Acid Suppression Therapy in Peptic Ulcer Disease

Acid Suppression Therapy
in Peptic Ulcer Disease
Dr Omer Khan
Medical Resident
Sultan Bin AbdulAziz Humanitarian City

Lecture Objectives
• Regulation of Gastric acid secretion
• Classification of drugs used in peptic ulcer
• Mechanism of action, Uses and Adverse effects, drug
interactions of Acid suppressing drugs
• Adverse Consequences of PPIs
• Drugs for eradication of H.pylori

How Peptic ulcer occurs
Imbalance primarily between Aggressive factors and Defensive
factors

Quiz
Name
Foveolar cells
Parietal (oxyntic) cells
Chief (zymogenic) cells
Enteroendocrine (APUD) cells
Endocrine K cells of the small
intestine
Endocrine M cells in small
intestine
Delta cells (δ-cells or D cells)
Secretion
mucus gel layer
gastric acid and ?
pepsinogen and gastric lipase
Hormones: gastrin, histamine,
endorphins, serotonin,
cholecystokinin and somatostatin
?
Motilin
Somatostatin

Regulation of gastric acid secretion

Classification Of Drugs Used In
Peptic Ulcer
• 1. Drugs that inhibit gastric acid secretion
• 2. Drugs that neutralize gastric acid (Antacids)
• 3. Ulcer protectives
• 4. Anti H. pylori drugs

Drugsthat inhibitgastric acidsecretion
• H2 receptor blockers
Cimetidine, Ranitidine, Famotidine
• Proton pump inhibitors
Omeprazole, Pantoprazole, esomeprazole
• Anticholinergics
Pirenzepine
• Prostaglandin analogues
Misoprostol

Drugs that neutralize gastric acid (Antacids)
Systemic:
• Sodium bicarbonate
• sodium citrate
Non systemic:
• Magnesium hydroxide
• Mag. Trisilicate
• Aluminium hydroxide gel
• Magaldrate

Ulcer protectives
• Sucralfate
• Colloidal Bismuth Sulfate (CBS)

Anti H. pyloridrugs
• Amoxicillin, Clarithromycin, Metronidazole, Tinidazole,
Tetracycline

H2 Antagonists
Mechanism of action
• Competitively block H2 receptors on parietal cell & inhibit
gastric acid production
• Supress secretion of acid in all phases but mainly nocturnal
acid secretion
• Also reduce acid secretion stimulated by Ach, gastrin, food,
etc.

H2 Antagonists
• H2 antagonists - Uses Promote the healing of gastric and
duodenal ulcers
• Duodenal ulcer – 70 to 90% at 8 weeks
• Gastric Ulcer – 50 to 75%
• NSAID ulcers induced ulcers
• Stress ulcer and gastritis
• GERD
• Zollinger-Ellison syndrome
• Prophylaxis of aspiration pneumonia

H2 Antagonists
Adverse effects:
• Headache
• Dizziness
• Bowel upset
• Dry mouth
• CNS: Confusion, restlessness
• Bolus IV – release histamine – bradycardia, arrhythmia, cardiac
arrest
• Cimetidine has antiandrogenic actions
Drug interactions:
• Cimetidine inhibits several CYP-450 isoenzymes and reduces hepatic
blood flow, so inhibits metabolism of many drugs like theophylline,
metronidazole, phenytoin, imipramine etc.
• Antacids reduce the absorption of all H2 blockers

Proton Pump Inhibitors
• Most effective drugs in anti-ulcer therapy ?

Mechanism of Action
• Prodrugs inactive at neutral pH
• At pH < 5 rearranges to two charged cationic forms
(sulfenamide + sulphenic acid) that bind covalently with SH
groups of H⁺K⁺ ATPase and inactivate it irreversibly
• Also inhibits gastric mucosal carbonic anhydrase

Pharmacokinetics
• -Available as enteric coated tablets
• They should be given 30 minutes to 1 hour before food intake
• half life is very short and only 1-2 Hrs
• Still the action persists for 24 Hrs to 48 hrs after a single dose
• Action lasts for 3-4 days even after stoppage of the drug

