Corticosteroids - names of drugs, indications and contraindications, features of use in children and adults, side effects. Inhaled glucocorticosteroids: effectiveness and safety Combined inhaled glucocorticoids

Knyazheskaya N.P., Chuchalin A.G.

Currently bronchial asthma(BA) is considered as a special chronic inflammatory disease of the respiratory tract with a progressive course of this inflammation without special therapy. There are a sufficient number of different medications that can effectively combat this inflammation. The basis of therapy for long-term control of the inflammatory process is ICS, which should be used for persistent BA of any severity.

Background

One of the most significant achievements of medicine of the twentieth century was the introduction of glucocorticosteroid drugs (GCS) into clinical practice. This group of drugs is also widely used in pulmonology.

GCS were synthesized in the late 40s of the last century and initially existed exclusively in the form of systemic drugs (oral and injectable forms). Almost immediately, their use began in the treatment of severe forms of bronchial asthma, however, despite the positive response to therapy, their use was limited by pronounced systemic side effects: the development of steroid vasculitis, systemic osteoporosis, steroid-induced diabetes mellitus, Itsenko-Cushing syndrome, etc. .d. Therefore, doctors and patients considered the use of corticosteroids as a last resort, a “therapy of despair.” Attempts to use systemic corticosteroids by inhalation were unsuccessful, since regardless of the method of administration of these drugs, their systemic complications persisted, and the therapeutic effect was minimal. Thus, it is not even possible to consider the use of systemic corticosteroids via a nebulizer.

And although almost immediately after the creation of systemic GCS, the question of developing topical forms arose, it took almost 30 years to solve this problem. The first publication on the successful use of topical steroids dates back to 1971 and concerned the use of beclomethasone dipropionate for allergic rhinitis, and in 1972 this drug was successfully used to treat bronchial asthma.

Currently, ICS are considered as first-line agents in the treatment of bronchial asthma. The higher the severity of bronchial asthma, the higher doses of inhaled steroids should be used. According to a number of studies, patients who began treatment with ICS no later than two years from the onset of the disease showed significant benefits in improving control over asthma symptoms compared with the group that began treatment with ICS after more than 5 years from the onset of the disease.

ICS are basic, that is, the main drugs in the treatment of all pathogenetic variants of persistent bronchial asthma (BA), starting with mild severity.

Topical forms are practically safe and do not cause systemic complications even with long-term use in high doses.

Untimely and inadequate ICS therapy can lead not only to uncontrolled asthma, but also to the development of life-threatening conditions that require much more serious systemic steroid therapy. In turn, long-term systemic steroid therapy, even in small doses, can cause iatrogenic diseases. It should be taken into account that drugs to control the disease (basic therapy) should be used daily and for a long time. Therefore, the main requirement for them is that they must not only be effective, but above all, safe.

The anti-inflammatory effect of ICS is associated with their inhibitory effect on inflammatory cells and their mediators, including the production of cytokines, interference with the metabolism of arachidonic acid and the synthesis of leukotrienes and prostaglandins, reducing microvascular permeability, preventing direct migration and activation of inflammatory cells, increasing the sensitivity of smooth muscle receptors. ICS increase the synthesis of anti-inflammatory proteins (lipocortin-1), increase apoptosis and reduce the number of eosinophils by inhibiting interleukin-5. Thus, ICS lead to the stabilization of cell membranes, reduce vascular permeability, improve the function of β-receptors both by synthesizing new ones and increasing their sensitivity, and stimulate epithelial cells.

ICS differ from systemic glucocorticosteroids in their pharmacological properties: lipophilicity, rapidity of inactivation, short half-life from blood plasma. It is important to consider that treatment with ICS is local (topical), which provides pronounced anti-inflammatory effects directly in the bronchial tree with minimal systemic manifestations. The amount of ICS delivered to the respiratory tract will depend on the nominal dose of the drug, the type of inhaler, the presence or absence of propellant, and the inhalation technique.

ICS include beclomethasone dipropionate (BDP), budesonide (BUD), fluticasone propionate (FP), mometasone furoate (MF). They are available in the form of metered aerosols, dry powder, and also in the form of solutions for use in nebulizers (Pulmicort).

Features of budesonide as an inhaled glucocorticosteroid

Of all inhaled glucocorticoids, budesonide has the most favorable therapeutic index, which is associated with its high affinity for glucocorticoid receptors and accelerated metabolism after systemic absorption in the lungs and intestines. Distinctive features of budesonide among other drugs in this group are: intermediate lipophilicity, long retention in tissue due to conjugation with fatty acids and high activity towards the corticosteroid receptor. The combination of these properties determines the exceptionally high effectiveness and safety of budesonide among other ICS. Budesonide is slightly less lipophilic compared to other modern ICS, such as fluticasone and mometasone. Less lipophilicity allows budesonide to penetrate the mucus layer covering the mucous membrane more quickly and more effectively compared to more lipophilic drugs. This very important feature of this drug largely determines its clinical effectiveness. It is assumed that the greater effectiveness of BUD in comparison with FP when used in the form of aqueous suspensions for allergic rhinitis is based on the lower lipophilicity of BUD. Once inside the cell, budesonide forms esters (conjugates) with long-chain fatty acids, such as oleic and a number of others. The lipophilicity of such conjugates is very high, due to which BUD can remain in tissues for a long time.

Budesonide is an ICS that has been proven to be suitable for single use. A factor contributing to the effectiveness of once-daily administration of budesonide is retention of budesonide in the respiratory tract through the formation of an intracellular depot due to reversible esterification (formation of fatty acid esters). Budesonide is capable of forming conjugates (esters in position 21) with long-chain fatty acids (oleic, stearic, palmitic, palmitoleic) inside cells. These conjugates are characterized by exceptionally high lipophilicity, which significantly exceeds that of other ICS. It was found that the intensity of formation of BUD esters is not the same in different tissues. When the drug is administered intramuscularly to rats, about 10% of the drug is esterified in muscle tissue, and 30-40% in pulmonary tissue. Moreover, with intratracheal administration, at least 70% of BUD is esterified, and its esters are not detected in plasma. Thus, BUD has pronounced selectivity for lung tissue. When the concentration of free budesonide in the cell decreases, intracellular lipases are activated, and budesonide released from esters again binds to the GC receptor. A similar mechanism is not characteristic of other glucocorticoids and contributes to the prolongation of the anti-inflammatory effect.

A number of studies have shown that intracellular storage may be more important in terms of drug activity than receptor affinity. BUD has been shown to remain in the tissue of the trachea and main bronchi of rats significantly longer than AF. It should be noted that conjugation with long-chain fatty acids is a unique feature of BUD, which creates an intracellular depot of the drug and ensures its long-lasting effect (up to 24 hours).

In addition, BUD is characterized by high affinity for the corticosteroid receptor and local corticosteroid activity, exceeding that of the “old” drugs beclomethasone (including its active metabolite B17MP), flunisolide and triamcinolone and comparable to the activity of AF.

The corticosteroid activity of BUD is practically no different from that of AF over a wide range of concentrations. Thus, BUD combines all the necessary properties of an inhaled corticosteroid that ensure the clinical effectiveness of this class of drugs: due to moderate lipophilicity, it quickly penetrates the mucosa; due to conjugation with fatty acids, it remains in the lung tissue for a long time; Moreover, the drug has exceptionally high corticosteroid activity.

There are some concerns with the use of inhaled corticosteroids due to the potential for systemic effects of these drugs. In general, the systemic activity of ICS depends on their systemic bioavailability, lipophilicity and volume of distribution, as well as on the degree of binding of the drug to blood proteins. Budesonide is characterized by a unique combination of these properties, which make this drug the safest among those known.

Information regarding the systemic effect of ICS is very contradictory. Systemic bioavailability consists of oral and pulmonary. Oral availability depends on absorption in the gastrointestinal tract and on the severity of the “first pass” effect through the liver, due to which inactive metabolites enter the systemic circulation (with the exception of beclomethasone 17-monopropionate, the active metabolite of beclomethasone dipropionate). Pulmonary bioavailability depends on the percentage of the drug reaching the lungs (which depends on the type of inhaler used), the presence or absence of a carrier (inhalers that do not contain Freon have the best results) and on the absorption of the drug in the respiratory tract.

The overall systemic bioavailability of ICS is determined by the portion of the drug that enters the systemic circulation from the surface of the bronchial mucosa and the portion of the ingested portion that was not metabolized during the first passage through the liver (oral bioavailability). On average, about 10-50% of the drug exerts its therapeutic effect in the lungs and subsequently enters the systemic circulation in an active state. This fraction is entirely dependent on the efficiency of pulmonary delivery. 50-90% of the drug is swallowed, and the final systemic bioavailability of this fraction is determined by the intensity of subsequent metabolism in the liver. BUD is among the drugs with the lowest oral bioavailability.

For most patients, to achieve control of bronchial asthma, it is enough to use low or medium doses of ICS, since the dose-effect curve is quite flat for indicators such as symptoms of the disease, parameters of pulmonary function, and airway hyperresponsiveness. Transfer to high and ultra-high doses does not significantly improve the control of bronchial asthma, but increases the risk of side effects. However, there is a clear relationship between the dose of ICS and the prevention of severe exacerbations of bronchial asthma. Therefore, in a number of patients with severe asthma, long-term administration of high doses of ICS is preferable, which allows reducing or eliminating the dose of oral GCS (or avoiding their long-term use). At the same time, the safety profile of high doses of ICS is clearly more favorable than that of oral GCS.

The next property that determines the safety of budesonide is its intermediate lipophilicity and volume of distribution. Drugs with high lipophilicity have a large volume of distribution. This means that a larger proportion of the drug may have a systemic effect, meaning less of the drug is in circulation and available to be converted to inactive metabolites. BUD has intermediate lipophilicity and a relatively small volume of distribution compared to BDP and FP, which certainly affects the safety profile of this inhaled corticosteroid. Lipophilicity also affects the potential ability of the drug to have a systemic effect. More lipophilic drugs have a significant volume of distribution, which theoretically may be accompanied by a slightly greater risk of systemic side effects. The larger the volume of distribution, the better the drug penetrates into tissues and cells; it has a longer half-life. In other words, ICS with greater lipophilicity will generally be more effective (especially when used by inhalation), but may have a worse safety profile.

Apart from fatty acids, BUD has the lowest lipophilicity among currently used ICS and, therefore, has a smaller volume of extrapulmonary distribution. This is also facilitated by the slight esterification of the drug in muscle tissue (determining a significant proportion of the systemic distribution of the drug in the body) and the absence of lipophilic esters in the systemic circulation. Taking into account that the proportion of free BUD not bound to plasma proteins, like many other ICSs, slightly exceeds 10%, and the half-life is only 2.8 hours, it can be assumed that the potential systemic activity of this drug will be quite insignificant. This probably explains the smaller effect of BUD on cortisol synthesis compared to more lipophilic drugs (when used in high doses). Budesonide is the only inhaled CS whose efficacy and safety have been confirmed in a significant number of studies in children aged 6 months and older.

The third component that provides the drug with low systemic activity is the degree of binding to blood plasma proteins. BUD refers to the IGCS that have the highest degree of connection, not differing from BDP, MF and FP.

Thus, BUD is characterized by high corticosteroid activity, long-lasting action, which ensures its clinical effectiveness, as well as low systemic bioavailability and systemic activity, which, in turn, makes this inhaled corticosteroid one of the safest.

It should also be noted that BUD is the only drug in this group that has no evidence of a risk of use during pregnancy (level of evidence B) and according to the FDA classification.

As you know, when registering any new drug, the FDA assigns a certain risk category when using this drug in pregnant women. The category is determined based on the results of teratogenicity studies in animals and information on previous use in pregnant women.

The instructions for budesonide (forms for inhalation and intranasal administration) under different trade names that are officially registered in the United States indicate the same category of use during pregnancy. In addition, all instructions refer to the results of the same studies in pregnant women conducted in Sweden, taking into account the data of which budesonide was assigned category B.

When conducting research, scientists from Sweden collected information about the course of pregnancy and its outcome from patients taking inhaled budesonide. Data were entered into a special registry, the Swedish Medical Birth Registry, where almost all pregnancies in Sweden are registered.

Thus, budesonide has the following properties:

effectiveness: control of asthma symptoms in most patients;

good safety profile, no systemic effects at therapeutic doses;

rapid accumulation in the mucous membranes of the respiratory tract and rapid onset of anti-inflammatory effect;

duration of action up to 24 hours;

does not affect final growth with long-term use in children, bone mineralization, cataracts, does not cause angiopathy;

allowed for use in pregnant women - does not cause an increase in the number of fetal abnormalities;

good tolerance; provides high compliance.

Undoubtedly, patients with persistent bronchial asthma should use adequate doses of inhaled corticosteroids to achieve an anti-inflammatory effect. But it should be noted that for ICS, accurate and correct execution of the respiratory maneuver is especially important (like for no other inhaled drug) to ensure the necessary deposition of the drug in the lungs.

The inhalation route of drug administration is the main route for bronchial asthma, as it effectively creates high concentrations of the drug in the respiratory tract and allows to minimize systemic undesirable effects. There are different types of delivery systems: metered dose inhalers, powder inhalers, nebulizers.

The word "nebulizer" (from the Latin "nebula" - fog, cloud) was first used in 1874 to refer to a device that "converts a liquid substance into an aerosol for medical purposes." Of course, modern nebulizers differ from their historical predecessors in their design, technical characteristics, dimensions, etc., but the principle of operation remains the same: the transformation of a liquid drug into a therapeutic aerosol with certain characteristics.

