General

1

Prostaglandins, cyclo-oxygenase and the GIT
HPETE
PGH
2
Eicosanoids

• Linoleic acid (diet)

Membrane Phospholipids
Phospho- lipase A2
Arachidonic acid
PG LTs LX
3

Cell membrane phospholipids
Phospholipase A2
Corticosteroids
lipoxins
isoprostanes
epoxygenase
Arachidonic acid
Cyclooxygenase
Lipoxygenase
NSAIDs
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
PGH2
VSM

• platelets

VSM GIT
PGI2
PGF2?
TXA2
6
Cyclo-oxygenase isoforms
COX-I
COX-II
constitutive
inducible
GIT Platelets renal vascular
inflammation
7
Pain inflammation
PGs sensitize nociceptors to bradykinin,
substance P, histamine PGs inflammation
pain NSAIDs decrease PGs
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
PGE2

• Only under compromised conditions
• renal failure
• severe dehydration
• antihypertensive
• furosemide

maintain GFR blood flow naturesis
11
Thrombosis

• prostacyclin

VSM
-ve
COX-I
Ca2
ve
Platelets
TXA2
aggregation
clots
12
Pain relief and NSAIDs

• 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 (NSAIDs)

• 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
Adverse effects cont.............................

• Bleeding
• Hypersensitivity
• 1 200 people
• Renal Effect
• Renal blood flow
• ? Antihypertensive

18
Prevent ulcers
PGE1 misoprostil
PPI
)
No acid, no ulcer
replace mucosal PG
diarrhoea cramp
prevent NSAIDs ulcers
19
Adverse effects NSAIDs

• 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
NSAIDs COX II selective /specific
meloxicam celecoxib

• MOA
• COX - II gt COX - I
• provide symptomatic relief
• not antiplatelet!!
• CVS effects??

22
Paracetamol

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

23
Paracetamol

• 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