Therapeutic uses:
1. Gastroesophageal reflux disease (GERD)
2. Peptic Ulcer - Gastric and duodenal ulcers
3. Bleeding peptic Ulcer
4. Zollinger Ellison Syndrome
5. Prevention of recurrence of nonsteroidal antiinflammatory
drug (NSAID) - associated gastric ulcers in patients who
continue NSAID use.
6. Reducing the risk of duodenal ulcer recurrence associated
with H. pylori infections
7. Aspiration Pneumonia

• Comparative success of therapy with PPI and H2 antagonist

Adverse Effects
• Nausea, loose stools, headache abdominal pain, constipation
• Muscle & joint pain, dizziness, rashes
• Rare : Gynaecomastia, erectile dysfunction , Leucopenia and
hepatic dysfunction
• Osteoporosis in elderly on prolonged use
• Hypergastrinemia
Drug interactions
Omeprazole inhibits the metabolism of warfarin, phenytoin,
diazepam, and cyclosporine.
However, drug interactions are not a problem with the other
PPIs.

• Lansoprazole : Partly reversible, more potent, slightly more
against H pylori, Higher BA, rapid onset
• Pantoprazole: More acid stable, I.V, CYP450 less affinity
• Rabeprazole: claimed to be most rapid
• Es-omeprazole : Better intragastric pH , higher healing rates

Should PPI’s be First-Line Treatment for Newly-Diagnosed
Dyspepsia or GERD?
• Yes or No

Adverse Consequences of PPIs
• PPI-Induced Rebound Hypersecretion of Acid
• PPI and Increased risk of pathological fracture.
• Clopidogrel -PPI Interaction
• Gastric Acid Influences Gut Flora
• PPIs in Cirrhotics with Ascites
• Use of PPI and the Risk of pneumonia
• PPIs and risk of dementia
• PPI and high costs of health care

PPIInducedReboundHypersecretionof Acid
• Since 1966, several studies have shown that as little as 2
months on omeprazole 40 mg/day can result in marked
rebound of gastric acid secretion upon PPI withdrawal.
• The effect is most evident in Helicobacter pylori-negative
individuals.
• The degree of acid rebound is proportional to the degree
elevation of intragastric pH during treatment, and fasting
plasma gastrin levels during PPI therapy.
• Presumed due to gastrin-induced increase in parietal cell mass
and EC cells.

• 5. Gastrin Exerts a Powerful Trophic Effect on Enterochromaffin-like
cells and Parietal cells
• 6. Rebound Hypersecretion of Acid on PPI’s• In HP-negative subjects
on omeprazole 40 mg/day for 8 weeks there was a median increase
in the BAO of 82%, and a 28% increase in the MAO 15 days after
discontinuation.• The response in HP-positive patients is similar but
more highly variable.• Presumed due to gastrin-induced increase in
parietal cell mass and EC cells.• The duration of the rebound acidity
was not determined Gastroenterology 1999;116:239-47
• 7. Rebound Hypersecretion of Acid on PPI’s:Basal Acid Output 6.8
3.0 3.0 1.9 Gastroenterology 1999;116:239-47
• 8. Rebound Hypersecretion of Acid on PPI’s: Maximal Acid Output
41.7 40.4 32.4 6.8 29.8 3.0 3.0 1.9 Gastroenterology 1999;116:239-
47
• 9. PPI Therapy Induces Acid-RelatedSymptoms in Previously
Asymptomatic Healthy Volunteers

Proton-Pump Inhibitor
Therapy Induces the Symptoms
it Is Used to Treat

• PPI Therapy Induces Acid-Related Symptoms in Healthy
Volunteers After Withdrawal of Rx• 120 subjects, without any
clinically significant history of reflux symptoms, randomized in
double-blind fashion to 2 months treatment with
esomeprazole 40 mg/d or placebo, and then 4 weeks all
received placebo
• During weeks 2, 3, and 4 post-treatment, clinically significant
symptoms of heartburn, acid reflux, or dyspepsia were
reported by 44% of those who had received omeprazole
versus only 15% of those who had received placebo
throughout (P < .001).
Gastroenterology 2009 ;Vol. 137(1): 20-22)

