Inhaled glucocorticosteroids (ICS) are first-line drugs that are 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 considered to be 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, improving lung function indicators, reducing variability in their fluctuations. Unlike systemic corticosteroids, inhaled corticosteroids have high selectivity, pronounced anti-inflammatory and minimal mineralocorticoid activity. When administered via inhalation, approximately 10-30% of the nominal dose is deposited in the lungs. The percentage of deposition depends on the ICS molecule, as well as on the drug delivery system into the respiratory tract (metered aerosols or dry powder), and when using dry powder, the proportion of pulmonary deposition is doubled compared to the use of metered aerosols, including the use of spacers. Most of the ICS dose is swallowed, absorbed from the gastrointestinal tract and rapidly metabolized in the liver, which provides a high therapeutic index of ICS compared to systemic GCS

Drugs for local inhalation use 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, drugs are produced 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 due to the insufficient ability of patients to use inhalers, it is necessary to take 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 the GCS, but also by the characteristics devices for drug delivery - 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 is conflicting information about the manifestation of adverse systemic effects (AE) of ICS, from their absence to pronounced manifestations that pose a risk to patients, especially children. These NEs include suppression of the function of the adrenal cortex, effects on bone metabolism, bruising and thinning of the skin, and the formation of cataracts.

The manifestations of systemic effects are predominantly determined by the pharmacokinetics of the drug and depend on the total amount of GCS entering the systemic circulation (systemic bioavailability, F) and the clearance of GCS. 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, ICS 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

ICS are rapidly absorbed from the gastrointestinal tract and respiratory tract. The absorption of corticosteroids from the lungs may be influenced by the size of the inhaled particles, since particles smaller than 0.3 mm are deposited in the alveoli and absorbed into the pulmonary bloodstream.

When inhaling aerosols from metered dose inhalers through a large-volume spacer (0.75 l - 0.8 l), the percentage of drug delivery to the peripheral respiratory tract increases (5.2%). When using metered dose inhalers with aerosols or dry powder GCS through a dischaler, 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 is swallowed. Next, this part of the ICS, absorbed from the gastrointestinal tract, enters the hepatic bloodstream, where most of the drug (up to 80% or more) is inactivated. IGS enter the systemic circulation predominantly 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 almost zero.

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

Thus, a high percentage of drug deposition in the intrapulmonary respiratory tract normally provides a better therapeutic index for those ICS that have low systemic bioavailability when administered orally. This applies, for example, to BDP, which has systemic bioavailability due to intestinal absorption, in contrast to budesonide, which has systemic bioavailability mainly due to pulmonary absorption.

For ICS with zero bioavailability after an oral dose (fluticasone), the nature of the device and inhalation technique determine only the effectiveness of 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 the low oral bioavailability (almost zero for fluticasone and 6-13% for budesonide), but also inhalation bioavailability, the average values ​​of which range from 20 (FP) to 39% ( flunisolide) () .

For ICS with a high fraction of inhaled bioavailability (budesonide, FP, BDP), 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 in terms of the level of reduction in plasma cortisol after a single administration of budesonide and BDP at a dose of 2 mg at 22 hours to 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.

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

Of great interest is mometasone furoate (MF), a new ICS with very high anti-inflammatory activity, which 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 lingers in the respiratory tract for a long time due to the formation of lipophilic conjugates with fatty acids. This is explained by the fact that MF has a highly lipophilic furoate group at the C17 position of the drug molecule, and therefore it enters the systemic circulation slowly and in quantities insufficient for detection. 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 quickly metabolized in the lungs and therefore does not reach the systemic circulation during inhalation. Finally, the assumption that MF does not enter the lungs is not confirmed, since there is evidence of the high effectiveness of MF at a dose of 400 mcg in patients with asthma. Therefore, the first three versions may, to some extent, explain the lack of bioavailability of MF, but this issue requires further study.

Thus, the systemic bioavailability of ICS is the sum of inhalation and oral bioavailability. Flunisolide and beclomethasone dipropionate have 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 ICS drug, ciclesonide, has been proposed, the oral bioavailability of which is practically zero. This is explained by the fact that ciclesonide is a prodrug; its affinity for GCS receptors is almost 8.5 times lower than that of dexamethasone. However, upon entering the lungs, the drug molecule is exposed to enzymes (esterases) and transforms 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 entry of ICS into the systemic circulation.