The absolute indications for nebulizer therapy (according to Muers M.F.) are: the impossibility of delivering the drug into the respiratory tract with any other type of inhaler; the need to deliver the drug to the alveoli; the patient's condition does not allow the use of any other type of inhalation therapy. Nebulizers are the only way to deliver some drugs: for antibiotics and mucolytics, metered-dose inhalers simply do not exist. Inhalation therapy for children under 2 years of age without the use of nebulizers is difficult to implement.

Thus, we can distinguish several categories of patients for whom nebulizer therapy is the optimal solution:

persons with intellectual disabilities

persons with reduced reactions

patients with exacerbation of asthma and COPD

some elderly patients

Place of Pulmicort suspension for nebulizers in the treatment of bronchial asthma

Basic therapy in case of ineffectiveness of other forms of inhaled glucocorticosteroid therapy or the impossibility of using other forms of delivery, including basic therapy for children under 2 years of age.

Su Suspension of Pulmicort can be used in children of the first years of life. The safety of Pulmicort for children consists of several components: low pulmonary bioavailability, retention of the drug in the bronchial tissues in esterified form, etc. In adults, the air flow created during inhalation is significantly greater than the flow created by a nebulizer. In adolescents, the tidal volume is smaller than in adults, therefore, since the flow of the nebulizer remains unchanged, children receive a more concentrated solution during inhalation than adults. But at the same time, after administration in the form of inhalations, Pulmicort is found in the blood of adults and children of different ages in the same concentrations, although the ratio of the dose taken to body weight in children 2-3 years old is several times higher than in adults. This unique feature is found only in Pulmicort, since regardless of the initial concentration, most of the drug is “retained” in the lungs and does not enter the blood. Thus, the Pulmicort suspension is not only safe for children, but even safer in children than in adults.

The effectiveness and safety of Pulmicort suspension has been confirmed by numerous studies conducted in a wide variety of age groups, from the neonatal period and very early age (this is the majority of studies) to adolescence and late adolescence. The effectiveness and safety of Pulmicort suspension for nebulizer therapy was assessed in groups of children with persistent bronchial asthma of varying severity, as well as during exacerbations of the disease. Thus, Pulmicort, suspension for nebulizer, is one of the most studied basic therapy drugs used in pediatrics.

The use of Pulmicort suspension using a nebulizer was accompanied by a significant reduction in the need for emergency medications, a positive effect on pulmonary function and the frequency of exacerbations.

It was also found that when treated with Pulmicort suspension, compared with placebo, significantly fewer children required additional administration of systemic corticosteroids.

Pulmicort suspension for nebulizer has also proven itself well as a means of starting therapy in children with bronchial asthma, starting from the age of 6 months.

Relief of exacerbations of bronchial asthma as an alternative to the administration of systemic steroids, and in some cases, joint administration of Pulmicort suspension and systemic steroids.

The use of high dose Pulmicort suspension has been found to be equivalent to the use of prednisolone for exacerbations of asthma and COPD. At the same time, the same changes in lung function were observed both after 24 and 48 hours of therapy.

Studies have also found that the use of inhaled corticosteroids, including Pulmicort suspension, is accompanied by a significantly higher FEV1 compared to the use of prednisolone already 6 hours after the start of treatment.

Moreover, it has been shown that during exacerbations of COPD or asthma in adult patients, the addition of a systemic corticosteroid to Pulmicort suspension therapy is not accompanied by an additional effect. At the same time, monotherapy with Pulmicort suspension also did not differ from that with a systemic corticosteroid. Studies have found that the use of Pulmicort suspension during exacerbations of COPD is accompanied by a significant and clinically significant (more than 100 ml) increase in FEV1.

When comparing the effectiveness of Pulmicort suspension with prednisolone in patients with exacerbation of COPD, it was found that this inhaled corticosteroid is not inferior to systemic drugs.

The use of nebulizer therapy with Pulmicort suspension in adults with exacerbations of bronchial asthma and COPD was not accompanied by changes in cortisol synthesis and calcium metabolism. While the use of prednisolone, without being more clinically effective, leads to a marked decrease in the synthesis of endogenous corticosteroids, a decrease in the level of serum osteocalcin and an increase in calcium excretion in the urine.

Thus, the use of nebulizer therapy with a Pulmicort suspension for exacerbations of asthma and COPD in adults is accompanied by a rapid and clinically significant improvement in lung function, and in general has an effectiveness comparable to that of systemic corticosteroids, in contrast to which it does not lead to suppression of adrenal function and changes in calcium metabolism.

Basic therapy to reduce the dose of systemic steroids.

The use of high-dose nebulizer therapy with Pulmicort suspension makes it possible to effectively withdraw systemic corticosteroids in patients whose asthma requires their regular use. It was found that during therapy with a Pulmicort suspension at a dose of 1 mg twice a day, it is possible to effectively reduce the dose of the systemic corticosteroid while maintaining asthma control. The high efficiency of nebulizer therapy with inhaled corticosteroids allows already after 2 months of use to reduce the dose of systemic glucocorticosteroids without deteriorating pulmonary function.

Reducing the dose of systemic corticosteroid while using budesonide suspension is accompanied by the prevention of exacerbations. It was shown that, compared with the use of placebo, patients using Pulmicort suspension had half the risk of developing exacerbations when the dose of the systemic drug was reduced.

It was also found that when systemic corticosteroids are discontinued during treatment with a Pulmicort suspension for 1 year, not only the basic synthesis of cortisol is restored, but also the function of the adrenal glands is normalized and their ability to provide “stressful” systemic corticosteroid activity.

Thus, the use of nebulizer therapy with a Pulmicort suspension in adults allows for an effective and rapid reduction in the dose of systemic corticosteroids while maintaining initial pulmonary function, improving symptoms and a lower frequency of exacerbations compared to placebo. This approach is also accompanied by a decrease in the incidence of side effects from systemic corticosteroids and restoration of adrenal function.

Literature
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2. Ovcharenko S.I., Peredelskaya O.A., Morozova N.V., Makolkin V.I. Nebulizer therapy with bronchodilators and pulmicort suspension in the treatment of severe exacerbation of bronchial asthma // Pulmonology. 2003. No. 6. P. 75-83.
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6. Barnes P.J. Inhaled glucocorticoids for asthma. N.Engl. Med. 1995; 332:868-75
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9. Code of Federal Regulations - Title 21 - Food and Drugs 21 CFR 201.57(f)(6) http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfmCrisholm S et al. Once-daily budesonide in mild asthma. Respir Med 1998; 421-5
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11. FDA Pregnancy Labeling Task Force http://www.fda.gov/cder/handbook/categc.htm.

S.N. Avdeev, O.E. Avdeeva

Research Institute of Pulmonology, Ministry of Health of the Russian Federation, Moscow

URL

List of abbreviations

IN It is now generally accepted that systemic and inhaled corticosteroids (CS) are the most effective anti-inflammatory drugs for the treatment of bronchial asthma (BA). However, compared to oral steroids, inhaled corticosteroids (ICS) have a safer clinical profile, i.e. with comparable effectiveness, they have a significantly lower potential to cause side effects. According to leading experts in the field of BA, the introduction of ICS into clinical practice is a revolutionary event in the treatment of BA, and due to the fact that the central role of the inflammatory process of the respiratory tract mucosa in BA has now been proven, ICS can be considered as first-line drugs for chronic BA. In addition, recent data have been obtained on the effectiveness of long-term inhaled steroid therapy in chronic obstructive pulmonary disease (COPD), which allows us to recommend their wider use in this disease.

Mechanism of action of ICS
ICS are highly lipophilic compounds; they quickly penetrate target cells, where they bind to cytosolic receptors. Corticosteroid-receptor complexes are rapidly transported to the nucleus, where they bind to KC-specific gene elements, leading to increased or decreased gene transcription. KS receptors can also interact with protein transcription factors in the cytoplasm and thus influence the synthesis of certain proteins independently of interaction with DNA in the cell nucleus. Direct inhibition of transcription factors such as AP-1 and NF-κB may be responsible for many of the anti-inflammatory effects of ICS in AD.
Table 1. Comparison of ICS activity.

A drug	Receptor affinity	Local activity	System activity	Activity ratio (systemic/local activity)	Relative bioavailability
Beclomethasone dipropionate		0,40	3,50	0,010
Budesonide		1,00	1,00	1,00
Fluticasone propionate	22,0	1,70	0,07	25,00	80-90
Flunisolide		0,70	12,80	0,050
Triamcinolone acetonide		0,30	5,30	0,050

Glucocorticoids have direct inhibitory effects on many cells involved in the inflammatory process, such as macrophages, T lymphocytes, eosinophils, epithelial cells (Fig. 1). CS may also reduce the number of mast cells in the respiratory tract, although they do not affect the release of mediators from them during allergic reactions. Airway epithelial cells may also be an important target for ICS, and inhibition of mediators released from these superficial cells helps control inflammation in the bronchial wall. CS suppress the formation of many mediators by lymphocytes and macrophages, such as interleukins 1, 2, 3, 4, 5, 13, TNFa, RANTES, GM-CFS, which may be the most important mechanism of the anti-inflammatory activity of glucocorticoids, since cytokines play a key role in the development and maintenance of eosinophilic and neutrophilic inflammation. CS reduce vascular permeability due to the action of inflammatory mediators and lead to resolution of airway edema. CS also have a direct inhibitory effect on the secretion of mucus glycoproteins from the submucosal glands of the respiratory tract, leading to a decrease in the formation of bronchial secretions.
Rice . 1. Cellular effects of corticosteroids (P.J.Barnes, S.Godfrey; Asthma Therapy, 1998).

ICS increase the sensitivity of bronchial smooth muscle cells to b 2 -agonists and prevent or lead to the reverse development of tachyphylaxis to these drugs. At the molecular level, CS increase gene transcription b 2 -receptors in human lungs.

Table 2. Deposition of ICS in the lungs

Drug, device,	Deposition (%) from
propellant	Delivered dose	measured dose
Beclomethasone, DI, CFC
Beclomethasone, DI Autohaler, HFA
Beclomethasone, CI, HFA
Budesonide, DI, CFC
Budesonide, DI - spacer
Nebuhaler, CFC
Budesonide suspension,
nebulizer Pari LC-Jet
Flunisolide, DI, CFC
Flunisolide, DI - spacer
Ingakort, CFC
Flunisolide, Respimat inhaler
Flunisolide, DI, HFA
Flunisolide, DI - spacer
Aerohaler, HFA
Fluticasone, MDI, CFC
Fluticasone, MDI, HFA
Budesonide, PI Turbuhaler
Fluticasone, PI Diskhaler
Fluticasone, PI Akkuhaler“/Diskus
Note. Data are presented as a % of the dose measured or delivered, where the delivered dose is the dose received by the patient; metered dose - dose received by the patient + dose remaining in the device. PI - powder inhaler, CFC - chlorofluorocarbon (freon), HFA - hydrofluoroalkane.

Table 3. In vitro study of budesonide delivery using nebulizer-compressor systems

Nebulizer	Compressor	Delivery, % aerosol (SD)
Pari LC Jet Plus	Pulmo-Aide	17,8 (1,0)
Pari LC Jet Plus	Pari Master	16,6 (0,4)
Intertech	Pulmo-Aide	14,8 (2,1)
Baxter Misty-Neb	Pulmo-Aide	14,6 (0,9)
Hudson T-Updraft II	Pulmo-Aide	14,6 (1,2)
Pari LC Jet	Pulmo-Aide	12,5 (1,1)
DeVilbiss Pulmo-Neb	Pulmo-Aide Traveler	11,8 (2,0)
DeVilbiss Pulmo-Neb	Pulmo-Aide	9,3 (1,4)

Inhaled glucocorticosteroids for asthma
Comparison of inhaled steroids
A large number of studies have been conducted comparing the relative effectiveness and safety of various ICS drugs. Comparative evaluation of ICS is very difficult because the dose-response curve has a flattened profile, and in addition, different ICS drugs are administered through different inhalers, which also affects the comparison results. It is currently accepted that the doses of beclomethasone, budesonide and flunisolide are comparable in their effectiveness and the incidence of side effects. The exception is fluticasone, the effective dose of which has a 1:2 ratio compared to other ICS.
A meta-analysis by N. Barnes et al. was devoted to comparing the effectiveness of fluticasone with the drugs budesonide and beclomethasone in doses twice as high as for fluticasone, which showed that fluticasone in half doses has the same effectiveness or even more effective (in terms of the effect on functional indicators ) than other ICS, and this positive effect is achieved with less suppression of the function of the adrenal cortex (Table 1), i.e. Compared to other drugs, fluticasone in patients with asthma has a better efficacy/safety ratio.
Impact of delivery devices on the effectiveness of ICS therapy
The effectiveness of ICS depends not only on their chemical structure, but also on the device for delivering the aerosol to the respiratory tract. An ideal delivery device should ensure the deposition of a large fraction of the drug in the lungs, be fairly easy to use, reliable, and be available for use at any age and in severe stages of the disease. Delivery of the drug to the respiratory tract depends on many factors, the most important of which is the particle size of the drug aerosol. For inhalation therapy, particles up to 5 µm in size (respirable particles) are of interest. The fraction of drug delivered to the respiratory tract depends more on the drug/delivery device combination than on the device itself. ICS deposition when using different drug/delivery device combinations can differ by an order of magnitude (Table 2).
Fig. 2. Therapy: adults and children over 5 years old
Preferred therapy is in bold.
* Patient education is necessary at every stage

