Drugs for the treatment of bronchial asthma. Inhaled glucocorticoids

For asthma, inhaled glucocorticosteroids are used, which are not common to most side effects 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. Most important property- lipophilicity, due to which ICS accumulate in the respiratory tract, their release from tissues slows down and their affinity for the glucocorticoid receptor increases. The pulmonary bioavailability of ICS depends on the percentage of the drug 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 GINA's global strategy, fixed combinations are the most effective means basic therapy for bronchial asthma, as they allow you to relieve an attack and at the same time serve as 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"

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

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The site provides reference information for informational purposes only. Diagnosis and treatment of diseases must be carried out under the supervision of a specialist. All drugs have contraindications. Expert advice is required!

Introduction (characteristics of drugs)

Natural corticosteroids

Corticosteroids- common name hormones adrenal cortex, which includes glucocorticoids and mineralocorticoids. The main glucocorticoids produced in the human adrenal cortex are cortisone and hydrocortisone, and the mineralocorticoid is aldosterone.

Corticosteroids perform many very important functions in the body.

Glucocorticoids refer to steroids, which have an anti-inflammatory effect, they are involved in the regulation of the metabolism of carbohydrates, fats and proteins, control puberty, kidney function, the body's response to stress, and contribute to the normal course of pregnancy. Corticosteroids are inactivated in the liver and excreted in the urine.

Aldosterone regulates the metabolism of sodium and potassium. Thus, under the influence mineralocorticoids Na+ is retained in the body and the excretion of K+ ions from the body increases.

Synthetic corticosteroids

Synthetic corticosteroids, which have the same properties as natural ones, have found practical application in medical practice. They are capable of temporarily suppressing the inflammatory process, but they have no effect on the infectious origin or pathogens of the disease. After the corticosteroid drug wears off, the infection returns.

Corticosteroids cause tension and stress in the body, and this leads to a decrease in immunity, since immunity is provided at a sufficient level only in a relaxed state. Given the above, we can say that the use of corticosteroids contributes to the protracted course of the disease, blocks the regeneration process.

In addition, synthetic corticosteroids suppress the function of natural corticosteroid hormones, which entails a violation of the function of the adrenal glands in general. Corticosteroids affect the work of other endocrine glands, the hormonal balance of the body is disturbed.

Corticosteroid drugs, eliminating inflammation, also have an analgesic effect. Synthetic corticosteroid drugs include Dexamethasone, Prednisolone, Sinalar, Triamcinolone and others. These drugs are more active and cause less side effects than natural ones.

Forms of release of corticosteroids

Corticosteroids are produced in the form of tablets, capsules, solutions in ampoules, ointments, liniments, and creams. (Prednisolone, Dexamethasone, Budenofalm, Cortisone, Cortinef, Medrol).

Preparations for internal use (in tablets and capsules)

• Prednisolone;
• Celeston;
• Triamcinolone;
• Kenacort;
• Cortineff;
• Polcortolon;
• Kenalog;
• Metipred;
• Berlicourt;
• Florinef;
• Medrol;
• Lemod;
• Decadron;
• Urbazon et al.

Preparations for injections

• Prednisolone;
• Hydrocortisone;
• Diprospan (betamethasone);
• Kenalog;
• Flosteron;
• Medrol et al.

Preparations for local use (topical)

• Prednisolone (ointment);
• Hydrocortisone (ointment);
• Lokoid (ointment);
• Cortade (ointment);
• Afloderm (cream);
• Laticort (cream);
• Dermovate (cream);
• Fluorocort (ointment);
• Lorinden (ointment, lotion);
• Sinaflan (ointment);
• Flucinar (ointment, gel);
• Clobetasol (ointment), etc.

Topical corticosteroids are divided into more and less active ones.
Weakly active agents: Prednisolone, Hydrocortisone, Cortade, Lokoid;
Moderately active: Afloderm, Laticort, Dermovate, Fluorocort, Lorinden;
Highly active: Akriderm, Advantan, Kuterid, Apulein, Cutivate, Sinaflan, Sinalar, Sinoderm, Flucinar.
Very highly active: Clobetasol.

Corticosteroids for inhalation

• Beclamethasone in the form of metered aerosols (Becotide, Aldecim, Beclomet, Beclocort); in the form of becodisks (powder in a single dose, inhaled using a diskhaler); in the form of a dosed aerosol for inhalation through the nose (Beclomethasone-nasal, Beconase, Aldecim);
• Flunisolide in the form of metered aerosols with a spacer (Ingacort), for nasal use (Sintaris);
• Budesonide – dosed aerosol (Pulmicort), for nasal use – Rhinocort;
• Fluticasone in the form of aerosols Flixotide and Flixonase;
• Triamcinolone - metered-dose aerosol with a spacer (Azmacort), for nasal use - Nazacort.

Indications for use

Corticosteroids are used to suppress inflammation in many branches of medicine and for many diseases.

Indications for the use of glucocorticoids

• Rheumatism;
• rheumatoid and other types of arthritis;
• collagenoses, autoimmune diseases(scleroderma, systemic lupus erythematosus, periarteritis nodosa, dermatomyositis);
• blood diseases (myeloid and lymphoblastic leukemias);
• some types of malignant neoplasms;
• skin diseases (neurodermatitis, psoriasis, eczema, seborrheic dermatitis, discoid lupus erythematosus, atopic dermatitis, erythroderma, lichen planus);
• bronchial asthma;
• allergic diseases;
• pneumonia and bronchitis, fibrosing alveolitis;
• ulcerative colitis and Crohn's disease;
• acute pancreatitis;
• hemolytic anemia;
• viral diseases(infectious mononucleosis, viral hepatitis and others);
• otitis externa (acute and chronic);
• treatment and prevention of shock;
• in ophthalmology (for non-infectious diseases: iritis, keratitis, iridocyclitis, scleritis, uveitis);
• neurological diseases (multiple sclerosis, acute trauma spinal cord, optic neuritis;
• in organ transplantation (to suppress rejection).

Indications for the use of mineralocorticoids

• Addison's disease ( chronic insufficiency hormones of the adrenal cortex);
• myasthenia gravis (an autoimmune disease manifested by muscle weakness);
• disorders of mineral metabolism;
• adynamia and muscle weakness.

Contraindications

Contraindications for the appointment of glucocorticoids:

• hypersensitivity to the drug;
• severe infections (except tuberculous meningitis and septic shock);
• immunization with a live vaccine.

Carefully Glucocorticosteroids should be used for diabetes mellitus, hypothyroidism, gastric and duodenal ulcers, ulcerative colitis, high blood pressure, liver cirrhosis, cardiovascular failure in the stage of decompensation, increased thrombus formation, tuberculosis, cataracts and glaucoma, mental illness.

Contraindications for prescribing mineralocorticoids:

• high blood pressure;
• diabetes;
• low potassium levels in the blood;
• renal and hepatic failure.

Adverse reactions and precautions

Corticosteroids can cause a wide variety of side effects. When using weakly or moderately active agents adverse reactions less pronounced and occur rarely. High doses of drugs and the use of highly active corticosteroids, their long-term use can cause such side effects:

• the appearance of edema due to sodium and water retention in the body;
• promotion blood pressure;
• increased blood sugar levels (possibly even the development of steroid diabetes mellitus);
• osteoporosis due to increased calcium secretion;
• aseptic necrosis of bone tissue;
• exacerbation or occurrence peptic ulcer stomach; gastrointestinal bleeding;
• increased thrombus formation;
• weight gain;
• the occurrence of bacterial and fungal infections due to a decrease in immunity (secondary immunodeficiency);
• menstrual irregularities;
• neurological disorders;
• development of glaucoma and cataracts;
• skin atrophy;
• increased sweating;
• the appearance of acne;
• suppression of the tissue regeneration process (slow wound healing);
• excess facial hair growth;
• suppression of adrenal function;
• mood instability, depression.

Long courses of corticosteroids may cause changes appearance patient (Itsenko-Cushing syndrome):

• excessive deposition of fat in certain parts of the body: on the face (the so-called "moon-shaped face"), on the neck ("bull neck"), chest, on the stomach;
• the muscles of the limbs are atrophied;
• bruising on the skin and stretch marks (stretch marks) on the abdomen.

With this syndrome, growth retardation, violations of the formation of sex hormones (menstrual disorders and male type of hair growth in women, and signs of feminization in men) are also noted.

To reduce the risk of adverse reactions, it is important to respond in a timely manner to their occurrence, adjust doses (using small doses if possible), control body weight and calorie content of foods consumed, and limit salt and fluid intake.

How to use corticosteroids?

Glucocorticosteroids can be used systemically (in the form of tablets and injections), locally (intra-articular, rectal administration), topically (ointments, drops, aerosols, creams).

The dosage regimen is prescribed by the doctor. The tablet preparation should be taken from 6 o'clock in the morning (first dose) and no later than 14 o'clock subsequent. Such intake conditions are necessary to approach the physiological intake of glucocorticoids into the blood when they are produced by the adrenal cortex.

In some cases, with large doses and depending on the nature of the disease, the dose is distributed by the doctor to be distributed evenly throughout the day in 3-4 doses.

The tablets should be taken with meals or immediately after meals with a small amount of water.

Treatment with corticosteroids

The following types of corticosteroid therapy are distinguished:

• intense;
• limiting;
• alternating;
• intermittent;
• pulse therapy.

At intensive care(in the case of an acute, life-threatening pathology), the drugs are administered intravenously and, when the effect is achieved, are canceled at once.

Limiting therapy used for long-term, chronic processes - as a rule, tablet forms are used for several months or even years.

