This document discusses drugs used to treat gastrointestinal tract disorders. It focuses on drugs for peptic ulcer disease, including proton pump inhibitors which irreversibly block acid production, and H2 receptor antagonists which reversibly compete with histamine. Proton pump inhibitors are more potent but H2 receptor antagonists adequately suppress nocturnal acid secretion. Cytoprotective drugs like misoprostol and sucralfate are also used. The document provides details on the physiology of acid secretion, mechanisms of action, pharmacokinetics, uses and side effects of these drug classes.

1. • Pharmacology of gastrointestinal tract
Drugs for treatment of peptic ulcer
Drug for treatment of constipation
Drugs for treatment of diarrhea
Drugs for treatment of vomiting
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2. Peptic Ulcer Disease
• Acid and pepsin in the stomach normally do not produce
damage because of intrinsic defense mechanisms.
• Barriers to the reflux of gastric contents into the esophagus
comprise the primary esophageal defense
If these protective barriers fail and reflux occurs, dyspepsia
and/or erosive esophagitis may result.
• In the stomach, mucus and bicarbonate, stimulated by the local
generation of PGs, protect the gastric mucosa
If these defenses are disrupted, a gastric or duodenal ulcer
may form. 2

3. • PUD is defined as an imbalance between mucosal defense factors
(bicarbonate, mucin, prostaglandin) and injurious factors (acid
and pepsin).
• On average, patients with duodenal ulcers produce more acid
than do control subjects, particularly at night (basal secretion).
• Although patients with gastric ulcers have normal or even
diminished acid production, ulcers rarely if ever occur in the
complete absence of acid.
 Presumably, a weakened mucosal defense and reduced
bicarbonate production contribute to the injury from the
relatively lower levels of acid in these patients
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4. • H. pylori and NSAIDs interact in complex ways to cause an
ulcer.
• Up to 60% of peptic ulcers are associated with H. pylori infection
of the stomach.
• Topical injury by the luminal presence of the drug appears to
play a minor role in the pathogenesis of these ulcers, as
evidenced by the fact that ulcers can occur with very low doses
of aspirin (10 mg) or with parenteral administration of NSAIDs.
The effects of these drugs are instead mediated systemically; the
critical element is suppression of the constitutive form of COX-1
in the mucosa
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5. • Generally the etiology of PUD :
 increased secretions ( both acid & pepsin )
 reduced mucosal resistance by irritant drugs e.g. Aspirin,
 inflammatory changes or reduced blood Supply
Predisposing factors :
 Heridity & certain genetic factors
 stress, smoking, alcoholic intake, bile reflux
 excessive use of irritant foods, use of irritant drugs ,
inflammatory conditions
 decrease blood supply e.g. By thrombosis
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6. Physiology of acid secretion
• Gastric acid secretion is a complex, continuous process in
which multiple central and peripheral factors contribute to a
common endpoint: the secretion of H+ by parietal cells.
• ACh, histamine, and gastrin all regulate acid secretion through
their specific receptors (M3, H2, and CCK2 receptors,
respectively) on parietal cells.
• In parietal cells, the cAMP and the Ca2+-dependent pathways
activate H+,K+-ATPase, which exchanges H+ and K+ ions across
the parietal cell membrane
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7. 7

8. • ACh released from vagal fibers directly stimulates gastric acid
secretion through M3 receptors on the parietal cells.
• ACh also indirectly affects parietal cells by increasing the
release of histamine and of gastrin in the gastric antrum.
• Enterocromafin like(ECL) cells, the source of gastric histamine
secretion, usually are in close proximity to parietal cells.
• Histamine acts as a paracrine mediator, diffusing from its site
of release to nearby parietal cells, where it activates H2
receptors
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9. • Gastrin, produced by antral G cells, is the most potent inducer
of acid secretion
• Gastrin stimulates acid secretion indirectly by inducing the
release of histamine by ECL cells; a direct effect also plays a
lesser role.
