Peptic Ulcer disease

A peptic ulcer is a defect in the gastric or

duodenal wall that extends through the
muscularis mucosa (the lowermost limit of the
mucosa) into the deeper layers of the wall
(submucosa or the muscularis propria )

American Society for Gastrointestinal Endoscopy GUIDELINE 2010

Spechler SJ. Peptic ulcer disease and its complications 2002.
• Ulkus peptikum adalah keadaan terputusnya
kontinuitas mukosa yang meluas di bawah epitel
atau kerusakan pada jaringan mukosa,submukosa
hingga lapisan muskularis mukosa dengan garis
tengah lebih atau sama dengan 5 mm dari suatu
daerah saluran cerna atas yang langsung
berhubungan dengan cairan asam
lambung/pepsin
• Erosi adalah kerusakan jaringan yang hanya
terbatas pada lapisan mukosa.
 Peptic ulcer disease as an infectious disease caused by
H pylori infection, or a side effect of NSAID use has almost
eliminated elective surgery for peptic ulcer disease.

Complications of peptic ulcer disease, either

bleeding or perforation, still frequently require surgical
intervention.

Bleeding peptic ulcers can usually be treated with

nonsurgical means, 5% to 10% will require emergent
surgery for hemostasis
THE EPIDEMIOLOGY OF PEPTIC ULCER
DISEASE (PUD )
• in the 21st century peptic ulcer disease is predominantly a disease of
the elderly.

• a marked decline in the incidence of all peptic

ulcer disease, with declines in ulcer hospitalization rates of 40% to 50%
over the past 3 decades

• Duodenal ulcer is more common than gastric ulcer , but decreasing

significantly

• The rate of ulcer complications and the need for emergent ulcer surgery
may have increased slightly over the past 30 years

Eradication H pylori infection, effective PPI treatment,

elderly population
Acid Related Disease: Significant
Health Care Cost in Indonesia
Annual Cost for PPI orals and IV in Indonesia
account for Rp. 1 Trillion

1. Indonesia Total Market Audit, IMS 2013 2. Indonesia Medical Data Index 2011
 Peptic Ulcer disease

Common causes

• Helicobacter pylori ( Hp) infection

• NSAIDs , Antiplatelet Aspirin low dose ,Clopidogrel or

combination

• Non Hp, Non NSAIDs

 Mechanism of Gastric Mucosal Injuries by
H. pylori Infection
NH3 Urea
Mucus Urease
Cytotoxin

Gastric
Mucosal
Cell
IL-8
NAP
O2 DNA damage
Mononuclear cell
O2

Neutrophil H2O2 NH3

MPO
HOCI
NH2CI

Microcirculation

H.pylori
 NSAIDs GI mucosal Injury
Comprehensive mechanisms
 Need for Aspirin/NSAIDs & Risks
 Aspirin, like all NSAIDs,
injures the gut by
causing topical injury to
the mucosa and by
systemic effects induced
by prostaglandin
depletion.1
 L-ASA (75-325 mg per
day) was associated with
a 2- to 4-fold increase of
the risk for upper
gastrointestinal (GI)
events.2

1. J Am Coll Cardiol. 2008 Oct 28;52(18):1502–1517. 2. Intern Med 49: 2537-2545, 2010
Risk factors for L-ASA-induced GI injury

• A high aspirin dose

• History of peptic ulcer or ulcer complication
• Use of NSAIDs
• Advanced age
• Concurrent use of anticoagulants
• Presence of severe disease
• Antiplatelet therapy

J Am Coll Cardiol. 2008 Oct 28;52(18):1502–1517.

 Need for Antiplatelet Therapy & Risks
 Gastrointestinal (GI) complications
such as ulceration and related
bleeding.

 Antiplatelet therapy
- primary and
secondary
treatment strategies
for cardiovascular
disease.

J Am Coll Cardiol. 2008 Oct 28;52(18):1502–1517.

 Risks with Antiplatelet Therapy
 ADP receptor antagonists impair the healing of gastric ulcers by
inhibiting platelet release of pro-angiogenic growth factors.
 This may then, in the presence of acid, lead to clinically significant
ulceration and related complications.

J Am Coll Cardiol. 2008 Oct 28;52(18):1502–1517.

