Drugs used in acid peptic disease Pharmacology GIT Drugs used in Git disorders

1. Treatment of acid peptic disease
Drugs to inhibit or neutralize gastric
acid secretion

2. Acid peptic disease
(Erosion or ulceration of the mucosal lining of the GIT)
• Peptic ulcers – gastric or
duodenal ulcers
• GERD/ Heartburn
• Nonulcer dyspepsia
• Acute stress ulcers
• Zollinger Ellison syndrome

3. Mucosal damaging
Mucosal protecting

4. The genesis of peptic ulcer
An imbalance between the mucosal
Protecting agents
•Mucus
•Bicarbonate
•PG E2 & I2 &
• nitric oxide
Damaging
• Acid
• pepsin
• Infection of
gastric mucosa --
Helicobacter
pylori

5. Regulation of gastric secretion
Secretagogues
• 3 endogenous
secretagogues for acid
• Gastrin
• Acetylcholine
• Histamine (local
hormone)
Protection
• PG E2 & I2
• Inhibit acid
• Stimulate mucus
and bicarbonate
secretion, &
• Dilate mucosal
blood vessels

10. Acid is secreted from gastric parietal cells
by a proton pump (K+/H+ ATPase)

11. M1 ----Vagal
ganglion cells

12. M3 --- Gq

13. Drugs for acid peptic disease
• Antacids
• Proton pump inhibitors (PPI)
• H2 blockers
• M1 selective inhibitors (Pirenzipine)
• Mucosal protective agents – Misoprostol,
Sucralfate, Bismuth compounds
• Antibiotics --- Anti H. pylori drugs

14. Antacids
orally --- Gels, suspensions, tablets
• Weak bases -- Neutralize gastric acid by
chemical antagonism – react with gastric
acid to form water & a salt
• ↑ pH to greater than 4
–One dose given 1 hr after food neutralizes
the acid for 2 hrs
–Reduce the activity of peptic enzymes,
which practically ceases at pH 5

15. Antacids
Systemic
• Absorbed, large &
frequent doses may
produce systemic
alkalosis
• Sodium bicarbonate
(baking soda),
sodium citrate
• Calcium carbonate
Non-systemic
• Not absorbed & do not
produce systemic
alkalosis
• Magnesium
hydroxide,
Mag-trisilicate
• Aluminum
hydroxide gel

16. Alginate or simeticone
• Sometimes combined with antacids
• Alginate --- ↑ viscosity & adherence of mucus
to the esophageal mucosa forming a
protective barrier
• Simeticone --- a surface active compound
that by preventing “foaming”, can relieve
bloating & flatulence

18. Antacids – clinical uses
•Dyspepsia
•Symptomatic relief in
peptic ulcer or
•(alginate) esophageal reflux
• Healing of duodenal ulcer but are less
effective for gastric ulcers

19. Non-systemic antacids
• Magnesium hydroxide, Mag-trisilicate
– Quick and prolong action
– Rebound acidity is mild
– Osmotic purgative --- mild diarrhoea
• Aluminum hydroxide gel
– Slow acting
– Binds phosphate and prevent its absorption –
hypophosphatemia
– Delays gastric emptying -- constipating

20. Systemic Antacids
• Sodium bicarbonate (baking soda) –
– Action is rapid but short acting (NaCl+Co2) -- CO2
is released – escapes as eructation -- (gastric
distension & belching)
• Calcium carbonate –
– less soluble & reacts more slowly than
bicarbonate -- (CO2 + CaCl2)
– Constipation & hypercalcemia

21. Systemic Antacids are Not
recommended for long term use
• Rebound hyperacidity as gastrin level ↑ due
to raised gastric pH
• Systemic alkalosis
• Milk Alkali Syndrome -- Excessive NaHCO3 or
CaCo3 with Ca++ containing dairy products can
lead ---hypercalcemia, renal
insufficiency& metabolic alkalosis

