Inhaled glucocorticosteroids (ICS). Treatment Inhaled glucocorticoids include
For quotation: Princely N.P. Glucocorticosteroids in the treatment of bronchial asthma // Breast Cancer. 2002. No. 5. P. 245
Department of Pulmonology, Federal Institute of Internal Medicine, Russian State Medical University
IN Recent years have seen significant progress in treatment bronchial asthma (BA). Apparently, this is due to the definition of asthma as a chronic inflammatory disease of the respiratory tract, and as a result, with the widespread use of inhaled glucocorticosteroids (GCS) as basic anti-inflammatory drugs. However, despite the progress achieved, the level of control over the course of the disease cannot be considered satisfactory. For example, almost every third patient with asthma wakes up at least once a month at night due to symptoms of the disease. More than half of patients have limitations in physical activity, and more than a third are forced to miss school or be absent from work. More than 40% of patients are forced to seek emergency care due to exacerbation of the disease. The reasons for this situation are diverse, and not the least role in this is played by the doctor’s lack of awareness of the pathogenesis of asthma and, accordingly, the choice of incorrect treatment tactics.
Definition and classification of asthma Bronchial asthma is a chronic disease of the airways in which many cells are involved: mast cells, eosinophils and T-lymphocytes. In susceptible individuals, this inflammation leads to repeated episodes of wheezing, shortness of breath, chest tightness and cough, especially at night and/or in the early morning. These symptoms are accompanied by widespread but variable bronchial obstruction that is at least partially reversible, either spontaneously or with treatment. Inflammation also causes the airways to increase their response to various stimuli (hyperresponsiveness).
The key provisions of the definition should be considered the following:
1. Asthma is a chronic persistent inflammatory disease of the respiratory tract, regardless of severity.
2. The inflammatory process leads to bronchial hyperreactivity, obstruction and the appearance of respiratory symptoms.
3. Airway obstruction is at least partially reversible.
4. Atopy - a genetic predisposition to the production of class E immunoglobulins (may not always be present).
Bronchial asthma can be classified based on etiology, severity and characteristics of the manifestation of bronchial obstruction.
However, at present, bronchial asthma should first of all be classified according to severity, since this is what reflects the severity of the inflammatory process in the respiratory tract and determines the tactics of anti-inflammatory therapy.
Severity determined by the following indicators:
- Number of nighttime symptoms per week.
- Number of daytime symptoms per day and per week.
- Frequency of use of short-acting b 2 -agonists.
- The severity of physical activity and sleep disorders.
- Peak expiratory flow (PEF) values and its percentage with the proper or best value.
- Daily fluctuations of PSV.
- The volume of therapy provided.
There are 5 degrees of severity of asthma: mild intermittent; mild persistent; moderately severe persistent; severe persistent; severe persistent steroid-dependent (Table 1).
BA intermittent: asthma symptoms less than once a week; short exacerbations (from several hours to several days). Night symptoms 2 times a month or less often; absence of symptoms and normal lung function between exacerbations: peak expiratory flow (PEF) > 80% predicted and PEF fluctuations less than 20%.Mild persistent asthma. Symptoms once a week or more often, but less than once a day. Exacerbations of the disease can interfere with activity and sleep. Nighttime symptoms occur more often than twice a month. PEF is more than 80% of the expected value; fluctuations in PSV 20-30%.
Moderate asthma. Daily symptoms. Exacerbations disrupt activity and sleep. Nighttime symptoms occur more than once a week. Daily use of short-acting b2-agonists. PSV 60-80% of due. PEF fluctuations are more than 30%.
Severe asthma: persistent symptoms, frequent exacerbations, frequent nighttime symptoms, physical activity limited by asthma symptoms. PEF is less than 60% of the expected value; fluctuations of more than 30%.
It should be noted that determining the severity of asthma using these indicators is possible only before starting treatment. If the patient is already receiving the necessary therapy, then its volume should also be taken into account. Thus, if a patient’s clinical picture is determined to have mild persistent asthma, but at the same time he receives drug treatment corresponding to severe persistent asthma, then this patient is diagnosed with severe asthma.
Severe steroid-dependent asthma: Regardless of the clinical picture, a patient receiving long-term treatment with systemic corticosteroids should be regarded as suffering from severe asthma.
Inhaled corticosteroids Recommended stepwise approach to asthma therapy depending on the severity of its course (Table 1). All drugs for the treatment of asthma are divided into two main groups: for long-term control of the inflammatory process and for the relief of acute asthma symptoms. The basis of therapy for long-term control of the inflammatory process are inhaled glucocorticosteroids (ICS), which should be used from the second stage (mild persistent course) to the fifth (severe steroid-dependent course). Therefore, ICS are currently considered as first-line agents for the treatment of asthma. The higher the severity of asthma, the higher doses of ICS should be used. According to a number of studies, patients who began treatment with ICS no later than two years from the onset of the disease showed significant benefits in improving control over asthma symptoms compared with the group that began treatment with ICS after more than 5 years from the onset of the disease.
Mechanisms of action and pharmacokinetics
ICS are able to bind to specific receptors in the cytoplasm, activate them and form a complex with them, which then dimerizes and moves into the cell nucleus, where it binds to DNA and interacts with the transcription mechanisms of key enzymes, receptors and other complex proteins. This leads to the manifestation of pharmacological and therapeutic effects.
The anti-inflammatory effect of ICS is associated with their inhibitory effect on inflammatory cells and their mediators, including the production of cytokines, interference with the metabolism of arachidonic acid and the synthesis of leukotrienes and prostaglandins, and prevention of migration and activation of inflammatory cells. ICS increase the synthesis of anti-inflammatory proteins (lipocortin-1), increase apoptosis and reduce the number of eosinophils by inhibiting interleukin-5. Thus, ICS lead to the stabilization of cell membranes, reduce vascular permeability, improve the function of b-receptors both by synthesizing new ones and increasing their sensitivity, and stimulate epithelial cells.
ICS differ from systemic glucocorticosteroids in their pharmacological properties: lipophilicity, rapidity of inactivation, short half-life from blood plasma. It is important to consider that treatment with ICS is local (topical), which provides pronounced anti-inflammatory effects directly in the bronchial tree with minimal systemic manifestations. The amount of ICS delivered to the respiratory tract depends on the nominal dose of the drug, the type of inhaler, the presence or absence of propellant, and the inhalation technique. Up to 80% of patients experience difficulty using metered dose aerosols.
The most important characteristic for the manifestation of selectivity and retention time of the drug in tissues is lipophilicity. Due to their lipophilicity, ICS accumulate in the respiratory tract, slowing down their release from tissues and increasing their affinity for the glucocorticoid receptor. Highly lipophilic ICS are absorbed faster and better from the bronchial lumen and remain for a long time in the tissues of the respiratory tract. What distinguishes ICS from systemic drugs is their topical (local) effect. Therefore, it is useless to prescribe inhaled systemic corticosteroids (hydrocortisone, prednisolone and dexamethasone): these drugs, regardless of the method of administration, have only a systemic effect.
Numerous randomized placebo-controlled studies in patients with asthma have shown the effectiveness of all doses of ICS compared with placebo.
System bioavailability consists of oral and inhalation. From 20 to 40% of the inhaled dose of the drug enters the respiratory tract (this value varies significantly depending on the delivery vehicle and the patient’s inhalation technique). Pulmonary bioavailability depends on the percentage of the drug reaching the lungs, the presence or absence of a carrier (inhalers that do not contain freon have the best results) and on the absorption of the drug in the respiratory tract. 60-80% of the inhalation dose settles in the oropharynx and is swallowed, then undergoing complete or partial metabolism in the gastrointestinal tract and liver. Oral availability depends on absorption in the gastrointestinal tract and on the severity of the “first pass” effect through the liver, due to which inactive metabolites enter the systemic circulation (with the exception of beclomethasone 17-monopropionate, the active metabolite of beclomethasone dipropionate). Doses of ICS up to 1000 mcg/day (for fluticasone up to 500 mcg/day) have little systemic effect.
All ICS have fast system clearance, comparable to the magnitude of hepatic blood flow. This is one of the factors that reduces the systemic effect of ICS.