To reduce the inhibitory effect on the function of the endocrine glands, intermittent drug dosing regimens are used:

• alternating therapy – use glucocorticoids with short and medium duration of action (Prednisolone, Methylprednisolone) once from 6 to 8 am every 48 hours;
• intermittent therapy – short, 3-4-day courses of taking the drug with 4-day breaks between them;
• pulse therapy– rapid intravenous administration of a large dose (at least 1 g) of the drug to provide emergency care. The drug of choice for such treatment is Methylprednisolone (it is more accessible for injection into the affected areas and produces less side effects).

Daily doses of drugs(in terms of Prednisolone):

• Low – less than 7.5 mg;
• Medium – 7.5 -30 mg;
• High – 30-100 mg;
• Very high – above 100 mg;
• Pulse therapy – above 250 mg.

Treatment with corticosteroids should be accompanied by the prescription of calcium and vitamin D supplements for the prevention of osteoporosis. The patient's diet should be rich in proteins, calcium and include a limited amount of carbohydrates and table salt (up to 5 g per day), fluids (up to 1.5 liters per day).

For prevention undesirable effects of corticosteroids on the gastrointestinal tract, before taking the tablets, it is possible to recommend the use of Almagel, jelly. It is recommended to eliminate smoking and abuse alcoholic drinks; moderate exercise.

Corticosteroids for children

Systemic glucocorticoids are prescribed to children exclusively for absolute indications. For bronchial obstruction syndrome that threatens the life of a child, intravenous prednisolone is used at a dose of 2-4 mg per 1 kg of the child’s body weight (depending on the severity of the disease), and if there is no effect, the dose is increased by 20-50% every 2-4 hours until getting the effect. After this, the drug is discontinued immediately, without gradually reducing the dosage.

Children with hormonal dependence (with bronchial asthma, for example), after intravenous administration of the drug, are gradually transferred to a maintenance dose of prednisolone. For frequent relapses of asthma, Beclamethasone dipropionate is used in the form of inhalations - the dose is selected individually. After obtaining the effect, the dose is gradually reduced to a maintenance dose (selected individually).

Topical glucocorticoids(creams, ointments, lotions) are used in pediatric practice, but children have a higher predisposition to the systemic effects of drugs than adult patients (delayed development and growth, Itsenko-Cushing syndrome, inhibition of the function of the endocrine glands). This is because children have a larger body surface area to body weight ratio than adults.

For this reason, topical glucocorticoids should be used in children only in limited areas and for a short course. This is especially true for newborns. For children in the first year of life, you can only use ointments containing no more than 1% hydrocortisone or a fourth-generation drug - Prednicarbate (Dermatol), and for children under 5 years of age - Hydrocortisone 17-butyrate or ointments with medium strength drugs.

For the treatment of children over 2 years old, Mometasone can be used as prescribed by a doctor (ointment, has a prolonged effect, applied once a day).

There are other drugs for the treatment of atopic dermatitis in children, with a less pronounced systemic effect, for example, Advantan. It can be used for up to 4 weeks, but its use is limited due to the possibility of local adverse reactions (dryness and thinning of the skin). In any case, the choice of drug for the treatment of the child remains with the doctor.

Corticosteroids during pregnancy and lactation

The use of glucocorticoids, even short-term, can “program” for decades to come the work of many organs and systems in the unborn child (blood pressure control, metabolic processes, behavior formation). The synthetic hormone imitates the stress signal for the fetus from the mother and thereby causes the fetus to speed up the use of reserves.

This negative effect of glucocorticoids is enhanced by the fact that modern drugs long-acting medications (Metypred, Dexamethasone) are not deactivated by placental enzymes and have a long-lasting effect on the fetus. Glucocorticoids, by suppressing the immune system, help reduce a pregnant woman's resistance to bacterial and viral infections, which can also negatively affect the fetus.

Glucocorticoid drugs can be prescribed to a pregnant woman only if the result of their use significantly outweighs the risk of possible negative consequences for the fetus.

Such indications may be:
1. Threat of premature birth (a short course of hormones improves the readiness of the premature fetus for birth); the use of surfactant for the child after birth has allowed us to minimize the use of hormones for this indication.
2. Rheumatism and autoimmune diseases in the active phase.
3. Hereditary (intrauterine) hyperplasia of the fetal adrenal cortex is a difficult disease to diagnose.

Previously, there was a practice of prescribing glucocorticoids to maintain pregnancy. But no convincing data on the effectiveness of this technique have been obtained, so it is not currently used.

IN obstetric practice Metipred, Prednisolone and Dexamethasone are more commonly used. They penetrate the placenta in different ways: Prednisolone is destroyed by enzymes in the placenta to a greater extent, and Dexamethasone and Metipred - by only 50%. Therefore, if hormonal drugs are used to treat a pregnant woman, it is preferable to prescribe Prednisolone, and if to treat the fetus, it is preferable to prescribe Dexamethasone or Metypred. In this regard, Prednisolone causes less adverse reactions in the fetus.

For severe allergies, glucocorticoids are prescribed both systemically (injections or tablets) and local (ointments, gels, drops, inhalations). They have a powerful antiallergic effect. The following drugs are mainly used: Hydrocortisone, Prednisolone, Dexamethasone, Betamethasone, Beclomethasone.

From topical glucocorticoids (for local treatment) In most cases, intranasal aerosols are used: for hay fever, allergic rhinitis, nasal congestion (sneezing). Usually they provide good effect. Fluticasone, Dipropionate, Propionate and others have found wide application.

In allergic conjunctivitis, due to the higher risk of side effects, glucocorticoids are rarely used. In any case, in case of allergic manifestations, hormonal medications cannot be used independently in order to avoid undesirable consequences.

Corticosteroids for psoriasis

Glucocorticoids for psoriasis should be used mainly in the form of ointments and creams. Systemic (injections or tablets) hormonal drugs can contribute to the development of a more severe form of psoriasis (pustular or pustular), so their use is not recommended.

Glucocorticoids for topical use (ointments, creams) are usually used 2 r. per day: creams during the day without dressings, and at night together with coal tar or anthralin using an occlusive dressing. For extensive lesions, approximately 30 g of the drug is used to treat the entire body.

The choice of glucocorticoid drug according to the degree of activity for topical use depends on the severity of psoriasis and its prevalence. As the psoriasis lesions decrease during treatment, the drug should be changed to a less active one (or used less frequently) to minimize the occurrence of side effects. When you get the effect after about 3 weeks, it is better to replace hormonal drug emollient for 1-2 weeks.

The use of glucocorticoids over large areas over a long period can aggravate the process. Relapse of psoriasis after stopping the use of the drug occurs earlier than with treatment without the use of glucocorticoids.
, Coaxil, Imipramine and others) in combination with glucocorticoids can cause an increase in intraocular pressure.

Glucocorticoids (with long-term use) enhance the effectiveness of adrenomimetics (Adrenaline, Dopamine, Norepinephrine).

Theophylline in combination with glucocorticoids contributes to the appearance of a cardiotoxic effect; enhances the anti-inflammatory effect of glucocorticoids.

Amphotericin and diuretics in combination with corticosteroids increase the risk of hypokalemia (low potassium levels in the blood) and increased diuretic effects (and sometimes sodium retention).

The combined use of mineralocorticoids and glucocorticoids increases hypokalemia and hypernatremia. With hypokalemia, side effects of cardiac glycosides may occur. Laxatives may potentiate hypokalemia.

Indirect anticoagulants, Butadione, Ethacrynic acid, Ibuprofen in combination with glucocorticoids can cause hemorrhagic manifestations (bleeding), and salicylates and Indomethacin can cause the formation of ulcers in the digestive organs.

Glucocorticoids enhance the toxic effect on the liver of paracetamol.

Retinol preparations reduce the anti-inflammatory effect of glucocorticoids and improve wound healing.

The use of hormones together with Azathioprine, Methandrostenolone and Chingamin increases the risk of developing cataracts and other adverse reactions.

Glucocorticoids reduce the effect of Cyclophosphamide, antiviral effect Idoxuridine, the effectiveness of glucose-lowering drugs.

Estrogens enhance the effect of glucocorticoids, which may make it possible to reduce their dosage.

Androgens (male sex hormones) and iron supplements enhance erythropoiesis (the formation of red blood cells) when combined with glucocorticoids; reduce the process of hormone elimination, contribute to the appearance of side effects (increased blood clotting, sodium retention, menstrual irregularities).

The initial stage of anesthesia when using glucocorticoids is lengthened and the duration of anesthesia is reduced; Fentanyl doses are reduced.

Rules for withdrawing corticosteroids

With long-term use of glucocorticoids, drug withdrawal should be gradual. Glucocorticoids suppress the function of the adrenal cortex, so if the drug is stopped quickly or suddenly, adrenal insufficiency may develop. There is no standardized regimen for discontinuing corticosteroids. The mode of withdrawal and dose reduction depends on the duration of the previous course of treatment.

If the duration of the glucocorticoid course is up to several months, then you can reduce the dose of Prednisolone by 2.5 mg (0.5 tablets) every 3-5 days. With a longer course duration, the dose is reduced more slowly - by 2.5 mg every 1-3 weeks. With great caution, reduce the dose below 10 mg - 0.25 tablets every 3-5-7 days.

If the initial dose of Prednisolone was high, then at first the reduction is carried out more intensively: by 5-10 mg every 3 days. Upon reaching daily dose equal to 1/3 of the original dose, reduce by 1.25 mg (1/4 tablet) every 2-3 weeks. As a result of this reduction, the patient receives maintenance doses for a year or more.

The drug reduction regimen is prescribed by the doctor, and violation of this regimen can lead to an exacerbation of the disease - treatment will have to be started again with a higher dose.

