Receptors for steroids are located in the cytoplasm of cells. However, their density in different cells is not the same: from 10 to 100 steroid-sensitive receptors, which may cause different sensitivity tissues to GCS. In addition, GCS may have different tropism to GKR. Quantity glucocorticosteroid receptors (GCR) can vary significantly and change during GCS therapy.
Research recent years showed that the effect of glucocorticosteroid hormones on the biosynthesis of messenger RNA (mRNA) is the main step in the implementation of the biological effects of GCS in the cells of target organs.
GCS can have both a specific stimulating effect and an inhibitory effect on the synthesis of various RNAs. Multidirectional effects can manifest themselves in the same organ and, perhaps, the final response of the cell to a hormonal signal depends on their ratio. GCS also affect the activity of RNA polymerase.
1. The anti-inflammatory effect of GCS manifests itself in the form of antiexudative and stabilization of cellular and subcellular membranes (mitochondria and lysosomes);
decreased permeability of the vascular wall, in particular capillaries;
vasoconstriction at the site of inflammation;
reducing the release of biologically active amines (histamine, serotonin, kinins and prostaglandins) from mast cells;
reduction in the intensity of energy formation processes in the source of inflammation;
inhibition of migration of neutrophils and macrophages to the site of inflammation, disruption of their functional activity (chemotactic and phagocytic), peripheral leukocytosis;
suppression of monocyte migration, slowing down the release of mature monocytes from bone marrow and a decrease in their functional activity;
inducing the synthesis of lipomodulin, which blocks phospholipase A of cell membranes, disrupts the release of phospholipid-bound arachidonic acid and the formation of pro-inflammatory prostaglandins, leukotrienes and thromboxane A2;
inhibition of the formation of leukotrienes (leukotriene B4 reduces the chemotaxis of leukocytes, and leukotrienes C4 and D4 (slowly reacting substance) reduce contractile ability smooth muscles, vascular permeability and mucus secretion in the airways);
suppression of the synthesis of some pro-inflammatory cytokines and blockade of the synthesis of cytokine receptor proteins in tissues.
antiproliferative effects. suppression of nucleic acid synthesis;
impaired differentiation of fibrocytes from fibroblasts;
decrease in the functional activity of fibrocytes
2. Immunosuppressive effect: a decrease in the number of lymphocytes in the peripheral blood (lymphopenia), due to the transition of circulating lymphocytes (mainly T cells) into lymphoid tissue, possibly accumulating them in the bone marrow;
increased apoptosis of immature or activated T- and B-lymphocytes;
suppression of T cell proliferation;
decreased function of T-helpers, T-suppressors, cytotoxic T-lymphocytes;
inhibition of the activity of the complement system;
inhibition of the formation of fixed immune complexes;
decrease in the level of immunoglobulins (high doses of glucocorticoids);
inhibition of delayed type hypersensitivity reactions (type IV allergic reactions), in particular the tuberculin test;
violation of cooperation between T - and B - lymphocytes;
disruption of the synthesis of immunoglobulins and antibodies, including autoantibodies;
decrease in the number of monocytes in the vascular bed.
For the right one, coordinated work every organ and system of the body requires maintenance normal level hormones. Adrenal glands - paired glands internal secretion. This is a component of the endocrine regulatory system that controls all processes occurring in the human body. Main function adrenal glands - producing hormones called corticosteroids. They support immune forces, protect the body from harmful external factors, suppress inflammation, regulate metabolism and other important physiological processes. Depending on the functions performed, glucocorticosteroid hormones (glucocorticoids) and mineralocorticoids are distinguished. The role of glucocorticosteroids was first discovered by rheumatologist F. Hench in 1948. He noticed that a woman suffering rheumatoid arthritis, during pregnancy the severity of articular syndrome decreased significantly. This gave rise to the creation of analogues of glucocorticosteroids produced by the adrenal cortex and their widespread use in clinical medicine.
What are glucocorticosteroids? - All drugs included in the group - steroids, have a certain biological activity. They are divided into substances of natural (cortisone, hydrocortisone) and synthetic origin (synthesized analogs natural hormones, derivatives, incl. fluorinated, the most active natural hormone hydrocortisone). Artificially created substances are stronger, are used in smaller dosages, and do not affect mineral metabolism. Their use does not pose a high risk of side effects. Most clinically significant classification of glucocorticosteroids– according to the duration of the therapeutic effect. According to these parameters, drugs are distinguished:
Short-acting - with a biological half-life of 8-12 hours. These are basic remedies for the treatment of skin pathologies, inflammatory and allergic manifestations, usually used externally, in this case they have the least effect on water-salt balance. Tablets and injections are used primarily as a replacement hormone therapy, with a decrease or cessation of their natural production.
Co average duration effect - with a half-life of 18-36 hours. Most used in clinical practice group of drugs. The strength of the effect is 5 times greater than short-acting glucocorticosteroids, inferior to them in mineralocorticoid activity, and is less likely to cause adverse effects for the body.
Long-acting - drugs with active component, the concentration of which in the plasma will be halved after 36-54 hours. The anti-inflammatory effect of such drugs is 6-7 times stronger than Prednisolone, they do not affect the processes mineral metabolism. When using them, various adverse reactions often occur. Not recommended for long-term use.
The extensive and multifaceted effects exerted by glucocorticosteroids are due to the ability of the molecule active substance penetrate the membrane into the cell and act on the genetic apparatus at the level of transcription and processing of ribonucleic acid. By binding to cytoplasmic receptors located inside target cells, they form an active complex that penetrates the cell nucleus and affects the synthesis of activator proteins, which are natural regulators of genes. By interacting with nuclear factors, glucocorticosteroids change the immune response, directly and indirectly reducing the formation of substances that contribute to the development of inflammation - prostaglandins, highly active lipid inflammatory mediators leukotrienes, membrane phospholipid mediators PAF (platelet aggregation factor). The full mechanism of influence has not yet been fully studied.