PPI-Induced Dyspepsia:
Statistically Significant but Relatively MildP <0.0011= No
Bothersome Symptoms 7= Very Bothersome Symptoms
Gastroenterology 2009 ;Vol. 137, Issue 1, Pages 20-22

Implications of Rebound
Hypersecretion of Acid on PPI’s
• PPI should not be first-line therapy for dyspepsia/GERD
• The greater the acid suppression, the greater the rebound –
Acid rebound lasts for at least 2 months
• Once you start PPI’s for GERD be prepared to use as long-term
therapy – Discontinuation of PPI or switching to H2RA may be
difficult
• When treating acid-like dyspepsia or GERD, start with H2-
receptor antagonist as initial therapy
• If H2-RA’s fail, use the lowest does PPI once a day
• If nocturnal symptoms predominate, try PPI before dinner, or
add an evening H2RA before bid dosing of PPI

• Never use omeprazole 40 as initial therapy.
• Implications of Rebound Hypersecretion of Acid on PPI’s
• Empiric PPI trials should be brief (2-4 wks) – It is not necessary
to test the efficacy of PPIs over several months as the
maximal acid suppression occurs within 2-5 days.
• Try different PPI’s before going to high-dose PPI
• Once symptoms have been controlled for several months, try
to back down to lowest effective PPI dose periodically

PPIand Hip Fractures:
Overview
• Since 2006, 4 published studies have shown an association
between chronic PPI use and fractures of the hip – 2 of the
studies show greater risk with longer duration or higher
intensities of use or both
• One study was unable to detect an effect of PPI use on the
occurrence of hip fracture in the absence of other risk factors
for hip fracture
• PPI use does not affect bone density – Association between
PPIs and hip fracture may be due to the presence of
unmeasured confounders

IsTherea BiologicallyPlausibleMechanismfor
PPI-InducedFractures?
• Direct PPI Effect on Bone Fragility?
• Approximately 50% of low-velocity fractures occur in patients without
osteoporotic BMD as determined by DXA scanning
• PPIs are capable of blocking the osteoclast-based vacuolar proton
pump, leading to decreased bone turnover.
• Inhibition of proton pump activity in osteoclasts has direct inhibitory
effects on bone resorption and release of bone calcium
• Decreased bone turnover may promote slight increases in BMD but may
increase fracture risk by blocking the repair of microfractures and
microarchitectural defects
• Physiologic Mechanisms by Which use of PPI Could Affect Bone Mineral
Metabolism
• The dissociation of food calcium complexes and the liberation of Ca2+
from calcium salts is strongly dependent on pH.
• Calcium carbonate, which is the most common calcium salt found in
dietary supplements, is relatively insoluble at high pH levels, which
could potentially hinder its absorption
• PPI use may reduce absorption of inorganic calcium by as much as 60%

PPI and Hip Fractures
• PPI therapy 1st linked to an increased risk for hip fractures in 2006
• UK General Practice Research Database (1987 - 2003), – Cases included all
patients with an incident hip fracture (n = 13,556), and 135,386 controls.• The
strength of the association between hip fracture and PPI therapy increased with
increasing duration of PPI therapy. JAMA. 2006;296:2947-2953.
• PPI and Hip Fractures• United Kingdom General Practice Database• 4414 hip
fractures 1995-2005 with at least 2 years of GERD therapy• 3316 had at least
one major risk factor for hip fracture (ETOH, seizure, dementia, steroids)• 1098
without risks factors compared to 10,923 controls• In patients with no other
risks for hip fractures, PPI use did not increase the risk of hip fracture
Pharmacology 2008; 28:951-959.
• PPI Use Is Not Associated With Osteoporosis or Accelerated Bone Mineral
Density Loss• Manitoba Bone Mineral Density Database : 2000-2007.• 2193
subjects had evidence of osteoporosis at the hip and were matched to 5527
controls with normal hip measurements.• A total of 3596 subjects had BMD
measurements consistent with osteoporosis at the lumbar spine and were in
turn matched to 10,257 normal controls.• The researchers found PPI use was not
associated with having osteoporosis at either the hip or the lumbar spine for
proton-pump inhibitor use over 1500 doses over the previous 5 years. Targown,
et al. Gastroenterology 2010; 138:869

