Undesirable effects of GCS. Glucocorticoid drugs

You've probably heard of steroid hormones at least once. Our body continuously produces them to regulate vital processes. In this article, we will look at glucocorticoids, steroid hormones that are produced in the adrenal cortex. Although most of all we are interested in their synthetic analogs - GCS. What is it in medicine? What are they used for and what harm do they do? Let's get a look.

General information about the GCS. What is it in medicine?

Our body synthesizes steroid hormones such as glucocorticoids. They are produced by the adrenal cortex and their use is mainly associated with the treatment of adrenal insufficiency. Nowadays, not only natural glucocorticoids are used, but also their synthetic analogs - GCS. What is it in medicine? For mankind, these analogues mean a lot, as they have anti-inflammatory, immunosuppressive, anti-shock, anti-allergic effects on the body.

Glucocorticoids began to be used as medicines (hereinafter referred to as drugs) back in the 40s of the twentieth century. By the end of the 30s of the twentieth century, scientists discovered steroid hormonal compounds in the human adrenal cortex, and already in 1937 the mineralocorticoid deoxycorticosterone was isolated. In the early 1940s, the glucocorticoids hydrocortisone and cortisone were also withdrawn. The pharmacological effects of cortisone and hydrocortisone were so diverse that it was decided to use them as drugs. After a while, scientists carried out their synthesis.

The most active glucocorticoid in the human body is cortisol (analogous to hydrocortisone, the price of which is 100-150 rubles), and it is considered the main one. You can also distinguish less active: corticosterone, cortisone, 11-deoxycortisol, 11-dehydrocorticosterone.

Of all natural glucocorticoids, only hydrocortisone and cortisone have found use as drugs. However, the latter causes side effects more often than any other hormone, which is why its use in medicine is currently limited. To date, only hydrocortisone or its esters (hydrocortisone hemisuccinate and hydrocortisone acetate) are used from glucocorticoids.

As for glucocorticosteroids (synthetic glucocorticoids), a number of such agents have been synthesized nowadays, among which fluorinated (flumethasone, triamcinolone, betamethasone, dexamethasone, etc.) and non-fluorinated (methylprednisolone, prednisolone, prednisone) glucocorticoids can be distinguished.

Such agents are more active than their natural counterparts and require smaller doses for treatment.

Mechanism of action of GCS

The effect of glucocorticosteroids at the molecular level is not fully understood. Scientists believe that these drugs act on cells at the level of gene transcription regulation.

When glucocorticosteroids penetrate into the cell (through the membrane), they bind to receptors and activate the "glucocorticoid + receptor" complex, after which it enters the cell nucleus and interacts with DNA regions located in the promoter fragment of the steroid-responding gene (they are also called glucocorticoid -responding elements). The "glucocorticoid + receptor" complex is capable of regulating (suppressing or, conversely, activating) the transcription process of some genes. This is what leads to the suppression or stimulation of mRNA formation, as well as to a change in the synthesis of various regulatory enzymes and proteins that mediate cellular effects.

Various studies show that the glucocorticoid + receptor complex interacts with different transcription factors, such as nuclear factor kappa B (NF-kB) or activator transcription protein (AP-1), which regulate genes involved in the immune response and inflammation (adhesion molecules, genes for cytokines, proteinases, etc.).

The main effects of GCS

The effects of glucocorticosteroids on the human body are numerous. These hormones have anti-toxic, anti-shock, immunodepressive, anti-allergic, desensitizing and anti-inflammatory effects. Let's take a closer look at how the GCS work.

• Anti-inflammatory action of GCS. It is caused by the suppression of the activity of phospholipase A 2. When this enzyme is inhibited in the human body, the liberation (release) of arachidonic acid is suppressed and the formation of some inflammatory mediators (such as prostaglandins, leukotrienes, troboxan, etc.) is inhibited. Moreover, taking glucocorticosteroids leads to a decrease in fluid exudation, vasoconstriction (narrowing) of capillaries, and an improvement in microcirculation in the focus of inflammation.
• Antiallergic action of GCS. It occurs as a result of a decrease in the secretion and synthesis of allergy mediators, a decrease in circulating basophils, inhibition of the release of histamine from basophils and sensitized mast cells, a decrease in the number of B- and T-lymphocytes, a decrease in the sensitivity of cells to allergy mediators, a change in the body's immune response, and inhibition of antibody production.
• Immunosuppressive activity of GCS. What is it in medicine? This means that drugs inhibit immunogenesis, suppress the production of antibodies. Glucocorticosteroids inhibit the migration of bone marrow stem cells, inhibit the activity of B- and T-lymphocytes, and inhibit the release of cytokines from macrophages and leukocytes.
• Antitoxic and antishock action of GCS. This effect from hormones is due to an increase in blood pressure in humans, as well as the activation of liver enzymes that are involved in the metabolism of xeno- and endobiotics.
• Mineralocorticoid activity. Glucocorticosteroids have the ability to retain sodium and water in the human body, stimulate the excretion of potassium. In this, synthetic substitutes are not as good as natural hormones, but they still have such an effect on the body.

Pharmacokinetics

If, during the use of GCS, the patient suffers an infectious disease (chickenpox, measles, etc.), it can be very difficult.

In the treatment of corticosteroids in patients with autoimmune or inflammatory diseases (rheumatoid arthritis, bowel disease, systemic lupus erythematosus, etc.), there may be cases of steroid resistance.

Patients receiving oral glucocorticosteroids for a long time should periodically take a fecal occult blood test and undergo fibroesophagogastroduodenoscopy, since steroid ulcers during GCS treatment may not bother.

Osteoporosis develops in 30-50% of patients treated with glucocorticosteroids for a long time. As a rule, it affects the feet, hands, pelvic bones, ribs, spine.

Interaction with other drugs

All glucocorticosteroids (classification does not matter here) upon contact with other drugs give a certain effect, and this effect is not always positive for our body. Here's what you need to know before using glucocorticosteroids with other drugs:

1. GCS and antacids - the absorption of glucocorticosteroids decreases.
2. GCS and barbiturates, diphenin, hexamidine, diphenhydramine, carbamazepine, rifampicin - the biotransformation of glucocorticosteroids in the liver increases.
3. GCS and isoniazid, erythromycin - the biotransformation of glucocorticosteroids in the liver decreases.
4. GCS and salicylates, butadione, barbiturates, digitoxin, penicillin, chloramphenicol - all of these drugs have increased elimination.
5. GCS and isoniazid are disorders of the human psyche.
6. GCS and reserpine - the appearance of a depressive state.
7. GCS and tricyclic antidepressants - intraocular pressure increases.
8. GCS and adrenergic agonists - the effect of these drugs is enhanced.
9. GCS and theophylline - the anti-inflammatory effect of glucocorticosteroids increases, cardiotoxic effects develop.
10. GCS and diuretics, amphotericin, mineralocorticoids - the risk of hypokalemia increases.
11. GCS and fibrinolytics, butadine, ibuprofen - hemorrhagic complications may follow.
12. GCS and indomethacin, salicylates - this combination can lead to ulcerative lesions of the digestive tract.
13. GCS and paracetamol - the toxicity of this drug increases.
14. GCS and azathioprine - the risk of cataracts and myopathies increases.
15. GCS and mercaptopurine - the combination can lead to an increase in the concentration of uric acid in the blood.
16. GCS and hingamin - the undesirable effects of this drug are enhanced (corneal opacity, myopathy, dermatitis).
17. GCS and methandrostenolone - the unwanted effects of glucocorticosteroids are enhanced.
18. GCS and iron preparations, androgens - an increase in the synthesis of erythropoietin, and against this background, an increase in erythropoiesis.
19. GCS and sugar-reducing drugs - an almost complete decrease in their effectiveness.

