DRUGS FOR PEPTIC ULCER

 Acid-peptic diseases include gastroesophageal reflux, peptic ulcer (gastric

and duodenal), and stress-related mucosal injury
 In all these conditions, mucosal erosions or ulceration arise when there is an
imbalance between the aggressive (acid, pepsin, bile and H. pylori) and the
defensive (gastric mucus and bicarbonate secretion, prostaglandins, high
mucosal blood flow) factors

1. Classify drugs used in acid peptic disease based on their mechanism of

action.
A. Drugs which neutralize gastric acid (Antacids):
 Systemic antacids: Sodium bicarbonate
 Non-systemic antacids: Aluminium hydroxide, magnesium
hydroxide, calcium carbonate, magaldrate
B. Drugs which reduce gastric acid secretion:
 H2-receptor antagonists: Ranitidine, famotidine, nizatidine
 Proton pump inhibitors (PPIs): Omeprazole, esomeprazole,
pantoprazole, lansoprazole, dexlansoprazole, rabeprazole,
dexrabeprazole
 Prostaglandin analogues: Misoprostol
 Anticholinergics: Pirenzepine
C. Mucosal protective drugs: Sucralfate, bismuth subsalicylate,
colloidal bismuth subcitrate, misoprostol
D. Anti-Helicobacter pylori drugs: Amoxicillin, clarithromycin,
tetracycline, metronidazole, bismuth subsalicylate
2. Explain the mechanism of action of following drugs in acid peptic
disease: ranitidine, omeprazole, antacids, sucralfate, colloidal bismuth
subcitrate (CBS) and misoprostol.
A. Mechanism of action of antacids:
Antacids are weak bases react with gastric hydrochloric acid to form
salt and water (neutralize gastric hydrochloric acid) increase the pH
of stomach contents decrease the acid load delivered to duodenum 
reduction of intragastric acidity
B. Mechanism of action of ranitidine:
Ranitidine blocks H2-receptors of gastric parietal cells  prevents
binding of histamine, which is released from enterochromaffin-like
(ECL) cells by gastrin or vagal stimulation  reduces the gastric acid
secretion
Note-
 H2 blockers block more than 90% nocturnal acid only 60-70%
of day-time food stimulated acid secretion
 Recommended doses of H2 blockers maintain at least 50%
inhibition up to 10 h; hence these drugs are usually given on
twice daily basis
C. Mechanism of action of omeprazole:
Omeprazole is prodrug and weak base  gets absorbed by passive
diffusion across lipid membranes from intestine reaches the parietal
cell canaliculus gets exposed to acidic environmentrapidly
ionizes gets trapped and cannot diffuse back undergoes a
molecular rearrangement to an active “sulfenamide cation”  makes a
covalent disulfide bond with the SH group of the proton pump
(H+/K+/ATPase) inactivates it irreversibly shutting off the gastric
acid secretion
 Note-
 The best way to administer PPIs is to give in the morning just
before breakfast so that their peak serum concentration
coincides with the maximal activity of proton pumps
 PPIs have short serum half-lives but the duration of acid
inhibition lasts up to 24 h (as PPIs are irreversible inactivators
of proton pump and at least 18 h are needed for the synthesis of
new H+/K+/ATPase pumps)
 There is a biological lag 3-4 days before a full acid inhibiting
activity of PPIs is achieved
 Similarly, it takes 3-4 days again for the return of normal acid
secretion once PPIs are withdrawn
D. Mechanism of action of sucralfate:
In gastric acidic environment (pH < 4), sucralfate polymerises by
cross-linking of molecules forms a sticky-like gel over ulcer crater
acts as acid-resistant physical barrier
E. Mechanism of action of colloidal bismuth subcitrate (CBS):
In gastric acid media, colloidal bismuth subcitrate forms an acid-
resistant protective coating over ulcer base. It also dislodges H. pylori
from the surface of gastric mucosa and has direct antimicrobial
activity against this ulcer-causative organism.
F. Mechanism of action of misoprostol:
Misoprostol is a prostaglandin analogue inhibits adenylate cyclase in
parietal cells decreases formation of cyclic AMP  reduces the
gastric acid secretion
In addition, misoprostol enhances gastric mucosal blood flow and
stimulates the secretion of mucus and bicarbonates protection from
gastric acidity
3. Apply the mechanism of action of H2 blockers and proton pump
inhibitors (PPIs) to provide rationale for their use.
A. Therapeutic uses of H2 blockers:
 Gastroesophageal Reflux Disease (GERD):
H2 blockers block H2-receptors of gastric parietal cells 

