1. Treatment of Peptic ulcer
Department of Pharmacology

2. Introduction
Peptic ulcer is a disruption of the mucosal integrity of the stomach and/or duodenum
Symptoms - Burning epigastric pain exacerbated by
fasting and lessened by meals.
Normal
Peptic ulcer

3. Genesis of peptic ulcer
Genesis of peptic ulcer involves:
Imbalance between the mucosal
defensive (mucus, bicarbonate,
local synthesis of prostaglandins)
and damaging mechanisms (acid, pepsin). +
Infection of the gastric mucosa
with Helicobacter pylori

4. Gastric mucosal integrity is based on the balance between
Defensive mechanisms
Prostaglandins – stimulate the secretion of mucus & bicarbonate & inhibit the secretion of acid.
Mucus – alkaline, neutralizes acid
Bicarbonate ions, trapped in the mucus, create a pH gradient from 1-2 in the lumen to 6-7 at the mucosal surface. Mucous & bicarbonate form a gel like layer protecting the gastric mucosa from acid.
Mucosal blood flow
Active repair mechanisms
Aggressive factors
Acid & Pepsin
H. pylori infection
NSAIDs
Smoking
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5. Pathogenesis - not really understood
Mucosal resistant theory
- Defect in the mechanism which normally prevents the gastric secretion from damaging & digesting the mucosa
Acid and Pepsin theory
- Excessive secretion of acid ( esp: in DU)
- ↑ gastrin secretion
- ↑ Sensitivity of parietal cells to action of gastrin
Infection in the mucosa with bac:
H pylori
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6. “Leaking roof hypothesis”
Excessive acids in the gut lumen act upon weakened mucosa. Mucosa is weakened by bacteria ( H. pylori )
PU - imbalance between mucosal defense factors & aggressive factors
Aggressive factors- acid, pepsin, smoking, H pylori, hereditary (blood gp ‘O’, male)
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7. Helicobacter pylori Helicobacter pylori, a gram –negative rod,
lives in the human stomach exclusively &
survives in the highly acidic environment. It is helix-shaped (hence the name helicobacter) & can literally screw itself into the stomach lining to colonize. It can remain dormant & survive for long periods.
H. pylori infection can cause gastritis, peptic ulcer, predispose to gastric cancer etc. About 80% of people are infected with H. pylori, but, only 10 – 15% develop peptic ulcer while % of peptic ulcer patients are infected with H. pylori.
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8. Development of H. pylori induced peptic ulcer
Produce ammonia & neutralizes acid
Penetration & adherence
Proliferate & form infection focus
Peptic ulcer
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9. Gastric mucosa
H. pylori

10. Physiology of acid secretion:
Acid is secreted from
parietal cells by a
proton pump (H+/K+ ATPase)
Receptors for gastrin, histamine (H2), and acetylcholine (M3) are present on the parietal cell, stimulation of which leads to acid secretion.
Prostaglandins decrease acid secretion
H+/K+ ATPase (the proton pump) exchanges intraluminal K+ for intracellular H+, secreting acid.
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11. To achieve relief of pain To heal ulcer To prevent recurrences
Aim of therapy
To achieve relief of pain
To heal ulcer
To prevent recurrences
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12. Principles of treatment of peptic ulcer
To decrease intragastric pH (& inhibit activation
of pepsinogen) –
Neutralization of secreted acid
Reduction of acid secretion
To enhance mucosal resistance & protect ulcer
area
To eradicate H.pylori

13. Drugs used in the treatment of peptic ulcer
Neutralization of secreted acid – Antacids
Reduction of acid secretion –
Proton pump inhibitors – Omeprazole
H2 receptor blockers – Ranitidine
Muscarinic (M3) blockers – Pirenzepine
To enhance mucosal resistance & protect ulcer
area – Mucosal protectives
To eradicate H.pylori – Various regimens

14. Misoprostol Pirenzepine Ranitidine Histamine _ + _ ACh Gastrin _ + + +
PGE2
Ranitidine
Histamine _ + _
ACh
Gastrin H2 M3 _
Adenyl cyclase + + +
Ca++
ATP
cAMP
Ca++ + + +
Protein kinase
(Activated)
Parietal cell K+ H+ K +
Proton pump _
Lumen of stomach _
Omeprazole _
Gastric acid
Antacid

15. ANTACIDS

16. Antacids
Antacids are weak bases that neutralize acid and inhibit peptic activity.
Magnesium and aluminium salts - Hydroxide / trisilicate / bicarbonate / carbonate – neutralise acid & also adsorb pepsin.
Slow onset and long action
May promote mucosal defense by PG production.
Available as OTC drugs
Sodium bicarbonate acts rapidly and relieves pain. As it can lead to systemic alkalosis & release carbon dioxide in the stomach which may stimulate acid production, it is not advised.
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17. Antacids …
Duration of action: taken on empty stomach - 30 min &
after meal – 2h
Liquid formulations are more effective & fast acting than solids.
Regimen: 7 times/day
ADR:
Al3+ antacids cause constipation & Mg2+ antacids cause osmotic diarrhoea. Both together in a formulation nullify these side effects.
In impaired renal function, aluminium & magnesium may accumulate producing toxicity.
By altering pH, may interfere with absorption of concurrently administered drugs. To avoid this, antacids may be taken 1h before or 3 h after ingestion of other drugs.

