Corticosteroids - names of drugs, indications and contraindications, features of use in children and adults, side effects. Inhaled glucocorticosteroids are the most effective and safe anti-inflammatory drugs for the treatment of asthma.

Inhaled glucocorticosteroids (IGCS)

They are the main group of drugs for the prevention of asthma attacks.

The main advantage is a powerful local anti-inflammatory effect without pronounced systemic effects. Like any GCS, they act in the early stages of inflammation, disrupting the production of its mediators (arachidonic acid, interleukins, cooperation of T- and B-lymphocytes). The drugs stabilize mast cell membranes, inhibit the release of mediators from leukocytes, have a powerful anti-inflammatory, anti-edematous effect, improve mucociliary clearance, restore the sensitivity of β-adrenergic receptors to catecholamines. Reduce bronchial hyperactivity, suppress eosinophilia. They can be used at fairly early stages of the disease. They can be used to stop the withdrawal syndrome of systemic corticosteroids.

The first drug was beclomethasone dipropionate ( becotide, beclomet, aldecin, etc.). The usual dose of beclomethasone is 400-800 mcg per day in 4, less often in 2 doses (1 breath - 50 mcg). This is believed to be equivalent in efficacy to about 15 mg of prednisolone. In children - 100-600 mcg. With a mild course of BA, either long-term administration of relatively low doses is possible (it can cause remission for 5 or more years), or short-term high doses. Long-term administration of high doses is carried out with a more severe course. In this case, you can use the drug beclocort with an increased dose (200 mcg in 1 breath) of beclomethasone. When using very high doses of ICS, a proportional increase in the effect is not observed.

Side effects are rare (usually if the daily dose exceeds 1200 mcg) and are mostly local in nature: oropharyngeal candidiasis, more often in the elderly (in this case, sublingual nystatin is prescribed 4 times a day, rinsing with drugs such as chlorhexidine is possible), dysphonia, apparently, due to steroid myopathy of the larynx (reduce the dose, reduce the speech load), cough and irritation of the respiratory mucosa.

Beclomethasone has a number of newer analogues:

Budesonide ( pulmicort, benacort) - about 2-3 times more active than beclomethasone, penetrates well into cells; This is a long acting drug. Budesonide is the most lipophilic ICS, which increases its retention in the bronchial mucosa. When administered by nebulizer, the drug can improve the situation with acute laryngotracheobronchitis in children (false croup), also accompanied by symptoms of suffocation.

Minimal systemic absorption is noted for fluticasone propionate ( flixotide). Powerful drug. Due to relative safety, up to 2000 mcg per day can be prescribed, it can be effective in more severe BA.

Initially, medium doses are prescribed, which can then be reduced or increased, but the current trend is towards initial treatment with high (effective) doses of ICS, followed by a decrease to maintenance. Reduce doses by 25-50% after three months of stable condition of the patient.

Inhaled corticosteroids do not relieve an asthma attack, they are not effective in status asthmaticus. If there is no effect, the patient is treated with systemic corticosteroids according to the general rules.

Professor A.N. Choi
MMA named after I.M. Sechenov

Bronchial asthma (BA), regardless of the severity of the course, is considered as a chronic inflammatory disease of the airways of an eosinophilic nature. Therefore, one of the major changes in asthma management introduced into national and international guidelines has been the introduction inhaled glucocorticosteroids (IGCS) as first-line agents and recommend their long-term use. Inhaled corticosteroids are recognized as the most effective anti-inflammatory drugs, with their help it is possible to control the course of asthma. Nevertheless, for the initial anti-inflammatory therapy, the doctor has other groups of drugs with an anti-inflammatory effect in the arsenal: nedocromil sodium, sodium cromoglycate, theophylline preparations, long-acting b2-antagonists (formoterol, salmeterol), leukotriene antagonists. This gives the doctor the opportunity to choose anti-asthma drugs for individualized pharmacotherapy, which depends on the nature of the course of the disease, age, history, duration of the disease in a particular patient, the severity of clinical symptoms, indicators of pulmonary functional tests, the effectiveness of previous therapy and knowledge of physicochemical, pharmacokinetic and other the properties of the drugs themselves.

After the publication of GINA, information began to appear that was contradictory in nature and required a revision of some of the provisions of the document. As a result, a group of experts from the National Heart, Lung and Blood Institute (USA) prepared and published the report "Recommendations for the Diagnosis and Treatment of Asthma" (EPR-2) . In particular, the report changed the term “anti-inflammatory agents” to “long-term control agents used to achieve and maintain control of persistent asthma.” One of the reasons for this seems to be the lack of a clear indication within the FDA of what actually means the “gold standard” of anti-inflammatory therapy for asthma. As for bronchodilators, short-acting b2-agonists, they are referred to as “rapid aids for the relief of acute symptoms and exacerbations”.

Thus, drugs for the treatment of asthma are divided into 2 groups: drugs for long-term control and drugs for the relief of acute symptoms of bronchial constriction. The primary goal of asthma treatment should be to prevent exacerbations of the disease and maintain the quality of life of patients, achieved by adequate control of the symptoms of the disease with the help of long-term therapy with ICS.

Inhaled corticosteroids are recommended to be used starting from stage 2 (asthma severity from mild persistent and above), and, unlike the GINA recommendation, the initial dose of inhaled corticosteroids should be high and exceed 800 mcg / day, when the condition is stabilized, the dose should be gradually reduced to the lowest effective, low dose (Table

In patients with moderately severe course or exacerbation of asthma, the daily dose of ICS, if necessary, may be increased and exceed 2 mg / day, or treatment may be supplemented with long-acting b2-agonists - salmeterol, formoterol, or prolonged theophylline preparations. As an example, the results of a multicenter study with budesonide (FACET), which showed that in cases of exacerbation against the background of taking low doses of ICS in patients with moderate persistent asthma, the benefit in effect, including a decrease in the frequency of exacerbations, was observed from an increase in the dose of budesonide, while maintaining asthma symptoms and suboptimal lung function values, it was more effective to increase the dose of budesonide (up to 800 mcg / day) in combination with formoterol.

In a comparative assessment results of early IGCS appointment in patients who started treatment no later than 2 years from the onset of the disease or who had a short history of the disease, after 1 year of treatment with budesonide, an advantage was found in improving respiratory function (RF) and in controlling asthma symptoms, compared with the group that started treatment after 5 years from the onset of the disease or patients with a long history of asthma. As for leukotriene antagonists, they are recommended for patients with mild persistent asthma as an alternative to ICS.

Long-term treatment with ICS improves or normalizes lung function, reduces daily fluctuations in peak expiratory flow and the need for systemic glucocorticosteroids (GCS), up to their complete abolition. Moreover, long-term use of drugs prevents antigen-induced bronchospasm and the development of irreversible airway obstruction, as well as reduces the frequency of exacerbations, hospitalizations and mortality of patients.

