Glucocorticoids

In clinical practice, natural glucocorticoids - cortisone and hydrocortisone and their synthetic and semisynthetic derivatives are used. Depending on the presence or absence of fluoride or chlorine ions in the drug structure, glucocorticoids are divided into unhalogenized (prednisone, prednisolone, methylprednisolone) and halogenated compounds (triamcinolone, dexamethasone and betamethasone).

Natural glucocorticoids have mineralocorticoid activity, although weaker than true mineralocorticoids. Nonhalogenated semisynthetic glucocorticoids also have mineralocorticoid effects, the severity of which, in turn, is inferior to the effects of natural glucocorticoids. In halogenated drugs, mineralocorticoid activity is practically absent.

A purposeful change in the structure of natural glucocorticoids led to an increase in glucocorticoid activity and a decrease in mineralocorticoid activity. At present, halogenated metazones (beclomethasone, dexamethasone, mometasone) are the most potent glucocorticoid activity. The combination of GCS with various ethers (succinates and phosphates) gives LS a solubility and the ability to administer them parenterally. Depot-effect is achieved by using a suspension of crystals, insoluble in water. These glucocorticoids have a reduced absorption and are convenient for topical use.

In anesthesia and resuscitation practice, water-soluble glucocorticoids for intravenous administration are used.

[1], [2], [3], [4]

Glucocorticoids: a place in therapy

For pharmacodynamic therapy (in contrast to substitution therapy), it is preferable to use drugs with low mineralocorticoid activity. The glucocorticoids used in clinical practice have certain differences in the strength of the main therapeutic effects, pharmacokinetics and the spectrum of side effects that must be taken into account in the appointment.

Glucocorticoids are used in anesthesia and resuscitation practice under the following conditions: in hypotension with massive bleeding and their relapses; hypotension in acute cardiovascular insufficiency;

• traumatic, hemorrhagic
• infectious-toxic shock;
• allergic or anaphylactic reaction (Quincke's edema, acute urticaria, asthmatic status, acute toxic-allergic reactions, etc.);
• allergic reactions to narcotic analgesics or other pharmacological drugs;
• acute adrenal insufficiency.

For emergency therapy of conditions such as shock, allergic reactions, intoxication, glucocorticoids are administered iv. The introduction can be single or repeated for several days.

The main indication for the use of glucocorticoids during anesthesia and in the early postoperative period is a decrease in SBP below 80 mmHg. Which can be observed in many pathological conditions. Intravenous injection of GCS during induction of anesthesia and its maintenance allows to achieve rapid stabilization of hemodynamics against the background of complex treatment within 10 minutes from the moment of the initial dose administration.

Usually during surgery, glucocorticoids are used in a wide range of doses: from 20 to 100 mg when recalculating to prednisolone doses. At the same time, the effectiveness of their use in complex therapy can reach 96%. Only in a small number of cases, drugs are ineffective. Most often, the absence of hemodynamic effect is noted in patients with a decrease in blood pressure in response to the introduction of a local anesthetic (for example, trimecaine). There was no effect of single doses of glucocorticoids in patients with severe intoxication in case of its source preservation, and also in rare cases of initial resistance of the organism to drugs.

In severe circulatory disorders, the therapeutic effect of glucocorticoids is realized through an increase in tissue perfusion, an increase in venous outflow, normalization of peripheral resistance and CB, stabilization of cell and lysosomal membranes and other effects. Despite the traditional use of glucocorticoids for various types of shock, their effectiveness under these conditions remains unproven. This is due to the complexity of taking into account the variety of factors that underlies the development of the shock state and affects the effectiveness of therapy. The use of glucocorticoids in these conditions should be carried out in conjunction with the entire pharmacological symptomatic arsenal of correction of complications.

Widespread use of glucocorticoids is found in the treatment of allergic reactions that occur during anesthesia of surgical interventions. With severe manifestations of allergy to / in the introduction of adequate doses of glucocorticoids has a suppressive effect. The onset of action of glucocorticoids in allergic diseases is delayed. So, for example, the main biological effects of hydrocortisone develop only 2-8 hours after its administration. Therefore, patients with severe allergic reactions to avoid bronchospasm need immediate appointment of epinephrine.

Glucocorticoids exert a pronounced effect on adrenal insufficiency, which developed before and during surgical interventions. Hydrocortisone, cortisone and prednisolone are used for replacement therapy.