It takes from half an hour to several hours for genomic effects to develop. At higher doses, non-genomic or receptor-mediated effects are realized. Action of glucocorticosteroids in this case, it appears within 1-2 minutes after application. The ability to quickly, within a few seconds, act on the membranes of target cells, changing them physical and chemical properties and reducing the process of release of allergic and inflammatory mediators, allows you to instantly alleviate the patient’s condition and save his life. The main effects of taking glucocorticosteroids are as follows:
anti-inflammatory effect - inhibit inflammatory phenomena of any nature and stage of development, reduce the permeability of the cell membrane for inflammatory mediators, migration immune cells to the site of inflammation;
anti-shock, anti-stress – increases blood pressure, stimulate the production large quantity blood cells, which allows you to combat shock and quickly replenish blood loss;
immunoregulatory effect - in low doses they slightly increase immunity, in high concentrations they suppress functions many times immune system, which determines the use of glucocorticosteroids in transplantology during tissue and organ transplantation - bone marrow, kidneys, radiation, chemotherapy malignant neoplasms, during the treatment of autoimmune diseases;
affect metabolism - slow down the excretion of sodium, water, chlorine from the body, increase the leaching of potassium and calcium from the bones, suppress its absorption. They increase glucose levels, impair sugar processing, disrupt protein and lipid metabolism, redistributing subcutaneous fatty tissue– increasing its volume on the face, neck, chest and decreasing it in the limbs. Promote muscle atrophy, the appearance of stretch marks on the skin, delayed scarring of wounds, hemorrhages, and the development of osteoporosis;
antiallergic effect – suppress clinical manifestations allergies;
pain relief – reduce severity pain, improve the functionality of joints;
antipyretic, anti-edematous effect - eliminate fever, reduce or completely remove swelling, incl. mucous membranes;
adaptogenic – increases the body’s resistance to harmful effects physical, chemical, biological factors;
facilitate the work of the heart and blood vessels - reduce capillary permeability, tone, strengthen the walls of blood vessels, normalize contractile function heart muscle;
affect the endocrine system - reduce the production of sex hormones, suppress the connection between various parts brain and adrenal glands, interacts with other hormones, reduces the sensitivity of tissues to them;
hemodynamic, hematological effect - greatly changes the blood picture, causes a deficiency of lymphocytes, leukocyte cells, stimulates the production of platelets and red blood cells.
A wide spectrum of pharmacological action makes glucocorticosteroids practically generic drugs. In addition to independent medicinal properties they have the ability to enhance the effect of other drugs. This allows them to be used in the treatment of severe, non-steroidal anti-inflammatory drug-resistant diseases of the spine and joints that require complex therapy. Thus, treatment with glucocorticosteroids is indicated for the following pathologies:
inflammation of individual joints, small and large, accompanied by severe swelling, severe pain, rapid accumulation in the tissues and joint cavity, released from blood vessels inflammatory fluid, which can lead to rapid destruction of articular cartilage;
defeat connective tissue joints, tendons and other organs caused by autoimmune or rheumatic diseases - systemic lupus erythematosus, scleroderma, Sjögren's syndrome, Still's syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis;
non-infectious joint changes - arthrosis deformans, rheumatoid arthritis;
inflammatory processes in the synovial tissue, articular capsule, V spinal cord and shells;
spinal injuries, postoperative period;
damage to the axial skeleton, peripheral joints in ankylosing spondylitis.
Beyond rheumatology glucocorticosteroid therapy prescribed in many other areas clinical medicine. Indications for use are:
respiratory failure - interstitial pneumonia, bronchial asthma, status asthmaticus, COPD;
exudative enteropathy, celiac disease, inflammatory diseases of the gastrointestinal tract - Crohn's disease, ulcerative colitis;
kidney dysfunction, viral, chronic hepatitis, liver cirrhosis, glomerular nephritis, adrenal insufficiency;
skin diseases - dermatitis, scaly lichen, eczema, diseases of the neurogenic-allergic type;
pathology nervous system, optic neuritis, non-infectious inflammation of the cornea, conjunctiva, iris, ciliary body eyeball, scleritis of the eyes, uveitis;
spicy and chronic inflammation ear, nasal mucosa, eczema of the outer ear;
hematological pathologies, thyrotoxicosis thyroid gland, transplant rejection, myocardial damage;
allergic reactions, oncological processes, traumatic shock.
The dosage and regimen depend on the route of administration. Sharing is not recommended daily dose for 3 doses, it is preferable to take GK in the morning or in the morning and evening hours. For each disease, a specific form of the drug is prescribed. There are several of them:
Glucocorticosteroid tablets are used for systemic diseases and chronic pathologies. This is the main method of application. Depending on the degree of activity of the disease, a one-time dose or a course of treatment is prescribed, lasting no more than a month. The daily dosage is determined based on the patient’s weight and is usually 1 mg/kg. The tablets are quickly and almost completely absorbed. Should be taken separately from food, because it slows down absorption.
Injectable forms of drugs are the most effective way administration differ in their maximum duration of action. Available in the form of ethers, solutions for intra-articular, intramuscular injections and for intravenous infusion. They do not begin to act immediately - the effect develops after a few hours, and for suspensions that are poorly soluble in water after 1-2 days, maximum 4-8. The effect lasts up to 1 month. Water-soluble glucocorticosteroids act quickly, but for a short time. Practiced in emergency situations, when states of shock, severe forms of allergies - administered intravenously or inside the muscle. Intra-articular injections are used most often, because... act locally without significantly affecting other systems. The injection is given once, then the body’s response to the hormone is determined within a week, and if the prognosis is favorable, the injection is repeated.
