Inhaled corticosteroids in bronchial asthma. Pharmacokinetics of inhaled glucocorticosteroids. Influence of IGCS on bone tissue

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 maintain control over the disease for a long time. Treatment should begin with an assessment of current asthma control, and the amount of therapy should be reviewed regularly to ensure that control is being achieved.

Treatment of bronchial asthma (BA) includes:

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

PHARMACOTHERAPY

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

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

To basic therapy drugs relate:

• drugs (PM) with anti-inflammatory and / or prophylactic effect (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 efficacy is shown when using inhaled corticosteroids (IGCS). All means of basic anti-inflammatory therapy are taken daily and for a long time. The principle of regular use of basic drugs allows you to achieve control over the disease. It should be noted that in our country for the basic therapy of BA in children using combined preparations containing ICS (with a 12-hour break), only a stable dosing regimen was registered. Other schemes for the use of combined drugs in children are not allowed.

To symptomatic remedies relate:

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

Symptomatic drugs are also called emergency drugs. They should be used to eliminate bronchial obstruction and its accompanying acute symptoms (wheezing, chest tightness, cough). This regimen of drug use is called "on demand".

ROUTES OF DRUG DELIVERY

Drugs for the treatment of asthma are administered by various routes: oral, parenteral and inhalation (the latter is preferable). When choosing a device for inhalation, drug delivery efficiency, cost/efficiency, 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 aerosol inhalers (MAIs) and dry powder inhalers.

Table 1. Means of drug delivery in AD (age priorities)

Means	Recommended age group	Comments
Metered-dose aerosol inhaler (MAI)	> 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 settles in the oropharynx, it is necessary to rinse the mouth after each inhalation in order to reduce systemic absorption.
breath-activated ppm	> 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 PPIs. 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 with the use of PDI. Rinse your mouth after every use
spacer	> 4 years < 4 лет при application face mask	The use of a spacer reduces the sedimentation of the drug in the oropharynx, allows the use of PDI with greater efficiency, if a mask (complete with a spacer) is available, it can be used in children under 4 years of age
Nebulizer	< 2 лет (patients of any age, which can't use spacer or spacer/facial mask)	The optimal drug delivery vehicle for use in specialized units 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 combined agents containing glucocorticosteroids

Currently, inhaled corticosteroids are the most effective drugs for controlling asthma, therefore they are recommended for the treatment of persistent asthma of any severity. A. In school-age children with asthma, maintenance therapy with inhaled corticosteroids can control asthma symptoms, reduce the frequency of exacerbations and the number of hospitalizations, and improve the quality of life improves respiratory function, reduces bronchial hyperreactivity and reduces bronchoconstriction during exercise A. The use of inhaled corticosteroids in preschool children with asthma leads to a clinically significant improvement in the condition, including scoring of daytime and nighttime cough, wheezing and shortness of breath, physical activity, the use of rescue drugs; and the use of health system resources.

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

Table 2. Equipotent daily doses of ICS

A drug*	Low daily allowance doses (mcg)	Average daily 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 efficacy data.

Inhaled corticosteroids are part of combined drugs for the treatment of asthma. These drugs are Seretide (salmeterol + fluticasone propionate) and Symbicort (formoterol + budesonide). A large number of clinical studies have shown that the combination of long-acting β 2 -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 control of asthma than a long-acting β 2 -adrenergic agonist and ICS in separate inhalers. On the background of long-term therapy with salmeterol + fluticasone, almost every second patient can achieve complete control of asthma (according to a study that included patients aged 12 years and older). There is also a significant improvement in indicators of the effectiveness of therapy (PSV, FEV1, frequency of exacerbations, quality of life). In the event that the use of low doses of inhaled corticosteroids in children does not achieve control of asthma, a switch to combination therapy is recommended, which may be a good alternative to increasing the dose of inhaled corticosteroids. This was shown in a new prospective, multicenter, double-blind, randomized, parallel-group study of 12 weeks duration comparing the efficacy of the combination of salmeterol + fluticasone (50/100 µg twice daily) versus twice the dose of fluticasone propionate (200 µg twice daily). times a day) in 303 children aged 4–11 years with persistent symptoms of asthma, despite previous therapy with low doses of ICS. It turned out that the regular use of the combination of 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 tolerance: in the Seretide group, the increase in morning PSV is 46% higher, and the number of children with no need for "rescue therapy" is 53% more than in the fluticasone group. Therapy with the combination of formoterol + budesonide as part of a single inhaler provides better control of asthma symptoms compared with budesonide alone in patients in whom previously ICS 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 showed any statistically or clinically significant effect on the growth of ICG therapy at a dose of 100-200 mcg / day. Deceleration of linear growth is possible with long-term administration of any high-dose ICS. However, children with asthma receiving ICS achieve normal growth, although sometimes later than other children.

The effect of ICS on bone tissue

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

Influence of ICS on the hypothalamic-pituitary-adrenal system

IGCS therapy at a dose IGCS and oral candidiasis

Clinical thrush is rare and is likely associated with concomitant antibiotic therapy, high dose ICS, and high frequency of inhalation. The use of spacers and rinsing of the mouth 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 bronchoconstriction for several hours after administration. Adding antileukotriene to treatment when low-dose glucocorticosteroids are not effective provides modest clinical improvement, including a statistically significant reduction in exacerbations. Antileukotriene therapy has been shown to be clinically effective in children > 5 years of age in all grades of asthma, but these agents are generally less effective than low-dose ICS. Anti-leukotriene drugs can be used to enhance therapy in children with moderate asthma in cases where the disease is not sufficiently controlled with low-dose ICS. When using leukotriene receptor antagonists as monotherapy in patients with severe and moderate BA, a moderate improvement in lung function (in children 6 years of age and older) and BA control (in children 2 years of age and older) is noted B . Zafirlukast is moderately effective on respiratory function in children 12 years of age and older with moderate to severe asthma A.

III. Cromons

Nedocromil and cromoglycic acid are less effective than inhaled corticosteroids in relation to clinical symptoms, respiratory function, asthma of physical effort, airway hyperreactivity. Long-term therapy with cromoglycic acid in asthma in children does not differ significantly in efficacy from placebo A. Nedocromil, administered before exercise, reduces 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 therapy of asthma in children (especially preschoolers) is limited due to the lack of evidence of their effectiveness. A meta-analysis conducted in 2000 did not allow making 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 the drugs of this group cannot be used for the initial treatment of moderate and severe asthma. The use of cromones as a basic therapy is possible in patients with complete control of asthma symptoms. Cromones should not be combined with long-acting β 2 -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 the control of severe persistent atopic asthma. Omalizumab is the most studied, the first and only drug recommended for use in children over 12 years of age. The high cost of omalizumab treatment, as well as the need for monthly visits to the doctor for injection of the drug, are justified in patients requiring repeated hospitalizations, emergency medical care, using high doses of inhaled and / or systemic corticosteroids.

V. Long acting methylxanthines

Theophylline is significantly more effective than placebo in controlling asthma and improving lung function, even at doses below the commonly recommended therapeutic rangeA. However, the use of theophyllines for the treatment of asthma in children is problematic due to the potential for severe, rapid (cardiac arrhythmias, death) and delayed (behavioral, learning problems) side effects. In this connection, the use of theophyllines is possible only under strict pharmacodynamic control.

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

This group of drugs is effective in maintaining BA control (Fig. 1). On a permanent basis, they are used only in combination with ICS and are prescribed only when standard initial doses of ICS do not achieve asthma control. The effect of these drugs persists for 12 hours. Formoterol in the form of inhalation exerts its therapeutic effect (relaxation of the smooth muscles of the bronchi) after 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 the slow onset of action, salmeterol should not be used to treat acute symptoms of asthma. Since the action of formoterol develops faster than the action of salmeterol, this allows the use of formoterol not only for prevention, but also for the relief of asthma symptoms. However, according to the GINA 2006 recommendations, long-acting β 2 -adrenergic agonists can only be used in patients already receiving regular maintenance therapy with ICS.

Figure 1. Classification of β 2 -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). The drugs of this group should be prescribed only in conjunction with the basic therapy of ICS, since monotherapy with long-acting β 2 -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 who need to prescribe two or more maintenance drugs.

Oral β 2 -adrenergic agonists long-acting

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

VII. Anticholinergic drugs

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

VIII. Systemic GCS

Despite the fact that systemic corticosteroids are effective against AD, it is necessary to take into account the development of adverse events during long-term therapy, such as depression of the hypothalamic-pituitary-adrenal system, 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 the event of severe exacerbations, both against the background of a viral infection, and in its absence.

EMERGENCY REMEDIES

Fast-acting inhaled β 2 -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 medicines for asthma

A drug	Dose	Side effects	Comments
β 2 -agonists
Salbutamol (DAI)	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 (DAI)	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 (DAI) from 4 years	1 dose - 20 mcg 2-3 inhalations up to 4 times a day	Minor dryness and unpleasant taste in the mouth	Mainly used in children up to 2 years
Ipratropium bromide (solution for nebulizer therapy)	250 mcg/ml
Combined drugs
Fenoterol + ipratropium bromide (DAI)	2 inhalations up to 4 times a day	tachycardia, tremor, headache, irritability, slight dryness and bad taste in the mouth	Side effects are characteristic effects indicated for each of the incoming in combination funds
Fenoterol + ipratropium bromide (solution for nebulizer therapy)	1–2 ml
Theophylline short acting
Eufillin in any dosage form	150 mg > 3 years 12–24 mg/kg/day	Nausea, vomiting, headache, tachycardia, violations heart rate	Currently Usage eufillina 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 in asthma exacerbations showed that the use of an anticholinergic drug is accompanied by a statistically significant (albeit modest) improvement in lung function and a reduction in the risk of hospitalization.