Short-term introduction of long-acting GCS is practiced for the prevention of respiratory distress syndrome in premature infants, which reduces the risk of death and complications from this condition by 40-50%.

Mechanism of action and pharmacological effects

Glucocorticoids are hormonal drugs, the main effect of which is realized at the level of the nuclear structures of the cell and consists in regulating the expression of certain genes. Glucocorticoids interact with specific protein receptors of target cells in the cytoplasm of the cell (cytosolic receptors). The resulting hormone-receptor complex moves to the nucleus, where it binds to the co-activating molecules and the sensitive element of the genes. As a result, the processes of transcription of genes (genomic effect) are activated in the cells and, as a result, the formation of proteins with anti-inflammatory effect: lipocortin-1 (annexin-1), IL-10, IL-1 receptor antagonist, , neutral endopeptidase and some others. The effect of steroid hormones is not immediately apparent, but after a certain time (several hours), which is necessary for the expression of the gene and the subsequent synthesis of a specific protein. However, many effects of glucocorticoids are manifested rather quickly, so that they could be explained only by stimulating the transcription of genes. Probably, they are a consequence of extragenomic effects of glucocorticoids.

The extragenomic effect of glucocorticoids is in interaction with transcription factors and inhibitory proteins. The latter are regulators of several genes involved in the immune response and inflammation, including cytokine genes (IL-1-6, -8, -11, -13, -16-18, tumor necrosis factor a (TNF-a), granulocyte- macrophage colony-stimulating factor, eotaxin, macrophage inflammatory protein, chemotactic protein of monocytes, etc.), as well as their receptors, adhesion molecules, proteinases, etc. The result of this interaction is the inhibition of transcription of pro-inflammatory and immunomodulating genes.

Anti-inflammatory, anti-allergic and immunosuppressive action. Glucocorticoids inhibit the production of a variety of factors that are critical to the triggering and development of an inflammatory response and thereby cause the suppression of excess body reactions. The action of GCS is aimed at the main participants of the inflammatory reaction: mediators of inflammation, vascular and cellular components of inflammation. Glucocorticoids reduce the production of prostanoids and leukotrienes by inhibiting the induction of lipocortin biosynthesis, which inhibits the phospholipase A2, as well as the expression of the COX-2 gene. Due to the effect on the production of pro- and anti-inflammatory mediators, glucocorticoids stabilize lysosomal membranes, reduce capillary permeability, which explains their pronounced effect on the exudative phase of inflammation. Stabilization of lysosomal membranes leads to a restriction of the yield of various proteolytic enzymes beyond the limits of lysosomes and prevents destructive processes in the tissues. The accumulation of leukocytes in the area of inflammation decreases, the activity of macrophages and fibroblasts decreases. By inhibiting the multiplication of fibroblasts and their activity with respect to the synthesis of collagen and sclerotic processes in general, glucocorticoids are able to suppress the proliferative phase of inflammation. The inhibition of maturation of basophils under the action of glucocorticoids leads to a decrease in the synthesis of mediators of immediate allergy. Thus, glucocorticoids can suppress both early and late manifestations of the inflammatory response and inhibit proliferation reactions in chronic inflammation.

The anti-inflammatory effect of glucocorticoids is nonspecific and develops in response to any damaging stimuli: physical, chemical, bacterial or pathological immune, such as hypersensitivity or autoimmune reactions. The non-specific nature of the anti-inflammatory effect of GCS makes it suitable for influencing numerous pathological processes. Although the effect of GCS does not affect the underlying causes of inflammatory disease, and it never cures, suppression of clinical manifestations of inflammation is of great clinical importance.

It is impossible to draw a clear line between the mechanisms that provide anti-inflammatory and immunosuppressive effects of GCS, since many factors, including cytokines, play an important role in the development of both pathological processes.

The disruption of the production of regulatory and effector cytokines, as well as the expression of molecules that ensure the interaction of immunocompetent cells, leads to the resolution of the immune response and, as a consequence, to its incompleteness or complete blockade. By inhibiting the production of cytokines that regulate different phases of the immune response, glucocorticoids equally effectively block the immune response at any stage of its development.