18. Antacids – Uses & common additives
Uses: Dyspepsia
Symptomatic relief in peptic ulcer
Gastro Esophageal Reflux Disease (GERD) with alginates
Alginates - Form foamy layer on top of gastric contents & reduce reflux into esophagus.
Simethicone - Decreases surface tension thereby reduces bubble formation - Added to reduce flatulence.
Oxethazaine - Surface anaesthetic

19. taken hourly for severe symptom or uncontrolled reflux
Administration
taken hourly for severe symptom or uncontrolled reflux
taken at least one and three hours after each meal and at bedtime for uncomplicated ulcer
should be administered as suspension form (greater neutralization)
tablet should be thoroughly chewed for maximum effect
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20. Systemic (absorbable) antacids (NaHCO3)
absorbed into blood stream -► alkalosis, sodium retention in renal insufficiency, precipitates hypertension (not recommended for long-term use)
release CO2 -► belching, abdominal discomfort
Non-systemic (unabsorbable) antacids
not absorbed into blood stream -► no alkalosis
All Mg2+ salts cause diarrhoea and Al(OH)3 and CaCO3 cause constipation
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21. Magnesium trisilicate
relatively poor neutralizing action, react slowly with acid to form silicon dioxide that adsorbs pepsin, forms gelatinous SiO2, which has demulcent action (coating on ulcer crater) and also useful for heartburn
Mg (OH)2
has prompt action, long duration, cathartic with large doses is due to osmotic effect (also used as osmotic cathartic)
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22. also useful for heartburn adsorbs & inactivates pepsin
Al (OH)3
also useful for heartburn
adsorbs & inactivates pepsin
it also adsorbs phosphate in the intestine & are excreted in faeces, decreases blood phosphate and increase resorption from bone
untoward effects of Al(OH)3 are constipation, phosphate deficiency, osteoporosis, osteodystrophy, encephalopathy, myopathy in renal disease
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23. Drug Interactions with Antacids
decrease absorption of tetracycline, ciprofloxacin due to chelation with Mg2+, Al3+
decrease the dissolution and absorption of ketoconazole due to decreased acidity
interfere the action of sucralfate due to decreased acidity
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24. I am prescribing
Low carb diet for your diabetes
High carb diet for your constipation
Low fat diet for your heart disease
High fat diet for your nerves
And “one gallon of antacid daily for your stomach ulcer”

25. H2 receptor antagonists
Competitive blockers of histamine at H2 receptors
H2 antagonists are more effective in inhibiting nocturnal acid secretion (which depends largely on histamine) but have a modest effect on meal-stimulated acid secretion (by gastrin, ACh & histamine). Thus, they block more than 90% of nocturnal acid but only 60–80% of daytime acid secretion.
Promote healing of duodenal & gastric ulcers
prevent stress ulcers.
Relapses are likely when the drugs are discontinued.

26. H2 recepter Antagonists
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27. H2 receptor antagonists
Cimetidine is an enzyme inhibitor (↑ses conc. of Warfarin, theophylline, phenytoin, ethanol) & no more used due to various side effects such as gynecomastia, galactorrhea (antiandrogenic & ↑ prolactin levels)
Ranitidine is given twice a day or as a single nocturnal dose.
Famotidine and nizatidine are given once a day.
Other e.g. Roxatidine, Loxatidine

28. H2 receptor antagonists
Uses: Peptic ulcer
Reflux esophagitis
Nonulcer dyspepsia
↓ bleeding in stress-related gastritis in seriously ill patients in ICU (administered iv either as intermittent injections or continuous infusions).
ADR: Well tolerated with minimal ADR.
diarrhea, rash, hypergastrinaemia, Headache,
myalgia, bradycardia

29. - peptic ulcer (DU, GU, reflux oesophagitis)
Uses:
- peptic ulcer (DU, GU, reflux oesophagitis)
- uncomplicated GERD
- stress ulcer
- Zollinger-Ellison syndrome
- GI bleeding due to hepatic failure
- preanaesthetic medication
- systemic mastocytosis, basophilic leukaemia
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30. Proton Pump Inhibitors
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31. Proton Pump Inhibitors (PPIs)
Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole, Esomeprazole
Most effective in suppressing acid production as they act on the terminal step in the acid secretory pathway & irreversibly inhibit the proton pump (H+ K+ ATPase).
Drugs of choice in peptic ulcer and have replaced H2 blockers to a large extent due to their safety and high efficacy.
As they are acid labile, the prodrugs of PPI are given as enteric coated granules.
PPI undergo activation in the parietal cells.

