Corticosteroids Flashcards
How is asthma managed?
Increase adrenergic tone = adrenergic agonist
Decrease cholinergic tone = anticholinergic
What is an example of adrenergic agonist?
Salbutamol
What is an example of corticosteroid?
Beclomethasone
Describe steroid structure
4 rings labelled A-D
ALL SAME STRUCTURE
What are the 4 main classes of steroids?
Sex hormones
Bile acids
Vitamins
Adrenocorticoids
Describe the structure of all substituted pregnanes
Rings A, B + C have chair conformations
= all ring junctions are trans
Bind receptor via beta face
What do all steroids come from?
Cholesterol
What are adrenocortical synthesised by?
Adrenal cortex
What are steroids?
Gene active
= directly effects the gene
Describe the gene active steroid hormone process
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
What are glucocorticoids used for?
Suppress inflammation, allergy + immune responses
What are the problem with glucocorticoids?
Severe adverse effects
BUT highly predictable effects
= process understood = can predict item
= we can treat them
What does lipocortin do?
Anti-inflammatory
Inhibit phospholipase A2
What do they inhibit?
Inhibition of cytokines
Inhibition of mast cell release of autocoids
How do they inhibit cytokines?
Inhibit IL
IL stimulates proliferation of T + B lymphocytes = responsible for production of cytokines
= decrease in T + B lymphocytes = immunosuppressant
How do they inhibit mast cell release?
Inhibit release of histamine + autocoids from mast cells
Autocoid = vasoconstrictor + vasodilator properties
Describe the binding
DNA binding protein
Found in cytosol
Unique binding pocket
Binding enclosed
Hydrophobic + philic interaction
H bonding
What do natural glucocorticoids interact with?
Mineralocorticoid receptor
= has salt-retaining properties
How is mineralocorticoid receptor interaction reduced?
Large number of synthetic analogues prepared to decrease mineralocorticoid effect
In favour of increasing glucocorticoid effects
How do you increase anti-inflammatory + mineralocorticoid activity?
Introduce functional groups
17a-OH
9a-F
9a-Cl
21-OH
How do you increase anti-inflammatory activity?
1-dehydro
6a-F
11b-OH
How do you decrease mineralocorticoid activity?
6a-CH3
16a-& 16b-CH3
16a,17a-acetonide
16a-OH
What are the 3 major metabolic reactions?
Ring A reaction
C-17 oxidation
C-11 keto-enol isomerisation
What may hydroxyl groups be in steroids?
Esterified
= increase or decrease lipophilicity
= change logP
What can esters be used for?
Increase they hydrophilicity of glucocorticoids making them H2O-soluble prodrugs
