Glucocorticoids (e.g., cortisol, prednisone, dexamethasone) exert their effects primarily through intracellular receptor-mediated gene regulation.

They influence metabolism, immune response, and inflammation.

See drug class:

• Corticosteroids

Glucocorticoids are lipid-soluble.

• Diffuse freely across cell membranes
• No surface receptor required

Inside the cytoplasm:

• Glucocorticoid binds to the glucocorticoid receptor (GR)
• Receptor is normally bound to heat shock proteins (HSP90)
• Binding causes conformational change
• Heat shock proteins dissociate

Now activated GR–steroid complex forms.

The activated glucocorticoid-receptor complex:

• Translocates into the nucleus
• Binds glucocorticoid response elements (GREs) on DNA

This alters gene transcription.

• Annexin-1 (inhibits phospholipase A2)
• IkB (inhibits NF-kB)
• Anti-inflammatory proteins

• IL-1
• IL-2
• IL-4
• IL-5
• IL-6
• TNF-α
• COX-2
• Adhesion molecules

Net effect:

↓ Inflammation
↓ Immune cell activation
↓ Eosinophil survival

Onset:

Hours to days (requires gene transcription)

Some rapid effects occur within minutes.

Mechanisms may include:

• Membrane-associated glucocorticoid receptors
• Interaction with intracellular signaling pathways
• Direct suppression of immune cell activation

These effects are less well defined but clinically relevant in acute settings.

Key downstream effect:

↓ Phospholipase A2 activity
↓ Arachidonic acid production
↓ Prostaglandins
↓ Leukotrienes

This explains synergy with:

• Antihistamines
• Leukotriene Modifiers

Glucocorticoids:

• Suppress Th1 and Th2 responses
• Reduce cytokine production
• Reduce T-cell proliferation
• Decrease macrophage activation
• Promote lymphocyte apoptosis (dose dependent)

Clinical implication:

Broad immunosuppression.

Glucocorticoids also:

• Increase gluconeogenesis
• Promote protein catabolism
• Increase lipolysis
• Decrease peripheral glucose uptake

Explains:

• Hyperglycemia
• Muscle wasting
• Cushingoid appearance

Endogenous cortisol secretion is regulated by:

Hypothalamus → CRH  
Pituitary → ACTH  
Adrenal cortex → Cortisol  

Cortisol provides negative feedback at hypothalamus and pituitary.

Exogenous glucocorticoids suppress ACTH production → adrenal atrophy.

See:

• HPA Axis Physiology

Glucocorticoid signaling explains therapeutic use in:

• Allergic Rhinitis
• Asthma
• Atopic Dermatitis
• Rheumatoid Arthritis
• Inflammatory Bowel Disease

• Glucocorticoids act through intracellular receptors.
• Effects are primarily genomic (slow onset).
• They suppress both cytokine production and eicosanoid synthesis.
• Long-term use suppresses the HPA axis.
• They are broad anti-inflammatory agents — not targeted therapies.