1. Drugs used for acid peptic
disease

2. Introduction
 Acid peptic disorders include a number of
conditions whose pathophysiology is believed to
be the result of damage from acid and peptic
activity in gastric secretions.
 It include gastroesophageal reflux, peptic ulcer
(gastric and duodenal), and stress-related
mucosal injury.
 In all these conditions, mucosal erosions or
ulceration arise when the caustic effects of
aggressive factors overwhelm the defensive
factors of the gastrointestinal mucosa

3. Pathogenesis
Therapy is directed at enhancing host defense or
eliminating aggressive factors; i.e., H. pylori.
Aggressive Factors
Defensive Factors
 Acid, pepsin
 Mucus, bicarbonate layer
 Bile salts
 Blood flow, cell renewal
 Drugs (NSAIDs)
 Prostaglandins
 H. pylori
 Phospholipid

4. Imbalance of Factors
Defensive
Factors
Aggressive
Factors

5. Gastric Acid Secretion
 Acid secretion can be viewed as under basal and
stimulated conditions
 Basal acid production occurs in a circardian
pattern with highest levels occurring during night
 Cholinergic and histaminergic inputs are main
contributors to basal acid secretion
 Gastrin (after the meals) is the main stimulant for
increased acid secretion

6. Gastric Acid Secretion (Basal)
Resting
 Proton pumps are
located within
canaliculus and in
Canaliculus
cytoplasmic
tubulovesicles
H+, K+-ATPase  The distribution of
proton pumps between
canaliculus and vesicles
varies according to cell
activity
 Under resting conditions
Tubulovesicles
only 5% pumps are
within canaliculus

7. Gastric Acid Secretion
(Stimulated)
Stimulated
Canaliculus
HCl
H+, K+-ATPase
KCl
H3O+
Gastrin
Ca
KCl
AMP
c
ACh Histamine
Active Pumps
 On stimulation of
parietal cell (after a
meal) 60-70% pumps
are transferred to
canaliculus
membrane.
 Once cell activation
stops, pumps are
recycled back to
cytoplasmic vesicles
 The tubulovesicular
pumps are inactive

8. Regulation of gastric acid secretion at
the cellular level

9. ACh
Histamine
Pirenzepine
H2Blocker
M3
PGE2
Gastrin
H2
-
-
+
+
PPI
+
Misoprostol
-
+
Adenylate
cyclase
-
K-
+
H+
H+
K-
PUMP
H+
Octretide
-

10. Drugs Therapy
1.Drugs which reduce gastric acid secretion
 H2-Receptors antagonists
 Proton pump inhibitors
 Anticholinergics
 Prostaglandin agonists

11. Drugs Therapy
2.Mucosal protective agents
3.Drugs which neutralise gastric
acid(Antacids)
4. Ulcer healing drugs
5.Antibiotics for H. pylori eradication

12. H2-Receptor Antagonists
 Exhibit competitive inhibition at the parietal cell
H2 receptor, and suppress basal and mealstimulated acid secretion in a linear, dosedependent manner.
 The volume of gastric secretion and concentration
of pepsinare also reduced.
 Reduce acid secretion stimulated by histamine as
well as by gastrin and cholinomimetic agents.

13. H2-Receptors Antagonists
 Inhibit 60–70% of total 24-hour acid secretion in
usual prescription doses.
 They block more than 90% of nocturnal acid but
only 60–80% of daytime acid secretion.
 Nocturnal and fasting intragastric pH is raised to
4–5 but the impact upon the daytime, mealstimulated pH profile is less.

14. Clinical Comparisons of H2 Receptor Blockers.
Drug
Relative
Potency
Dose to
Achieve
>50% Acid
Inhibition
for 10 hrs
Dose for
Acute
Duodenal
or Gastric
Ulcer
Dose for
Dose for
Gastro
Prevention of
eosophage Stress-Related
al Reflux
Bleeding
Disease
Cimetidine
1
400–800
mg
800 mg HS
or 400mg
bid
800 mg bid
50 mg/h
Continuous inf
Ranitidine
4-10
150 mg
300 mg HS
or 150 mg
bid
150 mg bid
6.25 mg/h
Continuous inf or
50mg IV every 6–
8h
Nizatidine
4-10
150mg
300 mg HS
or
150mgbid
150 mg bid
Not available
Famotidine
20-50
20mg
40 mg HS
or
20 mg bid
20 mg bid
20 mg IV every
12hr

15. H2-Receptors Antagonists
Pharmacokinetics
 Rapidly absorbed 1-3 hrs to peak
 Ranitidine & Cimetidine hepatically
metabolized whereas Famotidine &
Nizatidine are renally excreted
 Dose adjustment is needed in some renal &
hepatic failure patients

16. H2-Receptors Antagonists
Side Effects
 Usually minor; include headache, dizziness,
diarrhea, & muscular pain
 Hallucinations & confusion in elderly
patients;
 Cimetidine elevates serum prolactin & alters
estrogen metabolism in men
 Gynecomastia or impotence in men and
Galactorrhea in women.