• Somatostatin (SST), produced by antral D cells, inhibits gastric
acid secretion.
• Acidification of the gastric luminal pH to <3 stimulates SST
release, which in turn suppresses gastrin release in a negative
feedback loop.
• SST-producing cells are decreased in patients with H. pylori
infection; may contribute to excess gastrin production. 9

10. Treatment
• Aims of treatment: relieve of symptoms, healing of the ulcer,
prevention of complications
• General measures
• rest in bed (better in hospital)
• light small frequent meals , non irritant foods .
• salty foods should be avoided
• avoid smoking , coffee, tea or alcohol .
• avoid irritant drugs e.g. Aspirin; corticosteroids; Reserpine
• avoid stress
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11. Drug categories
1. Suppressors of gastric acid secretion
a. Proton pump inhibitors
b. H2-receptor antagonists
2. Agents that enhance mucosal defense
a. prostaglandin analogs
b. sulfated polysaccharides
3. Antacids
4. Antibacterial
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12. Proton pump inhibitors(PPI)
• Most potent suppressors of gastric acid secretion.
• Diminish the daily production of acid (basal and stimulated) by
80% to 95%.
• Omeprazole, esomeprazole, lansoprazole, pantoprazole.
• Omeprazole is a racemic mixture of R- and S-isomers;
esomeprazole (S-omeprazole), is eliminated less rapidly than R-
omeprazole, which theoretically provides a therapeutic
advantage because of the increased half-life.
• After absorption , the prodrug diffuses into the parietal cells of
the stomach and accumulates in the acidic secretory canaliculi
where it is activated.
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13. 13

14. Pharmacological effects
• The activated form binds covalently with H+,K+-ATPase,
irreversibly inactivating the pump molecule.
• Acid secretion resumes only after new pump molecules are
synthesized and inserted into the luminal membrane,
providing a prolonged (24-48hrs) suppression of acid
secretion, despite the much shorter plasma half-lives (0.5-2 hrs)
of the parent compounds.
• Because they block the final step in acid production, the PPIs
are effective in acid suppression regardless of other
stimulating factors.
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15. Pharmacokinetics
• To prevent degradation of proton pump inhibitors by
acid in the gastric lumen, oral dosage forms are
supplied in different formulations. E.g. enteric-
coating, combining with NaCO3.
• Rapidly absorbed, highly protein bound, and
extensively metabolized by hepatic CYPs, particularly
CYP2C19 and CYP3A4.
• Chronic renal failure does not lead to drug
accumulation with once-a-day dosing of the proton
pump inhibitors.
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16. Adverse Effects and Drug Interactions
• The most common side effects are nausea, abdominal pain,
constipation, flatulence, and diarrhea.
• Sub acute myopathy, arthralgias, headaches, and skin rashes
also have been reported.
• Proton pump inhibitors are metabolized by hepatic CYPs and
therefore may interfere with the elimination of other drugs
cleared by this route.
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17. Therapeutic Uses
• PUD(Gastric and duodenal ulcers)
• Gastroesophageal reflux disease (GERD)
• Zollinger-Ellison syndrome.
• In addition, all PPIs are FDA approved for reducing the risk of
duodenal ulcer recurrence due to H. pylori infections.
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18. H2-receptor antagonists
• Inhibit acid production by reversibly competing with
histamine for H2 receptors on the parietal cells.
• Cimetidine, ranitidine, famotidine, nizatidine.
• Less potent than PPIs but still suppress 24-hr gastric acid
secretion by about 70%.
• Predominantly inhibit basal acid secretion, which accounts for
their efficacy in suppressing nocturnal acid secretion
• Because the most important determinant of duodenal ulcer
healing is the level of nocturnal acidity, evening dosing of H2-
receptor antagonists is adequate therapy in most instances.
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19. Pharmacokinetics
• Rapidly absorbed after oral administration, with peak
concentrations achieved within 1-3 hrs.
