Dyspepsia, Peptic Ulcer Dyspepsia, Peptic Ulcer

Disease and Disease and

Helicobacter PyloriHelicobacter Pylori

Pharmacology & Therapeutics February Pharmacology & Therapeutics February 20072007

DyspepsiaDyspepsia

40% of all adults40% of all adults

4% GP consultations4% GP consultations

10% further investigations10% further investigations

10-20% NSAID users10-20% NSAID users

Endoscopy findingsEndoscopy findings

15% Duodenal or Gastric ulcer15% Duodenal or Gastric ulcer

15% Oesophagitis = GORD15% Oesophagitis = GORD

30% Gastritis duodenitis or hiatus 30% Gastritis duodenitis or hiatus

herniahernia

30% Normal = functional dyspepsia30% Normal = functional dyspepsia

Pathogenesis of DyspepsiaPathogenesis of Dyspepsia

FactorFactor Treatment approachTreatment approach

Infection with Infection with H. pyloriH. pylori Eradication of H. pylori Eradication of H. pylori infection, e.g. triple txinfection, e.g. triple tx

↑ ↑ gastric HCl secretiongastric HCl secretion ↓ ↓ HCl secretion or HCl secretion or neutralizing it, e.g. H2 neutralizing it, e.g. H2 antagonists, pirenzepine, antagonists, pirenzepine, antacids , PPIsantacids , PPIs

Inadequate mucosal Inadequate mucosal defence against gastric defence against gastric HClHCl

Agents that protect Agents that protect gastric mucosa, e.g. gastric mucosa, e.g. sucralfatesucralfate

Altered gastric motilityAltered gastric motility Prokinetic agents eg Prokinetic agents eg metoclopramidemetoclopramide

Gastric acid secretionGastric acid secretion

Helicobacter PyloriHelicobacter Pylori

Symptomatic Symptomatic treatmenttreatment

AntacidsAntacids

• MOA: Weak bases that MOA: Weak bases that react with gastric acid to react with gastric acid to form H20+salt. ↓pepsin form H20+salt. ↓pepsin activity as pepsin activity as pepsin inactive at pH>4inactive at pH>4

• Symptom relief, Symptom relief, liquids>tabletsliquids>tablets

• E.g. Maalox = Mg(OH)2 E.g. Maalox = Mg(OH)2 + Al(OH)3+ Al(OH)3

DrugDrug Side effectSide effect

MagnesiumMagnesium severe osmotic severe osmotic diarrhoea diarrhoea (therefore (therefore combined with combined with AlOH)AlOH)

↓ ↓ drug drug absorptionabsorption

AluminiumAluminium ↓↓phosphate, phosphate, ↓absorption of ↓absorption of tetracycline, tetracycline, thyroxine & thyroxine & chlorpromazinechlorpromazine, constipation, constipation

CalciumCalcium ↑↑Ca in blood & Ca in blood & urine (high urine (high doses)doses)

Mucosal Protective AgentsMucosal Protective Agents

1)1) SulcralfateSulcralfateMOA: Binds to positively charged proteins present on damaged MOA: Binds to positively charged proteins present on damaged mucosa forming a protective coatmucosa forming a protective coat

Useful in “stress ulceration”Useful in “stress ulceration”

As effective as H2-R antagonists/high dose antacids As effective as H2-R antagonists/high dose antacids

SE: ConstipationSE: Constipation

↓↓absorption of cimetidine, digoxin, phenytoin & tetracyclineabsorption of cimetidine, digoxin, phenytoin & tetracycline

2)2) BismuthBismuthMOA: Antimicrobial action. Also inhibit pepsin activity, ↑mucus MOA: Antimicrobial action. Also inhibit pepsin activity, ↑mucus secretion & interact with proteins in necrotic mucosal tissue to coat & secretion & interact with proteins in necrotic mucosal tissue to coat & protect the ulcer craterprotect the ulcer crater

Additional agentsAdditional agents

Antifoaming agentAntifoaming agent

– – Dimethicone to relieve flatulence (surfactant)Dimethicone to relieve flatulence (surfactant)

Alginates Alginates

- form a raft on surface of stomach contents to reduce reflux- form a raft on surface of stomach contents to reduce reflux

CarbenoxoloneCarbenoxolone

- liquorice derivative ? Alters mucin s/e H2O retention - liquorice derivative ? Alters mucin s/e H2O retention

↓K+↓K+

H2-receptor antagonistsH2-receptor antagonists

DrugDrug Side effectsSide effects

CimetidineCimetidine -reversible impotence, gynaecomastia & -reversible impotence, gynaecomastia & ↓ ↓ sperm count (high doses) (nonsteroidal sperm count (high doses) (nonsteroidal antiandrogen)antiandrogen)

-mental status abnormalities-confusion, -mental status abnormalities-confusion, hallucinations (elderly/renal impairment)hallucinations (elderly/renal impairment)

-leukopenia & thrombocytopenia (rare)-leukopenia & thrombocytopenia (rare)

-cytochrome P450 inhibitor (e.g. impairs -cytochrome P450 inhibitor (e.g. impairs metabolism of warfarin, theophylline & metabolism of warfarin, theophylline & phenytoin)phenytoin)

Ranitidine,famotidiRanitidine,famotidinene

-Impotence, gynaecomastia & confusion less -Impotence, gynaecomastia & confusion less frequently than cimetidine.frequently than cimetidine.