17. H2-Receptors Antagonists
 Although there are no known harmful effects
on the fetus, these agents cross the
placenta.
 Therefore, they should not be administered
to pregnant women unless absolutely
necessary.
 Secreted into breast milk and may
therefore affect nursing infants .

18. PROTON PUMP INHIBITORS
 Most potent suppressors of gastric acid
secretion which act by inhibiting gastric H+,K+ATPase (proton pump)
 In typical doses, these drugs diminish the daily
production of acid (basal and stimulated) by
80% to 95%.
 Five proton pump inhibitors are available for
clinical use: omeprazole and its S-isomer
esomeprazole , lansoprazole, rabeprazole, and
pantoprazole.

19. PROTON PUMP INHIBITORS
 PPI are Pro-drugs - require acidic environment
for activation.
 Activated in acidic canaliculi to sulfenamide,
trapping the drug so that it cannot diffuse back
across the canalicular membrane.
 The activated form then binds covalently with
sulfhydryl groups of cysteines in the H+,K+ATPase, irreversibly inactivating the pump
molecule.
 Acid secretion resumes only after new pump
molecules are synthesized and inserted into
the luminal membrane.

20. PROTON PUMP INHIBITORS
 Provides a prolonged (up to 24 - 48hrs)
suppression of acid secretion, despite the
much shorter plasma half-lives (0.5 - 2 hrs) of
the parent compounds.
 Inhibit both fasting and meal-stimulated
secretion because they block the final
common pathway of acid secretion.
 In standard doses, PPIs inhibit 90–98% of
24-hour acid secretion

21. PROTON PUMP INHIBITORS
Pharmacokinetics.
 Ideally should be given about 30 min before
meals so that the peak serum conc coincides with
the maximal activity of proton pump secretion.
 Rapidly absorbed in the small bowel
 Highly protein bound, and extensively
metabolized by hepatic CYP450, particularly
CYP2C19 and CYP3A4.

22. Clinical Comparisons of PPIs
Agent
Usual Dosage for Maintenance
Peptic Ulcer or
Therapy
GERD
Esomeprazole
20–40 mg qd
20 mg qd
Lansoprazole
30 mg qd
15 mg qd
Omeprazole
20 mg qd
20 mg qd
Pantoprazole
40 mg qd
40 mg qd
Rabeprazole
20 mg qd
20 mg qd

23. PROTON PUMP INHIBITORS
Comparative Anti-secretory Efficacy of the
Different PPIs
 Among different PPIs administered at standard
doses, esomeprazole 40 mg/day has a greater
anti-secretory potency
 Rabeprazole 20 mg/day & lansoprazole 30 mg/day
show a faster action, & slightly greater acid
inhibition capacity than omeprazole 20 mg/day &
pantoprazole 40 mg/day

24. Adverse Effects
 Nausea, abdominal pain, constipation,
flatulence
 Subacute myopathy, arthralgias, headaches,
and skin rashes.
 In some patients continuously taking PPIs, a
mild vitamin B12 deficiency has been seen as the
result of decreased vitamin absorption due to
impaired release of the vitamin from food.

25. ANTICHOLINERGIC DRUGS
 Non selectivePropantheline,Oxyphenonium.
 Selective M1– Pirenzepine,Telenzepine
 Block muscarinic M1 receptors in stomach
inhibiting acid secretion.
 Minimal atropine like side effects on
CVS,GIT or urinary bladder.
 Effectively heal as well as prevent the
recurrence of peptic ulcer.

26. Prostaglandin Agonists
 Misoprostol (PGE1)
 It is a methyl analog of PGE1
 Stimulate secretion of mucus & bicarbonate
 Binds to a prostaglandin receptor on
parietal cells, reducing histamine-stimulated
cAMP production and cause modest acid
inhibition
 Stimulates intestinal electrolyte and fluid
secretion, intestinal motility and uterine
contractions.

27. Misoprostol
Administration
Should be given 4 time/ day
Side effects
Up to 20% develop diarrhea & cramps
 Should not be used during pregnancy.

28. Misoprostol
 Misoprostol reduces the incidence of
NSAID-induced ulcers to less than 3% and
the incidence of ulcer complications by
50%.
 It is approved for prevention of NSAIDinduced ulcers in high-risk patients.

29. Mucosal Protective Agents
 These potentiate the mucosal defensive
mechanisms for the prevention and
treatment of acid-peptic disorders .
 Sucralfate =salt of sucrose complexed to
=
sulfated aluminium hydroxide
 Forms a viscous, tenacious paste in water
or acidic solutions that binds to ulcers or
erosions for up to 6 hours.

30. Sucralfate
Mechanism of action:
 Breaks down into sucrose sulfate (strongly
negatively charged) and an aluminium salt.
 The negatively charged sucrose sulfate binds to
positively charged proteins in the base of ulcers or
erosion, forming a physical barrier that restricts
further caustic damage.
 Stimulates mucosal prostaglandin and bicarbonate
secretion.
 It also bind to epithelial growth factor and
fibroblast growth factor, enhancing mucosal repair.