22. Interaction with drugs --- absorption
• By binding the drugs or By ↑ing intra
gastric pH – weak basic or acidic drugs
• Should not be given within 2
hours of the dose of ---
Tetracycline, Fluoroquinolone,
Itraconazole and Iron

23. Antacids are given in combination
• Quick and prolong effect
– Fast acting Mg(OH)2 and slow acting Al (OH)3
• Neutralizing side effects
– Mg salts cause diarrhoea while Al salts cause
constipation
• Gastric emptying
– Mg salts hasten while Al salts delay gastric
emptying

24. Proton pump inhibitors (PPI)
• Omperazole
• Esomeprazole (isomer of
omperazole)
• Lansoprazole
• Pantoprazole
• Rabeprazole

26. PPI -----specific effect on parietal cells
• Covalent , PPI irreversibly inhibit the
H+/K+ ATPase (the proton pump)
• Both basal & stimulated gastric acid secretion
is reduced
• It has specific effect on parietal cells
– Lipophilic weak base, and accumulates in the acid
environment of the canaliculi (>1000 fold) of the
stimulated parietal cells where it is activated

27. PPI -----specific effect on parietal cells
• Covalent , PPI irreversibly inhibit the
H+/K+ ATPase (the proton pump)
• Both basal & stimulated gastric acid secretion
is reduced
• Lipophilic weak base, and accumulates in the
acid environment of the canaliculi (>1000 fold)
of the stimulated parietal cells where it is
activated

30. PPI --- clinical uses
• GERD ----- Reflux esophagitis
• Peptic ulcer -Ulcers refractory to H2RB
• Reduce gastric damage induced by
NSAIDS therapy (more effective than H2
blockers)
• Prevention of stress related gastric
mucosal bleeding

31. PPI --- clinical uses
• As one of the component of therapy
for Halicobacter Pylori infection
• Zollinger-Ellison syndrome (a
rare condition caused by gastrin-
secreting tumours)

32. PPI --- adverse effects -- uncommon
• Diarrhea, abdominal pain in 1-5%
• Headache, Dizziness, somnolence, mental
confusion, impotence, gynecomastia, and pain
in muscles and joints
• Reduction of acid secretion may permit
bacterial overgrowth
– ↑ risk of pneumonia
– A small ↑ in risk of enteric infection- clostridium
difficile infection

33. PPI --- adverse effects -- uncommon
• To be used with precaution ---
Pregnancy or lactating mother, liver
disease
• PPI may mask the symptoms of
gastric cancer
• Hypochlorhydria

34. Hypochlorhydria
• Prolong suppression of gastric acid
• Nutritional -- may result in ↓vitamin B12
• secondary hypergastrinemia -- ↑ed
incidence of gastric carcinoid tumor in
animals
• Routine monitoring of serum gastrin level
not recommended in patients taking
prolong PPI therapy

35. PPI --- drug interaction
• ↓ed acidity may alter absorption of drugs ---
ketoconazole, and digoxin
• Omperazole inhibit the metabolism of
coumarin, diazepam, Phenytoin, cyclosporin
• Drug interaction is not a problem with other
PPI

36. PPI --- pharmacokinetics
• It is degraded rapidly at low pH
– Oral formulation is enteric coated to prevent
inactivation in stomach / IV
– Capsule containing enteric coated granules. It is
absorbed and, from blood, passes into the parietal
cells, then into the cannanuli
• t ½ -- about 1 hour, a single dose affects acid
secretion for 2-3 days, because it accumulates in
cannanuli
• Inhibits H+/K+ ATPase irreversibly

37. Receptors for histamine --H1, H2, H3, H4
• H1-receptors – in smooth muscles
– Bronchoconscriction
– Vasodilatation & ↑ capillary permeability
• H2 receptors -- Gs coupled receptors ---
adenylyl cyclase -- ↑ intracellular cAMP
• Mediate gastric acid secretion in stomach
• (H2 ) Not clinically significant
– Cardiac stimulant effect
– ↓ histamine release from mast cells (–Ve feedback effect)
• H3 & H4 receptors not important pharmacology