-Little interference with cytochrome P450-Little interference with cytochrome P450

-Reversible drug-induced hepatitis with all H2--Reversible drug-induced hepatitis with all H2-antagonistsantagonists

Proton-pump Inhibitors (PPI)Proton-pump Inhibitors (PPI)

• MOA: block parietal cell HMOA: block parietal cell H+/K+ ATPase enzyme system +/K+ ATPase enzyme system

(proton pump) ↓ secretion of H+ ions into gastric lumen(proton pump) ↓ secretion of H+ ions into gastric lumen

• More effective than H2-antagonists or antacidsMore effective than H2-antagonists or antacids

• Used in antimicrobial regimens to eradicate H. pyloriUsed in antimicrobial regimens to eradicate H. pylori

• SE: n&v, diarrhoea, dizziness, headaches, SE: n&v, diarrhoea, dizziness, headaches,

gynaecomastia & impotence (rare), thrombocytopenia, gynaecomastia & impotence (rare), thrombocytopenia,

rashesrashes

Helicobacter PyloriHelicobacter Pylori

95% Duodenal ulcers95% Duodenal ulcers

70% Gastric ulcers70% Gastric ulcers

10% Non-ulcer dyspepsia10% Non-ulcer dyspepsia

Treatment benefits gastritis more Treatment benefits gastritis more

than reflux symptomsthan reflux symptoms

Diagnosing Diagnosing H. pyloriH. pylori

Urea breath test Urea breath test 95% sensitive & specific95% sensitive & specific

Stool antigen test Stool antigen test 92%92% sensitive & specificsensitive & specific

Serology Serology 80%80% sensitive & specificsensitive & specific

Endoscopy – CLO test Endoscopy – CLO test 98% 98% sensitive & specificsensitive & specific

(urea and phenol red, a dye that turns pink in a pH of 6.0 or (urea and phenol red, a dye that turns pink in a pH of 6.0 or

greater)greater)

H. PyloriH. Pylori Eradication Eradication

1st line eradication tx 1st line eradication tx for H. pylorifor H. pylori

22ndnd line tx line tx

Preferred tx= PPI PO + Preferred tx= PPI PO + Clarithromycin 500mg BD PO + Clarithromycin 500mg BD PO + Amoxicillin 1 gm BD PO for 7 Amoxicillin 1 gm BD PO for 7 daysdays

If Penicillin allergic= PPI + If Penicillin allergic= PPI + Clarithromycin 500mg BD PO + Clarithromycin 500mg BD PO + Metronidazole 400mg BD PO for Metronidazole 400mg BD PO for 7 days7 days

E.g. of PPI: Lansoprazole 30mg E.g. of PPI: Lansoprazole 30mg BD POBD PO

PPI + Bismuth 120mg QDS PO PPI + Bismuth 120mg QDS PO + Metronidazole 500mg TDS + Metronidazole 500mg TDS PO + Tetracycline 500mg QDS PO + Tetracycline 500mg QDS PO for 7 daysPO for 7 days

Subsequent failures handled Subsequent failures handled on individual basis with advice on individual basis with advice from gastro/microfrom gastro/micro

H. PyloriH. Pylori eradication eradication

1 week triple-therapy regimens eradicate 1 week triple-therapy regimens eradicate H. H. PyloriPylori in >90% cases. Usually no need for in >90% cases. Usually no need for continued antisecretory tx unless ulcer continued antisecretory tx unless ulcer complicated by bleeding/perforationcomplicated by bleeding/perforation

2 week triple-therapy offer higher eradication 2 week triple-therapy offer higher eradication rates cf 1 week but SE common & poor rates cf 1 week but SE common & poor compliancecompliance

2-week dual-therapy with PPI & antibacterial 2-week dual-therapy with PPI & antibacterial produce low rates of H. pylori eradication & produce low rates of H. pylori eradication & not recommendednot recommended

H. pylori eradicationH. pylori eradication

Treatment failure may be due toTreatment failure may be due to

- Resistance to antibacterial drugs- Resistance to antibacterial drugs

- Poor compliance- Poor compliance

DrugDrug Side effectsSide effects

BismuthBismuth n&v, unpleasant taste, darkening of tongue & n&v, unpleasant taste, darkening of tongue & stools, caution in renal diseasestools, caution in renal disease

MetronidazolMetronidazolee

n&v, unpleasant taste, n&v, unpleasant taste, ↓effectiveness OCP, care ↓effectiveness OCP, care with lithium/warfarinwith lithium/warfarin

Amoxicillin Amoxicillin

& tetracycline& tetracyclineGI side effects, GI side effects, ↓ effectiveness OCP, ↓ effectiveness OCP, pseudomenbranous colitispseudomenbranous colitis