In clinical practice the effectiveness and safety of ICS is determined by the value of the therapeutic index , which is the ratio of the severity of clinical (desirable) effects and systemic (undesirable) effects (NE) or their selectivity for the airways . The desired effects of ICS are achieved by local action of drugs on glucocorticoid receptors (GCR) in the respiratory tract, and undesirable side effects are the result of the systemic action of drugs on all GCR of the body. Therefore, with a high therapeutic index, a better benefit/risk ratio is expected.

Anti-inflammatory action of ICS

The anti-inflammatory effect is associated with the inhibitory effect of ICS on inflammatory cells and their mediators, including the production of cytokines (interleukins), pro-inflammatory mediators and their interactions with target cells.

Inhaled corticosteroids affect all phases of inflammation, regardless of its nature, while epithelial cells of the respiratory tract can be a key cellular target. IGCS directly or indirectly regulate the transcription of target cell genes. They increase the synthesis of anti-inflammatory proteins (lipocortin-1) or reduce the synthesis of pro-inflammatory cytokines - interleukins (IL-1, IL-6 and IL-8), tumor necrosis factor (TNF-a), granulocyte-macrophage colony-stimulating factor (GM / CSF) and etc. .

Inhaled corticosteroids significantly alter cellular immunity, reducing the number of T cells, and are able to suppress delayed-type hypersensitivity reactions without changing the production of antibodies by B cells. ICS increase apoptosis and decrease the number of eosinophils by inhibiting IL-5. With long-term therapy of patients with BA, IGCS significantly reduces the number of mast cells on the mucous membranes of the respiratory tract. IGCS reduce the transcription of inflammatory protein genes, including inducible cyclooxygenase-2 and prostaglandin A2, as well as endothelin, lead to the stabilization of cell membranes, lysosome membranes and a decrease in vascular permeability.

GCS suppress the expression of inducible nitric oxide synthase (iNOS). ICS reduce bronchial hyperactivity. Inhaled corticosteroids improve the function of b2-adrenergic receptors (b2-AR) both by synthesizing new b2-AR and by increasing their sensitivity. Therefore, ICS potentiate the effects of b2-agonists: bronchodilation, inhibition of mast cell mediators and mediators of the cholinergic nervous system, stimulation of epithelial cells with an increase in mucociliary clearance.

IGCS include flunisolide , triamcinolone acetonide (TAA), beclomethasone dipropionate (BDP) and drugs of modern generation: budesonide and fluticasone propionate (FP). They are available as metered-dose aerosol inhalers; dry powder with appropriate inhalers for their use: turbuhaler, cyclohaler, etc., as well as solutions or suspensions for use with nebulizers.

Inhaled corticosteroids differ from systemic corticosteroids mainly in their pharmacokinetic properties: lipophilicity, rapid inactivation, short half-life (T1 / 2) from blood plasma. Inhalation use creates high concentrations of drugs in the respiratory tract, which provides the most pronounced local (desirable) anti-inflammatory effect and minimal manifestations of systemic (undesirable) effects.

The anti-inflammatory (local) activity of ICS is determined by the following properties: lipophilicity, the ability of the drug to linger in tissues; non-specific (non-receptor) tissue affinity and affinity for HCR, the level of primary inactivation in the liver, and the duration of association with target cells.

Pharmacokinetics

The amount of ICS delivered to the respiratory tract in the form of aerosols or dry powder will depend not only on the nominal dose of GCS, but also on the characteristics of the inhaler: the type of inhaler designed to deliver aqueous solutions, dry powder (see table.

1), the presence of chlorofluorocarbon (Freon) as a propellant or its absence (CFC-free inhalers), the volume of the spacer used, as well as the technique for performing inhalation by patients. 30% of adults and 70-90% of children experience difficulties when using metered-dose aerosol inhalers due to the problem of synchronizing pressing the canister with the breathing maneuver. Poor technique affects the delivery of dose to the respiratory tract and affects the value of the therapeutic index, reducing pulmonary bioavailability and, accordingly, the selectivity of the drug. Moreover, poor technique leads to an unsatisfactory response to treatment. Patients who have difficulty using inhalers feel that the drug does not improve and stop using it. Therefore, in the treatment of IGCS, it is necessary to constantly monitor the technique of inhalation and to educate patients.

IGCS are rapidly absorbed from the cell membranes of the gastrointestinal tract and respiratory tract. Only 10-20% of the inhaled dose is deposited in the oropharyngeal region, swallowed and, after absorption, enters the hepatic circulation, where most (~80%) is inactivated, i.e. ICS are subject to the primary effect of passage through the liver. They enter the systemic circulation in the form of inactive metabolites (with the exception of beclomethasone 17-monopropionate (17-BMP) - the active metabolite of BDP) and a small amount (from 23% TAA to less than 1% FP) - in the form of an unchanged drug). Thus, the system oral bioavailability(In oral) IGCS is very low, down to 0 in AF.

On the other hand, approximately 20% of the nominally accepted dose entering the respiratory tract is rapidly absorbed and enters the pulmonary, i.e. into the systemic circulation and is an inhalation, pulmonary bioavailability(A pulmonary), which can cause extrapulmonary, systemic AEs, especially with high doses of ICS. In this case, the type of inhaler used is of great importance, since when inhaling dry powder of budesonide through a turbuhaler, the pulmonary deposition of the drug increased by 2 times or more compared with inhalation of metered-dose aerosols, which was taken into account when establishing comparative doses of various ICS (Table 1).

Moreover, in a comparative study of the bioavailability of BDP metered-dose aerosols containing freon(F-BDP) or without it (BF-BDP), a significant advantage of local pulmonary absorption over systemic oral absorption was revealed when using the drug without freon: the ratio of "lung / oral fraction" of bioavailability was 0.92 (BF-BDP) versus 0.27 (F-BDP).

These results suggest that lower doses of BF-BDP than P-BDP should be required for an equivalent response.

The percentage of drug delivery to the peripheral respiratory tract increases with inhalation of metered-dose aerosols. through the spacer with a large volume (0.75 l). The absorption of ICS from the lungs is influenced by the size of inhaled particles, particles smaller than 0.3 microns are deposited in the alveoli and absorbed into the pulmonary circulation. A high percentage of drug deposition in the intrapulmonary airways will result in a better therapeutic index for more selective ICSs that have low systemic oral bioavailability (e.g., fluticasone and budesonide, which have systemic bioavailability predominantly due to pulmonary absorption, in contrast to BDP, which has systemic bioavailability due to intestinal absorption). absorption).

For ICS with zero oral bioavailability (fluticasone), the nature of the device and the technique of inhalation of the patient determine only the effectiveness of the treatment and do not affect the therapeutic index.