40. Histamine H2 antagonists (H2 blockers)
• Cimetidine
• Ranitidine
• Famotidine
• Nizatidine
• --- roxatidine, loxatidine

41. Histamine H2 antagonists (H2 blockers)
• These drugs do not resemble antihistamines
structurally
• Highly selective and do not affect H1
receptors
• Act as competitive inhibitors (surmountable
pharmacologic blockade) at the parietal cell H2
receptors, resulting in marked ↓ in gastric
acid secretion

43. Histamine H2 antagonists (H2 blockers)
• Block 90% of nocturnal acid secretion
– Very effective since it is mainly mediated by
histamine
– Nocturnal & fasting pH raised to 4-5
• For meal stimulated acid release,
– Not as useful and have a modest effect, since this
process is stimulated by gastrin & Ach as well as
histamine
– Block only 60-80% of day time secretion

44. H2 blockers – clinical uses
• Peptic ulcer disease
– Due to their superior acid inhibition and safety profile
PPI has largely replaced H2 blockers
• No significant role in H pylori
eradication therapy
• NSAIDS induced ulcer
– Provided rapid ulcer healing as long as the NSAID is
discontinued
– If NSAIDS must be continued, PPI is preferred for
ulcer healing

45. H2 blockers – clinical uses
• Nonulcer dyspepsia --- Available as
OTC product
• Prevention of bleeding from stress-
related gastritis
–I/V
–pH is to be maintained higher than 4

46. H2 blockers – adverse effects
• Extremely safe drugs -- < 3 % -- diarrhoea,
headache, fatigue, myalgia, and constipation
• More common with cimetidine
• CNS -- Mental status changes – confusion,
hallucinations, agitation – in elderly, renal and
hepatic dysfunction or after I/V injection

47. Endocrine effects –
specific to cimetidine
• Inhibits binding of
dihydrotestosterone in androgen
receptors,
• Inhibit metabolism of estradiol, &
• ↑ serum prolactin level
• Gynecomastia or impotence in male and
galactorrhea in women

48. H2RA
• Not to be given in pregnancy
• Secreted in breast milk
• Rarely cause blood dyscrasias
• I/v injection ---May cause
bradycardia & hypotension --
blockade of H2 cardiac receptors –
not significant clinically

51. Anticholinergic (antimuscarinic)
•M3 receptors antagonists --
obsolete
• Atropine, Methylscopolamine, Propentheline
– most sensitive to atropine are salivary, bronchial,
& sweat glands
– Secretion of acid by gatric parietal cells is least
sensitive

52. Anticholinergic (antimuscarinic)
•M1 selective inhibitors
Pirenzepine,
Telenzepine
• Block excitatory M1 receptors on
vagal ganglion cells innervating the
stomach

55. Drugs for acid peptic disease
• Antacids
• Proton pump inhibitors (PPI)
• H2 blockers (H2RA)
• M1 selective inhibitors --- Pirenzipine
• Mucosal protective agents – sucralfate,
misoprostol, bismuth compounds
• Antibiotics --- Anti H. pylori drugs

56. Misoprostol ( PG E1 analog)
• Cytoprotective effects (PG E2 )
• Produced by the gastric mucosa, inhibit
secretion of HCl & stimulates secretion of
mucus & bicarbonate
• A deficiency in endogenous PG
production (after ingestion of NSAID)
may contribute to ulcer formation

58. Misoprostol ( PG E1 analog)
• ↑ mucosal production & inhibits acid
secretion
• It exert a direct action on parietal cell,
inhibiting the basal secretion of gastric acid as
well as the stimulation of production seen
response to meal, histamine, pentagastrin, &
caffeine
• It also ↑es mucosal blood flow & augments
the secretion of mucus and bicarbonate

59. Misoprostol – clinical uses
• Misoprostol is approved for prevention of
NSAID-induced ulcer
– Peptic ulcer develops in 10-20% of patients who
receive long-term NSAIDs therapy
– Misoprostol reduce the incidence to less than 3%
& incidence of ulcer complication by 50%