Conclusion

Glucocorticosteroids are drugs that modern medicine is unlikely to do without. They are used both for the treatment of very severe stages of diseases, and simply for enhancing the action of any drug. However, like all drugs, glucocorticosteroids also have side effects and contraindications. Do not forget about this. Above, we have listed all the cases when glucocorticosteroids should not be used, and also provided a list of the interaction of GCS with other drugs. Also here was described in detail the mechanism of action of GCS and all their effects. Now everything you need to know about GCS is in one place - this article. However, in no case start treatment only after reading the general information about GCS. These drugs, of course, can be purchased without a doctor's prescription, but why do you need it? Before using any medicines, you must first consult a specialist. Be healthy and do not self-medicate!

Side effects of the glucocorticosteroid therapy system

E.O. Borisov

Glucocorticosteroids (GCS) have a complex and multifaceted effect on body functions. They interfere with carbohydrate, protein, fat, water and electrolyte metabolism, play an important role in the regulation of the cardiovascular system, kidneys, skeletal muscles, nervous system and other organs and tissues. Therefore, it is not surprising that systemic therapy with corticosteroids in pharmacological doses causes a variety of undesirable side effects (PE) from many organs and systems, which, on average, develop in 50% of patients.

Many side effects, as well as therapeutic ones, are dose-dependent and develop in the range of low and medium doses. PE GCS-therapy can be divided into 2 groups: developing in the course of treatment (manifestations of exogenous hypercorticism) and resulting from the rapid withdrawal of drugs after prolonged therapy (withdrawal syndrome).

The first group includes such manifestations of exogenous hypercorticism as fluid retention and electrolyte disturbances, arterial hypertension, hyperglycemia and glucosuria, and increased susceptibility to infections (including tuberculosis). peptic ulcers, osteoporosis, myopathy, mental disorders, posterior subcapsular cataract, glaucoma, growth retardation in children, cushingoid habitus (obesity with a characteristic redistribution of fat

Elena Olegovna Borisova - Cand.

honey. Sci., Associate Professor, Department of Clinical Pharmacology, Russian State Medical University.

tissues, striae, ecchymosis, acne and hirsutism).

Symptoms of exogenous hypercorticism in their spectrum differ little from the endogenous Cushing's syndrome - Cushing's disease (pituitary adenoma producing adreno-corticotropic hormone - ACTH). However, with endogenous Cushing's syndrome, there are practically no benign increases in intracranial pressure, glaucoma, posterior subcapsular cataract, pancreatitis, and aseptic necrosis of bones, which are characteristic of long-term intake of large doses of corticosteroids. At the same time, with Cushing's disease, arterial hypertension is more often observed.

body weight, mental disorders, edema and impaired wound healing are equally characteristic for both forms of the syndrome. These differences are associated with the fact that in Cushing's disease, an increase in ACTH synthesis occurs, and in iatrogenic hypercorticism, the synthesis of this hormone is suppressed (the secretion of androgens and mineralocorticoids does not increase).

At the beginning of treatment with corticosteroids, such PEs as sleep disturbances, emotional lability, increased appetite and body weight often develop. With long-term administration of large doses, many patients develop skin-trophic changes: dryness and thinning of the skin, striae, acne, increased capillary pattern on the palms. Frequent reaction

Typical for the initial stages of treatment; essentially inevitable:

Insomnia;

Emotional lability;

Increased appetite and / or weight gain.

Typical in patients with risk factors or toxic effects of other drugs:

Arterial hypertension;

Hyperglycemia (up to the development of diabetes mellitus);

Ulceration in the stomach

and the duodenum;

Expected when using high doses for a long time:

"Cushingoid" appearance;

Suppression of the hypothalamic-pituitary-adrenal axis;

Propensity to infectious diseases;

Osteonecrosis;

Myopathy;

Poor wound healing.

Late and progressively developing (probably due to cumulative dose):

Osteoporosis;

Cataract;

Atherosclerosis;

Growth retardation in children;

Fatty hepatosis.

Rare and unpredictable:

Benign intracranial hypertension (pseudotumor cerebri);

Glaucoma;

Epidural lipomatosis;

Pancreatitis

Time and conditions for the development of PE in the treatment of GCS.

gaping, acne formation, menstrual irregularities, hirsutism and

Side effects of systemic therapy with GCS develop in half of the patients.

virilization in women, impotence in men, striae and purpura. Magnification

leukocytosis is a treatment for corticosteroids. Hypokalemia may occur. These changes do not pose a threat to health, but they are usually difficult to avoid.

The likelihood of PE hormone therapy is related to many factors. They are more often caused by long-acting corticosteroids (triamcinolone, betamethasone and dexamethasone) than drugs with a shorter half-life (prednisolone, methylprednisolone, hydrocortisone). Most of PE is dose-dependent, therefore, the prescription of even short-acting drugs in large doses significantly increases the frequency of their development. The duration of therapy along with the dose is of decisive importance in the development of PE. Long-term GCS therapy, even in small doses, can lead to the development of PE. The risk of PE associated with long-term administration or the use of large doses of GCS can be reduced by rational use of doses, sparing prescription regimens and careful monitoring of expected PE. Many PEs depend not only on the dose and duration of treatment, but also on the individual characteristics of the patient, his genetic and constitutional predisposition. These PEs often develop in patients who already have the corresponding diseases or are prone to their development. Some PEs are quite rare, but their development can be difficult to predict (figure).

Metabolic disorders

Hyperglycemia is associated with a decrease in tissue sensitivity to insulin and the counterinsular action of GCS. Although GCS treatment can complicate glycemic control in patients with existing diabetes mellitus and provoke hyperglycemia in predisposed patients, the appearance of glucosuria does not prevent the continuation of GCS intake, just as the presence of diabetes is not a contraindication for starting GCS therapy. When

glucosuria is usually limited to diet, and oral antidiabetic drugs or insulin are prescribed only when necessary. Most often, steroid diabetes develops with the use of dexamethasone and betamethasone.

The effect of GCS on fat metabolism is manifested by a sharp redistribution of fat from the limbs to the trunk and face. It is believed that the adipocytes of the extremities and trunk differ in their sensitivity to insulin and lipolytic stimuli of other endogenous substances. Trunk adipocytes predominantly respond to increased insulin levels in response to hyperglycemia induced by GCS. Extremity adipocytes are less sensitive to insulin and, in the presence of GCS, respond mainly to lipolytic stimuli of other hormones. As a result of the deposition of fat on the back of the neck, supraclavicular areas and face and loss of adipose tissue on the limbs, a characteristic cushingoid habitus develops.

Disorders of water-electrolyte metabolism are manifested by hypokalemia, hypocalcemia, sodium and water retention. Fluid retention and hypochloremic alkalosis are rarely detected in patients receiving synthetic corticosteroids, and even less often when taking corticosteroids with low mineralocorticoid activity. The risk of hypokalemia increases with diuretics.

Arterial hypertension

An increase in blood pressure can be observed in patients taking GCS for a long time or in high doses. The mechanism of the hypertensive action of GCS has not been studied enough. It is probably due to the ability of GCS to increase the expression of adrenergic receptors of the vascular wall. Threatening Gu-

pertension is possible during pulse therapy. For its treatment, you can use calcium antagonists, potassium-sparing diuretics, angiotensin II receptor antagonists.

Ulcerogenic effect

Stomach or duodenal ulcers are uncommon but severe PE. It is believed (although there are no unambiguous data in the literature) that GCS therapy increases the risk of developing ulcers by almost 2 times, more often they are caused by prednisolone. However, in most cases this happens with the combined use of non-steroidal anti-inflammatory drugs. The formation of ulcers can be manifested by pain in the epigastric region and dyspepsia, but often occurs with little or no symptoms, manifested by bleeding or perforation. The mechanism of the ulcerogenic action of GCS is to increase the secretion of hydrochloric acid, reduce the synthesis of mucus and inhibit the regeneration of the epithelium.