On the other hand, the calculation of the absorbed lung fraction (L) to the total systemic bioavailability (C) can serve as a way to compare the effectiveness of an inhalation device for the same ICS. The ideal ratio is L / C = 1.0, which means that all the drug has been absorbed from the lungs.

Volume of distribution(Vd) ICS indicates the degree of extrapulmonary tissue distribution of the drug, so a large Vd indicates that a larger part of the drug is distributed in peripheral tissues, but it cannot be an indicator of high systemic pharmacological activity of ICS, since the latter depends on the amount of the free fraction of the drug capable of communicating with the GKR. The highest Vd was found in EP (12.1 l/kg) (Table 2), which may indicate a high lipophilicity of EP.

Lipophilicity is a key component for the manifestation of selectivity and drug retention time in tissues, since it contributes to the accumulation of ICS in the respiratory tract, slows down their release from tissues, increases affinity and lengthens the association with GCR. Highly lipophilic glucocorticosteroids (FP, budesonide, and BDP) are more rapidly and better captured from the respiratory lumen and retained in the tissues of the respiratory tract for a longer time compared to non-inhaled glucocorticosteroids - hydrocortisone and dexamethasone, administered by inhalation, which may explain the poor anti-asthmatic activity and selectivity of the latter.

At the same time, it has been shown that the less lipophilic budesonide lingers in the lung tissue for a longer time than AF and BDP.

The reason for this is the esterification of budesonide and the formation of conjugates of budesonide with fatty acids, which occurs intracellularly in the tissues of the lungs, respiratory tract and hepatic microsomes. The lipophilicity of the conjugates is many tens of times higher than the lipophilicity of intact budesonide (see Table 2), which explains the duration of its stay in the tissues of the respiratory tract. The process of conjugation of budesonide in the airways and lungs is fast. Budesonide conjugates have a very low affinity for GCR and no pharmacological activity. Conjugated budesonide is hydrolyzed by intracellular lipases, gradually releasing the free pharmacologically active budesonide, which may prolong the glucocorticoid activity of the drug. To the greatest extent, lipophilicity is manifested in FP, then in BDP, budesonide, and TAA and flunisolide are water-soluble drugs.

The connection of GCS with the receptor and the formation of the GCS + GCR complex leads to the manifestation of a prolonged pharmacological and therapeutic effect of ICS. The onset of association of budesonide with HCR is slower than AF, but faster than dexamethasone. However, after 4 hours, there was no difference in the total amount of binding to HCR between budesonide and AF, while for dexamethasone it was only 1/3 of the bound fraction of AF and budesonide.

The dissociation of the receptor from the budesonide+HCR complex is faster compared to AF. The duration of the existence of the complex budesonide + HCR in vitro is only 5-6 hours compared to 10 hours for AF and 8 hours for 17-BMP, but it is more stable than dexamethasone. From this it follows that the differences between budesonide, FP and BDP in local tissue communication are determined not by interactions with receptors, but mainly by differences in the degree of nonspecific communication of GCS with cellular and subcellular membranes, i.e. correlate directly with lipophilicity.

IGCS have fast clearance(CL), its value is approximately the same as the value of hepatic blood flow and this is one of the reasons for the minimal manifestations of systemic NE. 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 BDP (3.8 l / min or 230 l / h) (see Table 2), which suggests the presence of extrahepatic metabolism of BDP (the active metabolite 17-BMP is formed in the lungs ) .

Half-life (T1 / 2) from plasma depends on the volume of distribution and systemic clearance and indicates a change in the concentration of the drug over time.

T1 / 2 IGCS is quite short - from 1.5 to 2.8 hours (TAA, flunisolide and budesonide) and longer - 6.5 hours for 17-BMP. T1 / 2 AF differs depending on the method of drug administration: after intravenous administration it is 7-8 hours, and after inhalation T1 / 2 from the peripheral chamber is 10 hours. There are other data, for example, if T1 / 2 from blood plasma after intravenous administration was equal to 2.7 hours, then T1 / 2 from the peripheral chamber, calculated according to the three-phase model, averaged 14.4 hours, which is associated with a relatively fast absorption of the drug from the lungs (T1 / 2 2.0 h) compared with the slow systemic elimination of the drug. The latter can lead to accumulation of the drug with prolonged use. After a 7-day administration of the drug through a diskhaler at a dose of 1000 mcg 2 times a day, the concentration of AF in plasma increased by 1.7 times compared with the concentration after a single dose of 1000 mcg. The accumulation was accompanied by a progressive suppression of endogenous cortisol secretion (95% versus 47%).

Efficacy and safety assessment

Numerous randomized, placebo-controlled and comparative dose-dependent studies of ICS in patients with asthma have shown that there are significant and statistically significant differences between the effectiveness of all doses of ICS and placebo. In most cases, a significant dependence of the effect on the dose was revealed. However, there are no significant differences between the manifestation of clinical effects of selected doses and the dose-response curve. The results of the study of the effectiveness of ICS in asthma revealed a phenomenon that often goes unrecognized: the dose-response curve differs for different parameters. Doses of inhaled corticosteroids that have a significant effect on the severity of symptoms and respiratory function are different from those needed to normalize the level of nitric oxide in the exhaled air. The dose of ICS needed to prevent an asthma exacerbation may be different from that needed to control the symptoms of stable asthma. All this indicates the need to change the dosage or the ICS itself, depending on the condition of the patient with asthma and taking into account the pharmacokinetic profile of ICS.

Information about systemic adverse effects of ICS are of the most controversial nature, from their absence up to pronounced ones, which pose a risk to patients, especially in children. Such effects include suppression of the function of the adrenal cortex, the effect on bone metabolism, bruising and thinning of the skin, and the formation of cataracts.

Numerous publications devoted to the problem of systemic effects are associated with the ability to control the level of various tissue-specific markers and relate mainly to markers of 3 different tissues: adrenal glands, bone tissue and blood. The most widely used and sensitive markers for determining the systemic bioavailability of GCS are the suppression of the function of the adrenal cortex and the number of eosinophils in the blood. Another important issue is the changes observed in bone metabolism and the associated risk of fractures due to the development of osteoporosis. The predominant effect on bone metabolism of corticosteroids is a decrease in osteoblast activity, which can be determined by measuring the level of osteocalcin in blood plasma.

Thus, with local administration of ICS, they are retained in the tissues of the respiratory tract for a longer time, high selectivity, especially for fluticasone propionate and budesonide, a better benefit/risk ratio, and a high therapeutic index of drugs is ensured. All these data should be taken into account when choosing ICS, establishing an adequate dosing regimen and duration of therapy in patients with bronchial asthma.

Literature:

1. Bronchial asthma. Global strategy. The main directions of treatment and prevention of asthma. Joint report of the National Heart, Lung, and Blood Institute and the World Health Organization. Russian version under the general editorship of Academician A.G. Chuchalina // Pulmonology. 1996 (applications); 1-157.

