high need for inhaled short-acting β 2 -agonists in patients receiving high doses of inhaled glucocorticosteroids (IGCS) (> 1000 mcg beclomethasone /day) .

In the bronchi there are non-innervated β 2 -adrenergic receptors, the stimulation of which causes bronchodilation at all levels of the bronchial hierarchy. β 2 -receptors are widely represented in the respiratory tract. Their density increases as the diameter of the bronchi decreases, and in patients with BA, the density of β 2 receptors in the airway is higher than in healthy ones. This is due to an increase in the level of cAMP and a decrease in the content of intracellular Ca 2+ in the smooth muscles of the respiratory tract. ARs are transmembrane receptors, the structure of which is based on a polypeptide chain of several hundred amino acids. β 2 -AP forms a hydrophobic region in the cell membrane, consisting of 7 transmembrane domains; The N-terminal region is located outside the cell, the C-terminal region is in the cytoplasm. The structure responsible for interaction with the β 2 -agonist is located on the outer surface of the cell. Inside the cell, β 2 -AP are associated with regulatory G-proteins of various types. 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 the phosphorylation of myosin light chains, the hydrolysis of phosphoinositide, activates the redistribution of calcium from the intra- to the extracellular space, and the opening of large calcium-activated potassium channels. In addition, β 2 -agonists can bind to potassium channels and directly cause relaxation of smooth muscle cells, regardless of the increase in intracellular cAMP concentration.

Numerous β 2 receptors are found on the surface of mast cells, neutrophils, eosinophils, and lymphocytes.

Effects of respiratory β 2 -agonists.β 2 -agonists are considered as functional antagonists, causing the reverse development of bronchoconstriction, regardless of the constrictor effect that has taken place. This circumstance seems to be extremely important, since many mediators of inflammation and neurotransmitters have a bronchoconstrictor effect.

As a result of the impact on β-adrenergic receptors localized in different parts of the DP, additional effects of β 2 -agonists are revealed, which explain the possibility of their preventive use.

Stimulation of β 2 -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 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 β 2 -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 β 2 -agonists. Formoterol is intermediate 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, getting into the aquatic 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 β 2 -AP.

Racemates. Preparations of selective β 2 -agonists are racemic mixtures of two optical isomers R and S in a ratio of 50: 50. It has been established that the pharmacological activity of R-isomers is 20-100 times higher than that of S-isomers. The R-isomer of salbutamol has been shown to exhibit bronchodilator properties. At the same time, the S-isomer has opposite properties: it has a pro-inflammatory effect, increases hyperreactivity, enhances bronchospasm; in addition, it is much more slowly metabolized. Recently, a new formulation for nebulizers has been developed containing only the R-isomer, effective at a dose of 25% of the racemic mixture.

Full and partial agonists β 2 -AP. 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 "pedunculated salbutamol": its molecule consists of an active part (which interacts directly 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. At the same time, partial β 2 -agonists increase the concentration of cAMP by 2-2.5 times. The "hinged" mechanism of activation of β 2 -AR by salmeterol and the need to occupy 1 of its 30 possible spatial positions cause partial agonism. Formoterol is a full agonist of β 2 -AR: after its use, the intracellular concentration of cAMP increases by 4 times. This circumstance is clinically most pronounced in patients who do not respond to salmeterol therapy (EFORA, 2003) .

Development of tolerance. Intense stimulation with β 2 -agonists of β 2 -AR leads to inhibition of signal transmission (receptor desensitization), receptor interning (reduction in the number of receptors on the membrane surface), and subsequently to the cessation of the synthesis of new receptors (down-regulation). The desensitization of β 2 -AR 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 DP have a rather significant reserve, and therefore they are more resistant to desensitization than the receptors of non-respiratory zones. Desensitization of β 2 -AR 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 BA, tolerance to the bronchodilator effect of β 2 -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 BA, their bronchodilator effect does not decrease, the bronchoprotective effect is higher in formoterol, but the bronchodilator effect of salbutamol is much less pronounced. Restoration of β 2 -AR during desensitization occurs within a few hours, with down-regulation - within a few days. Inhaled corticosteroids provide fast (within 1 hour) recovery and high density of β 2 -AR on the membranes of target cells, preventing the development of the down-regulation phenomenon.

