Adrenocorticoids As Anti-inflammatories W3 Flashcards

1
Q

Structure and numbering

A

There is a six ring on the left and a five ring on the right (for example, cholesterol has four fused rings, three hexagon and one pentagon)

The rings are labelled ABCD from left to right

The rings are numbered in a specific order that looks like a penis

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2
Q

Stereo chemistry

A

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)

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3
Q

Key types of steroid hormones in asthma/COPD

A

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

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4
Q

What do glucocorticoids interfere with

A

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

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5
Q

Mineralcorticoid axivity is

A

Unwanted and needs to be minimised

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6
Q

Natural corticoids

A

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

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7
Q

3 structural changes that were very valuable

A
  1. Introduction of ∆1,2 double bond
  2. Introduction of a 9a fluoro substituent
  3. Introduction of an a-hydroxy substituent in the 16 position
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8
Q
  1. Introduction of ∆1,2 double bond
A

Another = bond added to A ring

From a half chair conformation(C4,C5) to a flattened boat (C1,C2 and C4, C5)

increases GC activity and decreases MC activity

increased GC receptor affinity

Cortisol -> prednisolone = addition of a double bond

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9
Q
  1. Introduction of a 9a fluoro substituent
A

Adding a F group onto the 9 carbon alpha atom in ring B

In the 60s, GC activity was that The smaller the halogen the greater the activity of GC

The 9a fluoro fluorocortisone is 11 times more potent than cortisone but the problem is that it increased GC and MC activity

The increase in MC activity is greater than a GC by 300 to 800 fold

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

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10
Q
  1. Introduction of an a-methyl substituent in the 16 position
A

Inserting a 16a hydroxyl group into a 9a fluoroprednisolone resulted in triamcinolone with GC activity equivalent to predisolone but with decreases MC activity

But adding 17b ketone side chain also reduces MC effects

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11
Q

Why is structural modification 2 and 3 great bedfellows

A

9a fluoro sub increases overall activity

Sub at 16 decreases the unwanted MC effects

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12
Q

Pro drugs

A

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

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13
Q

Most common anti inflammatory steroids in pharmacy

A

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

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14
Q

The 6a Fluro is..

A

Common site of CYP metabolism

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15
Q

Triad of alterations

A

A ring double bond
9a Fluoro
C16 methyl

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