prevent binding of histamine, which is released from

enterochromaffin-like (ECL) cells by gastrin or vagal
stimulation  reduce the gastric acid secretion  reduce the
infrequent heart burn or dyspepsia (symptomatic relief) as well
as promote healing of esophageal lesions in GERD patients
Note-
 Proton pump inhibitors are preferred because of their
superior acid inhibition.
 Peptic ulcer disease:
H2 blockers block H2-receptors of gastric parietal cells 

prevent binding of histamine, which is released from

enterochromaffin-like (ECL) cells by gastrin or vagal
stimulation  reduce the gastric acid secretion  promote
effective ulcer healing in patients with uncomplicated gastric
and duodenal ulcers
Note-
 For patients with peptic ulcers caused by aspirin or other
NSAIDs, the NSAID should be discontinued. If the
NSAID must be continued for clinical reasons despite
active ulceration, a proton pump inhibitor should be
given instead of an H2 blocker to more reliably promote
ulcer healing
  For patients with acute peptic ulcers caused by
Helicobacter pylori (H. pylori), H2 blockers no longer
play a significant therapeutic role
 Nonulcer dyspepsia:
H2 blockers block H2-receptors of gastric parietal cells 

prevent binding of histamine, which is released from

enterochromaffin-like (ECL) cells by gastrin or vagal
stimulation  reduce the gastric acid secretion  reduce
intermittent dyspepsia
Note-
 H2 blockers are commonly used as over-the-counter
agents and prescription agents for treatment of
intermittent dyspepsia not caused by peptic ulcer
 Prevention of bleeding from stress-related gastritis:
Although most critically ill patients suffering from stress-related
gastritis have normal or decreased gastric acid secretion,
numerous studies have shown that agents that increase
intragastric pH (H2 blockers or PPIs) reduce the incidence of
clinically significant bleeding which might be because of
enhancement of coagulation and platelet aggregation at
increased intragastric pH (higher than 6)
B. Therapeutic uses of PPIs:
 Gastroesophageal Reflux Disease (GERD):
PPIs are prodrugs and weak bases get absorbed by passive
diffusion across lipid membranes from intestine reach the
parietal cell canaliculus get exposed to acidic
environmentrapidly ionized get trapped and cannot diffuse
back undergo a molecular rearrangement to an active
“sulfenamide cation” make a covalent disulfide bond with the
 SH group of the proton pump (H+/K+/ATPase) inactivate it
irreversibly shutting off the gastric acid secretion  reduce the
infrequent heart burn or dyspepsia (symptomatic relief) as well
as promote healing of esophageal lesions in GERD patients
Note-
 Proton pump inhibitors are preferred because of their
superior acid inhibition.
 Peptic ulcer disease:
PPIs are prodrugs and weak bases get absorbed by passive
diffusion across lipid membranes from intestine reach the
parietal cell canaliculus get exposed to acidic
environmentrapidly ionized get trapped and cannot diffuse
back undergo a molecular rearrangement to an active
“sulfenamide cation” make a covalent disulfide bond with the
SH group of the proton pump (H+/K+/ATPase) inactivate it
irreversibly shutting off the gastric acid secretion afford
more rapid symptom relief and faster ulcer healing for duodenal
ulcers and, to a lesser extent, gastric ulcers compared to H2
blockers
Note-
 For patients with peptic ulcers caused by aspirin or other
NSAIDs, the NSAID should be discontinued. If the
NSAID must be continued for clinical reasons despite
active ulceration, a proton pump inhibitor should be
given instead of an H2 blocker to more reliably promote
ulcer healing
 For patients with acute peptic ulcers caused by H. pylori,
PPIs play a significant therapeutic role
  PPIs promote eradication of H. pylori through direct
antimicrobial properties (minor) and by raising
intragastric pH lowering the minimal inhibitory
concentrations of antibiotics against H. pylori
 PPIs prevent rebleeding from peptic ulcers might be
because of enhancement of coagulation and platelet
aggregation at increased intragastric pH (higher than 6)
 Nonulcer dyspepsia:
PPIs are prodrugs and weak bases get absorbed by passive
diffusion across lipid membranes from intestine reach the
parietal cell canaliculus get exposed to acidic
environmentrapidly ionized get trapped and cannot diffuse
back undergo a molecular rearrangement to an active
“sulfenamide cation” make a covalent disulfide bond with the
SH group of the proton pump (H+/K+/ATPase) inactivate it
irreversibly shutting off the gastric acid secretion  reduce
intermittent dyspepsia
 Prevention of bleeding from stress-related gastritis:
Although most critically ill patients suffering from stress-related
gastritis have normal or decreased gastric acid secretion,
numerous studies have shown that agents that increase
intragastric pH (PPIs or H2 blockers) reduce the incidence of
clinically significant bleeding which might be because of
enhancement of coagulation and platelet aggregation at
increased intragastric pH (higher than 6)