Communication with blood plasma proteins

ICS have a fairly high association with blood plasma proteins (); for budesonide and fluticasone this relationship is slightly higher (88 and 90%) compared to 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. For modern, more active ICS - budesonide and FP, it is 12 and 10%, respectively, which is slightly lower than for 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 the drugs also play an important role.

Volume of distribution

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

Lipophilicity

The pharmacokinetic properties of ICS at the tissue level are predominantly determined by their lipophilicity, which is a key component for the manifestation of selectivity and retention time of the drug in tissues. Lipophilicity increases the concentration of 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 FP, followed by BDP, budesonide, and TAA and flunisolide are water-soluble drugs. Highly lipophilic drugs - FP, budesonide and BDP - are absorbed more quickly from the respiratory tract and remain longer in the tissues of the respiratory tract compared to non-inhaled corticosteroids - hydrocortisone and dexamethasone, prescribed by inhalation. This fact may explain the relatively unsatisfactory antiasthmatic 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 the blood plasma, and this ratio persists for 1.5-4 hours after inhalation Another study showed a wide distribution of FP in the lungs, as 6.5 hours after administration of 1 mg of the drug, high concentrations of FP were found in 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 mucous membrane of the respiratory tract in the form of a “microdepot” of drugs, which allows them to prolong their local anti-inflammatory effect, since it takes more than 5-8 hours to dissolve BDP and FP crystals in the bronchial mucus, whereas for budesonide and flunisolide, which have rapid solubility, this indicator is 6 minutes and less than 2 minutes, respectively. It has been shown that the water solubility of the crystals, which ensures the solubility of GCS in bronchial mucus, is an important property in the manifestation of the local activity of ICS.

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

These data contradict the generally accepted view that there is a correlation between the lipophilicity of ICS and their ability to bind to tissues, since the less lipophilic budesonide is retained longer than FP 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 budesonide conjugates with fatty acids. This process occurs intracellularly in the tissues of the lungs and respiratory tract and in liver microsomes, where fatty acid esters (oleates, palmitates, etc.) are identified. Conjugation of budesonide in the respiratory tract and lungs occurs quickly, since already 20 minutes after administration 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% of conjugates of the initial level of conjugation, and in the same proportion they were detected in the trachea and lungs, indicating the absence of unidentified metabolites. Budesonide conjugates have very low affinity for GCR and therefore have no pharmacological activity.

Intracellular conjugation of budesonide with fatty acids can occur in many cell types, and budesonide can accumulate in an inactive but reversible form. Lipophilic conjugates of budesonide 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 or peripheral tissues.

Conjugated budesonide is hydrolyzed by intracellular lipases, gradually releasing pharmacologically active budesonide, which can prolong receptor saturation 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 compared to BDP, then the lipophilicity of budesonide conjugates with fatty acids is tens of times higher than the lipophilicity of intact budesonide (Table 3), than explains the duration of its stay in the tissues of the respiratory tract.

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

Thus, after inhalation of budesonide, a “depot” of the inactive drug is formed in the respiratory tract and lungs in the form of reversible conjugates with fatty acids, which can prolong its anti-inflammatory activity. This is undoubtedly of great importance for the treatment of patients with asthma. As for BDP, which is more lipophilic than FP (Table 4), its retention time in the respiratory tract tissues is shorter than that of FP and coincides with this indicator for dexamethasone, which is apparently the result of hydrolysis of BDP to 17- BMP and beclomethasone, the lipophilicity of the latter and dexamethasone are the same. Moreover, in an in vitro study, the duration of residence of the Ra tag in the trachea after inhalation of BDP was longer than after its perfusion, which is associated with the very slow dissolution of BDP crystals deposited in the respiratory lumens 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 GCR more slowly than AF, but faster than dexamethasone, but after 4 hours there was no difference in the total amount of binding to GCR between budesonide and AF, while for dexamethasone it was only 1/3 of the bound fraction of AF and budesonide.

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

As shown above (), FP has the greatest 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 influenced by the configuration of the GCS molecule. For example, in budesonide, its dextro- and levorotatory isomers (22R and 22S) have not only different affinities for GCR, but also different anti-inflammatory activity (Table 4).