Prices for corticosteroids

Since there are so many corticosteroids available in different forms, prices for just a few are listed here:

• Hydrocortisone – suspension – 1 bottle 88 rubles; eye ointment 3 g – 108 rubles;
• Prednisolone – 100 tablets of 5 mg – 96 rubles;
• Metypred – 30 tablets of 4 mg – 194 rubles;
• Metypred – 250 mg 1 bottle – 397 rubles;
• Triderm - ointment 15 g - 613 rubles;
• Triderm – cream 15 g – 520 rubles;
• Dexamed – 100 ampoules of 2 ml (8 mg) – 1377 rubles;
• Dexamethasone – 50 tablets of 0.5 mg – 29 rubles;
• Dexamethasone – 10 ampoules of 1 ml (4 mg) – 63 rubles;
• Oftan Dexamethasone – eye drops 5 ml – 107 rubles;
• Medrol – 50 tablets of 16 mg – 1083 rubles;
• Flixotide – aerosol 60 doses – 603 rubles;
• Pulmicort – aerosol 100 doses – 942 rubles;
• Benacort – aerosol 200 doses – 393 rubles;
• Symbicort - aerosol with a dispenser of 60 doses - 1313 rubles;
• Beclazon - aerosol 200 doses - 475 rubles.

Before use, you should consult a specialist.

Knyazheskaya N.P., Chuchalin A.G.

Currently bronchial asthma(BA) is considered a special chronic inflammatory disease respiratory tract with a progressive course of this inflammation without special therapy. There are a sufficient number of different drugs that can effectively deal with this inflammation. The basis of therapy for long-term control of the inflammatory process are ICS, which should be used in persistent asthma of any severity.

Background

One of the most significant achievements of medicine in the 20th century was the introduction of glucocorticosteroid drugs (GCS) into clinical practice. This group of drugs is also widely used in pulmonology.

GCS were synthesized in the late 40s of the last century and initially existed exclusively in the form of systemic drugs (oral and injectable forms). Almost immediately, their use began in the treatment of severe forms of bronchial asthma, however, despite a positive response to therapy, their use was limited by severe systemic side effects: the development of steroid vasculitis, systemic osteoporosis, steroid-induced diabetes mellitus, Itsenko-Cushing's syndrome, etc. .d. Therefore, doctors and patients considered the use of corticosteroids as a last resort, a “therapy of despair.” Attempts to use systemic corticosteroids by inhalation were unsuccessful, since regardless of the method of administration of these drugs, their systemic complications persisted, and the therapeutic effect was minimal. Thus, it is not even possible to consider the use of systemic corticosteroids via a nebulizer.

And although almost immediately after the creation of systemic GCS, the question of developing topical forms arose, it took almost 30 years to solve this problem. The first publication on the successful use of topical steroids dates back to 1971 and concerned the use of beclomethasone dipropionate for allergic rhinitis, and in 1972 this drug was successfully used to treat bronchial asthma.

Currently, ICS are considered as first-line agents in the treatment of bronchial asthma. The higher the severity of bronchial asthma, the higher doses of inhaled steroids 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.

ICS are basic, that is, the main drugs in the treatment of all pathogenetic variants of persistent bronchial asthma (BA), starting with mild severity.

Topical forms are practically safe and do not cause systemic complications even with long-term use in high doses.

Untimely and inadequate ICS therapy can lead not only to uncontrolled asthma, but also to the development of life-threatening conditions that require much more serious systemic steroid therapy. In turn, long-term systemic steroid therapy, even in small doses, can cause iatrogenic diseases. It should be taken into account that drugs to control the disease (basic therapy) should be used daily and for a long time. Therefore, the main requirement for them is that they must not only be effective, but above all, safe.

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, reducing microvascular permeability, preventing direct migration and activation of inflammatory cells, increasing the sensitivity of smooth muscle receptors. 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 β-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 will depend on the nominal dose of the drug, the type of inhaler, the presence or absence of propellant, and the inhalation technique.

ICS include beclomethasone dipropionate (BDP), budesonide (BUD), fluticasone propionate (FP), mometasone furoate (MF). They are available in the form of metered aerosols, dry powder, and also in the form of solutions for use in nebulizers (Pulmicort).

Features of budesonide as an inhaled glucocorticosteroid

Of all inhaled glucocorticoids, 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. The distinctive features of budesonide among other drugs in this group are: intermediate lipophilicity, long retention in tissue due to conjugation with fatty acids and high activity against the corticosteroid receptor. The combination of these properties determines the exceptionally high effectiveness and safety of budesonide among other ICS. Budesonide is slightly less lipophilic compared to other modern ICS, such as fluticasone and mometasone. Less lipophilicity allows budesonide to penetrate the mucus layer covering the mucous membrane more quickly and more effectively compared to more lipophilic drugs. This very important feature of this drug largely determines its clinical effectiveness. It is assumed that the greater effectiveness of BUD in comparison with FP when used in the form of aqueous suspensions for allergic rhinitis is based on the lower lipophilicity of BUD. Once inside the cell, budesonide forms esters (conjugates) with long-chain fatty acids, such as oleic and a number of others. The lipophilicity of such conjugates is very high, due to which BUD can remain in tissues for a long time.

Budesonide is an ICS that has been proven to be suitable for single use. A factor contributing to the effectiveness of once-daily administration of budesonide is retention of budesonide in the respiratory tract through the formation of an intracellular depot due to reversible esterification (formation of fatty acid esters). Budesonide is able to form conjugates inside cells (esters in position 21) with long-chain fatty acids (oleic, stearic, palmitic, palmitoleic). These conjugates are characterized by exceptionally high lipophilicity, which is significantly higher than that of other ICS. It was found that the intensity of the formation of BUD esters is not the same in different tissues. At intramuscular injection drug for rats muscle tissue About 10% of the drug is esterified, and in the pulmonary - 30-40%. At the same time, with intratracheal administration, at least 70% of the BUD is esterified, and its esters are not detected in plasma. Thus, BUD has a pronounced selectivity for lung tissue. With a decrease in the concentration of free budesonide in the cell, intracellular lipases are activated, and the budesonide released from the esters again binds to the GK receptor. This mechanism is not characteristic of other glucocorticoids and contributes to the prolongation of the anti-inflammatory effect.

Several studies have shown that intracellular storage may be more important in terms of drug activity than receptor affinity. It has been shown that BUD lingers in the tissue of the rat trachea and main bronchi much longer than AF. It should be noted that conjugation with long-chain fatty acids is a unique feature of BUD, which creates an intracellular depot of the drug and ensures its long-lasting effect (up to 24 hours).

In addition, BUD is characterized by high affinity for the corticosteroid receptor and local corticosteroid activity, exceeding that of the “old” drugs beclomethasone (including its active metabolite B17MP), flunisolide and triamcinolone and comparable to the activity of AF.

The corticosteroid activity of BUD practically does not differ from that of AF in a wide range of concentrations. Thus, BUD combines all the necessary properties of an inhaled corticosteroid, ensuring the clinical effectiveness of this class medicines: due to moderate lipophilicity, it quickly penetrates the mucous membrane; due to conjugation with fatty acids, it is retained for a long time in lung tissue; while the drug has an exceptionally high corticosteroid activity.

When using inhaled corticosteroids, there are some concerns related to the potential ability of these drugs to have a systemic effect. In general, the systemic activity of ICS depends on their systemic bioavailability, lipophilicity and volume of distribution, as well as on the degree of drug binding to blood proteins. Budesonide has a unique combination of these properties that make it the safest drug known.

Information regarding the systemic effect of ICS is very contradictory. Systemic bioavailability consists of oral and pulmonary. Oral availability depends on absorption in the gastrointestinal tract and on the severity of the "first pass" effect through the liver, due to which already inactive metabolites enter the systemic circulation (with the exception of beclomethasone 17-monopropionate, the active metabolite of beclomethasone dipropionate). Pulmonary bioavailability depends on the percentage of the drug in the lungs (which depends on the type of inhaler used), 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.

The total systemic bioavailability of ICS is determined by the proportion of the drug that entered the systemic circulation from the surface of the bronchial mucosa, and the part of the ingested proportion that was not metabolized during the first passage through the liver (oral bioavailability). On average, about 10-50% of the drug exerts its therapeutic effect in the lungs and subsequently enters the systemic circulation in active state. This fraction is entirely dependent on the efficiency of pulmonary delivery. 50-90% of the drug is swallowed, and the final systemic bioavailability of this fraction is determined by the intensity of subsequent metabolism in the liver. BUD is among the drugs with the lowest oral bioavailability.

For most patients, to achieve control of bronchial asthma, it is enough to use low or medium doses of ICS, since the dose-effect curve is quite flat for indicators such as symptoms of the disease, parameters of pulmonary function, and airway hyperresponsiveness. Transfer to high and ultra-high doses does not significantly improve the control of bronchial asthma, but increases the risk of side effects. However, there is a clear relationship between the dose of ICS and the prevention of severe exacerbations of bronchial asthma. Therefore, in a number of patients with severe asthma, long-term administration of high doses of ICS is preferable, which allows reducing or eliminating the dose of oral GCS (or avoiding their long-term use). At the same time, the safety profile of high doses of ICS is clearly more favorable than that of oral GCS.

The next property that determines the safety of budesonide is its intermediate lipophilicity and volume of distribution. Drugs with high lipophilicity have a large volume of distribution. This means that a larger proportion of the drug may have a systemic effect, meaning less of the drug is in circulation and available to be converted to inactive metabolites. BUD has intermediate lipophilicity and a relatively small volume of distribution compared to BDP and FP, which certainly affects the safety profile of this inhaled corticosteroid. Lipophilicity also affects the potential ability of the drug to have a systemic effect. More lipophilic drugs have a significant volume of distribution, which theoretically may be accompanied by a slightly greater risk of systemic side effects. The larger the volume of distribution, the better drug penetrates into tissues and inside cells, it has a longer half-life. In other words, ICS with higher lipophilicity will generally be more effective (especially for inhaled use), but may have a worse safety profile.

