Terapi peptic ulcer disease

1. Update Treatment of
Peptic Ulcer Disease

3. The Stomach Functions & Glands
 Acts as storage tank for food
Breaking down the food into a liquidly mixture called chyme
Mixing enzymes which is are chemicals that break down food.
Delivers chyme to the small intestine
Glands:
Cardiac
Pyloric
Gastric  contain parietal cells that produce and secret HCL (primary site of action for
many acid controller drugs.

4. Parietal cells
Parietal cells, are the stomach epithelium cells that secrete gastric acid
The parietal cell contains receptor for gastrin histamine (H2) & acethylcholine (M3)
When acetylcholine, histamine or gastrin (released from G cells into the blood) bind to the
parietal cell receptors, that stimulate acid secretion from a H+,K+ ATPase (the proton
pump) on the canalicular surface.
Olbe, L., Carlsson, E., & Lindberg, P. (2003).Nature Reviews Drug Discovery, 2, 132-139.

5. Parietal Cells
Gastric acid is secreted by parietal cells of
the stomach in response to stimuli such as
the presence of food in the stomach or
intestine and the taste, smell, sight or
thought of food. Such stimuli result in the
activation of histamine, acetylcholine or
gastrin receptors (the H2, M3 and CCK2
receptors, respectively) located in the
basolateral membrane of the parietal cell,
which initiates signal transduction
pathways that converge on the activation
of the H+K+-ATPase the final step of acid
secretion.
Inhibition of this proton pump has the
advantage that it will reduce acid secretion
independently of how secretion is
stimulated, in contrast to other
pharmacological approaches to the
regulation of acid secretion; for example,
the inhibition of acid secretion by H2
receptor antagonists can be overcome by
food-induced stimulation of acid secretion
via gastrin or acetylcholine receptors.
Olbe, L., Carlsson, E., & Lindberg, P. (2003).Nature Reviews Drug Discovery, 2, 132-139.

6. Acid Controlling Agents – Proton Pump
Inhibitors
Mechanism of Action: Irreversibly bind to H+/K+ ATPase enzyme
Result: ALL gastric acid secretion is blocked
Proton Pump Inhibitors:
Esomeperazole  works by binding irreversibly to the H+/K+ ATPase in the proton pump.
Because the proton pump is the final pathway for secretion of hydrochloric acid by the parietal
cells in the stomach, its inhibition dramatically decreases the secretion of hydrochloric acid into
the stomach and alters gastric pH. This is the same mechanism of action as omeprazole and
the other PPIs.
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole
Olbe, L., Carlsson, E., & Lindberg, P. (2003).Nature Reviews Drug Discovery, 2, 132-139.

7. ROLE OF PPI AS 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 stabilized
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

8. GASTRIC PH: RATIONALE FOR ACID SUPPRESSION
FOR MANAGEMENT PEPTIC ULCER
Gastric
pH
Clinical Effect
>4 Pepsin inactivated
>5 99% acid neutralized
>6
Functional coagulation
and platelet aggregation
>7 Pepsin destruction
Vorder Bruegge J Clin Gastroenterol. 1990;12:S35.
Stress Ulcer Prophylaxis
Reduction of rebleeding after
endoscopic intervention

9. Peptic Ulcer
Peptic ulcers are open sores that develop in the inner lining of the stomach and the upper part of the small
intestine. The most common symptom of peptic ulcers is abdominal pain.
 Peptic ulcers include:
Stomach ulcers that occur in the stomach
Duodenal ulcers that occur in the duodenum (duodenum)

10. CAL

11. Symptoms of Peptic Ulcer
Pain in the stomach. This pain arises due to irritation of the stomach acid that wets the wound.
Usually, the pain appears at night and gets worse when the stomach is empty. In more severe
conditions, the pain felt can spread to the neck, navel, to the back.
 Indigestion.
Vomiting or vomiting blood — which may appear red or black Dark blood in the stool, or black or
mushy stools
Difficulty breathing, Feeling weak, Nausea or vomiting, Unexplained weight loss, Changes in
appetite

12. Cause
Helicobacter pylori infection
Use of non-steroidal anti-inflammatory drugs, such as ibuprofen, aspirin, or diclofenac.
Smoking and drinking habits.
Stress that is not immediately addressed.
Health problems, such as pancreatic tumors and radiation treatment to the stomach area.

13. Complications
◦ Bleeding in the stomach
◦ Perforation
◦ Peritonitis (inflammation of the thin lining of the inner wall of the
abdomen)
◦ Obstruction
◦ Stomach cancer.