ACHIEVING ASTHMA CONTROL

In the course of treatment, constant evaluation and correction of therapy should be carried out based on changes in the level of asthma control. The whole cycle of therapy includes:

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

Assessing the level of control over asthma

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

• minimal or no (≤ 2 episodes per week) daytime symptoms of asthma;
• lack of restrictions in daily activity and physical activity;
• absence of nocturnal symptoms and awakenings due to asthma;
• minimal or no need (≤ 2 episodes per week) for short-acting bronchodilators;
• normal or near-normal lung function;
• 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 the integral assessment of the level of control over asthma. One of these tools is the Childhood Asthma Control Test (Childhood Asthma Control Test) aged 4–11 years, a validated questionnaire that allows the doctor and patient (parent) to quickly assess the severity of asthma manifestations and the need for an increase in the volume of therapy. The test consists of 7 questions, with questions 1-4 for the child (4-point rating scale: 0 to 3 points) and questions 5-7 for parents (6-point scale: 0 to 5 points). The result of the test is the sum of marks for all answers in points (the maximum mark is 27 points). A score of 20 or more corresponds to controlled asthma, 19 or less means that asthma is not effectively controlled; the patient is advised to take the help of a doctor to revise the treatment plan. In this case, it is also necessary to ask the child and his parents about the preparations for daily use in order to make sure that the inhalation technique is correct and the treatment regimen is followed. Asthma control testing can be done at www.astmatest.ru.

Treatment to maintain control

The choice of medical therapy depends on the current level of asthma control and the patient's current therapy. So, if the current therapy does not provide control over asthma, it is necessary to increase the volume of therapy (move to a higher stage) until control is achieved. In the case of maintaining control over BA for 3 months or more, it is possible to reduce the amount of maintenance therapy in order to achieve the minimum amount of therapy and the lowest doses of drugs sufficient to maintain control. If partial control of asthma is achieved, consideration should be given to increasing the volume of therapy, 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 achieved level of control.

Most drugs for the treatment of AD have favorable benefit/risk profiles compared with drugs for the treatment of other chronic diseases. Each stage includes treatment options that can serve as alternatives for the choice of maintenance therapy for asthma, although they are not the same in terms of effectiveness. The volume of therapy increases from step 2 to step 5; although at step 5 the choice of treatment also depends on the availability and safety of drugs. In the majority of patients with symptoms of persistent asthma who have not previously received maintenance therapy, treatment should begin at stage 2. If asthma symptoms at the initial examination are extremely pronounced and indicate lack of control, treatment should be started at stage 3 (Table 4). Patients should use rapid-acting bronchodilators at each stage of therapy to provide rapid relief of asthma symptoms. However, the regular use of drugs 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 emergency drugs is an important goal of treatment and a criterion for the effectiveness of therapy.

Table 4 Correspondence of therapy steps to the clinical characteristics of AD

Stages of therapy	Clinical characteristics of patients
Stage 1	Short-term (up to several hours) daytime symptoms of asthma (cough, wheezing, dyspnea occurring ≤ 2 times a week or even more rarely nocturnal symptoms). In the interictal period, there are no manifestations of asthma and nocturnal awakenings, lung function is within normal limits. PSV ≥ 80% of the expected values
Stage 2	Symptoms of asthma more often than 1 time per week, but less than 1 time per day. Exacerbations can interfere with patients' activity and nocturnal sleep. Night symptoms more than 2 times a month. Functional indicators of external respiration within the age norm. In the interictal period, there are no manifestations of asthma and nocturnal awakenings, exercise tolerance is not reduced. PSV ≥ 80% of the expected values
Step 3	Asthma symptoms occur daily. Exacerbations disrupt the child's physical activity and night sleep. Nighttime symptoms more than once a week. In the interictal period, episodic symptoms are noted, changes in the function of external respiration persist. Exercise tolerance may be reduced. PSV 60–80% of the expected values
Step 4	Frequent (several times a week or daily, several times a day) occurrence of asthma symptoms, frequent nocturnal asthma attacks. Frequent exacerbations of the disease (1 time in 1-2 months). Limitation of physical activity and severe violations of the function of external respiration. In the period of remission, clinical and functional manifestations of bronchial obstruction persist. PSV ≤ 60% of the expected values
Step 5	Daily day and night symptoms, several times a day. Severe limitation of physical activity. Severe pulmonary dysfunction. Frequent exacerbations (1 time per month or more). In 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 drugs to relieve symptoms on demand, is intended only for patients who have not received maintenance therapy. Patients with more frequent onset of symptoms or episodic worsening of symptoms should receive regular maintenance therapy (in addition to drugs to relieve symptoms as needed.

Steps 2-5 include a combination of a drug to relieve symptoms (as needed) with regular maintenance therapy. Low-dose ICS are recommended as initial maintenance therapy for asthma in patients of any age at stage 2. Alternative agents are 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.

In step 3, a combination of a low-dose ICS with a long-acting inhaled (β 2 -agonist) fixed combination is recommended. Due to the additive effect of combination therapy, low doses of ICS are usually sufficient for patients; an increase in the dose of ICS is required only for patients whose asthma is under control. The long-acting β2-agonist formoterol, which has a rapid onset of action when used as monotherapy or as part of a fixed combination with budesonide, has been shown to be no less effective in relieving acute manifestations of AD than Short-acting β 2 agonists.However, formoterol monotherapy for symptomatic relief is not recommended, and this drug should always be used only together with ICS.In all children, and especially in children aged 5 years and younger, combination therapy has been studied to a lesser extent, than in adults.However, a recent study showed that that adding a long-acting β2-agonist is more effective than increasing the dose of ICS. The second treatment option is to increase the doses of ICS to medium doses. For patients of any age receiving medium or high doses of ICS using PAI, the use of a spacer is recommended to improve the delivery of the drug to the respiratory tract, reduce the risk of oropharyngeal side effects and systemic absorption of the drug. Another alternative treatment option in Step 3 is the combination of a low-dose ICS with an antileukotriene. A low dose of sustained release theophylline may be used instead of an antileukotriene. These treatment options have not been studied in children aged 5 years and younger.

The choice of drugs for steps 4 depends on prior prescribing at steps 2 and 3. However, the order in which additional drugs are added should be based on evidence of comparative efficacy from clinical trials. Patients who have not achieved control of asthma at stage 3 should be referred (if possible) to an asthma specialist to rule out alternative diagnoses and/or causes of asthma that are difficult to treat. The preferred approach to treatment at step 4 is the use of a combination of corticosteroids in a medium or high dose with a long-acting inhaled β 2 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 the effect of treatment against the background of the use of high doses of glucocorticosteroids in combination with long-acting β 2 -agonists and other drugs for maintenance therapy. The addition of oral corticosteroids to other maintenance drugs 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 BA

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

Another scheme for reducing the amount of basic therapy in patients receiving inhaled corticosteroids and a long-acting β 2 agonist and involves the abolition of the latter at the first stage while continuing with monotherapy with inhaled corticosteroids 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, while maintaining complete control over BA. Monotherapy with a long-acting β 2 -agonist 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 with the use of the minimum dose of anti-inflammatory drug, the absence of recurrence of symptoms within one year D .

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

Increasing the volume of basic therapy in response to loss of asthma control

The volume of therapy should be increased in case of loss of control over BA (increase in the frequency and severity of BA symptoms, the need for inhaled β 2 -agonists for 1–2 days, a decrease in peak flow measurements or a deterioration in exercise tolerance). The volume of BA therapy is adjusted throughout the year in accordance with the spectrum of sensitization of causally significant allergens. A combination of bronchodilators (β 2 -agonists, anticholinergics, methylxanthines) and corticosteroids is used to relieve acute bronchial obstruction in patients with BA. Preference should be given to inhaled delivery forms, which allow to achieve a rapid effect with minimal overall impact on the child's body.

The current recommendations for dose reduction of various baseline drugs 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 a reduced volume of therapy on inflammation activity and structural changes. with asthma. Thus, recommendations to reduce the volume of therapy require further research aimed at evaluating the processes underlying the disease, and not just the clinical manifestations.

PATIENT TRAINING

Education is a necessary part of a comprehensive treatment program for children with AD, and involves the establishment of a partnership between the patient, his family and the healthcare professional.

Objectives of educational programs:

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

FORECAST

In children with recurrent episodes of wheezing associated with SARS, without signs of atopy and atopic diseases in the family history, the symptoms of asthma usually disappear at preschool age and do not develop further, although minimal changes in lung function and bronchial hyperreactivity may persist. If wheezing occurs at an early age (before 2 years of age) 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 manifestations of atopy, the risk of developing asthma at the age of 6 years is significantly increased. Male gender is a risk factor for AD in the prepubertal period, but there is a high probability that the disease will disappear by 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 DPO "Russian Medical Academy of Postgraduate Education" of Roszdrav, Professor, Dr. 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 Scientific Center for Children's Health of the Russian Academy of Medical Sciences, Head of the Department of Allergology and Clinical Immunology of the Federal Educational Institution of Pediatrics of the State Educational Institution of Higher Professional Education “Moscow Medical Academy named after I.I. 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 Children's Diseases of the Medical Faculty of the 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, Ph.D. honey. Sciences

Galina Ivanovna Smirnova, Professor, Department of Pediatrics, Moscow Medical Academy named after V.I. THEM. Sechenov» Roszdrav, Dr. med. Sciences

Boris Anatolievich Chernyak, Head of the Department of Allergology and Pulmonology, Irkutsk State Institute for Postgraduate Medical Education, Roszdrav

For citation: Sutochnikova O.A. INHALATION GLUCOCORTICOSTEROIDS ARE THE MOST EFFECTIVE AND SAFE ANTI-INFLAMMATORY DRUGS FOR THE TREATMENT OF ASTHMA // BC. 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 therapeutical 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 of the last twenty-five years indicate that the incidence of asthma has reached the level of 5% among the adult population, and among children - 10%, representing a serious social, epidemiological and medical problem, attracting close attention of 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 drugs 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 AD, 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 inflammatory effector 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 1940s, doctors began to use systemic corticosteroids for the treatment of 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 stomach and intestinal ulcers, frequent occurrence of opportunistic infections, myopathies, which limits their clinical use.
Pharmacokinetics of inhaled corticosteroids

Index	A drug
	triamcinolone 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 the 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 a free and bound state. 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 the 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, which increases the period of their biological action. Only 60% of systemic corticosteroids bind to plasma protein, and 40% circulate 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 (Shimbach et al., 1988). It is difficult to dissociate the positive anti-asthma effect from the adverse systemic effects of oral steroids, and asthma is a disease of the respiratory tract, and therefore it has been suggested that topical corticosteroids may be used.

