Anti-Inflammatory Drugs · Module 3 of 4

Corticosteroids — Mechanisms, Pharmacology, and Clinical Use

GR pathway, potency comparison, ICS advantage, and HPA axis suppression

Corticosteroids outperform NSAIDs because they block inflammation at two upstream points simultaneously — transactivation induces annexin A1, which inhibits PLA2 and blocks both the COX and LOX pathways from the top; transrepression tethers the activated GR to NF-κB and AP-1, preventing transcription of IL-1, IL-6, IL-8, TNF-α, COX-2 gene, and matrix metalloproteinases; NSAIDs can only block the COX enzyme downstream, leaving the LOX pathway and cytokine production untouched.
Dexamethasone and betamethasone have zero mineralocorticoid activity — this makes them preferred when sodium retention must be avoided (cerebral edema, fetal lung maturation, congenital adrenal hyperplasia suppression); their very long biological half-life (36–54 h) also means they produce greater HPA axis suppression per anti-inflammatory dose than shorter-acting agents, so they are not preferred for long-term maintenance therapy despite high anti-inflammatory potency.
Prednisone is a prodrug requiring hepatic activation to prednisolone — in severe liver disease, use prednisolone (the active form) directly; anti-inflammatory dose equivalence: hydrocortisone 20 mg = prednisone/prednisolone 5 mg = methylprednisolone/triamcinolone 4 mg = dexamethasone/betamethasone 0.75 mg; fludrocortisone is mineralocorticoid-only (MC potency 125–150×, GC potency 10–15×) and is used exclusively for mineralocorticoid replacement.
ICS achieve high local airway anti-inflammatory potency while minimizing systemic exposure through two complementary pharmacokinetic features — direct particle deposition on airway mucosa produces high local concentrations from a small dose; swallowed or pulmonary-absorbed drug undergoes rapid CYP3A4 first-pass hepatic metabolism (fluticasone propionate: essentially zero oral bioavailability); LABAs and ICS are pharmacologically synergistic — LABAs enhance GR nuclear translocation and corticosteroid responsiveness, while ICS prevent LABA-induced beta-2 receptor downregulation; LABAs must never be used as asthma monotherapy without ICS (increased mortality shown in trials).
HPA axis suppression from prednisone ≥20 mg/day for ≥3 weeks is likely to be clinically significant — secondary adrenal insufficiency differs from primary (Addison disease) in that mineralocorticoid production is preserved (aldosterone is RAAS-regulated, not ACTH-dependent) and hyperpigmentation does not occur (ACTH is low); the dangerous event is adrenal crisis during physiological stress; sick day rules are mandatory for all patients on chronic corticosteroids; tapering must reduce by 1 mg/week once below physiological range (5–7.5 mg/day prednisone equivalent).

Abbreviations: GR = glucocorticoid receptor · GC = glucocorticoid · NF-κB = nuclear factor kappa B · AP-1 = activator protein-1 · PLA2 = phospholipase A2 · COX = cyclooxygenase · LOX = lipoxygenase · HPA = hypothalamic-pituitary-adrenal · ICS = inhaled corticosteroid · LABA = long-acting beta-2 agonist · ACTH = adrenocorticotropic hormone · CYP3A4 = cytochrome P450 3A4 · GRE = glucocorticoid response element · MC = mineralocorticoid · RAAS = renin-angiotensin-aldosterone system · PPI = proton pump inhibitor

Glucocorticoid Receptor Activation — Two Nuclear Mechanisms

Transactivation — Binds DNA at GRE

Anti-Inflammatory Gene Induction

Lipophilic GC crosses membrane freely; binds cytoplasmic GR; HSP90 complex dissociates; nuclear localization signal exposed; importin-mediated nuclear entry within minutes
GR dimer binds GRE promoters → induces annexin A1 → inhibits PLA2 → blocks arachidonic acid release → blocks BOTH COX and LOX simultaneously (unlike NSAIDs, which only block COX)
Also upregulates other anti-inflammatory signaling proteins
Transactivation also drives metabolic adverse effects: gluconeogenic enzyme induction, lipolysis, adipose redistribution, muscle protein catabolism — all GRE-driven
Onset of transcriptional changes: hours; leukocyte effects begin within hours

Transrepression — Tethers to Transcription Factors

Pro-Inflammatory Gene Silencing

GR does not bind DNA directly; instead tethers via protein-protein interaction to NF-κB and AP-1
Prevents NF-κB and AP-1 from binding target promoters → suppresses: IL-1β, IL-2, IL-6, IL-8, TNF-α, COX-2 gene transcription, and matrix metalloproteinases
COX-2 gene suppression adds a second layer of eicosanoid inhibition on top of PLA2 block from annexin A1
Leukocyte effects: neutrophilia (demargination within hours); eosinophil apoptosis (hours–days); lymphocyte redistribution to lymphoid organs; reduced vascular permeability