• Therapeutic levels are achieved rapidly after IV dosing and are
maintained for 4-5 hrs (cimetidine), 6-8 hrs (ranitidine), or 10-12
hrs (famotidine).
• Unlike PPIs, only a small percentage are protein-bound.
• Small amounts (from <10% to ~35%) of these drugs undergo
metabolism in the liver.
• Excreted (unchanged and metabolites) by filtration and renal
tubular secretion, and it is important to reduce dose in patients
with decreased creatinine clearance
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20. Adverse Reactions and Drug Interactions
• Side effects usually are minor and include diarrhea, headache,
drowsiness, fatigue, muscular pain, and constipation.
• Long-term use of cimetidine at high doses cause galactorrhea in
women and gynecomastia, reduced sperm count, and impotence
in men.
• Several reports have associated H2-receptor antagonists with
various blood dyscrasias e.g thrombocytopenia.
• Cimetidine inhibits CYPs (e.g., CYP1A2, CYP2C9, and CYP2D6)
• Ranitidine interferes minimally with hepatic metabolism of other
drugs. Famotidine and nizatidine are with no significant drug
interactions.
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21. Therapeutic Uses
• The major therapeutic indications for H2-receptor
antagonists are
to promote healing of gastric and duodenal ulcers
 to treat uncomplicated GERD
 to prevent the occurrence of stress ulcers.
• Tolerance to the acid-suppressing effects of H2-receptor
antagonists is well described and may account for a
diminished therapeutic effect with continued drug
administration.
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22. Cytoprotective Agent
a. Misoprostol
• A synthetic analog of prostaglandin E1
• The usual recommended dose for ulcer prophylaxis is 200 mg
four times a day.
• Diarrhea, with or without abdominal pain and cramps, occurs in
up to 30% of patients who take misoprostol.
• Can cause clinical exacerbations of inflammatory bowel disease
and should be avoided such cases.
• Contraindicated during pregnancy.
• FDA approved to prevent NSAID-induced mucosal injury.
• Lansoprazole also holds an FDA approved indication for this
purpose.
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23. b. Sucralfate
• Consists of the octasulfate of sucrose to which Al(OH)3 has
been added.
• At pH <4, it undergoes extensive cross-linking to produce a
viscous, sticky polymer that adheres to epithelial cells and
ulcer craters for up to 6 hours.
• Inhibit hydrolysis of mucosal proteins by pepsin.
• May have additional cytoprotective effects like stimulation of
local production of PGs.
• Should be taken on empty stomach 1 hour before meals.
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24. • Binds bile salts so used to treat syndromes of biliary
esophagitis or gastritis
• Offer an advantage over PPIs and H2-receptor antagonists
for the prophylaxis of stress ulcers
• The most common side effect is constipation.
• It may inhibit absorption of phenytoin, digoxin, cimetidine,
ketoconazole, and fluoroquinolones.
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25. c. Bismuth compounds
• May be as effective as cimetidine in patients with peptic ulcers
and are frequently prescribed in combination with antibiotics
to eradicate H. pylori and prevent ulcer recurrence.
• Bind to the base of the ulcer, promote mucin and bicarbonate
production, and have significant antibacterial effects.
• An important component of many anti-Helicobacter regimens
• The availability of more effective drugs, bismuth compounds
seldom are used alone as cytoprotective agents.
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26. Antacids
• Although respected by tradition, they largely have been
replaced by more effective and convenient drugs.
• Many factors, including palatability, determine the
effectiveness and choice of antacid.
• NaCO3 effectively neutralizes acid, but it is very water-soluble
and rapidly absorbed from the stomach, and the alkali and
sodium loads may pose a risk for patients with cardiac or renal
failure.
• CaCO3 rapidly and effectively neutralizes gastric H+, but the
release of CO2 from bicarbonate- and carbonate-containing
antacids can cause belching, nausea, abdominal distention, and
flatulence. 26

27. • Combinations of Mg2+ (rapidly reacting) and Al3+ (slowly
reacting) hydroxides provide a relatively balanced and
sustained neutralizing capacity.