The affinity of 22R for GCR 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 power of suppression of edema is 9.3 (the parameters of dexamethasone are taken as 1.0 ) (Table 4).

Metabolism

BDP is quickly, within 10 minutes, metabolized in the liver to form one active metabolite - 17-BMP and two inactive ones - 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 may be delayed. The metabolism of 17-BMP in the liver occurs 2-3 times slower than, for example, the metabolism of budesonide, which may be a limiting factor in the transition of BMP 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 greater than the activity of hydrocortisone and has a half-life of 4 hours.

FP is quickly and completely inactivated in the liver with the formation of one partially active (1% of FP 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 radiolabel): 11% of radiolabel in plasma was determined after 2.5 hours, this figure increased to 29% after 48 hours. Excretion of radiolabel with bile was 74% and in urine 8%, the total amount reached 88% after 168 hours.

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

Clearance and half-life

ICS have rapid clearance (CL), its value approximately coincides with the value of hepatic blood flow, and this is one of the reasons for minimal manifestations of systemic NE. On the other hand, rapid clearance provides ICS with a high therapeutic index. The clearance of ICS ranges from 0.7 l/min (TAA) to 0.9-1.4 l/min (FP and budesonide, in the latter case there is a dependence on the dose taken). System clearance for the 22R is 1.4 l/min and for the 22S 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 data - 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 ground 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 changes in drug concentration over time. For ICS, T1/2 from blood plasma varies widely - from 10 minutes (BDP) to 8-14 hours (AF) (). T1/2 of other ICS is quite short - from 1.5 to 2.8 hours (TAA, flunisolide and budesonide) and 2.7 hours for 17-BMP. For 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 hours (12.5-16.7 hours), which is associated with relatively rapid absorption of the drug from the lungs - T1/2 2 (1.6-2.5) hours compared to its slow systemic elimination. The latter can lead to the accumulation of the drug with long-term use, which was shown after a seven-day administration of FP through a discahaler at a dose of 1000 mcg 2 times a day to 12 healthy volunteers, in whom the concentration of FP in the blood plasma increased by 1.7 times compared with the concentration after single dose 1000 mcg. Accumulation was accompanied by an increase in suppression of plasma cortisol levels (95% versus 47%).

Conclusion

The bioavailability of inhaled corticosteroids depends on the molecule of the drug, on the system of drug delivery to the respiratory tract, on the inhalation technique, etc. When inhaled corticosteroids are administered locally, drugs are significantly better captured from the respiratory tract, they are retained longer in the tissues of the respiratory tract, and high selectivity of drugs is ensured, especially fluticasone propionate and budesonide, a better effect/risk ratio and a high therapeutic index of drugs. Intracellular esterification of budesonide with 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, the large intracellular supply of conjugated budesonide and the gradual release of free budesonide from the conjugated form may prolong receptor saturation and anti-inflammatory activity of budesonide, despite its lower affinity for the GCS receptor compared to fluticasone propionate and beclomethasone monopropionate. To date, there is limited information on pharmacokinetic studies of the very promising and highly effective drug mometasone furoate, which, in the absence of bioavailability during inhalation administration, exhibits high anti-inflammatory activity in patients with asthma.

