PGHPGHHPETEHPETE

PProstaglandinsrostaglandins, , cyclo-oxygenase cyclo-oxygenase

and the GITand the GIT

Eicosanoids

Linoleic acid Linoleic acid

(diet)(diet)

Arachidonic Arachidonic

acidacid

MembraneMembranePhospholipiPhospholipi

dsds

PG

LTs

LX

Phospho-Phospho-lipase Alipase A22

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

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

Prostaglandin synthesis

Cyclo-oxygenase

PGGPGG22

PGIPGI22

PGFPGF22TXATXA22

Arachidonic Arachidonic acidacid

PGEPGE22

plateletsplatelets

PGHPGH22VSM

Renal

GIT

VSM GIT

Cyclo-oxygenase isoforms

GIT GIT PlateletsPlatelets

renalrenalvascularvascular

inflammationinflammation

COX-ICOX-ICOX-IICOX-IIinducibl

e

constitutive

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

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

GIT peristalsis

long/circular long/circular musclemuscle

diarrhoeadiarrhoeacrampingcramping

PGEPGE22

PGFPGF22

Renal PGEPGE22

maintainmaintain

GFR GFR

blood flowblood flow

naturesisnaturesis

Only under compromised conditions

renal failurerenal failure

severe dehydrationsevere dehydration

antihypertensiveantihypertensive

furosemidefurosemide

Thrombosis

-ve-ve

aggregationaggregation

CaCa22++

prostacyclinprostacyclin

+ve+veTXATXA22

clotsclots

PlateletPlateletss

COX-I

VSMVSM

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

Anti-pyreticAnti-pyretic

PG synthesisPG synthesis

Central -hypothalamusCentral -hypothalamus

Interleukin 1 mediatedInterleukin 1 mediated

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?

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

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

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

BleedingBleeding Hypersensitivity Hypersensitivity

1: 200 people1: 200 people

Renal EffectRenal Effect

Renal blood flowRenal blood flow

AntihypertensiveAntihypertensive

Prevent ulcers

))

diarrhoeadiarrhoea

crampcramp

preventpreventNSAID’sNSAID’sulcersulcers

PPIPGE1misoprostil

replace mucosal PG

No acid, no ulcer

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

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

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

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

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