Patients receiving systemic corticosteroids must be examined for the exclusion of steroid ulcers (fibrogastroscopy, gastric fluoroscopy). Prevention of ulceration in patients with a history of ulcers or predisposed to this disease consists in the appointment of antisecretory agents.

Myopathy

Occasionally, in patients taking high doses of corticosteroids, myopathy is diagnosed, characterized by weakness and atrophy of the skeletal muscles of the shoulder girdle, legs and pelvic muscles. The mechanism of its development is associated with the negative effect of GCS on protein and mineral metabolism. Myopathy does not belong to the specific PE of synthetic corticosteroids, since it can also be observed in endogenous Cushing's syndrome. Most often, this complication is caused by fluorinated corticosteroids - triamcinolone (more often than others), dexamethasone and betamethasone.

Side effects are more often caused by long-acting GCS: triamcinolone, betamethasone and dexamethasone.

Myopathy develops shortly after starting therapy and can be quite severe, limiting the movement of patients. The process can extend to the respiratory muscles (intercostal muscles, diaphragm), contributing to the development of respiratory failure. The development of myopathy is considered an indication for the termination of GCS therapy. Recovery is slow and may not be complete. For treatment, potassium preparations and anabolic steroids are used.

Mental disorders

Mild mental disorders (nervousness, anxiety, mild euphoria, other mood changes, sleep disturbances) are often observed already at the beginning of GCS treatment. Their frequency can range from 4 to 36%. Severe steroid psychoses of the manic-depressive or schizophrenic type are rare. In this case, suicidal tendencies are possible. It was shown that the predisposition to mental disorders does not increase the risk of developing these PE, and, conversely, the absence of mental disorders in the anamnesis does not guarantee against the occurrence of psychosis during GCS therapy.

Eye diseases

With long-term treatment of GCS, the development of posterior subcapsular cataract and secondary open-angle glaucoma is possible.

Cataract is one of the late, but well-known complications of GCS therapy and can lead to a decrease in visual acuity. Its development may be facilitated by a certain predisposition of patients. The clouding of the lens is due to both the use of high doses of GCS and the duration of treatment. Children are especially susceptible to this complication, in whom ophthalmic disorders occur in 28-44% of cases. Discontinuation of therapy does not always lead to restoration of the transparency of the lens, moreover, progression is possible

cataracts. Patients receiving long-term prednisone at a dose of 10 mg per day or more should undergo periodic examination by an ophthalmologist.

Glaucoma is a rare and unpredictable complication of long-term GCS therapy. The risk of this PE is highest when there is a family history of open-angle glaucoma. In patients with a burdened heredity, an increase in intraocular pressure occurs in almost 90% of cases, and in the absence of such anamnesis, in no more than 5% of cases. The pathophysiological mechanisms of "steroid" glaucoma are not fully understood. Although the disease can proceed in different ways, in typical cases, intraocular pressure returns to normal after cessation of GCS therapy.

Skeleton lesions

Osteoporosis and compression fracture of the spine are frequent severe complications of GCS therapy in patients of all ages. It is estimated that 30-50% of all patients requiring long-term treatment ultimately develop osteoporosis. (This problem is discussed in detail in the article by I. A. Baranova in this issue of the journal. - Ed.)

Aseptic bone necrosis can complicate long-term therapy with corticosteroids, but when high doses are prescribed, they can develop in a short time. The mechanism of development of this complication is unknown. More often than other bones, the femoral head is affected. The first symptoms may be joint pain and stiffness. This complication is irreversible, the process often progresses and may require joint transplantation. It is necessary to warn patients about the possibility of such a complication. If any new joint pain occurs (especially in the hip, shoulder, or knee), aseptic bone necrosis should be ruled out.

Stunted growth

The appointment of even relatively small doses of GCS can lead to

delayed linear growth in children. This PE is most pronounced in boys. Although its exact mechanism is unknown, it is believed that it may be due to a decrease in sex hormone production and bone formation. There are reports in the literature that collagen synthesis and linear growth can be restored by the administration of growth hormone, but more research is required to clarify these results. Growth retardation can persist after the cancellation of GCS.

Decreased synthesis of sex hormones

Treatment of GCS is accompanied by a decrease in the concentration of estradiol, testosterone, luteinizing and follicle-stimulating hormones, which is associated with the suppression of the synthesis of ACTH and gonadotropic hormone. Possible AEs include menstrual irregularities in women and impotence in men. In addition, the deficiency of sex hormones with anabolic activity creates the prerequisites for the development of osteoporosis.

Infectious complications

The immunosuppressive effect of GCS (suppression of the activity of neutrophils and monocytes, cellular immunological reactions, lymphopenia) leads to increased susceptibility to infections and the risk of reactivation of latent diseases such as chicken pox, shingles, mycoses, pyelonephritis, osteomyelitis, tuberculosis. Infectious complications are especially susceptible to patients with initial impairment of immunity. As a rule, due to the anti-inflammatory effect of GCS, infections are low-symptom and tend to generalize and develop complications.

Most often, patients develop bacterial infections. They usually appear as pneumonia or septicemia. The main pathogens are staphylo-

cocci and gram-negative bacteria of the intestinal group.

Patients with positive tuberculin reactions are at risk of developing a severe form of tuberculosis, therefore, with prolonged therapy with GCS, they should receive isoniazid for prophylactic purposes.

The use of GCS increases the risk of dissemination of viral infections, including the described severe course of chickenpox. For the prevention of viral infections, specific immunoglobulins are used, which are prescribed in the first 48 hours after contact with a contagious patient.

In the presence of an infectious process, GCS therapy can be carried out only if absolutely necessary, under the guise of adequate antibacterial or antifungal drugs. Thanks to such prevention, infectious complications of hormone therapy are currently rare.

Blood changes

Thromboembolic complications are caused by the ability of GCS to suppress the formation of heparin by mast cells and, as a result, to increase blood clotting. Thrombus formation in deep veins is possible when high doses of GCS are prescribed to patients with hypovolemia and hypercoagulability. Therefore, in critically ill patients, primarily with nephrotic syndrome, for the prevention of pulmonary embolism, constant monitoring of the volume of circulating blood, correction of hypovolemia, prescription of anticoagulants and antithrombotic agents is necessary.

Possible neutrophilic leukocytosis without a shift of the leukocyte formula to the left. It is believed that it is due to the stimulating effect of GCS on granulopoiesis.

Steroid vasculitis is more often caused by fluorinated corticosteroids (dex-samethasone and triamcinolone). There is increased vascular permeability, hemorrhages on the forearms, mucous membranes of the

mouth, gastrointestinal tract, conjunctiva of the eyes.

Suppression of the function of the adrenal cortex

A special and intractable PE therapy for GCS is inhibition of the function of the adrenal cortex, which is caused by suppression of ACTH secretion by the pituitary gland in response to the circulation of exogenous GCS at doses exceeding physiological ones. With any long-term treatment with high doses of corticosteroids, one has to reckon with the possibility of reducing the reactivity of hypo-

the thalamo-pituitary-adrenal (HPA) system, although the severity of suppression is subject to large individual fluctuations, which makes it difficult to determine the risk in a particular patient. At first, the disorders are of a functional nature, later morphological changes in the adrenal cortex may occur, up to its atrophy. Common risk factors for inhibition of the HPA system include high doses of corticosteroids, long-term treatment, improper prescription of drugs and the use of long-acting corticosteroids.

When taking corticosteroids in physiological doses (2.5-5 mg / day of prednisone for adults), inhibition of cortisol production does not occur. However, higher doses (5-7.5 mg or more), used for 1-2 weeks, are already able to cause functional suppression of the adrenal cortex. With longer (for example, 4-5 months) therapy, the development of adrenal cortex atrophy should be expected in 40% of patients.