2. National Asthma Education and Prevention program. Expert panel report No 2/ Guidelines fot the Diagnosis and Management of asthma. Us Dept. 7-Health & Human Services - NIH Publication No. 97-4051/.

3. Buist S. Development of evidence for inhaled therapeutic interventions in asthma. // Eur Respir Rev. 1998; 8(58):322-3.

4. Thorsson L., Dahlstrom, S. Edsbacker et al. Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects. // Brit. J. Clinic Pharmacol. 1997; 43:155-61.

5.P.M. O Byrne. Effects of inhaled formoterol and budesonide in reducing asthma exacerbations // Eur Rspir Rev. 1998; 8(55):221-4.

6 Barnes P.J., S. Pedersen, W.W. busse. Efficacy and safety of inhaled corticosteroids. new developments. // Am J Respir Care Med. 1998; 157 (3) part 2 (Suppl.): s1-s53.

7. Tsoi A.N. Pharmacokinetic parameters of modern inhaled glycocorticosteroids. // Pulmonology. 1999; 2:73-9.

8 Harrison L.I. Emhanced topical lung availability of beclomethasone Dipropionate (BDP) from a new CFC-free BDP MDI // Eur Respir J. 1998; 12 (Suppl. 28) 624. 79s-80s.

9. Miller-Larsson A R.H. Maltson, E. Hjertberg et al. Reversible fatty acid conjugation of budesonide: novel mechanism for prolonged retention of topically applied steroid in airway tissue. drug metabol dispos. 1998; 26(7): 623-30.

Additional information: Drugs affecting bronchial patency

For the treatment of bronchial asthma, basic therapy drugs are used that affect the mechanism of the disease, through which patients control asthma, and symptomatic drugs that affect only the smooth muscles of the bronchial tree and relieve an attack.

To drugs symptomatic therapy include bronchodilators:

β 2 -agonists

xanthines

To drugs basic therapy refer

• inhaled glucocorticosteroids

  leukotriene receptor antagonists

  monoclonal antibodies

If basic therapy is not taken, the need for inhaled bronchodilators (symptomatic agents) will increase over time. In this case, and in case of insufficient dose of basic drugs, an increase in the need for bronchodilators is a sign of an uncontrolled course of the disease.

Cromons

Cromones include sodium cromoglycate (Intal) and inedocromil sodium (Thyled). These drugs are indicated as a basic therapy for bronchial asthma of intermittent and mild course. Cromones are inferior in their effectiveness to IGCS. Since there are indications for the appointment of ICS already with a mild degree of bronchial asthma, cromones are gradually being replaced by ICS that are more convenient to use. Switching to cromones with inhaled corticosteroids is also not justified, provided that symptoms are completely controlled with minimal doses of inhaled corticosteroids.

Glucocorticosteroids

In asthma, inhaled glucocorticosteroids are used, which do not have most of the side effects of systemic steroids. When inhaled corticosteroids are ineffective, glucocorticosteroids for systemic use are added.

Inhaled glucocorticosteroids (IGCS)

IGCS is the main group of drugs for the treatment of bronchial asthma. The following is a classification of inhaled glucocorticosteroids depending on the chemical structure:

Non-halogenated

• budesonide (Pulmicort, Benacort, Budenit Steri-Neb)

  ciclesonide (Alvesco)

Chlorinated

• beclomethasone dipropionate (Becotide, Beclodjet, Clenil, Beclazone Eco, Beclazone Eco Easy Breath)

  mometasone furoate (Asmanex)

Fluorinated

• flunisolide (Ingacort)

  triamcenolone acetonide

  azmocort

  fluticasone propionate (Flixotide)

The anti-inflammatory effect of ICS is associated with suppression of the activity of inflammatory cells, a decrease in the production of cytokines, interference with the metabolism of arachidonic acid and the synthesis of prostaglandin and leukotrienes, a decrease in vascular permeability of the microvasculature, prevention of direct migration and activation of inflammatory cells, and an increase in the sensitivity of smooth muscle b-receptors. Inhaled corticosteroids also increase the synthesis of the anti-inflammatory protein lipocortin-1, by inhibiting interleukin-5, they increase the apoptosis of eosinophils, thereby reducing their number, and lead to the stabilization of cell membranes. Unlike systemic glucocorticosteroids, ICS are lipophilic, have a short half-life, are quickly inactivated, and have a local (topical) effect, due to which they have minimal systemic manifestations. The most important property is lipophilicity, due to which ICS accumulate in the respiratory tract, their release from tissues slows down and their affinity for the glucocorticoid receptor increases. Pulmonary bioavailability of ICS depends on the percentage of the drug entering the lungs (which is determined by the type of inhaler used and the correct inhalation technique), the presence or absence of a carrier (inhalers that do not contain freon have the best indicators) and absorption of the drug in the respiratory tract.

Until recently, the dominant concept of inhaled corticosteroids was the concept of a stepwise approach, which means that in more severe forms of the disease, higher doses of inhaled corticosteroids are prescribed.

The basis of therapy for long-term control of the inflammatory process are ICS, which are used in persistent bronchial asthma of any severity and to this day remain the means of first-line therapy for bronchial asthma. According to the concept of a stepwise approach: "The higher the severity of the course of asthma, the larger doses of inhaled steroids should be used." A number of studies have shown that patients who started treatment with ICS within 2 years of the onset of the disease showed significant benefits in improving the control of asthma symptoms, compared with those who started such therapy after 5 years or more.

There are fixed combinations of inhaled corticosteroids and prolonged β 2 -adrenergic agonists that combine a basic therapy and a symptomatic agent. According to the GINA global strategy, fixed combinations are the most effective means of basic therapy for bronchial asthma, as they allow to relieve an attack and at the same time are a therapeutic agent. In Russia, two such fixed combinations are most popular:

salmeterol + fluticasone (Seretide 25/50, 25/125 and 25/250 mcg/dose, Seretide Multidisk 50/100, 50/250 and 50/500 mcg/dose, Tevacomb 25/50, 25/125 and 25/250 mcg /dose)

formoterol + budesonide (Symbicort Turbuhaler 4.5 / 80 and 4.5 / 160 mcg / dose, Seretide contains salmeterol at a dose of 25 mcg / dose in a metered-dose aerosol inhaler and 50 mcg / dose in the Multidisk apparatus. Maximum the allowable daily dose of salmeterol is 100 mcg, i.e. the maximum frequency of use of Seretide is 2 breaths 2 times for a metered dose inhaler and 1 breath 2 times for the Multidisk device. This gives Symbicort an advantage if it is necessary to increase the dose of ICS. Symbicort contains formoterol , the maximum allowable daily dose of which is 24 mcg, makes it possible to inhale Symbicort up to 8 times a day.In the SMART study, the risk associated with the use of salmeterol compared with placebo.In addition, the indisputable advantage of formoterol is that it begins to act immediately after inhalation, and not after 2 hours, like salmeterol.

