Glucocorticoids

How do glucocorticoids affect the cell?

The molecular mechanism of action of glucocorticoids (GCs) is implemented in several successive stages:

1. Penetration: the hormone easily passes through the plasma membrane into the cell.
2. Binding: in the cytosol, it interacts with a specific receptor protein.
3. Translocation: the resulting hormone-receptor complex enters the cell nucleus.
4. Interaction with the genome: the complex binds to an enhancer (a DNA region that enhances transcription — Glucocorticoid Response Element, GRE) or gene promoters.
5. Result: a conformational change in DNA occurs, leading to altered gene transcription and levels of corresponding mRNAs.

What are the main physiological and pharmacological effects?

Glucocorticoids exert a systemic effect on numerous processes in the body:

• Metabolism: stimulate gluconeogenesis (synthesis of glucose from amino acids and pyruvate).
• Anti-inflammatory effect: inhibit the activity of phospholipase A2, blocking the arachidonic acid cascade and reducing the production of prostaglandins and leukotrienes. 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.
• Antitumor effect: cause marked suppression of lymphoid tissue proliferation.

When are glucocorticoids prescribed?

Drugs of this group (e.g., prednisolone, dexamethasone, budesonide) are used for a wide range of pathologies:

• Respiratory diseases: to relieve bronchial obstruction in COPD and bronchial asthma. Both systemic (oral) and inhaled forms are used. Following discharge for an acute attack, inhaled budesonide at a dose of 2400 mcg/day for 7–10 days is equivalent in efficacy to 40 mg/day of oral prednisolone.
• Autoimmune and allergic reactions: rheumatoid arthritis, systemic lupus erythematosus, anaphylactic shock, angioedema, atopic dermatitis.
• Liver disorders: first-line therapy for drug-induced hepatotoxicity; the average duration of therapy is 1–3 months followed by dose tapering.
• Pericarditis: used as second-line therapy when ASA or NSAIDs are ineffective or contraindicated, in low doses, not exceeding 0.5 mg/kg.
• Oncology and transplantology: treatment of leukemias, lymphomas, prevention of graft rejection, and management of chemotherapy side effects (nausea, hypercalcemia, hemolysis).

Why is glucocorticoid therapy dangerous?

GC therapy may be accompanied by adverse events and the development of steroid dependence. The main side effects include:

• Systemic disorders: immunosuppression, hyperglycemia, impaired protein and mineral metabolism, redistribution of adipose tissue, osteoporosis, growth retardation in children.
• Organ damage: gastrointestinal mucosal ulceration (ulcerogenic effect), glaucoma, cataracts, mental disorders, and developmental delay in children.
• Specific complications: in patients with extremely severe COPD, prolonged use can cause steroid myopathy (muscle weakness), which can lead to respiratory failure.

Inhaled forms (for example, 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 being developed (for example, ciclesonide) — prodrugs that are activated by esterases in the lung tissue upon inhalation and have extremely low bioavailability when swallowed.

Class and exam questions

What else to study on this topic

• Gluconeogenesis
• Arachidonic acid cascade
• Phospholipase A2
• Major histocompatibility complex (MHC)

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.