Inhaled corticosteroids include: Place in inhaled corticosteroid therapy

Glucocorticosteroids as the main medications for the treatment of asthma. ICS.

As is known, the basis of the course of bronchial asthma isWe (BA) suffer from chronic inflammation, and the main method of treating this disease isuse of anti-inflammatory drugs. Today, glucocorticosteroids are recognizedthe main medications for the treatment of asthma.

Systemic corticosteroids remain today the drugs of choice in the treatment of exacerbation of asthma, but at the end of the 60s of the last century a new era in the treatment of asthma began and it is associated with the emergence and introduction into clinical practice of inhaled glucocorticosteroids (ICS).

ICS in the treatment of patients with asthma are currently considered as first-line drugs. The main advantage of ICS is the direct delivery of the active substance to the respiratory tract and the creation of higher concentrations of the drug there, while simultaneously eliminating or minimizing systemic side effects. The first ICS for the treatment of asthma were aerosols of water-soluble hydrocortisone and prednisolone. However, due to their high systemic and low anti-inflammatory effects, their use was ineffective. In the early 1970s. lipophilic glucocorticosteroids with high local anti-inflammatory activity and weak systemic effect were synthesized. Thus, at present, ICS have become the most effective drugs for the basic treatment of BA in patients of any age (level of evidence A).

ICS can reduce the severity of asthma symptoms, suppress the activity of allergic inflammation, reduce bronchial hyperreactivity to allergens and nonspecific irritants (physical activity, cold air, pollutants, etc.), improve bronchial patency, improve the quality of life of patients, reduce the number of absences from school and work. It has been shown that the use of ICS in patients with asthma leads to a significant reduction in the number of exacerbations and hospitalizations, reduces mortality from asthma, and also prevents the development of irreversible changes in the respiratory tract (evidence level A). ICS are also successfully used to treat COPD and allergic rhinitis as the most powerful drugs with anti-inflammatory activity.

Unlike systemic glucocorticosteroids, ICS are characterized by high affinity for receptors, lower therapeutic doses and minimal side effects.

The superiority of ICS in the treatment of BA over other groups of anti-inflammatory drugs is beyond doubt, and today, according to most domestic and foreign experts, ICS are the most effective drugs for the treatment of patients with BA. But even in well-studied areas of medicine, there are insufficiently substantiated and sometimes false ideas. To this day, discussions continue regarding how early it is necessary to start ICS therapy, in what doses, which ICS and through what delivery device, how long-term therapy should be carried out, and most importantly, how to be sure that the prescribed ICS therapy does not cause harm to the body, those. There is no systemic effect or other side effects of corticosteroids. Evidence-based medicine is aimed precisely at combating such trends, existing in the opinion of both doctors and patients, which reduce the effectiveness of treatment and prevention of asthma.

The following ICS are currently used in clinical practice: beclomethasone dipropionate (BDP), budesonide (BUD), fluticasone propionate (FP), triamcinolone acetonide (TAA), flunisolide (FLU) and mometasone furoate (MF). The effectiveness of ICS therapy directly depends on: the active substance, dose, form and method of delivery, compliance. timing of initiation of treatment, duration of therapy, severity (exacerbation) of asthma, as well as COPD.

Which ICS is more effective?

At equivalent doses, all ICSs are equally effective (level of evidence A). The pharmacokinetics of drugs, and therefore the therapeutic effectiveness, are determined by the physicochemical properties of GCS molecules. Because the molecular structure of ICS is different, they have different pharmacokinetics and pharmacodynamics. To compare the clinical effectiveness and possible side effects of ICS, it is proposed to use a therapeutic index, the ratio of positive (desirable) clinical and side (undesirable) effects, in other words, the effectiveness of ICS is assessed by their systemic action and local anti-inflammatory activity. With a high therapeutic index, there is a better effect/risk ratio. Many pharmacokinetic parameters are important for determining the therapeutic index. Thus, the anti-inflammatory (local) activity of ICS is determined by the following properties of the drugs: lipophilicity, which allows them to be absorbed faster and better from the respiratory tract and remain longer in the tissues of the respiratory organs; affinity for GCS receptors; high primary inactivation effect in the liver; duration of connection with target cells.

One of the most important indicators is lipophilicity, which correlates with the drug's affinity for steroid receptors and its half-life. The higher the lipophilicity, the more effective the drug, since it easily penetrates cell membranes and increases its accumulation in the lung tissue. This increases the duration of its action in general and the local anti-inflammatory effect by forming a reservoir of the drug.

Lipophilicity is most pronounced in FP, followed by BDP and BUD. . FP and MF are highly lipophilic compounds, as a result, they have a larger volume of distribution compared to drugs that are less lipophilic BUD, TAA. BUD is approximately 6-8 times less lipophilic than FP, and, accordingly, 40 times less lipophilic compared to BDP. At the same time, a number of studies have shown that the less lipophilic BUD remains in the lung tissue longer than AF and BDP. This is explained by the lipophilicity of budesonide conjugates with fatty acids, which is tens of times higher than the lipophilicity of intact BUD, which ensures the duration of its stay in the tissues of the respiratory tract. Intracellular esterification of BUD 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 BUD. Moreover, a large intracellular supply of conjugated BUD and the gradual release of free BUD from the conjugated form can prolong the saturation of the receptor and the anti-inflammatory activity of BUD, despite its lower affinity for the GCS receptor compared to FP and BDP.

FP has the greatest affinity for GCS receptors (approximately 20 times higher than that of dexamethasone, 1.5 times higher than that of the active metabolite of BDP -17-BMP, and 2 times higher than that of BUD). The affinity index for receptors is BUD - 235, BDP - 53, FP - 1800. But, despite the fact that the affinity index of BDP is the lowest, it is highly effective due to the conversion when it enters the body into monopropionate, which has an affinity index of 1400. That is, the most active by affinity for GCS receptors are FP and BDP.

As is known, the effectiveness of a drug is assessed by its bioavailability. The bioavailability of ICS consists of the bioavailability of the dose absorbed from the gastrointestinal tract and the bioavailability of the dose absorbed from the lungs.

A high percentage of drug deposition in the intrapulmonary respiratory tract normally provides the best therapeutic index for those ICS that have low systemic bioavailability due to absorption from the mucous membranes of the oral cavity and gastrointestinal tract. This applies, for example, to BDP, which has systemic bioavailability due to intestinal absorption, in contrast to BUD, which has systemic bioavailability primarily due to pulmonary absorption. For ICS with zero bioavailability (AF), the effectiveness of treatment is determined only by the type of drug delivery device and inhalation technique, and these parameters do not affect the therapeutic index.

As for the metabolism of ICS, BDP is quickly, within 10 minutes, metabolized in the liver with the formation of one active metabolite - 17BMP and two inactive ones - beclomethasone 21- monopropionate (21-BMN) and beclomethasone. FPis quickly and completely inactivated in the liver with the formation of one partially active (1% FP activity) metabolite - 17β-carboxylic acid. Budesonide is quickly 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) and16β-hydroxyprednisolone (forms only 22R). Both metabolites have weak pharmacologicalskaya activity.

Comparison of used ICS is difficult due to differences in their pharmacokinetics and pharmacodynamics. FP is superior to other ICS in all studied parameters of pharmacokinetics and pharmacodynamics. The results of recent studies indicate that FP is at least 2 times more effective than BDP and BUD at the same doses.

The results of a meta-analysis of 14 comparative clinical studies of AF with BDP (7 studies) or BUD (7 studies) were recently published. In all 14 studies, FP was given at half (or less) dose compared to BDP or BUD. When comparing the effectiveness of BDP (400/1600 mcg/day) with AF (200/800 mcg/day), the authors did not find significant differences in the dynamics of the morning maximum expiratory flow rate (PEFR) in any of the 7 studies analyzed. Clinical efficacy, as well as serum cortisol levels in the morning, were not significantly different. When comparing the effectiveness of BUD (400/1600 mcg/day) with FP (200/800 mcg/day), it was shown that AF statistically significantly increases PEFR more significantly than BUD. When using low doses of drugs, there is no difference between these drugs in terms of reducing serum cortisol levels in the morning, however, when using higher doses of drugs, it has been found that AF has a lesser effect on this indicator. In summary, the results of the meta-analysis suggest that the effectiveness of BDP and half-dose FP are equivalent in their effects on PEFR and clinical efficacy. FP at half dose is more effective than BUD in terms of its effect on PEFR. These data confirm the pharmacokinetic characteristics, the relative affinity of the three study drugs for steroid receptors.

Clinical trials comparing the effectiveness of ICS in the form of improvement of symptoms and indicators of respiratory function show that UD and BDP in aerosol inhalers at the same doses practically do not differ in effectiveness, FP provides the same effect ie, like a double dose of BDP or BUD in a metered aerosol.

The comparative clinical effectiveness of various ICS is currently being actively studied.

INsboron dose of ICS. Calculated recommended or optimal? Which is more effective? Of significant interest to physicians is the choice of daily dose of ICS and duration of therapy when conducting basic therapy for asthma in order to control asthma symptoms. Better control of asthma is achieved more quickly with higher doses of inhaled corticosteroids (Evidence A, Table 1).

The initial daily dose of ICS should usually be 400-1000 mcg (in terms of beclomethasone); for more severe asthma, higher doses of ICS may be recommended or treatment with systemic corticosteroids may be started (C). Standard doses of ICS (equivalent to 800 mcg of beclomethasone) if ineffective, can be increased to 2000 mcg in terms of beclomethasone (A).

Data on dose-related effects, such as AF, are mixed. Thus, some authors note a dose-dependent increase in the pharmacodynamic effects of this drug, while other researchers indicate that the use of low (100 mcg/day) and high doses (1000 mcg/day) of FP are almost equally effective.

