Clinical Therapeutics Discussion on the Pathophysiology down to Pharmacological Management of Peptic Ulcer Disease

1. Clinical Therapeutics
PEPTIC ULCER
DISEASE
Maripol U. Tucjang
MEDICINE 3C
Cagayan State University

2. Definition
• Ulcers are defined as a breach in the
mucosa of the alimentary tract, which
extends through the muscularis mucosa
into the submucosa or deeper.
• Erosion differs from an ulcer in being
partial thickness mucosal defect.
• Peptic Ulcers are Chronic most often
solitary lesions that occur in any portion
of GIT exposed to the aggressive action
of acid-peptic juices.

3. Gastric Anatomy
• The stomach is “gland with cavity”,
extending from its junction with lower
end of the esophagus (cardia) to its
junction with the duodenum (pylorus).
• The stomach has 5 anatomical regions:
1.Cardia
2. Fundus
3. Body
4. Pyloric antrum
5. Pylorus

4. Gastric Anatomy
• Gastric cardia comprises < 5% of the gastric
gland area and contain mucous and endocrine
cells.
• The 75% of gastric glands are found within the
oxyntic mucosa and contain mucous neck,
parietal, chief, endocrine, enterochromaffin,
and entero-chromaffin-like (ECL) cells.
• Pyloric glands contain mucous and endocrine
cells (including gastrin cells) and are found in
the antrum.

5. Physiology of Gastric Secretion
• Hydrochloric acid and pepsinogen- mucosal injury
• Basal Acid- circadian pattern
• Cholinergic (Acetylcholine, Gastrin) and Histaminergic (Histamine)
inputs- basal acid secretion
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6. Gastroduodenal
Mucosal Defense
• 3-level barrier mucosal defense system:
1. Pre-epithelial- mucus- bicarbonate-phospho
lipid layer
2. Epithelial- Surface epithelial cells
3. Subepithelial- microvascular system
- prostaglandins regulates the release of mucosal
bicarbonate and mucus, inhibit parietal cell
secretion, maintain mucosal blood flow and epithelial
cell restitution.

7. Pathogenesis
 Gastric acidity
 Peptic enzymes
Aggressive factors
• Surface mucus secretion
• Bicarbonate secretion into mucus
• Mucosal blood flow
• Apical surface membrane transport
• Epithelial regenerative capacity
• Elaboration of PG
Defensive Factors

8. Pathogenesis
• H. pylori infection
• NSAID
• Tobacco
• Alcohol
• Gastric hyperacidity
• Duodenal gatric-reflux
• Impaired Defenses
• Ischemia
• Shock
• Delayed gastric-emptying
PEPTIC ULCER

9. Risk Factors
• H. pylori infection
• NSAIDS
• COPD
• Cigarette use
• CHD
• Alcohol
• Obesity
• Physiological stress

10. Helicobacter pylori
Major cause of peptic ulcer disease
• Gram-negative, microaerophilic and spiral bacteria
• 50% of the world’s population estimated to be
infected.
• 80-90% in developing countries
• 35-40% in the United States
-50-70% of duodenal ulcers
-30-60% of gastric ulcers
• Transmission occurs from person to person- oral-oral or fecal-
oral route

11. Pathophysiology
H. pylori
Bacterial Gene products Lipopolysaccharide antigens
Urease Phospholipases Proteases
Pro-inflmmatory cytokines TNF, IL-8
IL-1, IL-6
Immunologic (T & B cells)
Thrombotic effect of PAF
Enhances acid secretion
Impairs duodenal HCO3-
MUCOSAL EPITHELIAL DAMAGE

12. Pathophysiology
Phospholipase A2
inhibits
NSAIDS COX
Membrane phospholipids
Arachidonic Acid
PG depletion
Endothelial Effects
Stasis Ischemia
Epithelial effects
Increase in HCl secretion
Decrease mucin secretion
Decrease HCO3- secretion
Decrease surface active phospholipids
secretion
Decrease epithelial cell proliferation