	Long-term control therapy	Therapy to relieve symptoms
* Stage 4 severe course	Daily therapy: · X 800-2000 mcg · long-acting bronchodilators: either slow-release theophyllines, or prolonged inhalation b 2 -agonists, or oral b 2 - long-acting agonists · Possible use of oral steroids	b 2 - agonists according to need
* Stage 3 moderate severity	Daily therapy: X more than 500 mcg, if necessary: · long-acting bronchodilators: or long-acting inhaled b 2 -agonists, or theophyllines, or oral b 2 - long-acting agonists (more effective control of asthma symptoms can be achieved with a combination of long-acting inhaled b 2 -agonists and low-moderate doses of inhaled steroids compared with increasing doses of steroids) · Consider leukotriene receptor antagonists, especially for aspirin-induced or exercise-induced asthma	Short acting bronchodilators: b 2
* Stage 2 mild persistent course	Daily therapy: · or ICS 200-500 mcg, or cromoglycate, or nedocromil, or prolonged inhalation b 2 -agonists, or slow-release theophyllines, leukotriene receptor antagonists, although their position needs clarification	Short acting bronchodilators: b 2 -agonists as needed no more than 3-4 times a day
* Stage 1 mild intermittent flow	Not required	· Short acting bronchodilators: b 2 -agonists as needed, less than once a week · The intensity of therapy depends on the severity of the attacks · Inhalation b 2 -agonists or cromoglycate before physical activity or contact with an allergen
	Step down Therapy assessment every 3-6 months. If control is ensured for 3 months, gradual reducing the intensity of therapy one step down.	Step up If control is not achieved, increase steps. But first: check the patient's inhalation technique, compliance, environmental control (elimination allergens and other environmental triggers).
*ICS doses: equivalent to beclomethasone dipropionate, budesonide and flunisolide. Global Initiative for Asthma (GINA). WHO/NHLBI, 1998

The creation of new CFC-free metered-dose inhalers (MDIs) with HFA-134a filler (HFA-beclomethasone) also made it possible to significantly reduce the size of aerosol particles: the median mass aerodynamic diameter of beclomethasone particles was reduced to 1.1 µm (compared to 3.5 µm when using DI with freon), which leads to an increase in drug deposition several times.
The use of a larger volume spacer (about 750 ml) allows not only to reduce unwanted deposition of the drug in the oral cavity and improve the patient’s performance of the respiratory maneuver, but also to significantly (up to 2 times) increase the delivery of the drug to the lungs.
For children, the elderly and seriously ill, nebulizers are the main means of delivering inhaled drugs into the respiratory tract. Taking into account the physical properties of the drug budesonide (suspension), it is recommended to use certain nebulizer-compressor combinations (Table 3). An ultrasonic nebulizer is an ineffective delivery system for drug suspensions.
Clinical effectiveness of ICS in asthma
ICS are the most effective drugs for the treatment of asthma. In one of the first randomized controlled studies on the use of ICS in patients with asthma, it was shown that systemic corticosteroids and ICS are equivalent in their clinical effectiveness, however, taking ICS significantly reduces the risk of side effects (5 and 30% in the ICS and oral corticosteroid groups) . The effectiveness of ICS was further confirmed by a decrease in symptoms and exacerbations of asthma, and an improvement in functional pulmonary parameters,reducing bronchial hyperreactivity, reducing the need to take short-acting bronchodilators, as well as improving the quality of life of patients with asthma.
Table 4. Effect of ICS on disease progression in patients with COPD

Smoking experience	Therapy period (months)	D FEV 1 (ml/year)		R
		placebo	budesonide
All patients				< 0,001
	9-36			0,39
< 36 пачка/лет				< 0,001
	9-36			0,08
> 36 pack/years				0,57
	9-36			0,65
D FEV 1 - dynamics of changes in FEV indicator 1 per ml for 1 year.

Table 5. Pharmacokinetics of ICS

A drug	Solubility in water (µg/ml)	Half-life in plasma (h)	Volume of distribution (l/kg)	Clearance(liter/kg)	Proportion of active drug after passing via the liver (%)
Beclomethasone dipropionate
Budesonide		2,3-2,8	2,7-4,3	0,9-1,4	6-13
Fluticasone propionate	0,04	3,7-14,4	3,7-8,9	0,9-1,3
Flunisolide
Triamcinolone acetonide

Table 6. Side effects of ICS

Local side effects

• dysphonia
• oropharyngeal candidiasis
• cough

Systemic side effects

• adrenal suppression
• growth slowdown
• petechiae
• osteoporosis
• cataract
• glaucoma
• metabolic disorders (glucose, insulin, triglycerides)
• mental disorders

ICS for steroid-dependent asthma
The effectiveness of ICS is shown in patients with asthma, which is controlled only by taking systemic steroids. Although systemic corticosteroids are also highly effective drugs, the risk of developing severe, disabling complications is very high. According to a long-term, 8-year study by I. Broder et al., about 78% of patients with hormone-dependent asthma are able to completely stop or reduce the dose of systemic steroids during ICS therapy. According to a large randomized controlled trial conducted by H. Nelson et al., ICS may be even more effective in their clinical effectiveness than systemic drugs.When inhaled budesonide 400–800 mg was used in 159 patients with steroid-dependent asthma, the percentage of patients who reduced their oral steroid dose was higher compared with placebo (80% vs. 27%, p< 0,001). Более того, функциональные показатели у больных, принимавших ИКС, значительно улучшились (среднее повышение объема форсированного выдоха за одну секунду (ОФВ 1 ) by 25%), which also reflected in the improvement of the clinical symptoms of patients, and the side effects associated with taking CS decreased.
In all age groups of patients with asthma, there are severe steroid-dependent patients who respond poorly to conventional inhaled corticosteroid therapy. The reason for this may be either poor compliance with inhalation therapy, or unsatisfactory inhalation technique, or, in a small group of patients, a poor response to oral corticosteroids. In this situation, reduction or complete cessation of oral steroids can be achieved by using ICS via nebulizers. The steroid-sparing effect of nebulized steroids was confirmed in a multicenter study by T. Higgenbottam et al., which included 42 patients with steroid-dependent asthma. After 12 weeks of therapy with budesonide at a dose of 2 mg per day via nebulizer, 23 patients reduced the dose of oral CS by an average of 59% of the initial dose (p< 0,0001). В то же время функциональные легочные показатели больных не изменились или даже улучшились: выявлено повышение утреннего показателя пиковой объемной скорости (ПОС) в среднем на 6% (р < 0,05).
ICS for mild asthma
The earliest studies of corticosteroids in asthma were conducted in patients with moderate to severe disease. When ICS were introduced in the early 1970s, their primary use was limited to cases of poorly controlled asthma, despite high doses of oral steroids and bronchodilators. However, with the understanding of the central role of the inflammatory process in the genesis of asthma, approaches to prescribing ICS have also changed: they are currently recommended as first-line drugs for almost all patients with asthma, including those with mild asthma. ICS is prescribed in cases where the need to take b 2 -agonists to control symptoms in a patient with asthma is more than 3 times a week. Arguments for early prescription of ICS for asthma are:

• inflammation of the mucous membrane of the respiratory tract is present even in the earliest stages of asthma;
• ICS are the most effective drugs compared to other known therapies;
• withdrawal of ICS in patients with mild asthma can lead to exacerbation of the disease.
• ICS prevent the progressive decline in pulmonary functional parameters that occurs in patients with asthma over time;
• ICS are safe drugs;
• ICS are cost-effective drugs, since the benefits to society and the patient due to the reduction in morbidity from asthma when taken are more significant compared to other drugs.

The main arguments against prescribing ICS for mild asthma are the possibility of developing local and side systemic effects, as well as the fact that many patients do not experience disease progression in the absence of any therapy.
One of the first evidence of the effectiveness of ICS in mild asthma was obtained by Finnish researchers who compared two treatment regimens in patients with asthma symptoms lasting less than 1 year and who have not previously taken anti-inflammatory drugs: inhaled b 2 -agonist (terbutaline 750 mcg/day) and ICS (budesonide 1200 mcg/day). Patients taking ICS had a greater reduction in symptoms of asthma and bronchial hyperresponsiveness, as well as an increase in POS compared with patients taking terbutaline. This difference was observed after 6 weeks and persisted throughout the 2 years of observation.
Many patients with mild asthma are not observed in specialized departments and are usually treated in outpatient care, and often both patients and general practitioners believe that such patients can do without ICS. One study showed that from 40 up to 70% of such patients, who, in the opinion of the general practitioner, had mild asthma and could not obtain additional clinical benefit from the administration of ICS, had night and early morning symptoms associated with asthma. In these same patients, the administration of inhaled budesonide at a daily dose of 400 mcg led to a significant improvement in clinical symptoms and an increase in PEF, as well as a decrease in patient admissions to the emergency department for exacerbation of asthma.
Early administration of ICS leads to a greater improvement in functional pulmonary parameters than in cases of delayed administration (when only bronchodilators are used for a long time), which was proven in a study by O. Serloos et al., who studied the effect of the duration of asthma symptoms on the improvement of clinical symptoms and indicators pulmonary function for 2 years after the appointment of ICS in 105 patients with asthma. The best results of ICS therapy were achieved in patients with the shortest duration of asthma symptoms (< 6 мес), хотя хороший эффект препаратов наблюдался и у больных с длительностью заболевания до 2 лет, у больных с более длительным анамнезом БА (до 10 лет) эффект стероидов был более скромным.
The results of these studies support the assumption that ICS are able to suppress the ongoing inflammatory process of the airways and prevent the development of structural changes (fibrosis, smooth muscle hyperplasia, etc.) that occur as a result of chronic inflammation. O. Sutochnikova et al. Based on a study of repeated cytological studies of bronchoalveolar lavages (BAL), they showed that even in patients with mild BA, inhaled budesonide therapy leads to a significant decrease in the activity of inflammation of the bronchial mucosa: a decrease in the number of eosinophils, BAL neutrophils, as well as a decrease in the intensity index of bronchial inflammation.
Recommended doses of ICS depending on the severity of asthma are presented in Fig. 2. There are no clear data yet on the initial doses of ICS for newly diagnosed asthma. One of the recommendations, based on the task of quickly achieving control over the inflammatory process in patients with asthma, is the initial prescription of an average dose of ICS (800–1200 mcg per day), which, as clinical symptoms and functional indicators improve, can be reduced to the minimally effective dose. On the other hand, several controlled studies have not provided evidence of the effectiveness of initial treatment with high doses of ICS: high and low doses of ICS (1000 μg and 100 μg fluticasone for 6 weeks in the study by N. Gershman et al., 200 μg and 800 μg budesonide for 8 weeks in a study by T. van der Mollen et al.) with newly diagnosed asthma had virtually no difference in their effect on clinical symptoms, functional indicators, and the need for b 2 -agonists, markers of inflammation and bronchial hyperreactivity.
When treating patients with mild asthma with ICS, traditional functional indicators (POS, FEV) are often 1 ) poorly reflect the effect of steroids on the inflammatory process in the respiratory tract. In these patients, it is recommended to monitor the effect of ICS using indicators such as bronchial hyperreactivity (provocative dose or provocative concentration), non-invasive markers of inflammation (induced sputum, exhaled NO).
High doses of ICS or combination of ICS with other drugs?
Often, when asthma is not controlled with prescribed doses of ICS, the question arises: should the dose of ICS be increased or another drug added.
The largest number of studies compared the effectiveness of a combination of salmeterol or formoterol/ICS and a double dose of ICS,and found that improved functional performance, decreased nighttime symptoms, and decreased on-demand use b 2 Short-acting -agonists were significantly more pronounced in the groups of patients taking salmeterol or formoterol. Some researchers have expressed doubts about the rationality of this approach, since there is a danger that b 2 Long-acting agonists can “mask” the decrease in control of asthma inflammation and lead to the development of more severe exacerbations of asthma. However, subsequent studies did not confirm the “masking” of inflammation, since data were even obtained on a decrease in the number of exacerbations of asthma.
The effectiveness of combination therapy may be explained by the inhibitory effect b 2 -agonists on stimulants of contraction of bronchial smooth muscles, leakage of plasma into the lumen of the respiratory tract, influx of inflammatory cells during exacerbation of asthma, as well as an increase in the deposition of ICS in the respiratory tract due to an increase in the lumen of the airways after inhalation b 2 -agonists.
There are relatively few studies on the combination of ICS with other drugs. Evidence has been obtained of the high clinical effectiveness of the theophylline/ICS combination. The effectiveness of the theophylline/ICS combination may be associated not only with the bronchodilator effect of theophylline, but also with its anti-inflammatory properties.
The combination of ICS with leukotriene receptor antagonists can also lead to better control of asthma compared to ICS monotherapy; the combinations of zafirlukast/ICS and montelukast/ICS have been shown to be highly effective.
The data from all these studies reflect the results of dose-response studies, where it is very difficult to determine the dose-dependent effect of ICS on pulmonary functional parameters. ICS are the most powerful anti-inflammatory drugs,however, high ICS may lead to an increased risk of local systemic side effects. Adding a drug with a different mechanism of action may be a better choice than increasing the ICS dose because other antiasthmatic drugs may have additional beneficial mechanisms of action.
The effect of ICS on the mortality of patients with asthma
A very important study on the ability of ICS to reduce mortality in patients with asthma was recently published by S. Suissa et al. The study was conducted on a database of asthma patients (30,569 patients) in the province of Saskatchewan (Canada), using a case-control method. Based on dose-response analysis, it was estimated that the risk of death from asthma was reduced by 21% for each additional canister of ICS during the previous year (odds ratio - OR - 0.79; 95% CI 0.65-0.97) . The number of deaths was significantly higher in patients who stopped taking ICS during the first 3 months from the moment of their discontinuation compared with patients who continued taking them. Thus, the first evidence has been obtained that the use of ICS is associated with a reduced risk of death from asthma.