Table 1. RCalculated equivalent doses of ICS (mcg) A.G. Chuchalin, 2002 modified

	Low	Average	High	Low	Average	High
BDP (Beklozon Eco Easy Breathing, Beklat, Beklofort)	200–500	500–1000	> 1000	100- 400	400- 800	> 800
BUD (Budesonide, Budecort)	200-400	400-800	> 800	100-200	200-400	> 400
FLU *	500-1000	1000 2000	> 2000	500 750	1000 1250	> 1250
FP (Flixotide, Flochal)	100-250	250-500	> 500	100-200	200-500	> 500
TA*	400 -1000	1000 2000	> 2000	400 800	800 1200	> 1200

* active substances, the preparations of which are not registered in Ukraine

However, with increasing dose of ICS, thethe severity of their systemic undesirable effects, while in low and medium doses these drugsattacks rarely cause clinically significant painlate drug reactions and are characterized by a good risk/benefit ratio (evidence level A).

ICS has been proven to be highly effective when administered 2 times a day; when using ICS 4 times a day at the same daily dose, the effectiveness of treatment increases slightly (A).

Pedersen S. et al. showed that low doses of ICS reduce the frequency of exacerbations and the need for beta2-agonists, improve respiratory function, but for better control of the inflammatory process in the airways and maximum reduction of bronchial hyperreactivity, high doses of these drugs are required.

Until recently, ICS was not used to treat exacerbations of asthma, because they were considered less effective in exacerbation than systemic corticosteroids. A number of studies indicate the high effectiveness of taking systemic corticosteroids during exacerbations of asthma (level of evidence A). However, since the 90s of the last century, when new active ICS (BUD and AF) appeared, they began to be used to treat exacerbations of asthma. A number of clinical studies have proven that the effectiveness of ICS BUD and FP in high doses in a short course (2–3 weeks) does not differ from the effectiveness of dexamethasone in the treatment of mild and severe exacerbation of asthma. The use of inhaled corticosteroids during exacerbation of asthma makes it possible to achieve normalization of the clinical condition of patients and respiratory function indicators without causing systemic side effects.

Most studies have found moderate effectiveness of ICS in the treatment of exacerbations of asthma, which ranged from 50 to 70% when using a double dose (of the dose of basic therapy) of AF, and an increase in treatment effectiveness with the additional use of the long-acting beta 2 agonist salmeterol by 10 to 15 %. In accordance with the recommendations of international consensus on the treatment of bronchial asthma, an alternative to increasing the dose of the drug if it is impossible to ensure optimal control of asthma using ICS in low and medium doses is the prescription of long-acting b-agonists.

The enhanced effect of ICS when combined with long-acting beta2-adrenergic receptor agonists in patients with COPD was proven in the randomized, controlled, double-blind trial TRISTAN (Trial of Inhaled Steroids and Long-acting beta2-agonists), which included 1465 patients. With combination therapy (FP 500 mcg + salmeterol 50 mcg 2 times a day), the frequency of exacerbations of COPD decreased by 25% compared with placebo. Combination therapy provided a more pronounced effect in patients with severe COPD, in whom of which the initial FEV1 was less than 50% of expected th.

The effectiveness of drugs used for asthma largely depends on the means of delivery , which affects the deposition of the drug in the respiratory tract. Pulmonary deposition of drugs when using various delivery systems ranges from 4 to 60% of the administered dose. There is a clear relationship between pulmonary deposition and the clinical effect of the drug. Introduced into clinical practice in 1956, metered-dose aerosol inhalers (MDIs) are the most common inhalation devices. When using a MDI, approximately 10-30% of the drug (in the case of inhalation without a spacer) enters the lungs and then into the systemic circulation. Most of the drug, which is approximately 70-80%, settles in the oral cavity and larynx and is swallowed. Errors when using MDIs reach 60%, lead to insufficient delivery of the drug into the respiratory tract and, thereby, reduce the effectiveness of ICS therapy. The use of a spacer allows you to reduce the distribution of the drug in the oral cavity by up to 10% and optimize the flow of the active substance into the respiratory tract, because does not require absolute coordination of patient actions.

The more severe the patient’s asthma, the less effective is therapy with conventional metered-dose aerosols, since only 20-40% of patients can reproduce the correct inhalation technique when using them. In this regard, new inhalers have recently been created that do not require the patient to coordinate movements during inhalation. In these delivery devices, the delivery of the drug is activated by the patient's inhalation; these are the so-called BOI (Breathe Operated Inhaler) - a breath-activated inhaler. These include the Easi-Breath inhaler (“easy-breeze” light breathing). Currently, Beclazon Eco Easy Breathing is registered in Ukraine. Dry powder inhalers (dipihaler (Flochal, Budecort), discus (Flixotide (FP), Seretide - FP + salmeterol), nebulizers are delivery devices that ensure optimal dose of ICS and reduce unwanted side effects of therapy. BUD administered through Turbuhaler has the same effect , as a double dose of BUD in a metered-dose aerosol.

Early initiation of anti-inflammatory therapy with ICS reduces the risk of developing irreversible changes in the airways and improves the course of asthma. Late initiation of ICS treatment subsequently results in lower performance on functional tests (Level of Evidence: C).

The randomized, double-blind, placebo-controlled study START (Inhaled Steroid Treatment as Regular Therapy in Early Asthma Study) showed that the earlier basic therapy with ICS is started for asthma, the milder the disease progresses. The START results were published in 2003. The effectiveness of early BUD therapy was confirmed by an increase in respiratory function indicators.

Long-term treatment with ICS improves or normalizes pulmonary function, reduces daily fluctuations in peak expiratory flow, the need for bronchodilators and corticosteroids for systemic use, up to their complete abolition. Moreover, with long-term use of drugs, the frequency of exacerbations, hospitalizations and mortality of patients decreases.

Ndesirable effects of ICS or safety of treatment

Despite the fact that ICS have 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, oral candidiasis, and cataract formation.

It has been convincingly proven that long-term therapy with ICS does not lead to a significant change in the structure of bone tissue, does not affect lipid metabolism, the state of the immune system, and does not increase the risk of developing subcapsular cataracts. However, questions regarding the potential impact of ICS on children's linear growth rate and the state of the hypothalamic-pituitary-adrenal (HPA) axis continue to be discussed.

Manifestations of systemic effects are predominantly determined by the pharmacokinetics of the drug and depend on the total amount of corticosteroids supplied into the systemic circulation (systemic bioavailability)and the clearance of GCS. Therefore, the main factor determining the effectiveness and safety of ICS is the selectivity of the drug forrelation to the respiratory tract - the presence of highlow local anti-inflammatory activity and low systemic activity (Table 2).

Table 2 . Selectivity of ICS and systemic activity of ICS

ICS	Local activity	System activity	Local/systemic activity ratio
BUD	1,0	1,0	1,0
BDP	0,4	3,5	0,1
FLU	0,7	12,8	0,05
TAA	0,3	5,8	0,05

The safety of ICS is determined mainly byThis is due to its bioavailability from the gastrointestinal tract and is inversely proportional to it. PeThe oral bioavailability of various ICS ranges from less than 1% to 23%. PrimaUsing a spacer and rinsing the mouth after inhalation significantly reduces oral bioavailabilityAvailability (level of evidence B). Oral bioavailability is almost zero for AF and 6-13% for BUD, and inhaled bioavailability of ICS isranges from 20 (FP) to 39% (FLU).

Systemic bioavailability of ICS is the sum of inhalation and oral bioavailability. BDP has a systemic bioavailability of approximately 62%, which is slightly higher than that of other ICS.

ICS have rapid clearance, 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. ICS enter the systemic circulation, after passing through the liver, 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% of TAA to less than 1 % FP) - in the form of unchanged drug. During the first passage through the liver, approximately 99% of FP and MF, 90% of BUD, 80-90% of TAA and 60-70% of BDP are inactivated. The high metabolic activity of new ICS (FP and MF, the main fraction that ensures their systemic activity, is no more than 20% of the dose taken (usually not exceeding 750-1000 µg/day)) may explain their better safety profile compared to other ICS, and the likelihood of developing clinically significant adverse drug events is extremely low, and if they exist, they are usually mild and do not require discontinuation of therapy.

All of the listed systemic effects of ICS are a consequence of their ability, as GCS receptor agonists, to influence hormonal regulation in the HPA axis. Therefore, the concerns of doctors and patients associated with the use of ICS may be completely justified. At the same time, some studies have not demonstrated a significant effect of ICS on the HPA axis.

Of great interest is MF, a new ICS with very high anti-inflammatory activity, which lacks bioavailability. In Ukraine, it is represented only by Nasonex nasal spray.

Some effects typical of GCS have never been observed with ICS, such as those associated with the immunosuppressive properties of this class of drugs or the development of subcapsular cataracts.

Table 3. WITHcomparative studies of ICS, which included determination of the therapeutic effectToTactivity and systemic activity based on baseline serum cortisol levels or an ACTH analogue stimulation test.

Number of patients	ICS/daily dose mcg of two drugs	Efficiency (morning PEF*)	System activity
672 adults	FP/100, 200, 400, 800 iBDP/400	FP 200 = BDP 400	FP 400 = BDP 400
36 adults	BDP/1500 and BUD/1600	BDP = BUD	BDP = BUD - no effect
398 children	BDP/400 and FP/200	FP > BDP	FP = BDP - no effect
30 adults	BDP/400 and BUD/400	BDP = BUD	BDP = BUD - no effect
28 adults	BDP/1500 and BUD/1600	BDP = BUD	BDP = BUD
154 adults	BDP/2000 and FP/1000	FP = BDP	BDP > FP
585 adults	BDP/1000 and FP/500	FP = BDP	FP = BDP - no effect
274 adults	BDP/1500 and FP/1500	FP > BDP	BDP = AF – no effect
261 adults	BDP/400 and FP/200	FP = BDP	BDP > FP
671 adults	BUD/1600 and FP/1000,2000	FP 1000 > BUD, FP 2000 > BUD	FP 1000 = BUD, FP 2000 > BUD
134 adults	BDP/1600 and FP/2000	FP = BDP	FP > BDP
518 adults	BUD/1600 and FP/800	FP > BUD	BUD > FP
229 children	BUD/400 and FP/400	FP > BUD	BUD > FP
291 adults	TAA/800 and FP/500	FP > TAA	FP = TAA
440 adults	FLU/1000 and FP/500	FP > FLU	FP = FLU
227 adults	BUD/1200 and FP/500	BUD = AF	BUD > FP

Note: * PEF peak expiratory flow

Dependence of the systemic effect of ICS on dosedrug is not obvious, research results are contradictory (Table 3). NotLooking at the questions that arise, the presented clinical cases make us think about the safetydangers of long-term therapy with high doses of ICS. There are probably patients who are highly sensitive to steroid therapy. Purposehigh doses of ICS in such persons may cause an increased incidence of systemicside effects. The factors that determine the patient’s high sensitivity to GCS are still unknown. One can only note that the number of suchThere are very few patients (4 described cases per16 million patients/years of use aloneFP since 1993).