Characteristics of the most commonly used drugs
ICS include beclomethasone dipropionate, budesonide, fluticasone propionate, flunisolide, triamsinolone acetonide, mometasone furoate. They are available in the form of metered-dose aerosols, powder inhalers, and also as solutions for inhalation through a nebulizer (budesonide).
Beclomethasone dipropionate . It has been used in clinical practice for more than 20 years and remains one of the most effective and frequently used drugs. The use of the drug in pregnant women is permitted. Available as a metered-dose aerosol inhaler (Bekotide 50 mcg, Bekloforte 250 mcg, Aldecin 50 mcg, Beklocort 50 and 250 mcg, Beclomet 50 and 250 mcg/dose), a breath-activated metered-dose inhaler (Beclazon Easy Breathing 100 and 250 mcg/dose) , powder inhaler (Bekodisk 100 and 250 mcg/dose, Diskhaler inhaler; Easyhaler multi-dose inhaler, Beklomet 200 mcg/dose). For Bekotide and Bekloforte inhalers, special spacers are produced - “Volyumatic” (large-volume valve spacer for adults) and “Babyhaler” (small-volume 2-valve spacer with a silicone face mask for young children).
Budesonide . A modern, highly active drug. Used as a metered dose aerosol inhaler (Budesonide-mite 50 mcg/dose; Budesonide-forte 200 mcg/dose), powder inhaler (Pulmicort Turbuhaler 200 mcg/dose; Benacort Cyclohaler 200 mcg/dose) and nebulizer suspension (Pulmicort 0.5 and 0.25 mg/dose). Pulmicort Turbuhaler is the only dosage form of ICS that does not contain a carrier. A spacer is produced for the metered dose inhalers Budesonide Mite and Budesonide Forte. Budesonide is part of the combination drug Symbicort.
Budesonide has the most favorable therapeutic index, which is associated with its high affinity for glucocorticoid receptors and accelerated metabolism after systemic absorption in the lungs and intestines. Budesonide is the only ICS for which single-dose use has been proven. The factor that ensures the effectiveness of budesonide once a day is the retention of budesonide in the respiratory tract in the form of an intracellular depot due to reversible esterification (formation of fatty acid esters). When the concentration of free budesonide in the cell decreases, intracellular lipases are activated, and budesonide released from the esters again binds to the receptor. This mechanism is not typical for other corticosteroids and makes it possible to prolong the anti-inflammatory effect. A number of studies have shown that intracellular storage may be more important in terms of drug activity than receptor affinity.
Recent studies on the drug Pulmicort Turbuhaler have proven that it does not affect final growth with long-term use in children, bone mineralization, and does not cause angiopathy and cataracts. Pulmicort is also recommended for use in pregnant women: it has been found that its use does not cause an increase in the number of fetal abnormalities. Pulmicort Turbuhaler is the first and only ICS to which the FDA (drug control organization in the United States) has assigned category “B” in the rating of drugs prescribed during pregnancy. This category includes medications that are safe to take during pregnancy. The remaining ICS belong to category “C” (taking them during pregnancy is not recommended).
Fluticasone propionate . The most highly active drug to date. Has minimal oral bioavailability (<1%). Эквивалентные терапевтические дозы флютиказона почти в два раза меньше, чем у беклометазона и будесонида в аэрозольном ингаляторе и сопоставимы с дозами будесонида в Турбухалере (табл. 2). По данным ряда исследований, флютиказона пропионат больше угнетает надпочечники, но в эквивалентных дозах имеет сходную с другими ИГКС активность в отношении надпочечников.
Presented in the form of a metered-dose aerosol inhaler (Flixotide 50, 125 and 250 mcg/dose) and a powder inhaler (Flixotide Diskhaler - rotadiscs 50, 100, 250 and 500 mcg/dose; Flixotide Multidisc 250 mcg/dose). Special spacers are produced for aerosol inhalers - “Volyumatic” (large-volume valve spacer for adults) and “Babyhaler” (small-volume 2-valve spacer with a silicone face mask for young children). Fluticasone is part of the combination drug Seretide Multidisk.
Flunisolide . A drug with low glucocorticoid activity. It is represented on the domestic market by the Ingacort trademark (metered-dose inhaler 250 mcg/dose, with a spacer). Despite high therapeutic doses, it has virtually no systemic effects due to the fact that already during the first passage through the liver it is 95% converted into an inactive substance. Currently used quite rarely in clinical practice.
Triamsinolone acetonide . A drug with low hormonal activity. Metered dose inhaler 100 mcg/dose. The Azmacort brand is not represented on the Russian market.
Mometasone furoate . A drug with high glucocorticoid activity. It is presented on the Russian market only in the form of Nazonex nasal spray.
Clinical trials comparing the effectiveness of ICS in improving symptoms and respiratory function show that:
- Budesonide and beclomethasone dipropionate in aerosol inhalers at the same doses practically do not differ in effectiveness.
- Fluticasone propionate provides the same effect as twice the dose of beclomethasone or budesonide in a metered-dose aerosol.
- Budesonide administered through Turbuhaler has the same effect as twice the dose of budesonide in a metered dose aerosol.
Undesirable effects
Modern ICS are drugs with a high therapeutic index and have a high safety profile even with long-term use. Systemic and local undesirable effects are distinguished. Systemic adverse effects may only become clinically significant when high doses are used. They depend on the drug's affinity for the receptor, lipophilicity, volume of distribution, half-life, bioavailability and other factors. The risk of systemic adverse effects for all currently available ICS correlates with the desired effects in the respiratory tract. The use of ICS in moderate therapeutic doses reduces the risk of systemic effects.
The main side effects of ICS are related to their route of administration and include oral candidiasis, hoarseness, mucosal irritation and cough. To avoid these phenomena, proper inhalation technique and individual selection of ICS are necessary.
Combination drugs
Despite the fact that ICS are the basis of BA therapy, they do not always allow complete control of the inflammatory process in the bronchial tree and, accordingly, the manifestations of BA. In this regard, there was a need to prescribe short-acting b 2 -agonists on an as-needed or regular basis. Thus, there is an urgent need for a new class of drugs, free from the disadvantages that are inherent in short-acting b 2 -agonists, and with a proven long-term protective and anti-inflammatory effect on the respiratory tract.
Long-acting b2-agonists have been created and are currently widely used, which are represented on the pharmaceutical market by two drugs: formoterol fumarate and salmeterol xinafoate. Modern guidelines for the treatment of asthma recommend the addition of long-acting b2-agonists in case of insufficient control of asthma with monotherapy with inhaled corticosteroids (starting from the second stage). A number of studies have shown that the combination of inhaled corticosteroids with a long-acting b 2 -agonist is more effective than doubling the dose of inhaled corticosteroids, and leads to a more significant improvement in lung function and better control of asthma symptoms. A reduction in the number of exacerbations and a significant improvement in quality of life in patients receiving combination therapy have also been shown. Thus, the emergence of combination drugs containing inhaled corticosteroids and a long-acting b 2 agonist is a reflection of the evolution of views on asthma therapy.
The main advantage of combination therapy is the increased effectiveness of treatment when using lower doses of ICS. In addition, combining two drugs in one inhaler makes it easier for the patient to follow doctor's orders and potentially improves compliance.
Seretide Multidisk . The constituent components are salmeterol xinafoate and fluticasone propionate. Provides a high level of control over asthma symptoms. Used only as basic therapy, can be prescribed starting from the second stage. The drug is presented in various dosages: 50/100, 50/250, 50/500 mcg salmeterol/fluticasone in 1 dose. Multidisc is a low-resistance inhalation device, which allows it to be used in patients with reduced inspiratory flow.
Symbicort Turbuhaler . The constituent components are budesonide and formoterol fumarate. It is presented on the Russian market in a dosage of 160/4.5 mcg in 1 dose (doses of drugs are indicated as the output dose). An important feature of Symbicort is the ability to use it both for basic therapy (to control the inflammatory process) and for immediate relief of asthma symptoms. This is primarily due to the properties of formoterol (quick onset of action) and the ability of budesonide to actively act within 24 hours on the mucous membrane of the bronchial tree.