32. Avoid during pregnancy & lactation
Act for more than 24 hrs (irreversible inhibition) & duration of action increases following continuous administration.
Cause marked inhibition of basal & stimulated acid secretion & acid secretion resumes only after synthesis of new molecules.
ADR: Extremely safe, well tolerated - Abdominal pain, GI upset, pain in joints, confusion etc.
Avoid during pregnancy & lactation
Causes hypergastrinemia – produces carcinoid tumor in rats (not reported in humans)
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33. Enzyme inhibition may decrease the metabolism of drugs like warfarin, diazepam etc.
Uses: efficacy is more if given in the morning before breakfast.
Peptic ulcer
Reflux esophagitis
Component of H. pylori eradication regimens
Zollinger-Ellison syndrome – hypersecretory state caused by a gastrin producing tumor

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35. Mucosal protective agents
Also known as cytoprotectives, they enhance the mucosal protection mechanisms and or provide a physical barrier over the surface of the ulcer.
Sucralfate
Misoprostol
Colloidal bismuth compounds (subcitrate)
Carbenoxolone (ulcer healing)

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37. Sucralfate
Sucralfate is a complex of aluminium hydroxide and sulfated sucrose & forms a viscous gel in acidic pH that adheres to ulcer base
ses peptic activity
↑ses local PG synthesis, ↑ses mucous & bicarbonate secretion
Given orally on empty stomach 1 hr before meals
As it needs acid for activation, avoid concurrent acid suppressing agents.
As effective as H2 blockers
ADR: very few, constipation, dry mouth, nausea, vomiting,  ses absorption of other drugs (fluoroquinolones, digoxin etc.)

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39. Misoprostol
NSAID produce gastric ulceration by Inhibition of PG production in the gastric mucosa.
Misoprostol is a PGE1 analogue.
Acts on parietal cell to reduce acid secretion
Enhance mucosal blood flow, increases mucus & bicarbonate secretion
Uses: with NSAID as prophylactic agent.
ADR: Diarrhoea & abdominal cramps
PPI are more effective & better tolerated
Other e.g. Enprostil, Rioprostil

40. Colloidal bismuth compounds
Coats ulcer base, adsorbs pepsin, increases local PG, stimulates mucus & bicarbonate secretion
↓ses peptic activity
On H. pylori – bactericidal, prevents its adherence to gastric mucosa, inhibits bacterial enzymes.
Use in H. pylori control regimens.
ADR: Not used for long periods – bismuth toxicity, blacken stools & tongue
Preparations: Colloidal bismuth subcitrate etc.

41. Carbenoxolone
It is an ulcer protective obtained from a plant
Increases production, secretion & viscosity of mucus which covers the ulcer area
ADR limit its use
Pirenzepine:
Anticholinergic drug
decreases acid production
Status: not used due to availability of better drugs

42. Drug regimens to eradicate H. pylori
Amoxicillin
Clarithromycin
Metronidazole
Bismuth salts
Acid suppressors
H Pylori–Associated Ulcers
For H pylori–associated ulcers, there are two therapeutic goals: heal the ulcer and eradicate the organism. The most effective regimens for H pylori eradication are combinations of two antibiotics and a proton pump inhibitor. Proton pump inhibitors promote eradication of H pylori through several mechanisms: direct antimicrobial properties (minor) and—by raising intragastric pH— lowering the minimal inhibitory concentrations of antibiotics against H pylori. The best treatment regimen consists of a 10–14 day regimen of "triple therapy": a proton pump inhibitor twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily. For patients who are allergic to penicillin, metronidazole 500 mg twice daily should be substituted for amoxicillin. After completion of triple therapy, the proton pump inhibitor should be continued once daily for a total of 4–6 weeks to ensure complete ulcer healing.
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43. DRUGS FOR ERADICATION OF H. pylori
Triple therapy (1 week regimen)
ACID SUPPRESSANTS ANTIBIOTICS
E/L/O/P/R/Ranitidine Amoxicillin Clarithromycin
L/O/Ranitidine Amoxicillin Metronidazole
E/L/O/P/R/Ranitidine Clarithromycin Metronidazole
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44. H. pylori eradication
The most effective regimens for H pylori eradication are combinations of two antibiotics + PPI or H2 blocker for 2 weeks.
Choose two AMA from:
metronidazole – 500 mg x 2 /d
clarithromycin – mg x 2 /d
amoxicillin – 1 g x 2 /d
plus
H2-blockers or PPI (twice a day) to ↓se acid secretion
Acid suppressors to be continued for 4 – 6 weeks.
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45. Treatment of Gastro-Esophageal Reflux disease (GERD)
Antacids & antacid adjuncts
H2 receptor blockers
Prokinetic- metoclopramide, domperidone, cisapride
Sucralfate
PPIs

46. list the ulcer promoting and preventing factors.
Objectives for Self study & Learning outcomes: The learner should be able to
list the ulcer promoting and preventing factors.
explain the applied physiology of acid secretion & the sites of drug action.
classify drugs useful in peptic ulcer based on their mechanism of action with suitable examples.
discuss the pharmacology of antacids, H2 receptor antagonists, proton pump inhibitors and mucosal protectives
explain the basis of NSAIDs induced peptic ulcer and preventive measures
mention regimens to eradicate H pylori.