 Gastro-duodenal lesions in NSAIDs
long term users
Many of the patients using NSAIDs have gastrointestinal tract lesions.
All abnormal lesions 62.2
Gastric ulcers 15.5
Gastric ulcer scar 8.0
Duodenal ulcer 1.9
Duodenal ulcer scar 3.0 Subjects: 1,008 patients
with arthritis who were
Gastritis 38.5
using NSAIDs for 3 months
Duodenitis 2.7 or longer and received
endoscopy.
AGML 0.6
Esophagal involvement 2.4

0 10 20 30 40 50 60 70 （%）
Morbidity of upper GI tract injuries
Yuichi Shiokawa et al.: Rheumatism. 1991;31: 96.
 PUD Clinical presentation

Without complication
• Dyspepsia
• Pain, epi-gastric, Night pain
• Functional dyspepsia : overlapping
With Complication

• Pain, epi-gastric, severe, penetrating ,perforating

• Anemia
• Hematemesis-melena
Complicated Peptic Ulcer disease (PUD )
• Bleeding ulcers
• Acute bleeding
• chronic, occult bleeding in elderly, NSAIDs /Aspirin users

• Perforated peptic ulcer

• Currently rare complication
• Need Surgery

• Penetrating ulcer
Penetration through serosa into organs adjacent to the stomach and
duodenum, including the Liver, pancreas and spleen

• Gastric outlet obstruction

• Chronic inflammation and scarring of the pylorus and/or duodenum.
• Biopsies to exclude malignancy should be considered
• Endoscopic balloon dilation has been used to manage benign
gastric outlet obstruction.
Pain characteristic of PUD

Site of the pain

Character of the pain
Relation to meals
Night waking
Esophagogastroduodenoscopy (EGD)

Indication for Endoscopy

in patients with dyspepsia ( Uninvestigated )

• Patients older than age 50 with new-onset dyspepsia

• Patients of any age with alarm features

• Alarm features include

• family history of upper GI malignancy
• unintended weight loss
• overt GI bleeding
• iron deficiency anemia
• progressive dysphagia or odynophagia
• persistent vomiting
 Characteristics of Gastroduodenal Ulcers
During Treatment with LDA/NSAIDs
1. Higher prevalence of bleeding
complication
2. multiple ulcers
3. Smaller in diameter
4. More frequently found in the
gastric antrum
5. less symptomatic
6. prevalence: approximately 10 %

1. Yeomans ND et al. Aliment Pharmacol Ther 2005.

2. Shiotani A et al. J Gastroenterol 2009.
3. Hart J et al. Aliment Pharmacol Ther 2009.
 Role of Acid Suppression Agent
• Pharmacological agents that suppress acid secretion are
widely considered the standard of care for the prevention
of ulcer re-bleeding after initial endoscopic hemostasis in
ulcer with high risk stigmata (those with active bleeding,
non bleeding visible vessel and possibly adherent clot)1-5
• The therapeutic goal in these patients is to achieve an
intragastric pH>6, a point at which the clotting process is
optimized and any formed clot is stabilized1,6-7

1. Lin H-J, et al. Arch Intern Med 1998; 158: 54-8. 2. Lau JWY, et al. N Eng J Med 2000; 343: 310-6. 3. Liontiadis GI, et
al. Aliment Pharmacol ther 2005; 22: 169-74. 4. Sung JJ, et al. Ann Intern Med 2003; 139: 237-43. 5. Barkun A, et al.
Gastroenterology 2004; 126: A78 (Abstract). 6. Vorder Bruegge WF, et al. J Clin Gastroenterol 1990; 12: (Suppl 2):
S35-40. 7. van Resburg, et al. Am J Gastroenterol 2003; 98: 2635-41
 Gastric Acid Inhibition

Histamine 2 Cholinergic Stimulation (Vagus)

Ranitidine Gastrozepin
(H2 Receptor Blocker) (Anti-cholinergic)
Proton Pump
(Parietal Cell)
Omeprazole
(Proton Pump Inhibitor)

Acid Secretion
 Food effect to gastric acid secretion

Nutriens Intake Gastric acid

Meat intake Increase Secretion
Fish Intake Decrease Secretion
Salt Intake Increase Secretion

