Inhaled glucocorticosteroids: effectiveness and safety. Inhaled glucocorticosteroids (ICS) VIII

Professor A.N. Tsoi
MMA named after I.M. Sechenov

Bronchial asthma (BA), regardless of its severity, is considered a chronic inflammatory disease respiratory tract eosinophilic nature. Therefore, one of the major changes in asthma treatment made to national and international guidelines has been the introduction inhaled glucocorticosteroids (ICS) as first-line agents and recommending their long-term use. ICS are recognized as the most effective anti-inflammatory drugs; they can be used to control the course of asthma. However, for initial anti-inflammatory therapy, there are other groups in the doctor’s arsenal medicines that have an anti-inflammatory effect: nedocromil sodium, sodium cromoglycate, theophylline preparations, long-acting b2-antagonists (formoterol, salmeterol), leukotriene antagonists. This gives the doctor the opportunity to choose anti-asthmatic drugs for individualized pharmacotherapy, which depends on the nature of the disease, age, medical history, duration of the disease in a particular patient, the severity of clinical symptoms, pulmonary function tests, the effectiveness of previous therapy and knowledge of physicochemical, pharmacokinetic and other properties of the drugs themselves.

After the publication of GINA, information began to appear that was contradictory and required a revision of some provisions of the document. As a result, a group of experts from the National Heart, Lung and Blood Institute (USA) prepared and published the report “Recommendations for the diagnosis and treatment of asthma” (EPR-2). Specifically, the report replaced the term “anti-inflammatory drugs” with “long-term control agents used to achieve and maintain control of persistent asthma.” One reason for this appears to be the lack of clarity within the FDA as to what “gold standard” anti-inflammatory therapy for asthma actually means. As for bronchodilators, short-acting b2-agonists, they are classified as “quick aid drugs for the relief of acute symptoms and exacerbations.”

Thus, drugs for the treatment of asthma are divided into 2 groups: drugs for long-term control and drugs for relieving acute symptoms of bronchoconstriction. The primary goal of asthma treatment should be to prevent exacerbations of the disease and maintain the quality of life of patients, achieved by adequate control of the symptoms of the disease using long-term ICS therapy.

ICS is recommended for use starting from the 2nd stage (the severity of asthma is from mild persistent and higher), and, in contrast to the GINA recommendation, the initial dose of ICS should be high and exceed 800 mcg/day; when the condition is stabilized, the dose should be gradually reduced to the minimum effective, low dose (Table

In patients with moderately severe or exacerbation of asthma daily dose If necessary, ICS can be increased and exceed 2 mg/day, or treatment can be supplemented with long-acting b2-agonists - salmeterol, formoterol or long-acting theophylline preparations. As an example, we can cite the results of the multicenter study with budesonide (FACET), which showed that in cases of exacerbation development while taking low doses of ICS in patients with moderate persistent asthma, an advantage in the effect, including a decrease in the frequency of exacerbations, was observed from increasing the dose of budesonide, while when asthma symptoms and suboptimal values ​​of pulmonary function parameters persisted, increasing the dose of budesonide (up to 800 mcg/day) in combination with formoterol was more effective.

In a comparative assessment results of early administration of ICS in patients who began treatment no later than 2 years from the onset of the disease or who had a short history of the disease, after 1 year of treatment with budesonide, an advantage was found in improving pulmonary function (RF) and in controlling asthma symptoms, compared with the group that began treatment after 5 years from the onset of the disease or patients with a long history of asthma. As for leukotriene antagonists, they are recommended to be prescribed to patients with mild persistent asthma as an alternative to ICS.

Long-term treatment with ICS improves or normalizes lung function, reduces daily fluctuations in peak expiratory flow and the need for systemic glucocorticosteroids (GCS), up to their complete abolition. Moreover, with long-term use of the drugs, antigen-induced bronchospasm and the development of irreversible airway obstruction are prevented, and the frequency of exacerbations, hospitalizations and mortality of patients is reduced.

In clinical practice the effectiveness and safety of ICS is determined by the value of the therapeutic index , which is the ratio of the severity of clinical (desirable) effects and systemic (undesirable) effects (NE) or their selectivity towards the respiratory tract . The desired effects of ICS are achieved by local action of drugs on glucocorticoid receptors (GCRs) in the respiratory tract, and undesirable side effects are the result of the systemic action of drugs on all GCRs of the body. Therefore, with a high therapeutic index, a better benefit/risk ratio is expected.

Anti-inflammatory effect of ICS

The anti-inflammatory effect is associated with the inhibitory effect of ICS on inflammatory cells and their mediators, including the production of cytokines (interleukins), pro-inflammatory mediators and their interaction with target cells.

ICS have an effect on all phases of inflammation, regardless of its nature, and the key cellular target may be epithelial cells of the respiratory tract. ICS directly or indirectly regulate the transcription of target cell genes. They increase the synthesis of anti-inflammatory proteins (lipocortin-1) or reduce the synthesis of pro-inflammatory cytokines - interleukins (IL-1, IL-6 and IL-8), tumor necrosis factor (TNF-a), granulocyte-macrophage colony-stimulating factor (GM/CSF) and etc. .

ICS significantly alter cellular immunity, reducing the number of T cells, and are able to suppress delayed-type hypersensitivity reactions without changing the production of antibodies by B cells. ICS increase apoptosis and reduce the number of eosinophils by inhibiting IL-5. With long-term therapy of patients with asthma, inhaled corticosteroids significantly reduce the number of mast cells on the mucous membranes of the respiratory tract. ICS reduce the transcription of inflammatory protein genes, including induced cyclooxygenase-2 and prostaglandin A2, as well as endothelin, leading to the stabilization of cell membranes, lysosome membranes and a decrease in vascular permeability.

GCS suppress the expression of inducible nitric oxide synthase (iNOS). ICS reduce bronchial hyperactivity. ICS improve the function of b2-adrenergic receptors (b2-AR) both by synthesizing new b2-AR and increasing their sensitivity. Therefore, ICS potentiate the effects of b2-agonists: bronchodilation, inhibition of mast cell mediators and cholinergic mediators nervous system, stimulation of epithelial cells with increased mucociliary clearance.

ICS include flunisolide , triamsinolone acetonide (TAA), beclomethasone dipropionate (BDP) and modern generation drugs: budesonide And fluticasone propionate (FP). They are available in the form of metered dose aerosol inhalers; dry powder with appropriate inhalers for their use: turbuhaler, cyclohaler, etc., as well as solutions or suspensions for use with nebulizers.

ICS differ from systemic GCS mainly in their pharmacokinetic properties: lipophilicity, speed of inactivation, short half-life (T1/2) from blood plasma. Inhalation use creates high concentrations of drugs in the respiratory tract, which ensures the most pronounced local (desirable) anti-inflammatory effect and minimal manifestations of systemic (undesirable) effects.

The anti-inflammatory (local) activity of ICS is determined by the following properties: lipophilicity, the ability of the drug to remain in tissues; nonspecific (non-receptor) tissue affinity and affinity for GCR, the level of primary inactivation in the liver and the duration of communication with target cells.

Pharmacokinetics

The amount of ICS delivered to the respiratory tract in the form of aerosols or dry powder will depend not only on the nominal dose of the GCS, but also on the characteristics of the inhaler: the type of inhaler designed to deliver aqueous solutions, dry powder (see Table.

1), the presence of chlorofluorocarbon (Freon) as a propellant or its absence (Freon-free inhalers), the volume of the spacer used, as well as the technique for performing inhalation by the patient. 30% of adults and 70-90% of children experience difficulties when using metered-dose aerosol inhalers due to the problem of synchronizing pressing the canister with the breathing maneuver. Poor technique affects dose delivery to the respiratory tract and affects the therapeutic index, reducing pulmonary bioavailability and, accordingly, selectivity of the drug. Moreover, poor technique results in poor treatment response. Patients who have difficulty using inhalers feel that the drug does not provide improvement and stop using it. Therefore, during ICS therapy, it is necessary to constantly monitor the inhalation technique and provide patient education.