The greatest concern is the potential for ICS to affect the growth of children, since these drugs are usually used for a long time. The growth of children with asthma who do not receive corticosteroids in any form can be influenced by a number of factors, such as: concomitant atopy, severity of asthma, gender and others. Childhood asthma is likely to be associated with some growth retardation, although it does not result in a reduction in final adult height. Because of the many factors that influence growth in children with asthma, research has focused concerned with the effect of inhaled corticosteroids or systemic corticosteroids on growth,have conflicting results.

Local side effects of ICS include: candidiasis of the oral cavity and oropharynx, dysphonia, sometimes cough resulting from irritation of the upper respiratory tract, paradoxical bronchospasm.

When taking low doses of ICS, the incidence of local side effects is low. Thus, oral candidiasis occurs in 5% of patients using low doses of ICS, and in up to 34% of patients using high doses of these drugs. Dysphonia is observed in 5-50% of patients using ICS; its development is also associated with higher doses of drugs. In some cases, when using ICS, a reflex cough may develop. Paradoxical bronchospasm may develop in response to the administration of ICS carried out using a MDI. In clinical practice, the use of bronchodilator drugs often masks this type of bronchoconstriction.

Thus, ICS have been and remain the cornerstone of asthma therapy in children and adults. The safety of long-term use of low and medium doses of ICS is beyond doubt. Long-term administration of high doses of ICS can lead to the development of systemic effects, the most significant of which are a slowdown in CPR in children and suppression of adrenal function.

The latest international recommendations for the treatment of asthma in adults and children suggest the prescription of combination therapy with ICS and long-acting beta-2 agonists in all cases where the use of low doses of ICS does not achieve an effect. The feasibility of this approach is confirmed not only by its higher efficiency, but also by its better safety profile.

Prescribing high doses of ICS is advisable only if combination therapy is ineffective. Probably, in this case, the decision to use high doses of ICS should be made by a pulmonologist or allergist. After achieving a clinical effect, it is advisable to titrate the dose of ICS to the lowest effective one. In the case of long-term treatment of asthma with high doses of ICS, safety monitoring is necessary, which may include measuring CPR in children and determining cortisol levels in the morning.

The key to successful therapy is the relationship between the patient and the doctor and the patient’s attitude towards treatment compliance.

Please remember that this is a general setting. An individual approach to the treatment of patients with asthma is not excluded, when the doctor chooses the drug, regimen and dose of its administration. If the doctor, based on the recommendations of agreements on the management of asthma, is guided by his knowledge, existing information and personal experience, then the success of treatment is guaranteed.

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Peculiarities: Considered the most effective drugs for basic maintenance therapy of bronchial asthma. Taken daily and for a long time. It has been established that patients who regularly use inhaled glucocorticoids almost never suffer from status asthmaticus, and mortality from bronchial asthma during treatment with this group of drugs is reduced to almost zero. The main thing is to apply them constantly, and not occasionally. If discontinued, the course of the disease may worsen.

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

Main contraindications: individual intolerance, non-asthmatic bronchitis.

Important information for the patient:

• The drugs are intended for long-term treatment, and not for relieving attacks.
• Improvement occurs slowly, the onset of the effect is noted after 5-7 days, and maximum - after 1-3 months from the start of regular use.
• To prevent side effects from using drugs, after each 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, Teva) Beclazon Eco Light Breath (aerosol) (Norton Healthcare) Klenil (aerosol) (Chiesi)
Active ingredient: Mometasone
Asmanex Twistheiler(powder for inhalation) (Merck Sharp and Dome)		A powerful drug. Can be used if other inhalation agents are ineffective. Contraindicated in children under 12 years of age. Use with caution during pregnancy, breastfeeding, pulmonary tuberculosis, fungal, bacterial and viral infections, and herpetic eye infections.
Active ingredient: Budesonide
Budenit Steri-Neb (suspension for inhalation via nebulizer) (various manufacturers) Pulmicort(suspension for inhalation via nebulizer) (AstraZeneca) Pulmicort Turbuhaler (powder for inhalations) (AstraZeneca)		A frequently used effective inhalation drug. The anti-inflammatory effect is 2-3 times stronger than beclomethasone. Contraindicated for children under 6 months. Can be used in minimal doses during pregnancy and is allowed during breastfeeding. Use with caution for pulmonary tuberculosis, fungal, bacterial and viral infections, liver cirrhosis.
Active ingredient: Fluticasone
Flixotide (aerosol) (GlaxoSmithKline)
Active ingredient: Cyclesonide
Alvesco (aerosol) (Nycomed)		A new generation glucocorticoid for the treatment of adult patients and children over 6 years of age suffering from bronchial asthma. 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. Use with caution for tuberculosis, bacterial, fungal and viral infections, pregnancy and breastfeeding.

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

For quotation: Sutochnikova O.A. INHALED GLUCOCORTICOSTEROIDS – THE MOST EFFECTIVE AND SAFE ANTI-INFLAMMATORY DRUGS FOR THE TREATMENT OF ASTHMA // Breast cancer. 1997. No. 17. S. 5

The review form provides an analysis of inhaled corticosteroids, the most effective anti-inflammatory drugs for the treatment of bronchial asthma.

The mechanisms of therapeutic action and possible local complications are shown depending on the dosage, combination of drugs and methods of their administration.

The paper analyzes inhaled glycocorticosteroids, the most effective antiinflammatory drugs in the treatment of asthma, shows the mechanisms of therapeutic action and possible local complications resulting from the dosage, combinations of drugs and routes of their administration.

O. A. Sutochnikova
Research Institute of Pulmonology, Ministry of Health of the Russian Federation, Moscow
O. A. Sutochnikova
Research Institute of Pulmonology, Ministry of Health of the Russian Federation, Moscow

Introduction

Bronchial asthma (BA) is currently one of the most common human diseases. Epidemiological studies over the past twenty-five years indicate that the incidence of asthma has reached a level of 5% among adults and 10% among children, representing a serious social, epidemiological and medical problem, attracting close attention from medical societies. An international consensus (1995) formulated a working definition of asthma based on pathological changes and functional disorders as a consequence of airway inflammation.
The main goal of treatment for asthma is to improve the patient’s quality of life by preventing exacerbations, ensuring normal lung function, maintaining a normal level of physical activity, and eliminating the side effects of medications used in treatment (National Heart, Lung & Blood Institute, National Institutes of Health. International Consensus Report on diagnosis and management of asthma // Eur Respir J. - 1992). Based on the leading role of inflammation in the pathogenesis of asthma, treatment involves the use of anti-inflammatory drugs, the most effective of which are corticosteroids, which reduce vascular permeability, prevent swelling of the bronchial wall, reduce the release of effector inflammatory cells into the bronchoalveolar space and block the production of inflammatory mediators from effector cells (A. P. Chuchalin, 1994; Bergner, 1994; Fuller et al., 1984).
Back in the late 40s, doctors began to use systemic corticosteroids to treat asthma (Carryer et al., 1950; Gelfand ML, 1951), which played a significant role in the treatment of this disease. The mechanism of action of corticosteroids is due to their ability to bind to specific glucocorticoid receptors in the cytoplasm of the cell. However, long-term use of systemic corticosteroids leads to undesirable systemic effects: Itsenko-Cushing syndrome, steroid diabetes and osteoporosis, arterial hypertension, drug-induced gastric and intestinal ulcers, frequent occurrence of opportunistic infections, myopathies, which limits their clinical use.
Pharmacokinetics of inhaled corticosteroids

Indicator	Preparation
	triamsinolone acetonide	beclomethasone dipropionate	flunisolide	budesonide	fluticasone propionate
1/2 period of stay in plasma, h
Volume of distribution, l/kg
Plasma clearance, l/kg
Activity after first passage through the liver, %
Local anti-inflammatory activity, units.
Literature	I. M. Kakhanovsky, 1995; R. Brattsand, 1982; R. Dahl, 1994	J. H. Toogood, 1977	I. M. Kakhanovsky, 1995; C. Chaplin, 1980	P. Anderson, 1984; C. Chaplin, 1980; S. Clissold, 1984; S. Johansson, 1982; S. Pedersen, 1987; A. Ryrfeldt, 1982; J. Toogood, 1988	S. Harding, 1990; G. Phillips, 1990; U. Svendsen, 1990

Corticosteroids circulate in the blood in free and bound states. Corticosteroids bind to plasma albumin and transcortin. Only free corticosteroids are biologically active. On the amount of free corticosteroids, i.e. Metabolically active hormones that enter cells are influenced by 3 factors:

• degree of binding to plasma protein;
• their metabolic rate;
• the ability of corticosteroids to bind to specific intracellular receptors (Muller et al, 1991; Ellul-Micallef, 1992).

Systemic corticosteroids have a long half-life, and therefore their period of biological action increases. Only 60% of systemic corticosteroids are bound to plasma protein, and 40% circulates freely. In addition, with protein deficiency or the use of a high dose of systemic corticosteroids, the free, biologically active part of corticosteroids in the blood increases. This contributes to the development of the systemic side effects listed above (Schimbach et al., 1988). It is difficult to separate the positive anti-asthmatic effect and undesirable systemic manifestations of tablet steroids, and asthma is a disease of the respiratory tract, and therefore it has been suggested that topical use of corticosteroids is possible.