60. Misoprostol ---adverse effects
• Not widely used because of
–Need for multiple daily dosing– 3-4
times daily
–Poorly tolerated adverse effects
• Diarrhea & abdominal cramps
• Uterine contraction --- Contraindicated in
pregnancy -- abortifacient

61. mifepristone (RU 486) +
misoprostol

62. Mucosal protective agents
• Coats ulcers & erosions, creating a protective
layer against acid and pepsin
• Sucralfate
• Colloidal bismuth compounds
Bismuth subsalicylate, bismuth
subcitrate, & bismuth dinitrate

63. Sucralfate
• A polysaccharide complexed with Al(OH)2
• It binds to positively charged groups in proteins
of both normal & necrotic mucosa
– has a particular affinity for exposed proteins in the
crater of the duodenal ulcer
• It creates a physical barrier that impairs the
diffusion of HCl & prevent degradation of mucus
by pepsin & acid
• It stimulates mucosal production of PGs and
inhibit pepsin

64. Sucralfate
• It requires an acidic pH for
activation---- it should not be
administered with PPI, H2RA or
antacids
• Must be taken 4 times a day –given
on an empty stomach (at least one
hour before meal)

65. Sucralfate
• For stress related gastritis -- Slightly less effective
than H2 blockers
• Toxicity is very low– not absorbed to have
significant systemic effects. Due to its aluminum
salt
–Constipation in 2% & nausea
–Should not be used for prolong periods
in patient with renal insufficiency
• It can interfere with the absorption of other drugs
by binding to them

66. Colloidal bismuth compounds
• Bismuth subsalicylate, bismuth subcitrate
Potassium
– Bismuth subsalicylate undergoes rapid
dissociation within the stomach allowing
absorption of salicylate
• Over 99% bismuth appears in the stool
• < 1 % of bismuth is absorbed, it is stored in
many tissues and has low renal excretion

67. Colloidal bismuth compounds
• Bismuth salts do not neutralize
stomach acid
• It coats ulcers & erosions,
creating a protective layer
against acid and pepsin
• It may also stimulate PG , mucus
and bicarbonate secretion

68. Colloidal bismuth compounds
• Has direct antibacterial
activity against H pylori
• Prevent & treat travelers
diarrhea -- Direct antimicrobial
effects & bind enterotoxins

69. Bismuth compounds---Clinical uses
• Non specific treatment of dyspepsia
and acute diarrhoea
• Used for prevention of travelers
diarrhea
• Eradication of H pylori --
Tripple therapy regimen

70. Colloidal bismuth compounds--
Adverse effects
• N & V, and blackening of the tongue and
faeces
– Blackening of stools – may be confused with GI
bleeding
– Liquid formulation -- harmless darkening of
tongue
• Should be avoided in renal failure --- < 1 % is
absorbed, stored in many tissues and has low
renal excretion

71. Colloidal bismuth compounds--
Adverse effects
• Bismuth subsalicylate on prolong
therapy (does not occur with B subcitrate
or dinitrate)
–Encephalopathy -- ataxia,
headache, confusion and seizures
–High doses may lead to salicylate
toxicity

72. Helicobacter pylori
• Ulcer ---- Causative agent in the production of
gastric and more particularly, duodenal ulcer
• Gastric Cancer --A risk factor for gastric cancer
• Eradication of H pylori promotes rapid and
long term healing of ulcers – ↓ the rate of
recurrence --- 90% or greater eradication rate
• Triple therapy
• Quadruple therapy

73. Triple therapy
• Twice daily doses – for two weeks
• PPI
• Clarithromycin --- 500 mg
• Amoxicillin (1g) or Metronidazole (500
mg)
• After completion of triple therapy PPI X once
daily for 4-6 weeks to ensure complete ulcer
healing

74. “Sequential treatment”
• 10 days of “sequential treatment”
• Twice daily
• Days 1-5 ---- PPI + Amoxicillin
• Days 6-10 ---- PPI +
Clarithromycin + Tinidazole
(500mg)