ICS are rapidly absorbed from cell membranes gastrointestinal tract and respiratory tract. Only 10-20% of the inhaled dose is deposited in the oropharyngeal region, swallowed and, after absorption, enters the hepatic bloodstream, where the majority (~80%) is inactivated, i.e. ICS undergo a primary effect of passage through the liver. They enter the systemic circulation in the form of inactive metabolites (with the exception of beclomethasone 17-monopropionate (17-BMP), an active metabolite of BDP) and a small amount (from 23% TAA to less than 1% FP) - in the form of unchanged drug). Thus, the system oral bioavailability(Oralized) ICS is very low, down to 0 in AF.

On the other hand, approximately 20% of the nominal dose entering the respiratory tract is quickly absorbed and enters the pulmonary, i.e. into the systemic circulation and represents inhalation, pulmonary bioavailability(A pulmonary), which can cause extrapulmonary, systemic NE, especially when prescribing high doses of ICS. In this case, the type of inhaler used is of great importance, since when inhaling dry budesonide powder through a turbuhaler, the pulmonary deposition of the drug increased by 2 times or more compared with inhalation of metered-dose aerosols, which was taken into account when establishing comparative doses of various ICS (Table 1).

Moreover, in a comparative study of the bioavailability of metered dose aerosols of BDP containing freon(F-BDP) or without it (BF-BDP), a significant advantage of local pulmonary absorption over systemic oral absorption was revealed when using the drug without freon: the ratio of “pulmonary/oral fraction” of bioavailability was 0.92 (BF-BDP) versus 0.27 (F-BDP).

These results suggest that an equivalent response would require more low doses BF-BDP than F-BDP.

The percentage of drug delivery to the peripheral respiratory tract increases when inhaled metered aerosols via spacer with a large volume (0.75 l). The absorption of ICS from the lungs is influenced by the size of the inhaled particles; particles smaller than 0.3 µm are deposited in the alveoli and absorbed into the pulmonary bloodstream. A high percentage of drug deposition in the intrapulmonary airways will lead to a better therapeutic index for more selective ICS that have low systemic oral bioavailability (for example, fluticasone and budesonide, which have systemic bioavailability primarily due to pulmonary absorption, in contrast to BDP, which has systemic bioavailability due to intestinal absorption).

For ICS with zero oral bioavailability (fluticasone), the nature of the device and the patient’s inhalation technique determine only the effectiveness of treatment and do not affect the therapeutic index.

On the other hand, calculating the absorbed pulmonary fraction (L) to the total systemic bioavailability (C) can serve as a way to compare the effectiveness of an inhalation device for the same ICS. The ideal ratio is L/C = 1.0, meaning that all the drug has been absorbed from the lungs.

Volume of distribution(Vd) ICS indicates the degree of extrapulmonary tissue distribution of the drug, so a large Vd indicates that a larger part of the drug is distributed in peripheral tissues, but it cannot serve as an indicator of the high systemic pharmacological activity of ICS, since the latter depends on the amount of the free fraction of the drug , capable of communicating with the GKR. The highest Vd was detected in AF (12.1 l/kg) (Table 2), which may indicate the high lipophilicity of AF.

Lipophilicity is a key component for the manifestation of selectivity and retention time of the drug in tissues, since it promotes the accumulation of ICS in the respiratory tract, slows down their release from tissues, increases affinity and lengthens bonds with GCR. Highly lipophilic ICS (FP, budesonide and BDP) are absorbed faster and better from the respiratory lumens and remain longer in the tissues of the respiratory tract compared to non-inhaled ICS - hydrocortisone and dexamethasone prescribed by inhalation, which may explain the unsatisfactory anti-asthmatic activity and selectivity of the latter.

At the same time, it has been shown that the less lipophilic budesonide remains in the lung tissue longer than AF and BDP.

The reason for this is the esterification of budesonide and the formation of budesonide conjugates with fatty acids, which occurs intracellularly in lung tissue, respiratory tract and liver microsomes. The lipophilicity of the conjugates is many tens of times higher than the lipophilicity of intact budesonide (see Table 2), which explains the duration of its stay in the tissues of the respiratory tract. The process of budesonide conjugation in the respiratory tract and lungs occurs quickly. Budesonide conjugates have very low affinity for GCR and have no pharmacological activity. Conjugated budesonide is hydrolyzed by intracellular lipases, gradually releasing free pharmacologically active budesonide, which may prolong the glucocorticoid activity of the drug. Lipophilicity is most pronounced in FP, followed by BDP, budesonide, and TAA and flunisolide are water-soluble drugs.

Relationship between GCS and receptor and the formation of the GCS+GCR complex leads to the manifestation of a long-lasting pharmacological and therapeutic effect of ICS. The onset of interaction between budesonide and GCR is slower than with AF, but faster than with dexamethasone. However, after 4 hours there was no difference in the total amount of binding to SERS between budesonide and FP, while for dexamethasone it was only 1/3 of the bound fraction of FP and budesonide.

Dissociation of the receptor from the budesonide + GCR complex occurs faster compared to AF. The duration of existence of the budesonide + GCR complex in vitro is only 5-6 hours compared to 10 hours for AF and 8 hours for 17-BMP, but it is more stable compared to dexamethasone. It follows from this that the differences between budesonide, FP and BDP in local tissue communication are determined not by interactions with receptors, but mainly by differences in the degree of nonspecific communication of GCS with cellular and subcellular membranes, i.e. directly correlate with lipophilicity.

ICS have fast clearance(CL), its value is approximately the same as the value of hepatic blood flow and this is one of the reasons for the minimal manifestations of systemic NE. 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 BDP (3.8 l/min or 230 l/h) (see Table 2), which suggests the presence of extrahepatic metabolism of BDP (an active metabolite 17-BMP is formed in the lungs ) .

Half-life (T1/2) from blood plasma depends on the volume of distribution and systemic clearance and indicates changes in drug concentration over time.

T1/2 of ICS is quite short - from 1.5 to 2.8 hours (TAA, flunisolide and budesonide) and longer - 6.5 hours for 17-BMP. T1/2 of AF varies depending on the method of drug administration: after intravenous administration it is 7-8 hours, and after inhalation T1/2 from the peripheral chamber is 10 hours. There are other data, for example, if T1/2 from blood plasma after intravenous administration was equal to 2.7 hours, then T1/2 from the peripheral chamber, calculated according to the triphasic model, averaged 14.4 hours, which is associated with a relatively fast absorption of the drug from the lungs (T1/2 2.0 hours) compared with the slow systemic elimination of the drug. The latter can lead to accumulation of the drug with prolonged use. After a 7-day administration of the drug via a diskhaler at a dose of 1000 mcg 2 times a day, the concentration of FP in plasma increased by 1.7 times compared with the concentration after a single dose of 1000 mcg. The accumulation was accompanied by a progressive suppression of endogenous cortisol secretion (95% versus 47%).

Efficacy and safety assessment

Numerous randomized, placebo-controlled and comparative dose-dependent studies of ICS in patients with asthma have shown that there are significant and statistically significant differences between the effectiveness of all doses of ICS and placebo. In most cases, a significant dose-dependent effect was found. However, there are no significant differences between the clinical effects of selected doses and the dose-response curve. Results from studies of the effectiveness of ICS in asthma have revealed a phenomenon that often goes unrecognized: the dose-response curve differs for different parameters. The doses of ICS that have a significant effect on the severity of symptoms and respiratory function differ from those needed to normalize the level of nitric oxide in exhaled air. The dose of ICS needed to prevent asthma exacerbation may differ from that needed to control symptoms of stable asthma. All this indicates the need to change the dosage or the ICS itself, depending on the condition of the patient with asthma and taking into account the pharmacokinetic profile of the ICS.