Inhalation drugs are prescribed for respiratory diseases. Hormones are delivered to the affected organ using a nebulizer, are not absorbed into the blood, and do not act systemically. The effect is slow - it occurs after 7 days, reaching a maximum after 6 weeks.
Topical – used for treatment skin allergies, dermatitis, subcutaneous inflammation. Apply to the skin directly in the affected area - local drugs, are available in the form of ointments, lotions, gels, and creams. Systemic absorption of the active substance with this method of administration is 5%. Lotions are convenient for applying to the scalp, ointments are greasy - they are chosen for dry skin, creams are quickly absorbed and are recommended for diaper rash. It should be taken into account that the more powerful glucocorticosteroids used in dermatology have less adverse reactions than drugs of weak potency.
To achieve more therapeutic effect in the case of severe, progressive inflammatory processes, acute relapses, injections into the joint are combined with a shortened course of tablets.
For speedy withdrawal painful symptoms During the period of exacerbation, pulse therapy is also used - rapid infusion of large doses of the drug over 0.5-1 hours. Systemic diseases often require long-term, multi-year therapy.
With a one-time dose, the only limitation is established - individual intolerance to drugs of this series. Long-term use is not allowed for everyone. If it is necessary to use these potent drugs, the following conditions should be excluded:
diabetes, severe obesity, neuroendocrine disorder;
infectious blood poisoning, clotting disorders, frequent nosebleeds;
tuberculosis, immunodeficiency, syphilis, purulent infections, mycoses;
progressive osteoporosis of bones, infectious arthritis, fractures, joint surgeries;
violation mental activity, hypertension, thromboembolism;
gastrointestinal diseases, severe renal failure, erosive and ulcerative lesions;
increased intraocular pressure, diseases of the cornea;
period of bearing a child, breastfeeding, for 8 weeks before and 2 weeks after vaccination.
Change hormonal balance leads to numerous undesirable consequences. They manifest themselves in varying degrees and forms, so the drug is prescribed only by a qualified doctor and in exceptional cases. Glucocorticosteroids can cause the following: side effects:
neuromuscular diseases, osteoporosis, fractures, bone necrosis;
thinning of the skin, baldness, delayed scarring, acne;
mental disorders, depression, insomnia;
hoarseness, vision problems, cataracts, displacement of the eyeball;
atherosclerosis, high blood pressure, heart failure;
adrenal insufficiency, malfunction endocrine system, metabolism, high level glucose;
digestive dysfunction, reproductive system, bleeding, thrush;
increased swelling, stomach pain, cough, dyspepsia.
From the group of short-acting drugs, the following are often prescribed:
ointment with glucocorticosteroids Hydrocortisone 1%, 10g – 28 rub., eye ointment 0.5%, 5g – 56, Russia; Laticort 0.1%, 15g – 147 rubles, Poland; Lokoid 0.1%, 30g – 290 rub., Italy;
suspension for injections Hydrocortisone-Richter, 5 ml bottle – 230 rubles, Hungary;
emulsion Lokoid Crelo 0.1%, 30g – 315 rub., Italy;
tablets Kortef 0.01, 100 pcs. – 415 rubles, Canada; Cortisone 0.025, 80 pcs. – 900, Russia;
lyophilized powder for IV, IM Solu-Cortef 0.1, 100 mg – 94 rubles, Belgium.
The most popular are representatives of the group of glucocorticosteroids with an effect of medium duration:
tablets Medrol 0.032, 20 pcs. – 660 rub., Italy; Metypred 0.004, 30 pcs. – 204, Finland; Prednisolone 0.05 100 pcs. – 70, Russia; Kenalog 0.004, 50 pcs. – 374, Slovenia; Polcortolon 0.004, 50 pcs. – 393, Poland;
lyophilisate for IV, IM Solu-Medrol 1.0, 15.6 ml – 473 rubles, Belgium;
solution for intravenous, intramuscular injections Prednisolone Bufus 0.03, 10 ampoules – 162 rubles, Russia; Medopred 0.03, 10 ampoules – 153, Cyprus; Prednisol 3%, 3 amp. – 33, India;
Maxidex eye drops 0.1%, 5 ml – 310, Belgium; Oftan-Dexamethasone 0.001, 5 ml – 220, Finland; Dexamethasone 0.1%, 10 ml – 120, Romania;
injection solution Dexamethasone 0.004, 10 amp. – 76, Russia; 25 amp. – 160, India; Dexamethasone-Vial 0.004, 25 amp. – 116, China.
Glucocorticosteroids – powerful tool therapy, patients who require their use are recommended to undergo treatment in a hospital setting. This is constant medical control, the ability to promptly take everything necessary tests(laboratory tests, ultrasound, ECG), observation of a specialist over the body’s reaction, and, if necessary, adjustment of the treatment regimen. It is important to consider the presence of withdrawal syndrome, which requires a gradual reduction in dosage in order to prevent Addisonian crisis. simultaneous use with other drugs. During treatment with glucocorticosteroids, certain safety precautions should be observed:
Take the minimum dose, do not exceed determined by the doctor daily dosage and frequency of administration.
To avoid addiction, avoid unnecessarily prolonged treatment with GCs.
Before intra-articular administration, it is necessary to remove the exudate accumulated in the joint cavity and prevent the drug from entering the joint cavity and muscle tissue.
Intra-articular and intravenous injections are performed by a specialist under particularly sterile conditions, observing the restriction - no more than 3-4 injections into one joint during the year.