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 proved ineffective (Brokbank et al., 1956; Langlands et al., 1960) due to the fact that they had a low anti-asthma and high systemic effect, which can be compared with the effect of tableted corticosteroids. In the early 1970s, a group of fat-soluble corticosteroids for topical use by aerosol was synthesized, which, unlike water-soluble ones, had high local anti-inflammatory activity, were characterized by low systemic action or its absence within the therapeutic concentration. The clinical efficacy of this form of drugs has been shown in a number of experimental studies (Clark, 1972; Morrow-Brown et al., 1972). The most significant in the local anti-inflammatory action of inhaled corticosteroids is (Borson et al., 1991; Cox et al., 1991; Venge et al., 1992):

• inhibition of synthesis or decrease in IgE-dependent release of inflammatory mediators from leukocytes;
• reduced survival of eosinophils and the 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;
• decrease in the permeability of the epithelium of the respiratory tract and plasma exudation through the endothelial-epithelial barrier;
• decrease in 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 limits the release of various proteolytic enzymes outside the lysosomes and prevents destructive processes in the wall of the bronchial tree. They inhibit the proliferation of fibroblasts and reduce the synthesis of collagen, 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 repair of damaged bronchial epithelium (Laitinen et al., 1991a,b), reduce non-specific bronchial hyperreactivity (Juniper et al., 1991; Sterk, 1994).
Inhalation 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 with dependence on systemic corticosteroids reduces the need for their continuous intake. It has been established that inhaled corticosteroids do not have a side effect 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 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, when analyzing bronchobiopsies in patients receiving inhaled corticosteroids, it was found that the ratio of goblet and ciliated cells increases to a level similar to that observed in healthy volunteers (Laitinen, 1994), and when analyzing the 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 decreases, the production and release of adrenocorticotropic hormone (ACTH) by the pituitary gland decreases, and, as a result, the production of cortisol by the adrenal glands decreases (Taylor et al., 1988).
Long-term treatment with systemic corticosteroids tends to suppress the function of the hypothalamic-pituitary-adrenal system. There were significant individual differences in the pituitary response to corticotropin-releasing factor, while the dose of prednisolone received every other day did not explain these differences (Schurmeyer et al., 1985). The value of persistent adrenocortical hypofunction in patients who are dependent on systemic corticosteroids should not be underestimated (Yu. S. Landyshev et al., 1994), since acute severe asthma episodes that develop against such a background can be fatal.
Of great interest is the degree of hypothalamic-pituitary-adrenal suppression with the use of inhaled corticosteroids (Broide 1995; Jennings et al., 1990; 1991). Inhaled corticosteroids have a moderate systemic effect due to the part 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, are rapidly 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 systemic adverse events (Selroos et al., 1991). The effect of inhaled corticosteroids on the hypothalamic-pituitary-adrenal system in patients who have not previously taken them is significantly less than in patients who have used inhaled corticosteroids previously (Toogood et al., 1992). The frequency and severity of suppression increase with the use of high doses of inhaled corticosteroids in patients receiving both systemic and inhaled corticosteroid therapy, and when long-term therapy with systemic corticosteroids is replaced with high-dose inhaled corticosteroids (Brown et al., 1991; Wong et al., 1992) . The existing suppression of the hypothalamic-pituitary-adrenal system can be restored, but this process can be delayed up to three years or more. Systemic side effects of inhaled corticosteroids include partial eosinopenia (Chaplin et al., 1980; Evans et al., 1991; 1993). The development of osteoporosis, growth retardation, and cataract formation with inhaled corticosteroids continues to be debated (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 and receiving inhaled corticosteroids is more often associated with disorders in puberty, but does not depend on 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 cross the placental barrier, causing teratogenic and fetotoxic effects. However, the clinical use of low and medium therapeutic doses of these drugs by pregnant women with 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). However, 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 inhibitory effect of inhaled corticosteroids on the protective functions of neutrophils, macrophages and T-lymphocytes on their mucosal surface (Toogood et al., 1984). Dysphonia with the use of inhaled corticosteroids has been associated with dyskinesia of the musculature that controls vocal cord tension (Williams et al., 1983). Non-specific irritation of the vocal cords by the propellant - freon, contained in a metered-dose aerosol inhaler as a propellant gas, can also cause dysphonia. The most frequent, severe dysphonia is observed in patients who, by the nature of their activities, have a load on the vocal cords - priests, dispatchers, teachers, trainers, etc. (Toogood et al., 1980).

Modern inhaled corticosteroids

Currently, the main drugs in the group of inhaled corticosteroids include the following: beclomethasone dipropionate, betamethasone valerate, budesonide, triamcinolone acetonide, flunisolide and fluticasone propionate, which are widely used in the world pulmonological practice and have high efficiency (Harding, 1990; Svendsen, 1990; Toogood and et 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 inhaled corticosteroids, budesonide has the most favorable therapeutic index (Dahl et al. 1994; Johansson et al. 1982; Phillips 1990) due to its high glucocorticoid receptor affinity and accelerated metabolism after systemic absorption in the lungs and intestines ( Anderson et al., 1984; Brattsand et al. 1982; Chaplin et al., 1980; Clissold et al., 1984; Phillips 1990; Ryrfeldt et al., 1982).
For inhaled corticosteroids (aerosol form), it was found that 10% of the drug enters the lungs, and 70% remains in the oral cavity and large bronchi (IM Kakhanovsky et al., 1995; Dahl et al., 1994). Patients have different sensitivity to inhaled corticosteroids (N. R. Paleev et al., 1994; Bogaska, 1994). Children are known to 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 is presented in the table.

Dosage and drug combination issues

Inhaled and systemic corticosteroids show a cumulative effect 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 the 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 inhalers are effective and reliable in patients with mild asthma, in short disease periods, and in most patients with moderately severe chronic asthma (Lee et al., 1991; Reed, 1991). An increased dose is necessary to achieve rapid control of asthma symptoms (Boe, 1994; Toogood, 1977; 1983). Continue treatment, if necessary, with high doses of inhaled corticosteroids until normalization or improvement of respiratory function (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 the combined use of inhaled and systemic corticosteroids is clinically necessary, the dose of each drug should be selected as minimally effective 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 the effect of the use of low or medium doses of inhalation 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, high doses of inhaled corticosteroids increase the risk of oropharyngeal complications and decreased morning plasma cortisol levels (Toogood et al., 1977). To select the optimal dosage and regimen for taking inhaled drugs, indicators of the function of external respiration, daily monitoring of peak flowmetry should be used. For long-term maintenance of disease remission, 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 AD is justified, which makes it possible 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 are achieved within 3 months of taking inhaled corticosteroids (IM 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 cases, such a decrease was achieved only after 15 months of treatment. With abrupt withdrawal of inhaled corticosteroids in patients with moderate asthma who were treated with low doses of inhaled drugs, 50% of cases relapse after 10 days and 100% after 50 days (Toogood et al., 1990). On the other hand, long-term and regular use of inhaled corticosteroids increases the disease remission period to 10 years or more (Boe et al., 1989).

Routes of administration of inhaled corticosteroids

The disadvantage of inhaled corticosteroids is the very method of drug administration, which requires special patient training. 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 a violation of the technique of inhalation. Many patients use the aerosol inhaler incorrectly, and poor inhalation technique is a major factor in its extremely poor performance (Crompton, 1982). Spacers and similar nozzles for aerosol inhalers eliminate the problem of synchronization of inhalation and dose release, reduce drug retention in the larynx, increase delivery to the lungs (Newman et al., 1984), reduce the incidence and severity of oropharyngeal candidiasis (Toogood et al., 1981; 1984 ), hypothalamic-pituitary-adrenal suppression (Prachl et al., 1987), increase anti-inflammatory efficacy. The use of a spacer is recommended when antibiotics or additional systemic corticosteroids are clinically needed (Moren, 1978). However, it is not yet possible to completely exclude local side effects in the form of oropharyngeal candidiasis, dysphonia, and sporadic cough. To eliminate them, a sparing voice mode, a decrease in the daily dose of corticosteroids are recommended (Moren, 1978).
A longer breath-hold after inhalation may reduce the deposition of the drug during exhalation in the oropharynx (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 has been 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 irritant effect of propellants and the retention of particles of the drug in the airways, improper inhalation technique, exacerbation of a concomitant respiratory tract infection, or a recent exacerbation of the underlying disease, after which increased hyperreactivity of the airways persists . In this case, most of the dose is thrown out with a reflex cough and there is an erroneous opinion about the ineffectiveness of the drug (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, and improving mucociliary clearance. Taken together, this will allow the inhaled drug to enter the peripheral respiratory tract, and not settle in the trachea and large bronchi, where the deposition of particles causes reflex cough and bronchospasm.
Given these side effects and some of the problems in the use of aerosol corticosteroids, inhaled corticosteroids in the form of a dry powder have been 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) because they are activated by breathing due to the maximum inspiratory rate, which eliminates the problem of coordinating inspiration with the release of the drug dose, in the absence of the toxic effect of the propellant. . Dry powder inhalers are environmentally friendly because they do not contain chlorofluorocarbons. In addition, dry powder inhaled corticosteroids have a more pronounced local anti-inflammatory effect and have advantages in clinical efficacy (De Graaft et al., 1992; Lundback, 1993).

Conclusion

Inhaled corticosteroids are currently the most effective anti-inflammatory drugs for the treatment of AD. Studies have shown their effectiveness, which manifested itself 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 main rule of corticosteroid therapy is the use of drugs in the minimum effective dose for the shortest possible period of time necessary to achieve the 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 tableted corticosteroids. This therapy has significantly less 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 respiratory function and daily monitoring of peak flow measurements should be used. The dose of corticosteroids should always be reduced gradually. Continuous monitoring of patients receiving corticosteroids is important to detect adverse reactions and ensure the 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. Proper inhalation technique accounts for 50% of success in the treatment of patients with bronchial asthma, which requires the development and implementation of methods for the correct use of inhalation devices in everyday practice in order to achieve the maximum effectiveness of inhaled drugs. It must be remembered that an 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 the drugs used.

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A complete list of references is available in the editorial

Glucocorticoids are steroid hormones synthesized by the adrenal cortex. Natural glucocorticoids and their synthetic analogues are used in medicine for adrenal insufficiency. In addition, in some diseases, anti-inflammatory, immunosuppressive, anti-allergic, anti-shock and other properties of these drugs are used.

