Corticosteroids Flashcards
What does the hypothalamus release to the anterior pituitary
Corticotropin Releasing Factor (CRF)
What does the anterior pituitary release to the adrenal cortex
Adrenocorticotropin releasing hormone (ACTH)
What 2 hormones does the adrenal gland release? what are their synthetic analogues? What do they cause?
Glucocorticoid (Cortisol)
Synthetic Analogue: Prednisolone
Effects: Metabolic, Anti-inflammatory, Immunosuppressive
Mineralocorticoid (Aldosterone)
Synthetic Analogue: Fludrocortisone
Effects: Sodium and water retention, K+ and H+ excretion
What are some pro-inflammatory cytokines?
TNF-a , IL-1, IL-6
What is the mechanism of action of aldosterone?
Binds to Mineralocorticoid receptors, causing upregulation of Basolateral Na+/K+-ATPase Gene Expression
Promotes NA+ re-absorption at distal renal tubules coupled to K+ and H+ excretion
What happens in excess of aldosterone?
Hypernatremia, Hypokalemia, Metabolic Alkalosis, Edema
What are the metabolic effects of cortisol?
- Increases gluconeogenesis and decreses peripheral glucose uptake => increases glucose level
- Increases glycogen deposition
- Increases Lipolysis (due to decrease glucose uptake into fat cells) and increases lipogenesis (due to increase glucose levels) => net increase in lipid level
- Has minerlocorticoid activity
What are the catabolic effects of cortisol
- Breaks down proteins in lymphoid, muscle, skin, bone, and connective tissues
- negative nitrogen and calcium balance
What is the negative feedback inhibition of cortisol
Decrease in adrenocorticotropin releasing hormone
What type of receptor is the steroid receptor?
Nuclear receptor which is a gene active receptor (functions like a transcription receptor)
Which 2 domains of the steroid receptor forms dimers?
- Transcription activating domain
2. DNA binding domain
What does the GRA and GRB receptors do?
GRA activates
GRB dominantly negatively inhibits
Hence, only 2 GRA receptor dimers can activate.
What is the genomic action of corticosteroids?
Transactivation/Transrepression
- Monomer Tethering Transactivation/Repression
- Monomer Transactivation/Repression - co-activator in between
- Dimer Transactivation/Repression
What are the anti-inflammatory targets of steroids
Decreased (Inflammatory cells):
- Cytokines (TnF-a, IL-1B, IL-6)
- Chemokines (Rantes)
- Inflammatory Enzymes (COX-2, 5-LOX, PLA2)
- Receptors (IL-2R, T-cell Receptor)
Increased (Protective proteins):
Annexin A1 (PLA2 inhibitor)
B2-adrenoceptor
IkB-a (Inhibitor of NF-kB)
What are the Anti-inflammatory actions of steroids
- Decrease circulating T cells, B cells, monocytes, eosinophils, basophils via increased apoptosis => immunosuppression
- Increase circulating neutrophils via increased production and reduced extravasation
- Decrease the size and lymphoid content of lymph nodes (through catabolic effect)
- More effect on cellular immunity than humoral immunity
- Increase macrophage efferocytosis and promotion of resolution of inflammation
- Decrease type 4 delayed hypersensitivity reaction (transplant rejection)
- First-line immunosuppressant in solid organ and hematopoietic stem cell transplantation