Inhaled glucocorticosteroids (IGCS) are first-line drugs used for long-term treatment of patients with bronchial asthma (BA). They effectively block the inflammatory process in the respiratory tract, and the clinical manifestation of the positive effect of ICS is a decrease in the severity of symptoms of the disease and, accordingly, a decrease in the need for oral glucocorticosteroids (GCS), short-acting β 2 -agonists, a decrease in the level of inflammatory mediators in the bronchoalveolar lavage fluid, improvement of lung function indicators, reduction of variability in their fluctuation. Unlike systemic corticosteroids, inhaled corticosteroids have high selectivity, pronounced anti-inflammatory and minimal mineralocorticoid activity. With the inhalation route of drug administration, approximately 10-30% of the nominal dose is deposited in the lungs. The percentage of deposition depends on the IGCS molecule, as well as on the drug delivery system to the respiratory tract (metered-dose aerosols or dry powder), and when using dry powder, the proportion of pulmonary deposition is doubled compared to using metered-dose aerosols, including the use of spacers. Most of the dose of ICS is swallowed, absorbed from the gastrointestinal tract and rapidly metabolized in the liver, which provides a high therapeutic index of ICS compared to systemic glucocorticosteroids.

Topical inhalation drugs include flunisolide (Ingacort), triamcinolone acetonide (TAA) (Azmacort), beclomethasone dipropionate (BDP) (Becotide, Beclomet) and modern generation drugs: budesonide (Pulmicort, Benacort), fluticasone propionate (FP) (Flixotide ), mometasone furoate (MF), and ciclesonide. For inhalation use, preparations are available in the form of aerosols, dry powder with appropriate devices for their use, as well as solutions or suspensions for use with nebulizers.

Due to the fact that there are many devices for inhalation of ICS, and also because of the insufficient ability of patients to use inhalers, it should be taken into account that the amount of ICS delivered to the respiratory tract in the form of aerosols or dry powder is determined not only by the nominal dose of glucocorticosteroids, but also by the characteristics devices for drug delivery - the type of inhaler, as well as the patient's inhalation technique.

Despite the fact that ICS has a local effect on the respiratory tract, there are conflicting reports on the manifestation of adverse systemic effects (NE) of ICS, from their absence to pronounced manifestations that pose a risk to patients, especially children. Such NEs include suppression of the function of the adrenal cortex, effects on bone metabolism, bruising and thinning of the skin, and cataract formation.

Manifestations of systemic effects are mainly determined by the pharmacokinetics of the drug and depend on the total amount of corticosteroids entering the systemic circulation (systemic bioavailability, F) and the magnitude of the clearance of corticosteroids. Based on this, it can be assumed that the severity of the manifestations of certain NEs depends not only on the dosage, but also, to a greater extent, on the pharmacokinetic properties of the drugs.

Therefore, the main factor determining the effectiveness and safety of ICS is the selectivity of the drug in relation to the respiratory tract - the presence of high local anti-inflammatory activity and low systemic activity (Table 1).

In clinical practice, inhaled corticosteroids differ in the value of the therapeutic index, which is the ratio between the severity of clinical (desirable) effects and systemic (undesirable) effects, therefore, with a high therapeutic index, there is a better effect / risk ratio.

Bioavailability

IGCS are rapidly absorbed in the gastrointestinal tract and respiratory tract. The absorption of corticosteroids from the lungs can be affected by the size of inhaled particles, since particles smaller than 0.3 microns are deposited in the alveoli and absorbed into the pulmonary circulation.

Inhalation of aerosols from metered-dose inhalers through a spacer with a large volume (0.75 l - 0.8 l) increases the percentage of drug delivery to the peripheral respiratory tract (5.2%). When using metered-dose inhalers with aerosols or dry powder GCS through a diskhaler, turbuhaler and other devices, only 10-20% of the inhaled dose is deposited in the respiratory tract, while up to 90% of the dose is deposited in the oropharyngeal region and swallowed. Further, this part of the ICS, being absorbed from the gastrointestinal tract, enters the hepatic circulation, where most of the drug (up to 80% or more) is inactivated. IHCs enter the systemic circulation mainly in the form of inactive metabolites, with the exception of the active metabolite of BDP - beclomethasone 17-monopropionate (17-BMP) (approximately 26%), and only a small part (from 23% TAA to less than 1% FP) - in the form unchanged drug. Therefore, the systemic oral bioavailability (Fora1) of ICS is very low, it is practically equal to zero.

However, it should be noted that part of the dose of ICS [about 20% of the nominally taken, and in the case of BDP (17-BMP) - up to 36%], entering the respiratory tract and being rapidly absorbed, enters the systemic circulation. Moreover, this part of the dose can cause extrapulmonary systemic NE, especially when prescribing high doses of ICS, and the type of ICS inhaler used is of no small importance here, since when dry powder of budesonide is inhaled through a turbuhaler, the pulmonary deposition of the drug increases by 2 times or more compared to with inhalation from metered-dose aerosols.

Thus, a high percentage of drug deposition in the intrapulmonary airways normally gives the best therapeutic index for those ICSs that have low systemic bioavailability when administered orally. This applies, for example, to BDP, which has systemic bioavailability through intestinal absorption, in contrast to budesonide, which has systemic bioavailability predominantly through pulmonary absorption.

For ICS with zero bioavailability after an oral dose (fluticasone), the nature of the device and the technique of inhalation only determine the effectiveness of the treatment, but do not affect the therapeutic index.

Therefore, when assessing systemic bioavailability, it is necessary to take into account the overall bioavailability, that is, not only low oral (almost zero for fluticasone and 6-13% for budesonide), but also inhalation bioavailability, the average values ​​of which range from 20 (AF) to 39% ( flunisolide) () .

For ICS with a high inhalation bioavailability fraction (budesonide, FP, BDP), systemic bioavailability may increase in the presence of inflammatory processes in the bronchial mucosa. This was established in a comparative study of systemic effects on the level of reduction of cortisol in blood plasma after a single administration of budesonide and BDP at a dose of 2 mg at 22 hours in healthy smokers and non-smokers. It should be noted that after inhalation of budesonide, the level of cortisol in smokers was 28% lower than in non-smokers.

This led to the conclusion that in the presence of inflammatory processes in the respiratory mucosa in asthma and chronic obstructive bronchitis, the systemic bioavailability of those ICSs that have pulmonary absorption (in this study, this is budesonide, but not BDP, which has intestinal absorption) may change.