Symbicort allows individual flexible dosing (1-4 inhalation doses per day). Symbicort can be used starting from stage 2, but it is especially indicated for patients with unstable asthma, which is characterized by sudden severe attacks of difficulty breathing.
System GCS Systemic corticosteroids are used mainly to relieve exacerbation of asthma. Oral corticosteroids are the most effective. Intravenous corticosteroids are prescribed for exacerbation of asthma, if intravenous access is more desirable, or for impaired absorption from the gastrointestinal tract, using high doses (up to 1 g of prednisolone, methylprednisolone and hydrocortisone). Corticosteroids lead to clinically significant improvement 4 hours after their administration.
During exacerbation of BA, a short course of oral corticosteroids (7-14 days) is indicated, starting with high doses (30-60 mg of prednisolone). Recent publications recommend the following short course of systemic corticosteroids for non-life-threatening exacerbations: 6 tablets of prednisolone in the morning (30 mg) for 10 days, followed by discontinuation of use. Although treatment regimens for systemic corticosteroids can be different, the fundamental principles are their administration in high doses to quickly achieve effect and subsequent rapid withdrawal. It should be remembered that as soon as the patient is ready to take inhaled corticosteroids, they should be prescribed to him in a stepwise manner.
Systemic glucocorticoids should be prescribed if:
- Moderate or severe exacerbation.
- The administration of short-acting inhaled b 2 -agonists at the beginning of treatment did not lead to improvement.
- The exacerbation developed despite the fact that the patient was on long-term treatment with oral corticosteroids.
- Oral corticosteroids were required to control previous exacerbations.
- Courses of glucocorticoids were administered 3 or more times a year.
- The patient is on mechanical ventilation.
- Previously there were life-threatening exacerbations.
It is undesirable to use long-acting forms of systemic steroids to relieve exacerbations and provide maintenance therapy for asthma.
For long-term therapy in severe asthma, systemic corticosteroids (methylprednisolone, prednisolone, triamsinolone, betamethasone) should be prescribed in the lowest effective dose. With long-term treatment, an alternating prescription regimen and administration in the first half of the day (to reduce the effect on the circadian rhythms of cortisol secretion) cause the least amount of side effects. It should be emphasized that in all cases of prescribing systemic steroids, the patient should be prescribed high doses of inhaled corticosteroids. Among oral corticosteroids, preference is given to those that have minimal mineralocorticoid activity, a relatively short half-life and limited effect on striated muscles (prednisolone, methylprednisolone).
Steroid addiction
Patients who are forced to constantly take systemic corticosteroids should pay special attention. There are several options for the formation of steroid dependence in patients with asthma and other diseases accompanied by bronchial obstruction:
- Lack of compliance (interaction) between doctor and patient.
- Not prescribing inhaled corticosteroids to patients. Many doctors believe that there is no need to prescribe inhaled corticosteroids to patients receiving systemic steroids. If a patient with asthma receives systemic steroids, he should be regarded as a patient with severe asthma who has a direct indication for high doses of inhaled corticosteroids.
- In patients with systemic diseases (including pulmonary vasculitis, for example, Charge-Strauss syndrome), bronchial obstruction can be regarded as asthma. Withdrawal of systemic steroids in these patients may be accompanied by severe manifestations of systemic disease.
- In 5% of cases, steroid resistance occurs, which is characterized by resistance of steroid receptors to steroid drugs. Currently, two subgroups are distinguished: patients with true steroid resistance (type II), who do not have side effects when taking high doses of systemic corticosteroids for a long time, and patients with acquired resistance (type I), who have side effects of systemic corticosteroids. In the latter subgroup, resistance can most likely be overcome by increasing the dose of GCS and prescribing drugs that have an additive effect.
1. Bronchial asthma. Global strategy: a joint report of the National Heart, Lung, and Blood Institute and the World Health Organization. Pulmonology, 1996.
2. Bronchial asthma. Guide for doctors in Russia (formulary system). “Pulmonology”, supplement-99.
3. Leading directions in the diagnosis and treatment of bronchial asthma. Highlights of the EPR-2 Expert Group Report. National Institute of Health. National Heart, Lung and Blood Institute. NIH publication-97. Translation ed. Prof. Tsoi A.N., M, Grant, 1998.
4. Ilyina N.I. Inhaled glucocorticoids. Asthma.ru. Allergic and respiratory diseases. 0*2001 (pilot episode).
5. Ogorodova L.M. Systems for inhalation delivery of drugs into the respiratory tract. Pulmonology, 1999; No. 1, 84-87
6. Formulary system: treatment of bronchial asthma. Asthma. ru ,0. 2001, 6-9
7. Chuchalin A.G. Bronchial asthma. Moscow, 1997.
8. Tsoi A.N. Inhaled glucocorticoids: effectiveness and safety. RMJ 2001; 9: 182-185
9. Tsoi A.N. Comparative pharmacokinetics of inhaled glucocorticoids. Allergology 1999; 3:25-33
10. Agertoft L., Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000; 343:1064-9
11. Ankerst J., Persson G., Weibull E. A high dose of budesonide/formoterol in a single inhaler was well tolerated by asthmatic patients. Eur Respir J 2000; 16 (Suppl 31): 33s+poster
12. Barnes P.J. Inhaled glucocorticoids for asthma. N.Engl. Med. 1995; 332:868-75
13. Beclomethasone Dipropionate and Budesonide. The clinical evidence Reviewed. Respir Med 1998; 92 (Suppl B)
14. The British Guidelines on Asthma Management. Thorax, 1997; 52 (Suppl. 1) 1-20.
15. Burney PGJ. Current questions in the epidemiology of asthma, in Holgate ST, et al, Asthma: Physiology. Immunology, and Treatment. London, Academic Press, 1993, pp. 3-25.
16. Crisholm S et al. Once-daily budesonide in mild asthma. Respir Med 1998; 421-5
17. Kips JC, O/Connor BJ, Inman MD, Svensson K, Pauwels RA, O/Byrne PM. A long-term study of the antiinflammatory effect of low-dose budesonide plus formoterol versus high-dose budesonide in asthma. Am Respir Crit Care Med 2000; 161:996-1001
18. McFadden ER, Casale TB, Edwards TB et al. Administration of budesonide once daily by means of Turbuhaler to subjects with stable asthma. J Allergy Clin Immunol 1999; 104:46-52
19. Miller-Larsson A., Mattsson H., Hjertberg E., Dahlback M., Tunek A., Brattsand R. Reversible fatty acid conjugation of budesonide: novel mechanism for prolonged retention of topically applied steroid in airway tissue. Drug Metab Dispos 1998; 26: 623-30
20. Miller-Larsson A. et al. Prolonged airway activity and improved selectivity of budesonide possibly due to esterification. Am J Respir Crit Care Med 2000;162:1455-1461
21. Pauwels RA et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997; 337:1405-11
22. Pedersen S, O/Byrne P. A comparison of the efficacy and safety of inhaled corticosteroids in asthma. Allergy 1997; 52 (Suppl 39): 1-34.
23. Woolcock A. et al. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996, 153, 1481-8.
For asthma, inhaled glucocorticosteroids are used, which do not have most of the side effects of systemic steroids. If inhaled corticosteroids are ineffective, glucocorticosteroids are added for systemic use. ICS is the main group of drugs for the treatment of bronchial asthma.
Classification inhaled glucocorticosteroids depending on the chemical structure:
Non-halogenated
Budesonide (Pulmicort, Benacort)
Cyclesonide (Alvesco)
Chlorinated
Beclomethasone dipropionate (Bekotide, Beklodzhet, Klenil, Beklazon Eco, Beklazon Eco Easy Breathing)
Mometasone furoate (Asmonex)
Fluoridated
Flunisolide (Ingacort)
Triamcenolone acetonide
Azmocort
Fluticasone propionate (Flixotide)
The anti-inflammatory effect of ICS is associated with suppression of the activity of inflammatory cells, a decrease in the production of cytokines, interference with the metabolism of arachidonic acid and the synthesis of prostaglandins and leukotrienes, a decrease in the permeability of microvasculature, prevention of direct migration and activation of inflammatory cells, and an increase in the sensitivity of β-smooth muscle receptors. ICS also increase the synthesis of the anti-inflammatory protein lipocortin-1; by inhibiting interleukin-5, they increase the apoptosis of eosinophils, thereby reducing their number, leading to the stabilization of cell membranes. Unlike systemic glucocorticosteroids, ICS are lipophilic, have a short half-life, are quickly inactivated, and have a local (topical) effect, due to which they have minimal systemic manifestations. The most important property is lipophilicity, due to which ICS accumulate in the respiratory tract, slows down their release from tissues and increases their affinity for the glucocorticoid receptor. The pulmonary bioavailability of ICS depends on the percentage of the drug reaching the lungs (which is determined by the type of inhaler used and the correct inhalation technique), the presence or absence of a carrier (inhalers that do not contain freon have the best results) and on the absorption of the drug in the respiratory tract.