Glucocorticoids are of great clinical importance in the treatment of diseases that are the result of unwanted immunological reactions. These diseases include both states that are predominantly the result of a violation of humoral immunity (such as urticaria) and conditions that are mediated by cellular immune mechanisms (such as transplant rejection). The suppression of antibody production develops when only very high doses of glucocorticoids are administered. This effect is observed only a week after the initiation of therapy.

The second mechanism that explains the immunosuppressive effect of glucocorticoids is the increase in production in endonuclease cells. Activation of endonucleases is the central event of late stages of apoptosis, or physiological programmed cell death. In accordance with this direct consequence of the action of GCS is the death of a large number of cells and, in particular, leukocytes. Glucocorticoid-induced apoptosis affects lymphocytes, monocytes, basophils, eosinophils, and mast cells. Clinically, the apoptogenic effect of GCS is manifested as the corresponding types of cytopenia. The effect of glucocorticoids on neutrophils is of an opposite nature, i.e. Under the influence of these drugs apoptosis of neutrophils is suppressed, and the duration of their circulation increases, which is one of the causes of neutrophilia. However, glucocorticoids cause a sharp decrease in the functional activity of neutrophils. For example, under the influence of GCS neutrophils lose the ability to leave the bloodstream (oppression of migration) and penetrate into the foci of inflammation.

Due to direct interaction with DNA, steroids induce or inhibit the synthesis of enzymes that participate in the regulation of metabolism, which is the main cause of adverse reactions of GCS. Most undesirable metabolic effects are not immediately apparent, but only with prolonged therapy with GCS.

Carbohydrate metabolism

One of the important effects of GCS is their stimulating effect on gluconeogenesis. Glucocorticoids cause an increase in the formation of glycogen and the production of glucose in the liver, inhibit the action of insulin and reduce the permeability of membranes for glucose in peripheral tissues. As a result, hyperglycemia and glucosuria may develop.

[5], [6], [7], [8], [9], [10], [11], [12]

Protein metabolism

Glucocorticoids reduce the synthesis of protein and increase its decay, which is manifested by a negative nitrogen balance. This effect is especially pronounced in muscle tissue, skin and bone tissue. Manifestations of negative nitrogen balance are weight loss, muscle weakness, skin and muscle atrophy, striae, hemorrhage. Reduction of protein synthesis is one of the reasons for the delay of regenerative processes. In children, the formation of tissues, including bone, is impaired, growth is slowed.

Lipid metabolism

Glucocorticoids cause redistribution of fat. The effect on fat metabolism is manifested by local lipolytic action in the limb region, and lipogenesis in the trunk region is simultaneously induced. As a result, with the systematic use of drugs, significant amounts of fat accumulate in the face, dorsal body, and shoulders with a decrease in fat tissue of the limbs. Glucocorticoids increase the synthesis of fatty acids and triglycerides, causing hypercholesterolemia.

Water-salt exchange

Long-term use of SCS leads to the realization of their mineralocorticoid activity. There is an increase in the reabsorption of sodium ions from the distal sections of the renal tubules and an increase in the tubular secretion of potassium ions. The delay of sodium ions in the body causes a gradual increase in BCC and an increase in blood pressure. Mineralocorticoid effects of GCS are more intrinsic to natural GCS - cortisone and hydrocortisone and to a lesser extent to semisynthetic GCS.

Glucocorticoids tend to cause a negative balance of calcium in the body, reducing absorption of calcium from the digestive tract and increasing its excretion by the kidneys, which can cause hypocalcemia and hypercalciuria. With long-term administration of calcium metabolism, coupled with the disintegration of the protein matrix leads to the development of osteoporosis.

Formal blood elements

Glucocorticoids decrease the amount of eosinophils, monocytes and lymphocytes in the blood. At the same time, the content of erythrocytes, reticulocytes, neutrophils and platelets increases. Most of these changes are noted after taking even a single dose of GCS with a maximum severity of the effect after 4-6 hours. Restoration of the initial state occurs after 24 hours. With prolonged treatment of GCS, changes in the blood pattern persist for 1-4 weeks.

On the principle of feedback, glucocorticoids have a depressing effect on the hypothalamic-pituitary-adrenal system (GGNS), thereby reducing the production of ACTH. Developing in this case, insufficiency of the function of the adrenal cortex can manifest itself with a sharp withdrawal of glucocorticoids. The risk of developing adrenal insufficiency is significantly increased with the regular intake of glucocorticoids for more than 2 weeks.

