corticosteroids

Question 1

how is cortisol released in the HPA axis?

Answer 1

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

Question 2

what are the main functions of glucocorticoids and mineralocorticoids in the body, respectively?

Answer 2

metabolic control (GC) and salt/water metabolism (MC)

Question 3

How does aldosterone function? (recall that many corticosteroids have mineralocorticoid activity)

Answer 3

upregulation of basolateral Na+/K+ ATPase, promotes Na+ reabsorption and K+/H+ excretion

Question 4

Systemic effects of cortisol

Answer 4

-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

Question 5

What are the two isoforms of the glucocorticoid receptor?

Answer 5

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

Question 6

What are the downregulated gene targets of glucocorticoids?

Answer 6

-inflammatory cytokines (TNFa, IL1b)
-RANTES chemokine
-Inflammatory enzymes (COX2, 5LOX, PLA2 –> arachidonic acid synthesis)
-adhesion molecules ICAM-1 and VCAM-1
-IL2R and TCR

Question 7

What are the upregulated gene targets of glucocorticoids?

Answer 7

-Annexin-A1 (endogenous PLA2 inhibitor)
-B2 receptor (smooth muscle relaxation)
-IL1R-2 (decoy IL-1 receptor)
-IkappaBalpha (inhibitor of NFkB)

Question 8

What is the net effect of corticosteroid administration?

Answer 8

Anti-inflammatory
-immunocytes (except neutrophils) die by apoptosis
-lymph nodes decrease in size
-macrophages increase their efferocytotic activity
-

Question 9

Most basic corticosteroid

Answer 9

cortisone, metabolised into hydrocortisone

Question 10

Cortisone + a double bond, less mineralocorticoid activity

Answer 10

prednisone, metabolised into prednisolone

Question 11

Methylated prednisone, no water retention effect

Answer 11

Methylprednisone

Question 12

Long-lasting and highly potent corticosteroids

Answer 12

dexamethasone

Question 13

What are the clinical uses of corticosteroids?

Answer 13

-leukemia (leukocyte apoptosis)
-more severe allergic disorders that don’t respond to 2nd gen antihistamines
-autoimmune disorders
-organ transplants

Question 14

Some side effects (drug-induced Cushing’s syndrome) of corticosteroids

Answer 14

-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