Kothari ML, et al. GUT 1969; 10(1): 71-73

Kragelund E, et al. Ann Surg 1974; 179(2): 174-178
Riber C, et al. Scand J Gastroenterol 1999; 34(4): 845-848
Gastric pH: Rationale for Acid Suppression
for Management Peptic Ulcer

Gastric
Clinical Effect
pH

>4 Pepsin inactivated Ulcer healing andStress

Ulcer Prophylaxis

>5 99% acid neutralized

Functional coagulation Reduction of rebleeding

>6
and platelet aggregation after endoscopic
intervention

>7 Pepsin destruction

Vorder Bruegge J Clin Gastroenterol. 1990;12:S35.

pH and platelet aggregation: Roles of
Acid Secretion
Aggregation (%)
ADP ADP, adenosine diphosphate

20 pH=6.0
Disaggregation=77%

40

60 Buffer
pH=6.4
Disaggregation=16%
80 pH=7.3
Disaggregation=0%
100
0 1 2 3 4 5 Time (minutes)

Green FW, et al. Gastroenterology 1978;74:38–43

 PPI pH(3-4) Holding and Antibiotic for Helicobacter pylori Eradication

24 H pH median
CLARITHROMYCIN

Stable
4

3 Proton Pump Inhibitor (PPI) pH holding

1 Unstable

Day 1 Day 7

Consistent acid supression,pH holding are determinant factor

for Hp eradication and peptic Ulcer healing
 Lansoprazole and esomeprazole:
equivalent acid suppression

Mean pH values over time per treatment group, day 1

7 Lansoprazole 15 mg

6 Esomeprazole 20 mg

5
Mean pH

1
0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500

Time (minutes)

Baxter et al., Scand J Gastroenterol 2001; 36(Suppl 233): 50.

Method: Lansoprazole I.V. for injection was administered for 5 days to the EM-type healthy
males in whom lansoprazole is promptly metabolized and to the PM-type healthy males in
whom it is slowly metabolized. 24-Hour gastric pH over time was examined during the
control period, 1 and 5 days after Lansoprazole administration.

Gastric pH over time on Day 1 to 5 of IV administration

with 30mg lansoprazole
Day 1 (PM group) Day 5 (PM group)
8 Control period Lansoprazole 8 Control Lansoprazole
7 7
6 6

Gastric pH
5 5
4 4
3 3
2 2
1 （n=8） 1 （n=8）
0 0
0 4 8 12 16 20 24 0 4 8 12 16 20 24
● ● （22:00） ● ● （22:00） ●
（10:00） （10:00）●
Supper Breakfast
↑ Lunch Supper ↑ Breakfast ↑ Lunch ↑
Drug Drug Drug Drug
 Effect of I.V. administration of 30mg lansoprazole on gastric pH
in patients with upper GI bleeding maintain pH>6 for first 3
critical day
8
7
6
Gastric pH

5
4
3 75 percentile
2 Median
1 25 percentile
0
Before 4 8 12 16 20 24 36 48 72 (hrs)
dosing
Lansoprazole I.V. for injection 30mg was administered twice daily to patients with upper
gastrointestinal tract bleeding. Gastric juice was collected by a gastric tube to examine
the gastric pH over time.

T. Kamata et al.: Journal of Clinical Therapeutics & Medicines .12（13）,2901-2925,1996.（partly modified)

Which PPI?
Fast and Sustained Healing Lansoprazole vs Rabeprazole
Two studies pooled with a total of 65 patients
p=0.001
80

72

60
p=0.001 p=0.001
55
% Healed

44 45
40

p=0.01
30
25
20 20

10

0
pH > 4 pH > 5 pH > 4 pH > 5
Day 1 Day 5
Lansoprazole 30 mg Rabeprazole 20 mg
29
Tolman K, et al. Am J Gastroenterol. 2000;95(9):2468-2469.
Goals of treatment in PUD

 pain relief and resolution of symptoms

 mucosal healing

 prevention of recurrence and complications.

