L2.1 NSAIDS

Question 1

When is inflammation treated?

Answer 1

• If symptoms disproportionate to infection OR immune response is maladaptive

Question 2

Metabolism of AA

Answer 2

Question 3

Features of NSAIDs

Answer 3

• Anti-inflam, analgesic, anti-pyretic, anti-aggregation (of platelets)
• Are palliative rather than curative

Question 4

PGI

Answer 4

• PGI & TXA have opposing function
• Anti-aggregator
• Vasodilator
• Anti-proliferative

Question 5

Synergistic effect of pain

Answer 5

• PG may have synergistic ‘algesic’ (Pain) effect with substances that are directly algesic
  
  • e.g. PGE2 + Bradykinin, both harmless by themselves
    
    • Together = ↑sensitised pain, prolonged
  • Chronic interaction: IL-1β (principle cytokine driver of inflammation) → ↑BK1 R. # → ↑COX2 & PLA2 expression
• Highlights benefits of inhibiting COX to desensitise pain

Question 6

How is fever developed?

Answer 6

• Inflam → macrophage activation → cytokines → ↑PGE2 (in hypothalamus) → cAMP → ↑Temp

Question 7

Adverse effects of NSAIDs: GI

Answer 7

• Ulceration & bleeding
  
  • Due to inhibition of PGI & PGE
  • PGI & PGE are
    
    • gastro-protective:
      
      • ↑ mucus secretion
      • ↓acid secretion
    • Aids repair:
      
      • ↑BF
      • Stimulate angiogenesis (repairs ulcers by replacing lost tissues)

Question 8

Adverse effects of NSAIDs: decrease TXA

Answer 8

• Impairs platelet aggregation
  
  • ↑bleeding time
  • ↑risk of haemorraghing stroke

Question 9

Adverse effects of NSAIDs: Renal & vascular

Answer 9

• PGE2 & PGI have diuretic effects → promotes loss of Na+
  
  • ∴NSAIDs promotes Na+ retention → ↑BV & BP → compromise renal function

Question 10

Adverse effects of NSAIDs: Pulmonary

Answer 10

• Bronchoconstriction → from overproduction of leukotrienes

Question 11

Aspirin

Answer 11

• Ligand for FPR2
• Acetylation (inhibits) COX → vascular protective effect (↑ PGI/TXA ratio)
  
  • Vascular endothelium has nucleus → resyn COX → increase PGI
  • Platelets have no nucleus → unable to resyn TXA
• Triggers lipoxins (by acetylated COX2) which are implicated in resolution of inflammation
• *Contra-indicated in children

Question 12

Aspirin and Gout

Answer 12

• Gout characterised by increase LT that cause inflammation response at joint
• But contractindicated in Gout
  
  • Competes with uric acid for renal transporter and thus exacerbates gout

Question 13

Lipoxins

Answer 13

• Non-inflamed tissue does not have the ability to produce lipoxins
  
  • Infiltrating cells (neutrophils/eisanophils…) confer ability to tissues to create lipoxin
    
    • Leukocytes → 5 LOX
    • Platelets → 12 LOX
      
      • Both joined to produce lipoxin A4

Question 14

Paracetamol

Answer 14

• Analgesic
• Antipyretic
• NOT anti-inflammatory
• Hepatotoxic in overdose (liver damage)

Question 15

COX 2 hypothesis

Answer 15

• COX 1 constitutively expressed → PGI & PGE for vessel and gastro-protection
• Inflammation → COX 2 mobilised to overproduce PG → hyperaemia/hyperalgesic
• Hypothesis: Block COX 2 → remove A.E, but keep beneficial effects of COX1
  
  • COX 2 has a hydrophobic pocket → allows selective inhibition

Question 16

Celecoxib

Answer 16

• selectively inhibits COX 2
• Less GI adverse effect
• ↓anti-platelet effect (COX1 unaffected)

Question 17

A.E of celecoxib

Answer 17

• ↑CV risks associated with COX 2
  
  • Risk may however be slow to realise
• Rofecoxib - drug withdrawn from market due to high risks of myocardial infarctions and strokes

Question 18

Why is there an increased myocardial infarction risk?

Answer 18

• COX 2 important for PGI2 syn, in endothelium, but TXA2 syn in platelets is COX 1 dependent
• Sheared stress in endothelium walls (from laminar blood flow) → promotes COX2 syn but doesn’t affect COX1
  
  • COX2 important for prostacyclin prod.
  • ∴inhibiting COX2 selectively → thrombotic capacity → ↑risk of myocardial infarction

Question 19

Trials determining CV toxicity

Answer 19

APPROVe and APC trials more readily detected CV tox

RA efficacy trials (VIGOR and CLASS) not structured to detect CV tox