dyspepsia, peptic ulcer disease and helicobacter pylori pharmacology & therapeutics february...
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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