15. •. 2015 Nov;32(11):1160-76.
ACG. ACG Clinical Guideline: Upper Gastrointestinal and Ulcer Bleeding.
Twice-daily PPI
therapy from days
4–14 after
indexendoscopy
reduces further
bleeding as
compared to once-
daily PPI in high-risk
patients who
received endoscopic
therapy followed by
3 days of high-dose
PPI therapy. This is
a new
recommendation
based on evidence
that became
available after
publication of the
2012 ACG
Guidelines.

16. •. 2015 Nov;32(11):1160-76.
ACG. ACG Clinical Guideline: Upper Gastrointestinal and Ulcer Bleeding.

17. •. 2015 Nov;32(11):1160-76.
ACG. ACG Clinical Guideline: Upper Gastrointestinal and Ulcer Bleeding.

18. •. 2015 Nov;32(11):1160-76.
In patients with a history of ulcers
receiving NSAID therapy, PPIs
with or without celecoxib are
recommended and the
administration of VPZis suggested
for the prevention of ulcer
recurrence.
Inpatients with a history of ulcers
receiving LDA therapy, PPIs or
VPZ are recommended and the
administration of ahistamine 2-
receptor antagonist is suggested
for the preventionof ulcer
recurrence.
Kamada, Tomoari, et.al. Evidence-based clinical practice guidelines for peptic ulcer disease

19. Kamada, Tomoari, et.al. Evidence-based clinical practice guidelines for peptic ulcer disease

20. Kamada, Tomoari, et.al. Evidence-based clinical practice guidelines for peptic ulcer disease

21. •. 2015 Nov;32(11):1160-76.
NICE. Managing peptic ulcer disease on adults. 2021
Initial treatment, for people using NSAIDs with diagnosed peptic ulcer, stop the
use of NSAIDs where possible. Offer full-dose PPI or H2RA therapy for 8 weeks
and, if H. pylori is present, subsequently offer eradication therapy.
Esomeprazole is first choice to treat peptic ulcer caused by NSAID &
Helicobacter pylori infection.

22. EFFECT OF PPIS ON OUTCOMES IN PATIENTS WITH
PUD BLEEDING ( COHRANE META ANALYSIS )
*Number of trials
0 0.5 1 1.5 2
Re-bleeding (19*)
Surgical Intervention (17*)
Outcome at 30 days after randomization
Odds Ratio (95% CI)
Mortality (9*)
0.53
0.46
0.59
Favors PPI Favors control
Modified from Leontiadis et al, The Cochrane Database of Systematic Reviews 2005 + update in 2006; Barkun et al., AJG 2004
PPI improve mortality in patients w HRS only if they
have initially undergone endoscopic hemostasis (i.e.:
mainly high-dose IV)
Also, these findings have been confirmed
in a “real-life” setting

23. PEPTIC ULCER BLEEDING STUDY WITH
ESOMEPRAZOLE IV
Sung JJ, et al. Aliment Pharmacol Ther 2008;27:666–77
oral treatment
(27 days)
i.v. treatment
(72 hours)
(0max 24 hours)
Esomeprazole i.v.,
80 mg for 30 minutes
followed by
esomeprazole i.v., 8
mg/hour for 71.5 hours
Placebo i.v. for
30 minutes followed
by placebo i.v. for
71.5 hours
Esomeprazole oral,
40 mg once daily
R
Esomeprazole oral,
40 mg once daily
Enrolment phase:
Endoscopic therapy
• Conduct in 91 centers in 16 countries – multicenter
• Including 3 ethnic (asian, african and caucasian) - heterogenous
• Used placebo as control – controlled study

24. ENDPOINT PRIMER:
RE-BLEEDING RATE AT 72 FIRST HOURS
0
2
4
6
8
10
12
Esomeprazole Placebo
5,9
10,3
%
patients
with
re-bleeding
42.7%
Sung JJ, et al. Aliment Pharmacol Ther 2008;27:666–77

25. CLINICALLY SIGNIFICANT REBLEEDING WITHIN 30 DAYS
(KAPLAN-MEIER ESTIMATE)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Days from randomisation
Log-Rank p=0.0092
Esomeprazole
Placebo
Cumulative percentage (%)
n at risk
Esomeprazole 375 347 335 330 327 325 324
Placebo 389 342 326 321 317 316 314 312 311 310 309
0
2
4
6
8
10
12
14
16
18
80%
30 days

26. Conclusion: Esomeprazole, given as a continuous high-
dose intravenous infusion followed by an oral regimen
after successful endoscopic therapy for Peptic Ulcer
Bleeding, was well tolerated, with no apparent safety
concerns from either the high-dose intravenous
treatment or oral phases.

