How do glucocorticoids act on the cell?
The molecular mechanism of action of glucocorticoids (GCs) occurs in several consecutive steps:
- Diffusion: the hormone easily crosses the plasma membrane into the cell.
- Binding: in the cytosol, it interacts with a specific receptor protein.
- Translocation: the resulting hormone-receptor complex enters the cell nucleus.
- Genomic interaction: the complex binds to an enhancer (Glucocorticoid Response Element, GRE) or gene promoters.
- Result: DNA conformation changes, altering gene transcription and the corresponding mRNA levels.
What are the main physiological and pharmacological effects?
Glucocorticoids exert systemic effects on multiple processes in the body:
- Metabolism: stimulate gluconeogenesis (synthesis of glucose from amino acids and pyruvate).
- Anti-inflammatory effect: inhibit phospholipase A2 activity, blocking the arachidonic acid cascade and decreasing prostaglandin and leukotriene production. They suppress the synthesis of pro-inflammatory factors (IL-1, TNF-α, COX-2), reduce vascular permeability, exudation, and phagocyte activity.
- Immunosuppressive effect: inhibit the transcription of major histocompatibility complex (MHC) genes and suppress T-lymphocyte proliferation.
- Anti-allergic effect: prevent mast cell degranulation and the release of allergy mediators.
- Antineoplastic effect: cause marked suppression of lymphoid tissue proliferation.
When are glucocorticoids prescribed?
Drugs in this group (e.g., prednisone, dexamethasone, budesonide) are used for a wide range of conditions:
- Respiratory diseases: to relieve bronchial obstruction in COPD and bronchial asthma. Both systemic (oral) and inhaled forms are used. For acute exacerbations, inhaled budesonide at a dose of 2400 mcg/day for 7–10 days is equivalent in efficacy to 40 mg/day of oral prednisone.
- Autoimmune and allergic reactions: rheumatoid arthritis, systemic lupus erythematosus, anaphylactic shock, angioedema, atopic dermatitis.
- Liver disorders: first-line therapy for drug-induced hepatotoxicity; average treatment duration is 1–3 months with subsequent tapering.
- Pericarditis: second-line therapy when aspirin or NSAIDs are ineffective or contraindicated, used in low doses (not exceeding 0.5 mg/kg).
- Oncology and transplant medicine: treatment of leukemias, lymphomas, prevention of transplant rejection, and mitigation of chemotherapy side effects (nausea, hypercalcemia, hemolysis).
What are the risks of glucocorticoid therapy?
GC therapy can be accompanied by adverse events and the development of steroid dependence. Major side effects include:
- Systemic disorders: immunosuppression, hyperglycemia, protein and mineral metabolism disturbances, redistribution of body fat, osteoporosis, growth retardation in children.
- Organ damage: gastrointestinal mucosal ulceration (ulcerogenic effect), glaucoma, cataracts, psychiatric disorders, and developmental delay in children.
- Specific complications: in patients with very severe COPD, long-term administration can cause steroid myopathy (muscle weakness), which may lead to respiratory failure.
Inhaled forms (e.g., beclometasone) have minimal systemic effects but can cause local reactions: hoarseness, cough, paradoxical bronchospasm, and oral candidiasis. To reduce risks, "soft" GCs with an improved safety profile are developed (e.g., ciclesonide)—prodrugs that are activated by esterases in the pulmonary tissue upon inhalation and have extremely low oral bioavailability.