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

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Literature

1. Affrime M. B., Cuss F., Padhi D. et al. Bioavailability and Metabolism of Mometasone Furoate following Administration by Metered-Dose and Dry-Powder Inhalers in Healthy Human Volunteers // J. Clin. Pharmacol. 2000: 40; 1227-1236.
2. Barnes P. J. Inhaled glucocorticoids: new developments relevant to updating the asthma management guidelines // Respir. Med. 1996; 9: 379-384
3. Barnes P. J., Pedersen S., Busse W. W. Efficacy and safety of inhaled corticosteroids //Am. J. Respira. Crit. Care Med 1998; 157: 51- 53
4. Barry P. W., Callaghan C. O. Inhalation drug delivery from seven different spacer devices Thorax 1996; 51: 835-840.
5. Borgstrom L. E., Derom E., Stahl E. et al. The inhalation device influences lung deposition and bronchodilating effect of terbutaline //Am. J. Respira. Crit. Care Med. 1996; 153: 1636-1640.
6. Brattsand R. What factors determine antiinflammatory activity and selectivity of inhaled steroids // Eur. Respira. Rev. 1997; 7: 356-361.
7. Daley-Yates P. T., Price A. C., Sisson J. R. et al. Beclomethasone dipropionat: absolute bioavailability, pharmacokinetics and metabolism following intravenous, oral, intranasal and inhaled administration in men // Br. J. Clin. Pharmacol. 2001; 51: 400-409.
8. Derendorf H. Pharmacokinetic and pharmacodynamic properties of inhaled corticosteroids in relation to efficacy and safety // Respir. Med. 1997; 91(Suppl. A): 22-28.
9. Esmailpour N., Hogger P., Rabe K. F. et al. Distribution of inhaled fluticason propionate between human lung tissue and serum in vivo // Eur. Respira. J. 1997; 10: 1496-1499.
10. Guidelines for the Diagnosis and Management of asthma. Expert panel report, No. 2. National institutes of health, Bethesda, MD. (NIP Publication No. 97-4051).
11. Hogger P., Ravert J., Rohdewald P. Dissolution, tissue binding and kinetics of receptor binding of inhaled glucocorticoids // Eur. Resip. J. 1993; 6: (Suppl. 17): 584 s.
12. Hogger P., Rohdewald P. Binding kinetics of fluticasone propionate to the human glucocorticoid receptor. Steroids 1994; 59: 597-602.
13. Hogger P., Erpenstein U., Sorg C. et al Receptor affinity, protein expression and clinical efficacy of inhaled glucocorticoids // Am. J. Respira. Crit. Care Med. 1996; 153:A 336.
14. Jackson W. F. Nebulized Budesonide Therapy in asthma scientific and practical review. Oxford, 1995: 1-64.
15. Jenner W. N., Kirkham D. J. Immunoassay of beclomethasone 17-, 21-dipropionate and metabolites. In: Reid E, Robinson JD, Wilson I, eds. Bioanalysis of drugs and metabolites, New York, 1988: 77-86.
16. Kenyon C. J., Thorsson L., Borgstrom L. Reduction in lung deposition of budesonide pressurized aerosol resulting from static change? In plastic spacer devices // Drug delivery to the lungs. 1996; 7: 17-18.
17. Miller-Larsson A., Maltson R. H., Ohlsson D. et al. Prolonged release from the airway tissue of glucocorticods budesonile and fluticasone propionate as compared to beclomethasone dipropionate and hydrocortisone (abstract) // Am. J. Respira. Crit. Care Med. 1994; 149:A466.
18. Miller-Larsson A., Maltson R. H., Hjertberg E. et al. Reversible fatty acid conjugation of budesonide: novel mechanism for prolonged retention of topically applied steroid in airway tissue // Drug. metabol. Dispos. 1998; v. 26 N 7: 623-630.
19. Pedersen S., Byrne P. O. A comparison of the efficacy and safety of inhaled corticosteroids in asthma // Eur J Allergy Clin Immunol 1997; 52 (Suppl. 39): 1-34
20. Selroos O., Pietinalho A., Lofroos A. B., Riska A. High-dose is more effective than low-dose inhaled corticosteroids when starting medication in patients with moderately severe asthma (abstract) // Am. J. Respira. Crit. Care Med. 1997; 155:A 349.
21. Thorsson L, Dahlstrom K, Edsbacker S et al. Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects // Br. J. Clin. Pharmacol. 1997; 43: 155-161.
22. Thorsson L., Edsbacker S. Conradson T. B. Lung deposition of budesonide from Turbuhaler is twice that from a pressured metered-dose-inhaler p-MDI // Eur. Respira. J. 1994; 10: 1839-1844.
23. Tood G., Danlop K. Cason D., Shields M. Adrenal suppression in asthmatic children treated with high-dose fluticasone propionate (abstract) // Am. J. Respira. Crit. Care Med. 1997; 155. No. 4 (part 2 of 2 parts): A 356l.
24. Trescoli-Serrano C., Ward W. J., Garcia-Zarco M. et al. Gastroinstestinal absorption of inhaled budesonide and beclomethasone: has it any significant systemic effect? //Am. J. Respira. Crit. Care Med. 1995; 151 (No. 4 part 2): A 3753.
25. Tunec A. K., Sjodin, Hallstrom G. Reversible formation of fatty acid esters of budesonide, an anti-asthma glucocorticoid, in human lung and liver microsomes // Drug. Metabolic. Dispos. 1997; 25: 1311-1317.
26. Van den Bosch J. M., Westermann C. J. J., Edsbacker J. et al. Relationship between lung tissue and blood plasma concentrations of inhaled budesonide // Biopharm Drug. Dispos. 1993; 14: 455-459.
27. Wieslander E., Delander E. L., Jarkelid L. et al. Pharmacological importance of the reversible fatty acid conjugation of budesonide stadied in a rat cell line in vitro // Am. J. Respira. Cell. Mol. Biol. 1998; 19:1-9.
28. Wurthwein G., Render S., Rodhewald P. Lipophility and receptor affinity of glucocorticoids // Pharm Ztg. Wiss. 1992; 137: 161-167.
29. Dietzel K. et al. Ciclesonide: an On-Site-Activate Steroid // Prog. Respira. Res. Basel. Karger. 2001: v. 31; p. 91-93.

