L2.1 NSAIDS Flashcards Preview

Pharmacology > L2.1 NSAIDS > Flashcards

Flashcards in L2.1 NSAIDS Deck (19):
1

When is inflammation treated?

  • If symptoms disproportionate to infection OR immune response is maladaptive

2

Metabolism of AA

3

Features of NSAIDs

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

4

PGI

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

5

Synergistic effect of pain

  • 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

6

How  is fever developed?

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

7

Adverse effects of NSAIDs: GI

  • 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)

8

Adverse effects of NSAIDs: decrease TXA

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

9

Adverse effects of NSAIDs: Renal & vascular

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

10

Adverse effects of NSAIDs: Pulmonary

  • Bronchoconstriction → from overproduction of leukotrienes

11

Aspirin

  • 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

12

Aspirin and Gout

  • 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

 

13

Lipoxins

  • 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

14

Paracetamol

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

15

COX 2 hypothesis

  • 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

16

Celecoxib

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

17

A.E of celecoxib

  • ↑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

18

Why is there an increased myocardial infarction risk?

  • 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

19

Trials determining CV toxicity

APPROVe and APC trials more readily detected CV tox

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