75. Quadruple therapy--- 4 drug regimen
• For 10 to 14 days
• PPI twice daily and
• 4 times daily
• Bismuth subsalicylate
(2 tablets of 262 mg each) +
• Metronidazole (500 mg) +
• Tetracycline (250 to 500 mg)

76. Quadruple therapy--- 4 drug regimen
• PPI twice daily and
• 3 capsules 4 times daily X 10 days.
Each capsule contain
• Bismuth subscitrate (140 mg) +
• Metronidazole (125 mg) +
• Tetracycline (125mg )

77. Eradication of H. Pylori infection
•GERD is not associated
with H pylori infection
and does not need
eradication therapy

78. Strategies for treatment / prophylaxis
of NSAID-related mucosal injury
• Use Selective Cox-2 inhibitor
• With NSAIDs use
• antisecretory agents
PPI or H2 RB or
• Prostaglandin E1 analog
Misoprostol

79. GERD/ heart burn
• Antisecretory agents
–PPI are preferred
–H2 RA --- no benefit in 50% of patients,
may not relief symptoms for at least 45
minutes, tolerance can be seen within 2
weeks of therapy
–Antacids more efficiently, but temporarily,
neutralize secreted acid already in the
stomach

80. GERD/ heart burn
• Antisecretory agents +
• Prokinetic agents
–Metoclopromide, domperidone
–Not effective in patients with
erosive esophagitis

81. •What regimen (triple or
quadruple) will you use
to eradicate H pylori in a
patient of GERD?

82. •GERD is not associated
with H pylori infection
and does not need
eradication therapy

83. •Why sucralfate should
not be administered
with H2RD or PPI or
antacids?

84. • Sucralfate requires an acidic
pH for activation ---- it should
not be administered with PPI
H2RA, or Antacids

85. • Which one of the following
drug causes Endocrine effects
and inhibit p 450 system?
• Ranitidine, famotidine,
cemitidine

86. • Endocrine effects – specific to cimetidine
• Inhibits binding of dihydrotestosterone
in androgen receptors, inhibit
metabolism of estradiol, and ↑ serum
prolactin level
• Gynecomastia or impotence in male and
galactorrhea in women

87. •What is the use of
misoprostol other than
mucosal protection?

88. mifepristone (RU 486) +
misoprostol

96. GERD/ heart burn
• Antisecretory agents
– PPI are preferred
– H2 antagonists --- no benefit in 50% of patients, may not relief
symptoms for at least 45 minutes, tolerance can be seen within
2 weeks of therapy
– Antacids more efficiently, but temporarily, neutralize secreted
acid already in the stomach
– Eradication therapy not indicated--- as it is not associated with
H. Pylori infection
• Antisecretory agents + prokinetic agents
• Prokinetic agents
– Metoclopromide, domperidone
– Not effective in patients with erosive esophagitis

106. PPI --- clinical uses
• GERD ----- Reflux esophagitis
• Peptic ulcer
– Ulcers refractory to H2 receptor antgonists
– H pylori associated ulcer
– NSAIDS associated ulcers
• Prevention of stress related gastric mucosal bleeding
• As one of the component of therapy for Halicobacter Pylori
infection
• Zollinger-Ellison syndrome (a rare condition caused by gastrin-
secreting tumours)
• Reduce gastric damage induced by NSAIDS threrapy
– Are more effective than H2 blockers
• More effective than H2 blockers
• Gastrinoma and other hypersecretory conditions

107. Histamine H2 antagonists (H2 blockers)
• Cimetidine, Ranitidine, Famotidine, Nizatidine ------roxatidine, loxatidine
• These drugs do not resemble antihistamines structurally
• Act as competitive inhibitors (surmountable pharmacologic blockade) at
the parietal cell H2 receptors, resulting in marked decrease in gastric acid
secretion
– Histamine is the predominant final mediator that stimulate parietal acid
secretion
– Highly selective and do not affect H1 receptors
• For nocturnal acid secretion,
– Block 90% of nocturnal but
– Very effective since it is mainly mediated by histamine
– Nocturnal and fasting pH raised to 4-5
• For meal stimulated acid release,
– Not as useful and have a modest effect, since this process is stimulated by
gastrin and Ach as well as histamine
– Block only 60-80% of day time secretion

