1. Prostaglandins,
cyclo-oxygenase
and the GIT
HPETE
PGH

2. Eicosanoids Linoleic acid (diet) Arachidonic acid Membrane
Phospholipids
Linoleic acid (diet)
Phospho-
lipase A2
Arachidonic acid PG
LTs LX

3. Arachidonic acid PGI TX PGE/F/D HETE LT lipoxins isoprostanes
Cell membrane phospholipids
Phospholipase A2
Corticosteroids
lipoxins
isoprostanes
epoxygenase
Arachidonic
acid
Cyclooxygenase
Lipoxygenase
NSAID’s
HPETE
PGH
PGI TX PGE/F/D
HETE LT

4. Leukotriene synthesis
Mast cells, macro-phages, leukocytes
Arachidonic acid
Lipo-oxygenase
LTC4
HPETE
LTB4
Broncho-constrictor
chemotaxis
LTD4
LTA4

5. Prostaglandin synthesis
Arachidonic acid
Cyclo-oxygenase
PGE2
PGG2
Renal
GIT
VSM
PGH2
platelets
VSM GIT
PGI2
PGF2
TXA2

6. Cyclo-oxygenase isoforms
COX-I
COX-II
constitutive
inducible
GIT
Platelets
renal
vascular
inflammation

7. Pain & inflammation
PG’s sensitize nociceptors to bradykinin, substance P, histamine
PG’s = inflammation = pain
NSAID’s decrease PG’s

8. GIT mucosal protection
protects
against
stomach acid
PGE2
decrease HCl
increase mucous
increase sub mucosal blood flow
increase bicarbonate

9. GIT peristalsis
long/circular muscle
PGE2
PGF2
diarrhoea
cramping

10. Renal Only under compromised conditions PGE2 renal failure
severe dehydration
antihypertensive
furosemide
maintain
GFR
blood flow
naturesis

11. Thrombosis COX-I Ca2+ -ve +ve TXA2 clots prostacyclin VSM Platelets
aggregation
clots

12. Pain relief and NSAID’s
Inhibit PG synthesis
Mainly peripheral
Cortical site?
Inhibition of COX-I
Inhibition of COX-II

13. Anti-pyretic
PG synthesis
Central -hypothalamus
Interleukin 1 mediated

14. Non steroidal anti-inflammatory drugs (NSAID’s)
Not related to corticosteroids
Inhibit cyclo-oxygenase I & II
Different kinetics
Effective as aspirin
Anti-inflammatory, analgesic, antipyretic
Less toxic?

15. Non steroid anti -inflammatory drugs
indomethacin
naproxen
diclofenac
ibuprofen
MOA
COX-II = COX-I
provide symptomatic relief
Adverse effects
Not antiplatelet?

16. Side effects of NSAID's & aspirin
GIT
Common but mild
Mild dyspepsia, heart burn, GORD
Rare but lethal
Perforation, ulcer, bleeds
Obstructions
PG via COX-I (mucosa)

17. Renal Effect Bleeding Hypersensitivity
Adverse effects cont
Bleeding
Hypersensitivity
1: 200 people
Renal Effect
Renal blood flow
 Antihypertensive

18. Prevent ulcers PGE1 PPI misoprostil ) diarrhoea prevent cramp NSAID’s
No acid, no ulcer
replace mucosal PG
diarrhoea
cramp
prevent
NSAID’s
ulcers

19. Adverse effects NSAID’s…
Misoprostil
Cramps, diarrhoea, women
other
sucralfate?
H2RA antagonists?
Proton pump inhibitors
COX-II specific

20. Non steroid anti -inflammatory drugs
Selective COX– II inhibitors
COX-II
COX-I
Inflammation
Synthesized de novo
House keeping
GIT, renal, platelets

21. NSAID’s COX II selective /specific
meloxicam
celecoxib
MOA
COX - II > COX - I
provide symptomatic relief
not antiplatelet!!
CVS effects??

22. Paracetamol Not anti-inflammatory Central site Analgesic Antipyretic
No action on peripheral cyclo-oxygenase
Less GIT Irritation
Alternative to aspirin

23. Paracetamol How strong analgesic? Toxicity 10g is toxic!!
N-acetyl cysteine antidote
Less if alcohol is added
How strong analgesic?
Very little dose response
500mg = 750 =1000mg
No response over 1000mg