Apart from fatty acids, BUD has the lowest lipophilicity among currently used ICS and, therefore, has a smaller volume of extrapulmonary distribution. This is also facilitated by the slight esterification of the drug in muscle tissue (determining a significant proportion of the systemic distribution of the drug in the body) and the absence of lipophilic esters in the systemic circulation. Taking into account that the proportion of free BUD not bound to plasma proteins, like many other ICSs, slightly exceeds 10%, and the half-life is only 2.8 hours, it can be assumed that the potential systemic activity of this drug will be quite insignificant. This probably explains the smaller effect of BUD on cortisol synthesis compared to more lipophilic drugs (when used in high doses). Budesonide is the only inhaled CS whose efficacy and safety have been confirmed in a significant number of studies in children aged 6 months and older.

The third component that provides the drug with low systemic activity is the degree of binding to blood plasma proteins. BUD refers to the IGCS that have the highest degree of connection, not differing from BDP, MF and FP.

Thus, BUD is characterized by high corticosteroid activity, long-lasting action, which ensures its clinical effectiveness, as well as low systemic bioavailability and systemic activity, which, in turn, makes this inhaled corticosteroid one of the safest.

It should also be noted that BUD is the only drug in this group that has no evidence of a risk of use during pregnancy (level of evidence B) and according to the FDA classification.

As you know, when registering any new drug, the FDA assigns a certain risk category for the use of this drug in pregnant women. Category determination is based on data from animal teratogenicity studies and information on previous use in pregnant women.

In the instructions for budesonide (forms for inhalation and intranasal administration) under different trade names, which are officially registered in the United States, the same category of use during pregnancy is indicated. In addition, all instructions refer to the results of the same studies in pregnant women conducted in Sweden, taking into account the data of which category B was assigned to budesonide.

During the research, scientists from Sweden collected information about the course of pregnancy and its outcome in patients taking inhaled budesonide. Data were entered into a special registry, the Swedish Medical Birth Registry, where almost all pregnancies in Sweden are registered.

Thus, budesonide has the following properties:

effectiveness: control of asthma symptoms in most patients;

good safety profile, no systemic effects at therapeutic doses;

rapid accumulation in the mucous membranes of the respiratory tract and rapid onset of anti-inflammatory effect;

duration of action up to 24 hours;

does not affect final growth with long-term use in children, bone mineralization, cataracts, does not cause angiopathy;

allowed for use in pregnant women - does not cause an increase in the number of fetal abnormalities;

good tolerance; provides high compliance.

Undoubtedly, patients with persistent bronchial asthma should use adequate doses of inhaled corticosteroids to achieve an anti-inflammatory effect. But it should be noted that for ICS, accurate and correct execution of the breathing maneuver is especially important (like for no other inhalation drug) to ensure the necessary deposition of the drug in the lungs.

The inhalation route of drug administration is the main one in bronchial asthma, since it effectively creates high concentrations of the drug in the respiratory tract and minimizes systemic undesirable effects. There are different types of delivery systems: metered-dose aerosol inhalers, powder inhalers, nebulizers.

The very word "nebulizer" (from the Latin "nebula" - fog, cloud), was first used in 1874 to refer to a device that "turns a liquid substance into an aerosol for medical purposes." Of course, modern nebulizers differ from their historical predecessors in their design, technical specifications, size, etc., but the principle of operation remains the same: the transformation of liquid medicinal product into a therapeutic aerosol with certain characteristics.

Absolute indications for nebulizer therapy (according to Muers M.F.) are: the impossibility of delivering the drug to the respiratory tract by any other type of inhaler; the need to deliver the drug to the alveoli; the patient's condition, which does not allow the use of any other type of inhalation therapy. Nebulizers are the only way to deliver some drugs: metered dose inhalers simply do not exist for antibiotics and mucolytics. Inhalation therapy children under 2 years of age without the use of nebulizers is difficult to implement.

Thus, we can distinguish several categories of patients for whom nebulizer therapy is the best solution:

persons with intellectual disabilities

persons with reduced reactions

patients with exacerbation of asthma and COPD

some elderly patients

Place of Pulmicort suspension for nebulizers in the treatment of bronchial asthma

Basic therapy in case of ineffectiveness of other forms of inhaled glucocorticosteroid therapy or the impossibility of using other forms of delivery, including basic therapy for children under 2 years of age.

Su Suspension of Pulmicort can be used in children of the first years of life. The safety of Pulmicort for children consists of several components: low pulmonary bioavailability, drug retention in bronchial tissues in the esterified form, etc. In adults, the air flow created by inhalation is significantly greater than the flow created by a nebulizer. Adolescents have a smaller tidal volume than adults, therefore, since the flow of the nebulizer remains unchanged, children receive a more concentrated solution when inhaled than adults. But at the same time, after administration in the form of inhalations in the blood of adults and children of different ages Pulmicort is found in the same concentrations, although the ratio of the dose taken to body weight in children 2-3 years old is several times higher than in adults. This unique feature is found only in Pulmicort, since regardless of the initial concentration, most of the drug is “retained” in the lungs and does not enter the blood. Thus, the Pulmicort suspension is not only safe for children, but even safer in children than in adults.

The effectiveness and safety of Pulmicort suspension have been confirmed by numerous studies conducted in a wide variety of age groups, starting from the neonatal period and early age(this is the majority of studies) until adolescence and early adolescence. The effectiveness and safety of Pulmicort suspension for nebulizer therapy was assessed in groups of children with persistent bronchial asthma of varying severity, as well as during exacerbations of the disease. Thus, Pulmicort, suspension for nebulizer, is one of the most studied basic therapy drugs used in pediatrics.

The use of Pulmicort suspension using a nebulizer was accompanied by a significant reduction in the need for emergency medications, a positive effect on pulmonary function and the frequency of exacerbations.

It was also found that when treated with Pulmicort suspension, compared with placebo, significantly fewer children required additional administration of systemic corticosteroids.

Pulmicort suspension for nebulizer has also proven itself well as a means of starting therapy in children with bronchial asthma, starting from the age of 6 months.

Relief of exacerbations of bronchial asthma as an alternative to the administration of systemic steroids, and in some cases, joint administration of Pulmicort suspension and systemic steroids.

The use of a high dose Pulmicort suspension has been found to be equivalent to the use of prednisolone in exacerbations of asthma and COPD. At the same time, the same changes in lung function were observed both after 24 and 48 hours of therapy.

The studies also found that the use of inhaled corticosteroids, including Pulmicort suspension, is accompanied by a significantly higher FEV1 compared with the use of prednisolone as early as 6 hours after the start of treatment.

Moreover, it has been shown that during exacerbations of COPD or asthma in adult patients, the addition of a systemic corticosteroid to therapy with Pulmicort suspension is not accompanied by an additional effect. At the same time, monotherapy with a suspension of Pulmicort also did not differ from that with a systemic corticosteroid. Studies have found that the use of Pulmicort suspension during exacerbations of COPD is accompanied by a significant and clinically significant (more than 100 ml) increase in FEV1.

When comparing the effectiveness of Pulmicort suspension with prednisolone in patients with exacerbation of COPD, it was found that this inhaled corticosteroid is not inferior to systemic drugs.

The use of nebulizer therapy with Pulmicort suspension in adults with exacerbations of bronchial asthma and COPD was not accompanied by changes in cortisol synthesis and calcium metabolism. While the use of prednisolone, without being more clinically effective, leads to a marked decrease in the synthesis of endogenous corticosteroids, a decrease in the level of serum osteocalcin and an increase in calcium excretion in the urine.

Thus, the use of nebulizer therapy with a Pulmicort suspension for exacerbations of asthma and COPD in adults is accompanied by a rapid and clinically significant improvement in lung function, and in general has an effectiveness comparable to that of systemic corticosteroids, in contrast to which it does not lead to suppression of adrenal function and changes in calcium metabolism.

Basic therapy to reduce the dose of systemic steroids.

The use of high-dose nebulizer therapy with Pulmicort suspension makes it possible to effectively withdraw systemic corticosteroids in patients whose asthma requires their regular use. It was found that during therapy with a Pulmicort suspension at a dose of 1 mg twice a day, it is possible to effectively reduce the dose of the systemic corticosteroid while maintaining asthma control. High efficiency nebulizer therapy with an inhaled corticosteroid allows, after 2 months of use, to reduce the dose of systemic glucocorticosteroids without deteriorating lung function.

Reducing the dose of systemic corticosteroid while using budesonide suspension is accompanied by the prevention of exacerbations. It was shown that, compared with the use of placebo, patients using Pulmicort suspension had half the risk of developing exacerbations when the dose of the systemic drug was reduced.

It was also found that when systemic corticosteroids are discontinued during treatment with a Pulmicort suspension for 1 year, not only the basic synthesis of cortisol is restored, but also the function of the adrenal glands is normalized and their ability to provide “stressful” systemic corticosteroid activity.

Thus, the use of nebulizer therapy with a Pulmicort suspension in adults allows for an effective and rapid reduction in the dose of systemic corticosteroids while maintaining initial pulmonary function, improving symptoms and a lower frequency of exacerbations compared to placebo. This approach is also accompanied by a decrease in the incidence of side effects from systemic corticosteroids and restoration of adrenal function.