• 23. PPI and Hip Fractures• 2008 Canadian, retrospective, case–control study
matched 15,792 cases of osteoporosis-related fractures with 47,289 controls .•
Long-term exposure to PPI therapy, defined as 7 or more years, was significantly
associated with an increased risk of any osteoporosis-related fractures (hip,
vertebral, wrist) P = 0.011)• Hip fracture risk was increased after only 5 years of
continuous use. Targownik et al CMAJ 2008;179(4):319
• 24. PPI and Hip Fractures• Northern California Kaiser database to identify
patients with a hip fracture (cases, n = 33,752) and matched these 4:1 to
controls (n = 130,471).• PPI use > 2 years• Cases, men and women, were 30%
more likely than controls to have taken PPIs for at least 2 years (odds ratio [OR]
1.30 [95% CI 1.21–1.39]) and 18% more likely to have consumed H2-blockers for
2 years (1.18 [1.08–1.28]).• The greatest relative risk of hip fractures in patient
50-59 on PPI>2 years (OR 2.31)• Risk declines after discontinuation
Gastroenterology. 2009:136(suppl 1):A–70.
• 25. PPI and Fracture Risk• 161,806 postmenopausal women aged 50 to 79 years,
without a history of hip fracture, who participated in the Womens Health
Initiative (WHI) Observational Study and Clinical Trials.• The investigators
analyzed data from 130,487 women with complete information during mean
follow-up of 7.8 ± 1.6 years.• Primary endpoints were self-reported hip
(adjudicated) fractures, clinical spine fractures, forearm or wrist fractures, and
total fractures.• In addition, 3-year change in BMD was determined Arch Intern
Med. 2010;170:747-748

• 26. PPI and Fracture Risk• During 1,005,126 person-years of follow-up, there
were – 1500 hip fractures, – 4881 forearm or wrist fractures, – 2315 clinical
spine fractures, and – 21,247 total fractures identified.• Use of PPIs was
associated with only a marginal effect on 3-year BMD change at the hip (P=.05)
but not at other sites• Multivariate-adjusted hazard ratios were 1.00 for hip
fracture, – 1.47 for clinical spine fracture, – 1.26 for forearm or wrist fracture,
and – 1.25 for total fractures• Use of PPIs was not associated with hip fractures
but was modestly associated with clinical spine, forearm or wrist, and total
fractures. Arch Intern Med. 2010;170:747-748
• 27. PPIs and Fractures• A Japanese study 18 women with esophagitis taking PPI
therapy and 57 age-matched controls without PPI.• There was a greater risk of
multiple vertebral fractures assessed by X-ray in the esophagitis group.• There
was no statistically significant difference in bone mineral density between the
two groups J Bone Miner Metab 2005;23:36–40.
• 28. PPI’s and Osteoporosis: Conclusions• 4 of 5 case-control studies do appear to
confirm an increased risk of pathological fractures with long-term PPI use as
short as 2 years, and a lesser degree with H2RA.• Risk appears related to dose
and duration of acid suppression; possibly reversible.• No measurable decrease
in bone density.• Impaired absorption of calcium may be a contributing factor –
Whether additional calcium/vitamin D supplementation will offset this risk is
unknown.

Clopidogrel -PPI Interaction•
• 30. Widely accepted explanation is the competitive inhibition of cytochrome
450-2C19 – The isoenzyme responsible for conversion of clopidogrel to it’s active
form• A PPI’s metabolized to some degree by CYP2C19• Omeprazole,
esomeprazole, lansoprazole showed the greatest CYP2C19 inhibition, followed
by pantoprazole and rabeprazole
• 31. Clopidogrel plus PPI After Hospitalization for ACS Increased Risk of Adverse
Outcomes• Retrospective cohort study published in the JAMA demonstrated
that concomitant use of clopidogrel and a PPI after hospital discharge for acute
coronary syndrome (ACS) is associated with an increased risk of all-cause
mortality and rehospitalization for ACS.• 8,205 patients with ACS were taking
clopidogrel after hospital discharge.• 63.9% were prescribed a PPI at discharge,
during follow-up, or both, and 36.1% were not prescribed a PPI.• The median
follow-up was 521 days. JAMA. 2009;301:937–944.
• 32. Clopidogrel plus PPI After Hospitalization for ACS Increased Risk of Adverse
Outcomes• Multivariable analysis demonstrated that the use of a PPI during
clopidogrel treatment was associated with an increased risk of death or
rehospitalization for ACS (adjusted OR=1.25; 95% CI, 1.11–1.41).• Patients taking
a PPI with clopidogrel also demonstrated – Increased rates of recurrent
hospitalization for ACS (14.6% vs 6.9%; P<.001). – Revascularization procedures
(15.5% vs 11.9%; P<.001), and – Death (19.9% vs 16.6%; P<.001) compared with
patients taking clopidogrel without a PPI JAMA. 2009;301:937–944.

