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CHAPTER 1

PepticUlcer

M.ASHOKKUMAR DEPTOFPHARMACYPRACTICE SRMCOLLEGEOFPHARMACY SRMUNIVERSITY

Contents • • • •

PhysiologyofGastricacidsecretion AnintroductiontoPepticUlcerDisease AnoutlineontheDrugsusedinsuchdisorders PharmacokineticsandPharmacodynamicsof importantgroupsofDrugs • ClinicalpharmacologyofPepticUlcerDisease

PhysiologyofGastricSecretion Food

•H2 – cAMP •M3 & CCK2 – IP3-DAG

CNS

GC Vagus

Phasesofgastricsecretion Phase

Stimuli

Pathway

Cephalic(stimulate)

Sight,smell,tasteor thoughtoffood

1) Vagus(M3receptors) 2) Histamine(H2receptor) 3) Gastrin

Gastric(stimulate)

Foodinthestomach

1) Stretch:localreflex(M3 receptors) 2) Chemicalsubstancesinfood (gastrin) 3) IncreasepH:Inhibitionof somatostatin(GHIH)release

Intestinal(inhibit)

Chymeinthe duodenum

WhatisPepticUlcer? • ApepticulcerdiseaseorPUDisanulcer(definedas mucosalerosionsequaltoorgreaterthan0.5 cm)of anareaofthegastrointestinaltractexposedtothe acidandpepsinsecretion • GastritisistheprecursortoPUDanditisclinically difficulttodifferentiatethetwo – – – –

Stomach(calledgastriculcer) Duodenum(calledduodenalulcer) Esophagus(calledEsophagealulcer) Meckel'sDiverticulum(calledMeckel'sDiverticulumulcer)

DuodenalVsGastricUlcers Duodenal

Gastric

• •

• •

• •

Age:25‐75years Gnawingorburningupper abdomenpainrelievedbyfood butreappears1‐3hrsaftermeals Worsepainwhenstomachempty Bleedingoccurswithdeep erosion – Hematemesis – Melena

• • • •

Age:55‐65years Relievedbyfoodbutpainmay persistevenaftereating Anorexia,wtloss,vomiting Infrequentorabsentremissions Small%becomecancerous Severeulcersmayerodethrough stomachwall

GastroesophagealRefluxDisease (GERD) • • • • •

CommonandGImotilitydisorder AcidityofGastriccontents– mostcommonfactor Acidcontentsrefluxbackintoesophagus Intenseburning,sometimesbelching Canleadtoesophagitis,esophagealulcers,and strictures – Barrett’sesophagus • Commonlyassociatedwithobesity • Improveswithlifestylemanagement

WhyUlcerationOccurs? • High[H+]inthegastriclumen • Requiredefensemechanismstoprotectoesophagus andstomach • Oesophagus– LES • Stomach:anumberofmechanisms – – – –

Mucussecretion:slowsiondiffusion Prostaglandins:I2 andE2 (alcohol,aspirin,andotherdrugs) Bicabonateions HighBloodFlow(nitricoxide)

BecauseofImbalance • ImbalanceprimarilybetweenAggressivefactors andDefensivefactors:

Whatmaycontributeimbalance? • Helicobacterpylori • NSAIDs • Ethanol • Tobacco • Severephysiologic stress(Burns,CNStrauma, Surgery,Severemedicalillness) • Steroids

H.pylori • Gram(‐)rodwithflagella • Hpyloriismostcommoncauseof PUD • Transmissionroutefecal‐oral • Secretesurease→convertureato ammonia • Producesalkalineenvironment enablingsurvivalinstomach • Almostallduodenaland2/3gastric ulcerpt’sinfectedwithHP • Consideredclass1carcinogen→ gastriccancer • HigherprevalenceinLowSES

Whoarethey? Nobel Laureates of Medicine – 2005

Discovery of H. pylori & its role in peptic ulcer Barry J Marshall

J. Robin Warren

NSAIDS Damage to the cytoprotective role of PGs – PGE2 and PGI2

DifferentiatingbetweenH.pylori andNSAID‐inducedulcer UlcersassociatedwithH. pylori

Ulcersassociatedwith NSAIDs

• Moreoftenin duodenum • Oftensuperficial • LesssevereGIbleeding

• Moreofteninstomach • Oftendeep • MoresevereGI bleeding • Sometimes asymptomatic

Drugs of Ulcer treatment

ACh

_

M3

+

Ranitidine Gastrin _ Proglumide _

Misoprostol Histamine +

PGE2

PGE receptor

Adenyl cyclase

ATP

Ca++ +

+

H2

+

cAMP

+

Gastrin receptor

Ca++ +

Protein Kinase (Activated) + K H+ K +

Parietal cell

_ Omeprazole

Proton pump

Gastric acid

Lumen of stomach

_

Antacid

PepticUlcers Therapy Purpose Therapyisdirectedat enhancinghost defenseoreliminating aggressivefactors;i.e., H.pylori

Classification 1.