Anti-inflammatory effects of inhaled corticosteroids

In the late 60s, aerosols of water-soluble hydrocortisone and prednisolone were created. However, attempts to treat asthma with these drugs were ineffective (Brokbank et al., 1956; Langlands et al., 1960) due to the fact that they had a low anti-asthmatic and high systemic effect, which can be compared with the effect of tableted corticosteroids. In the early 70s, a group of fat-soluble corticosteroids was synthesized for local aerosol use, which, unlike water-soluble ones, had high local anti-inflammatory activity and were characterized by low systemic effect or its absence within the therapeutic concentration. The clinical effectiveness of this form of drugs has been shown in a number of experimental studies (Clark, 1972; Morrow-Brown et al., 1972). The most significant local anti-inflammatory effect of inhaled corticosteroids is (Borson et al., 1991; Cox et al., 1991; Venge et al., 1992):

• inhibition of synthesis or reduction of IgE-dependent release of inflammatory mediators from leukocytes;
• decreased survival of eosinophils and formation of colonies of granulocytes and macrophages;
• increased activity of neutral endopeptidase, an enzyme that destroys inflammatory mediators;
• suppression of cytotoxicity mediated by monocytes, eosinophilic cationic proteins and a decrease in their content in the bronchoalveolar space;
• decreased permeability of the respiratory tract epithelium and plasma exudation through the endothelial-epithelial barrier;
• reduction of bronchial hyperreactivity;
• inhibition of M-cholinergic stimulation by reducing the amount and effectiveness of cGMP.

The anti-inflammatory effect of inhaled corticosteroids is associated with an effect on biological membranes and a decrease in capillary permeability. Inhaled corticosteroids stabilize lysosomal membranes, which leads to limitation of the release of various proteolytic enzymes beyond the lysosomes and prevents destructive processes in the wall of the bronchial tree. They inhibit the proliferation of fibroblasts and reduce collagen synthesis, which reduces the rate of development of the sclerotic process in the bronchial wall (Burke et al., 1992; Jeffery et al., 1992), inhibit the formation of antibodies and immune complexes, reduce the sensitivity of effector tissues to allergic reactions, promote bronchial ciliogenesis and restoration of damaged bronchial epithelium (Laitinen et al., 1991a, b), reduce nonspecific bronchial hyperreactivity (Juniper et al., 1991; Sterk, 1994).
Inhaled administration of corticosteroids quickly creates a high concentration of the drug directly in the tracheobronchial tree and avoids the development of systemic side effects (Agertoft et al., 1993). This use of drugs in patients dependent on systemic corticosteroids reduces the need for constant use. It has been established that inhaled corticosteroids do not have side effects on mucociliary clearance (Dechatean et al., 1986). Long-term treatment with inhaled corticosteroids in medium and intermediate doses (up to 1.6 mg/day) not only does not lead to morphologically visible damage to the epithelium and connective tissue of the bronchial wall, which is confirmed at the light and electron microscopic levels, but also promotes bronchial ciliogenesis and recovery damaged epithelium (Laursen et al., 1988; Lundgren et al., 1977; 1988). In experimental studies, analyzing bronchobiopsies from patients receiving inhaled corticosteroids, it was found that the ratio of goblet cells to ciliated cells increases to a level similar to that observed in healthy volunteers (Laitinen, 1994), and when analyzing a cytogram of bronchoalveolar fluid, the disappearance of specific inflammatory cells is observed – eosinophils (Janson-Bjerklie, 1993).

Systemic action of corticosteroids

Glucocorticoids affect the hypothalamic-pituitary-adrenal system. When exposed to the hypothalamus, the production and release of corticotropin-releasing factor by it is reduced, the production and release of adrenocorticotropic hormone (ACTH) by the pituitary gland is reduced, and, as a result, the production of cortisol by the adrenal glands is reduced (Taylor et al., 1988).
Long-term treatment with systemic corticosteroids tends to suppress the function of the hypothalamic-pituitary-adrenal axis. Significant individual differences were found in the pituitary response to corticotropin-releasing factor, and the dose of prednisolone administered every other day did not explain these differences (Schurmeyer et al., 1985). The importance of persistent adrenocortical hypofunction in patients dependent on systemic corticosteroids should not be underestimated (Yu. S. Landyshev et al., 1994), since acute severe episodes of asthma that develop against this background can be fatal.
Of great interest is the degree of hypothalamic-pituitary-adrenal suppression when using inhaled corticosteroids (Broide 1995; Jennings et al., 1990; 1991). Inhaled corticosteroids have a moderate systemic effect due to the portion of the drug that is absorbed in the bronchi, swallowed and absorbed in the intestine (Bisgard et al., 1991; Prahl, 1991). This is due to the fact that inhaled corticosteroids have a short half-life and are quickly biotransformed in the liver after systemic absorption, which significantly reduces the time of their biological action. When using high doses of inhaled corticosteroids (1.6 – 1.8 mg/day) or their combination with systemic corticosteroids, there is a risk of developing systemic side effects (Selroos et al., 1991). The effects of inhaled corticosteroids on the hypothalamic-pituitary-adrenal axis in patients who have not previously taken them are significantly less than in patients who have previously used inhaled corticosteroids (Toogood et al., 1992). The incidence and severity of suppression increases with the use of high-dose inhaled corticosteroids in patients receiving concurrent systemic and inhaled corticosteroid therapy, and when long-term systemic corticosteroid therapy is replaced by high-dose inhaled corticosteroids (Brown et al., 1991; Wong et al., 1992) . The existing suppression of the hypothalamic-pituitary-adrenal axis can be restored, but this process can take up to three years or more. Systemic side effects of inhaled corticosteroids include partial eosinopenia (Chaplin et al., 1980; Evans et al., 1991; 1993). There continues to be debate about the development of osteoporosis, growth retardation and cataract formation during treatment with inhaled corticosteroids (Nadasaka, 1994; Wolthers et al., 1992). However, the possibility of these complications is associated with the use of these drugs in high doses (1.2 – 2.4 mg/day) for a long period (Ali et al., 1991; Kewley, 1980; Toogood et al., 1988; 1991; 1992). On the other hand, growth retardation in some children with asthma receiving inhaled corticosteroids is more often associated with disturbances during puberty, but is independent of the effect of inhaled steroid therapy (Balfour-Lynn, 1988; Nassif et al., 1981; Wolthers et al. ., 1991). It is recognized that large doses of inhaled corticosteroids are able to penetrate the placental barrier, causing teratogenic and fetotoxic effects. However, the clinical use of low and moderate therapeutic doses of these drugs in pregnant women suffering from bronchial asthma is not reflected in an increase in the incidence of congenital anomalies in newborns (Fitzsimons et al., 1986).
In immunocompetent patients, the frequency, severity and duration of viral or bacterial infections do not increase with inhaled corticosteroid therapy (Frank et al., 1985). At the same time, due to the risk of opportunistic infection in immunocompromised patients, inhaled corticosteroids should be used with great caution. When asthma treated with inhaled drugs is combined with active tuberculosis, additional anti-tuberculosis therapy is usually not required (Horton et al., 1977; Schatz et al., 1976).

Local side effects of inhaled corticosteroids

Local complications of inhaled corticosteroid therapy include candidiasis and dysphonia (Toogood et al., 1980). These complications have been shown to be dependent on the daily dose of the drug (Toogood et al., 1977;1980). The growth of yeast-like fungi of the genus Candida in the oral cavity and pharynx is the result of the suppressive effect of inhaled corticosteroids on the protective functions of neutrophils, macrophages and T-lymphocytes on the surface of their mucosa (Toogood et al., 1984). Dysphonia with inhaled corticosteroid use has been associated with dyskinesia of the muscles that control vocal fold tension (Williams et al., 1983). Nonspecific irritation of the vocal cords by the propellant freon contained in a metered-dose aerosol inhaler as a propellant can also cause dysphonia. The most common, severe dysphonia is observed in patients who, due to their occupation, have a load on the vocal cords - priests, dispatchers, teachers, coaches, etc. (Toogood et al., 1980).

Modern inhaled corticosteroids

Currently, the main drugs of the group of inhaled corticosteroids include the following: beclomethasone dipropionate, betamethasone valerate, budesonide, triamsinolone acetonide, flunisolide and fluticasone propionate, which are widely used in world pulmonological practice and are highly effective (Harding, 1990; Svendsen, 1990; Toogood and al., 1992). However, they differ in the ratio of local anti-inflammatory activity and systemic action, as evidenced by such an indicator as the therapeutic index. Of all the inhaled corticosteroids, budesonide has the most favorable therapeutic index (Dahl et al., 1994; Johansson et al., 1982; Phillips, 1990), which is associated with its high affinity for glucocorticoid receptors and accelerated metabolism after systemic absorption in the lungs and intestines ( Anderson et al., 1984; Brattsand et al., 1980; Phillips et al., 1982).
For inhaled corticosteroids (aerosol form), it has been established that 10% of the drug enters the lungs, and 70% remains in the oral cavity and large bronchi (I.M. Kakhanovsky et al., 1995; Dahl et al., 1994). Patients have varying sensitivity to inhaled corticosteroids (N. R. Paleev et al., 1994; Bogaska, 1994). It is known that children metabolize drugs faster than adults (Jennings et al., 1991; Pedersen et al., 1987; Vaz et al., 1982). The pharmacokinetics of the main drugs of the group of inhaled corticosteroids are presented in the table.