Obviously, the longer the treatment, the higher the likelihood of suppressing adrenal function. Treatment even with very high doses of GCS for a short period (1-3 days) may not have serious consequences, which allows an abrupt discontinuation of treatment without undesirable consequences during

pulse therapy. The restoration of adrenal function, the suppression of which is observed in this case, occurs within about 4 weeks. Prescribing moderate doses for 7-14 days is also considered quite safe. Therefore, a short course of treatment with simultaneous cancellation of GCS is often used, for example, in exacerbation of bronchial asthma. If therapy needs to be continued longer than 2 weeks, then the abolition of GCS should be carried out already gradually under the control of the patient's condition. The higher the doses and the longer the course of treatment, the slower the withdrawal of the drug should be. In many patients, restoration of adrenal cortex function occurs within a few months, while in others it takes a year or even more.

To the greatest extent, the inhibition of the HPA system is observed when taking fluorinated (long-acting) GCS - triamcinolone, dexamethasone and betamethasone. Depot preparations (Kenalog, Diprospan) also cause a long-term suppressive effect.

Withdrawal syndrome

With the rapid cancellation of high doses of corticosteroids, withdrawal syndrome may develop, which is most often manifested by an exacerbation of the underlying disease. The severity of the withdrawal syndrome depends on how well the adrenal cortex function is preserved.

In mild cases, weakness, malaise, rapid fatigue, loss of appetite, nausea, muscle and headaches, insomnia, fever are possible.

In severe cases, with a significant suppression of adrenal function, a clinic of acute adrenal insufficiency, accompanied by vomiting, collapse, and convulsions, may develop. This condition threatens the patient's life, especially during stressful loads.

In rare cases, when GCS is canceled, there may be an increase in intracranial pressure with disc edema.

With a duration of therapy for more than 2 weeks, GCS is gradually canceled.

optic nerve, which is a symptom of a benign pseudotumor of the brain.

GCS reception mode

The greatest risk of PE with systemic use of corticosteroids arises when corticosteroids are taken in equal doses throughout the day. A single intake of the entire daily dose of GCS in the morning reduces the number of PE. This is due to the fact that in the morning hours and in the first half of the day, the sensitivity of the HPA system to

the depressing effects of exogenous GCS is the lowest, and in the evening hours - the highest. Taking 5 mg of prednisolone in the evening has a greater inhibitory effect on the HPA system than 20 mg in the morning. In most cases, the entire daily dose of corticosteroids is prescribed in the morning (primarily long-acting drugs) or 2 / 3-3 / 4 of the daily dose in the morning, and the remainder of the dose is about noon. An even distribution of the daily dose makes sense in the early phases of the most aggressive diseases, and then you need to strive to transfer the patient within 1-2 weeks to a single morning intake of the entire daily dose.

Reducing the inhibitory effect of pharmacological corticosteroids on the function of the adrenal cortex is facilitated by an alternating regimen of drug administration. It consists in taking a double daily dose of GCS every second day in the morning at a time, based on the assumption that anti-inflammatory

the inhibitory effect of GCS lasts longer than the suppressive effect on ACTH synthesis. The mode with a 48-hour interval between GCS administrations allows maintaining their anti-inflammatory effect and reducing the suppressive effect on the HPA system.

The most effective and safe in the alternating regimen were drugs with an average half-life (prednisolone and methylprednisolone). Fluorinated corticosteroids (triamcinolone, dexamethasone and betamethasone) circulate in the systemic circulation for a longer time and to a greater extent inhibit the secretion of ACTH, so they are not used for alternative therapy.

Although alternating administration of corticosteroids to a certain extent reduces the risk of suppression of adrenal function, in many cases, for example, with blood diseases, ulcerative colitis, malignant tumors, this regimen is not effective enough. It should also not be used in the initial stage of treatment, when the patient's condition has not been stabilized, or during an exacerbation of the disease. Unfortunately, in many patients, alternative therapy is difficult because of the deterioration in well-being in the intermediate day between doses.

Conclusion

Although the development of deficiency of the HPA system is more often associated with the appointment of high doses and

it is impossible to reliably predict its occurrence either by the dose of hormones taken, or by the duration of treatment, or by the level of endogenous plasma cortisol. Unfortunately, today we have to admit that it is impossible to completely avoid the development of adverse events during systemic therapy of GCS. Therefore, the doctor should warn the patient about the possible consequences of long-term systemic therapy with GCS. It should be especially warned about the inadmissibility of self-termination of treatment or rapid dose reduction without appropriate medical advice.

List of references

1. Zmushko E.I., Belozerov E.S. Medical complications. SPb., 2001.S. 281.

2. Nasonov E.L. // Rus. honey. zhurn. 1999.T. 8, p. 377.

3. Korovina N.A. and others. Glucocorticosteroid drugs for internal diseases of childhood. M., 2002.S. 17.

4. Boumpas D.T. et al. // Ann. Int. Med. 1993. V. 119. P. 1198.

5. The Pharmacological Basis of Therapeutics / Ed. by Hardman J.G. et al. New York,

6. Piper J.M. et al. // Ann. Intern. Med. 1991. V. 114. P. 735.

7. Strachunsky L.S., Kozlov S.N. Gluco-corticoid drugs. Smolensk,

8. Nasonov E.L., Chichasova N.V. // Rus. honey. zhurn. 1999, vol. 8, p. 371.

9. Boulet L. et al. // Canadian Med. Association J. 1999. V. 161. Suppl. 11.S.1.

10. Bereznyakov I.G. // http: // provisor. kharkov.ua/archive/1998/N10/glukokor/ htm

A single intake of the entire daily dose of GCS in the morning reduces the risk of side effects.

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The human body is a complex, continuously functioning system capable of producing active substances for self-elimination of disease symptoms and protection from negative factors of the external and internal environment. These active substances are called hormones and, in addition to their protective function, they also help regulate many processes in the body.

What are glucocorticosteroids

Glucocorticosteroids (glucocorticoids) are corticosteroid hormones produced by the adrenal cortex. The pituitary organ is responsible for the release of these steroid hormones, which produces a special substance in the blood - corticotropin. It is it that stimulates the adrenal cortex to secrete a large amount of glucocorticoids.

Specialist doctors believe that there are special mediators inside human cells that are responsible for the cell's response to chemicals that act on it. This is how they explain the mechanism of action of any hormones.

Glucocorticosteroids have a very extensive effect on the body:

• have anti-stress and anti-shock effects;
• accelerate the activity of the human adaptation mechanism;
• stimulate the production of blood cells in the bone marrow;
• increase the sensitivity of the myocardium and blood vessels, provoke an increase in blood pressure;
• increase and have a positive effect on gluconeogenesis occurring in the liver. The body can independently stop an attack of hypoglycemia, provoking the release of steroid hormones into the blood;
• increase the anabolism of fats, accelerate the exchange of beneficial electrolytes in the body;
• have a powerful immunoregulatory effect;
• reduce the release of mediators, providing an antihistamine effect;
• have a powerful anti-inflammatory effect, reducing the activity of enzymes that cause destructive processes in cells and tissues. Suppression of inflammatory mediators leads to a decrease in the exchange of fluids between healthy and affected cells, as a result of which inflammation does not grow and does not progress. In addition, GCS does not allow the production of lipocortin proteins from arachidonic acid - catalysts of the inflammatory process;

All these abilities of steroid hormones of the adrenal cortex were discovered by scientists in laboratory conditions, due to which there was a successful introduction of glucocorticosteroids into the pharmacological sphere. Later, the antipruritic effect of hormones was noted when applied externally.

The artificial addition of glucocorticoids to the human body, either internally or externally, helps the body to cope with a large number of problems faster.

Despite the high efficiency and benefits of these hormones, modern pharmacological industries use exclusively their synthetic analogs, since corticosteroid hormones used in their pure form can provoke a large number of negative side effects.

Indications for taking glucocorticosteroids

Glucocorticosteroids are prescribed by doctors when the body needs additional supportive therapy. These drugs are rarely prescribed as monotherapy, they are mainly included in the treatment of a specific disease.