Information regarding systemic adverse effects of ICS are of the most contradictory nature, from their absence to pronounced ones, posing a risk for patients, especially in children. These effects include suppression of the function of the adrenal cortex, effects on bone metabolism, bruising and thinning of the skin, and the formation of cataracts.

Numerous publications devoted to the problem of systemic effects are associated with the ability to control the level of various tissue-specific markers and relate mainly to markers of 3 different tissues: adrenal glands, bone tissue and blood. The most widely used and sensitive markers for determining the systemic bioavailability of GCS are suppression of adrenal function and the number of eosinophils in the blood. Another important issue is the changes observed in bone metabolism and the associated risk of fractures due to the development of osteoporosis. The predominant effect of GCS on bone turnover is a decrease in osteoblast activity, which can be determined by measuring plasma osteocalcin levels.

Thus, when ICS is administered locally, they are retained longer in the tissues of the respiratory tract, providing high selectivity, especially for fluticasone propionate and budesonide, a better benefit/risk ratio, and a high therapeutic index of the drugs. All these data should be taken into account when choosing ICS, establishing an adequate dosage regimen and duration of therapy for patients with bronchial asthma.

Literature:

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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 recovery processes, structural changes are formed in the respiratory tract, 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 the gastrointestinal tract (GIT) and rapidly metabolized in the liver, which provides a high therapeutic index for ICS.

Inhaled glucocorticosteroids (ICS) vary in activity and bioavailability, which provides some variability in clinical effectiveness and severity side effects for 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. a decrease in protein synthesis and an increase in its 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 inhalation medicines 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 ensures a significant proportion of extra-fine particles of the drug (size from 1.1 to 2.1 microns) and high deposition of the active substance in the small respiratory tract. 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 daily for 12 weeks did not suppress the function of the hypothalamic-pituitary-adrenal axis and did not 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

Inhaled glucocorticosteroids (ICS) are first-line drugs that are used for long-term treatment of patients with bronchial asthma (BA). They effectively block the inflammatory process in the respiratory tract, and clinical manifestation The positive effect of ICS is considered to be a decrease in the severity of symptoms of the disease and, accordingly, a decrease in the need for oral glucocorticosteroids (GCS), short-acting β 2-agonists, a decrease in the level of inflammatory mediators in the bronchoalveolar lavage fluid, an improvement in pulmonary function indicators, and a decrease in the variability in their fluctuations. Unlike systemic corticosteroids, inhaled corticosteroids have high selectivity, pronounced anti-inflammatory and minimal mineralocorticoid activity. When administered via inhalation, approximately 10-30% of the nominal dose is deposited in the lungs. The percentage of deposition depends on the ICS molecule, as well as on the drug delivery system into the respiratory tract (metered aerosols or dry powder), and when using dry powder, the proportion of pulmonary deposition is doubled compared to the use of metered aerosols, including the use of spacers. Most of the ICS dose is swallowed, absorbed from the gastrointestinal tract and rapidly metabolized in the liver, which provides a high therapeutic index of ICS compared to systemic GCS

Drugs for local inhalation use include flunisolide (Ingacort), triamcinolone acetonide (TAA) (Azmacort), beclomethasone dipropionate (BDP) (Becotide, Beclomet) and modern generation drugs: budesonide (Pulmicort, Benacort), fluticasone propionate (FP) (Flixotide ), mometasone furoate (MF) and ciclesonide. For inhalation use, drugs are produced in the form of aerosols, dry powder with appropriate devices for their use, as well as solutions or suspensions for use with nebulizers

Due to the fact that there are many devices for inhalation of ICS, and also due to the insufficient ability of patients to use inhalers, it is necessary to take into account that the amount of ICS delivered to the respiratory tract in the form of aerosols or dry powder is determined not only by the nominal dose of the GCS, but also by the characteristics devices for drug delivery - type of inhaler, as well as the patient’s inhalation technique.

Despite the fact that ICS has a local effect on the respiratory tract, there is conflicting information about the manifestation of adverse systemic effects (AE) of ICS, from their absence to pronounced manifestations that pose a risk to patients, especially children. These NEs include suppression of the function of the adrenal cortex, effects on bone metabolism, bruising and thinning of the skin, and the formation of cataracts.

The manifestations of systemic effects are predominantly determined by the pharmacokinetics of the drug and depend on the total amount of GCS entering the systemic circulation (systemic bioavailability, F) and the clearance of GCS. Based on this, it can be assumed that the severity of the manifestations of certain NEs depends not only on the dosage, but also, to a greater extent, on the pharmacokinetic properties of the drugs.

Therefore, the main factor determining the effectiveness and safety of ICS is the selectivity of the drug in relation to the respiratory tract - the presence of high local anti-inflammatory activity and low systemic activity (Table 1).

In clinical practice, ICS differ in the value of the therapeutic index, which is the ratio between the severity of clinical (desirable) effects and systemic (undesirable) effects, therefore, with a high therapeutic index, there is a better effect/risk ratio.

Bioavailability

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

When inhaling aerosols from metered dose inhalers through a large-volume spacer (0.75 l - 0.8 l), the percentage of drug delivery to the peripheral respiratory tract increases (5.2%). When using metered dose inhalers with aerosols or dry powder GCS through a dischaler, turbuhaler and other devices, only 10-20% of the inhaled dose is deposited in the respiratory tract, while up to 90% of the dose is deposited in the oropharyngeal region and is swallowed. Next, this part of the ICS, absorbed from the gastrointestinal tract, enters the hepatic bloodstream, where most of the drug (up to 80% or more) is inactivated. IGS enter the systemic circulation predominantly in the form of inactive metabolites, with the exception of the active metabolite of BDP - beclomethasone 17-monopropionate (17-BMP) (approximately 26%), and only a small part (from 23% TAA to less than 1% FP) - in the form unchanged drug. Therefore, the systemic oral bioavailability (Fora1) of ICS is very low, it is almost zero.

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

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

For ICS with zero bioavailability after an oral dose (fluticasone), the nature of the device and inhalation technique determine only the effectiveness of treatment, but do not affect the therapeutic index.

Therefore, when assessing systemic bioavailability, it is necessary to take into account the overall bioavailability, that is, not only the low oral bioavailability (almost zero for fluticasone and 6-13% for budesonide), but also inhalation bioavailability, the average values ​​of which range from 20 (FP) to 39% ( flunisolide) () .

For ICS with a high fraction of inhaled bioavailability (budesonide, FP, BDP), systemic bioavailability may increase in the presence of inflammatory processes in the mucous membrane of the bronchial tree. This was established in a comparative study of systemic effects in terms of the level of reduction in plasma cortisol after a single administration of budesonide and BDP at a dose of 2 mg at 22 hours to healthy smokers and non-smokers. It should be noted that after inhalation of budesonide, cortisol levels in smokers were 28% lower than in non-smokers.

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

Of great interest is mometasone furoate (MF), a new ICS with very high anti-inflammatory activity, which lacks bioavailability. There are several versions explaining this phenomenon. According to the first of them, 1 MF from the lungs does not immediately enter the systemic circulation, like budesonide, which lingers in the respiratory tract for a long time due to the formation of lipophilic conjugates with fatty acids. This is explained by the fact that MF has a highly lipophilic furoate group at the C17 position of the drug molecule, and therefore it enters the systemic circulation slowly and in quantities insufficient for detection. According to the second version, MF is rapidly metabolized in the liver. The third version says: lactose-MF agglomerates cause low bioavailability due to a decrease in the degree of solubility. According to the fourth version, MF is quickly metabolized in the lungs and therefore does not reach the systemic circulation during inhalation. And finally, the assumption that MF does not enter the lungs is not confirmed, since there is data on high efficiency MF at a dose of 400 mcg in patients with asthma. Therefore, the first three versions may, to some extent, explain the lack of bioavailability of MF, but this issue requires further study.