Until recently, the dominant concept for prescribing ICS was the concept of a stepwise approach, which means that for more severe forms of the disease, higher doses of ICS are prescribed. Equivalent doses of ICS (mcg):
International name Low doses Medium doses High doses
Beclomethasone dipropionate 200-500 500-1000 1000
Budesonide 200-400 400-800 800
Flunisolide 500-1000 1000-2000 2000
Fluticasone propionate 100-250 250-500 500
Triamsinolone acetonide 400-1000 1000-2000 2000
The basis of therapy for long-term control of the inflammatory process are ICS, which are used for persistent bronchial asthma of any severity and to this day remain the first-line treatment for bronchial asthma. According to the concept of a stepwise approach: “The higher the severity of asthma, the higher doses of inhaled steroids should be used.” A number of studies have shown that patients who began treatment with ICS no later than 2 years after the onset of the disease showed significant benefits in improving control over asthma symptoms, compared with those who began such therapy after 5 years or more.
Combinations of ICS and long-acting β2-agonists
Symbicort Turbuhaler
There are fixed combinations of ICS and long-acting β2-adrenergic agonists, combining a basic therapy and a symptomatic agent. According to the global strategy of GINA, fixed combinations are the most effective means of basic therapy for bronchial asthma, as they allow you to relieve an attack and at the same time are a therapeutic agent. The most popular are two such fixed combinations:
salmeterol + fluticasone (Seretide 25/50, 25/125 and 25/250 mcg/dose, Seretide Multidisc 50/100, 50/250 and 50/500 mcg/dose)
formoterol + budesonide (Symbicort Turbuhaler 4.5/80 and 4.5/160 mcg/dose)
Seretide. "Multidisc"
The composition of the drug Seretide includes salmeterol at a dose of 25 mcg/dose in a metered-dose aerosol inhaler and 50 mcg/dose in the Multidisc device. The maximum permissible daily dose of salmeterol is 100 mcg, that is, the maximum frequency of use of Seretide is 2 inhalations 2 times for a metered dose inhaler and 1 inhalation 2 times for the Multidisc device. This gives Symbicort an advantage if it is necessary to increase the dose of ICS. Symbicort contains formoterol, the maximum permissible daily dose of which is 24 mcg, making it possible to inhale Symbicort up to 8 times a day. The SMART trial identified a risk associated with salmeterol compared with placebo. In addition, the indisputable advantage of formoterol is that it begins to act immediately after inhalation, and not after 2 hours, like salmeterol.
Glucocorticosteroids as the main medications for the treatment of asthma. ICS.
As is known, the basis of the course of bronchial asthma isWe (BA) suffer from chronic inflammation, and the main method of treating this disease isuse of anti-inflammatory drugs. Today, glucocorticosteroids are recognizedthe main medications for the treatment of asthma.
Systemic corticosteroids remain today the drugs of choice in the treatment of exacerbation of asthma, but at the end of the 60s of the last century, a new era in the treatment of asthma began and it is associated with the emergence and introduction into clinical practice of inhaled glucocorticosteroids (ICS).
ICS in the treatment of patients with asthma are currently considered as first-line drugs. The main advantage of ICS is the direct delivery of the active substance to the respiratory tract and the creation of higher concentrations of the drug there, while simultaneously eliminating or minimizing systemic side effects. The first ICS for the treatment of asthma were aerosols of water-soluble hydrocortisone and prednisolone. However, due to their high systemic and low anti-inflammatory effects, their use was ineffective. In the early 1970s. lipophilic glucocorticosteroids with high local anti-inflammatory activity and weak systemic effect were synthesized. Thus, at present, ICS have become the most effective drugs for the basic treatment of BA in patients of any age (level of evidence A).
ICS can reduce the severity of asthma symptoms, suppress the activity of allergic inflammation, reduce bronchial hyperreactivity to allergens and nonspecific irritants (physical activity, cold air, pollutants, etc.), improve bronchial patency, improve the quality of life of patients, reduce the number of absences from school and work. It has been shown that the use of ICS in patients with asthma leads to a significant reduction in the number of exacerbations and hospitalizations, reduces mortality from asthma, and also prevents the development of irreversible changes in the respiratory tract (evidence level A). ICS are also successfully used to treat COPD and allergic rhinitis as the most powerful drugs with anti-inflammatory activity.
Unlike systemic glucocorticosteroids, ICS are characterized by high affinity for receptors, lower therapeutic doses and minimal side effects.
The superiority of ICS in the treatment of BA over other groups of anti-inflammatory drugs is beyond doubt, and today, according to the majority of domestic and foreign experts, ICS are the most effective drugs for the treatment of patients with BA. But even in well-studied areas of medicine, there are insufficiently substantiated and sometimes false ideas. To this day, discussions continue regarding how early it is necessary to start ICS therapy, in what doses, which ICS and through what delivery device, how long-term therapy should be carried out, and most importantly, how to be sure that the prescribed ICS therapy does not cause harm to the body, those. There is no systemic effect or other side effects of corticosteroids. Evidence-based medicine is aimed precisely at combating such trends, existing in the opinion of both doctors and patients, which reduce the effectiveness of treatment and prevention of asthma.
The following ICS are currently used in clinical practice: beclomethasone dipropionate (BDP), budesonide (BUD), fluticasone propionate (FP), triamcinolone acetonide (TAA), flunisolide (FLU) and mometasone furoate (MF). The effectiveness of ICS therapy directly depends on: the active substance, dose, form and method of delivery, compliance. timing of initiation of treatment, duration of therapy, severity (exacerbation) of asthma, as well as COPD.
Which ICS is more effective?
At equivalent doses, all ICS are equally effective (level of evidence A). The pharmacokinetics of drugs, and therefore the therapeutic effectiveness, are determined by the physicochemical properties of GCS molecules. Because the molecular structure of ICS is different, they have different pharmacokinetics and pharmacodynamics. To compare the clinical effectiveness and possible side effects of ICS, it is proposed to use a therapeutic index, the ratio of positive (desirable) clinical and side (undesirable) effects, in other words, the effectiveness of ICS is assessed by their systemic action and local anti-inflammatory activity. With a high therapeutic index, there is a better effect/risk ratio. Many pharmacokinetic parameters are important for determining the therapeutic index. Thus, the anti-inflammatory (local) activity of ICS is determined by the following properties of the drugs: lipophilicity, which allows them to be absorbed faster and better from the respiratory tract and remain longer in the tissues of the respiratory organs; affinity for GCS receptors; high primary inactivation effect in the liver; duration of connection with target cells.
One of the most important indicators is lipophilicity, which correlates with the drug's affinity for steroid receptors and its half-life. The higher the lipophilicity, the more effective the drug, since it easily penetrates cell membranes and increases its accumulation in the lung tissue. This increases the duration of its action in general and the local anti-inflammatory effect by forming a reservoir of the drug.
Lipophilicity is most pronounced in FP, followed by BDP and BUD. . FP and MF are highly lipophilic compounds, as a result, they have a larger volume of distribution compared to drugs that are less lipophilic BUD, TAA. BUD is approximately 6-8 times less lipophilic than FP, and, accordingly, 40 times less lipophilic compared to BDP. At the same time, a number of studies have shown that the less lipophilic BUD remains in the lung tissue longer than AF and BDP. This is explained by the lipophilicity of budesonide conjugates with fatty acids, which is tens of times higher than the lipophilicity of intact BUD, which ensures the duration of its stay in the tissues of the respiratory tract. Intracellular esterification of BUD with fatty acids in the tissues of the respiratory tract leads to local retention and the formation of a “depot” of inactive but slowly regenerating free BUD. Moreover, a large intracellular supply of conjugated BUD and the gradual release of free BUD from the conjugated form can prolong the saturation of the receptor and the anti-inflammatory activity of BUD, despite its lower affinity for the GCS receptor compared to FP and BDP.