Literature
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2. Ovcharenko S.I., Peredelskaya O.A., Morozova N.V., Makolkin V.I. Nebulizer therapy with bronchodilators and pulmicort suspension in the treatment of severe exacerbation of bronchial asthma // Pulmonology. 2003. No. 6. P. 75-83.
3. Tsoi A.N., Arzhakova L.S., Arkhipov V.V. Pharmacodynamics and clinical effectiveness of inhaled glucocorticosteroids in patients with exacerbation of bronchial asthma. Pulmonology 2002;- No. 3. - P. 88.
4. Tsoi A.N. Comparative pharmacokinetics of inhaled glucocorticoids. Allergology 1999; 3:25-33
5. Tsoi A.N. Inhaled glucocorticoids: effectiveness and safety. RMJ 2001; 9: 182-185
6. Barnes P.J. Inhaled glucocorticoids for asthma. N.Engl. Med. 1995; 332:868-75
7. Brattsand R., Miller-Larsson A. The role of intracellular esterification in budesonide once-daily dosing and airway selectivity // Clin Ther. - 2003. - Vol. 25. - P. C28-41.
8. Boorsma M. et al. Assessment of the relative systemic potency of inhaled fluticasone and budesonide // Eur Respir J. - 1996. - Vol. 9(7). - P. 1427-1432. Grimfeld A. et al. Longterm study of nebulised budesonide in young children with moderate to severe asthma // Eur Respir J. - 1994. - Vol. 7. - P. 27S.
9. Code of Federal Regulations - Title 21 - Food and Drugs 21 CFR 201.57(f)(6) http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfmCrisholm S et al. Once-daily budesonide in mild asthma. Respir Med 1998; 421-5
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11. FDA Pregnancy Labeling Task Force http://www.fda.gov/cder/handbook/categc.htm.

Catad_tema Bronchial asthma and COPD - articles

Catad_tema Pediatrics - articles

L.D. Goryachkina, N.I. Ilyina, L.S. Namazova, L.M. Ogorodova, I.V. Sidorenko, G.I. Smirnova, B.A. Chernyak

The main goal of treating patients with bronchial asthma is to achieve and long-term maintenance of disease control. Treatment should begin with an assessment of current asthma control, and the amount of therapy should be reviewed regularly to ensure that control is achieved.

Treatment of bronchial asthma (BA) includes:

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

PHARMACOTHERAPY

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

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

TO basic therapy drugs relate:

• drugs with anti-inflammatory and/or prophylactic effects (glucocorticosteroids (GCS), antileukotriene drugs, cromones, anti-IgE drugs);
• long-acting bronchodilators (long-acting β 2 -agonists, slow-release theophylline preparations).

The greatest clinical and pathogenetic effectiveness is shown with the use of inhaled corticosteroids (ICS). All basic anti-inflammatory therapy is taken daily and for a long time. The principle of regular use of basic drugs allows one to achieve control over the disease. It should be noted that in our country, for the basic therapy of BA in children using combination drugs containing ICS (with a 12-hour break), only a stable dosage regimen is registered. Other regimens for the use of combination drugs in children are not permitted.

TO symptomatic remedies relate:

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

Symptomatic drugs are also called “first aid” drugs. They must be used to eliminate bronchial obstruction and its accompanying acute symptoms(wheezing, chest tightness, cough). This mode of drug use is called “on demand”.

ROUTES OF DRUG DELIVERY

Drugs for the treatment of asthma are administered in various ways: oral, parenteral and inhalation (the latter is preferred). When choosing a device for inhalation, the efficiency of drug delivery, cost/effectiveness, ease of use and patient age are taken into account (Table 1). Three types of devices are used for inhalation in children: nebulizers, metered-dose inhalers (MDIs), and powder inhalers.

Table 1. Drug delivery vehicles for asthma (age priorities)

Means	Recommended age group	Comments
Metered aerosol inhaler (MDI)	> 5 years	It is difficult to coordinate the moment of inhalation and pressing the valve of the can (especially for children). About 80% of the dose is deposited in the oropharynx, it is necessary to rinse the mouth after each inhalation in order to reduce systemic absorption
Inhalation activated pMDI	> 5 years	The use of this delivery device is indicated for patients who are unable to coordinate the moment of inhalation and pressing the valve of conventional MDIs. Cannot be used with any of the existing spacers, except for the “optimizer” for this type of inhaler
Powder inhaler (PI)	≥ 5 years	With the correct technique of use, the effectiveness of inhalation can be higher than when using a MDI. It is necessary to rinse the mouth after each use
Spacer	> 4 years < 4 лет при application face mask	The use of a spacer reduces the deposition of the drug in the oropharynx, allows the use of pMDIs with greater efficiency; if a mask is available (complete with a spacer), it can be used in children under 4 years of age
Nebulizer	< 2 лет (patients of any ages that cannot use spacer or spacer/facial mask)	The optimal means of drug delivery for use in specialized departments and intensive care units, as well as in emergency care, as it requires the least effort from the patient and doctor

ANTI-INFLAMMATORY (BASIC) DRUGS

I. Inhaled glucocorticosteroids and combination drugs containing ICS

Currently, ICS are the most effective drugs to control BA, therefore they are recommended for the treatment of persistent BA of any severity A. In children school age suffering from asthma, maintenance therapy with ICS allows you to control the symptoms of asthma, reduces the frequency of exacerbations and the number of hospitalizations, improves the quality of life, improves the function of external respiration, reduces bronchial hyperreactivity and reduces bronchoconstriction during physical activity A. The use of ICS in preschool children suffering from asthma leads to to clinically significant improvements, including scores for daytime and nighttime cough, wheezing and shortness of breath, physical activity, use of rescue medications, and use of health care resources.

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

Table 2. Equipotent daily doses of ICS

A drug*	Low daily allowance doses (mcg)	Average daily allowance doses (mcg)	High daily allowance doses (mcg)
Doses for children under 12 years of age
Beclomethasone dipropionate	100–200	> 200–400	> 400
Budesonide	100–200	> 200–400	> 400
Fluticasone	100–200	> 200–500	> 500
Doses for children over 12 years of age
Beclomethasone dipropionate	200–500	> 500–1000	> 1000–2000
Budesonide	200–400	> 400–800	> 800–1600
Fluticasone	100–250	> 250–500	> 500–1000

*Drug comparisons are based on comparative effectiveness data.

ICS are included in combination drugs for the treatment of asthma. Such drugs are Seretide (salmeterol + fluticasone propionate) and Symbicort (formoterol + budesonide). A large number of clinical studies have shown that the combination of long-acting β2-agonists and low-dose ICS is more effective than increasing the dose of the latter. Combination therapy with salmeterol + fluticasone (in one inhaler) promotes better asthma control than a long-acting β 2 -adrenergic agonist and ICS in separate inhalers. With long-term therapy with salmeterol + fluticasone, complete asthma control can be achieved in almost every second patient (according to a study that included patients aged 12 years and older). There is also a significant improvement in treatment effectiveness indicators (PSF, FEV1, exacerbation frequency, quality of life). If the use of low doses of ICS in children does not allow achieving control of BA, it is recommended to switch to combination therapy, which can be a good alternative to increasing the dose of ICS. This was shown in a new prospective, multicenter, double-blind, randomized, parallel-group study lasting 12 weeks, which compared the effectiveness of the combination of salmeterol + fluticasone (at a dose of 50/100 mcg twice a day) and a 2-fold higher dose of fluticasone propionate (200 mcg 2 times a day) in 303 children 4–11 years old with persistent asthma symptoms despite previous therapy with low doses of ICS. It turned out that regular use of the combination salmeterol + fluticasone (Seretide) prevents symptoms and achieves asthma control as effectively as twice the dose of ICS. Treatment with Seretide is accompanied by a more pronounced improvement in lung function and a decrease in the need for drugs to relieve asthma symptoms with good tolerability: in the Seretide group, the increase in morning PEF is 46% higher, and the number of children with a complete absence of need for “rescue therapy” is 53% more than in the fluticasone group. Therapy using a combination of formoterol + budesonide as part of a single inhaler provides better control of asthma symptoms compared with budesonide alone in patients for whom ICS previously did not provide symptom control.

Impact of ICS on growth

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

Effect of ICS on bone tissue

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

Effect of ICS on the hypothalamic-pituitary-adrenal system

ICS therapy dose ICS and oral candidiasis

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

Other side effects

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

II. Leukotriene receptor antagonists

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

III. Cromony

Nedocromil and cromoglycic acid are less effective than ICS against clinical symptoms, external respiration functions, physical exertion asthma, airway hyperreactivity. Long-term therapy with cromoglycic acid for asthma in children does not differ significantly in effectiveness from placebo A. Nedocromil, prescribed before physical activity, can reduce the severity and duration of bronchoconstriction caused by it. Cromones are contraindicated during exacerbation of asthma, when intensive therapy with fast-acting bronchodilators is required. The role of cromones in the basic treatment of asthma in children (especially preschoolers) is limited due to the lack of evidence of their effectiveness. A meta-analysis conducted in 2000 did not allow us to draw an unambiguous conclusion about the effectiveness of cromoglycic acid as a means of basic therapy for BA in children B. It should be remembered that drugs in this group cannot be used for initial therapy of moderate and severe asthma. The use of cromones as basic therapy is possible in patients with complete control of asthma symptoms. Cromones should not be combined with long-acting β2-agonists, since the use of these drugs without ICS increases the risk of death from asthma.

IV. Anti-IgE drugs

This is a fundamentally new class of drugs used today to improve control of severe persistent atopic asthma. Omalizumab is the most studied, first and only drug recommended for use in children over 12 years of age. The high cost of treatment with omalizumab, as well as the need for monthly visits to the doctor for injection administration of the drug, are justified in patients who require 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 generally recommended therapeutic rangeA. However, the use of theophyllines for the treatment of asthma in children is problematic due to the possibility of severe immediate (cardiac arrhythmia, death) and delayed (behavioral disorders, learning problems) side effects. Therefore, the use of theophyllines is possible only under strict pharmacodynamic control.