13. PUD in the Philippines
• According to the latest WHO data published in 2018.
• Number of deaths: 6,283 (1.03%)
• Death Rate (Deaths per 100,000 population): 9.69
• Cause of death world rank: 18
Source: Peptic Ulcer Disease in Philippines
https://causesofdeathin.com/peptic-ulcer-disease-in-philippines/

14. Peptic Ulcer Disease
• Peptic Ulcer is the disruption of the mucosal integrity of stomach and/or
duodenum leading to a local defect or excavation due to active inflammation.
• Ulcers- > 5 mm in size, with depth to the submucosa

15. Epidemiology
• Duodenal Ulcers
- 6-15% of the Western population
- The incidence of DUs declined
• Gastric Ulcers
-occur later in life than duodenal lesions
-peak incidence reported in the 6th decade of
life
-more than one-half of gastric ulcers seen in
males

16. Duodenal vs. Gastric Ulcers
• Duodenal Ulcers
- first portion of the duodenum (> 95%)
- 1 cm in diameter – can reach 3-6 cm ( giant ulcer)
- Ulcers are sharply demarcated
- Malignant duodenal ulcers are extremely rare.
• Gastric Ulcers
- Gastric ulcers can represent a malignancy –
biopsied
- Benign- distal to the junction between the antrum
and the acid secretory mucosa.

17. Clinical manifestations
 Dyspepsia- most common symptoms
gnawing, burning, bloating
• Abdominal fullness
• Nausea and vomiting
• Epigastric pain
• Bleeding
• hematemesis
• melena
• Changes in weight

18. Duodenal vs. Gastric Ulcers
Gastric Ulcers Duodenal Ulcers
Malignancy risk Common (should be biopsied) Extremely rare
Usual Etiology H. pylori, NSAID- induced injury H. pylori, NSAID- induced injury
Pathophysiology Gastric acid output normal or
decreased
Gastric acid appears to be
increased
Bicarbonate secretion is
significantly decreased
Clinical features -Symptoms worse with eating
-epigastric pain 15-30 minutes
following a meal
-pain may be found to the right of the
midline in 20% of patients
-characterized as burning
-Epigastric pain 90 mins-3 hours
after a meal
-relieved by food and antacids
-may interrupt sleep
periods of symptoms alternating
with periods of remission

19. Gastric Ulcers- classified
based on location
• Type 1 – Gastric body – low gastric acid
production;
• Type II – Antrum. Gastric acid from low
to normal
• Type III- Within 3 cm of the pylorus,
accompanied by duodenal ulcers,
normal or high gastric acid production;
• Type IV- cardia, low gastric acid
production

20. PUD-related complications
1. Gastrointestinal bleeding – 15% of patients
-mortality rate- 2.5 -10%
2. Perforation – 6-7%
-mortality rate- > 20%
-penetration- ulcer bed tunnels into an adjacent organ
- GU: tends to penetrate into the left hepatic lobe
- DU: tends to penetrate posteriorly into the pancreas pancreatitis
3. Gastric Outlet Obstruction – 1-2%
-relative obstruction- edema in the peripyloric region, often resolves with ulcer healing
- fixed, mechanical obstruction- scar formation in the peripyloric area

21. Diagnostics for Ulcer Detection
DIAGNOSTICS REMARKS
Barium Studies of Proximal GIT  Previously used as a first test for documenting an ulcer.
 Sensitivity: single contrast= 80%, double contrast= 90%
 Decreased sensitivity in small ulcers of < .5cm.
Upper endoscopy (EGD)  Most sensitive and specific approach for examining the
upper GIT
 Allows direct visualization of the mucosa
 Facilitates documentation of a mucosal defect and tissue
biopsy to rule out malignancy (GU) or H. pylori
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22. Esophagoduodenoscopy (EGD)
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23. Diagnostics for H. pylori Detection