FP has the greatest affinity for GCS receptors (approximately 20 times higher than that of dexamethasone, 1.5 times higher than that of the active metabolite of BDP -17-BMP, and 2 times higher than that of BUD). The affinity index for receptors is BUD - 235, BDP - 53, FP - 1800. But, despite the fact that the affinity index of BDP is the lowest, it is highly effective due to the conversion when it enters the body into monopropionate, which has an affinity index of 1400. That is, the most active by affinity for GCS receptors are FP and BDP.
As is known, the effectiveness of a drug is assessed by its bioavailability. The bioavailability of ICS consists of the bioavailability of the dose absorbed from the gastrointestinal tract and the bioavailability of the dose absorbed from the lungs.
A high percentage of drug deposition in the intrapulmonary respiratory tract normally provides the best therapeutic index for those ICS that have low systemic bioavailability due to absorption from the mucous membranes of the oral cavity and gastrointestinal tract. This applies, for example, to BDP, which has systemic bioavailability due to intestinal absorption, in contrast to BUD, which has systemic bioavailability primarily due to pulmonary absorption. For ICS with zero bioavailability (AF), the effectiveness of treatment is determined only by the type of drug delivery device and inhalation technique, and these parameters do not affect the therapeutic index.
As for the metabolism of ICS, BDP is quickly, within 10 minutes, metabolized in the liver with the formation of one active metabolite - 17BMP and two inactive ones - beclomethasone 21- monopropionate (21-BMN) and beclomethasone. FPis quickly and completely inactivated in the liver with the formation of one partially active (1% FP activity) metabolite - 17β-carboxylic acid. Budesonide is quickly and completely metabolized in the liver with the participation of cytochrome p450 3A (CYP3A) with the formation of 2 main metabolites:6β-hydroxybudesonide (forms both isomers) and16β-hydroxyprednisolone (forms only 22R). Both metabolites have weak pharmacologicalskaya activity.
Comparison of used ICS is difficult due to differences in their pharmacokinetics and pharmacodynamics. FP is superior to other ICS in all studied parameters of pharmacokinetics and pharmacodynamics. The results of recent studies indicate that FP is at least 2 times more effective than BDP and BUD at the same doses.
The results of a meta-analysis of 14 comparative clinical studies of AF with BDP (7 studies) or BUD (7 studies) were recently published. In all 14 studies, FP was given at half (or less) dose compared to BDP or BUD. When comparing the effectiveness of BDP (400/1600 mcg/day) with AF (200/800 mcg/day), the authors did not find significant differences in the dynamics of the morning maximum expiratory flow rate (PEFR) in any of the 7 studies analyzed. Clinical efficacy, as well as serum cortisol levels in the morning, were not significantly different. When comparing the effectiveness of BUD (400/1600 mcg/day) with FP (200/800 mcg/day), it was shown that AF statistically significantly increases PEFR more significantly than BUD. When using low doses of drugs, there is no difference between these drugs in terms of reducing serum cortisol levels in the morning, however, when using higher doses of drugs, it has been found that AF has a lesser effect on this indicator. In summary, the results of the meta-analysis suggest that the effectiveness of BDP and half-dose FP are equivalent in their effects on PEFR and clinical efficacy. FP at half dose is more effective than BUD in terms of its effect on PEFR. These data confirm the pharmacokinetic characteristics, the relative affinity of the three study drugs for steroid receptors.
Clinical trials comparing the effectiveness of ICS in the form of improvement of symptoms and indicators of respiratory function show that UD and BDP in aerosol inhalers at the same doses practically do not differ in effectiveness, FP provides the same effect ie, like a double dose of BDP or BUD in a metered aerosol.
The comparative clinical effectiveness of various ICS is currently being actively studied.
INsboron dose of ICS. Calculated recommended or optimal? Which is more effective? Of significant interest to physicians is the choice of daily dose of ICS and duration of therapy when conducting basic therapy for asthma in order to control asthma symptoms. Better control of asthma is achieved more quickly with higher doses of inhaled corticosteroids (Evidence A, Table 1).
The initial daily dose of ICS should usually be 400-1000 mcg (in terms of beclomethasone); for more severe asthma, higher doses of ICS may be recommended or treatment with systemic corticosteroids may be started (C). Standard doses of ICS (equivalent to 800 mcg of beclomethasone) if ineffective, can be increased to 2000 mcg in terms of beclomethasone (A).
Data on dose-related effects, such as AF, are mixed. Thus, some authors note a dose-dependent increase in the pharmacodynamic effects of this drug, while other researchers indicate that the use of low (100 mcg/day) and high doses (1000 mcg/day) of FP are almost equally effective.
Table 1. RCalculated equivalent doses of ICS (mcg) A.G. Chuchalin, 2002 modified
| Low | Average | High | Low | Average | High | |
| BDP (Beklozon Eco Easy Breathing, Beklat, Beklofort) | 200–500 | 500–1000 | > 1000 | 100- 400 | 400- 800 | > 800 |
| BUD (Budesonide, Budecort) | 200-400 | 400-800 | > 800 | 100-200 | 200-400 | > 400 |
| FLU * | 500-1000 | 1000 2000 | > 2000 | 500 750 | 1000 1250 | > 1250 |
| FP (Flixotide, Flochal) | 100-250 | 250-500 | > 500 | 100-200 | 200-500 | > 500 |
| TA* | 400 -1000 | 1000 2000 | > 2000 | 400 800 | 800 1200 | > 1200 |
* active substances, the preparations of which are not registered in Ukraine
However, with increasing dose of ICS, thethe severity of their systemic undesirable effects, while in low and medium doses these drugsattacks rarely cause clinically significant painlate drug reactions and are characterized by a good risk/benefit ratio (evidence level A).
ICS has been proven to be highly effective when administered 2 times a day; when using ICS 4 times a day at the same daily dose, the effectiveness of treatment increases slightly (A).
Pedersen S. et al. showed that low doses of ICS reduce the frequency of exacerbations and the need for beta2-agonists, improve respiratory function, but for better control of the inflammatory process in the airways and maximum reduction of bronchial hyperreactivity, high doses of these drugs are required.
Until recently, ICS was not used to treat exacerbations of asthma, because they were considered less effective in exacerbation than systemic corticosteroids. A number of studies indicate the high effectiveness of taking systemic corticosteroids during exacerbations of asthma (level of evidence A). However, since the 90s of the last century, when new active ICS (BUD and AF) appeared, they began to be used to treat exacerbations of asthma. A number of clinical studies have proven that the effectiveness of ICS BUD and FP in high doses in a short course (2–3 weeks) does not differ from the effectiveness of dexamethasone in the treatment of mild and severe exacerbation of asthma. The use of inhaled corticosteroids during exacerbation of asthma makes it possible to achieve normalization of the clinical condition of patients and indicators of respiratory function, without causing side systemic effects.
Most studies have established a moderate effectiveness of ICS in the treatment of exacerbations of asthma, which ranged from 50 to 70% when using a double dose (from the dose of basic therapy) of AF, and an increase in the effectiveness of treatment with the additional use of the long-acting beta 2 agonist salmeterol by 10 to 15 %. In accordance with the recommendations of international consensus on the treatment of bronchial asthma, an alternative to increasing the dose of the drug if it is impossible to ensure optimal control of asthma using ICS in low and medium doses is the prescription of long-acting b-agonists.
The enhanced effect of ICS when combined with long-acting beta2-adrenergic receptor agonists in patients with COPD was proven in the randomized, controlled, double-blind trial TRISTAN (Trial of Inhaled Steroids and Long-acting beta2-agonists), which included 1465 patients. With combination therapy (FP 500 mcg + salmeterol 50 mcg 2 times a day), the frequency of exacerbations of COPD decreased by 25% compared with placebo. Combination therapy provided a more pronounced effect in patients with severe COPD, in whom of which the initial FEV1 was less than 50% of expected th.