Comparative Potency — Relative to Hydrocortisone

Agent	GC Potency	MC Potency	Anti-Inflam. Dose	Biological t½ / Notes
Hydrocortisone	1	1	20 mg	8–12 h; preferred for physiological replacement (replaces both GC and MC)
Prednisone / Prednisolone	4	0.8	5 mg	12–36 h; prednisone is prodrug → prednisolone; use prednisolone in severe liver disease
Methylprednisolone	5	0.5	4 mg	12–36 h; preferred IV for acute indications (sodium succinate salt); 1:1 oral-to-IV conversion
Triamcinolone	5	0	4 mg	12–36 h; zero MC activity; used topically and as intra-articular injection
Dexamethasone / Betamethasone	25–30	0	0.75 mg	36–54 h; zero MC activity — use when sodium retention undesirable; long t½ → greatest HPA suppression; preferred for cerebral edema, fetal lung maturation
Fludrocortisone	10–15	125–150	MC replacement only	12–36 h; used exclusively for mineralocorticoid replacement in primary adrenal insufficiency

CYP3A4 Drug Interactions and HPA Axis Suppression

CYP3A4 Inhibitors — Raise Corticosteroid Levels

Cushing Risk

Ritonavir: most dangerous — can raise fluticasone or triamcinolone to systemic Cushingoid levels even with non-systemic formulations; avoid combination or use budesonide (lower affinity)
Azole antifungals (ketoconazole, itraconazole, voriconazole): potent CYP3A4 inhibitors; dose adjustment needed when added to corticosteroids in immunosuppressed patients
Diltiazem, clarithromycin, erythromycin: moderate inhibitors

CYP3A4 Inducers — Lower Corticosteroid Levels

Therapeutic Failure Risk

Rifampin: most potent inducer; reduces prednisolone exposure 50–75%; can precipitate adrenal crisis in corticosteroid-dependent patients when started without dose adjustment (seen in TB co-treated with corticosteroids for another indication)
Carbamazepine, phenytoin, St. John’s wort: moderate inducers
Monitor for loss of corticosteroid efficacy; increase dose by 50–100% during rifampin course

HPA Axis Suppression

Threshold and Secondary AI

Likely significant HPA suppression: prednisone ≥20 mg/day for ≥3 weeks; lower doses and longer durations may also suppress
Morning dosing: less suppression than evening or divided (overlaps natural cortisol peak)
Alternate-day dosing: substantially reduces HPA suppression while preserving anti-inflammatory efficacy
Secondary AI vs. primary (Addison): MC preserved (RAAS intact, not ACTH-dependent); no hyperpigmentation (ACTH is low, not elevated); presents with fatigue, nausea, orthostatic hypotension

Sick Day Rules, Stress Dosing, and Tapering

Every patient on ≥20 mg prednisone/day for ≥3 weeks must be counseled: febrile illness or significant stress → double or triple oral dose until recovered; vomiting or unable to take orals → inject 100 mg hydrocortisone IM immediately and seek emergency care; major surgery → inform anesthetic team; stress-dose hydrocortisone 50–100 mg IV every 6–8 h perioperatively, taper to basal dose over 24–48 h postoperatively. Carry a steroid emergency card and prefilled hydrocortisone injection kit at all times during any taper period.

Tapering strategy: courses <3 weeks at any dose can generally be stopped abruptly (HPA suppression unlikely). Longer courses: reduce in steps of 5–10 mg/week until physiological replacement range (prednisone 5–7.5 mg/day equivalent), then reduce by 1 mg every 1–2 weeks monitoring for adrenal insufficiency symptoms. Morning serum cortisol <3 mcg/dL indicates incomplete recovery → pause taper temporarily. ICS: reduce oropharyngeal candidiasis and dysphonia with spacer use, mouth rinsing, and ciclesonide (prodrug, inactive at oropharyngeal mucosa).

Giant cell arteritis: never delay corticosteroid treatment pending biopsy — start prednisone 40–60 mg/day immediately when clinical picture is consistent; ophthalmic artery occlusion from ongoing granulomatous inflammation can produce permanent bilateral blindness; temporal artery biopsy findings persist for 1–2 weeks after starting steroids. Cerebral edema (vasogenic, from tumor or metastases): dexamethasone is preferred (zero MC activity, long t½); dexamethasone is NOT effective in cytotoxic edema from ischemic stroke — do not use in that setting.

Suggested References

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