Of great interest is mometasone furoate (MF), a novel ICS with very high anti-inflammatory activity that lacks bioavailability. There are several versions explaining this phenomenon. According to the first of them, 1 MF from the lungs does not immediately enter the systemic circulation, like budesonide, which is retained for a long time in the respiratory tract due to the formation of lipophilic conjugates with fatty acids. This is explained by the fact that MF has a highly lipophilic furoate group in position C17 of the drug molecule, and therefore it enters the systemic circulation slowly and in quantities insufficient for determination. According to the second version, MF is rapidly metabolized in the liver. The third version says: lactose-MF agglomerates cause low bioavailability due to a decrease in the degree of solubility. According to the fourth version, MF is rapidly metabolized in the lungs and therefore does not reach the systemic circulation when inhaled. Finally, the assumption that MF does not reach the lungs is not supported, as there is evidence of a high efficacy of MF at a dose of 400 μg in patients with asthma. Therefore, the first three versions can to some extent explain the fact that MF is not bioavailable, but this issue requires further study.

Thus, the systemic bioavailability of ICS is the sum of inhaled and oral bioavailability. Flunisolide and beclomethasone dipropionate have a systemic bioavailability of approximately 60% and 62%, respectively, which is slightly higher than the sum of the oral and inhaled bioavailability of other ICS.

Recently, a new IGCS drug, ciclesonide, has been proposed, the oral bioavailability of which is practically zero. This is due to the fact that ciclesonide is a prodrug, its affinity for GCS receptors is almost 8.5 times lower than that of dexamethasone. However, getting into the lungs, the drug molecule is exposed to the action of enzymes (esterases) and passes into its active form (the affinity of the active form of the drug is 12 times higher than that of dexamethasone). In this regard, ciclesonide is devoid of a number of undesirable side reactions associated with the ingestion of IGCS into the systemic circulation.

Communication with blood plasma proteins

IGCS have a fairly high connection with plasma proteins (); in budesonide and fluticasone, this relationship is slightly higher (88 and 90%) compared with flunisolide and triamcinolone - 80 and 71%, respectively. Usually, the level of the free fraction of the drug in the blood plasma is of great importance for the manifestation of the pharmacological activity of drugs. In modern, more active ICS - budesonide and AF, it is 12 and 10%, respectively, which is slightly lower than that of flunisolide and TAA - 20 and 29%. These data may indicate that in the manifestation of the activity of budesonide and AF, in addition to the level of the free fraction of drugs, other pharmacokinetic properties of drugs also play an important role.

Volume of distribution

The volume of distribution (Vd) of ICS indicates the degree of extrapulmonary tissue distribution of the drug. Large Vd indicates that a more significant part of the drug is distributed in peripheral tissues. However, a large Vd cannot serve as an indicator of the high systemic pharmacological activity of ICS, since the latter depends on the amount of the free fraction of the drug that can interact with HCC. At the level of equilibrium concentration, the highest Vd, which is many times higher than this indicator for other ICS, was found in AF (12.1 l / kg) (); in this case, this may indicate a high lipophilicity of the EP.

Lipophilicity

The pharmacokinetic properties of ICS at the tissue level are mainly determined by their lipophilicity, which is a key component for the manifestation of selectivity and drug retention time in tissues. Lipophilicity increases the concentration of ICS in the respiratory tract, slows down their release from tissues, increases affinity and lengthens the relationship with GCR, although the line of optimal lipophilicity of ICS has not yet been determined.

To the greatest extent, lipophilicity is manifested in FP, then in BDP, budesonide, and TAA and flunisolide are water-soluble drugs. Highly lipophilic drugs - FP, budesonide and BDP - are absorbed faster from the respiratory tract and stay longer in the tissues of the respiratory tract compared to non-inhaled corticosteroids - hydrocortisone and dexamethasone, administered by inhalation. This fact, perhaps, explains the relatively unsatisfactory anti-asthmatic activity and selectivity of the latter. The high selectivity of budesonide is evidenced by the fact that its concentration in the respiratory tract 1.5 hours after inhalation of 1.6 mg of the drug is 8 times higher than in blood plasma, and this ratio is maintained for 1.5-4 hours after inhalation. Another study revealed a large distribution of AF in the lungs, since 6.5 hours after taking 1 mg of the drug, a high concentration of AF was found in the lung tissue and low in plasma, in a ratio of 70:1 to 165:1.

Therefore, it is logical to assume that more lipophilic ICS can be deposited on the respiratory mucosa in the form of a “microdepot” of drugs, which allows prolonging their local anti-inflammatory effect, since it takes more than 5–8 hours to dissolve BDP and FP crystals in bronchial mucus, while budesonide and flunisolide, which have rapid solubility, this figure is 6 minutes and less than 2 minutes, respectively. It has been shown that the water solubility of crystals, which ensures the solubility of corticosteroids in bronchial mucus, is an important property in the manifestation of local activity of ICS.

Another key component for the manifestation of the anti-inflammatory activity of ICS is the ability of drugs to linger in the tissues of the respiratory tract. In vitro studies conducted on lung tissue preparations have shown that the ability of IGCS to linger in tissues correlates quite closely with lipophilicity. It is higher for AF and beclomethasone than for budesonide, flunisolide, and hydrocortisone. At the same time, in vivo studies have shown that budesonide and FP linger on the tracheal mucosa of rats longer than BDP, and budesonide lingers longer than AF. In the first 2 hours after intubation with budesonide, FP, BDP, and hydrocortisone, the release of a radioactive label (Ra-label) from the trachea in budesonide was slow and amounted to 40% versus 80% for AF and BDP and 100% for hydrocortisone. In the next 6 hours, there was a further increase in the release of budesonide by 25% and BDP by 15%, while in FP there was no further increase in the release of the Ra-label

These data contradict the generally accepted view that there is a correlation between the lipophilicity of ICSs and their ability to bind to tissue, since the less lipophilic budesonide lingers longer than AF and BDP. This fact should be explained by the fact that under the action of acetyl-coenzyme A and adenosine triphosphate, the hydroxyl group of budesonide at the carbon atom in position 21 (C-21) is replaced by a fatty acid ester, that is, esterification of budesonide occurs with the formation of conjugates of budesonide with fatty acids. This process proceeds intracellularly in the tissues of the lungs and respiratory tract and in hepatic microsomes, where fatty acid esters (oleates, palmitates, etc.) have been identified. Conjugation of budesonide in the respiratory tract and lungs occurs quickly, since already 20 minutes after the use of the drug, 70-80% of the Ra-label was determined in the form of conjugates and 20-30% in the form of intact budesonide, while after 24 hours only 3, 2% conjugates of the initial level of conjugation, and in the same proportion they were detected in the trachea and in the lungs, which indicates the absence of unidentified metabolites. Budesonide conjugates have a very low affinity for GCR and therefore have no pharmacological activity.

