Arachidonic Acid Metabolism and NSAIDs Flashcards Preview

#B32PAI Pharmacology and Therapeutics > Arachidonic Acid Metabolism and NSAIDs > Flashcards

Flashcards in Arachidonic Acid Metabolism and NSAIDs Deck (18)
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1
Q

What are COX enzymes responsible for?

A

One step in the conversion of membrane phospholipids into prostanoids

2
Q

Describe step 1 of the prostaglandin synthesis pathway

A

Phospholipid is cleaved to release arachidonic acid (catalysed by PLA2)

3
Q

How is PLA2 (the enzyme cutter of phospholipid) regulated?

A

Inflammatory mediators can upregulate cPLA2 expression

Glucocorticoids can down regulate cPLA2 or can induce protein repressor proteins

4
Q

Describe step 2 of prostaglandin synthesis pathway?

A

Another prostaglandin synthase (H2) converts arachidonic acid into prostaglandin H2 via G2.

5
Q

What are the two activities of prostaglandin synthase H2?

A

cycloxygenase and peroxidase (often simpy called COX)

6
Q

Where are COX enzymes found?

A

Bound to ER and nuclear envelope membranes

7
Q

Where is COX 1 expressed?

A

Most tissues

8
Q

What is COX-2 regulated by?

A

Regulated at an mRNA level - induced by growth factors and inflammatory mediators such as IL-4, TNF-apha, LPS, including immune cells endothelial cells and fibroblasts

9
Q

What suppresses COX-2 expression?

A

Anti inflammatory glucocorticoids suppress COX-2 but not COX-1

10
Q

How does PGH2 become prostanoids?

A

Prostaglandin synthase enzymes responsible

11
Q

How are differenct mixes of prostanoids produced in different tissues?

A

Tissue specificity is controlled by different synthases e.g. PGD2 (mast cells)
PGE2 (macrophages, fibroblasts, endothelial cells)
PGF2alpha (uterus)
PGI2 (endothelial cells)
TXA2 (platelets)

12
Q

Describe the transport stage in PG synthesis

A

PGs synthesised in the cell

Transported via ABC transporters aka P-glycoproteins

13
Q

What are the main effects of each prostaglandin receptor being stimulated?

A

Vasodilatation, inhibition of platelet aggregation
PGE2 - inhibition of gastric acid secretion
PGF2alpha - smooth muscle contraction

TXA2 (thromboxane) - vasoconstriction, platelet aggregation

14
Q

What part of the prostanoid pathway do enzymes inhibit?

A

Inhibit COX enzymes therefore the breakdown of arachidonic acid to PGH2 is not able to happen ; as a result all prostanoid synthesis ceases

15
Q

Do NSAIDs show selectivity?

A

Most show no selectivity or are COX-1 seletive (hence the many side effects).
It is more desirable for selective COX-2 inhibitors, the coxibs are selective for COX-2 but are more expensive so less readily synthesised or available

16
Q

What is the house-keeping role of COX-1?

A
Gastric cytoprotection (mucus and bicarbonate secretion, reduced H+ secretion)
Renal blood flow autoregulation (vasodilatory PGs)
Preventing platelet aggregation (apart from TXA2)
17
Q

What is the role of COX-2?

A

Induced in inflammatory response

18
Q

What are the problems potentially with some coxibs?

A

COX-2 present in vascular endothelium in present in some tissues including CNS and blood vessels.
May have increased CVS risk even though reduced GIT risk