The beginning of the use of glucocorticoids as drugs (drugs) refers to the 40s. XX century. Back in the late 30s. of the last century, it was shown that hormonal compounds of a steroid nature are formed in the adrenal cortex. In 1937, the mineralocorticoid deoxycorticosterone was isolated from the adrenal cortex, in the 40s. - glucocorticoids cortisone and hydrocortisone. A wide range of pharmacological effects of hydrocortisone and cortisone predetermined the possibility of their use as drugs. Their synthesis was soon carried out.

The main and most active glucocorticoid formed in the human body is hydrocortisone (cortisol), others, less active, are cortisone, corticosterone, 11-deoxycortisol, 11-dehydrocorticosterone.

The production of adrenal hormones is under the control of the central nervous system and is closely related to the function of the pituitary gland. Pituitary adrenocorticotropic hormone (ACTH, corticotropin) is a physiological stimulant of the adrenal cortex. Corticotropin enhances the formation and release of glucocorticoids. The latter, in turn, affect the pituitary gland, inhibiting the production of corticotropin and thus reducing further stimulation of the adrenal glands (by the principle of negative feedback). Long-term administration of glucocorticoids (cortisone and its analogs) into the body can lead to inhibition and atrophy of the adrenal cortex, as well as to inhibition of the formation of not only ACTH, but also gonadotropic and thyroid-stimulating hormones of the pituitary gland.

Cortisone and hydrocortisone have found practical use as drugs from natural glucocorticoids. Cortisone, however, is more likely than other glucocorticoids to cause side effects and, due to the advent of more effective and safer drugs, is currently of limited use. In medical practice, natural hydrocortisone or its esters (hydrocortisone acetate and hydrocortisone hemisuccinate) are used.

A number of synthetic glucocorticoids have been synthesized, among which are non-fluorinated (prednisone, prednisolone, methylprednisolone) and fluorinated (dexamethasone, betamethasone, triamcinolone, flumethasone, etc.) glucocorticoids. These compounds tend to be more active than natural glucocorticoids and act at lower doses. The action of synthetic steroids is similar to the action of natural corticosteroids, but they have a different ratio of glucocorticoid and mineralocorticoid activity. Fluorinated derivatives have a more favorable ratio between glucocorticoid/anti-inflammatory and mineralocorticoid activity. Thus, the anti-inflammatory activity of dexamethasone (compared to that of hydrocortisone) is 30 times higher, betamethasone - 25-40 times, triamcinolone - 5 times, while the effect on water-salt metabolism is minimal. Fluorinated derivatives are distinguished not only by high efficiency, but also by low absorption when applied topically, i.e. less likely to develop systemic side effects.

The mechanism of action of glucocorticoids at the molecular level is not fully understood. It is believed that the effect of glucocorticoids on target cells is carried out mainly at the level of regulation of gene transcription. It is mediated by the interaction of glucocorticoids with specific intracellular glucocorticoid receptors (alpha isoform). These nuclear receptors are capable of binding to DNA and belong to the family of ligand-sensitive transcriptional regulators. Glucocorticoid receptors are found in almost all cells. In different cells, however, the number of receptors varies, they can also differ in molecular weight, hormone affinity, and other physicochemical characteristics. In the absence of the hormone, intracellular receptors, which are cytosolic proteins, are inactive and are part of heterocomplexes, which also include heat shock proteins (heat shock protein, Hsp90 and Hsp70), immunophilin with a molecular weight of 56000, etc. Heat shock proteins help maintain the optimal conformation of the hormone-binding receptor domain and provide a high affinity of the receptor for the hormone.

After penetration through the membrane into the cell, glucocorticoids bind to receptors, which leads to the activation of the complex. In this case, the oligomeric protein complex dissociates - heat shock proteins (Hsp90 and Hsp70) and immunophilin are detached. As a result, the receptor protein included in the complex as a monomer acquires the ability to dimerize. Following this, the resulting “glucocorticoid + receptor” complexes are transported to the nucleus, where they interact with DNA regions located in the promoter fragment of the steroid-responding gene - the so-called. glucocorticoid response elements (GRE) and regulate (activate or suppress) the process of transcription of certain genes (genomic effect). This leads to stimulation or suppression of mRNA formation and changes in the synthesis of various regulatory proteins and enzymes that mediate cellular effects.

Recent studies show that GC receptors interact, in addition to GRE, with various transcription factors, such as transcription activator protein (AP-1), nuclear factor kappa B (NF-kB), etc. It has been shown that nuclear factors AP-1 and NF-kB are regulators of several genes involved in the immune response and inflammation, including genes for cytokines, adhesion molecules, proteinases, and others.

In addition, another mechanism of action of glucocorticoids has recently been discovered, associated with the effect on transcriptional activation of the cytoplasmic inhibitor of NF-kB, IkBa.

However, a number of effects of glucocorticoids (for example, the rapid inhibition of ACTH secretion by glucocorticoids) develop very quickly and cannot be explained by gene expression (the so-called extragenomic effects of glucocorticoids). Such properties may be mediated by non-transcriptor mechanisms, or by interaction with glucocorticoid receptors on the plasma membrane found in some cells. It is also believed that the effects of glucocorticoids can be realized at different levels depending on the dose. For example, at low concentrations of glucocorticoids (>10 -12 mol/l), genomic effects are manifested (their development requires more than 30 minutes), at high concentrations, they are extragenomic.

Glucorticoids cause many effects, tk. affect most cells in the body.

They have anti-inflammatory, desensitizing, anti-allergic and immunosuppressive effects, anti-shock and anti-toxic properties.

The anti-inflammatory effect of glucocorticoids is due to many factors, the leading of which is the suppression of the activity of phospholipase A 2 . At the same time, glucocorticoids act indirectly: they increase the expression of genes encoding the synthesis of lipocortins (annexins), induce the production of these proteins, one of which, lipomodulin, inhibits the activity of phospholipase A 2 . The inhibition of this enzyme leads to the suppression of the liberation of arachidonic acid and inhibition of the formation of a number of inflammatory mediators - prostaglandins, leukotrienes, thromboxane, platelet activating factor, etc. In addition, glucocorticoids reduce the expression of the gene encoding the synthesis of COX-2, further blocking the formation of pro-inflammatory prostaglandins.

In addition, glucocorticoids improve microcirculation in the focus of inflammation, cause capillary vasoconstriction, and reduce fluid exudation. Glucocorticoids stabilize cell membranes, incl. membranes of lysosomes, preventing the release of lysosomal enzymes and thereby reducing their concentration at the site of inflammation.

Thus, glucocorticoids affect the alterative and exudative phases of inflammation and prevent the spread of the inflammatory process.

Limiting the migration of monocytes to the focus of inflammation and inhibition of fibroblast proliferation determine the antiproliferative effect. Glucocorticoids inhibit the formation of mucopolysaccharides, thereby limiting the binding of water and plasma proteins in the focus of rheumatic inflammation. They inhibit the activity of collagenase, preventing the destruction of cartilage and bones in rheumatoid arthritis.

The antiallergic effect develops as a result of a decrease in the synthesis and secretion of allergy mediators, inhibition of the release of histamine and other biologically active substances from sensitized mast cells and basophils, a decrease in the number of circulating basophils, suppression of the proliferation of lymphoid and connective tissues, a decrease in the number of T- and B-lymphocytes, mast cells , reducing the sensitivity of effector cells to allergy mediators, inhibition of antibody formation, changes in the body's immune response.

A characteristic feature of glucocorticoids is their immunosuppressive activity. Unlike cytostatics, the immunosuppressive properties of glucocorticoids are not associated with a mitostatic effect, but are the result of suppression of various stages of the immune response: inhibition of the migration of bone marrow stem cells and B-lymphocytes, suppression of the activity of T- and B-lymphocytes, and inhibition of the release of cytokines (IL -1, IL-2, interferon-gamma) from leukocytes and macrophages. In addition, glucocorticoids reduce the formation and increase the breakdown of the components of the complement system, block the Fc receptors of immunoglobulins, and suppress the functions of leukocytes and macrophages.

The anti-shock and antitoxic effect of glucocorticoids is associated with an increase in blood pressure (due to an increase in the amount of circulating catecholamines, restoration of the sensitivity of adrenoreceptors to catecholamines and vasoconstriction), activation of liver enzymes involved in the metabolism of endo- and xenobiotics.

Glucocorticoids have a pronounced effect on all types of metabolism: carbohydrate, protein, fat and mineral. On the part of carbohydrate metabolism, this is manifested by the fact that they stimulate gluconeogenesis in the liver, increase the content of glucose in the blood (glucosuria is possible), and contribute to the accumulation of glycogen in the liver. The effect on protein metabolism is expressed in the inhibition of protein synthesis and the acceleration of protein catabolism, especially in the skin, in muscle and bone tissue. This is manifested by muscle weakness, atrophy of the skin and muscles, and slower wound healing. These drugs cause a redistribution of fat: they increase lipolysis in the tissues of the extremities, contribute to the accumulation of fat mainly in the face (moon-shaped face), shoulder girdle, and abdomen.

Glucocorticoids have mineralocorticoid activity: they retain sodium and water in the body by increasing reabsorption in the renal tubules, and stimulate the excretion of potassium. These effects are more typical for natural glucocorticoids (cortisone, hydrocortisone), to a lesser extent - for semi-synthetic ones (prednisone, prednisolone, methylprednisolone). The mineralocorticoid activity of fludrocortisone predominates. Fluorinated glucocorticoids (triamcinolone, dexamethasone, betamethasone) have practically no mineralocorticoid activity.

Glucocorticoids reduce the absorption of calcium in the intestine, promote its release from the bones and increase the excretion of calcium by the kidneys, resulting in the development of hypocalcemia, hypercalciuria, glucocorticoid osteoporosis.

After taking even one dose of glucocorticoids, changes in the blood are noted: a decrease in the number of lymphocytes, monocytes, eosinophils, basophils in the peripheral blood with the simultaneous development of neutrophilic leukocytosis, an increase in the content of erythrocytes.

With prolonged use, glucocorticoids suppress the function of the hypothalamus-pituitary-adrenal glands.