ICS for COPD
ICS play a crucial role in asthma, but their value in COPD has not yet been sufficiently studied. COPD is defined as a chronic, slowly progressive disease characterized by airway obstruction that does not change over several months. COPD includes a rather heterogeneous group of diseases, such as chronic bronchitis, emphysema, and diseases of the small airways. Functional impairments in COPD, unlike asthma, are fixed and only partially reversible in response to therapy with bronchodilators and other drugs. The prerequisites for the use of ICS in COPD are data on the proven importance of the inflammatory process in the progression of COPD, although in this case the nature of the inflammation is significantly different from inflammation in BA.
The effect of ICS on the progression of COPD
Assessing the effectiveness of therapeutic interventions for COPD, in contrast to that for asthma, includes two more important parameters: patient survival and disease progression. Only two therapeutic interventions have proven beneficial effects on the survival of patients with COPD: smoking cessation and long-term oxygen therapy. The progression of obstructive diseases is usually assessed by the rate of decline in FEV. 1 , in healthy people it is about 25–30 ml/year, and in patients with COPD – 40–80 ml/year. To assess the rate of disease progression, it is necessary to study a large number of patients over a fairly long period (several years).
Over the past 2 years, data from 4 large, double-blind, placebo-controlled, randomized, multicenter studies have been published,devoted to the effectiveness of long-term use of ICS (about 3 years) in patients with COPD, 3 studies were conducted in Europe (EUROSCOP, Copenhagen City Lung Study and ISOLDE) and 1 in the USA (Lung Heath Study II).
The EUROSCOP study included 1277 patients COPD without a previous history of asthma, all patients smoked and had mild to moderate bronchial obstruction (average FEV 1 about 77% of what should be). One group of patients (634 people) received budesonide at a dose of 800 mcg per day in 2 doses for 3 years, the other group (643 patients) received placebo for the same period. During the first 6 months of therapy in the group of patients receiving budesonide, an increase in FEV was observed 1 (17 ml/year) while in the placebo group the rate of decline in FEV 1 was 81 ml/year (p< 0,001). Однако к концу 3-го года терапии скорости снижения ОФВ 1 in both groups there was little difference: FEV 1 in patients taking ICS, it decreased by 140 ml/3 years, and in the placebo group - by 180 ml/3 years (p = 0.05). In addition, an interesting finding was the data that the beneficial effect of budesonide was more pronounced in patients who had less smoking history: in patients with less than 36 pack-years of smoking experience, taking budesonide, FEV 1 decreased over 3 years by 120 ml, and in the placebo group - by 190 ml (p< 0,001), в то время как у больных с большим стажем курения скорость прогрессирования заболевания оказалась сходной в обеих группах (табл. 4).
The Copenhagen City Lung Study included 290 patients with COPD with irreversible bronchial obstruction (increase in FEV 1 response to bronchodilators is less than 5% after a 10-day course of prednisone). The criterion for inclusion of patients was the FEV value 1 /FVC less than 70%, with the average FEV value 1 of patients at the time of inclusion in the study was 86%, and only 39% of patients had FEV 1 < 39%. Активная терапия включала ингаляционный будесонид в дозе 800 мкг утром и 400 мкг вечером в течение 6 мес, и затем по 400 мкг 2 раза в сутки в течение последующих 30 мес. Скорость снижения показателя ОФВ 1 was almost the same in the budesonide and placebo groups: 45.1 ml/year and 41.8 ml/year, respectively (p = 0.7). ICS therapy did not have a significant effect on the severity of respiratory symptoms and the number of exacerbations of the disease (155 and 161 exacerbations).
The ISOLDE study was somewhat different from the previous two: patient recruitment was carried out in respiratory clinics, so it included patients with more severe bronchial obstruction (mean FEV 1 – about 50%), a total of 751 patients aged from 40 to 75 years (average age 63.7 years) took part in the study. All patients received either fluticasone at a dose of 1000 mcg in 2 doses (376 patients) or placebo (375 patients) for 3 years. Annual decline in FEV 1 was similar in the two groups of patients: 50 ml/year in patients receiving ICS and 59 ml/year in patients receiving placebo (p = 0.16). Average FEV value 1 after taking bronchodilators throughout the study was significantly higher (at least 70 ml) in the fluticasone group compared with the placebo group (p< 0,001).
The results of the American study Lung Heath Study II were published recently. This study included 1116 patients with mild to moderate COPD, aged from 40 to 69 years, all patients continued to smoke or quit smoking within the last 2 years. One group of patients (559 people) received inhaled triamcinolone at a dose of 600 mg 2 times a day, the other (557 patients) received placebo. As in European studies, the rate of decline in FEV 1 by the 40th month of observation there was no significant difference: 44.2 ml/year and 47.0 ml/year in the ICS and placebo groups, respectively. In the active therapy group, a decrease in bone tissue density of the vertebrae (p = 0.007) and femur (p< 0,001).
The results of a meta-analysis, also devoted to the study of long-term ICS therapy in patients with COPD, differ from the results of these studies. The meta-analysis included data from three randomized, controlled trials that lasted at least 2 years. The group of patients receiving ICS (beclomethasone 1500 mcg/day, budesonide in doses of 1600 mcg and 800 mcg/day) consisted of 95 patients and the group receiving placebo – 88 patients. Patients included in this study had more severe disease compared with patients in prospective studies (mean FEV 1 = 45%). By the end of the 2nd year, patients in the ICS group compared with the placebo group showed an increase in FEV. 1 by 34 ml/year (p = 0.026). However, in contrast to large large European studies and the Lung Heath Study II, higher doses of ICS (1500/1600 mcg/day) were used in patients analyzed in the meta-analysis, moreover, the analysis showed that when using such high doses, an increase in FEV 1 was 39 ml/year, and when taking budesonide at a dose of 800 mcg/day - only 2 ml/year. Based on these data, it can be assumed that to achieve a significant effect in patients with COPD, higher doses are required compared to patients with asthma with the same values ​​of functional indicators. This need for high doses of ICS may be associated with different types and localization of the inflammatory process in these diseases. In asthma, the main cellular elements of inflammation are eosinophils, and the inflammatory process is more pronounced in the central bronchi, while in COPD, the distal parts of the airways are involved in the inflammation process and neutrophils and lymphocytes play a predominant role.
Effect of ICS on the frequency of exacerbations of COPD
The development of exacerbations in patients with COPD can be a consequence of various factors, which are not always limited to an infectious agent; in some cases, the exacerbation is based on an inflammatory process that is sensitive to steroid therapy. An important aspect of the effectiveness of ICS in COPD may be their ability to reduce the number of exacerbations of the disease.
The objective of a multicenter, randomized, double-blind, placebo-controlled study conducted by P. Piggiaro was to examine whether ICS reduce the number and severity of exacerbations and the severity of clinical symptoms in patients with COPD. A total of 281 patients with COPD were included in the study, 142 patients took fluticasone 500 mcg 2 times a day for 6 months and 139 patients took placebo for the same time. The total number of exacerbations of COPD and the percentage of patients who had one or more exacerbations in 6 months were approximately the same in both groups: 37% in the placebo group and 32% in the ICS group (p< 0,05), однако по числу тяжелых и обострений средней тяжести были значительные изменения в пользу группы ИКС: 86 и 60 % (р < 0,001). По данным исследования, наилучший ответ на ИКС наблюдали у больных, страдающих ХОБЛ более 10 лет. Таким образом, результаты данного исследования свидетельствуют в пользу назначения ИКС больным ХОБЛ.
The reduction in the number of exacerbations of COPD with the use of ICS was also confirmed by data from the ISOLDE study: the number of exacerbations was significantly lower (25%) in patients taking ICS (0.99 per year) compared with patients receiving placebo (1.32 exacerbations per year ); p = 0.026.
Effect of ICS on functional and clinical parameters in patients with COPD
The main method for the effectiveness of drugs in asthma is to assess their effect on functional indicators (FEV 1 , POS, etc.), however, given the irreversibility of bronchial obstruction in COPD, this approach is of little use for evaluating drugs, including ICS, for this disease. In almost all studies conducted on the use of ICS in COPD, with rare exceptions, no significant improvement in parameters was observed functional pulmonary tests.
Many studies have shown that ICS can significantly improve the clinical symptoms of the disease in the absence of significant changes in pulmonary functional parameters. In addition to the parameters of external respiration function, to assess the effectiveness of ICS in patients with COPD, it is proposed to evaluate such indicators as quality of life, functional status (for example, a 6-minute walk test). In the ISOLDE study, the quality of life of patients, assessed by the St. George scale, by the end of the observation period decreased significantly more in the group of patients who did not receive ICS (3.2 points/year versus 2.0 points/year in patients taking fluticasone,
R< 0,0001).
A study by R.Paggiaro et al. also showed that fluticasone resulted in to a significant reduction in the severity of clinical symptoms (cough and sputum volume; p = 0.004 and p = 0.016, respectively), improvement in functional pulmonary parameters (FEV 1 ; R< 0,001, и ФЖЕЛ; р < 0,001) и повышению физической работоспособности (увеличение дистанции пути во время теста с 6-минутной ходьбой: от 409 до 442 м; р = 0,032) . У больных, получавших ингаляционный триамцинолон в рамках исследования Lung Heath Study II, к концу 3-го года терапии по сравнению с больными группы плацебо отмечено reduction in the number of respiratory symptoms by 25% (21.1/100 people/year and 28.2/100 people/year; p = 0.005) and a decrease in the number of visits to the doctor for respiratory diseases by 50% (1.2/100 people /year and 2.1/100 people/year; p = 0.03).
Prospects for the use of ICS in COPD
Thus, these studies showed that in patients with moderate and severe COPD, ICS can improve the clinical symptoms of the disease and quality of life, which is a very important goal of COPD therapy. In addition, ICS can reduce the number of exacerbations of COPD and visits to the doctor regarding the disease. Considering that hospital treatment of patients with COPD accounts for about 75% of the total economic cost of the disease, this effect of ICS in COPD can be considered as one of the most important advances in the treatment of patients with COPD. Another potentially beneficial effect of ICS in COPD, shown in the LHS II study, is improvement in bronchial hyperresponsiveness, which, however, is not associated with any improvement in FEV. 1 , nor with slowing the progression of the disease. Taking into account the data of J. Hospers et al. about the importance of airway hyperresponsiveness as a predictor of mortality in patients with COPD, the effect of ICS on this indicator can also be assessed as a significant clinical task.
So, what is the role of ICS in patients with COPD? Based on the results of 4 large long-term studies, ICS can be recommended for the treatment of patients with moderate and severe COPD who have severe clinical symptoms and frequent exacerbations of the disease, but not for patients with mild COPD. The efficacy and safety of the ICS (fluticasone, budesonide, and triamcinolone) used in these studies were similar, with the exception of a more significant effect of triamcinolone on bone density.

Side effects of ICS
All side effects associated with taking ICS can be divided into local and systemic. Systemic effects develop due to systemic absorption, and local effects develop at the site of drug deposition (see Tables 5 and 6).Literature
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The article discusses factors influencing the degree of effectiveness and safety, features of the pharmacodynamics and pharmacokinetics of modern inhaled glucocorticosteroids, including a new inhaled glucocorticosteroid for the Russian market - ciclesonide.

Bronchial asthma (BA) is a chronic inflammatory disease of the airways, characterized by reversible bronchial obstruction and bronchial hyperresponsiveness. Along with inflammation, and possibly as a result of recovery processes, structural changes are formed in the respiratory tract, which are considered as a process of bronchial remodeling (irreversible transformation), which includes hyperplasia of goblet cells and goblet glands of the submucosal layer, hyperplasia and hypertrophy of smooth muscles, increased vascularization of the submucosal layer layer, collagen accumulation in areas below the basement membrane, and subepithelial fibrosis.

According to international (Global Initiative for Asthma - "Global strategy for the treatment and prevention of bronchial asthma", revision 2011) and national consensus documents, inhaled glucocorticosteroids (ICS), which have an anti-inflammatory effect, are the first-line treatment for moderate and severe bronchial asthma.

Inhaled glucocorticosteroids, with long-term use, improve or normalize lung function, daytime fluctuations in peak expiratory flow decrease, and the need for systemic glucocorticosteroids (GCS) is reduced until their complete abolition. With long-term use of the drugs, antigen-induced bronchospasm and the development of irreversible airway obstruction are prevented, the frequency of exacerbations of the disease, the number of hospitalizations and mortality of patients are reduced.
The mechanism of action of inhaled glucocorticosteroids is aimed at an antiallergic and anti-inflammatory effect; this effect is based on the molecular mechanisms of the two-stage model of action of GCS (genomic and extragenomic effects). The therapeutic effect of glucocorticosteroids (GCS) is associated with their ability to inhibit the formation of pro-inflammatory proteins in cells (cytokines, nitric oxide, phospholipase A2, leukocyte adhesion molecules, etc.) and activate the formation of proteins with an anti-inflammatory effect (lipocortin-1, neutral endopeptidase, etc. ).

The local effect of inhaled glucocorticosteroids (ICS) is manifested by an increase in the number of beta-2 adrenergic receptors on bronchial smooth muscle cells; a decrease in vascular permeability, a decrease in edema and mucus secretion in the bronchi, a decrease in the number of mast cells in the bronchial mucosa and increased apoptosis of eosinophils; decreased release of inflammatory cytokines by T lymphocytes, macrophages and epithelial cells; reduction of hypertrophy of the subepithelial membrane and suppression of tissue specific and nonspecific hyperreactivity. Inhaled corticosteroids inhibit the proliferation of fibroblasts and reduce collagen synthesis, which slows down the rate of development of the sclerotic process in the walls of the bronchi.

