DRUGS USED IN

PEPTIC ULCER DISEASE (PUD)

Prof. Dr. Rokhsana Dil Afroz

Professor & Head
Dept. of Pharmacology
Physiology of HCl secretion
In Gastric antrum

(+)
• Vagus & dietary peptide Gastrin
(-)

(-)
• Somatostatin Gastrin

(+)

Excess of luminal H+ in antrum

Physiology of HCl secretion
In Fundus

(+)
• Gastrin & vagus Parietal cell

(+)

• ECL cell Histamine H/K pump

H+ secretion
Aggressive factors for PUD:
• Acid secretion by the stomach
Three main stimuli : - Gastrin, Histamine
and Acetylcholine ( vagal stimuli)
• Helicobacter pylori (colonization of stomach
by H. Pylori is seen all patient’s with
duodenal ulcer and 70–80% of those with
gastric ulcer)
• NSAIDs
• Smoking
 Pathogenesis
• Acid Pepsin vs. mucosal defense
Exaggerated acid Impaired mucosal
secreation in resistance result
response to vs. from a combination
Stimulation by of [Link], NSAIDs
Gastrin & [Link] & smoking
Drugs used in PUD:
A) Acid neutralizers:
Absorbable antacids: -
▪ Sodium Bicarbonate
Non-absorbable antacids: -
▪ Calcium Carbonate
▪ Magnesium Hydroxide/Tricilicate
▪ Aluminum Hydroxide
Cont…
B) Inhibitors of acid secretion: -
a) H2 receptor antagonist : -
1 . Cimetidine
2 . Ranitidine
3 . Famotidine
4 . Nizatidine
Cont…
b) Proton pump inhibitors
1 . Omeprazole
2 . Lansoprazole
3 . Esomeprazole
4 . Pentoprazole
5 . Rabeprazole

c) Antimuscarinic :
Pirenzepine (used formerly, now obsolete)
Cont…
C) Drugs inhibit H . Pylori : -
1 . Clarithromycin
2 . Amoxicillin
3 . Tetracycline
4 . Metronidazole
D) Cytoprotective / Mucosal protective agents: -
1 . Sucralfate
2 . Prostaglandin analogs – Misoprostol
3 . Colloidal bismuth compound –
a) Bismuth subsalicylate
b) Bismuth subcitrate
c) Bismuth dinitrate
4 . Carbenoxolone (used formerly, now obsolete)
Site of drug action
 Acid neutralizers
• Absorbable or systemic antacids :-
Sodium Bicarbonate (NaHCO3):
It neutralize gastric HCl rapidly but readily
absorbs from gut. Thus it cause –
 Rebound acidity
 Alteration of blood PH ( Metabolic alkalosis)
 Distention &belching due to CO2 production
Mechanism of acid neutralization
 Non-absorbable antacids
Calcium carbonate :-
• React with HCl at a slower rate
• Also cause belching and Metabolic alkalosis
Mechanism of acid neutralization
 Non-absorbable antacids
Magnesium Hydroxide & Aluminum
Hydroxide:-
• Preferred above all because they do not
produce gas or belching
• Metabolic alkalosis is also uncommon
• Unabsorbed Magnesium salts cause osmotic
diarrhoea and Aluminum cause constipation
– thus combination of both counter each
other’s adverse effects
 Simethicone
• Simethicone, a silicon polymer, reduce
surface tension, sometimes included in many
antacid preparations.
• By preventing 'foaming', they can relieve
bloating and flatulence. It allows the small
bubbles of froth to coalesce into large
bubbles which can more easily be passed up
from the stomach or down from the colon.
 Acid secretion inhibitors
H2 receptor blockers :-
• Cimetidine is the prototype drug of this
family. It is not used now a days because of
its adverse effects.
• They are rapidly absorbed from intestine
• Undergo first pass metabolism
• T ½ ranges 1.1 - 4 hrs
 Mechanism of action
(+)
• ECL cell Gastrin & Vagus
secreat
• Histamine
bind with
• H2 receptor on parietal cell

