What is the mechanism of action of glucocorticoids (GCs), such as prednisone (generic name) and dexamethasone, and how do they perform various tasks?

Mechanism of Action of Glucocorticoids

Glucocorticoids exert their diverse therapeutic effects primarily through a genomic mechanism: they bind to cytoplasmic glucocorticoid receptors, which then translocate to the nucleus to suppress inflammatory gene expression and activate anti-inflammatory genes, though this process requires 4-6 hours to produce clinical effects. 1, 2

Primary Genomic Mechanism

The fundamental pathway involves receptor-mediated gene regulation:

• Glucocorticoids cross the cell membrane and bind to glucocorticoid receptors (GR) in the cytoplasm 2, 3
• The glucocorticoid-receptor complex undergoes activation and rapidly translocates to the nucleus 2, 4
• Once in the nucleus, the complex inhibits inflammatory gene expression through interaction with pro-inflammatory transcription factors like nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) 2, 3
• This process initiates changes in gene transcription that require 4-6 hours minimum to produce clinical improvement, regardless of administration route 1, 2

How Glucocorticoids Perform Multiple Tasks

Glucocorticoids achieve their diverse effects through several complementary mechanisms:

Anti-Inflammatory Actions

• Gene suppression: They suppress expression of multiple inflammatory genes encoding pro-inflammatory cytokines including TNF-α, IL-2, and IL-6 2, 3
• Chromatin remodeling: Glucocorticoids cause deacetylation of histone proteins, resulting in tighter coiling of DNA and reduced access of transcription factors to their binding sites, thereby suppressing inflammatory gene expression 3, 4
• Cellular effects: They inhibit leukocyte migration, suppress cytokine, prostaglandin, and leukotriene synthesis, and reduce oxidative stress through ketone body induction 2

Metabolic and Immunologic Effects

• Glucocorticoids cause profound and varied metabolic effects throughout the body 5, 6
• They modify the body's immune responses to diverse stimuli 5, 6
• They activate the hypothalamic-pituitary-adrenal axis, leading to endogenous anti-inflammatory signaling 2

Gene Activation

• While primarily suppressing inflammatory genes, glucocorticoids can also bind to glucocorticoid response elements (GRE) on DNA to increase transcription of anti-inflammatory proteins including lipocortin-1, interleukin-10, and interleukin-1 receptor antagonist 3

Critical Clinical Implications

The delayed onset of action has major therapeutic consequences:

• Clinical improvement requires a minimum of 4-6 hours after administration, making glucocorticoids ineffective for acute symptom reversal 1
• In anaphylaxis, glucocorticoids should never be administered prior to or in place of epinephrine due to their slow onset 1
• Early administration is crucial in conditions like severe alcoholic hepatitis to prevent cytokine storm progression, as the delay is unavoidable 2

Important pharmacologic distinctions exist between different glucocorticoids:

• Dexamethasone almost completely lacks sodium-retaining properties compared to hydrocortisone 5
• Dexamethasone binds only to glucocorticoid receptors and has been shown to cause hippocampal neuronal effects, while hydrocortisone (identical to native cortisol) does not show the same adverse memory effects 7
• Prednisone, prednisolone, and methylprednisolone are less available to the fetus (10% of maternal dose) compared to dexamethasone, making them preferred for treating maternal disorders during pregnancy 1

Mechanisms of Glucocorticoid Resistance

Some patients fail to respond adequately due to:

• Overexpression of GR-β (a non-functional receptor variant) 2
• Excessive activation of NF-κB and AP-1, which consumes activated glucocorticoid receptors 2, 3
• Compromised histone deacetylase-2 (HDAC-2) function 2
• Failure of GR to translocate into the nucleus 4

Dosing Considerations Based on Mechanism

The pharmacokinetics directly influence clinical dosing strategies:

• Plasma elimination half-life of hydrocortisone is approximately 90 minutes, but may be shorter with CYP3A4 inducers 1
• For glucocorticoid-induced hyperglycemia, intermediate-acting steroids like prednisone reach peak plasma levels in 4-6 hours but have pharmacologic actions lasting throughout the day 1
• NPH insulin should be administered concomitantly with intermediate-acting steroids to match the 4-6 hour peak action 1