For asthma, inhaled glucocorticosteroids are used, which do not have most of the side effects of systemic steroids. If inhaled corticosteroids are ineffective, glucocorticosteroids are added for systemic use. ICS 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 (Bekotide, Beklodzhet, Klenil, Beklazon Eco, Beklazon Eco Easy Breathing)

Mometasone furoate (Asmonex)

Fluoridated

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 prostaglandins and leukotrienes, a decrease in the permeability of microvasculature, prevention of direct migration and activation of inflammatory cells, and an increase in the sensitivity of β-smooth muscle receptors. ICS 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, leading 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, slows down their release from tissues and increases their affinity for the glucocorticoid receptor. The pulmonary bioavailability of ICS depends on the percentage of the drug reaching 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 on the absorption of the drug in the respiratory tract.

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

International name Low doses Medium doses High doses

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 for persistent bronchial asthma of any severity and to this day remain the first-line treatment for bronchial asthma. According to the concept of a stepwise approach: “The higher the severity of asthma, the higher doses of inhaled steroids should be used.” A number of studies have shown that patients who began treatment with ICS no later than 2 years after the onset of the disease showed significant benefits in improving control over asthma symptoms, compared with those who began such therapy after 5 years or more.

Combinations of ICS and long-acting β2-agonists

Symbicort Turbuhaler

There are fixed combinations of ICS and long-acting β2-adrenergic agonists, combining a basic therapy and a symptomatic agent. According to the global strategy of GINA, fixed combinations are the most effective means of basic therapy for bronchial asthma, as they allow you 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 composition of the drug Seretide includes salmeterol at a dose of 25 mcg/dose in a metered-dose aerosol inhaler and 50 mcg/dose in the Multidisc device. The maximum permissible daily dose of salmeterol is 100 mcg, that is, the maximum frequency of use of Seretide is 2 inhalations 2 times for a metered dose inhaler and 1 inhalation 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 permissible daily dose of which is 24 mcg, making it possible to inhale Symbicort up to 8 times a day. The SMART trial identified a risk associated with 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.

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 include:

• 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 include:

• 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

Preparation*	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 indicators of the effectiveness of therapy (PSV, 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 of 12 weeks duration, which compared the effectiveness of the combination of salmeterol + fluticasone (at a dose of 50/100 mcg twice daily) and a 2-fold higher dose of fluticasone propionate (200 mcg twice daily). times daily) in 303 children aged 4–11 years with persistent asthma symptoms despite previous low-dose ICS therapy. 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

Preparation	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 a 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 no (≤ 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 well controlled; 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 smallest 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 includes the use of medications 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 ICS. Combination therapy has been less studied in all children, and particularly in children aged 5 years and younger. 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 β2-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 β2 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 asthma 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 worsening 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 framacotherapy;
• 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 scientific work 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

Modern medicines for children Tamara Vladimirovna Pariyskaya

Inhaled glucocorticoids

Inhaled glucocorticoids

Glucocorticoid hormones, used in the form of inhalations, have a mainly local effect, reduce or eliminate bronchospasm, and help reduce swelling and inflammation of the airways. They are used for bronchial asthma, asthmatic, obstructive bronchitis along with other inhaled bronchospasmolytic drugs (ventolin, salamol, berotec, etc.).