LansoprazoleLansoprazole ↓ ↓ effectiveness OCPeffectiveness OCP

Practical Management Practical Management

of dyspepsiaof dyspepsia

Who needs Who needs endoscopy?endoscopy? GI bleedingGI bleeding

Unintentional weight lossUnintentional weight loss

DysphagiaDysphagia

Persistent vomitingPersistent vomiting

Iron deficiency anaemiaIron deficiency anaemia

Epigastric massEpigastric mass

>55 with unexplained persistent/recent onset >55 with unexplained persistent/recent onset

dyspepsiadyspepsia

PUD on endoscopyPUD on endoscopy

Stop NSAIDsStop NSAIDs

Start full dose PPI for 2 monthsStart full dose PPI for 2 months

Eradication treatment if Eradication treatment if H PyloriH Pylori

positivepositive

Repeat endoscopy for gastric ulcer 2% Repeat endoscopy for gastric ulcer 2%

cancer riskcancer risk

GORD on endoscopyGORD on endoscopy

Lifestyle adviceLifestyle advice

Full dose PPI for 1-2 monthsFull dose PPI for 1-2 months

H PyloriH Pylori Eradication may not benefit reflux symptoms Eradication may not benefit reflux symptoms

If recurrence - lowest dose PPI to control symptomsIf recurrence - lowest dose PPI to control symptoms

GORDGORDGORD = Symptoms of “heartburn”GORD = Symptoms of “heartburn”

General advice includes AVOIDINGGeneral advice includes AVOIDING Drug TxDrug TxMeals at night, lying down after Meals at night, lying down after mealsmealsElevate head of bedElevate head of bedHeavy lifting, tight clothing, Heavy lifting, tight clothing, bending bending Being overweightBeing overweightSmoking (nicotine relaxes lower Smoking (nicotine relaxes lower oesophageal sphincter)oesophageal sphincter)Aggravating substances (spicy Aggravating substances (spicy foods, C2H5OH)foods, C2H5OH)Drugs which encourage reflux Drugs which encourage reflux (e.g. antimuscarinic, smooth (e.g. antimuscarinic, smooth muscle relaxants, theophylline)muscle relaxants, theophylline)

antacids=+/-alginic acidantacids=+/-alginic acidPro-kinetic agent, e.g. Pro-kinetic agent, e.g. metoclopramidemetoclopramideH2-antagonistH2-antagonistPPIPPIIf severe sx when tx stopped, or If severe sx when tx stopped, or bleed from oesophagitis or bleed from oesophagitis or stricture maintenance tx with PPI stricture maintenance tx with PPI or surgery may be necessaryor surgery may be necessary

NSAID Induced NSAID Induced DyspepsiaDyspepsia 10-20% develop endoscopically visible PUD10-20% develop endoscopically visible PUD

1-5% perforation or major bleeding1-5% perforation or major bleeding

Endogenous prostaglandins (PGE2 & I2) contribute to GI mucosa Endogenous prostaglandins (PGE2 & I2) contribute to GI mucosa

integrity byintegrity by

- stimulation of mucus & bicarbonate secretion- stimulation of mucus & bicarbonate secretion

- maintenance of blood flow (allows removal of luminal H-ions)- maintenance of blood flow (allows removal of luminal H-ions)

- prevent luminal H-ions from diffusing into the mucosa- prevent luminal H-ions from diffusing into the mucosa

- - ↓ gastric acid secretion↓ gastric acid secretion

- helping to repair damaged epithelium- helping to repair damaged epithelium

NSAID Induced NSAID Induced DyspepsiaDyspepsia Elderly >65 years Elderly >65 years History PUDHistory PUD Other drugs – eg bisphosphonates, Other drugs – eg bisphosphonates,

SteroidsSteroids

PPI or misoprostol protection for at riskPPI or misoprostol protection for at risk Consider screening & eradicating Consider screening & eradicating H PyloriH Pylori

infectioninfection

Prostaglandin analoguesProstaglandin analogues

• MisoprostolMisoprostol = synthetic prostaglandin E1 analogue = synthetic prostaglandin E1 analogue

Prevents NSAID induced ulcers & heals chronic GU & DUPrevents NSAID induced ulcers & heals chronic GU & DU

SE: Abdo pain, n&v, diarrhoea, abortifacient (produces SE: Abdo pain, n&v, diarrhoea, abortifacient (produces

uterine contractions)uterine contractions)

Non ulcer dyspepsiaNon ulcer dyspepsia

Treat H pylori (no routine retesting)Treat H pylori (no routine retesting)

Symptomatic treatmentSymptomatic treatment

PPI (proven benefit)PPI (proven benefit)

Prokinetic agent eg Prokinetic agent eg

metoclopramide (probable benefit)metoclopramide (probable benefit)

Dyspepsia without alarm Dyspepsia without alarm

symptomssymptoms

Lifestyle advice Lifestyle advice

Antacids and medication reviewAntacids and medication review

Empiric PPIEmpiric PPI

Test and treat for H PyloriTest and treat for H Pylori

Copyright ©2007 BMJ Publishing Group Ltd.

Shah, R. BMJ 2007;334:41-43