The most common indications for the use of synthetic glucocorticoid hormones include the following conditions:

• the body, including vasomotor rhinitis;
• and pre-asthmatic conditions,;
• skin inflammations of various etiologies. Glucocorticosteroids are used even for infectious skin lesions, in combination with drugs that can cope with the microorganism that provoked the disease;
• of any origin, including traumatic ones caused by blood loss;
• , and other manifestations of connective tissue pathologies;
• a significant decrease due to internal pathologies;
• long-term recovery after organ and tissue transplants, blood transfusions. Steroid hormones of this type help the body to quickly adapt to foreign bodies and cells, significantly increasing tolerance;
• glucocorticosteroids are included in the complex of recovery after and radiation therapy of oncology;
• , the reduced ability of their cortex to provoke the physiological amount of hormones and other endocrine diseases in the acute and chronic stages;
• some diseases of the gastrointestinal tract:,;
• autoimmune liver disease;
• swelling of the brain;
• eye diseases: keratitis, cornea iritis.

It is necessary to take glucocorticosteroids only after a doctor's prescription, since if taken incorrectly and inaccurately calculated dose, these drugs can quickly provoke dangerous side effects.

Synthetic steroid hormones can cause withdrawal symptoms - deterioration of the patient's well-being after stopping medication, up to glucocorticoid insufficiency. To prevent this from happening, the doctor calculates not only the therapeutic dose of drugs with glucocorticoids. He also needs to build a treatment regimen with a gradual increase in the amount of a drug to stop the acute stage of the pathology, and lower the dose to the minimum after the peak of the disease has passed.

Classification of glucocorticoids

The duration of action of glucocorticosteroids was measured by experts artificially, according to the ability of a single dose of a particular drug to inhibit the adrenocorticotropic hormone, which is activated in almost all of the above pathological conditions. This classification divides this type of steroid hormones into the following types:

1. Short-acting - suppress the activity of ACTH for a period of just over a day (Cortisol, Hydrocortisone, Cortisone, Prednisolone, Metipred);
2. Average duration - validity period is approximately 2 days (Traimcinolone, Polcortolone);
3. Long-acting drugs - the effect lasts longer than 48 hours (Batmethasone, Dexamethasone).

In addition, there is a classical classification of drugs according to the method of their introduction into the patient's body:

1. Oral (tablets and capsules);
2. nasal drops and sprays;
3. inhalation forms of the drug (most often used by asthmatics);
4. ointments and creams for external use.

Depending on the state of the body and the type of pathology, both 1 and several forms of drugs containing glucocorticosteroids can be prescribed.

List of popular glucocorticosteroid drugs

Among the many drugs containing glucocorticosteroids in their composition, doctors and pharmacologists distinguish several drugs of various groups that are highly effective and have a low risk of provoking side effects:

note

Depending on the patient's condition and the stage of development of the disease, the form of the drug, dose and duration of use are selected. The use of glucocorticosteroids necessarily occurs under the constant supervision of a physician to monitor any changes in the patient's condition.

Side effects of glucocorticosteroids

Despite the fact that modern pharmacological centers are working to improve the safety of drugs containing hormones, with a high sensitivity of the patient's body, the following side effects may appear:

• increased nervous irritability;
• insomnia;
• causing discomfort;
• , thromboembolism;
• and intestines, gallbladder inflammation;
• weight gain;
• with prolonged use;

Glucocorticoid drugs (GCS) occupy a special place not only in allergology and pulmonology, but also in medicine in general. Irrational administration of GCS can lead to the appearance of a large number of side effects and dramatically change the quality and lifestyle of the patient. In such cases, the risk of complications from the appointment of GCS significantly exceeds the severity of the disease itself. On the other hand, fear of hormonal drugs, which arises not only in patients, but also in incompetent medical workers, is the second extreme of this problem, which requires advanced training of doctors and special work among the contingent of patients who need glucocorticoid therapy. Thus, the basic principle of GCS therapy is to achieve the maximum effect when using the minimum doses; it should be remembered that the use of insufficient doses increases the duration of treatment and, accordingly, increases the likelihood of side effects.

Classification. GCS are classified into short, intermediate and long-acting drugs, depending on the duration of ACTH inhibition after taking a single dose (Table 2).

Table 2. GCS classification by duration of action

A drug		Equivalent dose	gKS	Mineralo corticoid activity
Short-acting:
Cortisol (hydrocortisone)
Cortisone
Prednisone
Medium duration
Prednisolone
Methylprednisolone
Triamcinolone
Long-acting
Beclamethasone
Dexamethasone

For more than 40 years, glucocorticoid preparations with high activity when used topically have been widely used on the market. The created new class of corticosteroids for inhalation therapy must meet the following requirements: on the one hand, have a high affinity for glucocorticoid receptors and, on the other hand, an extremely low bioavailability, the reduction of which can be achieved by reducing the lipophilicity of corticosteroids and, accordingly, the degree of absorption. Below is the classification of GCS according to the method of application, indicating the forms of release, trade names and dosage regimes (Table 3).