The effectiveness of drugs used for asthma largely depends on the means of delivery , which affects the deposition of the drug in the respiratory tract. Pulmonary deposition of drugs when using various delivery systems ranges from 4 to 60% of the administered dose. There is a clear relationship between pulmonary deposition and the clinical effect of the drug. Introduced into clinical practice in 1956, metered-dose aerosol inhalers (MDIs) are the most common inhalation devices. When using a MDI, approximately 10-30% of the drug (in the case of inhalation without a spacer) enters the lungs and then into the systemic circulation. Most of the drug, which is approximately 70-80%, settles in the oral cavity and larynx and is swallowed. Errors when using MDIs reach 60%, lead to insufficient delivery of the drug into the respiratory tract and, thereby, reduce the effectiveness of ICS therapy. The use of a spacer allows you to reduce the distribution of the drug in the oral cavity by up to 10% and optimize the flow of the active substance into the respiratory tract, because does not require absolute coordination of patient actions.
The more severe the patient’s asthma, the less effective therapy with conventional metered-dose aerosols is, since only 20-40% of patients can reproduce the correct inhalation technique when using them. In this regard, new inhalers have recently been created that do not require the patient to coordinate movements during inhalation. In these delivery devices, the delivery of the drug is activated by the patient's inhalation; these are the so-called BOI (Breathe Operated Inhaler) - a breath-activated inhaler. These include the Easi-Breath inhaler (“easy-breeze” light breathing). Currently, Beclazon Eco Easy Breathing is registered in Ukraine. Dry powder inhalers (dipihaler (Flochal, Budecort), discus (Flixotide (FP), Seretide - FP + salmeterol), nebulizers are delivery devices that ensure optimal dose of ICS and reduce unwanted side effects of therapy. BUD administered through Turbuhaler has the same effect , as a double dose of BUD in a metered-dose aerosol.
Early initiation of anti-inflammatory therapy with ICS reduces the risk of developing irreversible changes in the airways and improves the course of asthma. Late initiation of ICS treatment subsequently leads to lower performance on functional tests (Level of Evidence: C).
The randomized, double-blind, placebo-controlled study START (Inhaled Steroid Treatment as Regular Therapy in Early Asthma Study) showed that the earlier basic therapy with ICS is started for asthma, the milder the disease progresses. The START results were published in 2003. The effectiveness of early BUD therapy was confirmed by an increase in respiratory function indicators.
Long-term treatment with ICS improves or normalizes pulmonary function, reduces daily fluctuations in peak expiratory flow, the need for bronchodilators and corticosteroids for systemic use, up to their complete abolition. Moreover, with long-term use of drugs, the frequency of exacerbations, hospitalizations and mortality of patients decreases.
Ndesirable effects of ICS or safety of treatment
Despite the fact that ICS have a local effect on the respiratory tract, there is conflicting information about the manifestation of adverse systemic effects (AE) of ICS, from their absence to pronounced manifestations that pose a risk to patients, especially children. These NEs include suppression of the function of the adrenal cortex, effects on bone metabolism, bruising and thinning of the skin, oral candidiasis, and cataract formation.
It has been convincingly proven that long-term therapy with ICS does not lead to a significant change in the structure of bone tissue, does not affect lipid metabolism, the state of the immune system, and does not increase the risk of developing subcapsular cataracts. However, questions regarding the potential impact of ICS on children's linear growth rate and the state of the hypothalamic-pituitary-adrenal (HPA) axis continue to be discussed.
Manifestations of systemic effects are predominantly determined by the pharmacokinetics of the drug and depend on the total amount of corticosteroids supplied into the systemic circulation (systemic bioavailability)and the clearance of GCS. Therefore, the main factor determining the effectiveness and safety of ICS is the selectivity of the drug forrelation to the respiratory tract - the presence of highlow local anti-inflammatory activity and low systemic activity (Table 2).
table 2 . Selectivity of ICS and systemic activity of ICS
| ICS | Local activity | System activity | Local/systemic activity ratio |
| BUD | 1,0 | 1,0 | 1,0 |
| BDP | 0,4 | 3,5 | 0,1 |
| FLU | 0,7 | 12,8 | 0,05 |
| TAA | 0,3 | 5,8 | 0,05 |
The safety of ICS is determined mainly byThis is due to its bioavailability from the gastrointestinal tract and is inversely proportional to it. PeThe oral bioavailability of various ICS ranges from less than 1% to 23%. PrimaUsing a spacer and rinsing the mouth after inhalation significantly reduces oral bioavailabilityAvailability (level of evidence B). Oral bioavailability is almost zero for AF and 6-13% for BUD, and inhaled bioavailability of ICS isranges from 20 (FP) to 39% (FLU).
Systemic bioavailability of ICS is the sum of inhalation and oral bioavailability. BDP has a systemic bioavailability of approximately 62%, which is slightly higher than that of other ICS.
ICS have rapid clearance, its value approximately coincides with the value of hepatic blood flow, and this is one of the reasons for the minimal manifestations of systemic NE. ICS enter the systemic circulation, after passing through the liver, mainly in the form of inactive metabolites, with the exception of the active metabolite of BDP - beclomethasone 17-monopropionate (17-BMP) (approximately 26%), and only a small part (from 23% of TAA to less than 1 % FP) - in the form of unchanged drug. During the first passage through the liver, approximately 99% of FP and MF, 90% of BUD, 80-90% of TAA and 60-70% of BDP are inactivated. The high metabolic activity of new ICS (FP and MF, the main fraction that ensures their systemic activity, is no more than 20% of the dose taken (usually not exceeding 750-1000 µg/day)) may explain their better safety profile compared to other ICS, and the likelihood of developing clinically significant adverse drug events is extremely low, and if any occur, they are usually mild and do not require discontinuation of therapy.
All of the listed systemic effects of ICS are a consequence of their ability, as GCS receptor agonists, to influence hormonal regulation in the HPA axis. Therefore, the concerns of doctors and patients associated with the use of ICS may be completely justified. At the same time, some studies have not demonstrated a significant effect of ICS on the HPA axis.
Of great interest is MF, a new ICS with very high anti-inflammatory activity, which lacks bioavailability. In Ukraine, it is represented only by Nasonex nasal spray.
Some typical effects of corticosteroids have never been observed with the use of inhaled corticosteroids, such as those associated with the immunosuppressive properties of this class of drugs or with the development of subcapsular cataracts.
Table 3. WITHcomparative studies of ICS, which included determination of the therapeutic effectToTactivity and systemic activity based on baseline serum cortisol levels or an ACTH analogue stimulation test.
| Number of patients | ICS/daily dose mcg of two drugs | Efficiency (morning PEF*) | System activity |
| 672 adults | FP/100, 200, 400, 800 iBDP/400 | FP 200 = BDP 400 | FP 400 = BDP 400 |
| 36 adults | BDP/1500 and BUD/1600 | BDP = BUD | BDP = BUD - no effect |
| 398 children | BDP/400 and FP/200 | FP > BDP | FP = BDP - no effect |
| 30 adults | BDP/400 and BUD/400 | BDP = BUD | BDP = BUD - no effect |
| 28 adults | BDP/1500 and BUD/1600 | BDP = BUD | BDP = BUD |
| 154 adults | BDP/2000 and FP/1000 | FP = BDP | BDP > FP |
| 585 adults | BDP/1000 and FP/500 | FP = BDP | FP = BDP - no effect |
| 274 adults | BDP/1500 and FP/1500 | FP > BDP | BDP = AF – no effect |
| 261 adults | BDP/400 and FP/200 | FP = BDP | BDP > FP |
| 671 adults | BUD/1600 and FP/1000,2000 | FP 1000 > BUD, FP 2000 > BUD | FP 1000 = BUD, FP 2000 > BUD |
| 134 adults | BDP/1600 and FP/2000 | FP = BDP | FP > BDP |
| 518 adults | BUD/1600 and FP/800 | FP > BUD | BUD > FP |
| 229 children | BUD/400 and FP/400 | FP > BUD | BUD > FP |
| 291 adults | TAA/800 and FP/500 | FP > TAA | FP = TAA |
| 440 adults | FLU/1000 and FP/500 | FP > FLU | FP = FLU |
| 227 adults | BUD/1200 and FP/500 | BUD = AF | BUD > FP |
Note: * PEF peak expiratory flow
Dependence of the systemic effect of ICS on dosedrug is not obvious, research results are contradictory (Table 3). NotLooking at the questions that arise, the presented clinical cases make us think about the safetydangers of long-term therapy with high doses of ICS. There are probably patients who are highly sensitive to steroid therapy. Purposehigh doses of ICS in such persons may cause an increased incidence of systemicside effects. The factors that determine the patient’s high sensitivity to GCS are still unknown. One can only note that the number of suchThere are very few patients (4 described cases per16 million patients/years of use aloneFP since 1993).
