Dexamethasone and Hydrocortisone

Mechanism

Pharmacological Class and Group

Systemic corticosteroids of natural origin (Hydrocortisone/Cortisol) or high-potency and long-lasting fluorinated synthetic corticosteroids (Dexamethasone).

Mechanism of Action

Glucocorticoids act through intracellular nuclear receptors widely distributed throughout the body, directly modulating genetic transcription and key physiological processes.

Genomic and Non-Genomic Mechanism of Action

1. Dissociation of the Heat Shock Protein Complex: The glucocorticoid passively diffuses through the cellular lipid membrane and binds to its specific cytosolic receptor (GR-alpha), which is inactive coupled to a multiprotein chaperone complex that includes Hsp90, Hsp70 and FKBP52. Ligand binding promotes the immediate dissociation of these proteins.

2. Nuclear Translocation and Transactivation Mechanism (Metabolic Effects): The activated dimer of the receptor translocates to the cell nucleus and binds to specific DNA sequences called glucocorticoid response elements (GRE). This induces the transcription of essential target genes:

• PEPCK and G6Pase: Stimulates de novo hepatic gluconeogenesis massively.
• Annexin-A1 (Lipocortin-1): Blocks the cellular activity of the enzyme Phospholipase A2, stopping in the bud the synthesis of arachidonic acid and the cascade of inflammatory eicosanoids (prostaglandins, leukotrienes).

3. Transrepression Mechanism (Potent Anti-inflammatory Effects): The activated GR receptor monomer physically binds and inactivates key proinflammatory transcription factors, such as nuclear factor kappa B (NF-κB) and activating protein 1 (AP-1). This silences the synthesis of primary inflammatory cytokines (IL-1, IL-2, IL-6, TNF-α).

Pharmacokinetics

High Resolution Pharmacokinetics

Indicators and dose

Clinical Indications and Off-Label Uses

• Primary, Secondary or Tertiary Adrenal Insufficiency: Lifelong physiological replacement therapy (Addison's disease or hypopituitarism, preferably using Hydrocortisone due to its mineralocorticoid profile and short-acting pharmacokinetics).
• Acute Adrenal Crisis: Emergency management with intravenous hydrocortisone infusion and aggressive replacement of physiological solution.
• Dynamic screening tests (Dexamethasone suppression test / Nugent Test): For the confirmatory diagnosis of Cushing's Syndrome.
• Congenital Adrenal Hyperplasia (CAH): To suppress the pathological excessive secretion of feedback pituitary ACTH and stop secondary virilization.
• Anti-inflammatory, immunosuppressive and oncological processes: Respiratory distress syndromes, tumor brain edema (Dexamethasone due to low mineralocorticoid activity), severe autoimmune diseases.

Dosage and Clinical Adjustment

Replacement Therapy in Chronic Adrenal Insufficiency (with Hydrocortisone):

• Guidative total daily dose of 15 mg to 25 mg per day orally. It should be divided to mimic the body's physiological circadian rhythm of cortisol secretion: 2/3 of the total dose administered early in the morning upon awakening (e.g., 15 mg at 7:00 AM) and the remaining third administered in the evening (e.g., 5 mg at 5:00 PM) to avoid insomnia.

Dose of Stress in Serious Clinical Situations:

• Moderate stress (minor infection, outpatient surgery): Double or triple the usual maintenance dose until the process is resolved.
• Severe stress / Major surgery / Trauma: Administer 100 mg of hydrocortisone intravenously followed by an additional 100-200 mg per day administered as a continuous infusion or divided every 6 hours.

Adjustment in Liver Failure: The metabolic clearance of corticosteroids is markedly reduced in Child-Pugh B or C cirrhosis, so it is recommended to reduce the maintenance dose by 25-50% to mitigate accelerated iatrogenic Cushing's.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Known hypersensitivity to the compound.
• Untreated systemic fungal infections or disseminated active tuberculosis (due to the profound immunosuppressive effect induced).
• Concomitant administration of live attenuated vaccines in patients receiving immunosuppressive doses of glucocorticoids.

Relative Contraindications

• Active peptic ulcer with risk of gastric perforation.
• Poorly controlled diabetes mellitus or severe refractory arterial hypertension.
• Severe osteoporosis or acute refractory psychosis induced by corticosteroids.

Adverse Effects (ADR) and Specific Toxicity

• The use of prolonged supraphysiological doses (>2 weeks) invariably produces the clinical picture of Iatrogenic Cushing's Syndrome and induces Secondary adrenal insufficiency due to adrenal atrophy.
• Adverse Effects of Prolonged Use of Devices and Systems:
  • Metabolic: Glucose intolerance and secondary diabetes mellitus, redistribution of body fat (moon facies, buffalo hump, central obesity), mixed dyslipidemia.
  • Osteomuscular: Severe osteoporosis, pathological vertebral crush fractures, avascular necrosis of the femoral head, predominantly proximal muscle weakness (corticosteroid myopathy).
  • Immunological: Increased susceptibility to opportunistic bacterial, viral or fungal infections, delayed wound healing.
  • Skin: Atrophy of the dermis, wide violet-purple striae on the abdomen, capillary fragility with multiple ecchymoses in the event of minimal trauma.
  • Psychiatric: Insomnia, initial psychomotor euphoria, severe emotional lability, refractory depression, symptoms of psychosis due to corticosteroids ("steroid psychosis").

Critical Toxicity: HPA Axis Suppression and Acute Adrenal Crisis

Continuous exposure to glucocorticoids at supraphysiological doses profoundly suppresses hypothalamic CRH and pituitary ACTH secretion. This chronic lack of trophic stimulation induces bilateral atrophy of the adrenal cortex (zona fasciculata and reticularis).