21 Adrenocorticoid Hormones Duncan Flashcards
What is the general process of Adrenocorticoid synthesis and release?
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
What is the HPA axis?
Hypothalamus/Pituitary/Adrenal axis
What happens once ACTH binds to its receptor?
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
How are Adrenocorticoids transported?
Transported in blood primarily in protein-bound form (albumin, transcortin). Only the unbound portion is active
What are the normal actions that Adrenocorticoids activate?
Carbohydrate biosynthesis (activates enzymes required for glucose formation, activates glycogen synthesis in the liver), lipid biosynthesis
What are the normal actions that Adrenocorticoids inhibit/suppress?
Inhibits protein biosynthesis. Suppresses immune function. Suppresses cell growth and promotes cell apoptosis
What pharmacological activity do adrenocorticoids provide?
Anti-inflammatory activity: rheumatoid disease, arthritis, tendonitis, other chornic inflammation, allergic responses, asthma, etc.
What is the mechanism of steroid action on cells?
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
What is Addison’s Disease?
Low adrenal gland function
What is Cushing’s Disease?
High adrenal gland function
What is Conn’s Syndrome?
Impaired C17-a modification, which blocks the biosynthesis of adrenocorticoids
What is the addition of the structure in red doing?
Cataolicaly blocking 17 a-methyltestosterone
What is the addition of the structure in red doing?
Catabolically blocking a progesterone
What is the addition of the structure in red doing?
Prodrug of an androgen
What is the addition of the structure in red doing (and blue)?
Prodrug of an estrogen
What is the addition of the structure in red doing?
Prodrug of an adrenocorticosteroid (purple is creating oral activity)
What are the therapeutically useful kinds of adrenocorticoids?
Glucocorticoids
What are the kinds of adrenocorticoids that we want less of since they create the unwanted side effects (from the therapeutic perspective)?
Mineralcorticoids
What are the SARs of ACSs?
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)
What is important about the C11 =O?
C11 =O makes the structure inactive, but OH and =O readily interconvert by 11 B-hydroxylsteroid dehydrogenase
What are the primary endogenous glucocorticoids?
Hydrocortisone (C11 OH) and Cortisone (C11 =O)
What modifications in ACS structures create prodrugs with different speeds of activity?
C21 modification. Hydrophilic = rapid activity, hydrophobic = long-lasting
What do alterations to the C9 alpha side chain in ACSs (H in parent) do?
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
What does adding a C1,2 double bond do for ACSs (C-C in parent)?
Increases glucocorticoid activity with very little effect on mineralcorticoid activity. The C1,2 double bond is not found naturally, always synthetic
Why does adding a C1,2 double bond in ACSs increase activity?
Makes the structure more rigid and forced into a specific receptor
What does having a C6 alpha side chain in ACSs do (H in parent)?
Catabolically blocked. Enhanced activity
What does having a C16 side chain (hydroxy) in ACSs do (H in parent)?
Endogenous C16 a-hydroxy forms have relatively low mineralcorticoid activity. The oxygen on C16 and C17 can form rings which increase lipophilicity
What does having a C16 side chain (methyl) in ACSs do (H in parent)?
Catabolically blocked (prevents attack on C17). Greater activity per dose-amount than prednisolone, but about equal usefulness in therapy
What does adding an “F” to C6a or C9a do for ACSs?
Makes the substance useful topically
What does having a C21 side chain on ACSs do?
Highly active topical ACSs. C21 chlorine potentiates activity
What are done to ACSs to increase inhaled effects?
Increased lipophilicity positively correlates with airway absorption. High receptor binding activity