The greatest concern is the potential for ICS to affect the growth of children, since these drugs are usually used for a long time. The growth of children with asthma who do not receive corticosteroids in any form can be influenced by a number of factors, such as: concomitant atopy, severity of asthma, gender and others. Childhood asthma is likely to be associated with some growth retardation, although it does not result in a reduction in final adult height. Because of the many factors that influence growth in children with asthma, research has focused concerned with the effect of inhaled corticosteroids or systemic corticosteroids on growth,have conflicting results.
Local side effects of ICS include: candidiasis of the oral cavity and oropharynx, dysphonia, sometimes cough resulting from irritation of the upper respiratory tract, paradoxical bronchospasm.
When taking low doses of ICS, the incidence of local side effects is low. Thus, oral candidiasis occurs in 5% of patients using low doses of ICS, and in up to 34% of patients using high doses of these drugs. Dysphonia is observed in 5-50% of patients using ICS; its development is also associated with higher doses of drugs. In some cases, when using ICS, a reflex cough may develop. Paradoxical bronchospasm may develop in response to the administration of ICS carried out using a MDI. In clinical practice, the use of bronchodilator drugs often masks this type of bronchoconstriction.
Thus, ICS have been and remain the cornerstone of asthma therapy in children and adults. The safety of long-term use of low and medium doses of ICS is beyond doubt. Long-term administration of high doses of ICS can lead to the development of systemic effects, the most significant of which are slowing down CPR in children and suppressing adrenal function.
The latest international recommendations for the treatment of asthma in adults and children suggest the prescription of combination therapy with ICS and long-acting beta-2 agonists in all cases where the use of low doses of ICS does not achieve an effect. The feasibility of this approach is confirmed not only by its higher efficiency, but also by its better safety profile.
Prescribing high doses of ICS is advisable only if combination therapy is ineffective. Probably, in this case, the decision to use high doses of ICS should be made by a pulmonologist or allergist. After achieving a clinical effect, it is advisable to titrate the dose of ICS to the lowest effective one. In the case of long-term treatment of asthma with high doses of ICS, safety monitoring is necessary, which may include measuring CPR in children and determining cortisol levels in the morning.
The key to successful therapy is the relationship between the patient and the doctor and the patient’s attitude towards treatment compliance.
Please remember that this is a general setting. An individual approach to the treatment of patients with asthma is not excluded, when the doctor chooses the drug, regimen and dose of its administration. If the doctor, based on the recommendations of agreements on the management of asthma, is guided by his knowledge, existing information and personal experience, then the success of treatment is guaranteed.
LITERATURE
1. Global Strategy for Asthma Management and Prevention. National Institutes of Health, National Heart, Lung and Blood Institute. Revised 2005. NIH publication No. 02-3659 // www.ginasthma.co m. Barnes PJ. Efficacy of inhaled corticosteroids in asthma. J Allergy Clin Immunol 1998;102(4 pt 1):531-8.
2. Barnes N.C., Hallet C., Harris A. Clinical experience with fluticasone propionate in asthma: a meta-analysis of efficacy and systemic activity compared with budesonide and beclomethasone dipropionate at half the microgram dose or less. Respira. Med., 1998; 92:95.104.
3. Pauwels R, Pedersen S, Busse W, et al. Early intervention with budesonide in mild persistent asthma: a randomized, double-blind trial. Lancet 2003;361:1071-76.
4. Main provisions of the EPR-2 expert group report: leading trends in the diagnosis and treatment of bronchial asthma. National Heart, Lung, and Blood Institute. NIH publication N 97-4051A. May 1997 / Transl. edited by A.N. Tsoi. M., 1998.
5. Crocker IC, Church MK, Newton S, Townley RG. Glucocorticoids inhibit proliferation and interleukin 4 and interleukin 5 secretion by aeroallergenspecific T-helper type 2 cell lines. Ann Allergy Asthma Immunol 1998;80:509-16.
6. Umland SP, Nahrebne DK, Razac S, et al. The inhibitory effect of topically active glucocorticoids on IL4, IL5 and interferon gamma production by cultured primary CD4+ T cells. J. Allergy Clin. Immunol 1997;100:511-19.
7. Derendorf H. Pharmacokinetik and pharmakodynamic properties of inhaled corticosteroids in rela tion to effectiveness and safety. Respir Med 1997;91(suppl. A):22-28.
8. Johnson M. Pharmacodynamics and pharmacokinetics of inhaled glucocorticoids. J Allergy Clin Immunol 1996;97:169-76.
9. Brokbank W, Brebner H, Pengelly CDR. Chronic asthma treated with aerosol hydrocortisone. Lancet 1956:807.
10. The Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma // N. Engl. J.Med. – 2000. – Vol. 343. – P. 1054-1063.
11. Suissa S, Ernst P. // J Allergy Clin Immunol.-2001.-Vol 107, N 6.-P.937-944.
12. Suissa S., Ernst P., Benayoun S. et al. // N Engl J Med.-2000.-Vol 343, N 5.-P.332. Lipworth B.J., Jackson C.M. Safety of inhaled and intranasal corticosteroids: lessons for the new millennium // Drug Safety. – 2000. – Vol. 23. – P. 11–33.
13. Smolenov I.V. Safety of inhaled glucocorticosteroids: new answers to old questions // Atmosphere. Pulmonology and allergology. 2002. No. 3. – pp. 10-14.
14. Burge P, Calverley P, Jones P, et al. Randomized, double bling, placebo controlled study of Fluticasone propionate in patient with moderate to severe chronic obstructive pulmonary diseases: the ISOLDE trial. BMJ 2000;320:1297-303.
15. Sutochnikova O.A., Chernyaev A.L., Chuchalin A.G. Inhaled glucocorticosteroids in the treatment of bronchial asthma // Pulmonology. –1995. – Volume 5. – P. 78 – 83.
16. Allen D.B., Mullen M., Mullen B. A meta-analysis of the effect of oral and inhaled corticosteroids on growth // J. Allergy Clin. Immunol. – 1994. – Vol. 93. – P. 967-976.
17. Hogger P, Ravert J, Rohdewald P. Dissolution, tissue binding and kinetics of receptor binding of inhaled glucocorticoids. Eur Respir J 1993;6(suppl.17):584S.
18. Tsoi A.N. Pharmacokinetic parameters of modern inhaled glycocorticosteroids // Pulmonology. 1999. No. 2. P. 73-79.
19. Miller-Larsson A., Maltson R. H., Hjertberg E. et al. Reversible fatty acid conjugation of budesonide: novel mechanism for prolonged retention of topically applied steroid in airway tissue // Drug.metabol. Dispos. 1998; v. 26 N 7: 623-630.A. K., Sjodin, Hallstrom G. Reversible formation of fatty acid esters of budesonide, an anti-asthma glucocorticoid, in human lung and liver microsomes // Drug. Metabolic. Dispos. 1997; 25: 1311-1317.
20. Van den Bosch J. M., Westermann C. J. J., Edsbacker J. et al. Relationship between lung tissue and blood plasma concentrations of inhaled budesonide // Biopharm Drug. Dispos. 1993; 14:455-459.
21. Wieslander E., Delander E. L., Jarkelid L. et al. Pharmacological importance of the reversible fatty acid conjugation of budesonide staged in a rat cell line in vitro // Am. J. Respira. Cell. Mol. Biol. 1998;19:1-9.
