Mechanism of action: how steroids block inflammation
Glucocorticoids act at the genomic level. Penetrating the target cell, the hormone binds to a receptor in the cytoplasm. This complex then moves into the nucleus, where it interacts with chromatin, stimulating or suppressing the synthesis of specific proteins.
The main anti-inflammatory effect is associated with the effect on arachidonic acid metabolism. The process proceeds in a cascade:
- The drugs induce the production of the protein lipocortin.
- Lipocortin blocks the enzyme phospholipase A2.
- Due to this, the release of arachidonic acid from the phospholipids of damaged cell membranes stops.
- Without the substrate, the synthesis of inflammatory mediators stops via two pathways simultaneously: the cyclooxygenase pathway (prostaglandins decrease) and the lipoxygenase pathway (leukotrienes decrease).
Additionally, the hormones suppress the transcription of pro-inflammatory cytokine genes (interleukins, tumor necrosis factor) and tissue-destroying enzymes (e.g., collagenase).
Main pharmacological effects
In clinical practice, the drugs are used for their powerful extrametabolic properties (pathogenetic therapy):
- Anti-inflammatory action: rapidly reduces pain, swelling, heat, and redness. They suppress the expression of adhesion molecules on the endothelium, preventing leukocytes from leaving the blood vessels into the inflammation focus.
- Immunosuppressive and antiallergic action: suppress the activity of tissue macrophages, reduce antibody production, and redistribute lymphocytes from the blood into lymphoid tissue.
- Anti-shock action: reduce the synthesis of platelet-activating factor and enhance the vasoconstrictor effect of catecholamines (adrenaline), maintaining blood pressure.
Interesting fact: a blood test while taking glucocorticoids shows neutrophilic leukocytosis. Neutrophils leave the bone marrow but cannot penetrate tissues, remaining in circulation within the vascular bed.
Drug classification
Drugs are classified by origin, chemical structure, and route of administration. The introduction of a fluorine atom into the molecule sharply enhances the anti-inflammatory effect and reduces the effect on water-salt metabolism.
| Group | Features | Representatives |
|---|---|---|
| Natural | Human hormone analogues | Hydrocortisone (Hydrocortisone) |
| Synthetic (non-fluorinated) | Stronger than natural ones, retain less water | Prednisolone, methylprednisolone |
| Synthetic (fluorinated) | Maximum activity, minimum sodium retention | Dexamethasone, triamcinolone |
| Topical | Ointments and creams for dermatology | Betamethasone, clobetasol |
| Inhalation | For pulmonology (asthma, COPD) | Budesonide, beclometasone |
Side effects of long-term therapy
Long-term use of high doses leads to iatrogenic Cushing's syndrome—a state of artificial hormone excess that affects all types of metabolism.
- Carbohydrate metabolism: stimulation of glucose synthesis and reduction of its uptake by tissues leads to hyperglycemia and the development of steroid diabetes mellitus.
- Protein metabolism: increased protein breakdown causes muscle atrophy and skin thinning.
- Fat metabolism: fat is redistributed dysplastically. The face becomes "moon-shaped" and crimson, adipose tissue is deposited on the trunk, and the limbs become thin. Striae (crimson stretch marks) appear.
- Gastrointestinal tract and bones: "steroid" gastric ulcers form (due to stimulation of hydrochloric acid secretion), osteoporosis occurs, and bone growth is delayed in children.
- CNS: direct excitatory action can cause steroid psychoses with fluctuations from euphoria to deep depression.
Briefly: answers to topical questions
What are the absolute contraindications to the systemic administration of glucocorticoids?
Absolute contraindications to the systemic administration of glucocorticoids generally do not exist. The exception is dexamethasone, which is strictly contraindicated during pregnancy. The pathogenesis of this limitation is related to the fact that the drug is not inactivated by the placental enzyme 3β-hydroxysteroid dehydrogenase. As a result, it crosses the placenta unchanged directly into the fetal blood, creating a high risk of adverse effects for the unborn child.
What is the complete pathogenesis of the ulcerogenic effect (formation of "steroid" ulcers) of glucocorticoids?
The pathogenesis of the ulcerogenic effect of glucocorticoids lies in the disruption of the balance between aggression and defense factors of the gastrointestinal mucosa. The formation of "steroid" ulcers is caused by three main mechanisms:
- Hydrochloric acid secretion—increases in the stomach, and pepsin secretion is also stimulated.
- Protective mucus—changes in its qualitative composition are observed.
- Surface epithelium—its regeneration is inhibited.
As a result of these processes, mucosal resistance decreases and a persistent ulcer defect forms.
How do glucocorticoids affect water and electrolyte metabolism?
Glucocorticoids affect water and electrolyte metabolism due to concomitant mineralocorticoid activity. The main mechanisms and clinical consequences include:
- Sodium ions—enhanced reabsorption, causing water retention, edema, and arterial hypertension.
- Potassium ions—enhanced excretion, leading to hypokalemia, muscle weakness, and cardiac arrhythmias.
The severity of the effect depends on the drug: natural hormones have the maximum effect, prednisolone retains sodium and water to a lesser extent, and dexamethasone has practically no effect on mineral metabolism.
With which drug groups do glucocorticoids have clinically significant interactions?
Glucocorticoids have clinically significant interactions with numerous drug groups, which requires therapy adjustment:
- Antacids—reduce the absorption of oral glucocorticoids.
- Oral contraceptives—cause an increase in the half-life of glucocorticoids.
- Cardiac glycosides—their combination increases the risk of arrhythmia and digitalis toxicity against the background of hypokalemia.
- Indirect anticoagulants — cause changes in blood coagulation.
- Diuretics — in combination with high doses of glucocorticoids provoke the development of hypokalemia.
- Nonsteroidal anti-inflammatory drugs — combined use significantly increases the risk of steroid ulcers.
To remember the anti-inflammatory cascade, use the chain: Glucocorticoids → Lipocortin → block of Phospholipase A2 → no Arachidonic acid (G-L-P-A).
Class and exam questions
Why is abrupt discontinuation of drugs dangerous?
Withdrawal syndrome develops — acute adrenal insufficiency. Due to the prolonged intake of exogenous hormones, the pituitary gland stops producing ACTH, and the adrenal glands atrophy, failing to resume function quickly enough.
What is the difference between water-soluble and insoluble drug forms?
Water-soluble forms (succinates, phosphates) act quickly but have a short duration — they are ideal for emergency care (shock). Insoluble forms (acetates) are used as suspensions and provide a prolonged, sustained effect.
What else to study on this topic
- Alternating therapy: how alternate-day administration protects the adrenal glands from atrophy.
- Mineralocorticoids: regulation of water and electrolyte balance and differences from glucocorticoids.
- Types of glucocorticoid therapy: replacement, suppressive, and pathogenetic.
- Addison's disease and acute adrenal insufficiency: symptoms of hormone deficiency.
- The effect of glucocorticoids on the transcription of matrix metalloproteinase genes and interleukin receptors.
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