Do not take it together with any other medicine without first consulting your doctor.
Following these simple rules will help cope with severe inflammatory process, chronic pathology, allergies, progressive joint disease without the risk of serious side effects. Self-medication and incorrectly selected dosage can result in various complications - hormonal imbalance, diabetes or osteoporosis.
Their use reduces pain, redness and swelling in the joints and surrounding tissues.
GCS is prescribed both orally and by injection.
Used for intra-articular injections special drugs, the action of which is quite long. GCS begin to act gradually within 24 hours, positive effect can persist for many days and even months.
As a rule, the question of the need to prescribe such injections arises in the following cases:
The procedure for injection into a joint is similar to injection into soft fabrics. Before the injection, a separate syringe is used to remove excess fluid from the joint. A doctor can then examine this fluid and send it to a laboratory for analysis.
Since GCS is administered directly into the inflamed area, a very small amount of the drug enters the bloodstream and has an effect on other organs and tissues of the body, especially compared to taking GCS orally. Due to this, the side effects of GCS during injections are minimal.
For quotation: Princely N.P. Glucocorticosteroids in the treatment of bronchial asthma // RMZh. 2002. No. 5. P. 245
Department of Pulmonology, Federal Institute of Internal Medicine, Russian State Medical University
IN Recent years have seen significant progress in treatment bronchial asthma (BA). Apparently, this is due to the definition of asthma as a chronic inflammatory disease of the respiratory tract, and as a result - with widespread use inhalation glucocorticosteroids (GCS) as basic anti-inflammatory drugs. However, despite the progress achieved, the level of control over the course of the disease cannot be considered satisfactory. For example, almost every third patient with asthma wakes up at least once a month at night due to symptoms of the disease. More than half of patients have limitations in physical activity, and more than a third are forced to miss school or be absent from work. More than 40% of patients are forced to seek emergency care due to exacerbation of the disease. The reasons for this situation are diverse, and not the least role in this is played by the doctor’s lack of awareness of the pathogenesis of asthma and, accordingly, the choice of incorrect treatment tactics.
Definition and classification of asthma Bronchial asthma - chronic disease respiratory tract, in which many cells take part: mast cells, eosinophils and T-lymphocytes. In predisposed individuals, this inflammation leads to repeated episodes of wheezing, shortness of breath, heaviness in the chest and cough, especially at night and/or early morning. These symptoms are accompanied by widespread but variable bronchial obstruction that is at least partially reversible, either spontaneously or with treatment. Inflammation also causes the airways to increase their response to various stimuli (hyperresponsiveness).
The key provisions of the definition should be considered the following:
1. BA - chronic persistent inflammatory disease respiratory tract, regardless of the severity of the disease.
2. The inflammatory process leads to bronchial hyperreactivity, obstruction and the appearance of respiratory symptoms.
3. Airway obstruction is at least partially reversible.
4. Atopy - genetic predisposition to the production of class E immunoglobulins (may not always be present).
Bronchial asthma can be classified based on etiology, severity and characteristics of the manifestation of bronchial obstruction.
However, currently bronchial asthma first of all, it should be classified according to the degree of severity, since this is what reflects the degree of severity inflammatory process V respiratory tract and determines the tactics of anti-inflammatory therapy.
Severity determined by the following indicators:
There are 5 degrees of severity of asthma: mild intermittent; mild persistent; moderate severity persistent; severe persistent; severe persistent steroid-dependent (Table 1).
BA intermittent: asthma symptoms less than once a week; short exacerbations (from several hours to several days). Night symptoms 2 times a month or less often; absence of symptoms and normal function lungs between exacerbations: peak expiratory flow (PEF) > 80% of predicted and PEF fluctuations less than 20%.Mild persistent asthma. Symptoms once a week or more often, but less than once a day. Exacerbations of the disease can interfere with activity and sleep. Nighttime symptoms occur more often than twice a month. PEF is more than 80% of the expected value; fluctuations in PSV 20-30%.
Moderate asthma. Daily symptoms. Exacerbations disrupt activity and sleep. Nighttime symptoms occur more than once a week. Daily use of short-acting b2-agonists. PSV 60-80% of due. PEF fluctuations are more than 30%.
BA severe course: persistent symptoms, frequent exacerbations, frequent nighttime symptoms, physical activity limited by asthma symptoms. PEF is less than 60% of the expected value; fluctuations of more than 30%.
It should be noted that determining the severity of asthma using these indicators is possible only before starting treatment. If the patient is already receiving necessary therapy, then its volume must also be taken into account. Thus, if a patient has mild persistent asthma based on the clinical picture, but at the same time he receives drug treatment, corresponding to severe persistent asthma, then this patient is diagnosed with severe asthma.
Severe steroid-dependent asthma: regardless of clinical picture patient receiving long-term treatment systemic corticosteroids should be considered to be suffering from severe asthma.
Inhaled corticosteroids Recommended stepwise approach to BA therapy depending on the severity of its course (Table 1). All drugs for the treatment of asthma are divided into two main groups: for long-term control of the inflammatory process and drugs for relief acute symptoms asthma. The basis of therapy for long-term control of the inflammatory process are inhaled glucocorticosteroids (ICS), which should be used from the second stage (mild persistent course) to the fifth (severe steroid-dependent course). Therefore, ICS are currently considered as first-line agents for the treatment of asthma. The higher the severity of asthma, the higher doses of ICS should be used. According to a number of studies, patients who began treatment with ICS no later than two years from the onset of the disease showed significant benefits in improving control over asthma symptoms compared with the group that began treatment with ICS after more than 5 years from the onset of the disease.
