corticosteroids Flashcards
how is cortisol released in the HPA axis?
hypothalamus released corticotropin releasing hormone to the anterior pituitary, which stimulates the release of adrenocorticotropic hormone –> production of glucocorticoids (cortisol) which has -ve feedback on the HPA axis
what are the main functions of glucocorticoids and mineralocorticoids in the body, respectively?
metabolic control (GC) and salt/water metabolism (MC)
How does aldosterone function? (recall that many corticosteroids have mineralocorticoid activity)
upregulation of basolateral Na+/K+ ATPase, promotes Na+ reabsorption and K+/H+ excretion
Systemic effects of cortisol
-Increased blood glucose due to higher gluconeogenesis and lower peripheral glucose absorption
-fat deposition
-glycogen deposition
-mineralocorticoid effects
-catabolic effect in many tissues (e.g. skeletal muscle, bone), leads to negative protein and calcium balance
What are the two isoforms of the glucocorticoid receptor?
GRalpha (active) and GRbeta (inactive decoy - if GRb dimerises with GRa, the heterodimer is inactive –> dominant -ve effect). These receptors bind to the glucocorticoid response elements in the genome, modulating gene expression
What are the downregulated gene targets of glucocorticoids?
-inflammatory cytokines (TNFa, IL1b)
-RANTES chemokine
-Inflammatory enzymes (COX2, 5LOX, PLA2 –> arachidonic acid synthesis)
-adhesion molecules ICAM-1 and VCAM-1
-IL2R and TCR
What are the upregulated gene targets of glucocorticoids?
-Annexin-A1 (endogenous PLA2 inhibitor)
-B2 receptor (smooth muscle relaxation)
-IL1R-2 (decoy IL-1 receptor)
-IkappaBalpha (inhibitor of NFkB)
What is the net effect of corticosteroid administration?
Anti-inflammatory
-immunocytes (except neutrophils) die by apoptosis
-lymph nodes decrease in size
-macrophages increase their efferocytotic activity
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Most basic corticosteroid
cortisone, metabolised into hydrocortisone
Cortisone + a double bond, less mineralocorticoid activity
prednisone, metabolised into prednisolone
Methylated prednisone, no water retention effect
Methylprednisone
Long-lasting and highly potent corticosteroids
dexamethasone
What are the clinical uses of corticosteroids?
-leukemia (leukocyte apoptosis)
-more severe allergic disorders that don’t respond to 2nd gen antihistamines
-autoimmune disorders
-organ transplants
Some side effects (drug-induced Cushing’s syndrome) of corticosteroids
-muscle wasting, osteoporosis
-withdrawal syndrome (type E ADR) due to HPA insufficiency crisis
-growth retardation
-fluid retention –> hypertension –> congestive heart failure
-acne, growth retardation, fat redistribution/deposition