 Management Strategy in PUD
• H Pylori testing in all patients with PUD, follow by eradication therapy

• PPI is the most effective treatment for gastric Ulcer ( 8 weeks), and Duodenal Ulcer (
4 weeks )
• Endoscopy :
Endoscopy accurate for diagnose and prognose of PUD , and an effective treatment for
bleeding Ulcer

• Duodenal ulcers are extremely unlikely to be malignant, and routine biopsy is not recommended

• Gastric ulcers should undergo biopsy because malignant gastric ulcers may appear
endoscopically benign

• Refractory PUD, suggested for surveillance endoscopy until the ulcer has healed or the etiology
has been defined

• Endoscopy is an effective tool in the diagnosis,prognostication, and therapy of bleeding peptic

ulcers, recommended early in the course of hospitalization

• Rebleeding after initial endoscopic hemostasis, repeat endoscopic therapy is recommended

before considering surgical or radiologic intervention

• Endoscopy is not recommended in patients with clinical evidence of acute perforation

• endoscopy is recommended for the evaluation of gastric outlet obstruction

Which PPI?
Fast and Sustained Healing Lansoprazole vs Rabeprazole
Two studies pooled with a total of 65 patients
p=0.001
80

72

60
p=0.001 p=0.001
55
% Healed

44 45
40

p=0.01
30
25
20 20

10

0
pH > 4 pH > 5 pH > 4 pH > 5
Day 1 Day 5
Lansoprazole 30 mg Rabeprazole 20 mg
32
Tolman K, et al. Am J Gastroenterol. 2000;95(9):2468-2469.
 Healing and prevention of
NSAID-associated ulcers

Patients continuing to take NSAIDs

Trials 1 & 2 Healing rate (n=551) Week 8

Ranitidine 150 mg bd 52%

Lansoprazole 15 mg od 73%**
Lansoprazole 30 mg od 75%**

Trial 3 Prevention rate (n=455) Week 12

Placebo 47%
Misoprostol 0.2 mg qds 87%***
Lansoprazole 15 mg od 80%***
Lansoprazole 30 mg od 81%***

**p<0.001 vs ranitidine; ***p<0.001 vs placebo

Goldstein et al., Gut 1999; 45(Suppl V): 101.

GU healing rates with continued NSAID
use, according to H. pylori status

100 *
88 Ranitidine 150 mg bd

* Lansoprazole 15 mg od
*
Patients healed (%)

* 71
68 Lansoprazole 30 mg od
64

53
44 *p<0.05, compared with
ranitidine group

0
n= 30 19 32 84 92 78
H. pylori-positive H. pylori-negative

Goldstein et al., Am J Gastroenterol 2000; 95: 142A.

 Lansoprazole Prevents Ulcer relapse in
NSAIDs continued patients after H.pylori
Eradication
 Lansoprazole significantly reduced
the cumulative relapse of
symptomatic and complicated
ulcers in patients requiring NSAIDs
after eradication of H. pylori.

 Significantly fewer patients (1/22,

4.5%) in the lansoprazole group
compared with the group that
received H. pylori eradication alone
(9/21, 42.8%) developed
recurrence of symptomatic and
complicated ulcers.

Aliment Pharmacol Ther. 2003 Oct 15;18(8):829–836.

PPIs and Drug Interactions

The need of Anti platelet drugs Clopidogrel,

single or in combination with Low dose aspirin
to prevent cardiovascular is increasing, with
significant risk of serious Gastrointestinal
bleeding raise the current issue of PPI drug
interaction

SC-FM-T3
 Clopidogrel Bisulfate
Use and Metabolism
• Description
– In the US, about 23.4 million patients were receiving clopidogrel therapy during
the 12-month period before May 11, 20111
– Clopidogrel is a dose-dependent inhibitor of platelet activation and aggregation
– Selectively binds to the P2Y12 class of ADP receptors on platelets
– Pro-drug metabolized by CYP450 enzymes, principally 2C19, in the liver to
active metabolite

• Indications
– Acute coronary syndrome
– Recent MI, recent stroke, or established peripheral arterial disease
– Also used following percutaneous coronary intervention (PCI) and other vascular
interventions to reduce stent thrombosis3

1. Based on SDI’s Source of Business and Concomitant data

2. Plavix® Package Insert. Accessed 2/2/12. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020839s051lbl.pdf
3. Abraham NS et al. J Am Coll Cardiol. 2010 ; 56:2051
 Potential Interaction of PPIs With
Clopidogrel
• CYP2C19, CYP3A4, and CYP2C9 play major roles in the metabolism of PPIs
• Competition for metabolism through CYP2C19 is a theoretical
mechanism by which clopidogrel antiplatelet action can be
attenuated by concurrent PPI use