Glucocorticoids differ in activity, pharmacokinetic parameters (degree of absorption, T 1/2, etc.), methods of application.

Systemic glucocorticoids can be divided into several groups.

According to their origin, they are divided into:

Natural (hydrocortisone, cortisone);

Synthetic (prednisolone, methylprednisolone, prednisone, triamcinolone, dexamethasone, betamethasone).

According to the duration of action, glucocorticoids for systemic use can be divided into three groups (in brackets - biological (from tissues) half-life (T 1/2 biol.):

Short-acting glucocorticoids (T 1/2 biol. - 8-12 hours): hydrocortisone, cortisone;

Glucocorticoids of medium duration of action (T 1/2 biol. - 18-36 hours): prednisolone, prednisone, methylprednisolone;

Long-acting glucocorticoids (T 1/2 biol. - 36-54 h): triamcinolone, dexamethasone, betamethasone.

The duration of action of glucocorticoids depends on the route / site of administration, the solubility of the dosage form (mazipredone is a water-soluble form of prednisolone), and the dose administered. After oral or intravenous administration, the duration of action depends on T 1/2 biol., With intramuscular administration - on the solubility of the dosage form and T 1/2 biol., After local injections - on the solubility of the dosage form and the specific route / site introductions.

When taken orally, glucocorticoids are rapidly and almost completely absorbed from the gastrointestinal tract. C max in the blood is noted after 0.5-1.5 hours. Glucocorticoids bind in the blood to transcortin (corticosteroid-binding alpha 1-globulin) and albumin, and natural glucocorticoids bind to proteins by 90-97%, synthetic ones by 40-60% . Glucocorticoids penetrate well through histohematic barriers, incl. through the BBB, pass through the placenta. Fluorinated derivatives (including dexamethasone, betamethasone, triamcinolone) pass through the histohematic barriers worse. Glucocorticoids undergo biotransformation in the liver with the formation of inactive metabolites (glucuronides or sulfates), which are excreted mainly by the kidneys. Natural drugs are metabolized faster than synthetic drugs and have a shorter half-life.

Modern glucocorticoids are a group of drugs widely used in clinical practice, incl. in rheumatology, pulmonology, endocrinology, dermatology, ophthalmology, otorhinolaryngology.

The main indications for the use of glucocorticoids are collagenosis, rheumatism, rheumatoid arthritis, bronchial asthma, acute lymphoblastic and myeloblastic leukemia, infectious mononucleosis, eczema and other skin diseases, various allergic diseases. For the treatment of atopic, autoimmune diseases, glucocorticoids are the basic pathogenetic agents. Glucocorticoids are also used for hemolytic anemia, glomerulonephritis, acute pancreatitis, viral hepatitis and respiratory diseases (COPD in the acute phase, acute respiratory distress syndrome, etc.). In connection with the anti-shock effect, glucocorticoids are prescribed for the prevention and treatment of shock (post-traumatic, surgical, toxic, anaphylactic, burn, cardiogenic, etc.).

The immunosuppressive effect of glucocorticoids makes it possible to use them in organ and tissue transplantation to suppress the rejection reaction, as well as in various autoimmune diseases.

The main principle of glucocorticoid therapy is to achieve the maximum therapeutic effect with minimal doses. The dosage regimen is selected strictly individually, to a greater extent depending on the nature of the disease, the patient's condition and the response to the treatment, than on age or body weight.

When prescribing glucocorticoids, it is necessary to take into account their equivalent doses: according to the anti-inflammatory effect, 5 mg of prednisolone correspond to 25 mg of cortisone, 20 mg of hydrocortisone, 4 mg of methylprednisolone, 4 mg of triamcinolone, 0.75 mg of dexamethasone, 0.75 mg of betamethasone.

There are 3 types of glucocorticoid therapy: substitution, suppressive, pharmacodynamic.

Replacement therapy glucocorticoids is necessary for adrenal insufficiency. In this type of therapy, physiological doses of glucocorticoids are used, in stressful situations (for example, surgery, trauma, acute illness), the doses are increased by 2-5 times. When prescribing, the daily circadian rhythm of endogenous secretion of glucocorticoids should be taken into account: at 6-8 o'clock in the morning, most (or all) of the dose is prescribed. In chronic adrenal insufficiency (Addison's disease), glucocorticoids can be used throughout life.

Suppressive therapy glucocorticoids is used for adrenogenital syndrome - congenital dysfunction of the adrenal cortex in children. At the same time, glucocorticoids are used in pharmacological (supraphysiological) doses, which leads to suppression of ACTH secretion by the pituitary gland and a subsequent decrease in the increased secretion of androgens by the adrenal glands. Most (2/3) of the dose is administered at night in order to prevent the peak of ACTH release, according to the principle of negative feedback.

Pharmacodynamic therapy used most often, incl. in the treatment of inflammatory and allergic diseases.

There are several types of pharmacodynamic therapy: intensive, limiting, long-term.

Intensive pharmacodynamic therapy: used in acute, life-threatening conditions, glucocorticoids are administered intravenously, starting with large doses (5 mg / kg - day); after the patient exits the acute state (1-2 days), glucocorticoids are canceled immediately, simultaneously.

Limiting pharmacodynamic therapy: prescribed for subacute and chronic processes, incl. inflammatory (systemic lupus erythematosus, systemic scleroderma, polymyalgia rheumatica, severe bronchial asthma, hemolytic anemia, acute leukemia, etc.). The duration of therapy is, as a rule, several months, glucocorticoids are used in doses exceeding physiological (2-5 mg / kg / day), taking into account the circadian rhythm.

To reduce the inhibitory effect of glucocorticoids on the hypothalamic-pituitary-adrenal system, various schemes for the intermittent administration of glucocorticoids have been proposed:

- alternative therapy- use glucocorticoids of short / medium duration of action (prednisolone, methylprednisolone), once, in the morning (about 8 hours), every 48 hours;

- intermittent circuit- glucocorticoids are prescribed in short courses (3-4 days) with 4-day breaks between courses;

-pulse therapy- rapid intravenous administration of a large dose of the drug (at least 1 g) - for emergency therapy. The drug of choice for pulse therapy is methylprednisolone (it enters inflamed tissues better than others and causes less side effects).

Long-term pharmacodynamic therapy: used in the treatment of chronic diseases. Glucocorticoids are prescribed orally, the doses exceed the physiological ones (2.5-10 mg / day), the therapy is prescribed for several years, the abolition of glucocorticoids with this type of therapy is carried out very slowly.

Dexamethasone and betamethasone are not used for long-term therapy, since with the strongest and longest, compared with other glucocorticoids, anti-inflammatory action, they also cause the most pronounced side effects, incl. inhibitory effect on lymphoid tissue and corticotropic function of the pituitary gland.

During treatment, it is possible to switch from one type of therapy to another.

Glucocorticoids are used orally, parenterally, intra- and periarticularly, inhalation, intranasally, retro- and parabulbarno, in the form of eye and ear drops, externally in the form of ointments, creams, lotions, etc.

For example, in rheumatic diseases, glucocorticoids are used for systemic, local or local (intraarticular, periarticular, external) therapy. In bronchial obstructive diseases, inhaled glucocorticoids are of particular importance.

Glucocorticoids are effective therapeutic agents in many cases. However, it must be taken into account that they can cause a number of side effects, including Itsenko-Cushing's symptom complex (sodium and water retention in the body with the possible appearance of edema, loss of potassium, increased blood pressure), hyperglycemia up to diabetes mellitus (steroid mellitus), slowing down the processes of tissue regeneration, exacerbation of peptic ulcer of the stomach and duodenum, ulceration of the digestive tract, perforation of an unrecognized ulcer, hemorrhagic pancreatitis, a decrease in the body's resistance to infections, hypercoagulability with the risk of thrombosis, the appearance of acne, a moon-shaped face, obesity, menstrual irregularities, etc. when taking glucocorticoids, there is an increased excretion of calcium and osteoporosis (with prolonged use of glucocorticoids in doses of more than 7.5 mg / day - in the equivalent of prednisolone - osteoporosis of long bones may develop). Prevention of steroid osteoporosis is carried out with calcium and vitamin D preparations from the moment you start taking glucocorticoids. The most pronounced changes in the musculoskeletal system are observed in the first 6 months of treatment. One of the dangerous complications is aseptic bone necrosis, so it is necessary to warn patients about the possibility of its development, and when “new” pains appear, especially in the shoulder, hip and knee joints, it is necessary to exclude aseptic bone necrosis. Glucocorticoids cause changes in the blood: lymphopenia, monocytopenia, eosinopenia, a decrease in the number of basophils in the peripheral blood, the development of neutrophilic leukocytosis, an increase in the content of red blood cells. Nervous and mental disorders are also possible: insomnia, agitation (with the development of psychosis in some cases), epileptiform convulsions, euphoria.

With prolonged use of glucocorticoids, one should take into account the probable inhibition of the function of the adrenal cortex (atrophy is not excluded) with the suppression of hormone biosynthesis. The introduction of corticotropin simultaneously with glucocorticoids prevents atrophy of the adrenal glands.

The frequency and strength of side effects caused by glucocorticoids can be expressed to varying degrees. Side effects, as a rule, are a manifestation of the actual glucocorticoid action of these drugs, but to a degree exceeding the physiological norm. With the correct selection of the dose, the observance of the necessary precautions, constant monitoring of the course of treatment, the incidence of side effects can be significantly reduced.

To prevent undesirable effects associated with the use of glucocorticoids, it is necessary, especially with long-term treatment, to carefully monitor the dynamics of growth and development in children, periodically conduct an ophthalmological examination (to detect glaucoma, cataracts, etc.), regularly monitor the function of the hypothalamic-pituitary-adrenal systems, glucose levels in blood and urine (especially in patients with diabetes mellitus), control blood pressure, ECG, electrolyte composition of the blood, monitor the state of the gastrointestinal tract, the musculoskeletal system, monitor the development of infectious complications, etc.

Most complications in the treatment of glucocorticoids are treatable and disappear after drug withdrawal. Irreversible side effects of glucocorticoids include growth retardation in children (occurs when treated with glucocorticoids for more than 1.5 years), subcapsular cataract (develops in the presence of a family predisposition), steroid diabetes.

