21 Adrenocorticoid Hormones Duncan

Question 1

What is the general process of Adrenocorticoid synthesis and release?

Answer 1

Hypothalamus releases CRH. CRH causes the pituitary to release ACTH. ACTH causes the adrenal gland to release ACS. ACS can then go to target tissues as well as have negative feedback on the pituitary and hypothalamus

Question 2

What is the HPA axis?

Answer 2

Hypothalamus/Pituitary/Adrenal axis

Question 3

What happens once ACTH binds to its receptor?

Answer 3

G-protein activates and causes Adenyl Cyclase to make cAMP which activates cholesterol esterase to convert cholesterol ester-rich lipid droplets to cholesterol. Cholesterol then enters the mitochondria where its side chain is cleaved, then goes to ER where it is hydroxylated and oxidated. Then goes back to mitochondria, where ACS is finally made

Question 4

How are Adrenocorticoids transported?

Answer 4

Transported in blood primarily in protein-bound form (albumin, transcortin). Only the unbound portion is active

Question 5

What are the normal actions that Adrenocorticoids activate?

Answer 5

Carbohydrate biosynthesis (activates enzymes required for glucose formation, activates glycogen synthesis in the liver), lipid biosynthesis

Question 6

What are the normal actions that Adrenocorticoids inhibit/suppress?

Answer 6

Inhibits protein biosynthesis. Suppresses immune function. Suppresses cell growth and promotes cell apoptosis

Question 7

What pharmacological activity do adrenocorticoids provide?

Answer 7

Anti-inflammatory activity: rheumatoid disease, arthritis, tendonitis, other chornic inflammation, allergic responses, asthma, etc.

Question 8

What is the mechanism of steroid action on cells?

Answer 8

Steroids are hydrophobic, so can easily cross the cell membrane. Once inside they bind to nuclear receptors which translocates them into the nucleus. This complex then binds to DNA, causing transcription, mRNA is transported out of the nucleus and translated

Question 9

What is Addison’s Disease?

Answer 9

Low adrenal gland function

Question 10

What is Cushing’s Disease?

Answer 10

High adrenal gland function

Question 11

What is Conn’s Syndrome?

Answer 11

Impaired C17-a modification, which blocks the biosynthesis of adrenocorticoids

Question 12

What is the addition of the structure in red doing?

Answer 12

Cataolicaly blocking 17 a-methyltestosterone

Question 13

What is the addition of the structure in red doing?

Answer 13

Catabolically blocking a progesterone

Question 14

What is the addition of the structure in red doing?

Answer 14

Prodrug of an androgen

Question 15

What is the addition of the structure in red doing (and blue)?

Answer 15

Prodrug of an estrogen

Question 16

What is the addition of the structure in red doing?

Answer 16

Prodrug of an adrenocorticosteroid (purple is creating oral activity)

Question 17

What are the therapeutically useful kinds of adrenocorticoids?

Answer 17

Glucocorticoids

Question 18

What are the kinds of adrenocorticoids that we want less of since they create the unwanted side effects (from the therapeutic perspective)?

Answer 18

Mineralcorticoids

Question 19

What are the SARs of ACSs?

Answer 19

1) C3 has a =O side chain (3 keto). 2) C4,5 are double bonded. 3) C11 has a B =O or -OH. 4) C17 has a B ketol side chain. 5) C21 has a terminal OH. 6) C17a-hydroxy (not strictly required for activity)

Question 20

What is important about the C11 =O?

Answer 20

C11 =O makes the structure inactive, but OH and =O readily interconvert by 11 B-hydroxylsteroid dehydrogenase

Question 21

What are the primary endogenous glucocorticoids?

Answer 21

Hydrocortisone (C11 OH) and Cortisone (C11 =O)

Question 22

What modifications in ACS structures create prodrugs with different speeds of activity?

Answer 22

C21 modification. Hydrophilic = rapid activity, hydrophobic = long-lasting

Question 23

What do alterations to the C9 alpha side chain in ACSs (H in parent) do?

Answer 23

Cause an increase in (10x) glucocorticoid effects, but a much greater increase in mineralocort (300-800x). Usually an “F” is put at R1, can be a “Br”. Fludrocortisol has utility as a synthetic mineralcorticoid

Question 24

What does adding a C1,2 double bond do for ACSs (C-C in parent)?

Answer 24

Increases glucocorticoid activity with very little effect on mineralcorticoid activity. The C1,2 double bond is not found naturally, always synthetic

Question 25

Why does adding a C1,2 double bond in ACSs increase activity?

Answer 25

Makes the structure more rigid and forced into a specific receptor

Question 26

What does having a C6 alpha side chain in ACSs do (H in parent)?

Answer 26

Catabolically blocked. Enhanced activity

Question 27

What does having a C16 side chain (hydroxy) in ACSs do (H in parent)?

Answer 27

Endogenous C16 a-hydroxy forms have relatively low mineralcorticoid activity. The oxygen on C16 and C17 can form rings which increase lipophilicity

Question 28

What does having a C16 side chain (methyl) in ACSs do (H in parent)?

Answer 28

Catabolically blocked (prevents attack on C17). Greater activity per dose-amount than prednisolone, but about equal usefulness in therapy

Question 29

What does adding an “F” to C6a or C9a do for ACSs?

Answer 29

Makes the substance useful topically

Question 30

What does having a C21 side chain on ACSs do?

Answer 30

Highly active topical ACSs. C21 chlorine potentiates activity

Question 31

What are done to ACSs to increase inhaled effects?

Answer 31

Increased lipophilicity positively correlates with airway absorption. High receptor binding activity