AcidNeutralizingagents:(ANTACIDS) • •

2. • • • •

Systemic:SodiumBicarbonateandSod.Citrate Nonsystemic:Magnesiumhydroxide,Mag.Treisilicate,Aluminium hydroxidegel,Magaldrateandcalciumcarbonate

ReductioninGastricacidsecretion: H2antihistamines:Cimetidine,Ranitidine,Famotidine, NizatidineandRoxatidine Protonpumpinhibitors:Omeprazole,Lansoprazole Pantoprazole,RabeprazoleandEsomeprazole Anticholinergics: Pirenzepine,Propanthelineand Oxyphenonium Prostaglandinanalogue:Misoprostol

Classification– contd. 3. Ulcerprotectives:Sucralfate,Colloidal Bismuthsudcitrate 4. Anti‐H.pyloriDrugs:Amoxicillin, Clarithromycin,metronidazole,tinidazole andtetracycline

Antacids • Weakbasesthatneutralizeacid • Alsoinhibitformationofpepsin (AspepsinogenconvertedtopepsinatacidicpH) • AcidNeutralizingCapacity: – PotencyofAntacids – ExpressedintermsofNumberof mEq of1NHCl thatarebroughtdowntopH3.5in15minutesby unitdoseofapreparation(1gm)

Antacids‐ TheOldestRemedy • SodiumBicarbonate: – Potentneutralizingcapacityandactsinstantly – ANC:1gm=12mEq

• NOTUSEDANYMOREFORITSDEMERITS: – Systemicalkalosis – Distension,discomfortandbelching– CO2 – Reboundacidity – Sodiumoverload

Antacids • Presentdayantacids: – AluminiumHydroxide(ANC1‐2.5mEq/g) – MagnesiumHydroxide(ANC30mEq)– milkofmagnesia – Magnesiumtrisilicate(ANC1mEq/g)

• Durationofaction:30minwhentakeninemptystomachand 2hrswhentakenafterameal • Sideeffects: – Aluminiumantacids– constipation (Astheyrelaxgastricsmooth muscle&delaygastricemptying)– alsohypophosphatemiaand osteomalcia – Mg2+antacids– Osmoticdiarrhoea

• InrenalfailureAl3+antacid– Aluminiumtoxicity &Encephalopathy (Magaldrate– hydratedhydroxymagnesiumaluminate)

Antacids– contd. • Simethicone:Decreasesurfacetension therebyreducebubbleformation‐ addedto preventreflux • Alginates: Formalayeroffoamontopof gastriccontents&reducereflux • Oxethazaine: Surfaceanaesthetic

TherapeuticQuestions • IsitrationaltocombineAluminiumhydroxide andmagnesiumhydroxideinantacid preparations? • Howtoavoidformationofinsoluble complexesofdrugsbyantacids,thatarenot absorbed?

Answers(!) • Interactionscanbeavoidedbytakingantacids 2hrsbeforeorafteringestionofotherdrugs • Combinationprovidesarelativelyfastand sustainedneutralizingcapacity – (MagnesiumHydroxide– Rapidlyacting – AluminiumHydroxide‐ Slowlyacting)

• Combinationpreservesnormalbowelfunction – (AluminiumHydroxide– constipation – Magnesiumhydroxide– diarrhoea)

TheReality • NotpartofPhysicianprescribedregimen– frequencyofdosingandreboundacidity • Overthecounter(OTC)drugforsymptomatic reliefofdyspepsia • Mayonlybeprescribedforveryshortterm: – Non‐ulcerdyspepsiaandminorepisodesofheart burn – AsadjuvantinGERD– quickrelieve

Sucralfate– ulcerprotective

• Saltofsucrosecomplexedtosulfatedaluminiumhydroxide (basicaluminiumsalt) • MOA: – InacidicpHpolymerises toviscousgelthatadherestoulcercrater‐ moreonduodenalulcer – Precipitatesproteinonsurfaceproteinsandactsasphysicalbarrier – Dietaryproteinsgetdepositedonthislayerforminganothercoat – DelaysgastricemptyingandcausesgastricPGsynthesis– protective action