• cAMP dependent pathway

• Inhibition of H/K pump

 Indications of H2 receptor blocker
• Gastro-esophagial reflux disease
• Peptic ulcer disease
• Nonulcer dyspepsia
• Prevention of bleeding from stress related
gastritis
 Adverse effects
• H2 blockers are extremely safe drugs
• Adverse effects occur in <3% pts which
include diarrhoea, headache, fatigue,
myalgias and constipation
• Confusion, hallucination, agitation may occur
with i/v drug in ICU pts and with Cimetidine.
• They rarely cause blood dyscrasias
Cont…
• Cimetidine inhibit DHT to androgen receptor,
inhibit metabolism of estradiol & ↑
Prolactine level. Thus in prolong use cause
gynecomastia or impotence in men and
galactorrhea in women
• Rapid i/v infusion cause bradicardia and
hypotension . So it is given over 30mi.
 Cont…
• They have no known teratogenicity, but it
cross BPB and secret in milk so no advised in
pregnant and lactating mother.
• Cimetidine is important enzyme inhibitor.
Others have less or negligible inhibitor effect.
• They compete with creatinin and certain
drugs like Procainamide for renal tubular
secretion.
 Proton Pump Inhibitors
• Introduced in late 1980
• Administered as an inactive prodrug
• To make it acid stable enteric coated capsule
or tablet preparation is available
• Absorbed from intestine
• Food hampers absorption so preferably
administered in empty stomach 1 hr before
meal.
Cont…
• After absorption the drug concentrate in
parietal cell canaliculi where it is converted
into active form – thiophilic Sulfenamide,
forms covalent bond with PP and irreversibly
block it.
• Drugs have short t ½ -1.5hrs but PP inhibition
persists upto 24hrs.
• Undergo rapid first pass metabolism and
negligible renal clearence, so no need for
dose reduction in renal insufficiency.
PPI
Structure and M/A of PPI
 Indications of PPI
1. Gastro –oesophagial reflux disease
2. Peptic ulcer disease
3. Erosive gastritis
4. NSAIDs associated ulcer
5. Prevention of peptic ulcer bleeding and
stress related mucosal bleeding
6. Non ulcer dyspepsia
7. Zollinger Ellison syndrome, Gastrinoma and
other hypersecretory conditions
 Adverse effects
• Extremely safe drug
• Diarrhoea, headache and abdominal pain
reported in 1-5% pts
• No teratogenicity reported in animal model,
however safety during pregnancy has not
established
• Vit –B12 and food bound minerals (non
haem iron, insoluble Ca & Mg) absorption is
hampered
Cont…
• Increase in gastric bacterial concentration
• Increased risk of hospital or community
acquired Clostridium difficile infection.
• ↓ed Intragastric acidity → ↑ Gastrin
secretion → Stimulate hyperplasia of ECL
cells → transient hyperacidity and↑
dyspepsia.
• ↑ed gastric inflammation may lead to
atrophic gastritis, intestinal metaplasia which
is a risk factor for adenocarcinoma.
 Why PPI is preferred over H2 blocker?