Mechanisms of action and pharmacokinetics
ICS are able to bind to specific receptors in the cytoplasm, activate them and form a complex with them, which then dimerizes and moves into the cell nucleus, where it binds to DNA and interacts with the transcription mechanisms of key enzymes, receptors and other complex proteins. This leads to the manifestation of pharmacological and therapeutic effects.
The anti-inflammatory effect of ICS is associated with their inhibitory effect on inflammatory cells and their mediators, including the production of cytokines, interference with the metabolism of arachidonic acid and the synthesis of leukotrienes and prostaglandins, and prevention of migration and activation of inflammatory cells. ICS increase the synthesis of anti-inflammatory proteins (lipocortin-1), increase apoptosis and reduce the number of eosinophils by inhibiting interleukin-5. Thus, ICS lead to the stabilization of cell membranes, reduce vascular permeability, improve the function of b-receptors both by synthesizing new ones and increasing their sensitivity, and stimulate epithelial cells.
ICS differ from systemic glucocorticosteroids in their pharmacological properties: lipophilicity, speed of inactivation, short period half-life from blood plasma. It is important to consider that ICS treatment is local (topical), which provides pronounced anti-inflammatory effects directly in the bronchial tree with minimal systemic manifestations. The amount of ICS delivered to the respiratory tract depends on the nominal dose of the drug, the type of inhaler, the presence or absence of propellant, and the inhalation technique. Up to 80% of patients experience difficulty using metered dose aerosols.
The most important characteristic for the manifestation of selectivity and retention time of the drug in tissues is lipophilicity. Due to their lipophilicity, ICS accumulate in the respiratory tract, slowing down their release from tissues and increasing their affinity for the glucocorticoid receptor. Highly lipophilic ICS are absorbed faster and better from the bronchial lumen and remain for a long time in the tissues of the respiratory tract. ICS differs from systemic drugs their topical (local) action. Therefore, it is useless to prescribe inhaled systemic corticosteroids (hydrocortisone, prednisolone and dexamethasone): these drugs, regardless of the method of administration, have only a systemic effect.
Numerous randomized placebo-controlled studies in patients with asthma have shown the effectiveness of all doses of ICS compared with placebo.
System bioavailability consists of oral and inhalation. From 20 to 40% of the inhaled dose of the drug enters the respiratory tract (this value varies significantly depending on the delivery vehicle and the patient’s inhalation technique). Pulmonary bioavailability depends on the percentage of drug reaching the lungs and the presence or absence of a carrier ( best performance have inhalers that do not contain freon) and from absorption of the drug in the respiratory tract. 60-80% of the inhalation dose settles in the oropharynx and is swallowed, then undergoing complete or partial metabolism in gastrointestinal tract and liver. Oral availability depends on absorption in the gastrointestinal tract and on the severity of the “first pass” effect through the liver, due to which inactive metabolites enter the systemic circulation (with the exception of beclomethasone 17-monopropionate, the active metabolite of beclomethasone dipropionate). Doses of ICS up to 1000 mcg/day (for fluticasone up to 500 mcg/day) have little systemic effect.
All ICS have fast system clearance, comparable to the magnitude of hepatic blood flow. This is one of the factors that reduces systemic action ICS.
Characteristics of the most commonly used drugs
ICS include beclomethasone dipropionate, budesonide, fluticasone propionate, flunisolide, triamsinolone acetonide, mometasone furoate. They are available in the form of metered-dose aerosols, powder inhalers, and also as solutions for inhalation through a nebulizer (budesonide).
Beclomethasone dipropionate . It has been used in clinical practice for more than 20 years and remains one of the most effective and frequently used drugs. The use of the drug in pregnant women is permitted. Available as a metered-dose aerosol inhaler (Bekotide 50 mcg, Bekloforte 250 mcg, Aldecin 50 mcg, Beklocort 50 and 250 mcg, Beclomet 50 and 250 mcg/dose), a breath-activated metered-dose inhaler (Beclazon Easy Breathing 100 and 250 mcg/dose), powder inhaler (Bekodisk 100 and 250 mcg/dose, Diskhaler inhaler; Easyhaler multi-dose inhaler, Beklomet 200 mcg/dose). For Bekotide and Bekloforte inhalers, special spacers are produced - “Volyumatic” (large-volume valve spacer for adults) and “Babyhaler” (small-volume 2-valve spacer with a silicone face mask for young children).
Budesonide . A modern, highly active drug. Used as a metered dose aerosol inhaler (Budesonide-mite 50 mcg/dose; Budesonide-forte 200 mcg/dose), powder inhaler (Pulmicort Turbuhaler 200 mcg/dose; Benacort Cyclohaler 200 mcg/dose) and nebulizer suspension (Pulmicort 0.5 and 0.25 mg/dose). Pulmicort Turbuhaler is the only one dosage form ICS that does not contain a carrier. A spacer is produced for the metered dose inhalers Budesonide Mite and Budesonide Forte. Budesonide is integral part combination drug Symbicort.
Budesonide has the most favorable therapeutic index, which is associated with its high affinity for glucocorticoid receptors, and accelerated metabolism after systemic absorption in the lungs and intestines. Budesonide is the only ICS for which single-dose use has been proven. The factor that ensures the effectiveness of budesonide once a day is the retention of budesonide in the respiratory tract in the form of an intracellular depot due to reversible esterification (formation of esters fatty acids). When the concentration of free budesonide in the cell decreases, intracellular lipases are activated, and budesonide released from the esters again binds to the receptor. This mechanism is not typical for other corticosteroids and makes it possible to prolong the anti-inflammatory effect. A number of studies have shown that intracellular storage may be more important in terms of drug activity than receptor affinity.
