Prednisolone: Mechanism of Action (MOA) and Adverse Drug Reactions (ADRs)

Mechanism of Action

1. Genomic (Nuclear Receptor) Mechanism

• After oral administration, prednisolone (or its active form) diffuses into cells and binds to the cytosolic glucocorticoid receptor (GR, NR3C1), releasing it from heat shock proteins (HSP90 complex).
• The ligand-GR complex translocates to the nucleus, where it binds glucocorticoid response elements (GREs) on DNA.
• This causes transactivation (upregulation of anti-inflammatory genes, e.g., annexin-1/lipocortin) and transrepression (inhibition of pro-inflammatory transcription factors like NF-κB and AP-1).
• Net result: decreased gene transcription of inflammatory mediators. Since this involves transcription and translation, many effects are delayed by hours.

2. Key Anti-inflammatory Actions

• Induces lipocortin (annexin-1), which inhibits phospholipase A2 (PLA2) - this blocks the liberation of arachidonic acid, thereby reducing both prostaglandins (via COX pathway) and leukotrienes (via lipoxygenase pathway).
• Reduces expression of IL-1, IL-2, IL-6, TNF-α, COX-2, and inducible nitric oxide synthase (iNOS).
• Decreased vasoactive and chemoattractant factors - reduced vascular permeability, reduced leukocyte migration and extravasation.
• Inhibits fibrosis via reduced connective tissue growth factors.
• Causes redistribution of lymphocytes, eosinophils, monocytes, and basophils away from the circulation (lymphopenia, eosinopenia) within 4-6 hours, while increasing circulating neutrophils (neutrophilia via increased marrow release and reduced margination).
• Induces lymphocyte apoptosis - useful in lymphoid malignancies.

3. Immunosuppressive Effects

• T lymphocytes are most affected (reduction in lymphocyte populations).
• Suppresses both humoral and cell-mediated immunity.

4. Non-genomic Effects

• Rapid effects (within minutes) independent of gene regulation - the exact mechanisms are not fully understood but may involve membrane-bound GR.

Goodman & Gilman's Pharmacological Basis of Therapeutics, Chapter 50 The Washington Manual of Medical Therapeutics - Glucocorticoids section

Clinical Uses (Indications)

Adverse Drug Reactions (ADRs)

Endocrine / Metabolic

• Hyperglycemia / steroid-induced diabetes - due to increased gluconeogenesis, insulin resistance
• Iatrogenic Cushing syndrome - moon face, buffalo hump, central obesity, striae
• HPA axis suppression - risk of adrenal crisis on abrupt withdrawal or during physiological stress (surgery, infection); "stress-dose" steroids required
• Weight gain
• Hypokalemia (especially at higher doses with mineralocorticoid activity)
• Dyslipidemia - elevated LDL, triglycerides

Musculoskeletal

• Osteoporosis - affects 30-50% of patients on chronic therapy; trabecular bone preferentially affected; vertebrae and ribs most commonly fractured. Prevention: calcium 1-1.5 g/day + vitamin D 1000 IU/day + bisphosphonates
• Avascular (ischemic) necrosis of bone - most commonly femoral head, also humeral head and tibial plateau
• Proximal myopathy - muscle weakness without tenderness; CK, aldolase, and EMG are normal; resolves slowly after stopping
• Impaired linear growth in children (>7.5 mg/day prednisolone equivalent)

Cardiovascular

• Hypertension - via sodium and water retention, increased vascular reactivity
• Dyslipidemia - increased cardiovascular risk
• Increased risk of atherosclerosis with long-term use

Ophthalmologic

• Posterior subcapsular cataracts
• Glaucoma (raised intraocular pressure - IOP)

Immunological / Infectious

• Increased susceptibility to infections - major cause of morbidity/mortality
  • Minor infections may become systemic
  • Latent infections reactivate (TB, fungal)
  • Opportunistic organisms: consider PCP prophylaxis (co-trimoxazole) in patients on prednisolone ≥20 mg/day for >1 month
• Fever may be masked (partially)

Dermatologic

• Acne, purpura, ecchymoses
• Cutaneous atrophy (thin, fragile skin)
• Poor wound healing
• Striae

Psychiatric / Neurological

• Mood changes - euphoria, irritability, insomnia (common with short-term use)
• Depression, anxiety, or frank psychosis with higher doses or prolonged use
• Benign intracranial hypertension (pseudotumor cerebri) - especially on dose reduction

Gastrointestinal

• Peptic ulcer disease - increased risk especially when combined with NSAIDs
• Nausea, dyspepsia

Summary Table of Key ADRs

Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics, 14e | The Washington Manual of Medical Therapeutics | Rheumatology, 2-Volume Set (Elsevier, 2022)