Thus, the systemic bioavailability of ICS is the sum of inhalation and oral bioavailability. Flunisolide and beclomethasone dipropionate have systemic bioavailability of approximately 60 and 62%, respectively, which is slightly higher than the sum of the oral and inhaled bioavailability of other ICS.

Recently, a new ICS drug, ciclesonide, has been proposed, the oral bioavailability of which is practically zero. This is explained by the fact that ciclesonide is a prodrug; its affinity for GCS receptors is almost 8.5 times lower than that of dexamethasone. However, upon entering the lungs, the drug molecule is exposed to enzymes (esterases) and transforms into its active form (the affinity of the active form of the drug is 12 times higher than that of dexamethasone). In this regard, ciclesonide is devoid of a number of undesirable adverse reactions associated with the entry of ICS into the systemic circulation.

Communication with blood plasma proteins

ICS have a fairly high association with blood plasma proteins (); for budesonide and fluticasone this relationship is slightly higher (88 and 90%) compared to flunisolide and triamcinolone - 80 and 71%, respectively. Usually, for the manifestation of the pharmacological activity of drugs, the level of the free fraction of the drug in the blood plasma is of great importance. For modern, more active ICS - budesonide and FP, it is 12 and 10%, respectively, which is slightly lower than for flunisolide and TAA - 20 and 29%. These data may indicate that in the manifestation of the activity of budesonide and AF, in addition to the level of the free fraction of drugs, other pharmacokinetic properties of the drugs also play an important role.

Volume of distribution

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

Lipophilicity

The pharmacokinetic properties of ICS at the tissue level are predominantly determined by their lipophilicity, which is a key component for the manifestation of selectivity and retention time of the drug in tissues. Lipophilicity increases the concentration of ICS in the respiratory tract, slows down their release from tissues, increases affinity and prolongs the connection with GCR, although the optimal lipophilicity of ICS has not yet been determined.

Lipophilicity is most pronounced in FP, followed by BDP, budesonide, and TAA and flunisolide are water-soluble drugs. Highly lipophilic drugs - FP, budesonide and BDP - are absorbed more quickly from the respiratory tract and remain longer in the tissues of the respiratory tract compared to non-inhaled corticosteroids - hydrocortisone and dexamethasone, prescribed by inhalation. This fact may explain the relatively unsatisfactory antiasthmatic activity and selectivity of the latter. The high selectivity of budesonide is evidenced by the fact that its concentration in the respiratory tract 1.5 hours after inhalation of 1.6 mg of the drug is 8 times higher than in the blood plasma, and this ratio persists for 1.5-4 hours after inhalation Another study showed a wide distribution of FP in the lungs, as 6.5 hours after administration of 1 mg of the drug, high concentrations of FP were found in lung tissue and low in plasma, in a ratio of 70:1 to 165:1.

Therefore, it is logical to assume that more lipophilic ICS can be deposited on the mucous membrane of the respiratory tract in the form of a “microdepot” of drugs, which allows them to prolong their local anti-inflammatory effect, since it takes more than 5-8 hours to dissolve BDP and FP crystals in the bronchial mucus, whereas for budesonide and flunisolide, which have rapid solubility, this indicator is 6 minutes and less than 2 minutes, respectively. It has been shown that the water solubility of the crystals, which ensures the solubility of GCS in bronchial mucus, is important property in the manifestation of local ICS activity.

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

These data contradict the generally accepted view that there is a correlation between the lipophilicity of ICS and their ability to bind to tissues, since the less lipophilic budesonide is retained longer than FP and BDP. This fact should be explained by the fact that under the influence of acetyl-coenzyme A and adenosine triphosphate hydroxyl group budesonide at the carbon atom in position 21 (C-21) is replaced by a fatty acid ester, that is, esterification of budesonide occurs with the formation of budesonide conjugates with fatty acids. This process occurs intracellularly in the tissues of the lungs and respiratory tract and in liver microsomes, where fatty acid esters (oleates, palmitates, etc.) are identified. Conjugation of budesonide in the respiratory tract and lungs occurs quickly, since already 20 minutes after administration of the drug, 70-80% of the Ra-label was determined in the form of conjugates and 20-30% in the form of intact budesonide, while after 24 hours only 3. 2% of conjugates of the initial level of conjugation, and in the same proportion they were detected in the trachea and lungs, indicating the absence of unidentified metabolites. Budesonide conjugates have very low affinity for GCR and therefore have no pharmacological activity.

Intracellular conjugation of budesonide with fatty acids can occur in many cell types, and budesonide can accumulate in an inactive but reversible form. Lipophilic conjugates of budesonide are formed in the lungs in the same proportions as in the trachea, indicating the absence of unidentified metabolites. Budesonide conjugates are not detected in plasma or peripheral tissues.

Conjugated budesonide is hydrolyzed by intracellular lipases, gradually releasing pharmacologically active budesonide, which can prolong receptor saturation and prolong the glucocorticoid activity of the drug.

If budesonide is approximately 6-8 times less lipophilic than FP, and, accordingly, 40 times less lipophilic compared to BDP, then the lipophilicity of budesonide conjugates with fatty acids is tens of times higher than the lipophilicity of intact budesonide (Table 3), than explains the duration of its stay in the tissues of the respiratory tract.

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

Thus, after inhalation of budesonide, a “depot” of the inactive drug is formed in the respiratory tract and lungs in the form of reversible conjugates with fatty acids, which can prolong its anti-inflammatory activity. This is undoubtedly of great importance for the treatment of patients with asthma. As for BDP, which is more lipophilic than FP (Table 4), its retention time in the respiratory tract tissues is shorter than that of FP and coincides with this indicator for dexamethasone, which is apparently the result of hydrolysis of BDP to 17- BMP and beclomethasone, the lipophilicity of the latter and dexamethasone are the same. Moreover, in an in vitro study, the duration of residence of the Ra tag in the trachea after inhalation of BDP was longer than after its perfusion, which is associated with the very slow dissolution of BDP crystals deposited in the respiratory lumens during inhalation.

The long-term pharmacological and therapeutic effect of ICS is explained by the connection of the GCS with the receptor and the formation of the GCS+GCR complex. Initially, budesonide binds to GCR more slowly than AF, but faster than dexamethasone, but after 4 hours there was no difference in the total amount of binding to GCR between budesonide and AF, while for dexamethasone it was only 1/3 of the bound fraction of AF and budesonide.

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

As shown above (), FP has the greatest affinity for GCR (approximately 20 times higher than that of dexamethasone, 1.5 times higher than that of 17-BMP, and 2 times higher than that of budesonide). The affinity of ICS for the GCS receptor can also be influenced by the configuration of the GCS molecule. For example, in budesonide, its dextro- and levorotatory isomers (22R and 22S) have not only different affinities for GCR, but also different anti-inflammatory activity (Table 4).

The affinity of 22R for GCR is more than 2 times greater than the affinity of 22S, and budesonide (22R22S) occupies an intermediate position in this gradation, its affinity for the receptor is 7.8, and the power of suppression of edema is 9.3 (the parameters of dexamethasone are taken as 1.0 ) (Table 4).

Metabolism

BDP is quickly, within 10 minutes, metabolized in the liver to form one active metabolite - 17-BMP and two inactive ones - beclomethasone 21-monopropionate (21-BMN) and beclomethasone.