• H2 receptor blocker inhibit H/K pump via

cAMP dependent pathway
• Ca dependent pathway (stimulated by
Gastrin and vagus) is still open
• PPI inhibit the final common pathway of HCl
secreation
 Drug interaction
• Decreased acidity may alter absorption of
Ketoconazole, Itraconazole, Digoxin and
Atazanavir.
• Omeprazole inhibit metabolism of Warfarin,
Diazepam and Phenytoin
• Esomeprazole decrease metabolism of
diazepam
• Lansoprazole enhance clearance of
Theophylline.
 Cytoprotective agents
Sucralfate :
• Sucralfate is a salt of sucrose complexed to
sulfated aluminum hydroxide.
• In water or acidic solutions it break down
into sucrose sulfate (strongly negatively
charged) and an aluminum salt, which form a
viscous, tenacious paste.
Cont…
• The negatively charged sucrose sulfate binds
to positively charged proteins in the base of
ulcers or erosion for up to 6 hours.
• The paste form a physical barrier that
restricts further acid-pepsin digestion.
• It also stimulates mucosal prostaglandin and
bicarbonate secretion.
Mechanism of action of Sucralfate
 Cont…
• Less than 3% of intact drug and aluminum is
absorbed from the intestinal tract; the
remainder is excreted in the feces.
• Sucralfate is administered in a dosage of 1 g
four times daily on an empty stomach (at
least 1 hour before meals).
 Indications
• At present, its clinical uses are limited.
• Sucralfate (administered as a slurry through a
nasogastric tube) reduces the incidence of
clinically significant upper gastrointestinal
bleeding in critically ill patients hospitalized
in the intensive care unit.
• Sucralfate is still used for prevention of
stress-related bleeding.
 Prostaglandin analogue
• Prostaglandin and Prostaglandin analogue
Misoprostol have dual effects :-
 Inhibition of acid secreation
 Mucosal protection
• They act Via EP-3 receptors of parietal cells
and superficial epithelial cells
Cont…
• On parietal cell :
Prostaglandin causes inhibition of histamine
mediated cAMP production thus cause
modest inhibition of HCl secreation.
• On superficial epithelial cell : They cause –
i. Stimulate mucous secreation
ii. Stimulate Bicarbonate ion secreation
iii. Enhance mucosal blood flow
Mechanism of action of Misoprostol
 How NSAID cause PUD ?

• NSAIDs inhibit Cox 1 enzyme thereby inhibit

prostaglandin (PGI2) synthesis

• Weakened mucosal barrier

• Aggressive action of acid/pepsin

• Peptic ulcer disease

 H pylori-associated ulcers
• For H pylori -associated ulcers, there are two
therapeutic goals:
to heal the ulcer
to eradicate the organism.
Eradication of Helicobacter pylori
 Triple therapy
1. PPI b.d. for 14days + once/d 4 - 6wks (total)
+
2. Clarithromycin 500 mg b.d. for 14 days
+
3. Amoxicillin 1 g b.d. for 14 days.
or
3. Metronidazole 400 mg b.d. for 14 days.
(in penicillin allergic pts )
Cont…
• ( Metronidazole is added when there is
Penicillin allergy.)
• After completion of triple therapy – PPI
should be continued once daily for a total of
4–6 weeks to ensure complete ulcer healing.
 Sequential treatment
Alternative ‘Sequential treatment’ for 10 days
consisting of –
• Day1– Day5 : a proton pump inhibitor twice daily
plus amoxicillin, 1 g twice daily
• Days6 – Day10 : a proton pump inhibitor twice
daily, plus Clarithromycin, 500 mg twice daily
+
• Tinidazole, 500 mg twice daily
has been shown to be a highly effective
treatment regimen
Role of PPI in H pylori eradication
Proton pump inhibitors promote eradication of
H pylori through several mechanisms:
 direct antimicrobial properties (minor)
 by raising intra-gastric pH—lowering the
minimal inhibitory concentrations of
antibiotics against H pylori.
 NSAID induced peptic ulcers
• In patients with ulcers caused by aspirin or
other NSAIDs - H2 antagonists or PPI provide
rapid ulcer healing so long as the NSAID is
discontinued
• In patients with NSAID-induced ulcers who
require continued NSAID therapy, treatment
is - once- or twice-daily proton pump
inhibitor more reliably promotes ulcer
healing.
 Prevention of recurrence
• Measures that can be taken to prevent
recurrence once peptic ulcer is healed :-
1. Diet – avoidance of hot food and other
foods that cause gastric irritation
2. Avoidance of alcohol intake and & cigarette
smoking
3. Chronic psychological stress should be
relieved
Cont…
4. Avoidance of irrational use of drugs like –
corticosteroid, NSAIDs – if needed should be
administered with H2 blocker / PPI
5. Treatment of disorders like duodeno-gastric
reflux of bile or disorders of gastric empting
6. If H. pylori cannot successfully eradicated
then H2 blockers are given at bed time to
prevent recurrence.