Abrupt withdrawal of glucocorticoids can cause an exacerbation of the process - a withdrawal syndrome, especially when long-term therapy is stopped. In this regard, treatment should end with a gradual decrease in dose. The severity of the withdrawal syndrome depends on the degree of preservation of the function of the adrenal cortex. In mild cases, the withdrawal syndrome is manifested by fever, myalgia, arthralgia, and malaise. In severe cases, especially with severe stress, an Addisonian crisis (accompanied by vomiting, collapse, convulsions) may develop.

In connection with side effects, glucocorticoids are used only if there are clear indications and under close medical supervision. Contraindications for the appointment of glucocorticoids are relative. In emergency situations, the only contraindication for short-term systemic use of glucocorticoids is hypersensitivity. In other cases, when planning long-term therapy, contraindications should be taken into account.

The therapeutic and toxic effects of glucocorticoids are reduced by inducers of microsomal liver enzymes, enhanced by estrogens and oral contraceptives. Digitalis glycosides, diuretics (causing potassium deficiency), amphotericin B, carbonic anhydrase inhibitors increase the likelihood of arrhythmias and hypokalemia. Alcohol and NSAIDs increase the risk of erosive and ulcerative lesions or bleeding in the gastrointestinal tract. Immunosuppressants increase the chance of developing infections. Glucocorticoids weaken the hypoglycemic activity of antidiabetic drugs and insulin, natriuretic and diuretic - diuretics, anticoagulant and fibrinolytic - derivatives of coumarin and indandione, heparin, streptokinase and urokinase, the activity of vaccines (due to a decrease in antibody production), reduce the concentration of salicylates, mexiletine in the blood. When using prednisolone and paracetamol, the risk of hepatotoxicity increases.

There are five known drugs that suppress the secretion of corticosteroids by the adrenal cortex. (inhibitors of synthesis and action of corticosteroids): mitotane, metyrapone, aminoglutethimide, ketoconazole, trilostane. Aminoglutethimide, metyrapone and ketoconazole inhibit the synthesis of steroid hormones due to the inhibition of hydroxylases (cytochrome P450 isoenzymes) involved in biosynthesis. All three drugs have specificity, tk. act on different hydroxylases. These drugs can cause acute adrenal insufficiency, so they should be used in strictly defined doses and with careful monitoring of the state of the patient's hypothalamic-pituitary-adrenal system.

Aminoglutethimide inhibits 20,22-desmolase, which catalyzes the initial (limiting) stage of steroidogenesis - the conversion of cholesterol to pregnenolone. As a result, the production of all steroid hormones is disrupted. In addition, aminoglutethimide inhibits 11-beta-hydroxylase as well as aromatase. Aminoglutethimide is used to treat Cushing's syndrome caused by unregulated excess cortisol secretion by adrenal cortical tumors or ectopic ACTH production. The ability of aminoglutethimide to inhibit aromatase is used in the treatment of hormone-dependent tumors such as prostate cancer, breast cancer.

Ketoconazole is mainly used as an antifungal agent. However, at higher doses, it inhibits several cytochrome P450 enzymes involved in steroidogenesis, incl. 17-alpha-hydroxylase, as well as 20,22-desmolase, and thus blocks steroidogenesis in all tissues. According to some data, ketoconazole is the most effective inhibitor of steroidogenesis in Cushing's disease. However, the feasibility of using ketoconazole in case of excessive production of steroid hormones requires further study.

Aminoglutethimide, ketoconazole, and metyrapone are used to diagnose and treat adrenal hyperplasia.

To glucocorticoid receptor antagonists refers to mifepristone. Mifepristone is a progesterone receptor antagonist that blocks glucocorticoid receptors in high doses, prevents inhibition of the hypothalamic-pituitary-adrenal system (by a negative feedback mechanism) and leads to a secondary increase in the secretion of ACTH and cortisol.

One of the most important areas of clinical application of glucocorticoids is the pathology of various parts of the respiratory tract.

Indications for appointment systemic glucocorticoids in respiratory diseases are bronchial asthma, COPD in the acute phase, severe pneumonia, interstitial lung disease, acute respiratory distress syndrome.

After systemic glucocorticoids (oral and injectable forms) were synthesized in the late 1940s, they immediately began to be used to treat severe bronchial asthma. Despite a good therapeutic effect, the use of glucocorticoids in bronchial asthma was limited by the development of complications - steroid vasculitis, systemic osteoporosis, and diabetes mellitus (steroid mellitus). Local forms of glucocorticoids began to be used in clinical practice only some time later - in the 70s. XX century. The publication of the successful use of the first topical glucocorticoid, beclomethasone (beclomethasone dipropionate), for the treatment of allergic rhinitis dates back to 1971. In 1972, a report appeared on the use of a topical form of beclomethasone for the treatment of bronchial asthma.

Inhaled glucocorticoids are basic drugs in the treatment of all pathogenetic variants of persistent bronchial asthma, are used in moderate and severe COPD (with a spirographically confirmed response to treatment).

Inhaled glucocorticoids include beclomethasone, budesonide, fluticasone, mometasone, triamcinolone. Inhaled glucocorticoids differ from systemic glucocorticoids in their pharmacological properties: high affinity for GC receptors (act in minimal doses), strong local anti-inflammatory effect, low systemic bioavailability (oral, pulmonary), rapid inactivation, short T 1/2 from the blood. Inhaled glucocorticoids inhibit all phases of inflammation in the bronchi and reduce their increased reactivity. Very important is their ability to lower bronchial secretion (reduce the volume of tracheobronchial secretion) and potentiate the action of beta 2-adrenergic agonists. The use of inhaled forms of glucocorticoids can reduce the need for tableted glucocorticoids. An important characteristic of inhaled glucocorticoids is the therapeutic index - the ratio of local anti-inflammatory activity and systemic action. Of the inhaled glucocorticoids, budesonide has the most favorable therapeutic index.

One of the factors that determine the efficacy and safety of inhaled glucocorticoids are systems for their delivery to the respiratory tract. Currently, metered-dose and powder inhalers (turbuhaler, etc.), nebulizers are used for this purpose.

With the right choice of inhalation system and technique, systemic side effects of inhaled glucocorticoids are insignificant due to the low bioavailability and rapid metabolic activation of these drugs in the liver. It should be borne in mind that all existing inhaled glucocorticoids are absorbed to some extent in the lungs. Local side effects of inhaled glucocorticoids, especially with prolonged use, are the occurrence of oropharyngeal candidiasis (in 5-25% of patients), less often - esophageal candidiasis, dysphonia (in 30-58% of patients), cough.

It has been shown that inhaled glucocorticoids and long-acting beta-agonists (salmeterol, formoterol) have a synergistic effect. This is due to stimulation of the biosynthesis of beta 2 -adrenergic receptors and an increase in their sensitivity to agonists under the influence of glucocorticoids. In this regard, combination drugs intended for long-term therapy, but not for relief of attacks, are effective in the treatment of bronchial asthma, for example, a fixed combination of salmeterol / fluticasone or formoterol / budesonide.

Inhalations with glucocorticoids are contraindicated in fungal infections of the respiratory tract, tuberculosis, and pregnancy.

Currently for intranasal applications in clinical practice use beclomethasone dipropionate, budesonide, fluticasone, mometasone furoate. In addition, dosage forms in the form of nasal aerosols exist for flunisolide and triamcinolone, but they are not currently used in Russia.

Nasal forms of glucocorticoids are effective in the treatment of non-infectious inflammatory processes in the nasal cavity, rhinitis, incl. medical, professional, seasonal (intermittent) and year-round (persistent) allergic rhinitis, to prevent the recurrence of polyps in the nasal cavity after their removal. Topical glucocorticoids are characterized by a relatively late onset of action (12-24 hours), a slow development of the effect - it manifests itself by the 3rd day, reaches a maximum on the 5-7th day, sometimes after a few weeks. Mometasone begins to act most quickly (12 hours).

Modern intranasal glucocorticoids are well tolerated; when used at recommended systemic doses (part of the dose is absorbed from the nasal mucosa and enters the systemic circulation), the effects are minimal. Among the local side effects in 2-10% of patients at the beginning of treatment, nosebleeds, dryness and burning in the nose, sneezing and itching are noted. Perhaps these side effects are due to the irritant effect of the propellant. Isolated cases of perforation of the nasal septum have been described with the use of intranasal glucocorticoids.

Intranasal use of glucocorticoids is contraindicated in hemorrhagic diathesis, as well as in repeated nosebleeds in history.

Thus, glucocorticoids (systemic, inhaled, nasal) are widely used in pulmonology and otorhinolaryngology. This is due to the ability of glucocorticoids to stop the main symptoms of diseases of the ENT and respiratory organs, and in the case of a persistent course of the process, to significantly prolong the interictal period. The obvious advantage of using topical dosage forms of glucocorticoids is the ability to minimize systemic side effects, thus increasing the effectiveness and safety of therapy.

In 1952, Sulzberger and Witten first reported the successful use of 2.5% hydrocortisone ointment for the topical treatment of dermatosis. Natural hydrocortisone is historically the first glucocorticoid used in dermatological practice, subsequently it became the standard for comparing the strength of different glucocorticoids. Hydrocortisone, however, is not effective enough, especially in severe dermatoses, due to relatively weak binding to skin cell steroid receptors and slow penetration through the epidermis.

Later, glucocorticoids were widely used in dermatology for the treatment of various skin diseases of a non-infectious nature: atopic dermatitis, psoriasis, eczema, lichen planus and other dermatoses. They have a local anti-inflammatory, anti-allergic effect, eliminate itching (use for itching is justified only if it is caused by an inflammatory process).

Topical glucocorticoids differ from each other in chemical structure, as well as in the strength of the local anti-inflammatory action.

The creation of halogenated compounds (the inclusion of halogens - fluorine or chlorine in the molecule) made it possible to increase the anti-inflammatory effect and reduce systemic side effects when applied topically due to less absorption of drugs. Compounds containing two fluorine atoms in their structure are characterized by the lowest absorption when applied to the skin - flumethasone, fluocinolone acetonide, etc.