• 33. Clopidogrel-PPI Interactions Remain Only Observational at This Time• Three
randomized databases that are not subject to confounding, and all suggest that there is no
significant adverse interaction between clopidogrel and PPIs. – CREDO trial, presented at
the AHA 2008 – TRITON trial – PRINCIPLE 44 trial• Several studies have also shown no
difference in in vitro platelet aggregation between eomeprazole, pantoprazole, and
lasoprazole when given with either clopidogrel or prasugrel. 1) Am. Heart Journal
2009;51:258 (pantoprazole/eosmeprazole/clopidogrel) 2) J. Clinical Pharm 2008;48:475
(lansoprazole/prasugrel/clopidogrel)
• 34. Two Randomized Trials of PPI/Clopidogrel• Two double-blind trials of 202 (Principle) &
13,608 (Triton) PTCA patients comparing clopidogrel vs prasurgrel – Platelet functions
measure day 1, 14, 28.• PPI use was at the discretion of the treating physician – 33% on PPI
at start of study• Mean inhibition of platelet aggregation was modestly but significantly
lower on PPIs for both clopidorgrel and prasurgrel• No association between use of PPI and
adverse cardiac events Lancet Sept 19, 2009; 374:989
• 35. Outcomes With Concurrent Use of Clopidogrel and PPI• 20 596 patients (including 7593
concurrent users of clopidogrel and PPIs) hospitalized for MI, coronary artery
revascularization, or unstable angina pectoris. (1999-2005) Tenn. Medicaid Database• 65%
pantoprazole 35% omeprazole• Adjusted incidence of hospitalization for gastroduodenal
bleeding in concurrent PPI users was 50% lower than that in nonusers [95% CI, 0.39 to
0.65]). Annals Int Med 2010; 152:337

• Meta-analysis of Outcomes With Concurrent Use of Clopidogrel and
PPI• Meta-analysis of 23 observational and randomized controlled trials
of CV and mortality risk in 93,278 patients on PPI and clopidogrel.•
Considerable heterogeneity in findings – Observational studies generally
showed a significant association of PPI and CV risk – Randomized and
propensity-matched trials showed no association of PPI with CV risk•
Meta-analysis of 13 studies showed no significant association between
PPI use and overall mortality (RR 1.09 95%CI 0.94-1.26, p=0.23) APT
2010;31:810-23
• 37. Clopidogrel-PPI Interactions: Conclusions/ Recommendations• Three
randomized, prospective databases all indicate that there is no clinically
important adverse interaction between clopidogrel and PPIs.• There
had been a recommendation that PPIs be given as blanket gastric
protection to all patients at risk of gastric problems taking dual anti-
platelet therapy, – No longer advisable, given the possibility of an
interaction• PPIs should be prescribed to patients taking clopidogrel
only if they have increased risk of GI bleeding or dyspeptic symptoms
that are not controlled with H2 antagonists.• Pantoprazole would
appears to be default PPI

Gastric Acid InfluencesGut Flora
• Gastric acid < pH 4.0 is bactericidal within 15 minutes for most
species of bacteria.
• Loss of the normal stomach acidity has been associated with
colonization of the normally sterile upper gastrointestinal tract
• Profound gastric acid suppression is associated with
significant increase in total colonic bacterial count of all
genera and significant changes in the mix of dominant flora
• Acid suppression increases the risk of enteric infections
Gastroenterology 2009;136(suppl1): W2001