Table 3 . GCS classification by route of administration

A drug	Trade names		Release forms
GCS for oral use
Betamethasone	Celeston		Tab. 0.005 No. 30
Dexamethasone	Dexazon Dexamed Fortecortin Dexamethasone		Tab. 0.005 No. 20 Tab. 0.005 No. 10 and No. 100 Tab. 0.005 No. 20 and No. 100, tab. 0, 0015 No. 20 and No. 100, elixir 100 ml in a bottle (5 ml \u003d 500 μg) Tab. 0.005 # 100 Tab. 0.005 No. 20, 0.0015 No. 50 and 0.004 # 50 and 100 Tab. 0.005 No. 20 and No. 1000
Methyl prednisolone	Metipred		Tab. 0.004 No. 30 and No. 100, tab. 0.016 No. 50, tab. 0.032 No. 20 and tab. 0.100 No. 20 Tab. 0.004 No. 30 and 100, tab. 0.016 No. 30
Prednisolone	Prednisolone Decorin N Medopred Prednisol		Tab. 0.005 No. 20, No. 30, No. 100, No. 1000 Tab. 0.005 No. 50 and No. 100, tab. 0.020 No. 10, No. 50, No. 100, tab. 0.05 No. 10 and No. 50 Tab. 0.005 No. 20 and No. 100 Tab. 0.005 No. 100
Prednisone	Apo-prednisone		Tab. 0.005 and 0.05 No. 100 and No. 1000
Triamcinolone	Polcortolone Triamcinolone Barleycourt Kenacourt		T ab. 0.004 No. 20 Tab. 0.002 and 0.004 No. 50, 100, 500 and 1000 Tab. 0.004 No. 25 Tab. 0.004 No. 100 Tab. 0.004 No. 50 Tab. 0.004 No. 100
GCS for injection
Betamethasone	Celeston		In 1 ml 0.004, No. 10 ampoules of 1 ml
Dexamethasone	Dexaven Dexabene Dexazon Dexamed Dexamethasone Fortecortin mono		In 1 ml 0.004, No. 10 ampoules of 1 and 2 ml In 1 ml 0.004, in a bottle 1 ml In 1 ml 0.004, no. 3 ampoules of 1 ml and 2 ml In 1 ml 0.004, No. 25 ampoules of 1 ml In 2 ml 0.008, No. 10 ampoules of 2 ml In 1 ml 0.004, No. 5 ampoules of 1 ml In 1 ml 0.004, No. 10 ampoules of 1 ml In 1 ml 0.004, No. 100 ampoules of 1 ml In 1 ml 0.004, # 3 ampoules of 1 ml and 2 ml, in 1 ml 0.008, # 1 ampoule of 5 ml
Hydrocortisone	Hydrocortisone Solu cortef Sopolkort N		Suspension in vials, in 1 vial 5 ml (125 mg) * Lyophilized powder in vials, 1 vial 2 ml (100 mg) Solution for injection, 1 ml in ampoule (25 mg) and 2 ml (50 mg)
Prednisolone	Metipred Solu-medrol		Suspension for injection, 1 ml in ampoule (40 mg) Lyophilized powder in vials, in 1 vial 40, 125, 250, 500 or 1000 mg Dry substance with solvent in ampoules No. 1 or No. 3, 250 mg each, No. 1 1000 mg
Prednisolone	Medopred Prednisol Prednisolone Hafslund Nycomed Prednisolone Prednisolone acetate Prednisolone hemisuccinate Solu-decortin N		In 1 ml 0.020, No. 10 ampoules of 2 ml In 1 ml 0.030, No. 3 ampoules of 1 ml In 1 ml 0.025, no. 3 ampoules of 1 ml In 1 ml 0.030, No. 3 ampoules of 1 ml In 1 ml 0.025, No. 10 or No. 100 ampoules of 1 ml In 5 ml 0.025, No. 10 lyophilized powder in ampoules of 5 ml In 1 ampoule 0.010, 0.025, 0.050 or 0.250, No. 1 or No. 3 ampoules
Triamcinolone	Triam-denk 40 for injection Triamcinolone		In 1 ml 0.010 or 0.040 in vials In 1 ml 0.040, No. 100 suspension in ampoules In 1 ml 0.010 or 0.040, suspension in ampoules
Depot - form: Triamcinolone	Triamcinolone acetonide		In 1 ml 0.040, No. 5 in ampoules of 1 ml In 1 ml 0.010, 0.040 or 0.080, suspension in ampoules
Depot form: Methylprednisolone acetate	Depo-medrol Methylprednisolone acetate		In 1 ml 0.040, vials of 1, 2 or 5 ml In 1 ml 0.040, No. 10 ampoules, 1 ml of suspension in an ampoule
Combination of depot and fast-acting form
Betamethasone	Diprospan Flosterone		In 1 ml 0.002 phosphate dinitrate and 0.005 dipropionate, No. 1 or 5 ampoules of 1 ml The composition is similar to diprospan
GCS for inhalation
Beclamethasone	Aldecin Beklazon Beclomet-Easyhailer Bekodisk Beklokort Beclofort Pliebecourt		1 dose 50, 100 or 250 mcg, aerosol 200 doses 1 dose 200 mcg, Easyhaler 200 doses 1 dose of 100 mcg or 200 mcg, 120 doses in dischaler 1 dose 50 mcg, aerosol 200 doses In 1 dose 50 mcg (mite), in aerosol 200 doses and 250 mcg (forte), aerosol 200 doses 1 dose 250 mcg, aerosol 80 or 200 doses 1 dose 50 mcg, aerosol 200 doses
Budesonide	Benacort Pulmicort Budesonide		In 1 dose 200 mcg, in the inhaler "Cyclohaler" 100 or 200 doses 1 dose 50 mcg, aerosol 200 doses and 1 dose 200 mcg, aerosol 100 doses Similar to Pulmikort
Fluticasone	Flixotide		In 1 dose 125 or 250 mcg, in aerosol 60 or 120 mcg; powder for inhalation in rotadiscs: 4 x 15 blisters, in 1 dose of 50, 100, 250 or 500 mcg
Triacinolone	Azmakort		1 dose 100 mcg, aerosol 240 doses
GCS for intranasal use
Beclomethasone	Aldecin Beconase	The same (see above) aerosol with a nasal mouthpiece 1 dose of 50 mcg, 200 dose aqueous aerosol for intranasal administration 1 dose 50 mcg, aerosol 50 doses
Flunisolide	Sintaris	1 dose 25 mcg, aerosol 200 doses
Fluticasone	Fliksonase	In 1 dose of 50 mcg, in an aqueous spray for intranasal use 120 doses
Mometasone	Nazonex	1 dose 50 mcg, aerosol 120 doses
GCS for local use in ophthalmology
	Prenacid	Eye drops 10 ml in a bottle (1 ml \u003d 2.5 mg), eye ointment 10.0 (1.0 \u003d 2.5 mg)
Dexamethasone	Dexamethasone	Eye drops 10 and 15 ml in a bottle (1 ml \u003d 1 mg), eye suspension 10 ml in a bottle (1 ml \u003d 1 mg)
Hydrocortisone	Hydrocortisone	Eye ointment in a tube 3.0 (1.0 \u003d 0.005)
Prednisolone	Prednisolone	Ophthalmic suspension in a bottle 10 ml (1 ml \u003d 0.005)
Combined. drugs: With dexamethasone, framycetin and gramicidin With dexamethasone and neomycin	Sofradex Dexon
GCS for local use in dentistry
Triamcinolone	Kenalog Orabase	Topical paste in dentistry (1.0 \u003d 0.001)
GCS for local use in gynecology
Combined. drugs: With prednisone	Terzhinan	Vaginal tablets of 6 and 10 pieces, which include prednisolone 0.005, ternidazole 0.2, neomycin 0.1, nystatin 100,000 U
GCS for use in proctology
Combined. drugs: With prednisone With hydrocortisone	Aurobin Posterisan forte Proctosedil	Ointment 20 each, in tubes (1.0 \u003d prednisolone 0.002, lidocaine 0.02, d-pantethol 0.02, triclosan 0.001) Rectal suppositories No. 10, (1.0 \u003d 0.005) Ointment 10.0 and 15.0 in a tube (1.0 \u003d 5.58 mg), rectal capsules No. 20, in 1 capsule 2.79 mg
GCS for external use
Betamethasone	Betnowate Diprolene Celestoderm -V	Cream and ointment 15.0 in tubes (1.0 \u003d 0.001) Cream and ointment 15.0 and 30.0 in tubes (1.0 \u003d 0.0005) Cream and ointment 15.0 and 30.0 in tubes (1.0 \u003d 0.001)
Betamethasone + Gentamicin	Diprogent	Ointment and cream 15.0 and 30.0 in tubes (1.0 \u003d 0.0005)
Betamethasone + Clotrimazole	Lotriderm	Ointment and cream 15.0 and 30.0 in tubes (1.0 \u003d 0.0005, clotrimazole 0.01)
Betamethasone + Acetylsalicylic acid	Diprosalik	Ointment 15.0 and 30.0 in tubes (1.0 \u003d 0.0005, salicylic acid 0.03); Lotion 30 ml in a bottle (1 ml \u003d 0.0005, salicylic acid 0.02)
Budesonide		Ointment and cream 15.0 in tubes (1.0 \u003d 0.00025)
Clobetasol	Dermovate	Cream and ointment 25.0 in tubes (1.0 \u003d 0.0005)
Fluticasone	Kutiveit	Ointment 15.0 in tubes (1.0 \u003d 0.0005) and cream 15.0 in tubes (1.0 \u003d 0.005)
Hydrocortisone	Laticort	Ointment 14.0 in tubes (1.0 \u003d 0.01) 15 ml ointment, cream or lotion (1.0 \u003d 0.001) Ointment, cream or lipokrem 0.1% 30.0 in tubes (1.0 \u003d 0.001), lotion 0.1%, 30 ml (1 ml \u003d 0.001)
Hydrocortisone + Natamycin + Neomycin	Pimafukort	Ointment and cream 15.0 in tubes (1.0 \u003d 0.010), lotion 20 ml in a bottle (1.0 \u003d 0.010)
Mazipredon	Deperzolone	Emulsion ointment 10.0 in tubes (1.0 \u003d 0.0025)
Mazipredon + Miconazole	Mycozolone	Ointment 15.0 in tubes (1.0 \u003d 0.0025, miconazole 0.02)
Methyl prednisolone	Advantan
Mometasone		Ointment, cream 15.0 in tubes and lotion 20 ml (1.0 \u003d 0.001)
Prednikarbat	Dermatol	Ointment and cream 10.0 in tubes (1.0 \u003d 0.0025)
Prednisolone + Clioquinol	Dermozolone	Ointment 5.0 in tubes (1.0 \u003d 0.005 and clioquinol 0.03)
Triamcinolone	Triacort Ftorocort	Ointment 10.0 in tubes (1.0 \u003d 0.00025 and 1.0 \u003d 0.001) Ointment 15.0 in tubes (1.0 \u003d 0.001)