Inhaled glucocorticosteroids (ICS), unlike systemic ones, have high selectivity, pronounced anti-inflammatory and minimal mineralocorticoid activity. When administered via inhalation, approximately 10-50% of the nominal dose is deposited in the lungs. The percentage of deposition depends on the properties of the ICS molecule, on the drug delivery system into the respiratory tract (type of inhaler) and on the inhalation technique. Most of the ICS dose is swallowed, absorbed from the gastrointestinal tract (GIT) and rapidly metabolized in the liver, which provides a high therapeutic index for ICS.

Inhaled glucocorticosteroids (ICS) vary in activity and bioavailability, which provides some variability in clinical effectiveness and severity of side effects among different drugs in this group. Modern inhaled glucocorticosteroids (ICS) have high lipophilicity (for better penetration of the cell membrane), a high degree of affinity for the glucocorticoid receptor (GCR), which ensures optimal local anti-inflammatory activity, and low systemic bioavailability, and therefore, a low likelihood of developing systemic effects.

The effectiveness of some drugs varies when different types of inhalers are used. With increasing dose of ICS, the anti-inflammatory effect increases, however, starting from a certain dose, the dose-effect curve takes on the appearance of a plateau, i.e. the effect of treatment does not increase, and the likelihood of developing side effects characteristic of systemic glucocorticosteroids (GCS) increases. The main undesirable metabolic effects of GCS are:

1. stimulating effect on gluconeogenesis (resulting in hyperglycemia and glycosuria);
2. decreased protein synthesis and increased protein breakdown, which is manifested by a negative nitrogen balance (weight loss, muscle weakness, skin and muscle atrophy, stretch marks, hemorrhages, growth retardation in children);
3. redistribution of fat, increased synthesis of fatty acids and triglycerides (hypercholesterolemia);
4. mineralocorticoid activity (leads to an increase in circulating blood volume and an increase in blood pressure);
5. negative calcium balance (osteoporosis);
6. inhibition of the hypothalamic-pituitary system, resulting in decreased production of adrenocorticotropic hormone and cortisol (adrenal insufficiency).

Due to the fact that treatment with inhaled glucocorticosteroids (ICS), as a rule, is long-term (and in some cases permanent) in nature, the concern of doctors and patients regarding the ability of inhaled glucocorticosteroids to cause systemic side effects naturally increases.

Preparations containing inhaled glucocorticosteroids

The following inhaled glucocorticosteroids are registered and approved for use on the territory of the Russian Federation: the drug budesonide (suspension for nebulizer used from 6 months, in the form of a powder inhaler - from 6 years), fluticasone propionate (used from 1 year), beclomethasone dipropionate (used from 6 years ), mometasone furoate (approved in the Russian Federation for children over 12 years of age) and ciclesonide (approved for children over 6 years of age). All drugs have proven effectiveness, however, differences in the chemical structure affect the pharmacodynamic and pharmacokinetic properties of ICS and, consequently, the degree of effectiveness and safety of the drug.

The effectiveness of inhaled glucocorticosteroids (ICS) depends primarily on local activity, which is determined by high affinity (affinity for the glucocorticoid receptor (GCR), high selectivity and duration of persistence in tissues. All known modern ICS have high local glucocorticoid activity, which is determined by the affinity of ICS for GCR (usually in comparison with dexamethasone, whose activity is taken as 100) and modified pharmacokinetic properties.

Cyclesonide (affinity 12) and beclomethasone dipropionate (affinity 53) do not have initial pharmacological activity, and only after inhalation, entering target organs and exposed to esterases, they are converted into their active metabolites - descyclesonide and beclomethasone 17-monopropionate - and become pharmacologically active. The affinity for the glucocorticoid receptor (GCR) is higher for active metabolites (1200 and 1345, respectively).

High lipophilicity and active binding to the respiratory epithelium, as well as the duration of association with GCR, determine the duration of action of the drug. Lipophilicity increases the concentration of inhaled glucocorticosteroids (ICS) in the respiratory tract, slows down their release from tissues, increases affinity and prolongs the connection with GCR, although the optimal lipophilicity of ICS has not yet been determined.

Lipophilicity is most pronounced in ciclesonide, mometasone furoate and fluticasone propionate. Ciclesonide and budesonide are characterized by esterification that occurs intracellularly in lung tissues and the formation of reversible conjugates of descyclesonide and budesonide with fatty acids. The lipophilicity of the conjugates is many tens of times higher than the lipophilicity of intact descyclesonide and budesonide, which determines the duration of the latter’s stay in the tissues of the respiratory tract.

The effects of inhaled glucocorticosteroids on the respiratory tract and their systemic effect depend largely on the inhalation device used. Considering that the processes of inflammation and remodeling occur in all parts of the respiratory tract, including the distal parts and peripheral bronchioles, the question arises about the optimal method of drug delivery to the lungs, regardless of the state of bronchial patency and compliance with inhalation technique. The preferred particle size of the inhaled drug, ensuring its uniform distribution in large and distal bronchi, is 1.0-5.0 microns for adults, and 1.1-3.0 microns for children.

To reduce the number of errors associated with the inhalation technique, leading to a decrease in the effectiveness of treatment and an increase in the frequency and severity of side effects, drug delivery methods are constantly being improved. A metered dose inhaler (MDI) can be used in conjunction with a spacer. The use of a nebulizer can effectively stop exacerbation of bronchial asthma (BA) in an outpatient setting, reducing or eliminating the need for infusion therapy.

According to the international agreement on the preservation of the earth's ozone layer (Montreal, 1987), all manufacturers of inhaled drugs have switched to CFC-free forms of metered-dose aerosol inhalers (MDIs). The new propellant norflurane (hydrofluoroalkane, HFA 134a) has significantly affected the particle size of some inhaled glucocorticosteroids (ICS), in particular ciclesonide: a significant proportion of the drug particles have a size of 1.1 to 2.1 μm (extrafine particles). In this regard, ICS in the form of MDIs with HFA 134a have the highest percentage of pulmonary deposition, for example, 52% for ciclesonide, and its deposition in the peripheral parts of the lungs is 55%.
The safety of inhaled glucocorticosteroids and the likelihood of developing systemic effects are determined by their systemic bioavailability (absorption from the gastrointestinal mucosa and pulmonary absorption), the level of the free fraction of the drug in the blood plasma (binding with plasma proteins) and the level of inactivation of GCS during the initial passage through the liver (presence/absence of active metabolites ).

Inhaled glucocorticosteroids are rapidly absorbed from the gastrointestinal tract and respiratory tract. The absorption of glucocorticosteroids (GCs) from the lungs may be influenced by the size of the inhaled particles, since particles smaller than 0.3 μm are deposited in the alveoli and absorbed into the pulmonary circulation.

When using a metered dose aerosol inhaler (MDI), only 10-20% of the inhaled dose is delivered to the respiratory tract, while up to 90% of the dose is deposited in the oropharyngeal region and swallowed. Next, this part of inhaled glucocorticosteroids (ICS), absorbed from the gastrointestinal tract, enters the hepatic bloodstream, where most of the drug (up to 80% or more) is inactivated. ICS enter the systemic circulation primarily in the form of inactive metabolites. Therefore, systemic oral bioavailability for most inhaled glucocorticosteroids (ciclesonide, mometasone furoate, fluticasone propionate) is very low, almost zero.

It should be borne in mind that part of the dose of ICS (approximately 20% of the nominally taken dose, and in the case of beclomethasone dipropionate (beclomethasone 17-monopropionate) - up to 36%), entering the respiratory tract and quickly absorbed, enters the systemic circulation. Moreover, this portion of the dose may cause extrapulmonary systemic adverse effects, especially when high doses of ICS are prescribed. Of no small importance in this aspect is the type of inhaler used with ICS, since when dry budesonide powder is inhaled through Turbuhaler, the pulmonary deposition of the drug increases by 2 times or more compared with the indicator for inhalation from a MDI.

For inhaled glucocorticosteroids (ICS) with a high fraction of inhaled bioavailability (budesonide, fluticasone propionate, beclomethasone 17-monopropionate), systemic bioavailability may increase in the presence of inflammatory processes in the mucous membrane of the bronchial tree. This was established in a comparative study of systemic effects based on the level of reduction in plasma cortisol after a single use of budesonide and beclomethasone propionate at a dose of 2 mg at 22 hours in healthy smokers and non-smokers. It should be noted that after inhalation of budesonide, cortisol levels in smokers were 28% lower than in non-smokers.

Inhaled glucocorticosteroids (ICS) have a fairly high binding to plasma proteins; for ciclesonide and mometasone furoate this relationship is slightly higher (98-99%) than for fluticasone propionate, budesonide and beclomethasone dipropionate (90, 88 and 87%, respectively). Inhaled glucocorticosteroids (ICS) have rapid clearance, its value is approximately the same as the amount of hepatic blood flow, and this is one of the reasons for minimal manifestations of systemic undesirable effects. On the other hand, rapid clearance provides ICS with a high therapeutic index. The fastest clearance, exceeding the rate of hepatic blood flow, was found in descyclesonide, which determines the high safety profile of the drug.

Thus, we can highlight the main properties of inhaled glucocorticosteroids (ICS), on which their effectiveness and safety primarily depend, especially during long-term therapy:

1. a large proportion of fine particles, ensuring high deposition of the drug in the distal parts of the lungs;
2. high local activity;
3. high lipophilicity or the ability to form fat conjugates;
4. low degree of absorption into the systemic circulation, high binding to plasma proteins and high hepatic clearance to prevent the interaction of GCS with GCR;
5. low mineralocorticoid activity;
6. high compliance and ease of dosing.

Cyclesonide (Alvesco)

Ciclesonide (Alvesco), a non-halogenated inhaled glucocorticosteroid (ICS), is a prodrug and, under the action of esterases in lung tissue, is converted into a pharmacologically active form - descyclesonide. Desciclesonide has 100 times greater affinity for the glucocorticoid receptor (GCR) than ciclesonide.

Reversible conjugation of descyclesonide with highly lipophilic fatty acids ensures the formation of a drug depot in the lung tissue and maintenance of an effective concentration for 24 hours, which allows Alvesco to be used once a day. The active metabolite molecule is characterized by high affinity, rapid association and slow dissociation with the glucocorticoid receptor (GCR).

The presence of norflurane (HFA 134a) as a propellant ensures a significant proportion of extra-fine particles of the drug (size from 1.1 to 2.1 microns) and high deposition of the active substance in the small respiratory tract. Considering that the processes of inflammation and remodeling occur in all parts of the respiratory tract, including the distal parts and peripheral bronchioles, the question arises about the optimal method of drug delivery to the lungs, regardless of the state of bronchial patency.

In a study by T.W. de Vries et al. Using laser diffraction analysis and the method of different inspiratory flows, the delivered dose and particle size of various inhaled glucocorticosteroids ICS were compared: fluticasone propionate 125 μg, budesonide 200 μg, beclomethasone (HFA) 100 μg and ciclesonide 160 μg.

The average aerodynamic particle size of budesonide was 3.5 µm, fluticasone propionate - 2.8 µm, beclomethasone and ciclesonide - 1.9 µm. Ambient air humidity and inspiratory flow rate did not have a significant effect on particle size. Ciclesonide and beclomethasone (BFA) had the largest fraction of fine particles ranging in size from 1.1 to 3.1 μm.

Due to the fact that ciclesonide is an inactive metabolite, its oral bioavailability tends to zero, and this also makes it possible to avoid such local undesirable effects as oropharyngeal candidiasis and dysphonia, which has been demonstrated in a number of studies.

Ciclesonide and its active metabolite descyclesonide, when released into the systemic circulation, are almost completely bound to plasma proteins (98-99%). In the liver, descyclesonide is inactivated by the enzyme CYP3A4 of the cytochrome P450 system to hydroxylated inactive metabolites. Ciclesonide and descyclesonide have the fastest clearance among inhaled glucocorticosteroids (ICS) (152 and 228 l/h, respectively), its value significantly exceeds the rate of hepatic blood flow and provides a high safety profile.

The safety issues of inhaled glucocorticosteroids (ICS) are most relevant in pediatric practice. A number of international studies have established high clinical efficacy and a good safety profile of ciclesonide. Two identical multicenter, double-blind, placebo-controlled studies examining the safety and efficacy of Alvesco (ciclesonide) included 1,031 children aged 4–11 years. The use of ciclesonide 40, 80 or 160 mcg once a day for 12 weeks did not suppress the function of the hypothalamic-pituitary-adrenal axis and change the level of cortisol in 24-hour urine (compared to placebo). In another study, treatment with ciclesonide for 6 months did not result in a statistically significant difference in linear growth rate in children in the active treatment group and the placebo group.

The extrafine particle size, high pulmonary deposition of ciclesonide and maintenance of effective concentration for 24 hours, on the one hand, low oral bioavailability, low level of the free fraction of the drug in the blood plasma and rapid clearance, on the other, provide a high therapeutic index and a good safety profile of Alvesco. The duration of ciclesonide persistence in tissues determines its high duration of action and the possibility of single use per day, which significantly increases the patient’s compliance with this drug.

© Oksana Kurbacheva, Ksenia Pavlova

Hydrocortisone (Hydrocortisone, Cortef, Laticort, Oxycort).

Dexamethasone (Ambene, Dex-Gentamicin, Maxidex, Maxitrol, Polidexa, Tobradex).

Methylprednisolone (Advantan, Metypred, Solu-Medrol).

Mometasone furoate (Momat, Nasonex, Elokom).