There are currently three types of inhalation systems:

1. Metered dose inhaler (MDI) and MDI with spacer.

2. Powder inhaler (PDI).

3. Nebulizer.

In a nebulizer, liquid is converted into “fog” (aerosol) under the influence of compressed air (compression nebulizer) or ultrasound (ultrasonic nebulizer). When using a nebulizer, the medicine penetrates well into the lower respiratory tract and acts more effectively. Nebulizers use the same substances as other inhalers, but medications for nebulizers are available in special bottles with a dropper or in plastic ampoules.

When prescribing drugs in the form of inhalations to children over 3 years of age, the mouthpiece of the inhaler should be at a distance of 2–4 cm from the wide open mouth. The valve is pressed during a deep inhalation, exhalation is done after 10–20 seconds. Inhalation duration is 5 minutes. The minimum interval between inhalations is 4 hours. The duration of use of inhaled corticosteroids in a full dose is on average 3–4 weeks, a maintenance dose is prescribed for several months (up to 6 months or more).

The reference book presents the following inhaled glucocorticoids:

Aldecin Syn.: Arumet; Beclazon; Beklat; Beclomethasone dipropionate; Bekodisk; Baconase; Becotide; Plibekot 93

Beklazon 93, 135

Beklomet 137

Beconase 93, 138

Pulmicort 369

Flixotide Syn.: Cutivate; Flixonase; Fluticasone 462

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Peculiarities: the drugs have anti-inflammatory, antiallergic and immunosuppressive effects. They are considered the most effective drugs for long-term daily maintenance therapy of bronchial asthma. With regular use they bring significant relief. If discontinued, the course of the disease may worsen.

Most common side effects: candidiasis of the oral mucosa and pharynx, hoarseness.

Main contraindications: individual intolerance, non-asthmatic bronchitis.

Important information for the patient:

• The drugs are intended for long-term treatment of bronchial asthma, and not for relieving attacks.
• Improvement occurs slowly, the onset of the effect is usually noted after 5-7 days, and the maximum effect appears after 1-3 months from the start of regular use.
• To prevent side effects of drugs, after inhalation you need to rinse your mouth and throat with boiled water.

Trade name of the drug	Price range (Russia, rub.)	Features of the drug that are important for the patient to know about
Active ingredient: Beclomethasone
Beclazon Eco(aerosol) (Norton Healthcare) Beclazon Eco Light Breath (aerosol) (Norton Healthcare) Klenil (aerosol) (Chiesi)		Classic inhaled glucocorticoid. "Beclazon Eco", "Beclazon Eco Easy Breathing" contraindicated for children under 4 years of age, "Klenil"- children under 4 years of age (at a dosage of 50 mcg) and children under 6 years of age (at a dosage of 250 mcg).
Active ingredient: Mometasone
Asmanex Twistheiler(powder for inhalation) (Merck Sharp and Dome)		A powerful drug that can be used when other inhalation agents are ineffective. Contraindicated under 12 years of age.
Active ingredient: Budesonide
Budenit Steri-Neb (suspension for inhalation via nebulizer) (different manufacturers) Pulmicort(suspension for inhalation via nebulizer) (AstraZeneca) Pulmicort Turbuhaler (powder for inhalation) (AstraZeneca)		A frequently used effective inhalation drug. The anti-inflammatory effect is 2-3 times stronger than beclomethasone. "Budenit Steri-Neb" contraindicated for children under 1 year, “Pulmicort” - up to 6 months, “Pulmicort Turbuhaler” - up to 6 years.
Active ingredient: Fluticasone
Flixotide (aerosol) (GlaxoSmithKline)		It has a pronounced anti-inflammatory and antiallergic effect. Contraindicated for children under 1 year of age.
Active ingredient: Cyclesonide
Alvesco (aerosol) (Nycomed)		New generation glucocorticoid. It accumulates well in lung tissue, providing a therapeutic effect at the level of not only large, but also small respiratory tracts. Rarely causes side effects. It acts faster than other inhaled glucocorticoids. Used in children over 6 years of age.

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