[13], [14], [15], [16], [17], [18], [19],

Anti-stress action

Glucocorticoids are adaptive hormones that increase the resistance of the body to stress. Under conditions of severe stress, the production of cortisol is significantly increased (at least 10 times). There are data on the relationship of the immunological system and the GGNS. These interactions can represent, at least, one of the mechanisms of the anti-stress action of glucocorticoids. It was shown that the function of HHH is regulated by many cytokines (IL-1, -2, -6, tumor necrosis factor TNF-a). All of them have a stimulating effect. Many have a wide range of effects. For example, IL-1 stimulates the release of corticotropin-releasing hormone by hypothalamic neurons, directly affects the pituitary gland (increases the release of ACTH) and the adrenal glands (increases the release of glucocorticoid). At the same time, glucocorticoids are able to inhibit expression of many parts of the immune system, for example, production of cytokines. Thus, the GGNS and the immune system have bilateral bonds during stress and these interactions are probably of great importance in maintaining homeostasis and protect the body from the potentially life-threatening consequences of the developed inflammatory reaction.

[20], [21], [22], [23], [24], [25], [26], [27]

Permissive action

Glucocorticoids can influence the action of other hormones, greatly potentiating their effects. This action of Glucocorticoid on the effects of other regulatory hormones is called permissive and reflects changes in the synthesis of proteins caused by GCS, which alter the response of tissues to certain stimuli.

Thus, small doses of glucocorticoids cause significant potentiation of the lipolytic action of catecholamines. Glucocorticoids also increase the sensitivity of adrenoreceptors to catecholamines and enhance the pressor action of angiotensin II. It is believed that due to this glucocorticoids exert a tonic effect on the cardiovascular system. As a result, the vascular tone is normalized, myocardial contractility increases and capillary permeability decreases. In contrast, the inadequacy of the production of natural SCS is characterized by low CB, arteriolar expansion and a weak response to adrenaline.

It is shown that glucocorticoids also increase the bronchodilating effect of catecholamines, restoring to them the sensitivity of beta-adrenoreceptors, which is associated with an increase in the biosynthesis of adrenergic receptors in the vascular wall.

Pharmacokinetics

Glucocorticoids are lipophilic molecules of small size that pass well through cell barriers through simple diffusion. When ingesting glucocorticoids are well absorbed from the upper parts of the jejunum. Stam in the blood is created after 0.5-1.5 hours. The rate of development of effects and the duration of action of GCS depends on the dosage form, solubility and metabolic rate of the drug.

Glucocorticoids are produced in many dosage forms. Features of injection forms are due to both the properties of the glucocorticoid itself and the ester bound to it. Succinates, hemisuccinates and phosphates are water soluble and have a quick but relatively short-term effect. They can be administered in / m and / in. Acetates and acetonides are fine crystalline suspensions, they are insoluble in water and absorbed slowly, for several hours. Water-insoluble esters are intended for insertion into the joint cavity and articular bags. Their action reaches a maximum after 4-8 days and lasts up to 4 weeks.

In the blood glucocorticoids form complexes with plasma proteins - albumins and transcortin. If natural glucocorticoids bind 90% transcortin and 10% albumin, synthetic glucocorticoids, with the exception of prednisolone, bind predominantly to albumin (about 60%), and about 40% circulate freely. At 25-35% free glucocorticoids are deposited by red blood cells and leukocytes.

Biologically active only non-protein-bound glucocorticoids. They easily pass through the mucous membranes and gistogematicheskie barriers, including. Hematoencephalic and placental, are rapidly removed from the plasma.

Metabolism of glucocorticoids occurs mainly in the liver, in part in the kidneys and other tissues. In the liver, there is hydroxylation of glucocorticoids and their conjugation with glucuronide or sulfate. Natural steroids cortisone and prednisone acquire pharmacological activity only after metabolization in the liver with the formation of hydrocortisone and prednisolone, respectively.

Metabolization of synthetic GCS in the liver by recovery and conjugation is slower compared to natural steroids. The introduction into the structure of GCS of halogen ions of fluorine or chlorine slows the metabolism of drugs and extends them T1 / 2. Due to this, the action of fluorinated GCS lasts longer, but at the same time they more depress the function of the adrenal cortex.

Glucocorticoids are excreted from the body by the kidneys through glomerular filtration in the form of inactive metabolites. Most of the SCS (85%) is reabsorbed in the tubules, and only about 15% is excreted from the body. With renal failure, dose adjustment is not performed.