According to the European classification (Niedner, Schopf, 1993), there are 4 classes according to the potential activity of local steroids:

Weak (class I) - hydrocortisone 0.1-1%, prednisolone 0.5%, fluocinolone acetonide 0.0025%;

Medium strength (class II) - alklomethasone 0.05%, betamethasone valerate 0.025%, triamcinolone acetonide 0.02%, 0.05%, fluocinolone acetonide 0.00625%, etc.;

Strong (class III) - betamethasone valerate 0.1%, betamethasone dipropionate 0.025%, 0.05%, hydrocortisone butyrate 0.1%, methylprednisolone aceponate 0.1%, mometasone furoate 0.1%, triamcinolone acetonide 0.025%, 0 .1%, fluticasone 0.05%, fluocinolone acetonide 0.025%, etc.

Very strong (class III) - clobetasol propionate 0.05%, etc.

Along with the increase in therapeutic effect when using fluorinated glucocorticoids, the incidence of side effects also increases. The most common local side effects when using strong glucocorticoids are skin atrophy, telangiectasia, steroid acne, striae, and skin infections. The likelihood of developing both local and systemic side effects increases when applied to large surfaces and long-term use of glucocorticoids. Due to the development of side effects, the use of fluorine-containing glucocorticoids is limited if long-term use is necessary, as well as in pediatric practice.

In recent years, by modifying the steroid molecule, local glucocorticoids of a new generation have been obtained, which do not contain fluorine atoms, but are characterized by high efficiency and a good safety profile (for example, mometasone in the form of furoate, a synthetic steroid that began to be produced in 1987 in the USA, methylprednisolone aceponate, which has been used in practice since 1994).

The therapeutic effect of topical glucocorticoids also depends on the dosage form used. Glucocorticoids for topical use in dermatology are available in the form of ointments, creams, gels, emulsions, lotions, etc. The ability to penetrate the skin (depth of penetration) decreases in the following order: fatty ointment> ointment> cream> lotion (emulsion). With chronic dry skin, the penetration of glucocorticoids into the epidermis and dermis is difficult; moisturizing the stratum corneum of the epidermis with an ointment base increases the penetration of drugs into the skin several times. In acute processes with pronounced weeping, it is more expedient to prescribe lotions, emulsions.

Since glucocorticoids for topical use reduce the resistance of the skin and mucous membranes, which can lead to the development of superinfection, in case of secondary infection, it is advisable to combine a glucocorticoid with an antibiotic in one dosage form, for example, Diprogent cream and ointment (betamethasone + gentamicin), Oxycort aerosols (hydrocortisone + oxytetracycline) and Polcortolone TS (triamcinolone + tetracycline), etc., or with an antibacterial and antifungal agent, such as Akriderm GK (betamethasone + clotrimazole + gentamicin).

Topical glucocorticoids are used in the treatment of complications of chronic venous insufficiency (CVI), such as trophic skin disorders, varicose eczema, hemosiderosis, contact dermatitis, etc. Their use is due to the suppression of inflammatory and toxic-allergic reactions in soft tissues that occur in severe forms of CVI. In some cases, local glucocorticoids are used to suppress vascular reactions that occur during phlebosclerosing treatment. Most often, ointments and gels containing hydrocortisone, prednisolone, betamethasone, triamcinolone, fluocinolone acetonide, mometasone furoate, etc. are used for this.

The use of glucocorticoids in ophthalmology based on their local anti-inflammatory, antiallergic, antipruritic action. Indications for the appointment of glucocorticoids are inflammatory diseases of the eye of non-infectious etiology, incl. after injuries and operations - iritis, iridocyclitis, scleritis, keratitis, uveitis, etc. For this purpose, hydrocortisone, betamethasone, desonide, triamcinolone, etc. are used. The most preferable is the use of local forms (eye drops or suspension, ointments), in severe cases - subconjunctival injections. With systemic (parenteral, oral) use of glucocorticoids in ophthalmology, one should be aware of the high probability (75%) of developing steroid cataracts with daily use for several months of prednisolone at a dose of more than 15 mg (as well as equivalent doses of other drugs), while the risk increases with increasing the duration of treatment.

Glucocorticoids are contraindicated in acute infectious eye diseases. If necessary, for example, in case of bacterial infections, combined preparations containing antibiotics are used, such as eye / ear drops Garazon (betamethasone + gentamicin) or Sofradex (dexamethasone + framycetin + gramicidin), etc. Combined preparations, which include HA and antibiotics are widely used in ophthalmic and otorhinolaryngological practice. In ophthalmology - for the treatment of inflammatory and allergic eye diseases in the presence of concomitant or suspected bacterial infection, for example, with certain types of conjunctivitis, in the postoperative period. In otorhinolaryngology - with otitis externa; rhinitis complicated by a secondary infection, etc. It should be borne in mind that the same bottle of the drug is not recommended for the treatment of otitis media, rhinitis and eye diseases in order to avoid the spread of infection.

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The central link in the pathogenesis of bronchial asthma (BA) is chronic allergic inflammation of the lower respiratory tract. This circumstance determines the choice of glucocorticosteroids (GCS) as the main and most effective drugs used for the basic (daily) therapy of BA and the treatment of exacerbations of this disease.

GCS are currently considered as the most effective drugs for the basic treatment of AD. According to the assessment scale adopted in evidence-based medicine, the use of GCS is a top-level recommendation (recommendation level A). In a large number of studies, the use of these drugs was accompanied by a significant improvement in respiratory function, an increase in spirometry, a decrease in the severity of symptoms of bronchial asthma, a decrease in bronchial hyperreactivity and an improvement in quality of life (Evidence level A). Thus, corticosteroids have a positive effect on almost all manifestations of AD and should be constantly used in all patients, with the exception of patients with a mild intermittent course of the disease.

The widespread introduction of corticosteroids into the practice of treating asthma became possible only with the advent of forms used for inhalation. The use of corticosteroid inhalations made it possible, firstly, to enhance the local (in relation to the respiratory tract) effects of corticosteroid therapy, and secondly, to reduce the severity and frequency of adverse drug reactions (ADRs) associated with the systemic action of these drugs.

The use of corticosteroids in the form of inhalations allows patients to completely avoid the development of such terrible complications of corticosteroid therapy, such as an ulcer of the upper gastrointestinal tract, steroid diabetes and hypertension. On the other hand, with the use of corticosteroids in the form of inhalations, NLRs such as Cushing's syndrome, secondary adrenal insufficiency, glaucoma, etc., occur less frequently.

However, with all the advantages of this method, inhaled corticosteroids in some cases are not effective enough.

• In patients with an exacerbation of asthma or a very severe course of the disease, accompanied by a significant decrease in bronchial patency, the use of inhaled corticosteroids is ineffective, since severe bronchial obstruction significantly reduces the flow of these drugs into the middle and lower respiratory tract. It is believed that with bronchial obstruction, in which the peak expiratory flow rate decreases to a level of less than 200 ml / s, the use of inhaled corticosteroids is ineffective.
• In a number of patients (old age, diseases occurring with impaired memory and intelligence), when using inhalers, there are significant problems that often cannot be eliminated, which in turn does not allow for a full-fledged inhalation therapy.
• In very severe asthma or the presence of relative resistance of the patient to the action of corticosteroids, there may be a complete or partial ineffectiveness of inhaled corticosteroids when used in large doses.
• Inhaled corticosteroids are practically ineffective in a number of patients suffering from special clinical forms of asthma, for example, asthma with a labile course1.

Thus, the question of the use of systemic corticosteroids (corticosteroids for oral, intravenous or intramuscular administration in the form of long-acting drugs - depot forms) remains quite relevant, despite the high risk of ADRs and the presence of less "dangerous" inhalation forms.

The choice of drug for systemic use

Modern clinical practice guidelines recommend the use of drugs for the treatment of AD that provide a combination of high anti-inflammatory and minimal mineralocorticoid activity. The table shows that such drugs as prednisolone and methylprednisolone meet these requirements to the greatest extent.

Pharmacokinetics of systemic corticosteroids used for the treatment of asthma

From the point of view of pharmacokinetics, these drugs are distinguished by high (about 100%) oral bioavailability. In prednisolone and methylprednisolone, the maximum concentration in the blood is observed already 0.5-1.5 hours after administration. The rate of their absorption can be affected by the simultaneous intake of food - while the rate of absorption decreases, but the bioavailability remains at the same level. These drugs are rapidly metabolized in the liver (half-life is 60 and 200 minutes, respectively) and excreted in the urine as conjugates of sulfuric and glucuronic acids.

At the same time, due to the high lipophilicity, prednisolone and methylprednisolone are actively distributed in the tissues of the body, and the half-life from tissues is 0.5–1.5 days. .

The effectiveness of corticosteroids is enhanced with the simultaneous administration of erythromycin (slows down the metabolism of glucocorticoids in the liver), salicylates (an increase in the fraction of glucocorticoids not associated with proteins), estrogens. Inducers of microsomal liver enzymes - phenobarbital, phenytoin, rifampicin - reduce the effectiveness of these drugs.

GCS weaken the effect of anticoagulants, antidiabetic and antihypertensive drugs and enhance the effect of theophylline, sympathomimetics, immunosuppressors, non-steroidal anti-inflammatory drugs.

Important for the treatment of asthma is the interaction of corticosteroids with b2-agonists. With the systematic use of b2-adrenergic stimulants, tolerance to their bronchodilator action develops quite quickly (there is a decrease in the sensitivity of receptors - desensitization and a decrease in their number - down-regulation). GCS are able to increase the number of b-adrenergic receptors, increasing their transcription, and prevent the development of desensitization and down-regulation.

Pharmacodynamics and NLR of systemic corticosteroids used for the treatment of AD

According to their pharmacodynamic features, prednisolone and methylprednisolone practically do not differ from each other. Both drugs have a pronounced anti-inflammatory effect (mainly in allergic and immune forms of the inflammatory process), inhibit the synthesis of prostaglandins, leukotrienes and cytokines, cause a decrease in capillary permeability, reduce the chemotaxis of immunocompetent cells and suppress the activity of fibroblasts, T-lymphocytes, macrophages and eosinophils.

On the other hand, the use of these drugs leads to a delay in the body of sodium and water (due to an increase in reabsorption in the distal renal tubules) and an increase in body weight.