Mechanism of action of GCS: Decoding the implementation anti-inflammatory effect GCS is extremely complex. Currently, it is believed that the leading link in the action of GCS on the cell is their effect on the activity of the genetic apparatus. Various classes of corticosteroids to one degree or another bind to specific receptors located on the cytoplasmic or cytosolic membrane. For example, cortisol (endogenous corticosteroids, with pronounced mineralocorticoid activity) has a preferential binding to the receptors of the cytoplasmic membrane, and dexamethasone (synthetic corticosteroids, characterized by minimal mineralocorticoid activity) binds to a greater extent to cytosolic receptors. After active (in the case of cortisone) or passive (in the example with dexamethasone) penetration of GCS into the cell, a structural rearrangement occurs in the complex formed by GCS, a receptor and a carrier protein, allowing it to interact with certain areas of nuclear DNA. The latter leads to an increase in RNA synthesis, which is the main stage in the realization of the biological effects of GCS in the cells of target organs. The determining factor in the mechanism of the anti-inflammatory effect of GCS is their ability to stimulate the synthesis of some (lipomodulin) and inhibit the synthesis of other (collagen) proteins in cells. Lipomodulin blocks cell membrane phospholipase A2, which is responsible for the release of phospholipid-linked arachidonic acid. Accordingly, the formation of active anti-inflammatory lipids-prostaglandins, leukotrienes and thromboxanes from arachidonic acid is also stimulated. Inhibition of leukotriene B4 reduces the chemotaxis of leukocytes, and leukotriene C4 and D4 reduces the contractile ability of smooth muscles, vascular permeability and mucus secretion in the respiratory tract. In addition, corticosteroids suppress the formation of some cytokines involved in inflammatory reactions in bronchial asthma. Also, one of the components of the anti-inflammatory effect of GCS is the stabilization of lysosomal membranes, which reduces the permeability of the capillary endothelium, improves microcirculation and reduces the exudation of leukocytes and mast cells.

The antiallergic action of GCS is multifactorial and includes: 1) the ability to reduce the number of circulating basophils, which leads to a decrease in the release of mediators of immediate allergic reactions; 2) direct inhibition of the synthesis and secretion of mediators of immediate allergic reactions due to an increase in intracellular cAMP and a decrease in cGMP; 3) a decrease in the interaction of allergy mediators with effector cells.

Currently, the mechanisms of the anti-shock effect of glucocorticoids are not fully understood. However, a sharp increase in the concentration of endogenous glucocorticoids in plasma with shocks of various etiologies, a significant decrease in the body's resistance to shockogenic factors with inhibition of the hypathalamic-pituitary-adrenal system has been proven. The confirmed high efficiency of GCS in shocks is also obvious. It is believed that GCS restore the sensitivity of adrenergic receptors to catecholamines, which, on the one hand, mediates the bronchodilator effect of GCS and maintenance of systemic hemodynamics, and on the other hand, the development of side effects: tachycardia, arterial hypertension, excitation of C.N.S.

The effect of GCS on metabolism. Carbohydrate metabolism... Gluconeogenesis increases and glucose utilization in tissues decreases due to antagonism with insulin, as a result of which hyperglycemia and glucosuria can develop. Protein metabolism... Anabolic processes in the liver and catabolic processes in other tissues are stimulated, the content of globulins in the blood plasma decreases. Lipid metabolism... Lipolysis is stimulated, the synthesis of higher fatty acids and triglycerides is enhanced, fat is redistributed with predominant deposition in the shoulder girdle, face, abdomen, hypercholesterolemia is recorded. Water-electrolyte exchange. Due to mineralocorticoid activity, sodium and water ions are retained in the body, and the excretion of potassium increases. Antagonism of corticosteroids in relation to vitamin D causes the leaching of Ca 2+ from bones and an increase in its renal excretion.

Other effects of GCS. GCS inhibit the growth of fibroblasts and collagen synthesis, cause a decrease in the reticuloendothelial clearance of cells with antibodies, reduce the level of immunoglobulins without affecting the production of specific antibodies. In high concentrations, GCS stabilize the lysosomal membranes, increase hemoglobin and the number of erythrocytes in peripheral blood.

Pharmacokinetics. GCS for systemic use are poorly soluble in water, well - in fats. Minor changes in chemical structure can lead to significant changes in the degree of absorption and duration of action. In plasma, 90% of cortisol binds reversibly to 2 types of proteins - globulin (glycoprotein) and albumin. Globulins have a high affinity, but a low binding capacity, while albumin, on the contrary, have a low affinity, but a high binding capacity. Metabolism of GCS is carried out in several ways: the main one is in the liver, the other is in extrahepatic tissues and even in the kidneys. Microsomal liver enzymes metabolize GCS to inactive compounds, which are then excreted by the kidneys. Liver metabolism is enhanced in hyperthyroidism and is induced by phenobarbital and ephedrine. Hypothyroidism, cirrhosis, concomitant treatment with erythromycin or oleandomycin leads to a decrease in hepatic GCS clearance. In patients with hepatocellular failure and low serum albumin, significantly more unbound prednisolone is circulating in the plasma. There is no correlation between T 1/2 and the duration of the physiological effect of a particular GCS drug. Different activity of GCS is determined by different degrees of binding to plasma proteins. So, most of the cortisol is in a bound state, while 3% methylprednisolone and less than 0.1% dexamethasone. The most active are fluorinated compounds (metazones). Beclomethasone contains chlorine as a halogen and is especially indicated for local endobronchial use. Esterification made it possible to obtain preparations with reduced absorption for local use in dermatology (fluocinolone pivalate). Succinates, or acetonides, are water-soluble and are used as preparations for injection (prednisolone succinate, triamcinolone acetonide).

Performance criteria when used orally prednisone the same as for cromoglycate.

Safety criteria with systemic use glucocorticosteroids the following:

1) Absence of 1 infectious disease, including tuberculosis, due to suppression of the immune response;

2) Lack of osteoporosis, including in postmenopausal women, due to the risk of fractures;

3) Compliance with a sufficiently active lifestyle and the absence of osteomyelitis due to the threat of aseptic bone necrosis;

4) Control of the glycemic profile and exclusion of diabetes mellitus due to the possibility of complications in the form of ketoacidosis, hyperosmolar coma;

5) Taking into account the mental status due to the possibility of the development of "steroid" psychosis;

6) Control of blood pressure and water-electrolyte balance due to sodium and water retention;

7) The absence of a history of peptic ulcers, as well as the threat of gastrointestinal bleeding due to a violation of the rate of reparation of the gastrointestinal mucosa;

8) Lack of glaucoma due to the possibility of provoking glaucomatous crises;

9) Absence of superficial wounds, fresh postoperative scars, burn injuries due to suppression of fibroplasia;

10) Absence of puberty due to cessation of growth and exclusion of pregnancy due to probable teratogenic effects.

Features of oral administration applicationGKS .

When choosing, preference is given to fast-acting drugs with an average duration of action, having 100% oral bioavailability and, to a lesser extent, inhibiting the hypothalamic-pituitary-adrenal system. A short course (3-10 days) can be prescribed to achieve the optimal effect at the beginning of a long course of therapy with a gradual deterioration of the patient's condition or to quickly stop a severe attack. For the treatment of severe forms of bronchial asthma, long-term therapy with GCS may be required according to one of the following schemes:

• Continuous regimen (used most often), with 2/3 of the daily dose prescribed in the morning and 1/3 in the afternoon. Due to the danger of an increase in the aggression of the acid-petic factor in conditions of a decrease in the rate of repair of the gastrointestinal mucosa, it is recommended to prescribe GCS after a meal, in some cases under the guise of antisecretory drugs and drugs that improve reparative processes in the gastrointestinal mucosa. However, the combination of admission with antacids is inappropriate, since the latter reduce the absorption of GCS by 46-60%.