31. Sucralfate
Administration
 Should not be given with food, give 1hr before or
3hr after meal
Dose: 1gm/ 4times daily or 2 gm/ 2times daily
Side Effects
 Constipation; black stool & dry mouth
 It is very safe in pregnancy

32. Colloidal Bismuth Compounds
 Bismuth subsalicylate
 Bismuth subcitrate
 Bismuth dinitrate

33.  Colloidal bismuth sulfate:
– Water soluble, precipitate at pH less than 5
– PG ↑ mucus secretion & bicarbonate
– Forms glycoprotein complex coats ulcer
– Detaches H.pylori from mucosa, kills directly
– Dose = 120 mg QID

34. Adverse Effects
 Bismuth causes blackening of the stool
 Prolonged usage may rarely lead to bismuth
toxicity resulting in encephalopathy (ataxia,
headaches, confusion, seizures).
 High dosages of bismuth subsalicylate may
lead to salicylate toxicity.

35. ULCER HEALING DRUGS
 Carbenoxolone sodium:
– Steroid like derivative of glycyretenic acid found
in liquorice root
– Augments viscid mucus production
– Prolongs life span of gastric epithelial cells,
prevents bile reflux
– Major problem = mineralocorticoid action so not
used now a days

36. Antacids
 Weak bases that react with gastric acid to
form water & salt (Neutralize acid)
 Also promote mucosal defense
mechanisms through stimulation of mucosal
PG production.
 A single dose of 156 meq antacid given 1 hr
after meal effectively neutralize gastric acid
for 2 hr.

37. Antacids
 Sodium bicarbonate reacts rapidly with
HCl to produce carbondioxide and NaCl.
 Formation of CO2 results in gastric
distention and belching.
 Unreacted alkali is readily absorbed,
potentially causing metabolic alkalosis
when given in high doses or to patients
with renal insufficiency.
 NaCl absorption may exacerbate fluid
retention in heart failure, hypertension,
and renal insufficiency.

38. Antacids
 Calcium carbonate is less soluble and
reacts more slowly than sodium bicarbonate
with HCl to form carbon dioxide and CaCl2
 Excessive doses of either sodium
bicarbonate or calcium carbonate with
calcium-containing dairy products can lead
to hypercalcemia, renal insufficiency, and
metabolic alkalosis(milk-alkali syndrome).

39. Antacids
 Magnesium hydroxide or Aluminum
hydroxide react slowly with HCl to form
magnesium chloride or aluminium chloride
and water.
 No gas is generated, belching does not
occur.
 Unabsorbed magnesium salts may cause
an osmotic diarrhea and aluminium salts
may cause constipation, these agents are
commonly administered together.

40. Antibiotics for H. pylori
eradication
 Many regimens for H. pylori eradication
have been proposed.
 Ideal regimen in this setting should achieve
a cure rate of at least 80%.
 Five important considerations influence the
selection of an eradication regimen

41. Helicobacter pylori

42. Antibiotics for H. pylori
eradication
 1.Combination therapy with two or three
antibiotics (plus acid-suppressive therapy) is
associated with the highest rate of H. pylori
eradication.
 2. A PPI or H2-receptor antagonist significantly
enhances the effectiveness of H. pylori
antibiotic regimens containing amoxicillin or
clarithromycin.
 3. A regimen of 10 to 14 days of treatment
appears to be better than shorter treatment
regimens

43. Antibiotics for H. pylori
eradication
 4. Packaging that combines the daily doses
into one convenient unit is available and
may improve patient compliance .
 5. The emergence of resistance to
clarithromycin and metronidazole
increasingly is recognized as an important
factor in the failure to eradicate H. pylori.

44. Therapy of Helicobacter pylori
 Dual therapy (7-10 days):
 Omeprazole 40mg OD + Clarithromycin 500
mg TDS or
 Ranitidine bismuth citrate 400mg BD
+Clarithromycin 500mg TDS or
 Omeprazole 40 mg OD +Amoxycillin 1g BD.

45. Therapy of Helicobacter pylori
 Triple therapy × 14 days: [PPI +
clarithromycin 500 mg + (metronidazole 500
mg or amoxicillin 1 g)] twice a day.
(Tetracycline 500 mg can be substituted
for amoxicillin or metronidazole.)

46. Therapy of Helicobacter pylori
 Quadruple therapy × 14 days: PPI twice a
day + metronidazole 500 mg three times
daily + (bismuth subsalicylate 525 mg +
tetracycline 500 mg four times daily)
Or
 H2-receptor antagonist twice a day +
(bismuth subsalicylate 525 mg +
metronidazole 250 mg + tetracycline 500
mg) four times daily

47. Adverse Effects
 The most commonly reported adverse events
were nausea, vomiting, & diarrhea
 A bitter or metallic taste in the mouth is associated
with eradication regimens containing
clarithromycin
 Bismuth subsalicylate may cause a temporary
grayish-black discoloration of the stool