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

Drugs in this group are effective in maintaining asthma control (Fig. 1). On an ongoing basis, they are used only in combination with ICS and are prescribed only when standard initial doses of ICS do not allow BA control to be achieved. The effect of these drugs lasts for 12 hours. Formoterol in the form of inhalation exerts its therapeutic effect (relaxation of bronchial smooth muscles) within 3 minutes, the maximum effect develops 30–60 minutes after inhalation. Salmeterol begins to act relatively slowly, a significant effect is noted 10–20 minutes after inhalation of a single dose (50 mcg), and an effect comparable to that after taking salbutamol develops after 30 minutes. Due to its slow onset of action, salmeterol should not be prescribed for the relief of acute asthma symptoms. Since the effect of formoterol develops faster than the effect of salmeterol, this allows formoterol to be used not only for prevention, but also for the relief of asthma symptoms. However, according to the GINA 2006 recommendations, long-acting β 2 -agonists can only be used in patients already receiving regular maintenance therapy with ICS.

Figure 1. Classification of β2-agonists

Children tolerate treatment with long-acting inhaled β 2 -agonists well, even with prolonged use, and their side effects are comparable to those of short-acting β 2 -agonists (if used on demand). Drugs in this group should be prescribed only in conjunction with basic ICS therapy, since monotherapy with long-acting β 2 -adrenergic agonists without ICS increases the likelihood of death in patients! Due to conflicting data on the effect on asthma exacerbations, these drugs are not the drugs of choice for patients requiring two or more maintenance therapies.

Long-acting oral β2-agonists

Drugs in this group include long-acting dosage forms of salbutamol. These drugs may help control nocturnal asthma symptoms. They can be used in addition to ICS if the latter at standard doses do not provide sufficient control of nighttime symptoms. Possible side effects include stimulation of cardio-vascular system, anxiety and tremor. In our country, drugs of this group are rarely used in pediatrics.

VII. Anticholinergic drugs

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

VIII. System GCS

Although systemic GCS effective against asthma, it is necessary to take into account the development of adverse effects during long-term therapy, such as suppression of the hypothalamic-pituitary-adrenal 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 cases of severe exacerbations, such as viral infection, and in her absence.

EMERGENCY THERAPY DRUGS

Inhaled fast-acting β 2 -adrenergic agonists (short-acting β 2 -agonists) are the most effective of the existing bronchodilators; they are the drugs of choice for the treatment of acute bronchospasm A (Fig. 1). This group of drugs includes salbutamol, fenoterol and terbutaline (Table 3).

Table 3. Emergency medications for asthma

A drug	Dose	Side effects	Comments
β 2 -adrenergic agonists
Salbutamol (MDI)	1 dose - 100 mcg 1–2 inhalations up to 4 times a day	tachycardia, tremor, headache, irritability	Recommended only in on-demand mode
Salbutamol (solution for nebulizer therapy)	2.5 mg/2.5 ml
Fenoterol (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 (IAI) from 4 years	1 dose – 20 mcg 2-3 inhalations up to 4 times a day	Minor dryness and unpleasant taste in mouth	Mainly used in children up to 2 years
Ipratropium bromide (solution for nebulizer therapy)	250 µg/ml
Combination drugs
Fenoterol + ipratropium bromide (MDI)	2 inhalations up to 4 times a day	Tachycardia, tremor, headache, irritability, slight dryness and unpleasant taste in the mouth	Side effects are characteristic effects indicated for each of the incoming as part of the combination funds
Fenoterol + ipratropium bromide (solution for nebulizer therapy)	1–2 ml
Short acting theophylline
Eufillin in any dosage form	150 mg > 3 years 12–24 mg/kg/day	Nausea, vomiting, headache, tachycardia, violations heart rate	Currently Usage aminophylline in children for relief of symptoms BA is not justified

Anticholinergics have a limited role in the treatment of asthma in children. A meta-analysis of studies of ipratropium bromide in combination with β 2 -agonists for exacerbation of asthma showed that the use of an anticholinergic drug is accompanied by a statistically significant (albeit moderate) improvement in pulmonary function and a reduced risk of hospitalization.

ACHIEVEMENT OF ASTHMA CONTROL

During treatment, ongoing assessment and adjustment of therapy should be carried out based on changes in the level of asthma control. The entire treatment cycle includes:

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

Assessment of the level of asthma control

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

• minimal or absent (≤ 2 episodes per week) daytime asthma symptoms;
• no restrictions in daily activity and physical activity;
• absence of nighttime symptoms and awakenings due to asthma;
• minimal or no need (≤ 2 episodes per week) for short-acting bronchodilators;
• normal or almost normal pulmonary function tests;
• no exacerbations of asthma.

According to GINA 2006, there are three levels of asthma control: controlled, partially controlled and uncontrolled asthma. Currently, several tools have been developed for integral assessment of the level of control over asthma. One of these tools is the Childhood Asthma Control Test for children aged 4–11 years - a validated questionnaire that allows the doctor and the patient (parent) to quickly assess the severity of asthma manifestations and the need to increase the volume of therapy. The test consists of 7 questions, with questions 1–4 for the child (4-point rating scale: 0 to 3 points), and questions 5–7 for parents (6-point scale: 0 to 5 points). The test result is the sum of marks for all answers in points (maximum score – 27 points). A score of 20 points and above corresponds to controlled asthma, 19 points and below means that asthma is not controlled effectively; the patient is advised to seek the help of a doctor to review the treatment plan. In this case, it is also necessary to ask the child and his parents about medications for daily use to ensure the correct inhalation technique and compliance with the treatment regimen. Testing for asthma control can be done on the website www.astmatest.ru.

Treatment to maintain control

The choice of drug therapy depends on the patient's current level of asthma control and current therapy. Thus, if current therapy does not provide control of asthma, it is necessary to increase the volume of therapy (move to a higher level) until control is achieved. If asthma control is maintained for 3 months or more, it is possible to reduce the volume of maintenance therapy in order to achieve the minimum volume of therapy and the lowest doses of drugs sufficient to maintain control. If partial control of asthma is achieved, the possibility of increasing the volume of therapy should be considered, taking into account the availability of more effective treatment approaches (i.e., the possibility of increasing doses or adding other drugs), their safety, cost, and patient satisfaction with the level of control achieved.

Most drugs for the treatment of asthma have favorable benefit/risk combinations compared with drugs for the treatment of other chronic diseases. Each stage includes treatment options that can serve as alternatives when choosing maintenance therapy for asthma, although they are not the same in effectiveness. The volume of therapy increases from step 2 to step 5; although at stage 5 the choice of treatment also depends on the availability and safety of drugs. In most patients with symptoms of persistent asthma who have not previously received maintenance therapy, treatment should begin at step 2. If asthma symptoms at the initial examination are extremely severe and indicate a lack of control, treatment should begin at step 3 (Table 4). At each stage of therapy, patients should use drugs to quickly relieve asthma symptoms (fast-acting bronchodilators). However, regular use of medications to relieve symptoms is one of the signs of uncontrolled asthma, indicating the need to increase maintenance therapy. Therefore, reducing or eliminating the need for rescue medications is an important goal of treatment and a criterion for the effectiveness of therapy.

Table 4. Correspondence of stages of therapy to clinical characteristics of asthma

Stages of therapy	Clinical characteristics of patients
Stage 1	Short-term (up to several hours) symptoms of asthma in daytime(cough, wheezing, shortness of breath occurring ≤ 2 times a week or even less frequent symptoms at night). During the interictal period, there are no manifestations of asthma or night awakenings, lung function is within normal limits. PEF ≥ 80% of the required values
Stage 2	Asthma symptoms occur more often than once a week, but less than once a day. Exacerbations can disrupt patients' activity and nighttime sleep. Night symptoms more than 2 times a month. Functional indicators of external respiration within the age norm. During the interictal period – there are no manifestations of asthma and nocturnal awakenings, tolerability physical activity not reduced. PSV ≥ 80% of the expected values
Stage 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
Stage 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 (once every 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 required values
Level 5	Daily day and night symptoms, several times a day. Marked limitation of physical activity. Severe pulmonary dysfunction. Frequent exacerbations (once a month or more often). 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 occasional worsening of symptoms should receive regular supportive care (in addition to on-demand symptom relief).

Stages 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, it is recommended to administer a combination of low-dose ICS with a long-acting inhaled (β 2 -agonist) fixed combination. 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 in patients whose asthma is under control. was not achieved after 3–4 months of therapy.The long-acting β2-agonist formoterol, which is characterized by a rapid onset of action when used as monotherapy or as part of a fixed combination with budesonide, 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 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 the addition of a long-acting β 2 -agonist is more effective than increasing the dose of ICS. The second treatment option is to increase the dose of ICS to medium doses. For patients of any age receiving moderate or high doses of ICS using a MDI, the use of a spacer is recommended to improve drug delivery to the respiratory tract, reduce the risk of oropharyngeal side effects and systemic absorption of the drug. Another alternative treatment option at step 3 is the combination of a low dose ICS with an anti-leukotriene drug. Instead of an antileukotriene drug, a low dose of sustained-release theophylline may be prescribed. These treatment options have not been studied in children 5 years of age and younger.