 An alternating regimen involves taking a double maintenance dose of the drug once in the morning every other day. This method can significantly reduce the risk of side effects while maintaining the effectiveness of the selected dose.

• Intermittent scheme involves the use of GCS in short courses of 3-4 days with 4-day intervals between them.

If indicated, a trial two-week course of corticosteroids is prescribed, based on prednisolone from 20 to 100 mg (usually 40 mg). Further treatment with these drugs is carried out only if a repeated study after 3 weeks revealed a significant improvement in the function of external respiration: an increase in FEV 1 by at least 15% and an increase in FVC by 20%. Subsequently, the dose is reduced to the minimum effective, preference is given to an alternating regimen. The minimum effective dose is selected by successively reducing the initial dose by 1 mg every 4-6 days with close observation of the patient. The maintenance dose of prednisolone is usually 5-10 mg, doses below 5 mg are ineffective in most cases. Systemic therapy of GCS in 16% of cases leads to the development of side effects and complications. After stopping the intake of GCS, the function of the adrenal cortex is restored gradually, over 16-20 weeks. Systemic GCS, if possible, replace inhalation forms.

Performance criteria use inhaled GCS the same as in other basic therapy for patients with bronchial asthma.

Safety criteria when applying inhaled GCS the following:

1) Administration of the drug in the minimum effective dose, by means of spacers or turbo-hailers, with constant monitoring of the state of the oral mucosa due to the possibility of developing oropharyngeal candidiasis; in rare cases - prophylactic intake of antifungal agents;

2) Lack of professional restrictions associated with the threat of hoarseness (possibly due to local steroid myopathy of the muscles of the larynx, which passes after the drug is discontinued); a similar side effect is less often recorded for powdery inhalation forms;

3) Absence of cough and mucosal irritation (mainly due to the additives that make up the aerosol).

Conditions for using inhaled GCS and features of individual drugs.

An inhalation dose of 400 mcg beclomethasone (becotide) is equivalent to approximately 5 mg of prednisolone taken by mouth. With an effective maintenance dose of prednisolone 15 mg, patients can be completely transferred to treatment with inhaled GCS. In this case, the dose of prednisolone begins to be reduced no earlier than a week after the addition of inhaled drugs. Inhibition of the function of the hypothalamic-pituitary-adrenal system occurs when inhaled beclomethasone at a dose exceeding 1500 mcg / day. If the patient's condition worsens against the background of a maintenance dose of inhaled GCS, an increase in the dose is required. The maximum possible dose is 1500 mcg / kg, if there is no therapeutic effect in this case, it is necessary to add oral corticosteroids.

Beclofort is an increased dosage of beclamethasone (200 mcg per dose).

Flunisolid (ingacort), in contrast to beclomethasone, is already in a biologically active form from the moment of administration and therefore immediately manifests its effect in the target organ. In comparative studies on the efficacy and tolerability of beclomethasone at a dose of 100 mcg 4 times a day and flunisolide at a dose of 500 mcg twice a day, the latter was significantly more effective. Flunisolid is equipped with a special spacer, which provides deeper penetration of the drug into the bronchi due to the inhalation of most of the small particles. At the same time, there is a decrease in the frequency of oropharyngeal complications, a decrease in bitterness in the mouth and cough, irritation of the mucous membrane and hoarseness. In addition, the presence of a spacer makes it possible to use metered aerosols in children, the elderly and in patients with difficulty in coordinating the process of inhalation and inhalation of the drug.

Triamcinolone acetonide (azmacort) is most commonly used in the United States. A fairly wide range of doses used (from 600 mcg to 1600 mcg in 3-4 doses) makes it possible to use this drug in patients with the most severe asthma.

Budesonide refers to drugs with prolonged action and, compared with beclomethasone, is 1.6-3 times more active in terms of anti-inflammatory activity. It is of interest that the drug is produced in 2 dosage forms for inhalation use. The first is a traditional metered-dose inhaler containing 50 and 200 mcg of budesonide per breath. The second form is a turbohaler, a special inhalation device that provides the administration of the drug in powder form. The air flow created thanks to the original design of the turbohaler captures the smallest particles of the drug powder, which leads to a significant improvement in the penetration of budesonide into the small-caliber bronchi.

Fluticasone propionate (flixotide) inhaled GCS with greater anti-inflammatory activity, pronounced affinity for glucocorticoid receptors, less manifestation of systemic side effects. Features of the pharmacokinetics of the drug are reflected in a high threshold dose - 1800-2000 mcg, only when exceeding which, systemic side reactions can develop.

Thus, inhaled corticosteroids are one of the most effective means of therapy for patients with bronchial asthma. Their use leads to a decrease in symptoms and exacerbations of bronchial asthma, an improvement in pulmonary functional parameters, a decrease in bronchial hyperreactivity, a decrease in the need for taking short-acting bronchodilators, as well as an improvement in the quality of life of patients with bronchial asthma.

Table 4. Estimated equivalent doses (μg) for inhalation

Systemic glucocorticoids

Systemic glucocorticoids are divided into several groups:
■ By origin:
- natural (hydrocortisone);
- synthetic: (prednisolone, methylprednisolone, triamcinolone, dexamethasone, betamethasone).
■ By duration:
- drugs of short (hydrocortisone), medium duration (prednisolone, methylprednisolone) and long (triamcinolone, dexamethasone, betamethasone) action.

Pharmacokinetics

When taken orally, glucocorticoids are well absorbed from the gastrointestinal tract. The maximum concentration in the blood is created after 1.5 hours.

Glucocorticoids bind to plasma proteins:
a) with α1-globulin (transcortin), forming complexes with it that do not penetrate into tissues, but create a depot of these hormones;
b) with albumin, forming complexes with them, penetrating into tissues. Only free glucocorticoids are biologically active.
They are quickly excreted from the plasma, easily penetrate the histohematological barriers, including the blood-brain, placental and breast milk, accumulating in tissues where they remain active for much longer. Free glucocorticoids are deposited by 25-35% by erythrocytes and leukocytes. If hydrocortisone binds to transcortin by 80-85%, with albumin - by 10%, then synthetic glucocorticoids bind to proteins by 60-70%, i.e. their free fraction, which penetrates well into tissues, is much larger. The amount of glucocorticoids entering cells is also influenced by their ability to bind to specific intracellular receptors.

Glucocorticoids undergo biotransformation in the liver, partly in the kidneys and other tissues, mainly by conjugation with glucuronide or sulfate. They are excreted with bile and urine by glomerular filtration and 80-90% are reabsorbed by the tubules. 20% of the dose is excreted by the kidneys unchanged. A small part (on average 0.025%) of the dose of intravenously administered prednisolone is excreted in breast milk. At the same time, the decrease in the concentration of glucocorticoid in breast milk occurs faster than in the blood serum. The half-life (Table 6.2) from plasma (T1 / 2) of hydrocortisone is 60-90 minutes, prednisone, prednisolone and methylprednisolone - 180-200 minutes, triamcinolone and fluocortolone - 210 minutes, dexamethasone, betamethasone and paramethasone - 190-300 minutes. That is, the elimination of synthetic glucocorticoids, especially fluorinated ones, occurs more slowly, and they have a greater inhibitory effect on the adrenal cortex. The half-life of hydrocortisone from tissues is 8-12 hours, prednisone, prednisolone and methylprednisolone - 12-36 hours, triamcinolone and fluocortolone - 24-48 hours, dexamethasone and betamethasone - 36-54 hours (up to 72 hours).