24. Forrest Classification
CLASSIFICATION DESCRIPTION RISK OF
REBLEEDING
IF UNTREATED
Acute Hemorrhage
Type 1A Arterial Spurting 100%
Type 1B Arterial oozing 55%
Signs of Recent
Hemorrhage
Type IIA Non-bleeding visible vessel 43%
Type IIB Adherent Clot 22%
Type IIC Pigmented flat spot 10%
Lesions without Active
Bleeding
Type III No stigmata of recent bleed
Fibrin-coated clean ulcer base
5%
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Type 1A Type1B
Type IIA Type IIB
Type IIC Type III

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26. MANAGEMENT OF
PEPTIC ULCER DSE
GOALS:
1. Relief of symptoms
2. Promote ulcer healing
3. Prevent ulcer recurrence and complications
A. ACID NEUTRALIZING/INHIBITORY DRUGS
• Antacids
• H2 Receptor Antagonists
• Proton pump inhibitors
B. CYTOPROTECTIVE AGENTS
• Sucralfate
• Bismuth-containing preparations
• Prostaglandin analogues

27. TREATMENT OF PEPTIC ULCER DISEASE
Class Examples MOA Side Effects
Antacids • Aluminum hydroxide
5-30 ml between meals and HS
Neutralize gastric acidity
• Constipation
• Magnesium hydrxide 400
mg PO q4 ( max of 4 doses
per day)
• Diarrhea
H2 Receptor
Antagonists
• Cimetidine 400 mg BID
• Ranitidine 300mg HS
• Famotidine 40 mg HS
• Competitive inhibition at the
parietal cell H2- receptor,
suppresses acid secretion
• Headache, fatigue, myalgias
Proton pump
inhibitors
• Omeprazole 20 mg BID
• Esomeprazole 40 mg BID
• Rabeprazole 20mg BID
• Pantoprazole 40mg BID
• Lanzoprazole 30mg BID
• Dexlansoprazole 30mg BID
• Covalently bind and
irreversibly inhibit H+, K+ -
ATPase
• Most potent acid inhibitory
agent
• Maximum efficacy if taken
(30-60 minutes) before a
meal
• Headache, abdominal pain,
diarrhea, flatulence,
dermatitis, pruritus, dry
mouth, blurred vision,
angioedema, elevated liver
enzymes
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A. ACID NEUTRALIZING/INHIBITORY DRUGS

28. TREATMENT OF PEPTIC ULCER DISEASE
Class Examples Description Side Effects
Sucralfate Sucralfate 1 g QID • Becomes a viscous paste within
the stomach and duodenum,
binding primarily to sites of active
ulceration
• Act as a physiochemical barrier
Constipation
Bismuth-
Containing
Preparations
Bismuth subsalicylate 300
mg QID
(BSS, Pepto-Bismol)
• Mechanism is unclear Black stools
Constipation
Darkening of the tongue
Neurotoxicity (long-term)
Prostaglandin
Analogues
Misoprostol 200 mcg QID • Enhancement of mucosal defense
and repair
Diarrhea
Contraindicate in
pregnancy
(Misoprostol)
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B. CYTOPROTECTIVE AGENTS

29. ACG H Pylori Infection Guidelines
The 2017 American College of Gastroenterology (ACG) guidelines for the treatment of H pylori infection (HPI) include the
following recommendations for testing for H pylori :
• All patients with active or past history of peptic ulcer disease (unless previous cure of HPI has been documented), or
• Those who have low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma
• History of endoscopic resection of early gastric cancer
• Patients with dyspepsia who are undergoing upper endoscopy (gastric biopsy specimens)
• Patients on long-term, low-dose aspirin
• Patients initiating long-term therapy with nonsteroidal anti-inflammatory agents (NSAIDs)
• Patients with unexplained iron deficiency anemia following standard workup
• Adults with idiopathic thrombocytopenic purpura