PPIand Bacterial Overgrowth
• Investigators used glucose hydrogen breath tests to look for small intestinal
bacterial overgrowth in 450 consecutive patients enrolled in 3 groups: – 200
GERD patients treated with PPIs for a median of 36 months; – 200 patients with
irritable bowel syndrome (IBS) who had not used PPIs for at least 3 years; and –
50 healthy controls who had not used PPIs for at least 10 years.• Small intestinal
bacterial overgrowth in 50% of the PPI users with GERD, 24.5% of the IBS
patients, and 6% of the healthy control Clin Gastroenterol Hepatol 2010;8(6):504
• PPI and Bacterial Overgrowth Prevalence of SIBO60% 50%50%40%30%
25%20%10% 6%0% PPI IBS Control Clin Gastroenterol Hepatol 2010;8(6):504
• PPI and Bacterial Overgrowth Prevalence of SIBO by Duration of Therapy80%
P<0.00170%60%50%40%30%20%10%0% 2-6 mo 7-12 mo 13-36 37-60 >60 Clin
Gastroenterol Hepatol 2010;8(6):504
• Systematic Review of the Risk of Enteric Infection in Patients Taking Acid
Suppression• Systematic review to evaluate any association between acid
suppression and enteric infections.• 12 papers evaluating 2,948 patients with
Clostridium difficile were included in the review.• A total of 6 studies evaluated
Salmonella, Campylobacter, and other enteric infections in 11,280 patients.•
Conclusion: Acid suppression increases risk of enteric infections (OR 2.55, 95% CI
1.53–4.26). Am . J Gastro. 2007 :102, 2047–2056

Riskfor NosocomialC. Diff InfectionIncreased
withAcid Suppression
• • Secondary analysis of prospectively collected data from 101,796 patients who were discharged
from a tertiary care medical center during a 5-year period.• Acid suppression treatment was the
primary exposure of interest, classified by intensity. – no acid suppression, – histamine2-receptor
antagonist [H2RA] treatment, – daily PPI use, and – PPI use more often than daily)• The risk for
nosocomial C difficile infection increased with increasing level of acid suppression.• The
association persisted after adjustment for comorbid conditions, age, antibiotics, and propensity
score–based likelihood of receiving no acid suppression treatment Arch Intern Med.
2010;170:747-748
• 45. Risk for Nosocomial CD Infection Increased with Increasing Acid Suppression1.60%
1.40%1.40%1.20%1.00% 0.90%0.80% 0.60%0.60%0.40% 0.30%0.20%0.00% No Suppression H2RA
PPI x 1 PPI> 1 Arch Intern Med. 2010;170:747-748
• 46. Role of PPI on Severity of CD• Retrospectively review 295 pts diagnoses of C. difficile-
associated diarrhea over a 12-month period at a tertiary hospital.• The records were examined to
determine duration of diarrhea, need for treatment escalation (such as ICU care), immunoglobulin
therapy, colectomy, death related to C. difficile diarrhea, and recurrence.• 164 of the 295 patients
received PPIs• In a multivariate analysis, PPI therapy doubled the likelihood of severe diarrheal
disease (P=0.002).• The only other independent predictor of severe illness was male sex.
Sravinthan A, et al "Role of proton pump inhibitors on severity of outcome of Clostridium difficile
associated disease" DDW 2010; Abstract T1782.
• 47. Acid Suppression and CD• The use of acid-suppressive therapy, particularly proton pump
inhibitors, is associated with an increased risk of both hospital and community-acquired C.
difficile.• The risk appears to be independent of antibiotic use and potentially additive• If a
patient has been treated for C. difficile, strongly consider stopping PPI, especially if there has been
a recurrence• Frequently reassess the indications for PPI, especially in elderly hospitalized or
institutionalized patients