In the lungs, due to the low solubility of BDP, which is a determining factor in the degree of formation of 17-BMP from BDP, the formation of the active metabolite may be delayed. The metabolism of 17-BMP in the liver occurs 2-3 times slower than, for example, the metabolism of budesonide, which may be a limiting factor in the transition of BMP to 17-BMP.

TAA is metabolized to form 3 inactive metabolites: 6β-trioxytriamcinolone acetonide, 21-carboxytriamcinolone acetonide and 21-carboxy-6β-hydroxytriamcinolone acetonide.

Flunisolide forms the main metabolite - 6β-hydroxyflunisolide, the pharmacological activity of which is 3 times greater than the activity of hydrocortisone and has a half-life of 4 hours.

FP is quickly and completely inactivated in the liver with the formation of one partially active (1% of FP activity) metabolite - 17β-carboxylic acid.

Budesonide is rapidly and completely metabolized in the liver with the participation of cytochrome p450 3A (CYP3A) with the formation of 2 main metabolites: 6β-hydroxybudesonide (forms both isomers) and 16β-hydroxyprednisolone (forms only 22R). Both metabolites have weak pharmacological activity.

Mometasone furoate (pharmacokinetic parameters of the drug were studied in 6 volunteers after inhalation of 1000 mcg - 5 inhalations of dry powder with radiolabel): 11% of radiolabel in plasma was determined after 2.5 hours, this figure increased to 29% after 48 hours. Excretion of radiolabel with bile was 74% and in urine 8%, the total amount reached 88% after 168 hours.

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

Clearance and half-life

ICS have rapid clearance (CL), its value approximately coincides with the value of hepatic blood flow, and this is one of the reasons for minimal manifestations of systemic NE. On the other hand, rapid clearance provides ICS with a high therapeutic index. The clearance of ICS ranges from 0.7 l/min (TAA) to 0.9-1.4 l/min (FP and budesonide, in the latter case there is a dependence on the dose taken). System clearance for the 22R is 1.4 l/min and for the 22S 1.0 l/min. The fastest clearance, exceeding the rate of hepatic blood flow, was found in BDP (150 l/h, and according to other data - 3.8 l/min, or 230 l/h) (), which suggests the presence of extrahepatic metabolism of BDP, in this case in the lungs, leading to the formation of the active metabolite 17-BMP. The clearance of the 17-BMP is 120 l/h.

The half-life (T1/2) from blood plasma depends on the volume of distribution and the magnitude of systemic clearance and indicates changes in drug concentration over time. For ICS, T1/2 from blood plasma varies widely - from 10 minutes (BDP) to 8-14 hours (AF) (). T1/2 of other ICS is quite short - from 1.5 to 2.8 hours (TAA, flunisolide and budesonide) and 2.7 hours for 17-BMP. For fluticasone, T1/2 after intravenous administration is 7-8 hours, while after inhalation from the peripheral chamber this figure is 10 hours. There are other data, for example, if T1/2 from blood plasma after intravenous administration was equal to 2.7 (1.4-5.4) hours, then T1/2 from the peripheral chamber, calculated according to the three-phase model, averaged 14 .4 hours (12.5-16.7 hours), which is associated with relatively rapid absorption of the drug from the lungs - T1/2 2 (1.6-2.5) hours compared to its slow systemic elimination. The latter can lead to the accumulation of the drug with long-term use, which was shown after a seven-day administration of FP through a discahaler at a dose of 1000 mcg 2 times a day to 12 healthy volunteers, in whom the concentration of FP in the blood plasma increased by 1.7 times compared with the concentration after single dose 1000 mcg. Accumulation was accompanied by an increase in suppression of plasma cortisol levels (95% versus 47%).

Conclusion

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

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

For questions about literature, please contact the editor

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

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

Main contraindications: individual intolerance, non-asthmatic bronchitis.

Important information for the patient:

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

Tradename drug	Price range (Russia, rub.)	Features of the drug that are important for the patient to know about
Active substance: Beclomethasone
Beclazon Eco(aerosol) (Norton Healthcare, Teva) Beclazon Eco Light Breath (aerosol) (Norton Healthcare) Klenil (aerosol) (Chiesi)
Active substance: Mometasone
Asmanex Twistheiler(powder for inhalation) (Merck Sharp and Dome)		A powerful drug. Can be used if other inhalation agents are ineffective. Contraindicated in children under 12 years of age. Use with caution during pregnancy, breastfeeding, pulmonary tuberculosis, fungal, bacterial and viral infections, with herpetic eye lesions.
Active substance: Budesonide
Budenit Steri-Neb (suspension for inhalation via nebulizer) (various manufacturers) Pulmicort(suspension for inhalation via nebulizer) (AstraZeneca) Pulmicort Turbuhaler (powder for inhalations) (AstraZeneca)		Frequently used effective inhalation drug. The anti-inflammatory effect is 2-3 times stronger than beclomethasone. Contraindicated for children under 6 months. Can be used in minimal doses during pregnancy and is allowed during breastfeeding. Use with caution for pulmonary tuberculosis, fungal, bacterial and viral infections, liver cirrhosis.
Active substance: Fluticasone
Flixotide (aerosol) (GlaxoSmithKline)
Active substance: Cyclesonide
Alvesco (aerosol) (Nycomed)		A new generation glucocorticoid for the treatment of adult patients and children over 6 years of age suffering from bronchial asthma. It accumulates well in lung tissue, providing a therapeutic effect at the level of not only large, but also small respiratory tracts. Rarely causes side effects. It acts faster than other inhaled glucocorticoids. Use with caution for tuberculosis, bacterial, fungal and viral infections, pregnancy and breastfeeding.

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

According to review data, doctors estimate that approximately 7% of Americans have asthma. The disease affects people of all races and ethnic groups worldwide, from infancy to old age, with a slight predominance among boys and, after puberty, among women. . The tragic increase in the prevalence of atopy and asthma has occurred over the past few decades in Western countries and more recently in developing countries, suggesting that approximately 300 million people suffer from asthma worldwide

In the 1970s and 1980s, in the United States, the number of severe asthma exacerbations increased sharply (as reflected by increased office attendance). emergency assistance and asthma-related hospitalizations) and asthma-related mortality. Yet despite the persistently high prevalence of the disease, the most recent available data indicate improved rates, and a reduction in the number of annual hospitalizations for asthma attacks and asthma-related deaths. One possible explanation for these favorable trends is the increased use of prophylactic inhaled corticosteroids and the introduction over the past 10 to 15 years of new, very effective drugs and improved asthma treatment protocols.

Airway obstruction in asthma and subsequent symptoms such as cough, shortness of breath, chest tightness, and wheezing are caused by several factors: spasm of the smooth muscles of the airways and inflammation of the bronchi. The spasm can be severe and result in life-threatening narrowing and closure of the airways, even in the absence of a mucus component. Both abnormal smooth muscle contraction and increased smooth muscle mass may contribute to this. Airway inflammation in asthma includes mucosal, submucosal, and interstitial edema; cellular infiltration, especially by eosinophils (and in some cases, neutrophils) and activated T-helper lymphocytes, as well as mast cells, which (unlike mast cells in other eosinophilic diseases of the respiratory tract) infiltrate smooth muscle bundles; increased secretions in the respiratory tract, including secreted sputum, desquamated epithelium, and intraluminal eosinophils; stagnation in capillaries; smooth muscle hyperplasia; and deposition of excess collagen, especially just beneath the epithelial basement membrane,

Traditionally, drugs used to treat asthma have been categorized according to their predominant effects—relaxing airway smooth muscle (bronchodilators) and suppressing airway inflammation (anti-inflammatory drugs). Newer drugs (eg, leukotriene modifiers) and drug combinations (eg, inhaled corticosteroids combined with long-acting beta-agonists) have a dual effect, as opposed to this traditional dichotomy. Now that asthma medications are classified according to their roles in holistic asthma control (short-acting and long-acting), this model is especially useful when discussing with patients their asthma medications.