Sucralfate– contd. • Takenonemptystomach1hr.beforemeals • Concurrentantacids,H2 antagonistavoided(asit needsacidforactivation) • Uses: – – – –

NSAIDinducedulcers Patientswithcontinuedsmoking ICU Topically– burn,bedsoreulcers,excoriatedskins

• Dose:1gm1Hrbeforemeals • ADRs:Constipation,hypophosphatemia

Chemicalreactionsofantacidswith HClinthestomach

Antacids Capsules&Tablets: • Powders • Chewabletablets • Suspensions • Effervescentgranulesandtablets

H2 Antagonists • Cimetidine,Ranitidine,Famotidine,Roxatidine,Nizatidine and • MOA: – – – – – – – –

ReversiblecompetitiveinhibitorsofH2 receptor Highlyselective,noactiononH1 orH3 receptors Allphasesofgastricacidsecretion Veryeffectiveininhibitingnocturnalacidsecretion(asitdepends largelyonHistamine) Modestimpactonmealstimulatedacidsecretion(asitdependson gastrin,acetylcholineandhistamine) VolumeofpepsincontentandIFarealsoreduced Volumereducedby60– 70%‐ antiulcerogeniceffect Noeffectonmotility

H2 antagonists • Kinetics: – Alldrugsareabsorbedorallyadequately – Bioavailabilityupto80% – Absorptionisnotinterferedbypresenceoffood – Cancrossplacentalbarrierandreachesmilk – PoorCNSpenetration – 2/3rd ofthedrugsareexcretedunchangedinbile andurine

• Preparations:availableastablets,injections

H2antagonists‐ ADRs • Extremelysafedrugsandwelltolerated • MainADRsarerelatedtoCimetidine: – Antiandrogeniceffects – Increasesprolactin secretionandinhibitsdegradationofestradiolby liver – CytochromeP450inhibition– theophylline,metronidazole,phenytoin, imipramineetc. – Antacids

• Others: – Headache,dizziness,bowelupset,drymouth – BolusIV– releasehistamine– bradycardia,arrhythmia,cardiacarrest – Elderly‐ precaution

Comparison of H2 antagonists Cimetidine

Ranitidine

Bioavailability 80 Relative Potency 1 Half life (hrs) 1.5 - 2.3 Duration of 6 action (hrs) Inhibition of 1 CYP 450 Dose mg (bd) 400

50 5 -10 1.6 - 2.4 8

Famotidine 40 32 2.5 - 4 12

0.1

0

150

20

Antiandrogenic effect, prolactin secretion and gynocomastia

Nizatidine >90 5 -10 1.1 -1.6 8 0 150

H2antagonists‐ Uses Promotethehealingofgastricandduodenalulcers • Duodenalulcer– 70to90% • GastricUlcer– 50to75%(NSAIDulcers)) • Stressulcerandgastritis • GERD • Zollinger‐Ellisonsyndrome • Prophylaxisofaspirationpneumonia • Urticaria Doses: • •

300mg/40mg/150mgatbedtimeofR,F,Roxrespectivelyfor healing Maintenance:150/20/150mgBDofR,F,Rox

H2 blockersTabletsinPepticulcer Cimetidine

800mgbedtime/400mgBd 400mgbedtime

Ranitidine

300mgbedtime/150mgBD 150mgbedtime

Famotidine

40mgbedtime

20mgbedtime

Roxatidine

150mgbedtime

75mgbedtime

Question YourfriendwantstotakeaH2 antagonistbefore hetakesalcoholtoavoidgastricirritation.He consultsyou.WhichH2 antagonistwillyouask himtotake ? Ranitidine/Famotidine/Roxatidine/Tiznidine ?

H2 antagonists– contd. • Answer: Famotidine • Explanation: AllH2 antagonistexceptfamotidine inhibit gastricfirstpassmetabolismofethanoland increaseitsbioavailability

ProtonPumpInhibitors

Omeprazole

• Mosteffectivedrugsinantiulcertherapy • Prodrugsrequiringactivationinacidenvironment • BlockenzymesresponsibleforsecretingHCl‐ binds irreversibly toH+K+ATPase • Prototype:Omeprazole(Prilosec) • Examples: – – – –

Lansoprazole Pantoprazole Rabeprazole Esomeprazole

Omeprazole‐ MOA • SubstitutedBenzimidazolederivative • ItsaProdrug • DiffusesintoG.canaliculi=accumulation pH...