Recent studies on the drug Pulmicort Turbuhaler have proven that it does not affect the final growth of long-term use in children, on bone mineralization, does not cause angiopathy and cataracts. Pulmicort is also recommended for use in pregnant women: it has been found that its use does not cause an increase in the number of fetal abnormalities. Pulmicort Turbuhaler is the first and only ICS approved by the FDA. medicines in the USA) assigned category “B” in the rating of drugs prescribed during pregnancy. This category includes medications that are safe to take during pregnancy. The remaining ICS belong to category “C” (taking them during pregnancy is not recommended).
Fluticasone propionate . The most highly active drug to date. Has minimal oral bioavailability (<1%). Эквивалентные терапевтические дозы флютиказона почти в два раза меньше, чем у беклометазона и будесонида в аэрозольном ингаляторе и сопоставимы с дозами будесонида в Турбухалере (табл. 2). По данным ряда исследований, флютиказона пропионат больше угнетает надпочечники, но в эквивалентных дозах имеет сходную с другими ИГКС активность в отношении надпочечников.
Presented in the form of a metered-dose aerosol inhaler (Flixotide 50, 125 and 250 mcg/dose) and a powder inhaler (Flixotide Diskhaler - rotadiscs 50, 100, 250 and 500 mcg/dose; Flixotide Multidisc 250 mcg/dose). Special spacers are produced for aerosol inhalers - “Volyumatic” (large-volume valve spacer for adults) and “Babyhaler” (small-volume 2-valve spacer with a silicone face mask for young children). Fluticasone is part of the combination drug Seretide Multidisk.
Flunisolide . A drug with low glucocorticoid activity. It is represented on the domestic market by the Ingacort trademark (metered-dose inhaler 250 mcg/dose, with spacer). Despite high therapeutic doses, it has virtually no systemic effects due to the fact that already during the first passage through the liver it is 95% converted into an inactive substance. Currently used quite rarely in clinical practice.
Triamsinolone acetonide . A drug with low hormonal activity. Metered dose inhaler 100 mcg/dose. The Azmacort brand is not represented on the Russian market.
Mometasone furoate . A drug with high glucocorticoid activity. It is presented on the Russian market only in the form of Nazonex nasal spray.
Clinical trials comparing the effectiveness of ICS in improving symptoms and respiratory function show that:
Undesirable effects
Modern ICS are drugs with a high therapeutic index and have a high safety profile even with long-term use. Systemic and local undesirable effects are distinguished. Systemic adverse effects may only become clinically significant when high doses are used. They depend on the drug's affinity for the receptor, lipophilicity, volume of distribution, half-life, bioavailability and other factors. The risk of systemic adverse effects for all currently available ICS correlates with the desired effects in the respiratory tract. The use of ICS in moderate therapeutic doses reduces the risk of systemic effects.
The main side effects of ICS are related to their route of administration and include oral candidiasis, hoarseness, mucosal irritation and cough. To avoid these phenomena, proper inhalation technique and individual selection of ICS are necessary.
Combination drugs
Despite the fact that ICS are the basis of BA therapy, they do not always allow complete control of the inflammatory process in the bronchial tree and, accordingly, the manifestations of BA. In this regard, there was a need to prescribe short-acting b 2 -agonists on an as-needed or regular basis. Thus, there is an urgent need for a new class of drugs, free from the disadvantages that are inherent in short-acting b 2 -agonists, and with a proven long-term protective and anti-inflammatory effect on the respiratory tract.
Long-acting b2-agonists have been created and are currently widely used, which are represented on the pharmaceutical market by two drugs: formoterol fumarate and salmeterol xinafoate. Modern guidelines for the treatment of asthma recommend the addition of long-acting b2-agonists in case of insufficient control of asthma with monotherapy with inhaled corticosteroids (starting from the second stage). A number of studies have shown that the combination of inhaled corticosteroids with a long-acting b 2 -agonist is more effective than doubling the dose of inhaled corticosteroids, and leads to a more significant improvement in lung function and better control of asthma symptoms. A reduction in the number of exacerbations and a significant improvement in quality of life in patients receiving combination therapy have also been shown. Thus, the emergence of combination drugs containing inhaled corticosteroids and a long-acting b 2 agonist is a reflection of the evolution of views on asthma therapy.
The main advantage of combination therapy is the increased effectiveness of treatment when using lower doses of ICS. In addition, combining two drugs in one inhaler makes it easier for the patient to follow doctor's orders and potentially improves compliance.
Seretide Multidisc . The constituent components are salmeterol xinafoate and fluticasone propionate. Provides a high level of control over asthma symptoms. Used only as basic therapy, can be prescribed starting from the second stage. The drug is presented in various dosages: 50/100, 50/250, 50/500 mcg salmeterol/fluticasone in 1 dose. Multidisc is a low-resistance inhalation device, which allows it to be used in patients with reduced inspiratory flow.
Symbicort Turbuhaler . The constituent components are budesonide and formoterol fumarate. It is presented on the Russian market in a dosage of 160/4.5 mcg in 1 dose (doses of the drugs are indicated as the output dose). An important feature of Symbicort is the ability to use it both for basic therapy (to control the inflammatory process) and for immediate relief of asthma symptoms. This is primarily due to the properties of formoterol (quick onset of action) and the ability of budesonide to actively act within 24 hours on the mucous membrane of the bronchial tree.
Symbicort allows individual flexible dosing (1-4 inhalation doses per day). Symbicort can be used starting from stage 2, but it is especially indicated for patients with unstable asthma, which is characterized by sudden severe attacks of difficulty breathing.