All patients with asthma should have a short-acting bronchodilator available for use as needed. It is generally accepted that when fast-acting bronchodilators are needed to relieve symptoms more than twice a week (or more than twice a month for night awakenings caused by asthmatic symptoms), controller medications should be prescribed. ,

Short-acting drugs.

Short-acting β-agonists, administered by inhalation, are the most effective therapy for rapid relief of airway obstruction and relief of asthmatic symptoms. The most widely used short-acting drugs, β2-selective adrenergic agonists: albuterol (commonly known as outside the United States), levalbuterol, and pirbuterol). Metaproterenol, supplied in a metered-dose inhaler (MDI), was recently discontinued.

Table 1. b - Short-acting adrenergic agonists.

All fast-acting b-agonists begin to act in 5 minutes or less, with peak effects in 30 to 60 minutes, and duration of action of 4 to 6 hours. With regular use of bronchodilators (four or more times daily), the potential effectiveness (measured by an increase in maximum exhaled flow) is not reduced, but the duration of action is slightly reduced. Because a regular four-times-daily dosing schedule does not improve outcomes compared with as-needed dosing (and in patients with certain beta-receptor genotypes, may have a detrimental effect), short-acting beta-agonists are recommended for use only when needed for relief. symptoms (or before expected exposure to known asthmatic factors). The practice of administering short-acting beta-agonists before using inhaled corticosteroids to improve delivery of the corticosteroid to the lower airways has been rejected as untenable. Likewise, there is no need for the patient to wait more than 10 to 15 seconds between inhalations when a dose of two or more inhalations is required

In patients with moderate to severe airway obstruction, a log-linear dose-response curve may demonstrate that large doses are required for bronchodilation with short-acting beta-agonists (up to 4000 µg of albuterol from a MDI). Dose-related side effects of sympathomimetics, such as tremor, restlessness, palpitations, and tachycardia (without hypertension), are common, and small dose-dependent decreases in serum potassium and magnesium levels may be observed. However, at the usual dose (two inhalations at a time), unpleasant side effects are rare. But their effectiveness may also be reduced in cases where patients are simultaneously taking beta blockers. ,

The decision about which short-acting beta-agonist to use is based largely on cost and patient and physician preference. Pirbuterol is available in a breath-activated metered-dose aerosol inhaler (BAI-AV), a device designed to optimize drug delivery by injecting the drug only when inspiration is initiated. Levalbuterol, a purified D-rotatory isomer of albuterol, was created to eliminate the side effects that some have reported to be unique to the S-rotatory isomers. However, when levalbuterol is used in a MDI, the efficacy and side effect profile is indistinguishable from that of the racemic mixture of molecules in albuterol. Albuterol has now become available in MDIs and does not contain chlorofluorocarbons (CFCs), and CFC-containing albuterol inhalers were discontinued on December 31, 2008. Like CFCs, the alternative propylene, hydrofluoroalkane (HFA), is inert in the human respiratory tract, but Unlike the CFC, it does not contribute to stratospheric ozone depletion. HFA inhalers are equivalent to CFC-containing inhalers, and can be used with spacers in patients with poor inhalation technique. They provide bronchodilation comparable to nebulized albuterol if the required number of breaths is regulated and the inhalation technique is quite good.

Short-acting beta-agonists taken orally in tablet or liquid form are not recommended despite their apparent convenience (especially for young children). They begin to act later, are weaker, and more often than inhalation forms, cause side effects. Likewise, anticholinergic bronchodilators such as ipratropium are not recommended (or approved by the Food and Drug Administration) for rapid relief of asthma symptoms. They take effect later (20 to 30 minutes) and cause weaker bronchodilation than inhaled b-bronchodilators. Anticholinergic bronchodilators should be used only in rare cases in patients intolerant to all b-mimetics, or for the treatment of a severe asthmatic attack, or asthmatic attacks. caused by beta blockers.

A new approach to treating asthma, not yet adopted in the United States, combines b-agonists with inhaled corticosteroids in one vial to treat symptoms as needed. The use of this combination resulted in more favorable outcomes in patients with moderate asthma compared with the use of albuterol alone as needed. Similarly, a long-acting, rapid-onset β-agonist (B) is used in combination with an inhaled corticosteroid in a single inhaler for maintenance and rescue therapy simultaneously, and the safety of this approach in a broad and heterogeneous population awaits confirmation.

Long-term Control.

Achieving good long-term asthma control (infrequent asthmatic symptoms, unrestricted level of activity, normal or near-normal lung function, and infrequent asthmatic attacks requiring emergency care), requires a multifaceted approach: limiting environmental factors that can cause bronchoconstriction and acute or chronic airway inflammation; monitoring changes in disease activity; in some cases, immunotherapy; And drug treatment. The use of controller medications should be increased until good asthma control is achieved, including reducing the number of asthma attacks requiring systemic corticosteroids to a maximum of one per year. Inhaled corticosteroids are the most effective class of medications for helping patients achieve good levels of asthma control.

Inhaled corticosteroids.

Corticosteroids have proven effective in treating asthma as they are effective in many other inflammatory diseases, due to its diverse anti-inflammatory effects, including multiple effects on transcription (both up- and down-regulation) of many genes. In biopsies of the respiratory tract of asthmatics who received long-term therapy with inhaled corticosteroids, histological abnormalities typical of asthma were less pronounced. Changes include a decrease in the number of mast cells, eosinophils, T lymphocytes, and dendritic cells in the mucosal and submucosal layers; reduction of goblet cell hyperplasia and epithelial cell damage; decrease in vascularization.

Along with suppression of airway inflammation, nonspecific bronchial hyperresponsiveness is usually reduced. Positive clinical outcomes include reduction in asthmatic symptoms, increased lung function, improvement in asthma-specific quality of life, and a reduction in asthmatic attacks, including severe ones resulting in hospitalization or death. While there are optimistic predictions, reliable evidence indicating that the progressive decline in lung function observed in some patients with asthma can be prevented by long-term use of inhaled corticosteroids is largely lacking. Inhaled steroids suppress but do not cure asthmatic inflammation: during the disease stabilization phase, markers of airway inflammation (eg, exhaled nitric oxide and sputum eosinophil concentrations), and bronchial hyperresponsiveness return to baseline levels approximately 2 weeks after use of inhaled corticosteroids was discontinued. ,

Not all patients benefit equally from inhaled corticosteroids. For example, smokers are less likely to get the same anti-asthma effect as non-smokers. Neutrophilic airway inflammation is less likely to respond to treatment as well as eosinophilic airway inflammation. Genetic differences in people with asthma may also cause resistance to corticosteroids.

Most currently available inhaled corticosteroids, after ingestion and systemic absorption from the gastrointestinal tract, undergo extensive primary metabolic inactivation in the liver before reaching the systemic circulation. In addition, because less than 20% of the ingested dose is retained in the respiratory tract, only a small amount can be absorbed through the mucous membrane of the respiratory tract. Using changes in hypothalamic-pituitary-adrenal function as a test, systemic effects can be noted with the administration of an inhaled corticosteroid at doses such as 88 µg fluticosone per day. However, virtually no clinically important, long-term adverse systemic effects have been observed among adults taking low to moderate doses of these drugs. At larger doses (usually >1000 µg of beclomethasone or equivalent per day), the risk of skin lesions, cataracts, increased intraocular pressure, and accelerated bone loss is increased. Children experience growth retardation. Expected growth delay averages approximately 1 cm in the first year after a child is prescribed inhaled corticosteroids, but data from studies in prepubertal and school-aged children suggests that even when these children continue to receive inhaled corticosteroids long-term, they eventually achieve their normal expected growth, .

