Mechanism of Action of Prednisone
Prednisone works primarily by inhibiting inflammatory gene expression through interaction with transcription factors and promoting anti-inflammatory gene transcription, resulting in potent anti-inflammatory and immunosuppressive effects. 1, 2
Molecular Mechanisms
Glucocorticoid Receptor Activation
- Prednisone binds to cytoplasmic glucocorticoid receptors (GR), which then dimerize and translocate to the nucleus 1, 2
- Once in the nucleus, the activated GR complex exerts its effects through several mechanisms 1
Anti-inflammatory Actions
- Genomic mechanisms:
- Transactivation: GR binds to glucocorticoid response elements (GRE) on DNA, increasing transcription of anti-inflammatory proteins 1, 2
- Transrepression: GR directly inhibits inflammatory gene expression by interfering with transcription factors like nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) 1, 2
- GR changes chromatin structure through histone deacetylation, leading to tighter DNA coiling and reduced access of transcription factors to binding sites 1
Specific Anti-inflammatory Effects
- Inhibits production of pro-inflammatory cytokines including IL-1β, TNF-α, IL-2, IL-6, and IL-8 3
- Suppresses expression of inflammatory enzymes (like COX-2) and adhesion molecules 1, 4
- Interacts with CREB-binding protein (CBP), which acts as a co-activator of transcription 1
- Upregulates anti-inflammatory proteins such as lipocortin-1, IL-10, IL-1 receptor antagonist, and neutral endopeptidase 1, 2
Physiological Effects
Immediate Effects
- Suppresses adrenal axis within 3 hours of administration 5
- Decreases inflammatory serum proteins within 6 hours 5
- Reduces IL-8 levels by 4 hours after administration 5
- Temporarily increases IL-10 levels (peaks at 4 hours, then decreases) 5
Metabolic and Endocrine Effects
- Directly affects T-cell function 6
- Promotes HBV DNA replication through interaction with the HBV glucocorticoid responsive element (in patients with hepatitis B) 6
- Increases insulin resistance at the liver 6
- Promotes a liver lipogenic program 6
- Has catabolic actions on bone and muscle, mobilizing amino acids for gluconeogenesis 6
- Suppresses the reproductive axis, resulting in sex steroid deficiency 6
Clinical Implications
- Prednisone's mechanism explains its effectiveness in inflammatory diseases including asthma, rheumatoid arthritis, inflammatory bowel disease, and autoimmune conditions 1, 4
- The anti-inflammatory effects are dose-dependent, with higher doses (>10 mg daily) having more pronounced effects but also more side effects 6, 4
- Low-dose prednisone (≤10 mg daily) can effectively control inflammatory features while minimizing adverse effects 4
- Prednisone's effects on chromatin structure and transcription factors explain its broad anti-inflammatory actions across multiple pathways 1, 2
Pharmacological Considerations
- Prednisone is a prodrug that must be converted to prednisolone in the liver to become active 6
- The dissociation between transrepression (beneficial anti-inflammatory effects) and transactivation (often associated with side effects) has led to development of "dissociated steroids" with potentially fewer side effects 1
- Prednisone and prednisolone are often used interchangeably in clinical practice with similar efficacy 6
Understanding prednisone's mechanism of action helps explain both its therapeutic benefits and side effect profile, allowing for more informed clinical decision-making when prescribing this medication.