Peptic Ulcer Disease Affects All Age Groups. Can occur in children, although rare. Duodenal ulcers tends to occur first at around the age 25 and continue until the age of 75. Gastric ulcers peak in people between the ages of 55 and 65. Men Have Twice The Risk as Women Do

1. Gastrointestinal Drugs
Drugs for Peptic Ulcer
Vinay Gupta
Lecturer
Department of Pharmacology
UP Rural Institute of Medical Sciences &
Research
Saifai, Etawah, India

2. What is Peptic Ulcer Disease
• Definition of Peptic Ulcer:
–A benign lesion of gastric or duodenal mucosa
occurring at a site where the mucosal epithelium is
exposed to acid and pepsin.
–It results due to an imbalance b/w the aggressive (acid,
pepsin, bile & H. pylori) & the defensive (gastric
mucus & bicarbonate secretion, PG etc.)
1) Excess acid production
2) Intrinsic defect in the mucosal defense barrier

3. A Gastric Peptic Ulcer

4. Who Gets Peptic Ulcers
• Peptic Ulcer Disease Affects All Age Groups
– Can occur in children, although rare
– Duodenal ulcers tends to occur first at around the age 25 and
continue until the age of 75
– Gastric ulcers peak in people between the ages of 55 and 65
• Men Have Twice The Risk as Women Do
• Genetic Factors
– High levels of acid production, weakness in mucosal layer,
abnormal nonprotective mucus production
• Increase Acid Production and/or Decrease in Bicarbonate and PG
Production
–Caffeine, Cigarettes, Alcohol, Fruit Juices, Stress

5. What Causes Peptic Ulcer Disease
•NSAIDs
Long term use of nonsteroidal anti-inflammatory
drugs. NSAIDs block COX enzymes and
decrease prostaglandins (PGs).
•Gastrinoma (Zollinger-Ellison Syndrome)
Tumors of the duodenum or pancreas secretes
abnormally high amounts of gastrin which
stimulates gastric acid.
•Stress ulcers
Result of physical trauma (i.e., burn patients).

6. Pathophysiological Processes Involved in
Duodenal and Gastric Ulcers
HP
NSAID
Cancer (ZE)
Other
Duodenal Ulcer Gastric Ulcer

7. Regulation of gastric acid secretion-
• In gastric ulcer generally acid secretion is normal
or low and in duodenal ulcer acid secretion is
usually high.
• Proton Pump (H+K+ATPase) secretes H+ ions
which can be activated by-
1. Histamine Paracrine
2. Ach Neural
3. Gastrin Hormonal

8. • They act via their own receptors located on the
basolateral membrane.
• Out of the three, histamine acts through H2
receptors & plays dominant role while gastrin &
Ach acts partly by releasing histamines.

9. H+, K+-ATPase (the proton pump) is the
final transport pathway for parietal cell
hydrogen ion secretion
• H+, K+-ATPase is located in the apical membrane of
the oxyntic cell along the secretory canaliculi;
• The pump requires large amounts of energy that is
supplied by intracellular ATP;
• Inhibition of H+, K+-ATPase blocks both basal and
stimulated acid secretion.

10. Each Secretagogue Binds to its Own
Receptor and Interacts with the Others
Gastrin
Histamine
Acetylcholine
H+
CCK2
H2
M3
cAMP dep. pathway
PP
Gastric
Lumen

11. Strategies for Protecting the Gastric Mucosa
from Acid Exposure
Inhibit
secretion
Prevent
contact
Neutralize
acid
Mechanisms Example
Cimetidine
Omeprazole
Prostaglandins
Muscarinic antagonists
Sucralfate
Antacids
H+
H+
H+

12. What is GERD?
•Gastroesophageal Reflux Disease (GERD):
GERD is when acid and pepsin from the
stomach flows backward up into the esophagus
often called heartburn;

14. What Causes GERD?
1) Overproduction of acid/pepsin
2) Over relaxation of the Lower Esophageal
Sphincter (LES);
Complications;
if not treated - severe chest pains, bleeding or
a pre-malignant change in the lining of the
esophagus called Barrett’s esophagus – can
result in adenocarcinoma.

15. Treatment of Peptic Ulcer
1) Reduction of gastric acid secretion
A) H2 antihistamines- (R2FC) Ranitidine,
Roxatidine,
Famotidine,
Cimetidine.
B) Proton Pump Inhibitors (PPI)- (PRO-LE)
Pantoprazole, Rabeprazole, Omeprazole,
Lansoprazole, Esomeprazole.
C) Anticholinergics -(PPO) Pirenzepine,
Propantheline, Oxyphenonium.
D) Prostaglandin Analogue- Misoprostol

16. Treatment of Peptic Ulcer Cont…
2) Neutralization of Gastric acid (Antacids)-
a) Systemic- Sod. bi carbonate, Sod. Citrate.
b) Nonsystemic- Mag Hydroxide, Mag tricilicate, Al
hydroxide gel, Calcium carbonate,
Magaldrate.
3) Ulcer Protectives- Sucralfate, Collidal bismuth subcitrate.
4) Anti Helicobacter pylori Drugs- Amoxicillin,
Clarithromycin, Metronidazole, Tinidazole, Tetracycline.