Contraindications

Relative contraindications are the states that are included in the spectrum of side effects of GCS therapy itself. Absolute contraindications are not present, if the expected benefit from treatment with glucocorticoids exceeds the increased risk of complications. This applies primarily to emergency situations and short-term use of glucocorticoids. Relative contraindications are taken into account only when planning long-term therapy. These include:

• Decompensated diabetes mellitus;
• productive symptoms in mental illness; and peptic ulcer of the stomach and duodenum in the phase of exacerbation; o severe osteoporosis;
• severe arterial hypertension; and severe heart failure;
• active form of tuberculosis, syphilis; and systemic mycoses and fungal skin lesions;
• acute viral infections;
• severe bacterial diseases; and primary glaucoma;
• pregnancy.

[28], [29], [30]

Tolerance and side effects

In general, glucocorticoids have good tolerability. The likelihood of side effects in many ways depends on the duration of treatment and the prescribed dose. They are more likely for long-term (more than 2 weeks) administration of glucocorticoids, especially in high doses. However, even very high doses of GCS when administered within 1-5 days do not cause unwanted effects. This is due to the fact that a significant part of the side effects of glucocorticoids is a consequence of metabolic disorders and requires more time for its development. Carrying out substitution therapy is also considered safe, because very low doses of glucocorticoids do not cause suppression of adrenal function and other undesirable effects associated with excess exogenous glucocorticoids.

A sharp cessation of short-term (during 7-10 days) therapy with glucocorticoids is not accompanied by the development of acute adrenal insufficiency, although some suppression of cortisone synthesis still occurs. Longer-term therapy with glucocorticoids (more than 10-14 days) requires the gradual elimination of drugs.

By timing and frequency of development, the side effects of glucocorticoids can be divided into:

• characteristic of the initial stages of treatment and essentially unavoidable:
  • insomnia;
  • emotional lability;
  • increased appetite and / or weight gain;
• late and developing gradually (probably due to cumulation):
  • osteoporosis;
  • cataract;
  • delayed growth;
  • fatty degeneration of the liver;
• rare and unpredictable:
  • psychosis;
  • benign intracranial hypertension;
  • glaucoma;
  • epidural lipomatosis;
  • pancreatitis.
  • According to the conditions of development, we can distinguish:
• 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 duodenum;
  • acne;
• Expected at application of high doses and developing for a long time:
  • "Cushingoid" appearance;
  • suppression of the hypothalamic-pituitary-adrenal axis;
  • propensity to infectious diseases;
  • osteonecrosis;
  • myopathy;
  • poor wound healing.

At daily long reception synthetic analogues of glucocorticoids with long T1 / 2 cause side effects more often than drugs with short or medium T1 / 2. A sharp cessation of treatment after prolonged therapy can lead to acute adrenal insufficiency due to the suppression of the ability of the adrenal cortex to synthesize corticosteroids. To fully restore the function of the adrenal gland, it can take from 2 months to 1.5 years.

There are isolated reports in the literature about the possibility of developing allergic reactions on the introduction of glucocorticoids. It is possible that these reactions are caused by components of drug forms of steroid drugs or possible interactions with other pharmacological drugs.

Interaction

Glucocorticoids can interact with a variety of medications. In the vast majority of cases, these interactions are of clinical significance only with prolonged therapy with glucocorticoids.

Caveats

In patients with hypothyroidism, liver cirrhosis, hypoalbuminemia, as well as in elderly and senile patients, the effect of glucocorticoids can be enhanced.

Glucocorticoids penetrate well through the placenta. Natural and nonfluorinated products are generally safe for the fetus and do not lead to intrauterine development of Cushing's syndrome and oppression of the GGNS.

Fluorinated glucocorticoids may cause undesirable reactions during long-term use, incl. And ugliness. A mother who has taken glucocorticoids for the last 1.5-2 years, to prevent acute adrenal insufficiency should additionally be administered hydrocortisone hemisuccinate 100 mg every 6 hours.

When breastfeeding low doses of glucocorticoids, equivalent to 5 mg of prednisolone, are not dangerous for the baby, as glucocorticoids penetrate into breast milk poorly. Higher doses of drugs and their long-term use may cause growth retardation and inhibition of GHGN.

[31], [32], [33], [34], [35], [36], [37]