Adrenocorticoids As Anti-inflammatories W3 Flashcards
Structure and numbering
There is a six ring on the left and a five ring on the right (for example, cholesterol has four fused rings, two hexagon and one pentagon)
The rings are labelled ABCD from left to right
The rings are numbered from the earring all the way through to the Dearing in a specific order that looks like a penis
Stereo chemistry
In natural steroids the A/B, the B/C and the C/D rings are transfused
There are examples of the A/B ring fusion having unsaturation (∆4,5 or∆5,6)
In some compound (oestrogen) ring a can be aromatic
Stereochemistry of the substituents is represented with alpha when on the lower face (dash)and beta went on the upper face (wedge)
Key types of steroid hormones in asthma/COPD
Glucocorticoids -> we want to increase this
- Responsible for the synthesis of carbohydrates from proteins
- Involves deposition of glycogen in the liver
- Important in inflammatory processes
Mineral corticosteroids -> we want to decrease this
- Control electrolyte balance (diuresis)
- promote retention of sodium and chloride
- promote loss of potassium
What do glucocorticoids interfere with
Prostaglandin biosynthesis which can give rise to:
- antirhumatic activity
- ant inflammatory activity
They only suppress symptoms, dont cure and long term use can lead to a wide range of side effects
Mineralcorticoid axivity is
Unwanted and needs to be minimised
Natural corticoids
Cortisol and hydrocortisone
- Highly effective for inflammatory skin diseases
- oral use shows mineralcorticoid side effects
An effort to optimise the anti-inflammatory activity of corticosteroids many thousands of chemical conversions to the basic structure were tried
3 structural changes that were very valuable
- Introduction of ∆1,2 double bond
- Introduction of a 9a fluoro substituent
- Introduction of an a-hydroxy substituent in the 16 position
- Introduction of ∆1,2 double bond
Another = bond added to A ring
From a half chair conformation(C4,C5) to a flattened boat (C1,C2 and C4, C5)
This increased glucocorticoid activity and decreased mineralcorticoid activity
The change in the a range geometry gives an increased GC receptor affinity
Pharmacokinetics are also altered, mainly metabolism
Cortisol -> prednisolone = addition of a double bond
- Introduction of a 9a fluoro substituent
Adding a F group onto the 9 carbon alpha atom in ring B - fludrocortisone
In the 60s, GC activity was shown to be inversely proportional to the 9a halogen size
- The smaller the halogen the greater the activity of GC
The 9a fluoro analog fluorocortisone is 11 times more potent than cortisone but the problem is that it increased glucocorticoid and mineral corticoid activity
The increase in mineral corticoid activity is greater than a glucocorticoid by 300 to 800 fold
The Covid is still increasing, so we don’t want to throw it out just yet, but it needs another change :
- adding in a ∆1,2 double bond on ring A as well as a 16a hydroxyl group (16C ring D) - triamcinolone
- Introduction of an a-methyl substituent in the 16 position
Inserting a 16a hydroxyl group into a 9a fluooprednisolone resukted in triamcinolone with GC activity equivalent to predisolone but with decreases mineral corticoid activity
But adding 17b ketone side chain also reduces MC effects
Why is structural modification 2 and 3 great bedfellows
9a fluoro sub increases overall activity
Sub at 16 decreases the unwanted MC effects
Pro drugs
Often formualed for topical use by preparation of esters at 17, diesters at 17 or 21, or ketals across 16,17
Very effective pro drugs with sub on 17
Most common anti inflammatory steroids in pharmacy
Triamcinolone (9aFluro, 16 and 17 OH)
Betamethasone (9aFluro, 17 OH and 16C)
Prednisolone (17 OH)
Dexamethasone (9aFluro, 17OH and 16C)
Fluticsone (9aFluro, 6aFluro, 17 sub and 16C)
All from cortisol
The 6a Fluro is..
Common site of CYP metabolism
Triad of alterations
A ring double bond
9a Fluoro
C16 methyl