Prodrugs Liver cell Metabolites

CYP3A4
PPIs Sulfenamide
CYP2C19
Clopidogrel
CYP2C9 R-130964

Competitive antagonism
↓ Active metabolites
Juhász M et al. Digestion. 2010;81:10-15.
 Risk of GI Bleeding in Patients Receiving
Clopidogrel Therapy
• Major side effect – GI bleeding
• Incidence rate 2% in patients on clopidogrel1
• Clopidogrel does not directly cause gastric injury2
• May impair healing of existing gastric erosions due to its antiplatelet effect and exacerbate GI
complications from:
– Concomitant administration of aspirin and NSAIDs
– H. pylori infection
• Established correlation between major bleeding with subsequent MI, stroke and death 2
• Concomitant administration of clopidogrel and PPI
– Prevalence of co-administration of Clopidogrel with PPI in the US is
31%–64%2
– Concomitant PPI administration reduces incidence of GI bleeding
compared to clopidogrel alone (RR: 0.19)3

1. http://www.sciencedirect.com/science/article/pii/S0140673696094573
2. Tantry U et al. JACC: Cardiovascular Interventions. 2011;4(4):365-380.
3. Lanas A et al. For the Investigators of the AEG. Am J Gastroenterol 2007;102:507-515.
Asia Pacific Consensus on Upper GI
Bleeding 2011 Summary
Dual antiplatelet therapy
• Among patients receiving clopidogrel and
aspirin as dual therapy, prophylactic use of
PPI reduces risk of adverse GI events

Asia Pacific Working Group Consensus. Gut 2011

 Interaction Persists in Omeprazole Despite
Increasing or Separating Clopidogrel Dose
• 4 randomized, placebo-controlled, crossover studies (282 healthy subjects) showed
omeprazole inhibited CYP2C19 activation of clopidogrel, even when administered
12 hours apart

Change in Platelet Reactivity

Treatment Dosing & Admin Index

Study 1 CLO + OPZ Simultaneous +20.7 (P<0.0001)

Study 2 CLO + OPZ 12 h apart +27.1 (P<0.0001)

Simultaneous;
Study 3 CLO + OPZ +19.0 (P<0.0001)
doubled dose of CLO

Study 4 CLO + PPZ Simultaneous No significant increase

CLO = clopidogrel; OPZ = omeprazole; PPZ = pantoprazole.

Angiolillo DJ et al. Clin Pharmacol Ther. 2011;89:65-74.
 Study results: Pharmacokinetics
All PPIs decreased clopidogrel Cmax

Dexlansoprazole and lansoprazole did not have a clinically significant impact on exposure to
the active metabolite of Plavix®, based on the AUC

Frelinger AL. J Am Coll Cardiol 2011;57:E1098.

Study results: Pharmacodynamics

IPA= inhibition of platelet aggregation;

PRI= platelet reactivity index

Dexlansoprazole and lansoprazole had no significant effect on the PD and

antiplatelet activity of Plavix®, while esomeprazole and omeprazole did
Frelinger AL. J Am Coll Cardiol 2011;57:E1098.
 Recent US FDA Drug Label Changes
lansoprazole
• Concomitant administration of lansoprazole and clopidogrel in
healthy subjects had no clinically important effect on exposure to
the active metabolite of clopidogrel or clopidogrel-induced platelet
inhibition
• No dose adjustment of clopidogrel is necessary when administered
with an approved dose of lansoprazole
clopidogrel

• Omeprazole and esomeprazole reduce the antiplatelet activity of

clopidigrel
• Dexlansoprazole, lansoprazole and pantoprazole had less effect on
the antiplatelet activity of clopidigrel than did omeprazole or
esomeprazole
 Summary

• PUD is one of the significant clinical problem for UGI diseases in

clinical practice.
• PUD as an infectious diseases is curable by H.pylori eradication
with a low recurrence rate
• NSAIDs , antiplatelet , low dose aspirin is now an increasing
factors for peptic ulcer etiology

• Anti acid supression drugs PPI is the most effective medical

treatment for PUD and ints complication

• Lansoprazole is one of the most effective PPI for the treatment for
symptoms and healing of PUD and its complication