IMMUNOLOGY TEXTBOOK - Mercury Podillya 2013

BASIC PRINCIPLES OF IMMUNODEFICIENCY TREATMENT

Methodology of Glucocorticosteroid Therapy

The primary Mechanisms of action of glucocorticosteroids are genomic and nongenomic. The genomic mechanism involves the Introduction/30.html">Regulation of Gene METABOLISM/31.html">Transcription controlling protein and DNA Synthesis. The binding of glucocorticosteroids to GC receptors triggers a cascade involving messenger and nuclear RNA, resulting in either the stimulation or suppression of gene transcription. Glucocorticosteroids affect genes that control The production of proinflammatory cytokines such as IL-1α, IL-4, IL-6, IL-9, and interferon-gamma.

Glucocorticosteroids affect both cellular and humoral immune Functions. Their influence leads to lymphocytopenia resulting from the inhibition of production and release of lymphoid Cells from the Bone Marrow, suppression of their migration, and redistribution of lymphocytes to other lymphoid compartments. Glucocorticosteroids affect the cooperative interaction of T AND B cells in the Immune Response. They exert a differential effect on various T-lymphocyte subpopulations, decreasing the level of T cells bearing receptors for the Fc fragment of IgM while leaving the level of T cells bearing receptors for the Fc fragment of IgG unchanged.

Unlike genomic effects, nongenomic effects of glucocorticosteroids result from direct physicochemical interactions with Biological Membranes and/or steroid-selective Membrane Receptors. The anti-inflammatory nongenomic effect of glucocorticosteroids is associated with the stabilization of lysosomal membranes, a decrease in Cell membrane permeability, a reduction in capillary permeability and local Blood FLOW IN inflammation sites, decreased Swelling of endothelial cells, a reduced ability of immune complexes to penetrate the basement membrane, inhibition of fibroblast growth, suppression of Collagen and mucopolysaccharide synthesis, vasoconstriction in the inflammation focus and decreased vascular permeability (partially due to the inhibition of prostaglandin synthesis), a reduction in the number of monocytes and mononuclear cells in the inflammation focus, as well as an effect on polymorphonuclear leukocytes. Thus, the leading role in the anti-inflammatory effect of glucocorticosteroids belongs to the reduction of leukocyte migration and accumulation in inflammation sites. Under The Influence of glucocorticosteroids, bactericidal activity is impaired, Fc-receptor-mediated binding of monocytes and macrophages is disrupted, and the levels of eosinophils, monocytes, and lymphocytes in the blood are decreased.

Furthermore, while at doses up to 30 mg in prednisolone equivalent the therapeutic outcome is almost entirely determined by genomic mechanisms, at doses exceeding 30 mg of prednisolone equivalent, nongenomic effects become significant, rapidly increasing in importance as the dose rises.

Daily doses of glucocorticosteroids can be classified as follows: low - 7.5 mg and below, medium - 7.5-30 mg, high - 30-100 mg, very high - more than 100 mg, pulse therapy - 250 mg i.v. calculated as prednisolone.

Depending on The Nature of the disease, its acuity and severity, as well as the involvement of vital Organs and systems in the pathological process, the routes of administration and dosage of glucocorticosteroids vary. When conducting oral therapy with medium and high doses of glucocorticosteroids, continuous and intermittent (alternate-day and interval) regimens are used. The continuous regimen involves daily intake of the total daily dose (either as a single morning dose or divided into several doses). The latter method is indicated in acute clinical situations accompanied by high fever and severe internal organ damage. A single dose in a continuous (daily) regimen reduces side effects on the gastrointestinal tract and adrenal function while maintaining sufficient clinical efficacy. In the alternate-day regimen, a determined 48-hour dose of glucocorticosteroids is administered as a single dose on alternative mornings, which reduces the frequency and severity of side effects such as adrenal suppression, intercurrent infections, and increased Catabolism. In the intermittent therapy regimen, the determined total weekly dose of the drug is administered over 3-4 days, followed by a break on the remaining days of the week, which also reduces the Adverse effects of the drugs.

Once remission or adequate disease control is achieved through glucocorticosteroid therapy, the dosage must be tapered or discontinued. The rate of tapering is determined by the initial dosage and duration of Treatment. In patients initially receiving high and very high doses of glucocorticosteroids for several weeks, the dose may be reduced by 10% at 4-day intervals. If the patient has been receiving this dose for several months, a 10% reduction of the initial dose should be carried out at intervals of several weeks. In patients receiving medium doses of GCs, they can be reduced by 10% every two weeks. In patients receiving long-term medium, high, and very high doses of glucocorticosteroids, once the dosage reaches 7.5 mg of prednisolone or 6 mg of medrol per day, further reduction should proceed at 1 mg per month for a more adequate recovery of hypothalamic-pituitary-adrenal function. The ACTH stimulation test allows for the Assessment of the recovery of the pituitary-adrenal axis. In this test, recovery is confirmed if, 30 minutes after the intramuscular injection of 250 mcg of ACTH, the plasma cortisol level increases by 6-20 mcg/mL.

The severity of the immunosuppressive effect of glucocorticosteroids does not always correlate with their anti-inflammatory effect. The most significant immunosuppressive effect in vitro is demonstrated by methylprednisolone and betamethasone, an intermediate effect by dexamethasone, prednisolone, and hydrocortisone, and the least by prednisone. Prednisolone equivalents of glucocorticosteroids are presented in Table 87 (one equivalent is equal to 5 mg of prednisolone).

Class="center">Table 87. Glucocorticosteroids for intramuscular and intravenous administration and their prednisolone equivalents

Note: one equivalent equals 5 mg of prednisolone.

The Use of glucocorticosteroids is associated with potential complications, the risk of which correlates with dosage levels and duration of use. The most frequent complications of glucocorticosteroid therapy are presented in Table 88.

Table 88. Complications of glucocorticosteroid therapy

Glucocorticosteroids are well tolerated by pregnant women. The Placenta has The ability to convert prednisolone and methylprednisolone into inactive metabolites. At the same time, dexamethasone freely crosses the placenta, resulting in equal concentrations in the mother and the fetus. Therefore, if glucocorticosteroids are indicated for treating a pregnant patient, prednisolone or methylprednisolone should be used.

The main indications for prescribing glucocorticosteroids in immune system pathologies include autoimmune diseases, systemic and hemorrhagic vasculitis, Glomerulonephritis, Crohn's disease, Ulcerative Colitis, autoimmune hepatitis, myocarditis, Bronchial Asthma, pulmonary sarcoidosis, hemoblastosis, allergic diseases including anaphylactic Shock, and transplant rejection syndrome.