Action of NSAIDs

Question 1

What is the selectivity profile of NSAIDs like?

Answer 1

• Most are non-selective (equal inhibition) or COX-1 selective

Question 2

Give examples of COX-1 selective and non-selective NSAIDs, starting with the most selective.

Answer 2

• Ketorolac (highly)
• Flurbiprofen (very)
• Indomethacin, Aspirin, Naproxen, Ibuprofen (weakly)
• Fenoprofen, Salicylate (non-selective)

Question 3

What is the difference between COX 1 and 2 regarding their amino acid make up?

Answer 3

• COX-1 has Ile-434 and -523 residues

- COX-2 has Val-434 and -523 residues

Question 4

How does COX-2 structurally differ from COX-1?

Answer 4

• Larger and more flexible substrate (AA) access channel

- 25% bigger inhibitor binding site

Question 5

List the COXIBs (COX-2 selective) starting with most selective

Answer 5

• Rofecoxib (highly)
• Valdecoxib, Etoricoxib (very)
• Diflunisal, Piroxicam, Meclofenamate, Sulindac, Diclofenac (weakly)

Question 6

What did initial clinical trials suggest about COXIBs efficacy for analgesia/COX-2 targeting?

Answer 6

• Supports COX-2 hypothesis
• Incidence of GI complications much reduced
• Similar efficacy as traditional NSAIDs though
• Better management of pain

Question 7

Why was Rofecoxib withdrawn from the market?

Answer 7

• Safety concerns over increased risk of CVS events inc. MI and stroke

Question 8

Where is COX-1 expressed and what is it involved in?

Answer 8

• Constitutively expressed in most tissues including platelets
• ‘Housekeeping role’;
  > Gastric cytoprotection (PGs stimulate mucus and bicarbonate secretion, decrease acid secretion - PGE2)
  > Renal blood flow autoregulation (vasodilatory prostaglandins)
• Platelet aggregation (enhanced by platelet TXA2, inhibited by endothelial PGI2)

Question 9

What is COX-2 in terms of the COX hypothesis and how does it actually differ?

Answer 9

OG thought:
- Induced in response to inflammatory stimuli

But also:

• Present in vascular endothelium where it helps produce PGI2 (vasodilator/inhibits platelet aggregation)
• Present in some tissues including CNS, kidneys and blood vessels

Question 10

How can the CVS side effects of COXIBs (e.g. Rofecoxib) be explained?

Answer 10

• Platelet aggregation is normally a balance between inhibiting PGI2 (vascular endothelium) and stimulating TXA2 (platelets)
• COXIBs are COX-2 specific; COX-2 is expressed in the vascular endothelium; less PGI2 (prostacyclin) production, and unaltered TXA2 production = thrombolytic effect.

Question 11

Why is Aspirin 75mg used after heart failure?

Answer 11

• NSAIDs largely block COX-1
• TXA2 (thromboxane; clotting factor from platelets) is expressed via COX-1 pathway
• Though PGI2 (prostacyclin) is also expressed via COX-1 at the vascular endothelium
• But vascular endothelium expresses COX-2 as well which still has activity; PGI2 still expressed whilst TXA2 is suppressed

Question 12

What is the broad recommendation for patients w/GI or CVS risk?

Answer 12

GI risk - COXIBs

CVS risk - NSAIDs