30. First-line therapies
of H. pylori Infection
• Antibiotic-resistants strains
are the most common
cause for treatment failure
in compliant patients
• Choice is based on bacterial
resistance patterns, local
recommendations and
availability.
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32. MANAGEMENT FOR NSAID-INDUCED ULCERS
• Intervention for NSAID-related mucosal injury includes:
-Treatment of active ulcers
-Prevention of future injury
A. Treatment of Active Ulcers
Medications Remarks
Proton Pump Inhibitors • Superior to standard-dose H2 RAs in healing NSAID-induced peptic ulcers
• Only PPIs can heal gastric/duodenal ulcers, independent of whether NSAIDS are
discontinued or not
H2 receptor Antagonists • More effective in healing DUs than GUs
• Not preferred agents in patients who require continuous NSAID therapy
Misoprostol • Not as effective as PPIs in NSAID-induced ulcer healing
• Only gastroprotective agent which can reduce risk of NSAID-induced ulcer
complications
• Full dose: misoprostol 200mcg QID

33. MANAGEMENT FOR NSAID-INDUCED ULCERS
B. Prevention of Further Injury
Approach to prevention includes:
 Avoidance of injurious agent or use the lowest possible dose of the agent.
 Use NSAIDS that are theoretically less injurious
 Use newer topical NSAID preparations
 Add concomitant medical therapy to prevent NSAID-induced injury
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Possible Preventive Measures REMARKS
Use nonselective NSAIDS associated with a lower
likelihood of GI toxicity
• Includes diclofenac, aceclofenac, ibuprofen
• However, beneficial effect may be eliminated if higher doses are
used.
Use concomitant medications prevent injury • Includes a PPI or misoprostol
• High-dose H2- receptor blockers (famotidine 40mg BID) have
shown promise in preventing ulcers, but PPIs are better
Use of selective COX-2 inhibitors like Celecoxib • Advantage of celecoxib in preventing GI complications is offset
when aspirin is used simultaneously.

34. GUIDE TO NSAID THERAPY
• Individuals not at risk for cardiovascular events
& do not use aspirin and are without risk for GI
complications can receive nonselective NSAIDs
without gastric protection.
• Individuals without cardiovascular risk but
with high risk for NSAID-induced GI injury may
cautiously use a selective COX-2 inhibitor +
high-dose PPI or misoprostol, or consider non-
NSAID therapy.
• Individuals with CV risk factors & require intake
of aspirin and have no risk factors for NSAID-
induced GI injury may consider using non-
NSAID agent or traditional NSAID with gastric
protection, or consider non-NSAID therapy.
• Individuals with CV and GI risk factors &
require intake of aspirin must consider non-
NSAID therapy, and if not possible, then gastric
protection must be considered.
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35. RISK STRATIFICATION SCORING
SYSTEM
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38. SURGICAL
THERAPY
1. Truncal vagotomy and Drainage (
gastrojejunostomy or pyroplasty)
- has intermediate complication rate
- has 10% ulcer recurrence rate
2. Highly selective vagotomy (which does not
require a drainage procedure)
- >10% ulcer recurrence rates
- lowest overall complication rates
3. Vagotomy and antrectomy (selective)
- 1% ulcer recurrence rate
- highest complication rates
Operations for Duodenal Ulcers:

39. SURGICAL THERAPY

41. • Selective Vagotomy
Selective Vagotomy is the
complete division of the
anterior and posterior branches
distal to the branching of the
hepatobiliary and celiac
branches.

42. 2 PRINCIPAL TYPES OF
REANASTOMOSES:
1. Gastroduodenostomy (Bilroth I)
- creation of an anastomosis
between the duodenum and the
gastric
remnant (gastroduodenostomy).
2. Gastrojejunostomy (Bilroth II)
- Constructed by sewing a loop of
jejunum to the gastric remnant
(gastrojejunostomy).
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43. Billroth 1 & Billroth II
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44. SURGICAL THERAPY
Operations for Gastric Ulcers:
1. Csendes’ Procedure- surgical treatment for
gastric ulcers high in the cardia, consisting of
subtotal gastrectomy and a large Roux en Y
anastomosis
2. Kelling- Madlener procedure-
operation for treatment of gastric ulcer located in
the proximal cardia that involves 75% gastrectomy
and gastrojejunostomy.

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