108. Drug interactions H2R
• Page 324 Lippincot

109. Sucralfate
• A polysaccharide complexed with aluminum hydroxide
• Sucralfate binds to positively charged groups in proteins of both normal
and necrotic mucosa
• At gastric pH it produces extensive cross linking and polymerization of
sucralfate
• It has a particular affinity for exposed proteins in the crater of the
duodenal ulcer
• It creats aphysical barrier that impairs the diffusion of HCl and prevent
degradation of mucus by pepsin and acid
• It protects the ulcerated area from further damage and promotes healing
• Sucralfate stimulates mucosal production of prostaglandins and inhibit
pepsin
• Sucralfate requires an acidic pH for activation , it should not be
adminstered with H2 receptor antagonists or antacids
• It can interfere with the absortion of other drugs by binding to them

110. Strategies for treatment of NSAID-
related mucosal injury
• Active ulcer
– NSAID discontinued --- H2 RB or PPI
– NSAID continued --- PPI
• Prophylactic therapy
– Misoprostol
– PPI
– Selective Cox-2 inhibitor
• H.Pylori infection
– Eradication if active ulcer present or there is a past
history of peptic ulcer disease

111. Colloidal bismuth compounds---Clinical
uses
• Non specific treatment of dyspepsia and acute diarrhoea
• Used for prevention of travellers diarrhoea
• Eradication of H pylori
• Tripple therapy regimen
– Bismuth subsalicylate
– Tetracycline
– And metronidazole
– Each taken 4 times daily for 14 days
– Quadruple therapy with resistent infectiontripple trerapy + PPI
twice daily
– Bismuth subcitrate is used instead of bismuth subsalicylate, and
treatment for 7-10 days may be sufficient

112. • Mucosal protective agents
– Sucralfate,
– Bismuth compounds – bismuth subsalicylate &
bismuth subcitrate potassium
– ( colloidal bismuth subcitrate?)
– Prostaglandin analogues
• Misoprostol, rioprostil, enprostil
• Ulcer healing drugs ????
– Carbinoxolone sodium

113. GERD/ heart burn
• Antisecretory agents
– PPI are preferred
– H2 antagonists --- no benefit in 50% of patients, may not relief
symptoms for at least 45 minutes, tolerance can be seen within
2 weeks of therapy
– Antacids more efficiently, but temporarily, neutralize secreted
acid already in the stomach
– Eradication therapy not indicated--- as it is not associated with
H. Pylori infection
• Antisecretory agents + prokinetic agents
• Prokinetic agents
– Metoclopromide, domperidone
– Not effective in patients with erosive esophagitis

114. Antacids
• Systemic – absorbed, large & frequent doses may
produce systemic alkalosis
– Sodium bicarbonate (baking soda) --- NaCl+Co2(
gastric distension & belching), sodium citrate
– Calcium carbonate – less soluble & reacts more slowly
-- (CO2 + CaCl2)
• Non-systemic --- Not absorbed & do not produce
systemic alkalosis
– Magnesium hydroxide, Mag-trisilicate,
– Aluminum hydroxide gel

115. Drugs reducing gastric acid secretion
• Proton pump inhibitors (PPI)
–Omperazole, Esomeprazole (isomer of
omperazole), Lansoprazole,
Pantoprazole, Rabeprazole
• H2 Receptor antagonists (H2 RB)
–Cimetidine, Ranitidine, Famotidine,
Nizatidine ------roxatidine, loxatidine

116. Drugs reducing gastric acid secretion
• Prostaglandin analogues
–Misoprostol
• Anticholinergics (antimuscarinic)
– M3 receptors antagonists ---- obsolete ---Atropine,
methylscopolamine, propentheline
–M1 selective inhibitors ---
Pirenzepine, Telenzepine