Corticosteroids

Question 1

How is asthma managed?

Answer 1

Increase adrenergic tone = adrenergic agonist
Decrease cholinergic tone = anticholinergic

Question 2

What is an example of adrenergic agonist?

Answer 2

Salbutamol

Question 3

What is an example of corticosteroid?

Answer 3

Beclomethasone

Question 4

Describe steroid structure

Answer 4

4 rings labelled A-D
ALL SAME STRUCTURE

Question 5

What are the 4 main classes of steroids?

Answer 5

Sex hormones
Bile acids
Vitamins
Adrenocorticoids

Question 6

Describe the structure of all substituted pregnanes

Answer 6

Rings A, B + C have chair conformations
= all ring junctions are trans
Bind receptor via beta face

Question 7

What do all steroids come from?

Answer 7

Cholesterol

Question 8

What are adrenocortical synthesised by?

Answer 8

Adrenal cortex

Question 9

What are steroids?

Answer 9

Gene active
= directly effects the gene

Question 10

Describe the gene active steroid hormone process

Answer 10

Enter cell diffusion
Combine with receptor
= conformational change = exposes DNA domain
= complex moves nucleus + binds to steroid response elements in DNA
Transcription of specific gene
Either “switched-on” or “switched-off”
= alter mRNA levels

Question 11

What are glucocorticoids used for?

Answer 11

Suppress inflammation, allergy + immune responses

Question 12

What are the problem with glucocorticoids?

Answer 12

Severe adverse effects
BUT highly predictable effects
= process understood = can predict item
= we can treat them

Question 13

What does lipocortin do?
Anti-inflammatory

Answer 13

Inhibit phospholipase A2

Question 14

What do they inhibit?

Answer 14

Inhibition of cytokines
Inhibition of mast cell release of autocoids

Question 15

How do they inhibit cytokines?

Answer 15

Inhibit IL
IL stimulates proliferation of T + B lymphocytes = responsible for production of cytokines
= decrease in T + B lymphocytes = immunosuppressant

Question 16

How do they inhibit mast cell release?

Answer 16

Inhibit release of histamine + autocoids from mast cells
Autocoid = vasoconstrictor + vasodilator properties

Question 17

Describe the binding

Answer 17

DNA binding protein
Found in cytosol
Unique binding pocket
Binding enclosed
Hydrophobic + philic interaction
H bonding

Question 18

What do natural glucocorticoids interact with?

Answer 18

Mineralocorticoid receptor
= has salt-retaining properties

Question 19

How is mineralocorticoid receptor interaction reduced?

Answer 19

Large number of synthetic analogues prepared to decrease mineralocorticoid effect
In favour of increasing glucocorticoid effects

Question 20

How do you increase anti-inflammatory + mineralocorticoid activity?

Answer 20

Introduce functional groups
17a-OH
9a-F
9a-Cl
21-OH

Question 21

How do you increase anti-inflammatory activity?

Answer 21

1-dehydro
6a-F
11b-OH

Question 22

How do you decrease mineralocorticoid activity?

Answer 22

6a-CH3
16a-& 16b-CH3
16a,17a-acetonide
16a-OH

Question 23

What are the 3 major metabolic reactions?

Answer 23

Ring A reaction
C-17 oxidation
C-11 keto-enol isomerisation

Question 24

What may hydroxyl groups be in steroids?

Answer 24

Esterified
= increase or decrease lipophilicity
= change logP

Question 25

What can esters be used for?

Answer 25

Increase they hydrophilicity of glucocorticoids making them H2O-soluble prodrugs