Prednisolone (Aurobin, Dermosolone, Prednisolone).

Triamcinolone acetonide (Kenalog, Polcortolone, Fluorocort).

Fluticasone propionate (Flixonase, Flixotide).

Flucortolone (Ultraproct).

• Mechanism of action

  Glucocorticosteroids penetrate into the cell cytoplasm by diffusion and interact with intracellular steroid receptors.

  Inactive glucocorticosteroid receptors are hetero-oligomeric complexes, which, in addition to the receptor itself, include heat shock proteins, various types of RNA and other structures.

  The C-terminus of steroid receptors is associated with a large protein complex that includes two subunits of the hsp90 protein. After the glucocorticosteroid interacts with the receptor, hsp90 is cleaved off, and the resulting hormone-receptor complex moves into the nucleus, where it acts on certain sections of DNA.

  Hormone-receptor complexes also interact with various transcription factors or nuclear factors. Nuclear factors (eg, activated transcription factor protein) are natural regulators of several genes involved in the immune response and inflammation, including genes for cytokines, their receptors, adhesion molecules, and proteins.

  By stimulating steroid receptors, glucocorticosteroids induce the synthesis of a special class of proteins - lipocortins, including lipomodulin, which inhibits the activity of phospholipase A 2.

  The main effects of glucocorticosteroids.
  

  Glucocorticosteroids, due to their multilateral influence on metabolism, mediate the body’s adaptation to stressors from the external environment.

  Glucocorticosteroids have anti-inflammatory, desensitizing, immunosuppressive, antishock and antitoxic effects.

  The anti-inflammatory effect of glucocorticosteroids is due to the stabilization of cell membranes, suppression of the activity of phospholipase A 2 and hyaluronidase, inhibition of the release of arachidonic acid from phospholipids of cell membranes (with a decrease in the levels of its metabolic products - prostaglandins, thromboxane, leukotrienes), as well as inhibition of the processes of degranulation of mast cells (with the release of histamine , serotonin, bradykinin), synthesis of platelet activating factor and connective tissue proliferation.

  The immunosuppressive activity of glucocorticosteroids is the total result of suppression of various stages of immunogenesis: migration of stem cells and B-lymphocytes, interaction of T- and B-lymphocytes.

  The antishock and antitoxic effect of glucocorticosteroids is explained mainly by an increase in blood pressure (due to an increase in the concentration of catecholamines circulating in the blood, restoration of the sensitivity of adrenoreceptors to them, as well as vasoconstriction), a decrease in vascular permeability and activation of liver enzymes involved in the biotransformation of endo- and xenobiotics.

  Glucocorticosteroids activate hepatic gluconeogenesis and enhance protein catabolism, thereby stimulating the release of amino acids - substrates of gluconeogenesis from peripheral tissues. These processes lead to the development of hyperglycemia.

  Glucocorticosteroids enhance the lipolytic effect of catecholamines and growth hormone, and also reduce the consumption and utilization of glucose by adipose tissue. Excessive amounts of glucocorticosteroids lead to stimulation of lipolysis in some parts of the body (extremities) and lipogenesis in others (face and torso), as well as an increase in the level of free fatty acids in plasma.

  Glucocorticosteroids have an anabolic effect on protein metabolism in the liver and a catabolic effect on protein metabolism in muscles, adipose and lymphoid tissues, skin, and bones. They inhibit the growth and division of fibroblasts and the formation of collagen.

  In the hypothalamus-pituitary-adrenal system, glucocorticosteroids suppress the formation of corticotropin-releasing hormone and adrenocorticotropic hormone.

  The biological effects of glucocorticosteroids persist for a long time.

  
  By duration of action highlight:
  • Short-acting glucocorticosteroids (hydrocortisone).
  • Medium-acting glucocorticosteroids (methylprednisolone, prednisolone).
  • Long-acting glucocorticosteroids (betamethasone, dexamethasone, triamcinolone acetonide).

• Pharmacokinetics By method of administration distinguish:
  • Oral glucocorticosteroids.
  • Inhaled glucocorticosteroids.
  • Intranasal glucocorticosteroids.
  Oral glucocorticosteroids.
  

  When taken orally, glucocorticosteroids are well absorbed from the gastrointestinal tract and actively bind to plasma proteins (albumin, transcortin).

  The maximum concentration of drugs in the blood is reached after about 1.5 hours. Glucocorticosteroids undergo biotransformation in the liver, partially in the kidneys and in other tissues, mainly by conjugation with glucuronide or sulfate.

  About 70% of conjugated glucocorticosteroids are excreted in the urine, 20% in feces, and the remainder through the skin and other biological fluids.

  The half-life of oral glucocorticosteroids averages 2-4 hours.

  
  Some pharmacokinetic parameters of glucocorticosteroids

  A drug	Plasma half-life, h	Tissue half-life, h
  Hydrocortisone	0,5-1,5	8-12
  Cortisone	0,7-2	8-12
  Prednisolone	2-4	18-36
  Methylprednisolone	2-4	18-36
  Fludrocortisone	3,5	18-36
  Dexamethasone	5	36-54

  
  Inhaled glucocorticosteroids.
  

  Currently, beclomethasone dipropionate, budesonide, mometasone furoate, flunisolide, fluticasone propionate and triamcinolone acetonide are used in clinical practice.

  
  Pharmacokinetic parameters of inhaled glucocorticosteroids

  Drugs	Bioavailability, %	First pass effect through the liver, %	Half-life from blood plasma, h	Volume of distribution, l/kg	Local anti-inflammatory activity, units
  Beclomethasone dipropionate	25	70	0,5	-	0,64
  Budesonide	26-38	90	1,7-3,4 (2,8)	4,3	1
  Triamcinolone acetonide	22	80-90	1,4-2 (1,5)	1,2	0,27
  Fluticasone propionate	16-30	99	3,1	3,7	1
  Flunisolide	30-40		1,6	1,8	0,34

  
  Intranasal glucocorticosteroids.
  

  Currently, beclomethasone dipropionate, budesonide, mometasone furoate, triamcinolone acetonide, flunisolide, and fluticasone propionate are used in clinical practice for intranasal use.

  After intranasal administration of glucocorticosteroids, part of the dose that settles in the pharynx is swallowed and absorbed in the intestine, while part enters the blood from the mucous membrane of the respiratory tract.

  Glucocorticosteroids entering the gastrointestinal tract after intranasal administration are absorbed by 1-8% and are almost completely biotransformed to inactive metabolites during the first passage through the liver.

  That part of the glucocorticosteroids that is absorbed from the mucous membrane of the respiratory tract is hydrolyzed to inactive substances.

  Bioavailability of glucocorticosteroids after intranasal administration

  A drug	Bioavailability when absorbed from the gastrointestinal tract,%	Bioavailability when absorbed from the mucous membrane of the respiratory tract, %
  Beclomethasone dipropionate	20-25	44
  Budesonide	11	34
  Triamcinolone acetonide	10,6-23	No data
  Mometasone furoate
  Flunisolide	21	40-50
  Fluticasone propionate		0,5-2

• Place in therapy Indications for the use of oral glucocorticosteroids.
  • Replacement therapy for primary adrenal insufficiency.
  • Replacement therapy for secondary chronic adrenal insufficiency.
  • Acute adrenal insufficiency.
  • Congenital dysfunction of the adrenal cortex.
  • Subacute thyroiditis.
  • Bronchial asthma.
  • Chronic obstructive pulmonary disease (in the acute phase).
  • Severe pneumonia.
  • Acute respiratory distress syndrome.
  • Interstitial lung diseases.
  • Nonspecific ulcerative colitis.
  • Crohn's disease.
  Indications for the use of intranasal glucocorticoids.
  • Seasonal (intermittent) allergic rhinitis.
  • Perennial (persistent) allergic rhinitis.
  • Nasal polyposis.
  • Non-allergic rhinitis with eosinophilia.
  • Idiopathic (vasomotor) rhinitis.

  Inhaled glucocorticosteroids used to treat bronchial asthma, chronic obstructive pulmonary disease.

• Contraindications Glucocorticosteroids are prescribed with caution in the following clinical situations:
  • Itsenko-Cushing's disease.
  • Diabetes.
  • Peptic ulcer of the stomach or duodenum.
  • Thromboembolism.
  • Arterial hypertension.
  • Severe renal failure.
  • Mental illnesses with productive symptoms.
  • Systemic mycoses.
  • Herpetic infection.
  • Tuberculosis (active form).
  • Syphilis.
  • Vaccination period.
  • Purulent infections.
  • Viral or fungal eye diseases.
  • Diseases of the cornea combined with epithelial defects.
  • Glaucoma.
  • Lactation period.
  Intranasal administration of glucocorticoids is contraindicated in the following cases:
  • Hypersensitivity.
  • Hemorrhagic diathesis.
  • History of repeated nosebleeds.

• Side effects Systemic side effects of glucocorticosteroids:
  • From the side of the central nervous system:
    • Increased nervous excitability.
    • Insomnia.
    • Euphoria.
    • Depression.
    • Psychoses.
  • From the cardiovascular system:
    • Myocardial dystrophy.
    • Increased blood pressure.
    • Deep vein thrombosis.
    • Thromboembolism.
  • From the digestive system:
    • Steroid ulcers of the stomach and intestines.
    • Bleeding from the gastrointestinal tract.
    • Pancreatitis.
    • Fatty liver degeneration.
  • From the senses:
    • Posterior subcapsular cataract.
    • Glaucoma.
  • From the endocrine system:
    • Depression of function and atrophy of the adrenal cortex.
    • Diabetes.
    • Obesity.
    • Cushing's syndrome.
  • From the skin:
    • Thinning of the skin.
    • Striae.
    • Alopecia.
  • From the musculoskeletal system:
    • Osteoporosis.
    • Fractures and aseptic necrosis of bones.
    • Growth retardation in children.
    • Myopathy.
    • Muscle wasting.
  • From the reproductive system:
    • Menstrual irregularities.
    • Sexual dysfunctions.
    • Delayed sexual development.
    • Hirsutism.
  • From the laboratory parameters:
    • Hypokalemia.
    • Hyperglycemia.
    • Hyperlipidemia.
    • Hypercholesterolemia.
    • Neutrophilic leukocytosis.
  • Other:
    • Sodium and water retention.
    • Edema.
    • Exacerbation of chronic infectious and inflammatory processes.
  Local side effects.
  Inhaled glucocorticosteroids:
  • Candidiasis of the oral cavity and pharynx.
  • Dysphonia.
  • Cough.
  Intranasal glucocorticosteroids:
  • Itchy nose.
  • Sneezing.
  • Dryness and burning of the nasal mucosa and pharynx.
  • Nosebleeds.
  • Perforation of the nasal septum.

• Precautionary measures

  In patients with hypothyroidism, liver cirrhosis, hypoalbuminemia, as well as in elderly and senile patients, the effect of glucocorticosteroids may be enhanced.

  When prescribing glucocorticosteroids during pregnancy, the expected therapeutic effect for the mother and the risk of negative effects on the fetus must be taken into account, since the use of these drugs can lead to impaired fetal growth, some developmental defects (cleft palate), atrophy of the adrenal cortex in the fetus (in the third trimester pregnancy).

  In children and adults taking glucocorticosteroids, infectious diseases such as measles and chicken pox can be severe.

  Live vaccines are contraindicated in patients taking immunosuppressive doses of glucocorticosteroids.

  Osteoporosis develops in 30-50% of patients who take systemic glucocorticosteroids (oral or injectable dosage forms) for a long time. As a rule, the spine, pelvic bones, ribs, hands, and feet are affected.

  Steroid ulcers during treatment with glucocorticosteroids can be mild or asymptomatic, manifesting with bleeding and perforation. Therefore, patients receiving oral glucocorticosteroids for a long time should periodically undergo fibroesophagogastroduodenoscopy and fecal occult blood testing.

  In various inflammatory or autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus and bowel diseases), cases of steroid resistance may occur.

Catad_tema Bronchial asthma and COPD - articles

Catad_tema Pediatrics - articles

L.D. Goryachkina, N.I. Ilyina, L.S. Namazova, L.M. Ogorodova, I.V. Sidorenko, G.I. Smirnova, B.A. Chernyak

The main goal of treating patients with bronchial asthma is to achieve and long-term maintenance of disease control. Treatment should begin with an assessment of current asthma control, and the amount of therapy should be reviewed regularly to ensure that control is achieved.

Treatment of bronchial asthma (BA) includes:

1. Elimination measures aimed at reducing or eliminating exposure to causative allergens ().
2. Pharmacotherapy.
3. Allergen-specific immunotherapy (ASIT).
4. Patient education.

PHARMACOTHERAPY

For the treatment of asthma in children, drugs are used that can be divided into two large groups:

1. Means of basic (supportive, anti-inflammatory) therapy.
2. Symptomatic remedies.

TO basic therapy drugs relate:

• drugs with anti-inflammatory and/or prophylactic effects (glucocorticosteroids (GCS), antileukotriene drugs, cromones, anti-IgE drugs);
• long-acting bronchodilators (long-acting β 2 -agonists, slow-release theophylline preparations).

The greatest clinical and pathogenetic effectiveness is shown with the use of inhaled corticosteroids (ICS). All basic anti-inflammatory therapy is taken daily and for a long time. The principle of regular use of basic drugs allows one to achieve control over the disease. It should be noted that in our country, for the basic therapy of BA in children using combination drugs containing ICS (with a 12-hour break), only a stable dosage regimen is registered. Other regimens for the use of combination drugs in children are not permitted.