Dosage and drug combination issues

Inhaled and systemic corticosteroids exhibit additive effects when used together (Toogood et al., 1978; Wya et al., 1978), but the systemic corticosteroid activity of combined treatment (inhaled + systemic corticosteroids) is several times lower than that of prednisolone used in daily dose required to achieve equivalent control of asthma symptoms.
The severity of asthma has been found to correlate with the degree of sensitivity to inhaled corticosteroids (Toogood et al., 1985). Low-dose inhaled medications are effective and reliable in patients with mild asthma, short-term asthma, and most patients with moderately severe chronic asthma (Lee et al., 1991; Reed, 1991). An increased dose is necessary to rapidly achieve control of asthma symptoms (Boe, 1994; Toogood, 1977; 1983). Treatment with high doses of inhaled corticosteroids should be continued, if necessary, until pulmonary function tests normalize or improve (Selroos et al., 1994; Van Essen-Zandvliet, 1994), which allows some patients to stop taking systemic corticosteroids or reduce their dose (Tarlo et al., 1988). When there is a clinical need for the combined use of inhaled and systemic corticosteroids, the dose of each drug should be selected at the minimum effective dose to achieve maximum symptomatic effect (Selroos, 1994; Toogood, 1990; Toogood et al., 1978). In patients with severe asthma who are dependent on systemic corticosteroids, as well as in some patients with moderately severe chronic asthma in the absence of effect from the use of low or medium doses of inhaled drugs, it is necessary to use their high doses - up to 1.6 - 1.8 mg / day. In such patients, their combination with systemic corticosteroids is justified. However, when taking high doses of inhaled corticosteroids, the risk of oropharyngeal complications and decreased morning plasma cortisol levels increases (Toogood et al., 1977). To select the optimal dosage and regimen for taking inhaled drugs, indicators of respiratory function and daily peak flow monitoring should be used. To maintain long-term remission of the disease, the dose of inhaled corticosteroids ranges from 0.2 to 1.8 mg per day. Due to the fact that when using low doses there are no systemic effects, prophylactic administration of such doses at an early stage of asthma is justified, which helps to delay the progression of the disease (Haahtela et al., 1994; Van Essen-Zandvliet, 1994). In patients with mild asthma, a decrease in bronchial hyperreactivity and stabilization of the disease is achieved within 3 months of taking inhaled corticosteroids (I.M. Kakhanovsky et al., 1995).
Patients with moderate asthma treated with beclomethasone dipropionate and budesonide require an average of 9 months of treatment to achieve a significant reduction in airway hyperresponsiveness (Woolcoch et al., 1988). In rare observations, such a reduction was achieved only after 15 months of treatment. When inhaled corticosteroids are abruptly discontinued in patients with moderate asthma who were treated with low doses of inhaled drugs, disease relapse occurs in 50% of cases after 10 days and in 100% after 50 days (Toogood et al., 1990). On the other hand, long-term and regular use of inhaled corticosteroids increases the period of remission of the disease to 10 years or more (Boe et al., 1989).

Methods of administration of inhaled corticosteroids

The disadvantage of inhaled corticosteroids is the method of drug administration itself, which requires special training for the patient. The effectiveness of the inhalation drug is associated with the retention of its active particles in the respiratory tract. However, such retention of the drug in an adequate dose is often difficult due to poor inhalation technique. Many patients use the aerosol inhaler incorrectly, and poor inhalation technique is a major factor in its extremely poor effectiveness (Crompton, 1982). Spacers and similar attachments for aerosol inhalers eliminate the problem of synchronizing inhalation and dose release, reduce drug retention in the larynx, increase delivery to the lungs (Newman et al., 1984), and reduce the frequency and severity of oropharyngeal candidiasis (Toogood et al., 1981; 1984 ), hypothalamic-pituitary-adrenal suppression (Prachl et al., 1987), increase anti-inflammatory effectiveness. The use of a spacer is recommended when antibiotics or additional systemic corticosteroids are clinically necessary (Moren, 1978). However, it is not yet possible to completely eliminate local side effects such as oropharyngeal candidiasis, dysphonia, and sporadic cough. To eliminate them, a gentle voice regimen and a reduction in the daily dose of corticosteroids are recommended (Moren, 1978).
Holding the breath longer after inhalation may reduce drug deposition in the oropharynx during exhalation (Newman et al., 1982). Rinsing the mouth and throat immediately after inhalation of the drug reduces local absorption to a minimum. Observations have shown that a 12-hour interval between corticosteroid inhalations is sufficient to temporarily restore the normal protective function of neutrophils, macrophages and T-lymphocytes on the surface of the oral mucosa. In studies with beclomethasone dipropionate and budesonide, dividing the daily dose into two doses was shown to prevent the development of Candida colonies in the oropharynx and eliminate thrush (Toogood et al., 1984). Paroxysmal cough or bronchospasm, which can be caused by aerosol inhalation, in patients is associated with the irritating effect of propellants and retention of drug particles in the respiratory tract, improper inhalation technique, exacerbation of concomitant respiratory tract infection, or a recent exacerbation of the underlying disease, after which increased airway hyperresponsiveness persists . In this case, most of the dose is thrown away with a reflex cough and a false belief arises that the drug is ineffective (Chim, 1987). However, a complete solution to this problem requires more effective measures to eliminate the primary causes: stopping the concomitant infectious process, reducing bronchial hyperreactivity, improving mucociliary clearance. Taken together, this will allow the inhaled drug to enter the peripheral respiratory tract, rather than settle in the trachea and large bronchi, where particle deposition causes reflex cough and bronchospasm.
Given these side effects and some problems in the use of aerosolized corticosteroids, inhaled corticosteroids in the form of dry powder were developed. For inhalation of this form of the drug, special devices have been designed: rotohaler, turbohaler, spinhaler, dischaler. These devices have advantages over the aerosol inhaler (Selroos et al., 1993a; Thorsoon et al., 1993) as they are activated by breathing due to the maximum inspiratory flow rate, which eliminates the problem of coordinating inhalation with the release of the drug dose, without the toxic effect of the propellant . Inhalers with a medicinal substance in the form of dry powder are environmentally friendly because they do not contain chlorofluorocarbons. In addition, inhaled corticosteroids in the form of dry powder have a more pronounced local anti-inflammatory effect and have advantages in clinical effectiveness (De Graaft et al., 1992; Lundback, 1993).

Conclusion

Inhaled corticosteroids are currently the most effective anti-inflammatory drugs for the treatment of asthma. Studies have shown their effectiveness, which was manifested in improving the function of external respiration, reducing bronchial hypersensitivity, reducing symptoms of the disease, reducing the frequency and severity of exacerbations and improving the quality of life of patients.
The basic rule of corticosteroid therapy is the use of drugs in the minimum effective dose for the shortest possible period of time necessary to achieve maximum symptomatic effect. For the treatment of severe asthma, it is necessary to prescribe high doses of inhaled corticosteroids for a long period of time, which will reduce the need for patients in tablet corticosteroids. This therapy has significantly fewer systemic side effects. The dose of drugs should be selected individually, since the optimal dose varies in individual patients and may change over time in the same patient. To select the optimal dosage and regimen for taking inhaled corticosteroids, indicators of pulmonary function and daily peak flow monitoring should be used. The dose of corticosteroids should always be reduced gradually. Constant monitoring of patients receiving corticosteroids is important to identify adverse reactions and ensure regularity of treatment. The development of local side effects of inhaled corticosteroids can often be prevented by using a spacer and rinsing the mouth after inhalation. Correct inhalation technique accounts for 50% of success in the treatment of patients with bronchial asthma, which requires the development and implementation in everyday practice of methods for the correct use of inhalation devices to achieve maximum effectiveness of inhaled drugs. It must be remembered that exacerbation of asthma may indicate the ineffectiveness of anti-inflammatory therapy for a chronic disease and requires a review of ongoing maintenance therapy and dosages of drugs used.

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20. Laitinen LA, Laitinen A, Haahtela T. Treatment of eosinophilic airway inflammation with inhaled corticosteroid, budesonide, in newly diagnosed asthmatic patients (abstract). Eur Respir J 1991;4(Suppl.14):342S.
21. Lundback B, Alexander M, Day J, et al. Evaluation of fluticasone propionate (500 micrograms day-1) administered either as dry powder via a Diskhaler inhaler or pressurized inhaler and compared with beclomethasone dipropionate (1000 micrograms day-1) administered by pressurized inhaler. Respir Med 1993;87(8):609–20.
22. Selroos O, Halme M. Effect of a volumatic spacer and mouth rinsing on systemic and metered dose inhaler and dry powder inhaler. Thorax 1991;46:891–4.
23. Toogood JH. Complications of topical steroid therapy for asthma. Am Rev Respir Dis 1990;141:89–96.
24. Toogood JH, Lefcoe NM, Haines DSM, et al. Minimum dose requirements of steroid-dependent asthmatic patients for aerosol beclomethasone and oral prednisolone. J Allergy Clin Immunol 1978;61:355–64.
25. Woolcock AJ, Yan K, Salome CM. Effect of therapy on bronchial hyperresponsiveness in the long-term management of asthma. Clin Allergy 1988;18:65.

A complete list of used literature is available in the editorial office

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; rinsing the mouth after each inhalation is necessary 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 treatment effectiveness indicators (PSF, FEV1, exacerbation frequency, quality of life). If the use of low doses of ICS in children does not allow achieving control of BA, it is recommended to switch to combination therapy, which can be a good alternative to increasing the dose of ICS. This was shown in a new prospective, multicenter, double-blind, randomized, parallel-group study lasting 12 weeks, which compared the effectiveness of the combination of salmeterol + fluticasone (at a dose of 50/100 mcg twice a day) and a 2-fold higher dose of fluticasone propionate (200 mcg 2 times a day) in 303 children 4–11 years old with persistent asthma symptoms despite previous therapy with low doses of ICS. It turned out that regular use of the combination salmeterol + fluticasone (Seretide) prevents symptoms and achieves asthma control as effectively as twice the dose of ICS. Treatment with Seretide is accompanied by a more pronounced improvement in lung function and a decrease in the need for drugs to relieve asthma symptoms with good tolerability: in the Seretide group, the increase in morning PEF is 46% higher, and the number of children with a complete absence of need for “rescue therapy” is 53% more than in the fluticasone group. Therapy using a combination of formoterol + budesonide as part of a single inhaler provides better control of asthma symptoms compared with budesonide alone in patients for whom ICS previously did not provide symptom control.