Choice of drugs for steps 4 depends on previous prescriptions in steps 2 and 3. However, the order in which additional drugs are added should be based on evidence of their comparative effectiveness obtained in clinical trials. Patients who have not achieved asthma control at stage 3 should be referred (if possible) to an asthma specialist to rule out alternative diagnoses and/or causes of asthma that is difficult to treat. The preferred approach to treatment at step 4 is the use of a combination of moderate-to-high-dose corticosteroids with a long-acting inhaled β2-agonist. Long-term use of ICS in high doses is accompanied by increased risk development of side effects.

Therapy steps 5 required for patients who have not achieved a treatment effect when using high doses of ICS in combination with long-acting β2-agonists and other drugs for maintenance therapy. The addition of oral corticosteroids to other drugs for maintenance therapy may increase the effect of treatment, but is accompanied by severe adverse events. The patient should be warned about the risk of side effects; All other alternatives to asthma therapy should also be considered.

Schemes for reducing the volume of basic therapy for asthma

If control of asthma is achieved during basic therapy with a combination of ICS and a long-acting β 2 agonist and is maintained for at least 3 months, a gradual reduction in its volume can begin: reducing the dose of ICS by no more than 50% for 3 months while continuing β 2 therapy -long-acting agonist. If complete control is maintained during therapy with low doses of ICS and a long-acting β2-agonist 2 times a day, the latter should be discontinued and ICS therapy should be continued. Achieving control with the use of cromones does not require reducing their dose.

Another scheme for reducing the volume of basic therapy in patients receiving ICS and a long-acting β2-agonist involves discontinuing the latter at the first stage while continuing ICS monotherapy at the same dose as contained in the fixed combination. Subsequently, gradually reduce the dose of ICS by no more than 50% over 3 months, provided that complete control of asthma is maintained. Long-acting β2-agonist monotherapy without ICS is unacceptable, as it may be accompanied by an increased risk of death in patients with asthma. Discontinuation of maintenance therapy is possible if complete control of asthma is maintained using a minimum dose of an anti-inflammatory drug and there is no relapse of symptoms within one year D.

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

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

The volume of therapy should be increased if asthma control is lost (increased frequency and severity of asthma symptoms, need for inhaled β2-agonists for 1–2 days, decreased peak flow readings, or worsening exercise tolerance). The volume of asthma therapy is regulated throughout the year in accordance with the spectrum of sensitization of causally significant allergens. To relieve acute bronchial obstruction in patients with asthma, a combination of bronchodilators (β 2 -agonists, anticholinergic drugs, methylxanthines) and corticosteroids is used. Preference should be given to inhalation forms of delivery, which allow achieving a quick effect with minimal overall impact on the child’s body.

Available recommendations for reducing doses of various basic therapy drugs may be sufficient high level evidence (predominantly B), but are based on data from studies that assessed only clinical indicators (symptoms, FEV1) and did not determine the effect of reduced therapy on inflammatory activity and structural changes in asthma. Thus, recommendations to reduce the amount of therapy require further research aimed at assessing the processes underlying the disease, and not just clinical manifestations.

PATIENT EDUCATION

Education is an essential part of a comprehensive treatment program for children with asthma and involves establishing a partnership between the patient, family, and health care provider.

Objectives of educational programs:

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

FORECAST

In children with 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) 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 age 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 of Further Professional Education "Russian medical Academy postgraduate education" of Roszdrav, professor, dr med. Sciences

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

Leila Seymurovna Namazova, Director of the Research Institute of Preventive Pediatrics and Rehabilitation Treatment of State University Science Center of 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, GOU VPO Moscow Medical Academy. 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, candidate of sciences. honey. Sciences

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

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

The article discusses factors influencing the degree of effectiveness and safety, features of the pharmacodynamics and pharmacokinetics of modern inhaled glucocorticosteroids, including a new inhaled glucocorticosteroid for the Russian market - ciclesonide.

Bronchial asthma (BA) is a chronic inflammatory disease respiratory tract, characterized by reversible bronchial obstruction and bronchial hyperreactivity. Along with inflammation, and possibly as a result of restorative processes in the respiratory tract, structural changes are formed, which are considered as a process of bronchial remodeling (irreversible transformation), which includes hyperplasia of goblet cells and goblet glands of the submucosal layer, hyperplasia and hypertrophy of smooth muscles, increased vascularization of the submucosal layer layer, collagen accumulation in areas below the basement membrane, and subepithelial fibrosis.

According to international (Global Initiative for Asthma - "Global strategy for the treatment and prevention of bronchial asthma", revision 2011) and national consensus documents, inhaled glucocorticosteroids (ICS), which have an anti-inflammatory effect, are the first-line treatment for moderate and severe bronchial asthma.

Inhaled glucocorticosteroids, with long-term use, improve or normalize lung function, daytime fluctuations in peak expiratory flow decrease, and the need for systemic glucocorticosteroids (GCS) is reduced until their complete abolition. With long-term use of the drugs, antigen-induced bronchospasm and the development of irreversible airway obstruction are prevented, the frequency of exacerbations of the disease, the number of hospitalizations and mortality of patients are reduced.
The mechanism of action of inhaled glucocorticosteroids is aimed at an antiallergic and anti-inflammatory effect; this effect is based on the molecular mechanisms of the two-stage model of action of GCS (genomic and extragenomic effects). The therapeutic effect of glucocorticosteroids (GCS) is associated with their ability to inhibit the formation of pro-inflammatory proteins in cells (cytokines, nitric oxide, phospholipase A2, leukocyte adhesion molecules, etc.) and activate the formation of proteins with an anti-inflammatory effect (lipocortin-1, neutral endopeptidase, etc. ).

The local effect of inhaled glucocorticosteroids (ICS) is manifested by an increase in the number of beta-2 adrenergic receptors on bronchial smooth muscle cells; a decrease in vascular permeability, a decrease in edema and mucus secretion in the bronchi, a decrease in the number of mast cells in the bronchial mucosa and increased apoptosis of eosinophils; decreased release of inflammatory cytokines by T lymphocytes, macrophages and epithelial cells; reduction of hypertrophy of the subepithelial membrane and suppression of tissue specific and nonspecific hyperreactivity. Inhaled corticosteroids inhibit the proliferation of fibroblasts and reduce collagen synthesis, which slows down the rate of development of the sclerotic process in the walls of the bronchi.

Inhaled glucocorticosteroids (ICS), unlike systemic ones, have high selectivity, pronounced anti-inflammatory and minimal mineralocorticoid activity. When administered via inhalation, approximately 10-50% of the nominal dose is deposited in the lungs. The percentage of deposition depends on the properties of the ICS molecule, on the drug delivery system into the respiratory tract (type of inhaler) and on the inhalation technique. Most of the ICS dose is swallowed, absorbed from gastrointestinal tract(Gastrointestinal tract) and is quickly metabolized in the liver, which provides a high therapeutic index of ICS.

Inhaled glucocorticosteroids (ICS) vary in activity and bioavailability, which provides some variability in clinical effectiveness and severity of side effects among different drugs in this group. Modern inhaled glucocorticosteroids (ICS) have high lipophilicity (for better penetration of the cell membrane), a high degree of affinity for the glucocorticoid receptor (GCR), which ensures optimal local anti-inflammatory activity, and low systemic bioavailability, and therefore, a low likelihood of developing systemic effects.

Using different types inhalers, the effectiveness of some drugs varies. With increasing dose of ICS, the anti-inflammatory effect increases, however, starting from a certain dose, the dose-effect curve takes on the appearance of a plateau, i.e. the effect of treatment does not increase, and the likelihood of developing side effects characteristic of systemic glucocorticosteroids (GCS) increases. The main undesirable metabolic effects of GCS are:

1. stimulating effect on gluconeogenesis (resulting in hyperglycemia and glycosuria);
2. decreased protein synthesis and increased protein breakdown, which is manifested by a negative nitrogen balance (weight loss, muscle weakness, skin and muscle atrophy, stretch marks, hemorrhages, growth retardation in children);
3. redistribution of fat, increased synthesis of fatty acids and triglycerides (hypercholesterolemia);
4. mineralocorticoid activity (leads to an increase in circulating blood volume and an increase in blood pressure);
5. negative calcium balance (osteoporosis);
6. inhibition of the hypothalamic-pituitary system, resulting in decreased production of adrenocorticotropic hormone and cortisol (adrenal insufficiency).

Due to the fact that treatment with inhaled glucocorticosteroids (ICS), as a rule, is long-term (and in some cases permanent) in nature, the concern of doctors and patients regarding the ability of inhaled glucocorticosteroids to cause systemic side effects naturally increases.

Preparations containing inhaled glucocorticosteroids

In the territory Russian Federation The following inhaled glucocorticosteroids are registered and approved for use: the drug budesonide (suspension for nebulizer used from 6 months, in the form of a powder inhaler - from 6 years), fluticasone propionate (used from 1 year), beclomethasone dipropionate (used from 6 years), mometasone furoate (approved in children over 12 years of age in the Russian Federation) and ciclesonide (approved in children over 6 years of age). All drugs have proven effectiveness, however, differences in the chemical structure affect the pharmacodynamic and pharmacokinetic properties of ICS and, consequently, the degree of effectiveness and safety of the drug.

The effectiveness of inhaled glucocorticosteroids (ICS) depends primarily on local activity, which is determined by high affinity (affinity for the glucocorticoid receptor (GCR), high selectivity and duration of persistence in tissues. All known modern ICS have high local glucocorticoid activity, which is determined by the affinity of ICS for GCR (usually in comparison with dexamethasone, whose activity is taken as 100) and modified pharmacokinetic properties.

Cyclesonide (affinity 12) and beclomethasone dipropionate (affinity 53) do not have initial pharmacological activity, and only after inhalation, entering target organs and exposed to esterases, they are converted into their active metabolites - descyclesonide and beclomethasone 17-monopropionate - and become pharmacologically active. The affinity for the glucocorticoid receptor (GCR) is higher for active metabolites (1200 and 1345, respectively).