Pharyngeal and laryngeal side effects of inhaled corticosteroids include laryngeal ulceration, cough when inhaling drugs, weak or hoarse voice, and candidiasis. Rinsing your mouth after each use of the drug and using a spacer with a pMDI are methods that help minimize the risk of developing oral candidiasis. (Use of a MDI spacer also reduces the amount of drug that can be absorbed from the oropharynx.) Cough can usually be controlled by changing the corticosteroid or inhalation system. Dysphonia, a generally intermittent symptom, is thought to arise from laryngeal edema and mucosal thickening or possibly myopathy 57 . This usually resolves with temporary cessation of treatment or after changing the aerosol generation and delivery pattern (eg, switching from a dry powder inhaler to a MDI with spacer).

When an inhaled corticosteroid was first introduced to treat asthma in the mid-1970s, it was given four times daily, and each puff of MDI sold in the United States contained only 42 µg of the hormone. Since then, other corticosteroids have become available, including more potent ones that deliver larger doses per inhalation and are given once or twice daily, leading to improved effectiveness and convenience.

Table 2. Inhaled corticosteroids.

Each of the inhaled corticosteroids has its own characteristics. For the most part, the choice is based on ease of administration (once to twice daily) and delivery method (MDI, dry powder inhaler, or nebulizer solution), starting dose and flexibility in dose control, cost of the drug, and side effects. However, only minor differences were found in the therapeutic effect.

The use of high-dose inhaled corticosteroids has been effective in treating severe persistent asthma. However, the dose-response curve (based on expiratory flow) for inhaled corticosteroids is relatively flat, whereas the systemic dose absorption curve appears to be more linear. As a result, strategies have become more acceptable in which asthma control can be achieved without the use of large doses of inhaled corticosteroids, and reducing their doses in patients with well-controlled asthma (so-called "tapering" therapy) can often be achieved without reducing control. asthma.

Long-acting inhaled b-adrenergic agonists.

The long-acting inhaled beta-agonists, salmeterol and formoterol (and), have largely replaced the earlier long-acting oral bronchodilators, slow-release albuterol and theophylline. Long-acting b-adrenergic agonists are powerful bronchodilators (with a bronchodilator effect similar to short-acting b-agonists), remain active for more than 12 hours, and due to their high b-2 adrenoselectivity, have a small number of side effects (mainly mild sympathomimetic effects, such as single myoclonus and tachycardia). . They do not interact with food and other drugs, unlike theophylline, making it difficult to use, and toxicity from drug overdose is extremely rare, unlike that of theophylline.

Table 3. Long-acting inhaled b-adrenergic agonists.

As with short-acting beta-agonists, regular use of long-acting beta-agonists results in only moderate tachyphylaxis and a maximum bronchodilator effect with a longer retention of activity of these drugs. In contrast, the bronchoprotective effect of long-acting beta-agonists (i.e., prevention of exercise-induced bronchoconstriction) decreases rapidly with regular use, an opposing pharmacological effect that has not been fully explained. With rare exceptions, the rapid relief of attacks provided by short-acting beta-agonists is not inhibited by long-acting beta-agonists when used regularly. Variations in beta-adrenergic receptor structure due to genetic polymorphisms, which are common in the American population (15-20%), may reduce the effectiveness of long-acting beta-agonists in some patients.

The fact that long-acting beta-agonists may provide improvements in pulmonary function may lead clinicians to use them as long-term treatment without the concomitant use of an inhaled corticosteroid with an anti-inflammatory effect. However, this strategy results in persistent airway inflammation and an unacceptably high incidence of asthmatic attacks. Long-acting inhaled beta-agonists should not be used without appropriate anti-inflammatory therapy for the treatment of asthma.

As adjunctive or combination therapy with inhaled corticosteroids, long-acting beta-agonists have been effective in reducing daytime and especially nighttime symptoms, improving pulmonary function, reducing the risk of seizures, and reducing the required dose of inhaled corticosteroids. A comparison of the use of inhaled corticosteroids in combination with long-acting beta-agonists and the use of higher doses of inhaled corticosteroids alone suggests that combination therapy produces more favorable results (with lower doses of corticosteroids). Pharmacological data provide a theoretical basis for a beneficial interaction between these two classes of drugs: laboratory research showed that corticosteroids improve β-receptor-mediated signaling in the lungs, and β-agonists increase gene transcription under the influence of corticosteroids. Combination therapy (long-acting beta-agonists combined with a corticosteroid in one inhaler) ensures co-use of an anti-inflammatory drug and optimizes compliance due to greater convenience. Its main disadvantage is that adjusting the dose of inhaled corticosteroids without changing the dose of b-mimetics (for example, increasing the dose of corticosteroid during an asthmatic attack) requires a change in the device or the availability of a separate inhaled corticosteroid.

The vital benefit that many patients with moderate to severe persistent asthma experienced when using a long-acting beta-agonist with an inhaled corticosteroid must be contrasted with the results of the Salmeterol Multicenter Asthma Research Trial (SMART), which found the addition of Long-acting beta-agonists added to "usual care" may cause an increased risk of fatal or near-fatal asthmatic attacks compared to "usual care". It was shown that the majority of SMART cases did not use inhaled corticosteroids, and among patients taking long-acting beta-agonists and inhaled corticosteroids, no increase in asthma-related mortality was ever reported. However, the mechanism by which salmeterol caused the increase in asthma-related deaths among both black and white subjects remains unclear, and therefore all drugs containing salmeterol or formoterol contain warnings throughout the package labels and labels. In addition, national and international expert groups have recommended the use of long-acting beta-agonists only in patients in whom inhaled corticosteroids alone either do not achieve good asthma control or for initial therapy if it is not expected to achieve good results. . Future guidelines for the treatment of asthma should take into account the recent observation that administration of a long-acting beta-agonist in combination with an inhaled corticosteroid once daily provides good control in patients with mild persistent asthma.

Both long-acting β-adrenergic agonists differ in their properties, both in practical and theoretical terms, the onset of action of formoterol is after 5 minutes, just like short-acting β-agonists, while the onset of action of salmeterol is slower (15 - 20 minutes). Therefore, in some countries other than the United States, the combination of formoterol and an inhaled corticosteroid in one inhaler is recommended for both rapid relief of an attack and, for regular use, for long-term control. Formoterol is a full β-adrenergic receptor agonist, while salmeterol is a partial agonist (and partial antagonist). The significance of this pharmacological difference, especially with regard to the risk of fatal asthmatic attacks, is questionable.

Leukotriene modifiers.

Cysteinyl leukotriene receptor antagonists: , and pranlukast (the latter, not available in the United States) block the action of leukotriene C4, D4, and E4 at cysteinyl leukotriene type 1 receptors. Bronchodilation occurs within a few hours after the first dose, and the maximum effect occurs within the first few days after the start of use. The level of eosinophils circulating in the blood decreases when treated with leukotriene receptor antagonists. . However, when using indirect measures of airway inflammation (eg, sputum eosinophil counts and exhaled nitric oxide levels) to determine outcomes, the effect of leukotriene receptor antagonists on airway inflammation, compared with placebo, was variable.

Table 4. Leukotriene modifiers.

Leukotriene receptor antagonists can be taken as tablets once (in the case of montelukast) or twice (in the case of zafirlukast) per day. Montelukast is available in chewable tablets and oral granules (to be mixed into food) for young children. The recommendation to take montelukast once daily in the evening was based on the timing of its administration in the original trials submitted to the FDA at the time of the drug's approval application. However, no data indicate a greater benefit when taken in the evening compared to use at any other time of the day.