Impact of ICS on growth

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

Effect of ICS on bone tissue

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

Effect of ICS on the hypothalamic-pituitary-adrenal system

ICS therapy dose ICS and oral candidiasis

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

Other side effects

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

II. Leukotriene receptor antagonists

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

III. Cromony

Nedocromil and cromoglycic acid are less effective than ICS in relation to clinical symptoms, respiratory function, exercise asthma, and airway hyperresponsiveness. Long-term therapy with cromoglycic acid for asthma in children does not differ significantly in effectiveness from placebo A. Nedocromil, prescribed before physical activity, can reduce the severity and duration of bronchoconstriction caused by it. Cromones are contraindicated during exacerbation of asthma, when intensive therapy with fast-acting bronchodilators is required. The role of cromones in the basic treatment of asthma in children (especially preschoolers) is limited due to the lack of evidence of their effectiveness. A meta-analysis carried out 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 for 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 symptoms and the need to increase the volume of therapy. The test consists of 7 questions, with questions 1–4 for the child (4-point response 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 ICS is 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 AD and pollen sensitization, it is strictly forbidden to reduce the dose of the basic agents used; on the contrary, the volume of anti-inflammatory therapy for this period should be increased!

Increasing basic therapy in response to loss of asthma control

The volume of therapy should be increased if asthma control is lost (increased frequency and severity of asthma symptoms, need for inhaled β2-agonists for 1–2 days, decreased peak flow readings, or 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 lung function and bronchial hyperresponsiveness may persist. If wheezing occurs at an early age (before 2 years) in the absence of other manifestations of familial atopy, the likelihood that symptoms will persist into later life is low. In young children with frequent episodes of wheezing, a family history of asthma, and evidence of atopy, the risk of developing asthma at age 6 years is significantly increased. Male gender is a risk factor for the occurrence of asthma in the prepubertal period, but there is a high probability that the disease will disappear upon reaching adulthood. Female gender is a risk factor for the persistence of asthma in adulthood.

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

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

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

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

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

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

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

Indications for the use of inhaled corticosteroids are:

■ Bronchial asthma; ■moderate and severe COPD (spirographically confirmed response to treatment).

Bronchial asthma Inhaled steroids are effective in patients with bronchial asthma of any age and severity. They have the following therapeutic effects: ■ reduce the severity of clinical symptoms of the disease (frequency of asthma attacks, need for short-acting β2-agonists, etc.); ■ improve the quality of life of patients; ■ improve bronchial patency and reduce bronchial hyperreactivity to allergens (early and late asthmatic reaction) and nonspecific irritants (physical activity, cold air, pollutants, histamine, methacholine, adenosine, bradykinin); ■ prevent exacerbations of bronchial asthma and reduce the frequency of hospitalizations of patients; ■ reduce the mortality of oasthma; ■ prevent the development of irreversible changes (remodeling) of the respiratory tract.

Inhaled glucocorticoids are indicated for patients with moderate to severe bronchial asthma. The earlier they are prescribed, the higher the effectiveness of their treatment. The need to use these drugs in patients with mild persistent asthma is debatable. International consensus documents recommend the use of low-dose inhaled glucocorticoids or cromones or antileukotriene drugs in such patients. The advantage of non-steroidal drugs is the minimal number of side effects. Apparently, inhaled glucocorticoids are indicated for patients with mild asthma when other drugs with anti-inflammatory activity are insufficient. When using inhaled glucocorticoids, you must be guided by the following rules: ■ Treatment with these drugs should begin with the maximum dose (depending on the severity of asthma), followed by a gradual reduction to the minimum required. Despite the rapid positive dynamics of clinical symptoms, improvement in bronchial patency and bronchial hyperreactivity occurs more slowly. Typically, it takes at least 3 months to achieve a lasting effect of therapy, after which the dose of the drug can be reduced by 25%. ■ Treatment with inhaled steroids should be long-term (at least 3 months) and regular. ■ A combination of long-acting (β2-adrenergic agonists, antileukotriene drugs or long-acting theophylline drugs with inhaled steroids is more effective than increasing the dose of the latter. The use of such therapy makes it possible to reduce the dose of topical glucocorticoids. In recent years, fixed combinations of drugs have been introduced into clinical practice: FP/salmeterol, BUD/formoterol, which indicated for moderate and severe bronchial asthma. ■ The use of inhaled steroids allows you to reduce the dose of tableted glucocorticoids. It has been established that 400-600 mcg/day of BDP is equivalent to 5-10 mg of prednisolone. When used simultaneously with tablet drugs, the dose of the latter can be reduced no earlier than this period. ■ For stable bronchial asthma, inhaled glucocorticoids are used 2 times a day. Budesonide for patients with mild and moderate bronchial asthma in the remission phase can be used once. In case of exacerbation, the frequency of administration is increased to 2-4 times a day. This technique allows you to achieve higher compliance. ■ High doses of inhaled glucocorticoids can be used instead of systemic steroids to treat and prevent asthma exacerbations.

Chronic obstructive pulmonary disease

Inhaled steroids have no effect on the progressive decrease in bronchial obstruction in patients with COPD. High doses of these drugs can improve the quality of life of patients and reduce the frequency of exacerbations of moderate and severe COPD. The reasons for the relative steroid resistance of airway inflammation in COPD are the subject of scientific research. It is possible that it is due to the fact that glucocorticoids increase the lifespan of neutrophils by inhibiting their apoptosis. The molecular mechanisms underlying resistance to glucocorticoids are not well understood. In recent years, there have been reports of a decrease in the activity of histone deacetylase, which is a target for the action of steroids, under the influence of smoking and free radicals. This may reduce the inhibitory effect of glucocorticoids on the transcription of “inflammatory” genes. Recently, new data have been obtained on the effectiveness of combination drugs (salmeterol + FPiformoterol + BUD) in patients with moderate and severe COPD. It has been shown that their long-term (for 1 year) administration improves bronchial patency, reduces the severity of symptoms, the need for bronchodilators, the frequency of moderate and severe exacerbations, and also improves the quality of life of patients compared to monotherapy with inhaled glucocorticoids (long-acting β2-adrenergic agonists and placebo.

Side effects of inhaled glucocorticoids

Oropharyngeal candidiasis(less commonly - esophageal candidiasis)

According to various authors, it occurs in 5-25% of patients. It manifests itself as a burning sensation in the mouth and whitish rashes on the mucous membranes. It has been established that its development is directly proportional to the dose and frequency of administration of inhaled glucocorticoids.

Prevention of candidiasis:

■ rinsing the mouth after each inhalation;

■ use of a metered-dose aerosol spacer or powder inhaler;

■ the use of inhaled steroids in smaller doses and with a smaller frequency of administration (in the remission phase of bronchial asthma).

It is observed in 30-58% of patients. Depends on the dose of steroids and the type of dosing device. Caused by deposition of the drug in the larynx and the development of steroid myopathy of its muscles. It develops more often in people whose profession is associated with increased vocal load (singers, lecturers, teachers, announcers, etc.). To treat dysphonia use:

■ replacement of DI with powder ones;

■ reducing the dose of inhaled steroids (in the remission phase).

Irritation of the upper respiratory tract

Manifested by cough and bronchospasm. Often caused by propellants contained in MDIs. Prevention of this complication:

■ use of rapid-acting β2-agonists before inhaled glucocorticoids;

■ use of a spacer;

■ replacement of DI with powder ones.

Systemic side effects of inhaled glucocorticoids

Suppression of the hypothalamic-pituitary-adrenal axis

Manifested by a decrease in the secretion of endogenous cortisol. Typically, this side effect is observed when using high doses of BDP, TAA, FLU, BUD (> 1500 mcg/day in adults and > 400 mcg/day in children) and FP (> 500-750 mcg/day in adults and > 200 mcg/day in children).

To prevent the systemic effect of inhaled glucocorticoids, it is recommended to use their minimum required dose. The use of these drugs must be combined with long-acting β2-agonists, theophylline or leukotriene antagonists.

Steroid osteopenia and osteoporosis

A few studies have shown a decrease in the functional activity of osteoblasts in patients receiving high doses of inhaled glucocorticoids. However, most studies have not yet provided convincing evidence of the development of osteoporosis and bone fractures in adults and children taking these drugs for a long time (1-6 years), which was confirmed in a recently published meta-analysis. However, some observations have found a significant relationship between the cumulative dose of inhaled steroids and a decrease in the density of the lumbar vertebrae and hip in patients with bronchial asthma, especially in women. A small number of studies have shown that BUD and AF have a lesser effect on bone tissue than BDP when using Freon-containing DIs.

Thus, the results of the studies cited above do not completely exclude the potential for the development of osteopenic syndrome in patients taking high doses of inhaled glucocorticoids for a long time. The risk group probably includes elderly patients, postmenopausal women, patients suffering from endocrine diseases (thyroid pathology, hypogonadism), having bad habits (smoking, alcoholism) and low physical activity. Prevention of this possible side effect is recommended with the help of calcitonin preparations, calcium salts (Ca+2 content 1500 mcg/day) and vitamin D3 (400 IU/day). In women, in the absence of contraindications, estrogen replacement therapy can probably be prescribed. Normalizing physical activity and giving up bad habits is of no small importance.

Bleeding skin

It is caused by its thinning due to a decrease in the production of the main substance by skin fibroblasts. It develops more often in elderly patients receiving high doses (>1000 mcg/day) of inhaled glucocorticoids. Often combined with a decrease in cortisol secretion. This complication is usually not a significant clinical problem, but may be an indicator of the systemic effect of steroids.

Cataracts and glaucoma

Most studies have not found an association between the use of inhaled glucocorticoids and the occurrence of ocular symptoms in children and adults. However, a large population-based study conducted in Australia, The Blue Mountains Eye Study, found a more frequent (3-fold) development of posterior subcapsular cataracts in patients over 50 years of age who took BDP. A significant relationship was found between the cumulative dose of this drug and lens opacification. It has been shown that the use of high (>1000 mcg) doses of BUD and BDP for more than 2 years significantly increases the risk of developing cataracts requiring surgical treatment in patients over 70 years of age. A significantly higher incidence of open-angle glaucoma was found in patients over 65 years of age receiving BDP, BUD, TAA<>1600 mcg/day).

Thus, the data presented do not allow us to exclude the negative effect of high doses of inhaled glucocorticoids on the lens and intraocular pressure in elderly patients. However, further research is required to confirm this assumption. To prevent possible eye complications, the correct inhalation technique is recommended (the drug should not get into the eyes) and prevention of ultraviolet irradiation of the eyes (wearing dark glasses, hats, etc.).