High lipophilicity and active binding to the respiratory epithelium, as well as the duration of association with GCR, determine the duration of action of the drug. Lipophilicity increases the concentration of inhaled glucocorticosteroids (ICS) in the respiratory tract, slows down their release from tissues, increases affinity and prolongs the connection with GCR, although the optimal lipophilicity of ICS has not yet been determined.

Lipophilicity is most pronounced in ciclesonide, mometasone furoate and fluticasone propionate. Ciclesonide and budesonide are characterized by esterification that occurs intracellularly in lung tissues and the formation of reversible conjugates of descyclesonide and budesonide with fatty acids. The lipophilicity of the conjugates is many tens of times higher than the lipophilicity of intact descyclesonide and budesonide, which determines the duration of the latter’s stay in the tissues of the respiratory tract.

The effects of inhaled glucocorticosteroids on the respiratory tract and their systemic effect depend largely on the inhalation device used. Considering that the processes of inflammation and remodeling occur in all parts of the respiratory tract, including distal sections and peripheral bronchioles, the question arises about the optimal method of delivering the drug to the lungs, regardless of the state of bronchial patency and compliance with the inhalation technique. The preferred particle size of the inhaled drug, ensuring its uniform distribution in large and distal bronchi, is 1.0-5.0 microns for adults, and 1.1-3.0 microns for children.

To reduce the number of errors associated with the inhalation technique, leading to a decrease in the effectiveness of treatment and an increase in the frequency and severity of side effects, drug delivery methods are constantly being improved. A metered dose inhaler (MDI) can be used in conjunction with a spacer. The use of a nebulizer allows you to effectively stop exacerbation of bronchial asthma (BA) in an outpatient setting, reducing or eliminating the need for infusion therapy.

According to the international agreement on the preservation of the earth's ozone layer (Montreal, 1987), all manufacturers of inhaled drugs have switched to CFC-free forms of metered-dose aerosol inhalers (MDIs). The new propellant norflurane (hydrofluoroalkane, HFA 134a) has significantly affected the particle size of some inhaled glucocorticosteroids (ICS), in particular ciclesonide: a significant proportion of the drug particles have a size of 1.1 to 2.1 μm (extrafine particles). In this regard, ICS in the form of MDIs with HFA 134a have the highest percentage of pulmonary deposition, for example, 52% for ciclesonide, and its deposition in peripheral parts lungs is 55%.
The safety of inhaled glucocorticosteroids and the likelihood of developing systemic effects are determined by their systemic bioavailability (absorption from the gastrointestinal mucosa and pulmonary absorption), the level of the free fraction of the drug in the blood plasma (binding with plasma proteins) and the level of inactivation of GCS during the initial passage through the liver (presence/absence of active metabolites ).

Inhaled glucocorticosteroids are rapidly absorbed from the gastrointestinal tract and respiratory tract. The absorption of glucocorticosteroids (GCs) from the lungs may be influenced by the size of the inhaled particles, since particles smaller than 0.3 μm are deposited in the alveoli and absorbed into the pulmonary circulation.

When using a metered dose aerosol inhaler (MDI), only 10-20% of the inhaled dose is delivered to the respiratory tract, while up to 90% of the dose is deposited in the oropharyngeal region and swallowed. Next, this part of inhaled glucocorticosteroids (ICS), absorbed from the gastrointestinal tract, enters the hepatic bloodstream, where most of the drug (up to 80% or more) is inactivated. ICS enter the systemic circulation primarily in the form of inactive metabolites. Therefore, systemic oral bioavailability for most inhaled glucocorticosteroids (ciclesonide, mometasone furoate, fluticasone propionate) is very low, almost zero.

It should be borne in mind that part of the dose of ICS (approximately 20% of the nominally taken dose, and in the case of beclomethasone dipropionate (beclomethasone 17-monopropionate) - up to 36%), entering the respiratory tract and quickly absorbed, enters the systemic circulation. Moreover, this portion of the dose may cause extrapulmonary systemic adverse effects, especially when high doses of ICS are prescribed. Of no small importance in this aspect is the type of inhaler used with ICS, since when dry budesonide powder is inhaled through Turbuhaler, the pulmonary deposition of the drug increases by 2 times or more compared with the indicator for inhalation from a MDI.

For inhaled glucocorticosteroids (ICS) with a high fraction of inhaled bioavailability (budesonide, fluticasone propionate, beclomethasone 17-monopropionate), systemic bioavailability may increase if inflammatory processes in the mucosa bronchial tree. This was established in a comparative study of systemic effects based on the level of reduction in plasma cortisol after a single use of budesonide and beclomethasone propionate at a dose of 2 mg at 22 hours in healthy smokers and non-smokers. It should be noted that after inhalation of budesonide, cortisol levels in smokers were 28% lower than in non-smokers.

Inhaled glucocorticosteroids (ICS) have a fairly high binding to plasma proteins; for ciclesonide and mometasone furoate this relationship is slightly higher (98-99%) than for fluticasone propionate, budesonide and beclomethasone dipropionate (90, 88 and 87%, respectively). Inhaled glucocorticosteroids (ICS) have rapid clearance, its value is approximately the same as the amount of hepatic blood flow, and this is one of the reasons for minimal manifestations of systemic undesirable effects. On the other hand, rapid clearance provides ICS with a high therapeutic index. The fastest clearance, exceeding the rate of hepatic blood flow, was found in descyclesonide, which determines the high safety profile of the drug.

Thus, we can highlight the main properties of inhaled glucocorticosteroids (ICS), on which their effectiveness and safety primarily depend, especially during long-term therapy:

1. a large proportion of fine particles, ensuring high deposition of the drug in the distal parts of the lungs;
2. high local activity;
3. high lipophilicity or the ability to form fat conjugates;
4. low degree of absorption into the systemic circulation, high binding to plasma proteins and high hepatic clearance to prevent the interaction of GCS with GCR;
5. low mineralocorticoid activity;
6. high compliance and ease of dosing.

Cyclesonide (Alvesco)

Ciclesonide (Alvesco), a non-halogenated inhaled glucocorticosteroid (ICS), is a prodrug and, under the action of esterases in lung tissue, is converted into a pharmacologically active form - descyclesonide. Desciclesonide has 100 times greater affinity for the glucocorticoid receptor (GCR) than ciclesonide.

Reversible conjugation of descyclesonide with highly lipophilic fatty acids ensures the formation of a drug depot in the lung tissue and maintenance of an effective concentration for 24 hours, which allows Alvesco to be used once a day. The active metabolite molecule is characterized by high affinity, rapid association and slow dissociation with the glucocorticoid receptor (GCR).

The presence of norflurane (HFA 134a) as a propellant provides a significant proportion of extra-fine particles of the drug (size from 1.1 to 2.1 microns) and high deposition active substance in the small airways. Considering that the processes of inflammation and remodeling occur in all parts of the respiratory tract, including the distal parts and peripheral bronchioles, the question arises about the optimal method of drug delivery to the lungs, regardless of the state of bronchial patency.

In a study by T.W. de Vries et al. Using laser diffraction analysis and the method of different inspiratory flows, the delivered dose and particle size of various inhaled glucocorticosteroids ICS were compared: fluticasone propionate 125 μg, budesonide 200 μg, beclomethasone (HFA) 100 μg and ciclesonide 160 μg.

The average aerodynamic particle size of budesonide was 3.5 µm, fluticasone propionate - 2.8 µm, beclomethasone and ciclesonide - 1.9 µm. Ambient air humidity and inspiratory flow rate did not have a significant effect on particle size. Ciclesonide and beclomethasone (BFA) had the largest fraction of fine particles ranging in size from 1.1 to 3.1 μm.

Due to the fact that ciclesonide is an inactive metabolite, its oral bioavailability tends to zero, and this also makes it possible to avoid such local undesirable effects as oropharyngeal candidiasis and dysphonia, which has been demonstrated in a number of studies.

Ciclesonide and its active metabolite descyclesonide, when released into the systemic circulation, are almost completely bound to plasma proteins (98-99%). In the liver, descyclesonide is inactivated by the enzyme CYP3A4 of the cytochrome P450 system to hydroxylated inactive metabolites. Ciclesonide and descyclesonide have the fastest clearance among inhaled glucocorticosteroids (ICS) (152 and 228 l/h, respectively), its value significantly exceeds the rate of hepatic blood flow and provides a high safety profile.

The safety issues of inhaled glucocorticosteroids (ICS) are most relevant in pediatric practice. A number of international studies have established high clinical efficacy and a good safety profile of ciclesonide. Two identical multicenter, double-blind, placebo-controlled studies examining the safety and efficacy of Alvesco (ciclesonide) included 1,031 children aged 4–11 years. The use of ciclesonide 40, 80 or 160 mcg once a day for 12 weeks did not suppress the function of the hypothalamic-pituitary-adrenal axis and change the level of cortisol in 24-hour urine (compared to placebo). In another study, treatment with ciclesonide for 6 months did not result in a statistically significant difference in linear growth rate in children in the active treatment group and the placebo group.

The extrafine particle size, high pulmonary deposition of ciclesonide and maintenance of effective concentration for 24 hours, on the one hand, low oral bioavailability, low level of the free fraction of the drug in the blood plasma and rapid clearance, on the other, provide a high therapeutic index and a good safety profile of Alvesco. The duration of ciclesonide persistence in tissues determines its high duration of action and the possibility of single use per day, which significantly increases the patient’s compliance with this drug.

© Oksana Kurbacheva, Ksenia Pavlova