Abbreviations: GR = glucocorticoid receptor · GC = glucocorticoid · NF-κB = nuclear factor kappa B · AP-1 = activator protein-1 · PLA2 = phospholipase A2 · COX-2 = cyclooxygenase-2 · HPA = hypothalamic-pituitary-adrenal · ICS = inhaled corticosteroid · LABA = long-acting beta-2 agonist · ACTH = adrenocorticotropic hormone · CYP3A4 = cytochrome P450 3A4
Glucocorticoid Receptor Activation Pathway
Cytoplasm
GC enters cell
Lipophilic → crosses membrane freely
→
Binds cytoplasmic GR
HSP90 complex dissociates; NLS exposed
→
Nuclear import
Importin-mediated entry (minutes)
Nucleus — Two Mechanisms
Transactivation — Binds DNA
↑ Annexin A1 → inhibits PLA2
→ Blocks arachidonic acid release
→ Suppresses BOTH COX and LOX (unlike NSAIDs)
Transrepression — Tethers to NF-κB / AP-1
↓ IL-1, IL-2, IL-6, IL-8, TNF-α
↓ COX-2 gene transcription
→ Blocks cytokine cascade at source
Onset: transcriptional changes over hours. Leukocyte effects: neutrophil demargination (hours), eosinophil apoptosis (hours–days), lymphocyte redistribution (hours).
Comparative Potency — Relative to Hydrocortisone
| Agent |
GC Potency |
MC Potency |
Equivalent Anti-Inflam. Dose |
Biological t½ |
| Hydrocortisone |
1 |
1 |
20 mg |
8–12 h |
| Prednisone / Prednisolone |
4 |
0.8 |
5 mg |
12–36 h |
| Methylprednisolone |
5 |
0.5 |
4 mg |
12–36 h |
| Triamcinolone |
5 |
0 |
4 mg |
12–36 h |
| Dexamethasone / Betamethasone |
25–30 |
0 |
0.75 mg |
36–54 h |
| Fludrocortisone |
10–15 |
125–150 |
MC replacement only |
12–36 h |
MC = mineralocorticoid. Dexamethasone and betamethasone: zero MC activity — use when sodium retention undesirable (cerebral edema, fetal lung maturation). Prednisone is a prodrug → requires hepatic activation to prednisolone; use prednisolone in severe liver disease.
Key CYP3A4 Drug Interactions
- Ritonavir — most dangerous (fluticasone → Cushing syndrome)
- Azole antifungals (ketoconazole, itraconazole, voriconazole)
- Clarithromycin, erythromycin
- Diltiazem, verapamil
- Rifampin — most potent; reduces levels 50–75%
- Can precipitate adrenal crisis in dependent patients
- Carbamazepine, phenytoin, St. John's wort
HPA Axis Suppression — Key Points
- Mechanism: exogenous GC → suppresses CRH (hypothalamus) and ACTH (pituitary) → adrenal atrophy
- Morning dosing: less suppression than evening or divided doses
- Dexamethasone: long half-life (36–54 h) → greater HPA suppression per anti-inflammatory dose
- Secondary AI: mineralocorticoid preserved (no salt craving, no hyperkalemia, no hyperpigmentation)
- Adrenal crisis risk: any physiological stress (surgery, severe infection) in suppressed patient
Sick Day Rules — Every Patient on Chronic Corticosteroids
Fever or illness: double or triple oral dose. Vomiting: inject 100 mg hydrocortisone IM immediately. Major surgery: stress-dose hydrocortisone 50–100 mg IV every 6–8 h. Never stop abruptly after >3 weeks. Carry emergency card and injectable kit.