Magnitudeand EconomicImpactof
InappropriateUse of Stress Ulcer Prophylaxis
• The practice of SUP has become increasingly more common in
general medicine patients, with little to no evidence to support it•
Several studies have demonstrated the inappropriate use of acid-
suppressive therapy (AST) in general medicine (non-ICU) patients,
based on current recommendations.• AST is commonly misused in
hospitals, with as many as 71% of patients in general medicine
wards receiving some sort of AST without an appropriate indication.
American Journal of Health-System Pharmacy. 2007;64(13):1396-
1400
• 49. Inappropriate PPI Use In Hospitals• Prospective evaluation of IV
PPI use in two Midwest community- based teaching hospitals .•
Identify all patients for whom an IV PPI was ordered• Fifty-six
percent of patients who received IV PPIs had no acceptable
indication for their use• Of the 126 patients who were started on
PPIs for the first time during their hospital stay, 102 (81%) were
discharged on a PPI. AJG 2004; 99:1233 - 1237

PPIsin CirrhoticswithAscites
• 52. Risk Factors for Spontaneous Bacterial Peritonitis• Ascitic fluid total protein
concentration less than 1 g/dl• Prior episode of SBP• Variceal hemorrhage•
Bilirubin above 2.5 mg/dl• Malnutrition• PPI use
• 53. MECHANISMS OF BACTERIAL TRANSLOCATION (BT) Mechanisms of Bacterial
Translocation and SBP Anaerobic Aerobic bacteria bacteriaIntestinal Bacterial
OvergrowthDysmotility Delayed transit timeNutrition? Intestinal Permeability
Enterocytes Mucosal Hypoxia, Acidosis ATP depletion, NO, LPS, TNF Impaired
Immunity Impaired Lamina propria chemotaxis, migration, phagocytic function,
complement deficiency, etc.
• 54. PPIs and SBP• Retrospective case controlled study of culture proven SBP
2002-2007• 70 SBP patients, age and Child’s class matched, 1:1 with cirrhotics
admitted for non-SBP indications• Pre-hospital PPI use in 69% of SBP vs 31%
non-SBP admissions (p<0.0001)• 47% of patients on PPI had no documented
indication for PPI use Am. J. Gastro 2009;104(5):1130
• 55. PPI and SBP• 2631 cirrhotics with ascites followed from 2002-2007• PPI use
strongly associated with SBP and hepatorenal syndrome – SBP on PPI 23.7% No
PPI 5.7% – HSR on PPI 15.3% No PPI 1.9%• Number needed to treat for harm
from PPI use: 5.5 for 1 episode of SBP Hepatology 2008;48:324A

Use of PPIand the Riskof Community-
AcquiredPneumonia
• Case-control study of 88,066 community-acquired pnemonia
and 799,886 controls• PPI use >30 days NOT associated with
increase risk of CAP• Short-term PPI use increased relative
risk!! – 1-2 days OR 6.5 (CI 3.9-10.8) – 7 days OR 3.8 (CI 2.6-
5.4) – 14 days OR 3.2 (2.4-4.2) Ann Intern Med. 2008;148:319

Use of PPIand the Riskof Hospital-Acquired
Pneumonia
• Cohort study of 63,878 adult patients admitted for >72 hours
over a 3 year period.• Assess PPI and H2RA use and hospital-
acquired pneumonia• 52% (32,922) of patients placed on acid
suppressive therapy• Corrected for age , sex, race, other
medications, season, and co-morbidities• Validated result via
a propensity matched analysis (whatever that is) JAMA
2009;301(20):2120-8
• Use of PPI and the Risk of Hospital-Acquired Pneumonia• PPI
use associated with increased risk of pneumonia (OR = 1.3)•
Trend towards similar effect with H2RA (OR =1.2) but not
stasticially significant• The association was stronger for
aspiration than non-aspiration pneumonia JAMA
2009;301(20):2120-8

Use of PPIs linked to Dementia

Conclusions
• FDA recommends that “ concomitant use of omeprazole with
clopidogril should be discouraged.”
• PPI are effective in management of GERD, acute acid peptic
bleeding and stress ulcer prophylaxis but carry significant
infectious risks and possible risk of pathologic fractures
• Up to 30-50% of acid suppression therapy may be
inappropriate in outpatients and hospital inpatients
• Consider H2RB in mild disease or small dose of PPIs
• Do not start high dose of PPIs in dyspepsia or GERD
• Consider low dose and short duration of PPIs in cirrhotics

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