Zileuton inhibits the production of cysteinyl leukotrienes (and leukotriene B4, a powerful chemokine for neutrophils), as it is an antagonist of 5-lipoxygenase. It is now widely believed that it should be taken twice a day. There are no clinical trials directly comparing the effectiveness of zileuton compared with leukotriene receptor antagonists or the effectiveness of their combined use. Some clinicians find zileuton superior to leukotriene receptor antagonists for the asthmatic triad (asthma, aspirin intolerance, and nasal polyposis), both for asthma control and for the reduction of nasal polyps.

Zileuton causes reversible toxic hepatitis in 2 - 4% of cases. Liver function should be monitored monthly during the first 3 months of therapy, every 3 months until the end of the first year, and periodically thereafter. Reports of Churg-Strauss syndrome (eosinophilic vasculitis and granulomatosis complicating asthma) in patients recently started on leukotriene receptor antagonists (often with concomitant reduction in oral corticosteroids), may reflect worsening of pre-existing Churg-Strauss syndrome, although a causal relationship is possible remains controversial. In general, leukotriene receptor antagonists were considered virtually free of side effects, and one (montelukast) was even approved for use in asthma in children under one year of age. Recent post-marketing reports describe several cases of montelukast causing depression and suicidality in children. But no evidence has been found to support this, and when reviewing all available data from placebo-controlled clinical trials, the FDA did not find an increased risk of suicidality or suicide with any of the leukotriene modifiers. The possibility of changes in mood and behavior under the influence of these drugs is being studied.

Because of awareness of their safety and convenience, leukotriene receptor antagonists have largely replaced cromoglycates (cromolyn and nedocromil) as the non-corticosteroid drugs of choice, especially in young children in whom aerosol treatment is often difficult. Cromolyn requires four daily dosing via a MDI or nebulizer, providing fairly limited long-term asthma control and, unlike leukotriene receptor antagonists, no additional benefit has been seen from its use in combination with inhaled corticosteroids.

Short-term, double-blind, placebo-controlled studies have found improvements in lung function, asthma-related quality of life questionnaires, and a reduction in asthma attacks in patients taking leukotriene modifiers. , , , Treatment with leukotriene modifiers may be especially beneficial in obese people, smokers, and those with increased sensitivity to aspirin. In the future, the identification of specific individual characteristics of genes encoding enzymes of the leukotriene metabolic pathway may prove clinically useful in predicting the effectiveness of treatment in a particular patient. Currently, a therapeutic trial is often used; if there is an improvement in symptoms and objective data, this is usually observed within the first month after the start of therapy.

In general, inhaled corticosteroids provide better asthma control than leukotriene modifiers. As a result, inhaled corticosteroids are recommended as the first choice in the treatment of patients with persistent asthma, including children of all ages. Leukotriene receptor antagonists are an alternative in treatment of mild persistent asthma. For patients of any age who do not achieve good asthma control with leukotriene modifiers, switching to inhaled corticosteroids is indicated. In patients with more severe asthma, adding a leukotriene receptor antagonist to a low-dose inhaled corticosteroid may improve asthma control, but other therapeutic combinations (namely, inhaled corticosteroids plus long-acting beta-agonists) are more effective.

Anti-IgE therapy.

The anti-IgE monoclonal antibody, omalizumab, is the first biological immunoregulatory agent available for the treatment of asthma. They bind that part of IgE to which receptors (Fc R1) on the surface of mast cells and basophils have high affinity. When administered intravenously, omalizumab reduces circulating IgE levels by 95% and free IgE levels may result in 10 IU per milliliter or less, with the goal of clinically significant inhibition of airway allergic reactions. Its use also leads to a decrease in the expression of receptors (Fc R1) on the surface of mast cells and other immunoregulatory cells (basophils, monocytes, and dendritic cells). Unlike hyposensitizing immunotherapy, treatment with omalizumab is not limited to targeting a specific allergen or group of allergens.

Omalizumab is given subcutaneously every 2 or 4 weeks, depending on the dose. The dose is calculated depending on the patient's weight and the level of IgE in the blood. Local allergic reactions(urticaria type) are rare, and systemic allergic reactions (ie, anaphylaxis) are possible in 1 to 2 patients in 1000. Most, but not all, systemic reactions occur within 2 hours after the first few doses. Patients are asked to remain under medical supervision for 2 hours after each of their first three injections and for 30 minutes after each subsequent injection and for the next 24 hours, to carry a pre-filled epinephrine-containing auto-injector with them for self-administration if necessary.

Omalizumab is indicated for the treatment of moderate to severe persistent asthma when inhaled corticosteroids, long-acting beta-agonists, and leukotriene modifiers have not provided adequate control or cannot be used due to intolerable side effects. The currently approved dosing range for omalizumab is limited to use in patients with IgE level in the blood from 30 to 700 IU per milliliter; a documented increase in sensitivity to a persistent aeroallergen (eg, dust, animal dander, mold, cockroaches) is an additional selection criterion.

Omalizumab has been approved for use in adults and children over 12 years of age. For patients in this age range, the drug does not appear to be disease-modifying, in the sense that it does not prevent long-term changes in lung function or cause disease remission (meaning a pause without recurrence of asthmatic symptoms). Treatment with omalizumab was found to reduce the frequency of asthmatic attacks, even among patients already taking many other medications. In patients receiving only an inhaled corticosteroid, the addition of omalizumab, compared with placebo, resulted in a significant reduction in corticosteroid dose, with preservation or some improvement in pulmonary function and reduced need for rescue bronchodilator.

One of the biggest drawbacks to more widespread use of omalizumab is the cost, approximately $10,000 to $30,000 annually for just one drug. Pharmacogenetic markers predicting beneficial effects of a drug would be highly desirable given the high cost of a therapeutic trial lasting 4 to 6 months. Observations to date indicate that traditional clinical data at baseline cannot reliably predict which patients will respond to anti-IgE therapy.

Conclusion.

If bronchial asthma manifests itself infrequently, short-term and mild symptoms, occasional use of a rapid-acting bronchodilator to relieve airway smooth muscle spasm is an acceptable approach. However, when symptoms become more frequent and more severe, the emphasis is on preventing symptoms (and asthmatic attacks). To suppress airway inflammation, inhaled corticosteroids, used once or twice daily, reduce the frequency of bronchoconstriction episodes and the risk of asthmatic attacks. In low to moderate doses, inhaled corticosteroids are safe for long-term use, even in young children. An alternative to corticosteroids for mild asthma is leukotriene receptor antagonists, which are aimed at blocking an asthma-specific inflammatory mediator. Anti-influenza and possibly anti-pneumococcal vaccines are indicated for patients along with regular anti-asthma therapy. ,

Picture 1. A stepwise approach to asthma therapy.

This simplified stepwise approach to asthma treatment is designed around the central role of inhaled corticosteroids. For each of the overlapping steps, the dose of inhaled corticosteroid can be adjusted to that needed to achieve good asthma control while minimizing the long-term risks associated with high doses. LABA stands for long-acting b-agonist, LTM stands for leukotriene modifier, LTRA stands for leukotriene receptor antagonist, and SABA stands for short-acting b-agonist.

When symptoms persist despite treatment, compliance and good inhalation technique, the use of long-acting beta-agonists in combination with inhaled corticosteroids has proven to be the most effective next step because it addresses both aspects of airway narrowing in asthma: bronchoconstriction and airway inflammation. A new option for patients with refractory allergic asthma is therapy with monoclonal anti-IgE antibodies.

Control of asthma can often be achieved by increasing the dose of inhaled corticosteroids. However, with large doses and long-term exposure, the potential risk of side effects increases. Thus, once control of asthma has been achieved for a period of 3 to 6 months, efforts should be made to reduce the dose of inhaled corticosteroids to a moderate or low dose. The use of long-acting beta-agonists, leukotriene modifiers, and anti-IgE therapy may facilitate dose reduction of inhaled corticosteroids once asthma is well controlled.

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