System GCS Systemic corticosteroids are used mainly to relieve exacerbation of asthma. Oral corticosteroids are the most effective. Intravenous corticosteroids are prescribed for exacerbation of asthma, if intravenous access is more desirable, or for impaired absorption from the gastrointestinal tract, using high doses (up to 1 g of prednisolone, methylprednisolone and hydrocortisone). Corticosteroids lead to clinically significant improvement 4 hours after their administration.
During exacerbation of BA, a short course of oral corticosteroids (7-14 days) is indicated, starting with high doses (30-60 mg of prednisolone). Recent publications recommend the following short course of systemic corticosteroids for non-life-threatening exacerbations: 6 tablets of prednisolone in the morning (30 mg) for 10 days, followed by discontinuation of use. Although treatment regimens for systemic corticosteroids can be different, the fundamental principles are their administration in high doses to quickly achieve an effect and subsequent rapid withdrawal. It should be remembered that as soon as the patient is ready to take inhaled corticosteroids, they should be prescribed to him in a stepwise manner.
Systemic glucocorticoids should be prescribed if:
It is undesirable to use long-acting forms of systemic steroids to relieve exacerbations and provide maintenance therapy for asthma.
For long-term therapy in severe asthma, systemic corticosteroids (methylprednisolone, prednisolone, triamsinolone, betamethasone) should be prescribed in the lowest effective dose. With long-term treatment, an alternating prescription schedule and administration in the first half of the day (to reduce the effect on the circadian rhythms of cortisol secretion) cause the least amount of side effects. It should be emphasized that in all cases of prescribing systemic steroids, the patient should be prescribed high doses of inhaled corticosteroids. Among oral corticosteroids, preference is given to those that have minimal mineralocorticoid activity, a relatively short half-life and limited effect on striated muscles (prednisolone, methylprednisolone).
Steroid addiction
Patients who are forced to constantly take systemic corticosteroids should pay special attention. There are several options for the formation of steroid dependence in patients with asthma and other diseases accompanied by bronchial obstruction:
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2. Bronchial asthma. Guide for doctors in Russia (formulary system). “Pulmonology”, supplement-99.
3. Leading directions in the diagnosis and treatment of bronchial asthma. Highlights of the EPR-2 Expert Group Report. National Institute of Health. National Heart, Lung and Blood Institute. NIH publication-97. Translation ed. Prof. Tsoi A.N., M, Grant, 1998.
4. Ilyina N.I. Inhaled glucocorticoids. Asthma.ru. Allergic and respiratory diseases. 0*2001 (pilot episode).
5. Ogorodova L.M. Systems for inhalation delivery of drugs into the respiratory tract. Pulmonology, 1999; No. 1, 84-87
6. Formulary system: treatment of bronchial asthma. Asthma. ru ,0. 2001, 6-9
7. Chuchalin A.G. Bronchial asthma. Moscow, 1997.
8. Tsoi A.N. Inhaled glucocorticoids: effectiveness and safety. RMJ 2001; 9: 182-185
9. Tsoi A.N. Comparative pharmacokinetics of inhaled glucocorticoids. Allergology 1999; 3:25-33
10. Agertoft L., Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000; 343:1064-9
11. Ankerst J., Persson G., Weibull E. A high dose of budesonide/formoterol in a single inhaler was well tolerated by asthmatic patients. Eur Respir J 2000; 16 (Suppl 31): 33s+poster
12. Barnes P.J. Inhaled glucocorticoids for asthma. N.Engl. Med. 1995; 332:868-75
13. Beclomethasone Dipropionate and Budesonide. The clinical evidence Reviewed. Respir Med 1998; 92 (Suppl B)
14. The British Guidelines on Asthma Management. Thorax, 1997; 52 (Suppl. 1) 1-20.
15. Burney PGJ. Current questions in the epidemiology of asthma, in Holgate ST, et al, Asthma: Physiology. Immunology, and Treatment. London, Academic Press, 1993, pp. 3-25.
16. Crisholm S et al. Once-daily budesonide in mild asthma. Respir Med 1998; 421-5
17. Kips JC, O/Connor BJ, Inman MD, Svensson K, Pauwels RA, O/Byrne PM. A long-term study of the antiinflammatory effect of low-dose budesonide plus formoterol versus high-dose budesonide in asthma. Am Respir Crit Care Med 2000; 161:996-1001
18. McFadden ER, Casale TB, Edwards TB et al. Administration of budesonide once daily by means of Turbuhaler to subjects with stable asthma. J Allergy Clin Immunol 1999; 104:46-52
19. Miller-Larsson A., Mattsson H., Hjertberg E., Dahlback M., Tunek A., Brattsand R. Reversible fatty acid conjugation of budesonide: novel mechanism for prolonged retention of topically applied steroid in airway tissue. Drug Metab Dispos 1998; 26: 623-30
20. Miller-Larsson A. et al. Prolonged airway activity and improved selectivity of budesonide possibly due to esterification. Am J Respir Crit Care Med 2000;162:1455-1461
21. Pauwels RA et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997; 337:1405-11
22. Pedersen S, O/Byrne P. A comparison of the efficacy and safety of inhaled corticosteroids in asthma. Allergy 1997; 52 (Suppl 39): 1-34.
23. Woolcock A. et al. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996, 153, 1481-8.
In the treatment of a number of diseases of the musculoskeletal system, especially those of an inflammatory nature, medications such as glucocorticosteroids have found quite widespread use. Before you understand the main therapeutic effects, indications and contraindications, you need to know what glucocorticosteroids (GCS) are.
Glucocorticosteroids are medications that belong to the group of steroid hormones and have anti-inflammatory, antiallergic, antishock, immunosuppressive and other properties.