 Gastrinoma (Zollinger-Ellison syndrome) and other

hypersecretory conditions:
 PPIs are prodrugs and weak bases get absorbed by passive
diffusion across lipid membranes from intestine reach the
parietal cell canaliculus get exposed to acidic
environmentrapidly ionized get trapped and cannot diffuse
back undergo a molecular rearrangement to an active
“sulfenamide cation” make a covalent disulfide bond with the
SH group of the proton pump (H+/K+/ATPase) inactivate it
irreversibly shutting off the gastric acid secretion relief from
peptic ulceration, erosive esophagitis and malabsorption
Note-
 Patients with isolated gastrinomas are best treated with
surgical resection
 In patients with metastatic or unresectable gastrinomas,
massive acid hypersecretion results in peptic ulceration,
erosive esophagitis and malabsorption

4. Explain the drug interaction between antacid/ H2 blocker/PPI and

sucralfate.
Antacid/H2 blocker/PPI  increases the intragastric pH sucralfate cannot
polymerise to form a sticky-like gel over ulcer crater (sucralfate requires
acidic pH to act)  decrease gastric mucosal protective effect of sucralfate

5. List the adverse effects of the following: H2 blockers, PPIs and antacids.
A. Adverse effects of H2 blockers:
 Headache
 Fatigue
 Myalgias
 Diarrhea/constipation
  Confusion, hallucinations, agitation
Note-
 H2 blockers are safe drugs

B. Adverse effects of PPIs:

 Headache
 Abdominal pain
 Diarrhea
 Vitamin B12 malabsorption
Note-
 PPIs are safe drugs
C. Adverse effects of antacids:
 Diarrhea (more common with magnesium containing antacids)
 Constipation (more common with calcium carbonate and
aluminium containing antacids)
 Hypophosphatemia (common with aluminium hydroxide)
 Rebound acidity (more common with sodium bicarbonate)
 Belching (common with sodium bicarbonate and calcium
carbonate)
 Milk-alkali syndrome- hypercalcemia, renal insufficiency and
metabolic alkalosis (common with sodium bicarbonate and calcium
carbonate if given along with milk)
6. Explain the rationale for using antacid combinations in acid peptic
disease.
A combination of two or more antacids is frequently used. These may be
superior to any single agent on the following basis –
 Fast (magnesium hydroxide) and slow (aluminium hydroxide) acting
components prompt as well as sustained effects
  Magnesium salts are laxative, while aluminium salts are constipating;
combination may counteract each other’s action and bowel movement
may be least affected
 Dose of individual components is reduced; systemic toxicity is
minimized

7. Describe the US-FDA approved triple drug regimen for H. pylori

eradication.
 Peptic ulcer, although a multifactorial disease, also occurs due to
colonization of duodenal mucosa by a gram negative bacillus
Helicobacter pylori
US-FDA approved triple drug regimen for H. pylori eradication:
 Lansoprazole 30 mg/omeprazole 20 mg + amoxicillin 1000
mg/metronidazole 500 mg + clarithromycin 500 mg, all given twice daily
for two weeks
 The above regimen has achieved high eradication rate
 For large ulcers (> 10 mm in diameter) or those complicated by
bleeding/perforation, the PPI should be continued till complete healing
occurs
 MODEL QUESTIONS
1. Mention groups of drugs with examples for each which inhibit gastric acid
secretion.
2. List mucosal protective drugs.
3. Explain the mechanism of action of following group of drugs in acid peptic
disease:
a. H2 blockers
b. Proton pump inhibitors
c. Antacids
d. Prostaglandin analogues
4. Explain the therapeutic uses of H2 blockers and proton pump inhibitors with
their pharmacological basis.
5. Explain the drug interaction between antacid/ H2 blocker/PPI and sucralfate.
6. List the adverse effects of antacids and H2 blockers
7. Explain the rationale for using antacid combinations in acid peptic disease.
8. Describe the US-FDA approved triple drug regimen for H. pylori
eradication.