Intracellular fatty acid conjugation of budesonide can occur in many cell types, and budesonide can accumulate in an inactive but reversible form. Lipophilic budesonide conjugates are formed in the lungs in the same proportions as in the trachea, indicating the absence of unidentified metabolites. Budesonide conjugates are not detected in plasma and peripheral tissues.

Conjugated budesonide is hydrolyzed by intracellular lipases, gradually releasing the pharmacologically active budesonide, which can prolong the saturation of the receptor and prolong the glucocorticoid activity of the drug.

If budesonide is approximately 6–8 times less lipophilic than FP, and, accordingly, 40 times less lipophilic than BDP, then the lipophilicity of conjugates of budesonide with fatty acids is tens of times higher than the lipophilicity of intact budesonide (Table 3). explains the duration of its stay in the tissues of the respiratory tract.

Studies have shown that fatty acid esterification of budesonide leads to a prolongation of its anti-inflammatory activity. With pulsatile administration of budesonide, a prolongation of the GCS effect was noted, in contrast to AF. At the same time, in an in vitro study with the constant presence of EP, it turned out to be 6 times more effective than budesonide. Perhaps this is due to the fact that FP is more easily and quickly removed from cells than the more conjugated budesonide, resulting in a decrease in the concentration of FP and, accordingly, its activity by about 50 times).

Thus, after inhalation of budesonide, a "depot" of an inactive drug in the form of reversible conjugates with fatty acids is formed in the respiratory tract and lungs, which can prolong its anti-inflammatory activity. This, of course, is of great importance for the treatment of patients with AD. As for BDP, which is more lipophilic than FP (Table 4), its retention time in the tissues of the respiratory tract is shorter than that of FP, and coincides with this indicator for dexamethasone, which is apparently the result of BDP hydrolysis to 17- BMP and beclomethasone, the lipophilicity of the latter and dexamethasone are the same. Moreover, in an in vitro study, the residence time of the Ra-label in the trachea after BDP inhalation was longer than after its perfusion, which is associated with a very slow dissolution of BDP crystals deposited in the respiratory lumen during inhalation.

The long-term pharmacological and therapeutic effect of ICS is explained by the connection of the GCS with the receptor and the formation of the GCS + GCR complex. Initially, budesonide binds to HCR more slowly than AF, but faster than dexamethasone, however, after 4 hours, the difference in the total amount of binding to HCR between budesonide and AF was not detected, while for dexamethasone it was only 1/3 of the bound fraction of AF and budesonide.

The dissociation of the receptor from the GCS + GCR complex differed in budesonide and AF, budesonide dissociates faster from the complex compared to AF. The duration of the budesonide + receptor complex in vitro is 5-6 hours, this indicator is lower compared with AF (10 hours) and 17-BMP (8 hours), but higher than with dexamethasone. From this it follows that differences in the local tissue connection of budesonide, FP, BDP are not determined at the level of receptors, and differences in the degree of nonspecific connection of GCS with cellular and subcellular membranes have a predominant effect on the difference in indicators.

As shown above (), AF has the highest affinity for GCR (approximately 20 times higher than that of dexamethasone, 1.5 times higher than that of 17-BMP, and 2 times higher than that of budesonide). The affinity of ICS for the GCS receptor can also be affected by the configuration of the GCS molecule. For example, in budesonide, its dextrorotatory and levorotatory isomers (22R and 22S) have not only different affinity for HCR, but also different anti-inflammatory activity (Table 4).

The affinity of 22R for HCR is more than 2 times greater than the affinity of 22S, and budesonide (22R22S) occupies an intermediate position in this gradation, its affinity for the receptor is 7.8, and the edema suppression power is 9.3 (dexamethasone parameters are taken as 1.0 ) (Table 4).

Metabolism

BDP is rapidly metabolized in the liver within 10 minutes to form one active metabolite, 17-BMP, and two inactive metabolites, beclomethasone 21-monopropionate (21-BMN) and beclomethasone.

In the lungs, due to the low solubility of BDP, which is a determining factor in the degree of formation of 17-BMP from BDP, the formation of the active metabolite can be slowed down. Metabolism of 17-BMP in the liver is 2-3 times slower than, for example, the metabolism of budesonide, which may be a limiting factor in the transition of BDP to 17-BMP.

TAA is metabolized to form 3 inactive metabolites: 6β-trioxytriamcinolone acetonide, 21-carboxytriamcinolone acetonide, and 21-carboxy-6β-hydroxytriamcinolone acetonide.

Flunisolide forms the main metabolite - 6β-hydroxyflunisolide, the pharmacological activity of which is 3 times higher than the activity of hydrocortisone and has a T1 / 2 equal to 4 hours.

PP is quickly and completely inactivated in the liver with the formation of one partially active (1% of EP activity) metabolite, 17β-carboxylic acid.

Budesonide is rapidly and completely metabolized in the liver with the participation of cytochrome p450 3A (CYP3A) with the formation of 2 main metabolites: 6β-hydroxybudesonide (forms both isomers) and 16β-hydroxyprednisolone (forms only 22R). Both metabolites have weak pharmacological activity.

Mometasone furoate (pharmacokinetic parameters of the drug were studied in 6 volunteers after inhalation of 1000 mcg - 5 inhalations of dry powder with a radiolabel): 11% of the radiolabel in plasma was determined after 2.5 hours, this figure increased to 29% after 48 hours. 74% and in the urine 8%, the total amount reached 88% after 168 hours.

Ketoconazole and cimetidine may increase plasma levels of budesonide following an oral dose as a result of blockade of CYP3A.

Clearance and half-life

Inhaled corticosteroids have a fast clearance (CL), its value approximately coincides with the value of hepatic blood flow, and this is one of the reasons for the minimal manifestations of systemic NE. On the other hand, rapid clearance provides ICS with a high therapeutic index. The clearance of IGCS ranges from 0.7 l/min (TAA) to 0.9-1.4 l/min (AF and budesonide, in the latter case there is a dependence on the dose taken). The systemic clearance for the 22R is 1.4 L/min and for the 22S is 1.0 L/min. The fastest clearance exceeding the rate of hepatic blood flow was found in BDP (150 l / h, and according to other sources - 3.8 l / min, or 230 l / h) (), which suggests the presence of extrahepatic metabolism of BDP, in this case in the lungs, leading to the formation of the active metabolite 17-BMP. The clearance of the 17-BMP is 120 l / h.