TO symptomatic remedies relate:

• inhaled short-acting β 2 -adrenergic agonists;
• anticholinergic drugs;
• immediate release theophylline preparations;
• oral short-acting β 2 -adrenergic agonists.

Symptomatic drugs are also called “first aid” drugs. They must be used to eliminate bronchial obstruction and its accompanying acute symptoms (wheezing, chest tightness, cough). This mode of drug use is called “on demand”.

ROUTES OF DRUG DELIVERY

Drugs for the treatment of asthma are administered in various ways: oral, parenteral and inhalation (the latter is preferred). When choosing a device for inhalation, the efficiency of drug delivery, cost/effectiveness, ease of use and patient age are taken into account (Table 1). Three types of devices are used for inhalation in children: nebulizers, metered-dose inhalers (MDIs), and powder inhalers.

Table 1. Drug delivery vehicles for asthma (age priorities)

Means	Recommended age group	Comments
Metered aerosol inhaler (MDI)	> 5 years	It is difficult to coordinate the moment of inhalation and pressing the valve of the can (especially for children). About 80% of the dose is deposited in the oropharynx, it is necessary to rinse the mouth after each inhalation in order to reduce systemic absorption
Inhalation activated pMDI	> 5 years	The use of this delivery device is indicated for patients who are unable to coordinate the moment of inhalation and pressing the valve of conventional MDIs. Cannot be used with any of the existing spacers, except for the “optimizer” for this type of inhaler
Powder inhaler (PI)	≥ 5 years	With the correct technique of use, the effectiveness of inhalation can be higher than when using a MDI. It is necessary to rinse the mouth after each use
Spacer	> 4 years < 4 лет при application face mask	The use of a spacer reduces the deposition of the drug in the oropharynx, allows the use of pMDIs with greater efficiency; if a mask is available (complete with a spacer), it can be used in children under 4 years of age
Nebulizer	< 2 лет (patients of any ages that cannot use spacer or spacer/facial mask)	The optimal means of drug delivery for use in specialized departments and intensive care units, as well as in emergency care, as it requires the least effort from the patient and doctor

ANTI-INFLAMMATORY (BASIC) DRUGS

I. Inhaled glucocorticosteroids and combination drugs containing ICS

Currently, ICS are the most effective drugs for the control of BA, therefore they are recommended for the treatment of persistent BA of any severity A. In school-age children suffering from BA, maintenance therapy with ICS helps control the symptoms of BA, reduces the frequency of exacerbations and the number of hospitalizations, and improves the quality of life , improves external respiratory function, reduces bronchial hyperreactivity and reduces bronchoconstriction during physical activity A. The use of ICS in preschool children suffering from asthma leads to a clinically significant improvement in the condition, including a score of daytime and nighttime cough, wheezing and shortness of breath, physical activity, use of emergency medications and use of health system resources.

The following ICS are used in children: beclomethasone, fluticasone, budesonide. Doses of drugs used for basic therapy are divided into low, medium and high. Taking ICS in low doses is safe; when prescribing higher doses, it is necessary to remember the possibility of side effects. The equipotent doses presented in Table 2 were developed empirically, therefore, when choosing and changing ICS, the individual characteristics of the patient (response to therapy) should be taken into account.

Table 2. Equipotent daily doses of ICS

A drug*	Low daily allowance doses (mcg)	Average daily allowance doses (mcg)	High daily allowance doses (mcg)
Doses for children under 12 years of age
Beclomethasone dipropionate	100–200	> 200–400	> 400
Budesonide	100–200	> 200–400	> 400
Fluticasone	100–200	> 200–500	> 500
Doses for children over 12 years of age
Beclomethasone dipropionate	200–500	> 500–1000	> 1000–2000
Budesonide	200–400	> 400–800	> 800–1600
Fluticasone	100–250	> 250–500	> 500–1000

*Drug comparisons are based on comparative effectiveness data.

ICS are included in combination drugs for the treatment of asthma. Such drugs are Seretide (salmeterol + fluticasone propionate) and Symbicort (formoterol + budesonide). A large number of clinical studies have shown that the combination of long-acting β2-agonists and low-dose ICS is more effective than increasing the dose of the latter. Combination therapy with salmeterol + fluticasone (in one inhaler) promotes better asthma control than a long-acting β 2 -adrenergic agonist and ICS in separate inhalers. With long-term therapy with salmeterol + fluticasone, complete asthma control can be achieved in almost every second patient (according to a study that included patients aged 12 years and older). There is also a significant improvement in treatment effectiveness indicators (PSF, FEV1, exacerbation frequency, quality of life). If the use of low doses of ICS in children does not allow achieving control of BA, it is recommended to switch to combination therapy, which can be a good alternative to increasing the dose of ICS. This was shown in a new prospective, multicenter, double-blind, randomized, parallel-group study lasting 12 weeks, which compared the effectiveness of the combination of salmeterol + fluticasone (at a dose of 50/100 mcg twice a day) and a 2-fold higher dose of fluticasone propionate (200 mcg 2 times a day) in 303 children 4–11 years old with persistent asthma symptoms despite previous therapy with low doses of ICS. It turned out that regular use of the combination salmeterol + fluticasone (Seretide) prevents symptoms and achieves asthma control as effectively as twice the dose of ICS. Treatment with Seretide is accompanied by a more pronounced improvement in lung function and a decrease in the need for drugs to relieve asthma symptoms with good tolerability: in the Seretide group, the increase in morning PEF is 46% higher, and the number of children with a complete absence of need for “rescue therapy” is 53% more than in the fluticasone group. Therapy using a combination of formoterol + budesonide as part of a single inhaler provides better control of asthma symptoms compared with budesonide alone in patients for whom ICS previously did not provide symptom control.

Impact of ICS on growth

Uncontrolled or severe asthma slows children's growth and reduces overall height. None of the long-term controlled studies have shown any statistically or clinically significant effect on growth of ICG therapy at a dose of 100-200 mcg/day. A slowdown in linear growth is possible with long-term administration of any ICS at a high dose. However, children with asthma treated with ICS achieve normal growth, although sometimes later than other children.

Effect of ICS on bone tissue

No studies have shown a statistically significant increase in the risk of bone fractures in children receiving ICS.

Effect of ICS on the hypothalamic-pituitary-adrenal system

ICS therapy dose ICS and oral candidiasis

Clinically significant thrush is rare and is probably associated with concomitant antibiotic therapy, the use of high doses of inhaled corticosteroids and a high frequency of inhalations. The use of spacers and mouth rinsing reduces the incidence of candidiasis.

Other side effects

Against the background of regular basic anti-inflammatory therapy, there was no increase in the risk of cataracts and tuberculosis.

II. Leukotriene receptor antagonists

Antileukotriene drugs (zafirlukast, montelukast) provide partial protection against exercise-induced bronchospasm for several hours after administration. The addition of antileukotriene drugs to treatment in case of insufficient effectiveness of low doses of ICS provides moderate clinical improvement, including a statistically significant reduction in the frequency of exacerbations. The clinical effectiveness of therapy with antileukotriene drugs has been shown in children aged > 5 years at all degrees of asthma severity, but these drugs are usually inferior in effectiveness to low-dose ICS. Antileukotriene drugs can be used to enhance therapy in children with moderate asthma in cases where the disease is not sufficiently controlled by low doses of ICS. When leukotriene receptor antagonists are used as monotherapy in patients with severe and moderate asthma, moderate improvements in pulmonary function (in children 6 years and older) and asthma control (in children 2 years and older) are noted B. Zafirlukast is moderately effective on respiratory function in children 12 years of age and older with moderate to severe BA A.

III. Cromony

Nedocromil and cromoglycic acid are less effective than ICS in relation to clinical symptoms, respiratory function, exercise asthma, and airway hyperresponsiveness. Long-term therapy with cromoglycic acid for asthma in children does not differ significantly in effectiveness from placebo A. Nedocromil, prescribed before physical activity, can reduce the severity and duration of bronchoconstriction caused by it. Cromones are contraindicated during exacerbation of asthma, when intensive therapy with fast-acting bronchodilators is required. The role of cromones in the basic treatment of asthma in children (especially preschoolers) is limited due to the lack of evidence of their effectiveness. A meta-analysis conducted in 2000 did not allow us to draw an unambiguous conclusion about the effectiveness of cromoglycic acid as a means of basic therapy for BA in children B. It should be remembered that drugs in this group cannot be used for initial therapy of moderate and severe asthma. The use of cromones as basic therapy is possible in patients with complete control of asthma symptoms. Cromones should not be combined with long-acting β2-agonists, since the use of these drugs without ICS increases the risk of death from asthma.

IV. Anti-IgE drugs

This is a fundamentally new class of drugs used today to improve control of severe persistent atopic asthma. Omalizumab is the most studied, first and only drug recommended for use in children over 12 years of age. The high cost of treatment with omalizumab, as well as the need for monthly visits to the doctor for injection administration of the drug, are justified in patients requiring repeated hospitalizations, emergency medical care, and using high doses of inhaled and/or systemic corticosteroids.

V. Long-acting methylxanthines

Theophylline is significantly more effective than placebo in controlling asthma and improving lung function, even at doses below the generally recommended therapeutic rangeA. However, the use of theophyllines for the treatment of asthma in children is problematic due to the possibility of severe immediate (cardiac arrhythmia, death) and delayed (behavioral disorders, learning problems) side effects. Therefore, the use of theophyllines is possible only under strict pharmacodynamic control.

VI. Long-acting β 2 -agonists Long-acting inhaled β 2 -adrenergic agonists

Drugs in this group are effective in maintaining asthma control (Fig. 1). On an ongoing basis, they are used only in combination with ICS and are prescribed only when standard initial doses of ICS do not allow BA control to be achieved. The effect of these drugs lasts for 12 hours. Formoterol in the form of inhalation exerts its therapeutic effect (relaxation of bronchial smooth muscles) within 3 minutes, the maximum effect develops 30–60 minutes after inhalation. Salmeterol begins to act relatively slowly, a significant effect is noted 10–20 minutes after inhalation of a single dose (50 mcg), and an effect comparable to that after taking salbutamol develops after 30 minutes. Due to its slow onset of action, salmeterol should not be prescribed for the relief of acute asthma symptoms. Since the effect of formoterol develops faster than the effect of salmeterol, this allows formoterol to be used not only for prevention, but also for the relief of asthma symptoms. However, according to the GINA 2006 recommendations, long-acting β 2 -agonists can only be used in patients already receiving regular maintenance therapy with ICS.

Figure 1. Classification of β2-agonists

Children tolerate treatment with long-acting inhaled β 2 -agonists well, even with prolonged use, and their side effects are comparable to those of short-acting β 2 -agonists (if used on demand). Drugs in this group should be prescribed only in conjunction with basic ICS therapy, since monotherapy with long-acting β 2 -adrenergic agonists without ICS increases the likelihood of death in patients! Due to conflicting data on the effect on asthma exacerbations, these drugs are not the drugs of choice for patients requiring two or more maintenance therapies.

Long-acting oral β2-agonists

Drugs in this group include long-acting dosage forms of salbutamol. These drugs may help control nocturnal asthma symptoms. They can be used in addition to ICS if the latter at standard doses do not provide sufficient control of nighttime symptoms. Possible side effects include cardiovascular stimulation, anxiety, and tremors. In our country, drugs of this group are rarely used in pediatrics.

VII. Anticholinergic drugs

Inhaled anticholinergic drugs are not recommended for long-term use (basic therapy) in children with asthma.

VIII. System GCS

Despite the fact that systemic corticosteroids are effective against asthma, it is necessary to take into account the development of adverse effects during long-term therapy, such as suppression of the hypothalamic-pituitary-adrenal axis, weight gain, steroid diabetes, cataracts, hypertension, growth retardation, immunosuppression, osteoporosis, mental disorders . Given the risk of side effects with long-term use, oral corticosteroids should be used in children with asthma only in cases of severe exacerbations, both with or without a viral infection.

EMERGENCY THERAPY DRUGS

Inhaled fast-acting β 2 -adrenergic agonists (short-acting β 2 -agonists) are the most effective of the existing bronchodilators; they are the drugs of choice for the treatment of acute bronchospasm A (Fig. 1). This group of drugs includes salbutamol, fenoterol and terbutaline (Table 3).

Table 3. Emergency medications for asthma

A drug	Dose	Side effects	Comments
β 2 -adrenergic agonists
Salbutamol (MDI)	1 dose – 100 mcg 1–2 inhalations up to 4 times a day	Tachycardia, tremor, headache, irritability	Recommended only in on-demand mode
Salbutamol (solution for nebulizer therapy)	2.5 mg/2.5 ml
Fenoterol (MDI)	1 dose – 100 mcg 1–2 inhalations up to 4 times a day
Fenoterol (solution for nebulizer therapy)	1 mg/ml
Anticholinergic drugs
Ipratropium bromide (IAI) from 4 years	1 dose – 20 mcg 2-3 inhalations up to 4 times a day	Minor dryness and unpleasant taste in mouth	Mostly used in children up to 2 years
Ipratropium bromide (solution for nebulizer therapy)	250 µg/ml
Combination drugs
Fenoterol + ipratropium bromide (MDI)	2 inhalations up to 4 times a day	Tachycardia, tremor, headache, irritability, slight dryness and unpleasant taste in the mouth	Characteristic side effects effects indicated for each of the incoming as part of the combination funds
Fenoterol + ipratropium bromide (solution for nebulizer therapy)	1–2 ml
Short acting theophylline
Eufillin in any dosage form	150 mg > 3 years 12–24 mg/kg/day	Nausea, vomiting, headache, tachycardia, violations heart rate	Currently Usage aminophylline in children for relief of symptoms BA is not justified

Anticholinergics have a limited role in the treatment of asthma in children. A meta-analysis of studies of ipratropium bromide in combination with β 2 -agonists for exacerbation of asthma showed that the use of an anticholinergic drug is accompanied by a statistically significant (albeit moderate) improvement in pulmonary function and a reduced risk of hospitalization.

