Glucocorticoids Flashcards
Overview of glucocorticoid action?
Prednisolone inhibits PLA2 preventing conversion of phospholipids to arachidonic acid.
This prevents synthesis of Leukotrienes AND Postraglandins…
= reduced inflammatory mediators.
Glucocorticoids are C21 steroids which promote gluconeogenesis, glycogenesis and are anti-inflammatory.
What are steroids?
Steroid are hormones derived from mevalonic acid and are highly lipophilic.
Produced by HMG-CoA reductase.
Lanosterol = first steroid, which is converted to cholesterol.
The steroid ring structure and sidechain of cholesterol can modified to derive many different classes of steroids.
Steroids bind to nuclear steroid receptors for transcription of various genes.
How is prednisolone made?
Prednisolone is a synthetic derivateive of cortisone.
Flattened A ring increases its activity compared to cortisone
Prednisolone is produced from Prenisone by drug metabolism (reduction).
What are NSAIDs?
NSAIDS decrease the production of prostaglandins.
By inhibiting COX-1 or COX-2.
COX control synthesis of PGH2 from arachidonic acid.
COX-1 is constitutive in all tissues at low levels and COX-2 is inducible in response to injury.
Most NSAIDS inhibit both, but will have preference.
What is aspirin?
Aspirin is an irreversible, Selective COX-1 inhibitor.
Acetylation of Ser529 in COX-1 active site.
Short half life but due to irreversibility of COX-1 inhibition, has a extended duration of action.
What are ibuprofen and naproxen?
Reversible inhibitors of COX-1 and COX-2.
COX-2 inhibition largely gives analgesic, anti-inflammatory effect.
- giving some CV risks.
S-enantiomer of ibuprofen is active (Though racemic mixture), naproxen is manufactured as S enantiomer.
COX-1 inhibition can give risk of peptic ulcers.
Aliphatic residues in both COX-1 and COX-2 can interact with ibuprofen = non-selective.
Why can ibuprofen cause allergic reactions?
As ibuprofen is administered as a racemic mixture, and only S-enantiomer is active, there is specific conversion from R to the S enantiomer during metabolism.
During conversion, Acyl-CoA ester derivatives can acylate other proteins and can lead to allergic reactions and toxicity.
What is diclofenac?
Stronger COX-2 inhibitor, than COX-1 (10 fold).
Use is associated with increased CV complications, but reduced risk of ulcers.
ACcumulates in synovial fluid and has a 6-8 duration of action despite its short half life.
= Arthritis.
Selective COX-2 inhibitors?
Celecoxib - selective COX-2 inhibitor.
Similar effictiveness to ibuprofen, naproxen etc.
But higher risk of CV complications.
Celecoxib is too large to fit COX-1 active site = steric clash.
But interactions are favourable in COX-2 active site.