Growth retardation (in children) High (BP > 400 mcg/day) doses of inhaled steroids can cause significant, although small, short-term (during the first year of treatment) growth retardation in children. However, long-term (4-9 years) observations have shown that children receiving BUD (> 400 mcg/day) have normal growth as adults.

The effect of inhaled glucocorticoids on the development of the lungs and other organs has not yet been sufficiently studied.

Thus, the results of the studies performed indicate the possibility of systemic side effects during treatment with inhaled glucocorticoids. Probably the risk groups for their development are: patients receiving high doses of these drugs; elderly patients; patients with concomitant diseases (diabetes mellitus, thyroid disease, hypogonadism); smokers and alcohol abusers; patients with limited physical activity. Dynamic monitoring of these patients should include: examination of the oral cavity and pharynx (to exclude fungal infection), ophthalmoscopy and measurement of intraocular pressure, bone densitometry (vertebrae, femoral neck) every 6-12 months.

Preventing possible side effects

■ Use the minimum required dose of inhaled steroids. Their use must be combined with long-acting β-adrenergic agonists, theophylline or antileukotriene drugs.

■ Use of spacers and powder inhalers.

■ Correct inhalation technique (the drug should not get into the eyes).

■ Rinse your mouth after taking steroids.

■ Prevention of ultraviolet exposure of the eyes (wearing dark glasses, hats, etc.).

■ Prescription of vitamin D3 and calcium.

■ Normalization of physical activity, giving up bad habits.

■ Patient education

Interactions

Long-acting β2-adrenergic agonists and inhaled glucocorticoids

It has been shown that long-acting β2-adrenergic agonists (salmeterol and formoterol) and inhaled glucocorticoids have a complementary effect and synergism. These drugs affect various parts of the pathological process in bronchial asthma (BA). It has been shown that steroids increase the synthesis of β2-adrenergic receptors and prevent the development of their desensitization during long-term use of β2-adrenergic receptors and under the influence of inflammatory mediators. In turn, long-acting β2-adrenergic agonists phosphorylate glucocorticoid receptors and increase their sensitivity to steroid molecules. They stimulate the translocation of cytosolic receptors into the cell nucleus and increase the residence time in it.

A meta-analysis of existing clinical observations has shown that adding salmeterol to low- and moderate-dose inhaled steroids is more effective than increasing the dose of the latter.

It has been shown that the use of a combination of budesonide and formoterol for a year significantly reduces the severity of symptoms, the frequency of exacerbations of bronchial asthma, improves the quality of life of patients and reduces the cost of treatment compared to monotherapy with low and high doses of budesonide. These data were a prerequisite for the creation of fixed combinations of salmeterol/fluticasone and formoterol/budesonide, which are highly effective agents for the treatment of bronchial asthma.

Recently, new data have been obtained on the effectiveness of combination drugs (salmeterol + FP and formoterol + BUD) in patients with moderate and severe COPD. It has been shown that their long-term (for 1 year) administration improves bronchial patency, reduces the severity of symptoms, the need for bronchodilators, the frequency of moderate and severe exacerbations, and also improves the quality of life of patients compared to monotherapy with inhaled glucocorticoids, long-acting β2-adrenergic agonists and placebo.

Theophylline and inhaled glucocorticoids

Recent studies have shown that theophylline in low doses has not only a bronchodilator, but also an anti-inflammatory effect. It is assumed that one of the mechanisms of action of this drug is the activation of histone deacetylase, leading to inhibition of the transcription of “inflammatory” genes. Glucocorticoids cause activation of the same enzyme in a different way. Thus, theophylline may enhance the anti-inflammatory activity of steroids.

Drugs

Budesonide

Trade name:

Budecort (Agio Pharmaceuticals Ltd, India) Budesonide-mite (GlaxoSmithKline, UK) Budesonide-forte (GlaxoSmithKline, UK), Budesonide

Dosage form:

dosed aerosol for inhalation, capsules with powder for inhalation, dosed powder for inhalation, solution for inhalation, dosed suspension for inhalation

see also:

Budesonide; nasal drops, dosed nasal spray

Pharmacological action:

GCS for local use has anti-inflammatory, antiallergic and immunosuppressive effects. Increases the production of lipocortin, which is an inhibitor of phospholipase A2, inhibits the release of arachidonic acid, inhibits the synthesis of arachidonic acid metabolic products - cyclic endoperoxides and Pg. Prevents the marginal accumulation of neutrophils, reduces inflammatory exudation and the production of cytokines, inhibits the migration of macrophages, reduces the severity of infiltration and granulation processes, the formation of a chemotaxis substance (which explains the effectiveness in “late” allergy reactions); inhibits the release of inflammatory mediators from mast cells (an “immediate” allergic reaction). Increases the number of “active” beta-adrenergic receptors, restores the patient’s response to bronchodilators, allowing them to reduce the frequency of their use, reduces swelling of the bronchial mucosa, mucus production, sputum formation and reduces airway hyperreactivity. Increases mucociliary transport. Has a fungicidal effect. It is well tolerated during long-term treatment, does not have MCS activity, and has virtually no resorptive effect. The therapeutic effect develops on average after 5-7 days. Inhaled budesonide can prevent an attack of bronchial asthma, but does not reduce acute bronchospasm.

Indications:

Bronchial asthma (as a basic therapy; with insufficient effectiveness of beta2-adrenergic stimulants, cromoglycic acid and ketotifen; to reduce the dose of oral corticosteroids), COPD.

Contraindications:

Side effects:

More often: cough, dry mouth, dysphonia, irritation of the pharyngeal mucosa. Less common: candidal stomatitis, dryness of the pharyngeal mucosa, headache, nausea, bruising or thinning of the skin, unpleasant taste. Rarely: severe bronchospasm, esophageal candidiasis, mental changes (nervousness, restlessness, depression or behavioral changes), allergic reactions (skin rash, contact dermatitis, urticaria).

Directions for use and dosage:

Inhalation, using a special inhaler (turbuhaler, cyclohaler, etc.). Each capsule of the inhaler contains 200 doses, one portion of the powder, separated from the capsule by the inhaler dispenser, contains 200 mcg of budesonide. 200-800 mcg/day is inhaled in 2-4 puffs. Powder for inhalation. If the previous treatment of bronchial asthma was carried out only with beta2-adrenergic stimulants or inhaled corticosteroids - 200-400 mcg (1-2 inhalations) 2 times a day; if systemic corticosteroids were used - 400-800 mcg (2-4 inhalations) 2 times a day. The maximum dose for patients receiving only beta2-agonists is 800 mcg/day; for patients previously treated with inhaled or systemic corticosteroids - 1600 mcg/day. Children over 6 years old: 1 inhalation (200 mcg/day), maximum - 2 inhalations 2 times a day (400 mcg/day). Suspension for inhalation. Adults - 1-2 mg, children 3 months-12 years old - 0.25-1 mg, if necessary, pre-diluted with 2-4 ml of NaCl solution, 2 times a day. Once the effect is achieved, the dose is reduced to the lowest effective dose necessary to maintain a stable condition. In cases where the patient has taken GCS orally, transfer to treatment with budesonide is possible in the stable phase of the disease (for 10-14 days they combine inhalation and oral GCS, then gradually reduce the dose prescribed orally until complete withdrawal).

Beclomethasone

Composition and release form

Beclazon Eco air. 250mcg 200doses

Beclazon Eco Easy breath. aer. 100mcg 200doses

Beclazon Eco Easy breath. aer. 250mcg 200doses

Becloforte: 250 mcg/1 dose: vial. 80 doses and 200 doses.

Pharmacological action

Glucocorticoid drug for inhalation use. Beclomethasone dipropionate is a precursor drug and has weak affinity for GCS receptors. Under the action of enzymes, it is converted into an active metabolite - beclomethasone-17-monopropionate (B-17-MP), which has a pronounced local anti-inflammatory effect.

Indications

– for basic anti-inflammatory therapy of various forms of bronchial asthma in adults and children aged 4 years and older, including patients with severe disease who are dependent on systemic corticosteroids.

Dosage regimen

Bekloforte is intended for inhalation use only.

Patients should be explained the preventive purpose of therapy with Becloforte, which is the need for its regular use even in the absence of symptoms of bronchial asthma.

The initial dose of beclomethasone dipropionate is selected taking into account the severity of the disease.

For adults and adolescents aged 12 years and older, the recommended initial doses of the drug for mild bronchial asthma are 500 mcg/day, moderate - 750 - 1000 mcg/day, severe - 1-2 mg/day.

The daily dose is divided into several doses.

Then, depending on the individual response to treatment, the dose of the drug can be increased until a clinical effect appears or reduced to the minimum effective dose.

The drug can be administered through a spacer (for example, Volumatic).

In children aged 4 to 12 years, a becotide inhaler containing 50 mcg of beclomethasone dipropionate per dose should be used, because The recommended initial dose of beclomethasone dipropionate for inhalation is up to 400 mcg/day.

The drug can be taken through a spacer (for example, Volumatic).

If after 7 days of treatment with Becloforte the symptoms of bronchial asthma have not decreased or have intensified, the patient should inform the doctor as soon as possible.

Side effect

Local reactions: possible candidiasis of the oral cavity and throat, hoarseness, irritation of the pharyngeal mucosa.

From the respiratory system: paradoxical bronchospasm is possible.

Allergic reactions: possible rash, hives, itching, redness and swelling of the eyes, face, lips and mucous membranes of the mouth and throat.

Systemic effects due to the action of GCS: possible decrease in the function of the adrenal cortex, osteoporosis, growth retardation in children, cataracts, glaucoma.

Contraindications

– hypersensitivity to the components of the drug.

Pregnancy and lactation

There is insufficient clinical data on the safety of Becloforte during pregnancy. Prescription is possible only in cases where the expected benefit of therapy for the mother outweighs the potential risk to the fetus.

When Becloforte is used inhaled at recommended doses, it is unlikely that concentrations of beclomethasone dipropionate in breast milk will be high. If it is necessary to use Becloforte during lactation, the expected benefits of therapy for the mother and the potential risk for the infant should be assessed.