Today, there are several classifications of glucocorticosteroids according to various parameters. The most clinically significant classification is considered to be one that divides drugs according to their duration of action. According to it, the following medicinal groups are distinguished:
GCS is the abbreviated name for glucocorticosteroid drugs, which is quite often used in medicine.
In the treatment of diseases of the joints and spine, the main indication for the use of glucocorticosteroids is considered to be a severe inflammatory process, which is particularly intense and cannot be treated with non-steroidal anti-inflammatory drugs. For what joint pathologies can it be used:
When prescribing GCS, the doctor tries to achieve the maximum therapeutic effect using the minimum dosage of the drug. The glucocorticosteroid treatment regimen depends more on the severity of the disease, the patient's condition and his response to therapy than on age and weight.
Several recent scientific studies have shown the high effectiveness of the use of glucocorticosteroids in the treatment of severe forms of joint inflammation. A rapid clinical effect can also be achieved with the simultaneous use of GCS in low doses and non-steroidal anti-inflammatory drugs. It has been established that the majority of patients with disabilities due to polyarthritis become much easier in functional terms after just a few days of GCS therapy. What does a doctor count on when prescribing glucocorticosteroids:
Clinical experience has shown that many patients suffering from rheumatoid arthritis often become functionally dependent on glucocorticosteroid therapy and are forced to switch to long-term courses of taking them, which undoubtedly leads to the development of side effects.
There are several possible routes of administration of GCS drugs. As a rule, when treating inflammatory pathology of the musculoskeletal system, glucocorticosteroids are injected into the joint. By directly acting on the source of inflammation, the maximum therapeutic effect is achieved.
It should be noted that quite often fluid (exudate) can accumulate in the cavity of large joints. In such cases, it is first necessary to remove this fluid, and only then carry out intra-articular administration of the drug. Sometimes, in order to achieve a better effect, they combine the administration of GCS inside the joint with glucocorticosteroid therapy in tablets. This type of treatment is used for severe forms of the inflammatory process with a pronounced tendency to progress.
Intra-articular injections of medications are performed only by a medical specialist under sterile conditions (a clean dressing room).
GCS preparations are also quite often prescribed orally in the form of tablets or administered parenterally (into a vein or muscle).
GCS drugs, like many other drugs, may not be prescribed to all patients. Depending on the route of administration of the drug, certain contraindications must be taken into account. For example, intravenous, intramuscular or oral glucocorticosteroids cannot be used for the following diseases or pathological conditions:
In addition, GCS is not administered inside the affected joint if there is increased bleeding, severe osteoporosis, or ineffectiveness from previous injections. Also, this route of administration for glucocorticosteroids is contraindicated for intra-articular fractures, periarthritis of an infectious nature, and before joint surgery (arthroplasty).
GCS preparations are never used for prophylactic purposes or for the treatment of joint inflammation, the cause of which has not been established.
According to clinical observation, despite the fact that most side effects from long-term use of GCS for inflammatory diseases of the joints and spine are considered quite severe, some of them appear an order of magnitude less frequently than during therapy with other anti-inflammatory drugs. Many experts conventionally divide the side effects of long-term systemic use of glucocorticosteroids into two groups:
At the same time, it has been established that taking non-steroidal anti-inflammatory drugs more often provokes the development of severe erosive and ulcerative pathology of the gastrointestinal tract than the use of drugs from the group of corticosteroids. Treatment with glucocorticoids is justifiably associated with an increased risk of infectious complications, but this is typical mainly for patients who receive high doses of drugs. The criteria for inadequate glucocorticosteroid therapy should be mentioned:
With intra-articular injection of GCS, one of the most dangerous, but quite rare complications is infection entering the joint cavity during the injection process. In addition, the immunosuppressive property of glucocorticoids contributes to the development of a purulent inflammatory process. In rare cases, “post-injection synovitis” may occur, when after an injection there is an increase in the inflammatory process in the synovium of the joint, which can last from several hours to 2-3 days.
It is extremely undesirable to introduce the drug into muscle tissue, since the development of atrophic or necrotic processes is possible.
One of the most unfavorable complications of long-term glucocorticosteroid treatment is. However, according to some experts, the high inflammatory activity of rheumatoid arthritis and decreased physical activity are considered no less important factors in the development of osteoporosis than long-term treatment with corticosteroids.
To reduce the risk of developing this complication, many doctors recommend significantly adjusting your lifestyle, especially for those patients who have been receiving glucocorticosteroids for a long time. What exactly needs to be done:
Targeted clinical studies on the safety of glucocorticosteroids during pregnancy have not been conducted. However, doctors can prescribe this drug to a pregnant woman, but only if the expected effect of treatment significantly exceeds the expected risk to the child. In addition, nursing mothers are strongly recommended to stop breastfeeding during glucocorticosteroid therapy.
If an overdose of GCS drugs occurs, a significant increase in blood pressure, swelling of the lower extremities, and increased side effects of the drug itself may occur. If an acute overdose is recorded, it is necessary to perform gastric lavage as quickly as possible or induce vomiting. If your condition worsens, you should immediately contact a specialized medical facility. A specific antidote has not yet been developed.
Repeated scientific studies have proven that glucocorticosteroids interact with many medications, provoking the development of various adverse reactions. To avoid unwanted effects, it is recommended to consult your doctor before combining the use of GCS with any other medicine.
To purchase any drug from the glucocorticosteroid group, you must have a prescription. It would not be superfluous to remind once again that all corticosteroids have very specific features of use and a very wide range of adverse reactions, so self-medication is strictly not recommended. For information purposes only, we present prices for some medications:
If your health worsens or any symptoms develop during or after glucocorticosteroid therapy, contact your doctor immediately.
