MD 4

what are the 6 hallmarks of a steriod

1. ABCD fused ring strucutre

2. typically with side chains

3. lipophillic in nauture

4. mostly saturated

5. contigouous stereochemsitry

6. beta hydroxy motif

what is essential in a sterioud for anti-infllammatory effect

substituation at C11 with OH or ketone

where to steriods originate from

mevalonic acid pathway

what enzyme produces mevalonic acid

HMG-CoA reductase which is the drug target for statins

what is the first steriod

lanosterol which is converted into cholesterol

how do steriods work?

enters cell

binds to receptor

changes gene transcription

what is digoxin

cardiac glycoside - derived from foxglove

inhibits Na+/K+ ATPase increasing intracellular calcium

what is the adrenal cortex

site of production and secretion of corticosterioud in response to signals from the pituitary gland, following signal from the hypothalmus

what are the main endogenous corticosteroids from the adrenal cortex

cortisol and corticonsterone - both have glucocortocoid and mineralcorticoid activity

what are the 3 key structural features of the two naturally occuring glucocoritcoid hormones

1. C-3 conjugated ketone

2. C-11 beta OH - to bind and activate glucocorticoid receptor

3. C-17 beta-alpha hydroxyketone

what are the 4 main effects of glucocorticoids

reduce inflammation

reduce immune response

redistribute fat

hyperglycaemia

what are the two desired properties for glucocorticoid activity

high potency and high selectivity - leads to fewer mineralcorticoid side effects

what does flattening the A ring by introducing a 1,2 double bond do

increases potency

eg.hydrocortisone has no double bond vs prednisolone which does

when does cortisol levels usually peak

in the morning - so prednisolone usually given in the morning to mimic physiology - reduced HPA axis suppresion

has GI side effects so best to take with food

what does introducing a halogen at the 9 position do and esterification at the C-17 position do

increases potency

what does adding a methyl at the C-16 position do

improves selectivity

what does esterificaiton do

important for increasing the potency and absorption

eg hydrocortisone butyrate - esterification at the C-17 position dramatically increases the potency of the hydrocortisone when topically used also increases the lipophillicity

what reaction does hydrocortisone butyrate under go?

hydrolysis to hydrocortisone - the slow and partial hydrolysis likely contributes to the potency