17. Histamine Receptors
•H1 receptors
– Smooth muscle
– Nerves
•H2 receptors
– Parietal cells

18. Histamine H2 Antagonists Decrease Acid Output
Histamine
Protein
Kinase
ATP
cAMP
K+
H+
Histamine
Antagonist
PP

19. 1. Reduction of gastric acid secretion
Histamine H2 Antagonists
 4 drugs are available- Ranitidine, Roxatidine, Famotidine
& Cimetidine. & have competitive interaction with H2
receptors.
 Cimetidine was the 1st H2blocker to be introduced &
Prototype..
 All H2 antagonist block histamine induced gastric
secretion.
 The ulcer healing dose produces 60-70% inhibition of 24
hr acid output.
 Cimetidine is absorbed orally (bioavailability is 60-80% d/t
1st pass hepatic metabolism).
 Mild adverse effects in 5% is common- headache,
dizziness, bowel upset, CNS effects- restlessness,

20. Drugs for Acid-Peptic Disorders - Cimetidine
Additional Side effects:
• In some patients, cimetidine acts as a nonsteroidal
antiandrogen (i.e., interferes with estrogen metabolism).
decrease in male sexual function
gynecomastia (swelling of the breasts and soreness of
the nipples in males)
• Can produce confusion and disorientation in elderly
patients;
• Diarrhea, rash and miscellaneous other effects in a small
number of patients.

21. Interactions-
 Antacids reduces absorption of all H2 blockers. A gap of
2 hr is recommended for concurrent use with antacids.
 Cimetidine dose – 400mg BD or 800mg HS. Orally
for stress ulcer – 50mg/hr IV
Ranitidine
 5 times more potent than cimetidine with a lower
incidence of side effects.
 Dose – 150 mg BD or 300mg HS
or 50mg IM / slow IV in 6-8 hr.
Roxatidine-
 Pk, Pd & side effect profile is similar to Ranitidine bt its
twice as potent & longer acting.
 Dose – 75 mg BD or 150 mg HS

22. Famotidine-
 It is 5-8 times more potent than ranitidine
 Dose- 20 mg BD or 40 mg HS or 20mg I.V. / 12 hr.
Proton Pump Inhibitors (PRO-LE)
Omeprazole-
 Inhibits final common step in gastric acid secretion &
have overtaken H2 blockers for acid –peptic disorders.
 Bioavailability of all PPIs is reduced by food, hence they
should be taken as empty stomach.
 Uses- Duodenal Ulcers, Gastric Ulcers, Stress Ulcers,
GERD (gastroesophageal reflux disesse)
 Dose- 40mg/Day

23. Interaction-
 Omeprazole inhibits oxidation of certain drugs like
Diagepam, Phenytoin and warfarin levels may be
increased.
 Clarithromycin inhibits omeprazole metabolism &
increases its plasma concentration.
Esomeprazole-
 It is S-enantiomer of omeprazole, have higher
bioavailability & to produce better control of intragastric
pH than omeprazole in GERD.
 Dose- 20-40 mg OD

24. Lansoprazole
 More potent than omeprazole.
 Higher bioavailability. Dose should be reduced in liver
diseases.
 Side effects are similar bt drug interactions are less
significant.
 Dose- 15-30 mg OD.
Pantoprazole
 It is more acid stable & has higher bioavilability.
 It is also available for I.V. Administration.
 Dose- 20mg OD.

25. Strategies for Inhibiting Parietal Cell Acid
Secretion
Gastrin
Histamine
Acetylcholine Ca2+
Protein
Kinase
ATP
cAMP
Prostaglandin
Agonists (-)
K+
H+
PP
H2M3
CCK2
EP3
Ca2+

26. Drugs for Acid-Peptic Disorders -
Prostaglandins
Misoprostol (Cytotec):
• Synthetic Analog of Prostaglandin E1
• Anti-acid secretory
• 0.1 to 0.2 mg results in 85% to 95% acid reduction
• Prevention of NSAID gastric ulcers
Side Effects
• Diarrhea
• Abortion
• Exacerbate IBD and should not be given

27. Neutralization of gastric acid
Drugs for Acid-Peptic Disorders - Antacids
• Antacids are weak bases that neutralize HCl in the
stomach;
• They do not decrease the secretion of acid, and in some
cases increase secretion;
• They do not suppress nocturnal acid secretion
1. Neutralize acid
2. Decrease acid load to duodenum
3. Diminish pepsin activity