Pharmacogenetics. Individual variability in response to β 2 -agonists and the development of tolerance to their bronchodilatory effect, many researchers associate with gene polymorphism. 9 polymorphism variants of the β 2 -adrenergic receptor gene have been identified, of which 2 are particularly common. They are associated with the replacement of amino acids in the extracellular N-fragment of the gene: β 2 -adrenergic receptors-16 with the replacement of arginine (Arg-16) with glycine (Gly-16) and β 2 -adrenergic receptors-27 with the replacement of glutamine (Gln-27) with glutamine acid (Glu-27). The Gly-16 variant is associated with the development of severe asthma with frequent nocturnal attacks and a decrease in the effectiveness of salbutamol. The second variant determines the high activity of methacholine in relation to bronchoconstriction. The β 2 -AP polymorphism (replacement of threonine by 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%.

Safety and potential risk. Salmeterol and formoterol exhibit the properties of long-acting β 2 -agonists only in the form of inhaled drugs, which explains the low frequency 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 undesirable effects. A feature of formoterol is the proven dose-dependent nature of the bronchodilator effect: with increasing doses, additional bronchodilation occurs.

The selectivity of β 2 -agonists is relative and dose-dependent. Slight activation of α- and β1-adrenergic receptors, imperceptible at usual average therapeutic doses, becomes clinically significant with an increase in the dose of the drug or the frequency of its administration during the day. The dose-dependent effect of β 2 -agonists must be taken into account in the treatment of asthma exacerbations, especially life-threatening conditions, when repeated inhalations for a short time exceed the allowable daily dose by 5-10 times.

β 2 -adrenergic receptors are found in various 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 events (> 100 mcg of salbutamol):

- tachycardia;

- myocardial ischemia;

- arrhythmia;

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

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

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

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

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

The anti-inflammatory effect of β 2 -agonists, contributing to the modification of acute bronchial inflammation, can be considered as inhibition of the release of inflammatory mediators from mast cells and a decrease in capillary permeability. At the same time, a biopsy of the bronchial mucosa of BA patients who regularly take β 2 -agonists showed that the number of inflammatory cells, including activated ones (macrophages, eosinophils, lymphocytes), does not decrease. Regular use of β 2 -agonists can mask the development of BA exacerbations, including fatal ones.

For the first time, serious doubts about the safety of inhaled β-agonists arose in the 1960s, when in a number of countries (England, Australia, New Zealand) an "epidemic of deaths" broke out among patients with asthma. At the age of 5 to 34 years 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. It was assumed that mortality was associated with the development of fatal arrhythmias and blockade of β-receptors by isoproterenol metabolites, although a causal relationship between the use of β-agonists and increased mortality has not been established.

An association was found between fenoterol intake and an increase in asthma mortality in New Zealand in the 1980s. As a result of an epidemiological study conducted in Canada (W.O. Spitzer et al., 1992), it was shown that an increase in the frequency of deaths is associated with high-dose therapy with inhaled β 2 -agonists. At the same time, patients with uncontrolled and severe asthma are less adherent to taking anti-inflammatory drugs - inhaled corticosteroids. The misconception that salmeterol can help relieve acute asthma attacks has led to at least 20 asthma deaths in the United States in the first 8 months since the drug was introduced to the pharmaceutical market. Based on the results of the SMART study, it was decided to use long-acting β 2 -agonists (LABA) only in combination with ICS. In this case, the addition of LABA is equivalent to doubling the dose of ICS.