27. •. 2015 Nov;32(11):1160-76.
Conclusion: In this phase 3, multicenter, randomized trial
conducted in China, esomeprazole showed a numerical
trend towards superior clinical benefit over cimetidine in the
prevention of rebleeding in patients who had successfully
undergone initial hemostatic therapy of a bleeding peptic
ulcer, with a similar safety and tolerability profile

28. Esomeprazole
• Esomeprazole is the S-isomer of omeprazole.it has a better
pharmacokinetic and pharmacodynamic profile than
omeprazole.1
• Pharmacodynamics: in an acidic environment, esomeprazole is
protonated and becomes the active form, then binds to the
sulfhydryl group in the proton pump of parietal cells and
inhibits gastric acid production.1
• Esomeprazole reduces acid secretion through inhibition of
the H+, K+-ATPase in gastric parietal cells. Esomeprazole acts as
an exosome inhibitor by blocking the exosome release via the
inhibition of V-H+-ATPases.2
• Esomeprazole increases gastric pH better than omeprazole,
lansoprazole, pantoprazole and rabeprazole.1
1. Hoed & Kuipers. Expert Rev. Gastroenterol. Hepatol 2010.
2. Christina Nelson, et al. Therapeutic Efficacy of Esomeprazole in Cotton Smoke-Induced Lung Injury Model. Front Pharmacol. 2017 Jan 26;8:16.

29. Indications of Esomeprazole Intravenous
Gastric anti-secretory treatment when the oral route is not possible, such as:
Gastro esophageal reflux disease in patients with esophagitis and/or severe
symptoms of reflux; Healing of gastric ulcers associated with NSAIDs
therapy.
The short-term maintenance of hemostasis and prevention of rebleeding in
patients following therapeutic endoscopy for acute bleeding gastric or
duodenal ulcers.
Mims Indonesia

30. Body Physiology
• Platelet Aggregation stability need PH > 6.1 • Pepsin activity decreases sharply after pH > 4:
The main target of PPI treatment.2
1. Green FW, et al. Gastroenterology 1978;74:38–43
2. Berstad A. Scand J Gastroenterol 1970;5:343-8

31. Esomeprazole has been shown to be more effective in maintaining pH
> 4 vs other PPIs
Miner P et al. Am J Gastroenterol 2006;101:404–5, 406

32. PERCENTAGE OF TIME PH>6 DURING
FIRST 3 HOURS WITH ESOMEPRAZOLE
I.V. (HEALTHY VOLUNTEERS)
0
20
40
60
80
100
Mean fraction of first 3 hours (%)
*p<0.05 versus 80 mg + 8 mg/hour
Baseline 40 mg
+ 8 mg/hour
80 mg
+ 4 mg/hour
80 mg
+ 8 mg/hour
120 mg
+8 mg/hour
120 mg (2hours)
+ 8 mg/hour
2%
23.3%*
36.6%*
46.7% 47.7% 43.3%
Röhss K, et al. Intl J Clin Pharm Ther 2007;45:345–54
n=25 n=23 n=24 n=24 n=22 n=20

33. PPIs Duration Comparison
0
4
8
12
16
Esomeprazole Pantoprazole Lansoprazole Omeprazole
Hours
Rev Esp Enferm Dig 2016; 108 (3): 145-153

34. Pharmacological Differences Between Various PPI
Rev Esp Enferm Dig 2016; 108 (3): 145-153
PPI Equivalent oral doses Routes of Administration Hours with gastric pH.4
Omeprazole 20 mg Oral/parenteral 11.8
Pantoprazole 40 mg Oral/ parenteral 10.1
Lansoprazole 30 mg Oral 11.5
Rabeprazole 20 mg Oral 12.1
Esomeprazole 20 mg Oral/parenteral 14

35. PPIs Adverse Drugs Reactions
42%
8%
17%
25%
8%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
Pantoprazole Lansoprazole Omeprazole Esomeprazole Others
Adverse Effects
Pantoprazole Lansoprazole Omeprazole Esomeprazole Others
Casciaro et al. Clin Mol Allergy (2019) 17:1
42%
8%
33%
8%
8%
0% 10% 20% 30% 40% 50%
Urticaria
Asthenia, Illness
Urticaria & Angioedema
Angioedema
Urticaria, Dyspnea
Adverse Effects
Urticaria Asthenia, Illness
Urticaria & Angioedema Angioedema
Urticaria, Dyspnea

36. TERIMA KASIH