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PGHPGHHPETEHPETE
PProstaglandinsrostaglandins, , cyclo-oxygenase cyclo-oxygenase
and the GITand the GIT
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Eicosanoids
Linoleic acid Linoleic acid
(diet)(diet)
Arachidonic Arachidonic
acidacid
MembraneMembranePhospholipiPhospholipi
dsds
PG
LTs
LX
Phospho-Phospho-lipase Alipase A22
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Cell membrane phospholipids
Phospholipase A2
ArachidoniArachidonicc
acidacid PGHPGHHPETEHPETE
HETE LTHETE LT PGI TX PGI TX PGE/F/DPGE/F/D
CyclooxygenaseLipoxygenase
NSAID’sNSAID’s
epoxygenase
lipoxinslipoxins
isoprostaneisoprostaness
CorticosteroidsCorticosteroids
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Leukotriene synthesisLeukotriene synthesis
Lipo-oxygenase
LTBLTB44
Arachidonic acidArachidonic acid
chemotaxis
HPETEHPETE
LTDLTD44
LTCLTC44
LTALTA44
Mast cells, macro-Mast cells, macro-phages, leukocytesphages, leukocytes
Broncho-constrictor
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Prostaglandin synthesis
Cyclo-oxygenase
PGGPGG22
PGIPGI22
PGFPGF22TXATXA22
Arachidonic Arachidonic acidacid
PGEPGE22
plateletsplatelets
PGHPGH22VSM
Renal
GIT
VSM GIT
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Cyclo-oxygenase isoforms
GIT GIT PlateletsPlatelets
renalrenalvascularvascular
inflammationinflammation
COX-ICOX-ICOX-IICOX-IIinducibl
e
constitutive
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Pain & inflammation
PG’s sensitize nociceptors PG’s sensitize nociceptors to bradykinin, substance P, to bradykinin, substance P,
histaminehistamine
PG’s = inflammation = painPG’s = inflammation = pain
NSAID’s decrease PG’sNSAID’s decrease PG’s
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GIT mucosal protectionprotects protects against against stomach stomach
acidacid
decrease HCldecrease HClincrease mucousincrease mucous
increase sub mucosal blood increase sub mucosal blood flowflow
increase bicarbonateincrease bicarbonate
PGEPGE22
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GIT peristalsis
long/circular long/circular musclemuscle
diarrhoeadiarrhoeacrampingcramping
PGEPGE22
PGFPGF22
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Renal PGEPGE22
maintainmaintain
GFR GFR
blood flowblood flow
naturesisnaturesis
Only under compromised conditions
renal failurerenal failure
severe dehydrationsevere dehydration
antihypertensiveantihypertensive
furosemidefurosemide
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Thrombosis
-ve-ve
aggregationaggregation
CaCa22++
prostacyclinprostacyclin
+ve+veTXATXA22
clotsclots
PlateletPlateletss
COX-I
VSMVSM
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Pain relief and NSAID’sPain relief and NSAID’s
Inhibit PG synthesisInhibit PG synthesis
Mainly peripheralMainly peripheral
Cortical site?Cortical site?
Inhibition of COX-IInhibition of COX-I
Inhibition of COX-IIInhibition of COX-II
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Anti-pyreticAnti-pyretic
PG synthesisPG synthesis
Central -hypothalamusCentral -hypothalamus
Interleukin 1 mediatedInterleukin 1 mediated
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Non steroidal anti-inflammatory drugs (NSAID’s)(NSAID’s)
Not related to corticosteroidsNot related to corticosteroids
Inhibit cyclo-oxygenase I & IIInhibit cyclo-oxygenase I & II
Different kineticsDifferent kinetics
Effective as aspirinEffective as aspirin
Anti-inflammatory, analgesic, Anti-inflammatory, analgesic, antipyreticantipyretic
Less toxic? Less toxic?
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indomethacin
naproxen
diclofenac
ibuprofen
MOAMOA COX-II = COX-I COX-II = COX-I provide symptomatic reliefprovide symptomatic relief Adverse effectsAdverse effects Not antiplateletNot antiplatelet??
Non steroid anti -inflammatory drugs
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Side effects of NSAID's & aspirinSide effects of NSAID's & aspirin
Common but mildCommon but mild Mild dyspepsia, heart burn, GORDMild dyspepsia, heart burn, GORD
Rare but lethal Perforation, ulcer, bleeds Obstructions
PG via COX-I (mucosa)
GIT GIT
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Adverse effects cont.............................
BleedingBleeding Hypersensitivity Hypersensitivity
1: 200 people1: 200 people
Renal EffectRenal Effect
Renal blood flowRenal blood flow
AntihypertensiveAntihypertensive
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Prevent ulcers
))
diarrhoeadiarrhoea
crampcramp
preventpreventNSAID’sNSAID’sulcersulcers
PPIPGE1misoprostil
replace mucosal PG
No acid, no ulcer
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Adverse effects NSAID’s…
Misoprostil Misoprostil Cramps, diarrhoea, womenCramps, diarrhoea, women
otherother sucralfate?sucralfate? HH22RA antagonists?RA antagonists?
Proton pump inhibitorsProton pump inhibitors
COX-II specificCOX-II specific
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Selective COX– II inhibitorsSelective COX– II inhibitors
COX-IICOX-II
House keepingHouse keepingGIT, renal, plateletsGIT, renal, platelets
InflammationInflammation
Synthesized de novoSynthesized de novo
Non steroid anti -inflammatory drugs
COX-ICOX-I
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meloxicam
celecoxib
MOAMOA COX - IICOX - II >> COX - ICOX - I provide symptomatic reliefprovide symptomatic relief not antiplateletnot antiplatelet!!!!CVS effects??CVS effects??
NSAID’s COX II selective /specific
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Paracetamol Central siteCentral site AnalgesicAnalgesic AntipyreticAntipyretic
Not Not anti-inflammatoryanti-inflammatory No action on peripheral cyclo-No action on peripheral cyclo-
oxygenaseoxygenase
Less GIT IrritationLess GIT Irritation
Alternative to aspirinAlternative to aspirin
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Paracetamol Toxicity Toxicity 10g is toxic!!10g is toxic!! N-acetyl cysteine antidoteN-acetyl cysteine antidote Less if alcohol is added Less if alcohol is added
How strong analgesic?How strong analgesic? Very little dose responseVery little dose response
500mg = 750 =1000mg500mg = 750 =1000mg
No response over 1000mgNo response over 1000mg