Steroids

Question 1

Where are corticosteroids produced?

Answer 1

Adrenal Cortex

Question 2

What is the function of Glucocorticoids?

Answer 2

Peripheral Actions - Metabolic, anti-inflammatory, immunosuppressive

Question 3

What is Aldosterone?

Answer 3

Mineralocorticoid

Question 4

What is Aldosterone Mechanism of action?

Answer 4

Aldosterone binds to mineralocorticoid receptor (nucleur) and upregulates basal Na+/K+ - ATPase Gene Expression

Question 5

What is the effect of Aldosterone?

Answer 5

Na+ Reabsorption at distal Renal Tubules coupled to K+ and H+ excretion

Question 6

What are the effects of Aldosterone IN EXCESS?

Answer 6

1) Hypernatremia (Excessive Sodium)
2) Hypokalemia (Potassium Loss)
3) Metabolic Alkalosis (pH of body increases)
4) Edema

Question 7

What is the function of Mineralocorticoids?

Answer 7

Peripheral Action on salt and water metabolism

Question 8

How is Corticosteroid secretion regulated?

Answer 8

Cortisol and prednisone exert a negative feedback mechanism
When too much produced,
it will inhibit the hypothalumus,
inhibit corticotropin stimulating hormone,
inhibit pituitary gland,
inhibit adrenocorticotropic hormone

THUS inhibit cortisol

Question 9

What are the metabolic effects of Cortisol (Hydrocortisone)?

Answer 9

Increased Gluconeogensis, Decreased peripheral glucose uptake (Increased glucose available in body)
Increase Glycogen deposition
Increase Lipolysis, Lipogenesis, Increased Net Fat Deposition
Mineralocorticoid activity

Question 10

What are the catabolic effects of Cortisol?

Answer 10

Breakdown of proteins in Lymphoid, Muscles, Skin, Bone and Conenctive Tissues
Negative Nitrogen and Calcium Balance -> calcium released leading to hypocalcimia

Question 11

What are the 2 types of Glucocorticoid receptors?

Answer 11

GR alpha (active), GR beta (inactive)

Question 12

What is the mechanism of action of steroid?

Answer 12

When Corticosteroid is produced by adrenal cortex, carried by corticosteroid binding globin (CBG) througout the body
Corticosteroid will then be released, enter the cell and bind to Glucocorticoid recptor, forming a homodimer which will enter the nucleus and modulate gene expression

Question 13

What is the differences between GRa and GRb?

Answer 13

Since homodimerisation occurs,

When GRa x GRa, binds to GRE leads to Transactivation and Transrepression

When GRa x GRb, since Grb is a dominant negative and usually inactive, it completely shuts down activity, blocking GRa signalling

Question 14

What are the gene targets DECREASED by corticosteroids?

Answer 14

1) Cytokines (TNF a, IL-1b, IL-6)
2) Chemokines (RANTES)
3) Inflammatory Enzymes (COX-2, 5-Lipoxygenase 5-LOX, Phospholipase A2)
4) Adhesion molecules (ICAM-1, VCAM-1)
5) Receptors (IL-2R, T-Cell Receptor)

Question 15

What are the gene targets INCREASED by corticosteroids?

Answer 15

1) Annexin-A1 : PLA2 inhibitor (phospholipase A2)
2) b2- adrenoceptor (Airway smooth muscle dilation)
3) IL-1 Receptor Antagonist (Blocking of IL-1 receptor)
4) IL-1RII (Decoy Receptor)

Question 16

What are the Anti-Inflammatory Biological outcomes of Steroids?

Answer 16

1) Decrease Circulating T cells, B cells, monocytes, eosinophils, basophils by increasing apoptosis
2) Increasing Circulating Neutrophils by increasing production and decreased extrvasation
3) Decrease size and lymphoid content of lymph nodes
4) More effect on Cellular immunity (apoptosis) rather than Humoral Immunity (Antibody production)
5) Increase macrophage efferocytosis nad promotion of resolution of inflammation
6) Decreased Type IV delayed hypersensitivity reaction (transplantation rejection)
7) First Line Immunosuppresant in solid organ and hematopoietic stem cell tranplant

Question 17

What are the effects of steroids on inflammatory cells?

Answer 17

Decrease Circulating T cells, B cells, monocytes, eosinophils, basophils via apoptosis
Increase circulating Neutrophils via increasing production, and reduced extravasation

Question 18

What are the effects of steroids on lymph nodes?

Answer 18

Decrease size and lymphoid content

Question 19

What is the difference in effect of steroids on immunity?

Answer 19

Steroids have more effect cellular immunity (apoptosis) than humoral immunity (antibody)

Question 20

What are the effects of steroids on macrophages?

Answer 20

Increased Macrophage efferocytosis and promotion of resolution of inflammation

Question 21

What are the effects of steroid on hypersensitivity reactions?

Answer 21

Decreased Type IV delayed hypersensitivity reaction such as transplantation rejection

Question 22

What is cortisone?

Answer 22

Cortisone (inactive pro drug) - > Hydrocortisone (cortisol) for rheumatoid arthritis
C11 ketone converted to C11 hydroxyl

Question 23

What is the difference between cortisone and prednisone?

Answer 23

Addition of C=C
Increases potency and duration of action as compared to cortisone and hydrocortisone

Question 24

What is prednisone?

Answer 24

Prednisone (prodrug) -> Prednisolone

Question 25

What is methylprednisolone?

Answer 25

Methylated at C6 Prednisolone - > No Water retention (aldosterone/mineralocorticoid) side effect

Question 26

What is Triamcinolone?

Answer 26

Addition of Fluorine to C9 -> Does not have water retention side effect (aldosterone/mineralocorticoid)

Question 27

What is Dexamethasone and Betamethasone?

Answer 27

Most potent corticosteroids Derived from Triamcinolone, Add methyl group in alpha and beta position at C16 Isomers Very Long duration of action

Question 28

What are the side effects of Steroids (Corticosteroids) ?

Answer 28

C ushing syndrome O steoperosis/myopathy/aceptic necrosis of femoral head R educed Growth T hin skin/ bruising I mmunosuppressaant C ataracts/glaucoma O edema S uppressed HPA T eratogenic (birth defects) E motional disturbances R ise in blood pressure O besity I ncreased hair growth D iabetes/ hyperglycemia S trae