Corticosteroids

Question 1

What does corticotrophin releasing factor do

Answer 1

Released from hypothalamus, stimulate anterior pituitary to release ACTH

Question 2

What does aldosterone do

Answer 2

Unregulated basolateral Na+-K+ ATPase gene expression. This increases Na+ reabsorption at distal renal tubules, coupled to K+ and H+ excretion

Question 3

What is fludrocortisone

Answer 3

Synthetic analogue of aldosterone

Question 4

What are the effects of too much aldosterone

Answer 4

Hypernatriemia, hypokalemia, metabolic alkalosis, edema

Question 5

What are the effects of hydrocortisone

Answer 5

Metabolic:

• increase gluconeogenesis
• decrease peripheral glucose uptake
• increase glycogen uptake
• increase lipolysis and lipogenesis resulting in net fat deposition
• aldosterone mineralcorticoid activity when there is too much corticosteroid

Catabolic:
- break down protein in lymph, muscle, skin, bone, connective tissue, releasing nitrogen which is excreted —> negative nitrogen and calcium balance

Feedback inhibition to decrease ACTH secretion

Question 6

How does steroid regulate gene expression

Answer 6

Highly lipophilic steroid passes the plasma membrane, binds to glucocorticoid receptor. Steroid receptor forms homodimer and enters nucleus

Question 7

What is the active form of steroid receptor

Answer 7

GR alphas. A-a homodimer necessary for active form

Question 8

What gene targets do steroids decrease

Answer 8

Cytokines eg Tng-a, is-6, chemokines, inflammatory molecules eg cox-2, 5-lox, pla2, adhesion molecules

Question 9

What gene targets are increased by steroids

Answer 9

Annexin a1 (PLA2) inhibitor

IL-1 receptor antagonist

IKB-a (inhibitor of NF-kB)

Question 10

What do steroids do

Answer 10

Increases apoptosis of immune cells eg circulating T cells, monocytes —> immunosuppressive

Increase production and decrease extravasation of neutrophils, hence increased circulating neutrophils (adhesion molecules decreased so cannot travel outside of circulation)

Protein catabolism decrease size and lymphoid content of lymph nodes

Promote macrophage efferocytosis to promote reduction of inflammation

Decrease type 4 delayed hypersensitivity reaction

Question 11

What drug is used as first line immunosuppressant in transplant

Answer 11

Steroids

Question 12

Compare effect of steroid on cellular vs humoral immunity

Answer 12

More effect on cellular than humoral immunity

Question 13

Cortisone vs cortisol/hydrocortisone

Answer 13

Cortisone is the prodrug form

Cortisone has ketone group while cortisol has hydroxy group

Question 14

Compare prednisone, Prednisolone, cortisone, cortisol

Answer 14

Prednisone has double bound compared to cortisone.

Prednisone is prodrug form of Prednisolone

Prednisolone is more potent than hydrocortisol, works for increased duration (12-36h vs 8-12h)

Prednisolone less water retention effect than cortisol

Question 15

Which steroids have no water retention effect

Answer 15

Methylprednisolone, triamcinolone, betamethasone, dexamethasone

(Also increasing potency and antiinflammatory effect)

Question 16

What can steroids be used for

Answer 16

• Allergic reaction
• Collagen vascular disease eg rheumatoid arthritis, lupus erythematous
• GI disease eg Crohns
• Hematologic disorders eg leukemia, hemolytic anemia
• Organ transplant: prevent graft vs host disease and transplant rejection
• Dental conditions eg surgical swelling, gingivitis

Question 17

Patient needs to stop taking steroid, what should be done

Answer 17

Do not immediately take patient off steroid. Must slowly taper dose as patient may not produce own cortisol

Question 18

Patient needs to start steroids. What would be good choice to start with

Answer 18

Prednisolone as it is shorter acting (12-36 hours vs 24-72 hours for betamethasone and dexamethasone) and also no water retention effect

Give pulse therapy or on alternate days to minimise effect on cortisol production

Question 19

What are the side effects of corticosteroids

Answer 19

Hyperglycemia (increase gluconeogenesis sand decrease peripheral glucose uptake)

Moon face, buffalo hump, truncal obesity due to lipid deposition

Muscle wasting due to protein catabolic effect

Growth retardation in pediatric patients

Acne, menstrual disturbances because steroid cross react with hormones

Skin thinning due to decreased collagen (catabolic)

Congestive heart failure, edema, hypertension due to Na+/fluid retention

Osteoporosis

Aseptic necrosis of femoral head as high dose of corticosteroid increase lipid level lead to lipid microemboli formation

Myopathy due to dexamethasone and triamcinolone breaking down muscle

Immunosuppression lead to opportunistic infections

Post subcapsular lens cataract

Peptic ulcer disease

Depression when corticosteroid suddenly withdrawn —> adrenal corticosteroid crisis

Question 20

What happens when you abruptly withdraw corticosteroid

Answer 20

Lethargy, headache, fever, hypothalamic-pituitary-adrenal axis insufficiency