28. Drugs for Acid-Peptic Disorders -
Antacids
• Magnesium hydroxide
• Magnesium trisilicate
• Magnesium-aluminum
mixtures
• Calcium carbonate
• Sodium bicarbonate

29. Characteristics of Common Antacids
Feature Sodium
Bicarbonate
Calcium Magnesium
Hydroxide
Aluminum
Onset of
action
rapid intermediate rapid slow
Duration of
action
short moderate moderate moderate
Systemic
alkalosis
yes ? no no
Effect on
stool
--- constipating laxative constipating

30. Ulcer Protectives
Drugs for Acid-Peptic Disorders – Sucralfate
• Sucralfate is a basic aluminum salt of sucrose
octasulfate;
• In the presence of acid (pH < 3-4) some of the aluminum
ions dissociate and the resulting negatively charged
molecule polymerizes to form a viscous paste-like
substance;
• This substance adheres strongly to gastric and duodenum
mucosa and adheres even more strongly to partially
denatured proteins such as those found at the base of the
ulcer.

31. Drugs for Acid-Peptic Disorders - Sucralfate
(Carafate)
•This compound does not decrease the concentration
or total amount of acid in the stomach;
•Sucralfate protects the gastric and duodenal mucosa
from acid/pepsin attack.
Side effects:
• The compound is not really absorbed and, therefore,
side-effects are minimal:
– constipation
– diarrhea
– nausea

32. Anti H. pylori drugs
• Helicobacter Pylori (H. pylori)
–Most ulcers are the result of infection with H.
pylori
–Not all of those infected with H. pylori develop
ulcers
– H. pylori MAY result in a weakening of the
mucosal defense systems, allowing for
development of ulcer subsequent to acid/pepsin
aggression; by producing ammonia which
maintains a neutral micro environment around the
bacteria & promotes back diffusion of H+ions.

33. Helicobacter pylori
Spiral shaped, flagellated, Gram negative bacterium

34. Helicobacter pylori on gastric mucus-
secreting epithelial cells

35. Role of H. pylori in Peptic Ulcer Disease
•The host reaction to H. pylori determines the
outcome of the infection:
– Gastritis
– GERD
– Gastric & Duodenal Ulcers
– Gastric Cancer (?)

36. Role of H. pylori in Peptic Ulcer Disease
•Treatment
–If H. pylori detected, eradication of the
bacteria, along with inhibition of acid.
–Eradication of H. pylori is a cure as
reinfection rates in Western countries is
less than 1%.

37. Role of H. pylori in Peptic Ulcer Disease
•Combination therapy with Omeprazole and
Amoxycillin

38. H. pylori Eradication Rates with Either Dual,
Triple or Quad Therapy (1999)
Treatment Pooled Eradication
Rate
Dual Therapy 72%
Triple Therapy 85%
Quad Therapy 90%

39. H. pylori Eradication Rates with Either Dual,
Triple or Quad Therapy (1999)
GENERIC NAME DOSING DURATION CURE RATE (%)
Dual therapies
omeprazole 500 mg TID 14 days 70-80
amoxycillin 1,000 mg TID 14 days
ranitidine 400 mg BID 28 days 73-84
clarithromycin 500 mg TID 14 days
lansoprazole 30 mg TID 14 days 66-77
amoxycillin 1,000 mg TID 14 days

40. H. pylori Eradication Rates with Either Dual,
Triple or Quad Therapy (1999) Cont.
GENERIC NAME DOSING DURATION CURE RATE (%)
Triple therapies
lansoprazole 30 mg BID 14 days 86-92
amoxycillin 1,000 mg BID 14 day
clarithromycin 500 mg BID 14 days

41. H. pylori Eradication Rates with Either Dual,
Triple or Quad Therapy (1999) Cont.
GENERIC NAME DOSING DURATION CURE RATE (%)
Quad therapies
bismuth subsalicylate Two tablets 7 days 85-95
525 mg QID
metronidazole 250 mg QID 7 days
tetracycline 500 mg QID 7 days
omeprazole 20 mg BID 7 days
or
lansoprazole 30 mg BID 7 days

42. New Strains of H. pylori
• Recently a more virulent genetic strain of H.
Pylori known as cytotoxin-associated gene A
(cagA) has been found in some people with
peptic ulcers

43. Functional Disorders of the GI
• Primary
–infection, inflammation, congenital defects (disorders
of the neuronal/muscular activity);
• Secondary
–metabolic disorders (hypo- or hyper-parathyroidism,
hypercalcemia), neurologic (diabetes mellitus -
damage to vagal and sympathetic extrinsic nerves,
intrinsic nerves; MS, heavy metal toxicity,
carcinoma);
• Examples of colonic dysfunction:
–IBS; chronic constipation; Hirschsprung’s disease
(agangliosis of myenteric plexus); sphincter
dysfunction, etc.