Dosing regimen for inhaled short-acting β 2 -agonists (SABA). They are the drugs of choice for situational symptomatic control of asthma, as well as for preventing the development of symptoms of exercise-induced asthma (AFA). Their regular use can lead to the loss of adequate control over the course of the disease. M.R. Sears et al. (1990) found in the group of patients with asthma who used fenoterol regularly (4 times a day), poor control of asthma symptoms, more frequent and severe exacerbations. In patients who used fenoterol on demand, there was an improvement in respiratory function, morning peak expiratory flow, a decrease in response to a bronchoprovocation test with methacholine. There is evidence that the regular use of salbutamol is accompanied by an increase in the frequency of AFU episodes and an increase in the severity of inflammation in the DP.

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

Dosing regimen of prolonged inhaled β 2 -agonists. The differences between salmeterol and formoterol are that bronchodilation after the use of the latter occurs quickly, adverse events are significantly less than with the use of 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, there have been no studies consistent with the principles of good clinical practice (GCP), in which the disease-modifying effect of LABA monotherapy would be proven.

Studies conducted to date indicate the possibility of an earlier appointment of prolonged inhaled β 2 -agonists. The addition of formoterol to 400-800 mcg/day of ICS (for budesonide) provides more complete and adequate control compared to increasing the dose of ICS.

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In the last 10 years, long-acting β 2 -agonists have taken a leading position in the international standards for the treatment of bronchial asthma and chronic obstructive pulmonary disease. If in the first version of the Global Strategy for Bronchial Asthma these drugs were given the role of second-line drugs, then in the new version of GINA 2002, long-acting β 2 -agonists are considered as an alternative to increasing daily doses of inhaled glucocorticosteroids with an insufficient patient response to anti-inflammatory therapy and the inability to exercise control bronchial asthma. In this case, the appointment of long-acting β 2 -agonists should always precede the next increase in the daily dose of inhaled glucocorticosteroids. This is due to the fact that the inclusion of long-acting β 2 -agonists in the treatment regimen with inhaled glucocorticosteroids for uncontrolled bronchial asthma is more effective than simply increasing the daily dose of inhaled glucocorticosteroids by 2 times or more. However, long-term therapy with long-acting β 2 -agonists does not appear to affect persistent inflammation in bronchial asthma, and therefore their use should always be combined with the appointment of inhaled glucocorticosteroids.

Long-acting inhaled β 2 -agonists include salmeterol and formoterol (more than 12 hours). The effect of most inhaled short-acting β 2 -agonists lasts from 4 to 6 hours. Salmeterol, like formoterol, relaxes bronchial smooth muscles, enhances mucocyl-par clearance, reduces vascular permeability and can affect the release of mediators from mast cells and basophils. The study of biopsy specimens shows that in the treatment of long-acting inhaled β 2 -agonists, signs of chronic inflammation in the airways in patients with bronchial asthma do not increase; in fact, even a slight anti-inflammatory effect is noted with prolonged use of these drugs. In addition, salmeterol also provides long-term (more than 12 hours) protection against factors leading to bronchoconstriction. Formoterol is a full β 2 receptor agonist while salmeterol is a partial agonist, but the clinical significance of these differences is unclear. Formoterol has a faster onset of action than salmeterol, making it more suitable for both symptomatic relief and prevention, although its efficacy and safety as a rescue agent requires further study.

Salmeterol (in particular, salmeter, Dr. Reddy's Laboratories) exhibits a higher specificity for β 2 receptors compared to other sympathomimetics. The bronchodilatory effect of the drug manifests itself 10-20 minutes after inhalation. 1) increases within 180 minutes, and a clinically significant bronchodilatory effect persists for 12 hours. The lipophilicity of salmeterol is 10,000 times higher than that of salbutamol, which contributes to the rapid penetration of the drug into cell membranes. Salmeterol has a stabilizing effect on mast cells, inhibits their release of histamine , reduces the permeability of pulmonary capillaries to a greater extent than inhaled glucocorticosteroids, reduces the production of cytokines by T-lymphocytes, inhibits IgE-dependent synthesis of TNF-α and the release of leukotriene C 4 and prostaglandin D.