A decrease in calcium absorption from food under the influence of GCS, a decrease in its accumulation in bone tissue and increased excretion of calcium in the urine create the prerequisites for the development of another NLR GCS - osteoporosis. With prolonged use of prednisolone and methylprednisolone, the development of Cushing's syndrome, steroid diabetes, stimulation of catabolic processes in the skin, bone tissue and muscles (up to the development of muscular dystrophy and skin lesions) is noted. These drugs can cause high blood pressure (steroid hypertension), lymphocytopenia, monocytopenia, and eosinopenia.

Long-term use of systemic corticosteroids (especially in combination with chronic hypoxia) causes the formation of steroid gastric ulcers and increases the risk of bleeding from the upper gastrointestinal tract.

One of the most unpleasant consequences of long-term use of corticosteroids is the development of secondary adrenal insufficiency with the abolition of corticosteroids. The risk of secondary adrenal insufficiency increases significantly:

• when using doses> 2.5-5 mg / day. (in terms of prednisolone2);
• with duration of treatment> 10-14 days;
• when taking drugs in the evening.

Features of the pharmacodynamics of systemic corticosteroids in patients with asthma

When taking 40 mg of prednisolone orally, the drug begins to act (an indicator estimated in patients with asthma by the increase in forced expiratory volume in 1 second - FEV1) already 3 hours after taking the drug. The maximum effect (in terms of the effect on bronchial patency) is observed 9 hours after taking the drug and persists even 24 hours after a single dose. The level of FEV1 reaches the initial value after 36 hours. These data refer to patients with asthma in stable condition. Meta-analysis of the use of corticosteroids in patients with severe (FEV1 level<50% от должной величины) обострением БА показал, что значимое увеличение ОФВ1 у больных с обострением наблюдается не ранее чем через 12—24 ч после начала лечения3 .

With repeated administration of GCS orally in patients with a stable course of BA (prednisolone 20 mg per day for 3 weeks), in the first week of treatment, 70% of patients showed an improvement in bronchial patency (increase in FEV1 > 10% from baseline). At the same time, the maximum response to prednisolone treatment was noted already after 5.1 days. .

In general, the effectiveness of systemic corticosteroids in patients with asthma is dose-dependent and increases with the constant intake of these drugs compared with alternating ones. The effectiveness of systemic corticosteroids in stopping asthma exacerbations (estimated by the number of patients who avoided hospitalization due to the use of systemic corticosteroids) is much higher if they are used within the first hour after the onset of exacerbation symptoms.

APPLICATION OF SYSTEMIC GCS IN PRACTICE FROM THE POINT OF VIEW OF EVIDENCE-BASED MEDICINE

From the point of view of evidence-based medicine, several indications can be distinguished for the appointment of systemic corticosteroids.

Therapy for exacerbation of asthma

According to the global asthma strategy, systemic corticosteroids should be used for all but the mildest exacerbations of asthma4 (recommendation level A), especially when:

• after the first administration of b2-agonists, there is no long-term improvement in the patient's condition;
• exacerbation of BA has developed despite the fact that the patient is already taking GCS orally;
• previous exacerbations required the use of systemic corticosteroids;
• it is necessary to increase the doses of inhaled corticosteroids during exacerbations of asthma (recommendation grade D).
• A similar opinion is shared by experts from the British Thoracic Society, which has also developed its own criteria for prescribing systemic corticosteroids for exacerbations of asthma (recommendation level D):
• deterioration and worsening of symptoms "day by day";
• drop in peak expiratory flow below 60% of the individual best;
• sleep disturbance due to asthma symptoms;
• the constant presence of asthma symptoms in the morning (before noon);
• decreased response to inhaled bronchodilators;
• the emergence / increase in the need for inhaled bronchodilators.

Based on these recommendations, for the relief of exacerbations, GCS should be taken orally, since the administration of these drugs intravenously does not provide additional benefits. Intravenous corticosteroids should be used only in those patients who, for a number of reasons, cannot take tableted drugs (recommendation grade A).

The best results are noted when prescribing corticosteroids within the first hour after the onset of exacerbation symptoms (recommendation grade B).

Treatment of an exacerbation begins with the use of oral prednisolone in doses of 60 to 80 mg or hydrocortisone - from 300 to 400 mg per day. These doses are adequate for most hospitalized patients (recommendation grade B).

GCS therapy should be continued for 10-14 days in adults and 3-5 days in children (recommendation level D), although in some cases, for example, with prolonged persistence of exacerbation symptoms, the course of treatment can be extended up to three weeks (recommendation level C) .

Evidence of the benefits of gradually reducing the dose of oral corticosteroids does not exist (recommendation grade B), so the abolition of corticosteroids should be carried out simultaneously. Of course, in this case, the patient must start taking inhaled corticosteroids in advance (a few days before prednisolone is cancelled).

Gradual dose reduction is indicated in cases where the patient has been taking systemic corticosteroids for more than 2-3 weeks. In this case, the dose is reduced gradually (over several weeks). A similar situation may arise in the case when the patient was not prescribed inhaled corticosteroids in advance, since it is impossible to cancel the oral intake of corticosteroids before joining the therapy with inhaled corticosteroids.

Usually, after discharge from the hospital, patients continue to receive systemic corticosteroids (30-60 mg / day) for at least 7-10 days5 (recommendation level A), especially if inhaled corticosteroids were not prescribed in the hospital.

Severe BA

Patients with a very severe course of asthma, whose symptoms of the disease persist despite the use of the maximum doses of inhaled corticosteroids, are candidates for therapy with systemic corticosteroids. In this case, the appointment of GCS inside should be preceded by the use of all additional means at the disposal of the doctor to control the course of asthma (prolonged b2-agonists, prolonged theophyllines, etc.) (recommendation level A). Patients requiring continuous oral corticosteroids should also receive inhaled corticosteroids (recommendation level A) in order to keep the maintenance dose at a minimum. For long-term therapy with oral corticosteroids, the drug should be administered once in the morning every day or every other day.

"Difficult" asthma

"Difficult" asthma is a medical term coined by Barnes in the mid-1990s. This concept combines several forms of bronchial asthma, which present particular difficulties for therapy: labile asthma (see above), asthma associated with the menstrual cycle, GCS-resistant asthma, asthma in patients with hypersensitivity to fungal and occupational allergens, etc. Distinctive A feature of most forms of "difficult" asthma is the need for daily intake of corticosteroids by mouth (in some cases in high doses).

Treatment safety

The use of corticosteroids inside requires constant monitoring by the doctor for the safety of treatment and correction of inevitable complications. The patient should be informed about possible ADRs, as well as use the simplest rules for their prevention (for example, taking the drug only in the morning).

The most relevant measures in this regard are the following:

• careful collection and analysis of complaints associated with the upper gastrointestinal tract, with suspicion of the development of a steroid ulcer - EGDS; prophylactic prescription of antiulcer drugs in patients with a history of stomach diseases (ranitidine or omeprozole 1 tablet at night);
• control of the level of blood pressure and its drug correction;
• regular testing of blood sugar levels;
• regular examination by an ophthalmologist;
• annual densitometry6, prophylactic administration of calcium and vitamin D3 preparations;
• studies aimed at identifying fungal invasions and tuberculosis.

In patients with herpes, as well as in persons who have been in contact with patients with chickenpox, the use of GCS should be stopped immediately.

Conclusion

Systemic corticosteroids continue to occupy an important place in the treatment of asthma due to their high efficiency, but their use is inevitably accompanied by the development of NLR. The doctor's goal is to correctly determine the indications for the use of systemic corticosteroids, to minimize their use by combining them with inhaled corticosteroids and other drugs (long-acting b2-agonists, prolonged theophyllines, etc.) or using alternating courses of treatment.

On the other hand, one should not neglect the appointment of short (and relatively safe) courses of corticosteroids in patients with exacerbation of asthma or delay their appointment until the last. The use of corticosteroids inside is a generally recognized therapeutic tactic for the treatment of asthma and primarily serves the interests of the patient himself.

However, in all cases of the use of GCS, targeted control and subsequent correction of the inevitable ADRs are necessary.

A. N. Tsoi, doctor of medical sciences, professor
V. V. Arkhipov
MMA them. I. M. Sechenov, Moscow

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1 Bronchial asthma with a labile course (brittle asthma) is one of the varieties of asthma with a severe refractory course, which occurs with a frequency of 0.05% in the patient population. A distinctive feature of this form of BA is the high lability of the peak expiratory flow rate and the clinical ineffectiveness of inhaled corticosteroids in high (beclomethasone at a daily dose of >1.5 mg/day) doses.
2 Prednisolone at a dose of 5 mg is equivalent in its GCS activity to 4 mg of methylprednisolone.
3 At the same time, it is difficult to differentiate the increase in FEV1 due to the anti-inflammatory effect of GCS from the increase in FEV1 under the influence of bronchodilators, which were received by all patients with severe exacerbation of BA.
4 Under the exacerbation of BA is understood:
- seeking emergency medical care and/or hospitalization in connection with the worsening of the course of BA;
- the need to take GCS inside;
- a significant (> 2 times) increase in the need for inhaled b2-agonists compared to the baseline for two or more days in a row;
- decrease in the level of peak expiratory flow or forced expiratory volume in 1 second<50% от должного значения.
5 Recommendation of Western specialists, where, as a rule, the duration of hospitalization is short.
6 It is especially important to control the indicators of bone mineral metabolism in women of menopausal age, in persons with unfavorable heredity, in patients with a history of fractures of the extremities, etc.

Inhaled corticosteroids are recommended for prophylactic purposes in patients with persistent asthma, starting with mild severity. Inhaled steroids have little to no systemic effects compared to systemic steroids, but high doses of inhaled steroids should be used with caution in patients at risk for developing glaucoma and cataracts.

At measured doses of inhaled corticosteroids of the 1st and 2nd generations, they do not cause suppression of the adrenal cortex, and also do not affect bone metabolism, however, when prescribing them to children, it is recommended to control the growth of the child. III generation drugs can be prescribed to children from the age of 1 year precisely because they have a minimum coefficient of systemic bioavailability. Inhaled corticosteroids must be used regularly to achieve a sustained effect. Reduction of asthma symptoms is usually achieved by the 3-7th day of therapy. If necessary, the simultaneous appointment of |1r-agonists and inhaled steroids for better penetration of the latter into the airways)