ACHIEVEMENT OF ASTHMA CONTROL

During treatment, ongoing assessment and adjustment of therapy should be carried out based on changes in the level of asthma control. The entire treatment cycle includes:

• assessment of the level of asthma control;
• treatment aimed at achieving control;
• treatment to maintain control.

Assessment of the level of asthma control

Asthma control is a complex concept that includes a combination of the following indicators:

• minimal or absent (≤ 2 episodes per week) daytime asthma symptoms;
• no restrictions in daily activity and physical activity;
• absence of nighttime symptoms and awakenings due to asthma;
• minimal or no need (≤ 2 episodes per week) for short-acting bronchodilators;
• normal or almost normal pulmonary function tests;
• no exacerbations of asthma.

According to GINA 2006, there are three levels of asthma control: controlled, partially controlled and uncontrolled asthma. Currently, several tools have been developed for integral assessment of the level of control over asthma. One of these tools is the Childhood Asthma Control Test for children aged 4–11 years - a validated questionnaire that allows the doctor and the patient (parent) to quickly assess the severity of asthma manifestations and the need to increase the volume of therapy. The test consists of 7 questions, with questions 1–4 for the child (4-point rating scale: 0 to 3 points), and questions 5–7 for parents (6-point scale: 0 to 5 points). The test result is the sum of marks for all answers in points (maximum score – 27 points). A score of 20 points and above corresponds to controlled asthma, 19 points and below means that asthma is not controlled effectively; the patient is advised to seek the help of a doctor to review the treatment plan. In this case, it is also necessary to ask the child and his parents about medications for daily use to ensure the correct inhalation technique and compliance with the treatment regimen. Testing for asthma control can be done on the website www.astmatest.ru.

Treatment to maintain control

The choice of drug therapy depends on the patient's current level of asthma control and current therapy. Thus, if current therapy does not provide control of asthma, it is necessary to increase the volume of therapy (move to a higher level) until control is achieved. If asthma control is maintained for 3 months or more, it is possible to reduce the volume of maintenance therapy in order to achieve the minimum volume of therapy and the lowest doses of drugs sufficient to maintain control. If partial control of asthma is achieved, the possibility of increasing the volume of therapy should be considered, taking into account the availability of more effective treatment approaches (i.e., the possibility of increasing doses or adding other drugs), their safety, cost, and patient satisfaction with the level of control achieved.

Most drugs for the treatment of asthma have favorable benefit/risk profiles compared to drugs for the treatment of other chronic diseases. Each stage includes treatment options that can serve as alternatives when choosing maintenance therapy for asthma, although they are not the same in effectiveness. The volume of therapy increases from step 2 to step 5; although at stage 5 the choice of treatment also depends on the availability and safety of drugs. In most patients with symptoms of persistent asthma who have not previously received maintenance therapy, treatment should begin at step 2. If asthma symptoms at the initial examination are extremely severe and indicate a lack of control, treatment should begin at step 3 (Table 4). At each stage of therapy, patients should use drugs to quickly relieve asthma symptoms (fast-acting bronchodilators). However, regular use of medications to relieve symptoms is one of the signs of uncontrolled asthma, indicating the need to increase maintenance therapy. Therefore, reducing or eliminating the need for rescue medications is an important goal of treatment and a criterion for the effectiveness of therapy.

Table 4. Correspondence of stages of therapy to clinical characteristics of asthma

Stages of therapy	Clinical characteristics of patients
Stage 1	Short-term (up to several hours) symptoms of asthma during the day (cough, wheezing, shortness of breath occurring ≤ 2 times a week or even more rare nighttime symptoms). During the interictal period, there are no manifestations of asthma or night awakenings, lung function is within normal limits. PEF ≥ 80% of the required values
Stage 2	Asthma symptoms occur more often than once a week, but less than once a day. Exacerbations can disrupt patients' activity and nighttime sleep. Nighttime symptoms more often than 2 times a month. Functional indicators of external respiration within the age norm. During the interictal period, there are no manifestations of asthma or night awakenings, and exercise tolerance is not reduced. PEF ≥ 80% of the required values
Stage 3	Symptoms of asthma are observed daily. Exacerbations disrupt the child’s physical activity and nighttime sleep. Nighttime symptoms more often than once a week. In the interictal period, episodic symptoms are observed, and changes in the function of external respiration persist. Exercise tolerance may be reduced. PSV 60–80% of proper values
Stage 4	Frequent (several times a week or daily, several times a day) appearance of asthma symptoms, frequent night attacks of breathlessness. Frequent exacerbations of the disease (once every 1–2 months). Limitation of physical activity and severe dysfunction of external respiration. During the period of remission, clinical and functional manifestations of bronchial obstruction persist. PSV ≤ 60% of the required values
Level 5	Daily day and night symptoms, several times a day. Marked limitation of physical activity. Severe pulmonary dysfunction. Frequent exacerbations (once a month or more often). During the period of remission, pronounced clinical and functional manifestations of bronchial obstruction persist. PSV< 60% от должных значений

Stage 1, which involves the use of drugs to relieve symptoms as needed, is intended only for patients who have not received maintenance therapy. If symptoms occur more frequently or if symptoms worsen intermittently, patients are advised to receive regular maintenance therapy (in addition to medications to relieve symptoms as needed.

Stages 2–5 include a combination of a drug to relieve symptoms (as needed) with regular maintenance therapy. Low-dose inhaled corticosteroids are recommended as initial maintenance therapy for asthma in patients of any age at stage 2. Alternatives include inhaled anticholinergics, short-acting oral β2-agonists, or short-acting theophylline. However, these drugs have a slower onset of action and a higher incidence of side effects.

At step 3, it is recommended to prescribe a combination of low-dose ICS with a long-acting inhaled β2-agonist in the form of a fixed combination. Due to the additive effect of combination therapy, patients usually benefit from low-dose ICS; increasing the dose of ICS is required only for patients whose asthma is controlled was not achieved after 3–4 months of therapy.It has been shown that the long-acting β2-agonist formoterol, which is characterized by a rapid onset of action when used as monotherapy or as part of a fixed combination with budesonide, is no less effective for relieving acute manifestations of asthma than Short-acting β2-agonists. However, formoterol monotherapy for symptomatic relief is not recommended and this drug should always be used only with an ICS. In all children, and especially in children aged 5 years and younger, combination therapy has been less studied. than in adults. However, a recent study showed that adding a long-acting β2-agonist is more effective than increasing the dose of ICS. The second treatment option is to increase the dose of ICS to medium doses. For patients of any age receiving moderate or high doses of ICS using a MDI, the use of a spacer is recommended to improve drug delivery to the respiratory tract, reduce the risk of oropharyngeal side effects and systemic absorption of the drug. Another alternative treatment option at step 3 is the combination of a low dose ICS with an anti-leukotriene drug. Instead of an antileukotriene drug, a low dose of sustained-release theophylline may be prescribed. These treatment options have not been studied in children 5 years of age and younger.

Choice of drugs for steps 4 depends on previous prescriptions in steps 2 and 3. However, the order in which additional drugs are added should be based on evidence of their comparative effectiveness obtained in clinical trials. Patients who have not achieved asthma control at stage 3 should be referred (if possible) to an asthma specialist to rule out alternative diagnoses and/or causes of asthma that is difficult to treat. The preferred approach to treatment at step 4 is the use of a combination of moderate-to-high-dose corticosteroids with a long-acting inhaled β2-agonist. Long-term use of ICS in high doses is accompanied by an increased risk of side effects.

Therapy steps 5 required for patients who have not achieved a treatment effect when using high doses of ICS in combination with long-acting β2-agonists and other drugs for maintenance therapy. The addition of oral corticosteroids to other drugs for maintenance therapy may increase the effect of treatment, but is accompanied by severe adverse events. The patient should be warned about the risk of side effects; All other alternatives to asthma therapy should also be considered.

Schemes for reducing the volume of basic therapy for asthma

If control of asthma is achieved during basic therapy with a combination of ICS and a long-acting β 2 agonist and is maintained for at least 3 months, a gradual reduction in its volume can begin: reducing the dose of ICS by no more than 50% for 3 months while continuing β 2 therapy -long-acting agonist. If complete control is maintained during therapy with low doses of ICS and a long-acting β2-agonist 2 times a day, the latter should be discontinued and ICS therapy should be continued. Achieving control with the use of cromones does not require reducing their dose.

Another scheme for reducing the volume of basic therapy in patients receiving ICS and a long-acting β2-agonist involves discontinuing the latter at the first stage while continuing ICS monotherapy at the same dose as contained in the fixed combination. Subsequently, gradually reduce the dose of ICS by no more than 50% over 3 months, provided that complete control of asthma is maintained. Long-acting β2-agonist monotherapy without ICS is unacceptable, as it may be accompanied by an increased risk of death in patients with asthma. Discontinuation of maintenance therapy is possible if complete control of asthma is maintained using a minimum dose of an anti-inflammatory drug and there is no relapse of symptoms within one year D.

When reducing the volume of anti-inflammatory therapy, the spectrum of sensitivity of patients to allergens should be taken into account. For example, before the flowering season in patients with AD and pollen sensitization, it is strictly forbidden to reduce the dose of the basic agents used; on the contrary, the volume of anti-inflammatory therapy for this period should be increased!

Increasing basic therapy in response to loss of asthma control

The volume of therapy should be increased if asthma control is lost (increased frequency and severity of asthma symptoms, need for inhaled β2-agonists for 1–2 days, decreased peak flow readings, or deterioration of exercise tolerance). The volume of asthma therapy is regulated throughout the year in accordance with the spectrum of sensitization of causally significant allergens. To relieve acute bronchial obstruction in patients with asthma, a combination of bronchodilators (β 2 -agonists, anticholinergic drugs, methylxanthines) and corticosteroids is used. Preference should be given to inhalation forms of delivery, which allow achieving a quick effect with minimal overall impact on the child’s body.

Existing recommendations for reducing the doses of various drugs of basic therapy may have a fairly high level of evidence (mainly B), but are based on data from studies that assessed only clinical indicators (symptoms, FEV1) and did not determine the effect of the reduced volume of therapy on the activity of inflammation and structural changes for asthma. Thus, recommendations to reduce the amount of therapy require further research aimed at assessing the processes underlying the disease, and not just clinical manifestations.

PATIENT EDUCATION

Education is an essential part of a comprehensive treatment program for children with asthma and involves establishing a partnership between the patient, family, and health care provider.

Objectives of educational programs:

• informing about the need for elimination measures;
• training in the technique of using drugs;
• information about the basics of phramcotherapy;
• training in monitoring disease symptoms, peak flow measurements (in children over 5 years old), keeping a self-monitoring diary;
• drawing up an individual action plan in case of exacerbation.

FORECAST

In children with repeated episodes of wheezing due to acute respiratory viral infections, who do not have signs of atopy or atopic diseases in the family history, asthma symptoms usually disappear in preschool age and do not develop further, although minimal changes in pulmonary function and bronchial hyperresponsiveness may persist. If wheezing occurs at an early age (before 2 years) in the absence of other manifestations of familial atopy, the likelihood that symptoms will persist into later life is low. In young children with frequent episodes of wheezing, a family history of asthma, and evidence of atopy, the risk of developing asthma at age 6 years is significantly increased. Male gender is a risk factor for the occurrence of asthma in the prepubertal period, but there is a high probability that the disease will disappear upon reaching adulthood. Female gender is a risk factor for the persistence of asthma in adulthood.

Lyudmila Aleksandrovna Goryachkina, Head of the Department of Allergology, State Educational Institution of Further Professional Education "Russian Medical Academy of Postgraduate Education" of Roszdrav, Professor, Dr. med. sciences

Natalya Ivanovna Ilyina, Chief Physician of the State Scientific Center of the Russian Federation "Institute of Immunology" FMBA, Professor, Dr. med. Sciences, Honored Doctor of the Russian Federation

Leila Seymurovna Namazova, Director of the Research Institute of Preventive Pediatrics and Rehabilitation Treatment of the State Scientific Center for Children's Health of the Russian Academy of Medical Sciences, Head of the Department of Allergology and Clinical Immunology of the Faculty of Professional Education of Pediatricians of the State Educational Institution of Higher Professional Education "Moscow Medical Academy named after. THEM. Sechenov" of Roszdrav, member of the Executive Committee of the Union of Pediatricians of Russia and the European Society of Pediatricians, Professor, Dr. med. Sci., editor-in-chief of the journal “Pediatric Pharmacology”

Lyudmila Mikhailovna Ogorodova, Vice-Rector for Research and Postgraduate Training, Head of the Department of Faculty Pediatrics with a Course of Childhood Diseases of the Medical Faculty of the State Educational Institution of Higher Professional Education "Siberian State Medical Academy" of Roszdrav, Corresponding Member of the Russian Academy of Medical Sciences, Dr. med. sciences, professor

Irina Valentinovna Sidorenko, chief allergist of the Moscow Health Committee, associate professor, candidate of sciences. honey. sciences

Galina Ivanovna Smirnova, Professor, Department of Pediatrics, State Educational Institution of Higher Professional Education "Moscow Medical Academy named after. THEM. Sechenov" of Roszdrav, Dr. med. sciences

Boris Anatolyevich Chernyak, Head of the Department of Allergology and Pulmonology, Irkutsk State Institute for Advanced Training of Physicians, Roszdrav