• Fixed combinations of magnesium and aluminum theoretically
counteract the adverse effects of each other on the bowel.
• The relative effectiveness of antacid preparations is expressed
as mEqs of acid-neutralizing capacity
• According to FDA requirements, antacids must have a
neutralizing capacity of at least 5 mEq per dose.
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28. • For uncomplicated ulcers, antacids are given orally 1-3 hours
after meals and at bedtime. For severe symptoms or
uncontrolled reflux, antacids can be given as often as every 30
to 60 minutes.
• In general, antacids should be administered in suspension form,
as this probably has a greater neutralizing capacity than do
solid dosage forms.
• Otherwise, they should be thoroughly chewed for maximum
effect.
• Cleared from the empty stomach in about 30 minutes. However,
the presence of food prolongs the neutralizing effects of
antacids for about 2-3 hrs.
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29. • With normal renal function, the modest accumulations of Al3+
and Mg2+ do not pose a problem; with renal insufficiency,
however, absorbed Al3+ can contribute to osteoporosis,
encephalopathy, and proximal myopathy.
• Al3+ and Mg2+ antacids also are notable for their propensity to
chelate other drugs.
• Most interactions can be avoided by taking antacids 2 hrs before
or after ingestion of other drugs.
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30. Treatment of Helicobacter pylori Infection
• H. pylori, a gram-negative rod, has been associated with
gastritis and the subsequent development of gastric and
duodenal ulcers.
• Eradicating H. pylori infection is standard care in patients with
gastric or duodenal ulcers.
• Many regimens for H. pylori eradication have been proposed.
Evidence-based literature review suggests that the ideal
regimen in this setting should achieve a cure rate of at least
80%.
• Amoxicillin, tetracycline, clarithromycin, metronidazole.
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31.  Five important considerations influence the selection of an
eradication regimen.
1. Single-antibiotic regimens are ineffective in eradicating H.
pylori infection and lead to microbial resistance. Combination
therapy with two or three antibiotics 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.
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32. 4. Poor patient adherence is linked to the medication-related
side effects and to the inconvenience of three- or four-drug
regimens administered several times per day. Packaging that
combines the daily doses into one convenient unit may
improve patient adherence.
5. The emergence of resistance to clarithromycin and
metronidazole increasingly is recognized. Amoxicillin should be
used instead of metronidazole in such cases. Moreover, a 14-
day, quadruple-drug regimen (three antibiotics combined with
a proton pump inhibitor) generally is effective therapy.
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33. • First Line:
• Amoxicillin (1g, p.o. 2×/d) + Clarithromycin, (500mg p.o.
2x/d) + Omeprazole, 20mg p.o. 2x/d (or 40mg once daily) =
all for 7 - 14 days
• Alternatives:
• Amoxicillin (1g, p.o. 2x/d) + Metronidazole (500mg, p.o.
2x/d) + Omeprazole (20 mg p.o. 2x/d or 40 mg once daily),
all for 7 - 10 days.
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34. Others
• M1 receptor antagonists :
Pirenzepine,Telenzepine
• Reversible inhibitors of the gastric H+,K+-ATPase:
AKU517, Revaprazan hydrochloride (YH-1885)
• Antagonists of the CCK2 gastrin receptor on parietal cells
also are under study
• Carbenoxolone: alter mucin content (cytoprotective)
Antiflatulent
• "Gas" is a common but relatively vague GI complaint, used
in reference not only to flatulence and eructation, but also
bloating or fullness.
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35. • Simethicone: a mixture of siloxane polymers stabilized with
silicon dioxide.
• It is an inert, nontoxic insoluble liquid. Because of its ability to
collapse bubbles by forming a thin layer on their surface, it is
an effective antifoaming agent.
• Although it may be effective in diminishing gas volumes in
the GI tract, it is not clear whether this accomplishes a
therapeutic effect.
• Available either by itself or in combination with other OTC
medications including antacids and digestants.
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