The half-life (T1 / 2) from blood plasma depends on the volume of distribution and the magnitude of systemic clearance and indicates a change in the concentration of the drug over time. In IGCS, T1 / 2 from blood plasma varies widely - from 10 minutes (BDP) to 8-14 hours (AF) (). T1 / 2 of other IGCS is quite short - from 1.5 to 2.8 hours (TAA, flunisolide and budesonide) and 2.7 hours for 17-BMP. In fluticasone, T1 / 2 after intravenous administration is 7-8 hours, while after inhalation from the peripheral chamber, this figure is 10 hours. There are other data, for example, if T1 / 2 from blood plasma after intravenous administration was equal to 2.7 (1.4-5.4) hours, then T1 / 2 from the peripheral chamber, calculated according to the three-phase model, averaged 14 .4 h (12.5-16.7 h), which is associated with relatively rapid absorption of the drug from the lungs - T1 / 2 2 (1.6-2.5) h compared with its slow systemic elimination. The latter can lead to accumulation of the drug during its long-term use, which was shown after a seven-day administration of AF via Diskakhaler at a dose of 1000 μg 2 times a day to 12 healthy volunteers, in whom the concentration of AF in the blood plasma increased by 1.7 times compared with the concentration after single dose of 1000 mcg. The accumulation was accompanied by an increase in plasma cortisol suppression (95% versus 47%).

Conclusion

The bioavailability of inhaled corticosteroids depends on the molecule of the drug, on the system for delivering the drug to the respiratory tract, on the technique of inhalation, etc. With local administration of ICS, there is a much better uptake of drugs from the respiratory tract, they are retained in the tissues of the respiratory tract longer, and high selectivity of drugs, especially fluticasone, is ensured. propionate and budesonide, the best ratio of effect / risk and a high therapeutic index of drugs. Intracellular esterification of budesonide by fatty acids in the tissues of the respiratory tract leads to local retention and the formation of a "depot" of inactive, but slowly regenerating free budesonide. Moreover, a large intracellular supply of conjugated budesonide and the gradual release of free budesonide from the conjugated form can prolong the saturation of the receptor and the anti-inflammatory activity of budesonide, despite its lower affinity for the GCS receptor compared to fluticasone propionate and beclomethasone monopropionate. To date, there are isolated data on pharmacokinetic studies of a very promising and highly effective drug mometasone furoate, which, in the absence of bioavailability upon inhalation, exhibits high anti-inflammatory activity in patients with asthma.

Long-term exposure and delayed saturation of the receptor provide a prolongation of the anti-inflammatory activity of budesonide and fluticasone in the respiratory tract, which can serve as a basis for a single prescription of drugs.

For literature inquiries, please contact the editor

Literature

In asthma, inhaled glucocorticosteroids are used, which do not have most of the side effects of systemic steroids. When inhaled corticosteroids are ineffective, glucocorticosteroids for systemic use are added. IGCS is the main group of drugs for the treatment of bronchial asthma.

Classification inhaled glucocorticosteroids depending on the chemical structure:

Non-halogenated

Budesonide (Pulmicort, Benacort)

Cyclesonide (Alvesco)

Chlorinated

Beclomethasone dipropionate (Becotide, Beclodjet, Clenil, Beclazone Eco, Beclazone Eco Easy Breath)

Mometasone furoate (Asmonex)

Fluorinated

Flunisolide (Ingacort)

Triamcenolone acetonide

Azmocourt

Fluticasone propionate (Flixotide)

The anti-inflammatory effect of ICS is associated with suppression of the activity of inflammatory cells, a decrease in the production of cytokines, interference with the metabolism of arachidonic acid and the synthesis of prostaglandins and leukotrienes, a decrease in the permeability of microvasculature vessels, prevention of direct migration and activation of inflammatory cells, and an increase in the sensitivity of smooth muscle β-receptors. Inhaled corticosteroids also increase the synthesis of the anti-inflammatory protein lipocortin-1, by inhibiting interleukin-5, increase the apoptosis of eosinophils, thereby reducing their number, and lead to the stabilization of cell membranes. Unlike systemic glucocorticosteroids, glucocorticosteroids are lipophilic, have a short half-life, are quickly inactivated, and have a local (topical) effect, due to which they have minimal systemic manifestations. The most important property is lipophilicity, due to which ICS accumulate in the respiratory tract, their release from tissues slows down and their affinity for the glucocorticoid receptor increases. The pulmonary bioavailability of ICS depends on the percentage of the drug entering the lungs (which is determined by the type of inhaler used and the correct inhalation technique), the presence or absence of a carrier (inhalers that do not contain freon have the best results), and absorption of the drug in the respiratory tract.

Until recently, the dominant concept of inhaled corticosteroids was the concept of a stepwise approach, which means that in more severe forms of the disease, higher doses of inhaled corticosteroids are prescribed. Equivalent doses of ICS (mcg):

International name Low dose Medium dose High dose

Beclomethasone dipropionate 200-500 500-1000 1000

Budesonide 200-400 400-800 800

Flunisolide 500-1000 1000-2000 2000

Fluticasone propionate 100-250 250-500 500

Triamsinolone acetonide 400-1000 1000-2000 2000

The basis of therapy for long-term control of the inflammatory process are ICS, which are used in persistent bronchial asthma of any severity and to this day remain the means of first-line therapy for bronchial asthma. According to the concept of a stepwise approach: "The higher the severity of the course of asthma, the larger doses of inhaled steroids should be used." A number of studies have shown that patients who started treatment with ICS within 2 years of the onset of the disease showed significant benefits in improving the control of asthma symptoms, compared with those who started such therapy after 5 years or more.

Combinations of ICS and long-acting β2-adrenergic agonists

Symbicort Turbuhaler

There are fixed combinations of inhaled corticosteroids and prolonged β2-adrenergic agonists that combine a basic therapy agent and a symptomatic agent. According to the GINA global strategy, fixed combinations are the most effective means of basic therapy for bronchial asthma, as they allow to relieve an attack and at the same time are a therapeutic agent. The most popular are two such fixed combinations:

salmeterol + fluticasone (Seretide 25/50, 25/125 and 25/250 mcg/dose, Seretide Multidisk 50/100, 50/250 and 50/500 mcg/dose)

formoterol + budesonide (Symbicort Turbuhaler 4.5/80 and 4.5/160 mcg/dose)

Seretide. "Multidisc"

The Seretide preparation contains salmeterol at a dose of 25 mcg/dose in a metered-dose aerosol inhaler and 50 mcg/dose in the Multidisk apparatus. The maximum allowable daily dose of salmeterol is 100 mcg, that is, the maximum frequency of use of Seretide is 2 breaths 2 times for a metered-dose inhaler and 1 breath 2 times for the Multidisk device. This gives Symbicort an advantage in the event that it is necessary to increase the dose of ICS. Symbicort contains formoterol, the maximum allowable daily dose of which is 24 mcg, which makes it possible to inhale Symbicort up to 8 times a day. The SMART study identified a risk associated with the use of salmeterol compared with placebo. In addition, the indisputable advantage of formoterol is that it begins to act immediately after inhalation, and not after 2 hours, like salmeterol.