In most patients with bronchial asthma, it is possible to achieve symptom control when prescribing the drug at a dose of 50 mcg 2 times a day. A large randomized trial showed that salmeterol intake for 12 weeks was accompanied by an increase in peak expiratory flow rate (PEF) in the morning by 7.1% compared with baseline (p< 0,001). При этом число дней без симптомов возросло с 35 до 67%. На 20% увеличилось количество ночей без приступов удушья, использование сальбутамола сократилось более чем в 3 раза. Применение сальметерола 2 раза в сутки более эффективно, чем 4-кратное ежедневное использование симпатомиметиков короткого действия, особенно при бронхиальной астме физического усилия.

In persons with chronic obstructive pulmonary disease, salmeterol is usually prescribed in a daily dose of 50 mcg 2 times. The results of 3 large randomized placebo-controlled studies revealed a significant decrease in the severity of symptoms of the disease and an improvement in FEV 1. There were no signs of tolerance to the drug during the study, the frequency of exacerbations did not differ from that in the placebo group. Nevertheless, a significant improvement in the quality of life while taking salmeterol makes it reasonable to include it in the treatment regimen for patients with chronic obstructive pulmonary disease.

Due to the relatively slowly developing effect, salmeterol is not recommended for the relief of acute symptoms of bronchial asthma; in this case, short-acting inhaled bronchodilators are preferable. When prescribing salmeterol twice a day (morning and evening), the physician should additionally provide the patient with a short-acting β 2 -agonist inhaler for the treatment of acutely developing symptoms in parallel with the constant intake of salmeterol.

The increasing frequency of taking bronchodilators, in particular inhaled forms of short-acting β 2 -agonists, reduces the curability of bronchial asthma. The patient should be warned about the need to seek medical help in case of a decrease in the effectiveness of prescribed short-acting bronchodilators or to increase the frequency of taking the drug. In this situation, an examination is necessary, after which recommendations are made to increase anti-inflammatory therapy (for example, higher doses of corticosteroids in the form of inhalations or orally). Increasing the daily dose of salmeterol in this case is not justified.

Salmeterol should not be taken more than twice a day (morning and evening) at the recommended dose (two inhalations). Taking large doses of salmeterol in the form of inhalations or in oral form (12-20 times the recommended dose) will lead to a clinically significant prolongation of the QT interval, which means the beginning of the formation of ventricular arrhythmias. At recommended doses, salmeterol has no effect on the cardiovascular system. Violations of the functions of the cardiovascular and central nervous systems caused by all sympathomimetic drugs (increased blood pressure, tachycardia, agitation, ECG changes) after taking salmeterol are observed in rare cases. Such effects are uncommon, and if they occur, the drug should be discontinued. However, salmeterol, like all sympathomimetics, is prescribed with caution to patients with cardiovascular disorders, especially coronary insufficiency, arrhythmias, hypertension; persons with convulsive syndrome, thyrotoxicosis, inadequate response to sympathomimetic drugs.

Salmeterol cannot be used as a substitute for inhaled or oral corticosteroids or sodium cromoglycate, and the patient should be warned not to stop taking these drugs even if salmeterol provides greater relief.

Salmeterol inhalation may be complicated by acute hypersensitivity in the form of paradoxical bronchospasm, angioedema, urticaria, rash, hypotension, collaptoid reaction and symptoms of laryngospasm, irritation or laryngeal edema, leading to stridor and asphyxia. Due to the fact that bronchospasm is a life-threatening condition, the patient must be warned about the possible discontinuation of the drug and the appointment of alternative treatment.

Conducted multicenter studies prove the high efficiency of long-acting β 2 -agonists. The appearance of these drugs has significantly changed approaches to the treatment of broncho-obstructive diseases. The inclusion of salmeter in the scheme of drug exposure will significantly improve the results of long-term basic therapy of chronic broncho-obstructive pathology, especially since the drug has advantages not only in terms of efficiency and safety, but also cost.

(Lapteva I.M. Research Institute of Pulmonology and Phthisiology of the Ministry of Health of the Republic of Belarus. Published: "Medical Panorama" No. 10, November 2004)