22. Thorsson L., Edsbacker S. Conradson T. B. Lung deposition of budesonide from Turbuhaler is twice that from a pressured metered-dose-inhaler p-MDI // Eur. Respira. J. 1994; 10: 1839-1844
23. Derendorf H. Pharmacokinetic and pharmacodynamic properties of inhaled corticosteroids in relation to efficacy and safety // Respir. Med. 1997; 91 (Suppl. A): 22-28
24. Jackson W. F. Nebulized Budesonide Therapy in asthma scientific and practical review. Oxford,1995: 1-64
25. Trescoli-Serrano C., Ward W. J., Garcia-Zarco M. et al. Gastroinstestinal absorption of inhaled budesonide and beclomethasone: has it any significant systemic effect? //Am. J. Respira. Crit. Care Med. 1995; 151 (No. 4 part 2):A. Borgstrom L. E., Derom E., Stahl E. et al. The inhalation device influences lung deposition and bronchodilating effect of terbutaline //Am. J. Respira. Crit. Care Med. 1996; 153: 1636-1640.
26. Ayres J.G., Bateman E.D., Lundback E., Harris T.A.J. High dose fluticasone propionate, 1 mg daily, versus fluticasone propionate, 2 mg daily, or budesonide, 1.6 mg daily, in patients with chronic severe asthma // Eur. Respira. J. – 1995. – Vol.8(4). – P. 579-586.
27. Boe J., Bakke P., Rodolen T., et al. High-dose inhaled steroids in asthmatics: Moderate efficacy gain and suppression of the hypothalamic pituitary-adrenal (HPA) axis // Eur. Respira. J. –1994. – Vol. 7. – P. 2179-2184.
28. Dahl R., Lundback E., Malo J.L., et al. A doseranging study of fluticasone propionate in adult patients with moderate asthma // Chest. – 1993. – Vol. 104. – P. 1352-1358.
29. Daley-Yates P.T., Price A.C., Sisson J.R. et al. Beclomethasone dipropionate: absolute bioavailability, pharmacokinetics and metabolism following intravenous, oral, intranasal and inhaled administration in man // J. Clin. Pharmacol. – 2001. – Vol. 51. – P. 400-409.
30. Mollmann H., Wagner M., Meibohm B. et al. Pharmacokinetic and pharmacodynamic evolution of fluticasone propionate after inhaled administrationtion // Eur. J. Clin. Pharmacol. – 1999. – Vol. 53. – P. 459–467.
31. Ninan T.K., Russell G. Asthma, inhaled corticosteroid treatment, and growth // Arch. Dis. Child. –1992. – Vol. 67(6). – P. 703 705.
32. Pedersen S., Byrne P. O. A comparison of the efficacy and safety of inhaled corticosteroids in asthma // Eur. J. Allergy. Clin. Immunol. – 1997. – V.52 (39). – P.1-34
33. Thompson P. I. Drug delivery to the small airways // Amer. J. Repir. Crit. Med. – 1998. – V. 157. – P.199 – 202.
34. Boker J., McTavish D., Budesonide. An updated review of its pharmacological properties, and therapeutic efficacy in asthma and rhinitis // Drugs. –1992. – v. 44. – No. 3. – 375 – 407.
35. Calverley P, Pauwels R, Vestibo J, et al. Combined salmeterol and Fluticasone in the treatment of chronic obstructive pulmonary disease: a randomized controlled trial. Lancet 2003;361:449-56.
36. Assessment of airway inflammation in asthma / A.M. Vignola. J. Bousquet, P. Chanez et al. //Am. J. Respira. Crit. Care Med. – 1998. – V. 157. – P. 184–187.
37. Yashina L.O., Gogunska I.V. Efficacy and safety of inhaled corticosteroids in the treatment of bronchial asthma // Asthma and allergies. – 2002. No. 2. – P. 21 – 26.
38. Effectiveness and safety of inhaled corticosteroids in controlling acute asthma attacks in children who were treated in the emergency department: controlled comparative study with oral prednisolone / B. Volovits, B. Bentur, Y. Finkelshtein et al. // J. Allergy Clin. Immunol. – 1998. – V. 102. – N. 4. – P.605 – 609.
39. Sinopalnikov A.I., Klyachkina I.L. Means for delivering drugs to the respiratory tract for bronchial asthma // Russian medical news. -2003. No. 1. pp. 15-21.
40. Nicklas RA. Paradoxical bronchospasm associated with the use of inhaled beta agonists. J Allergy Clin Immunol 1990;85:959-64.
41. Pedersen S. Asthma: Basic Mechanisms and Clinical Management. Ed. P. J. Barnes. London 1992, p. 701-722
42. Ebden P., Jenkins A., Houston G., et al. Comparison of two high dose corticosteroid aerosol treatments, beclomethasone dipropionate (1500 mcg/day) and budesonide (1600 mcg/day), for chronic asthma // Thorax. – 1986. – Vol. 41. – P.869-874.
43. Brown P.H., Matusiewicz S.P., Shearing C. et al. Systemic effects of high dose inhaled steroids: comparison of beclomethasone dipropionate and budesonide in healthy subjects // Thorax. – 1993.– Vol. 48. – P. 967-973.
44. Safety of inhaled and intranasal corticosteroids: benefits for the new millennium // Drug Safety. –2000. – Vol. 23. – P. 11–33.
45. Doull I.J.M., Freezer N.J., Holgate S.T. Growth of pre-pubertal children with mild asthma treated with inhaled beclomethasone dipropionate // Am. J.Respira. Crit. Care Med. – 1995. – Vol. 151. – P.1715-1719.
46. Goldstein D.E., Konig P. Effect of inhaled beclomethasone dipropionate on hypothalamic pituitary-adrenal axis function in children with asthma // Pediatrics. – 1983. – Vol. 72. – P. 60-64.
47. Kamada A.K., Szefler S.J. Glucocorticoids and growth in asthmatic children // Pediatr. Allergy Immunol. – 1995. – Vol. 6. – P. 145-154.
48. Prahl P., Jensen T., Bjerregaard-Andersen H. Adrenocortical function in children on high-dose steroid aerosol therapy // Allergy. – 1987. – Vol.42. – P. 541-544.
49. Priftis K., Milner A.D., Conway E., Honor J.W. Adrenal function in asthma // Arch. Dis. Child. –1990. – Vol. 65. – P. 838-840.
50. Balfour-Lynn L. Growth and childhood asthma // Arch. Dis. Child. – 1986. – Vol. 61(11). – P. 1049-1055.
51. Kannisto S., Korppi M., Remes K., Voutilainen R. Adrenal Suppression, Evaluated by a Low Dose Adrenocorticotropin Test, and Growth in Asthmatic Children Treated with Inhaled Steroids // Journal of Clinical Endocrinology and Metabolism. – 2000. – Vol. 85. – P. 652 – 657.
52. Prahl P. Adrenocortical suppression following treatment with beclomethasone dipropionate and budesonide // Clin. Exp. Allergy. – 1991. – Vol. 21.– P. 145-146.
53. Tabachnik E., Zadik Z. Diurnal cortisol secretion during therapy with inhaled beclomethasone dipropionate in children with asthma // J. Pediatr. –1991. – Vol. 118. – P. 294-297.
54. Capewell S., Reynolds S., Shuttleworth D. et al. Purpura and dermal thinning associated with high dose inhaled corticosteroids // BMJ. – 1990. Vol.300. – P. 1548-1551.
Inhaled corticosteroids are recommended for prophylactic purposes in patients with persistent bronchial asthma, starting with mild severity. Inhaled steroids have virtually 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.
Moderate doses of inhaled corticosteroids of the first and second generation 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 monitor the child’s growth. III generation drugs can be prescribed to children from the age of 1 year precisely because they have a minimum coefficient of systemic bioavailability. In order to achieve a sustainable effect, inhaled forms of corticosteroids must be used regularly. Reduction in asthma symptoms is usually achieved by days 3-7 of therapy. If necessary, simultaneous administration of Ig-agonists and inhaled steroids for better penetration of the latter into the airways)