Mometasone

Pharmacological properties:

Pharmacodynamics. Mometasone (9,21-dichloro-17[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methylpregna-1,4-diene-3,20-dione monohydrate) is a corticosteroid for inhalation with a local anti-inflammatory effect. The mechanism of the antiallergic and anti-inflammatory effects of mometasone furoate is largely due to its ability to reduce the release of inflammatory mediators. Significantly inhibits the release of leukotrienes from leukocytes in patients with allergies, inhibits the synthesis and release of interleukins 1, 5, 6, as well as tumor necrosis factor alpha (IL-1 , IL-5, IL-6 and TNF-α); is also a strong inhibitor of the production of leukotrienes, and in addition a very strong inhibitor of the production of Th2 cytokines, IL-4, IL-5 by human CD4+ T cells.

Mometasone furoate in in vitro studies demonstrated an affinity and ability to bind to human GCS receptors 16 times greater than that of dexamethasone, 7 times greater than that of triamcinolone acetonide, 5 times greater than that of budesonide, and 1.5 times more than fluticasone.

The use of Asmanex at a dose of 200–800 mcg/day led to an improvement in pulmonary function in terms of peak expiratory flow and forced expiratory volume in 1 s (FEV1), to more complete control of symptoms of bronchial asthma and reduced the need for the use of inhaled β2-adrenergic receptor agonists. Improvement in external respiratory function in some patients was noted already in the first 24 hours after the start of therapy, but the maximum effect was achieved after 1–2 weeks of use. Improvement in external respiration function persists throughout the entire treatment period. In patients with bronchial asthma, with repeated administration of Asmanex over 4 weeks at a dose of 200 mcg 2 times a day to 1200 mcg/day, no significant inhibition of the hypothalamic-pituitary-adrenal system was detected at any dose level, and a noticeable level of systemic activity was observed at a dose 1600 mcg per day. In long-term clinical trials using doses up to 800 mcg/day, no signs of suppression of the hypothalamic-pituitary-adrenal system (including a decrease in morning plasma cortisol levels) were detected.

Pharmacokinetics. Since the drug exhibits an extremely low level of systemic bioavailability (≤1%) when administered by inhalation, the pharmacokinetics of the drug have not been studied. When used in recommended doses, the concentration of the drug in the blood plasma was at or below the limit of quantitation (50 pg/ml).

After inhalation, neither the half-life nor the volume of distribution could be determined. Clinical studies have proven that part of mometasone furoate that enters the gastrointestinal tract during inhalation is completely metabolized during the first passage through the liver.

Indications: Broncho-obstructive pulmonary diseases (bronchial asthma, COPD, etc.).

Application:: the drug is intended for inhalation through the mouth. The dose depends on the severity of the disease. The drug is used for the systematic treatment of adults and children aged 12 years and older.

For mild to moderate asthma, a dose of 400 mcg is prescribed once a day. Inhalation is recommended in the evening. In some patients who have previously received inhaled corticosteroids in high doses, the use of 200 mg 2 times a day is more effective. In some patients, the maintenance dose may be reduced to 200 mcg once daily in the evening. The dose is determined individually and gradually reduced to the minimum effective.

For severe bronchial asthma, the recommended initial dose of the drug is 400 mcg 2 times a day (maximum recommended dose). After achieving effective control of the symptoms of bronchial asthma, the dose is reduced to the minimum effective.

Twisthaler is an inhaler that is activated by inhalation. Before removing the cap from the Twistheiler, make sure that the dose counter and the mark on the cap are aligned. The twisttailer is opened by turning the white cap counterclockwise while holding the colored lower part in a fixed position. The dose counter marks the use of 1 dose. After this, the patient should squeeze the mouthpiece with his lips, inhale quickly and deeply, then remove the inhaler from his mouth and hold his breath for approximately 10 seconds. You should not exhale through an inhaler. After inhalation, the cap is replaced, holding the device upright, and the next dose is loaded into the device by turning the cap clockwise while gently pressing it. The device should be kept clean and dry. The outer surface of the mouthpiece can be cleaned with a dry cloth or tissue. Twistailer cannot be washed with water.

Contraindications: hypersensitivity to the components of the drug.

Side effects: The most common side effects are oral thrush, pharyngitis, dysphonia and headache. There is no evidence of an increased risk of side effects in adolescents or patients aged 65 years and older. Systemic effects of inhaled corticosteroids may occur if they are prescribed in high doses over an extended period.

When using inhaled corticosteroids, isolated cases of glaucoma, increased intraocular pressure, and the development of cataracts have been reported. As with the use of other corticosteroids, the potential for allergic reactions, including rash, urticaria, itching and erythema, as well as angioedema of the face, lips and throat, should be taken into account.

Fluticasone

Dosage form:

dosed aerosol for inhalation, dosed powder for inhalation

Pharmacological action:

GCS for inhalation use. Suppresses the proliferation of mast cells, eosinophils, lymphocytes, macrophages, neutrophils, reduces the production and release of inflammatory mediators and other biologically active substances (histamine, Pg, leukotrienes, cytokines). In recommended doses, it has a pronounced anti-inflammatory and anti-allergic effect, which helps reduce symptoms, frequency and severity of exacerbations of diseases accompanied by airway obstruction (bronchial asthma, chronic bronchitis, emphysema). The systemic effect is minimal: in therapeutic doses it has virtually no effect on the hypothalamic-pituitary-adrenal system. Restores the patient's response to bronchodilators, allowing them to be used less often. The therapeutic effect after inhalation use begins within 24 hours, reaches a maximum within 1-2 weeks or more after the start of treatment and persists for several days after discontinuation.

Indications:

Bronchial asthma (basic therapy, including in severe cases of the disease and dependence on systemic corticosteroids), COPD.

Contraindications:

Side effects:

Local reactions: candidiasis of the oral mucosa and pharynx, hoarseness, paradoxical bronchospasm. Systemic side effects: with long-term use in high doses, concomitant or previous use of systemic GCS, in rare cases, decreased function of the adrenal cortex, osteoporosis, growth retardation in children, cataracts, and increased intraocular pressure are observed. Extremely rare - allergic reactions. Overdose. Symptoms: in case of acute overdose, a temporary decrease in the function of the adrenal cortex is possible, in case of chronic overdose - persistent suppression of their function. In case of acute overdose, emergency treatment is not required, because the function of the adrenal cortex is restored within a few days. In case of chronic overdose, it is recommended to monitor the reserve function of the adrenal cortex. Treatment should be continued in doses sufficient to maintain the therapeutic effect.

Directions for use and dosage:

Inhalation only. The drug should be used regularly, even in the absence of symptoms of the disease. The frequency of inhalations is 2 times a day. The therapeutic effect usually occurs 4-7 days after the start of treatment. In patients who have not previously taken inhaled corticosteroids, improvement may be observed within 24 hours after the start of inhalation. Depending on the individual response to treatment, the initial dose can be increased until the effect appears or decreased to the minimum effective dose. The initial dose of fluticasone propionate corresponds to 1/2 the daily dose of beclomethasone dipropionate. The drug can be administered through a spacer (for example, Volumatic). For adults and adolescents over 16 years of age, the initial dose for mild bronchial asthma is 100-250 mcg 2 times a day; moderate severity - 250-500 mcg 2 times a day; in severe cases - 0.5-1 mg 2 times a day. Children over 4 years old are prescribed 50-100 mcg 2 times a day. Dose for children 1-4 years old - 100 mcg 2 times a day. Young children require higher doses compared to older children (due to difficult delivery of the drug during inhalation - smaller bronchial lumen, use of a spacer, intense nasal breathing in young children). The drug is especially indicated for young children with severe bronchial asthma and is administered using an inhaler through a spacer with a face mask (for example, Babyhaler). For the treatment of COPD, adults are prescribed 500 mcg per day. Patients with impaired liver or kidney function, as well as elderly people, do not require dose adjustment.

Seretide Multidisc aerosol pores 100/250 mcg. 60 doses

Composition and dosage form: 1 dose of powder for inhalation contains salmeterol (in the form of xinafoate) 50 mcg and fluticasone propionate 100, 250 or 500 mcg; in the Multidisc inhaler 28 or 60 doses, 1 pc in a box.

Pharmacological action of the drug Seretide discus: Antiasthmatic, bronchodilator, anti-inflammatory.

Indications for use of the drug Seretide discus: Reversible airway obstruction, including bronchial asthma in children and adults, incl. if monotherapy with beta-agonists or glucocorticoids is insufficiently effective.

Contraindications to the use of the drug Seretide discus: Hypersensitivity.

Use during pregnancy and breastfeeding: Possible if the expected effect of therapy exceeds the potential risk to the fetus and newborn.

Side effects of the drug Seretide discus: From the nervous system and sensory organs: headache, tremor.

From the cardiovascular system and blood (hematopoiesis, hemostasis): palpitations; in predisposed patients - heart rhythm disturbances (including atrial fibrillation, supraventricular tachycardia, extrasystole).

From the respiratory system: hoarseness, paradoxical bronchospasm.

From the musculoskeletal system: arthralgia, in isolated cases - convulsions.

Allergic reactions: rash, angioedema.

Other: candidiasis of the mouth and pharynx, swelling.

Interaction: CYP3A4 inhibitors (ketoconazole, ritonavir, etc.) increase the systemic effect of fluticasone propionate.

Method of administration and dosage of Seretide discus por. 50/250 mcg. 60 doses: Inhalation. The initial dose is determined based on the dose of fluticasone propionate, which is recommended for the treatment of the disease of this severity, with its subsequent reduction to the minimum effective.

Adults and adolescents aged 12 years and older - 1 inhalation 2 times a day.

Children aged 4 years and older - one inhalation (50 mcg of salmeterol and 100 mcg of fluticasone propionate) 2 times a day.

Precautions: In case of hoarseness and oropharyngeal candidiasis, it is recommended to rinse your mouth and throat with water after inhalation. To treat candidiasis, topical antifungal drugs can be used. It is not recommended to abruptly stop treatment. The occurrence of paradoxical bronchospasm necessitates discontinuation of treatment and revision of therapy. Caution should be exercised when treating patients with active or inactive tuberculosis and thyrotoxicosis.