The document discusses anti-ulcer drugs and the physiology of the gastrointestinal tract. It provides details on: 1) The neuronal and hormonal control of the GI tract, including the enteric nervous system and hormones like gastrin and somatostatin. 2) The regulation of acid secretion by parietal cells and mediators like histamine, acetylcholine, and prostaglandins. 3) The pathophysiology of peptic ulcers involving an imbalance between aggressive factors like acid and protective mucosal defenses. Common causes include H. pylori infection and NSAID use. 4) Approaches for treating peptic ulcers including reducing acid with H2 blockers or

1. Anti ulcer drugs
SUBMITTED BY
KAVYA RAVEENDRAN
M-PHARM PHARMACOLOGY

2. Physiology of gastro intestinal tract

3. THE INNERVATION ANDHORMONES OF THE GASTROINTESTINALTRACT
The blood vessels and the glands of the GIT are under both neuronal and hormonal
control.
Neuronal control
There are two principal intramural plexuses in the tract:
• Myenteric plexus (auerbach’s plexus) : lies between the outer, longitudinal and the
middle, circular muscle layers,
• Submucous plexus (meissner’s plexus) : lies on the lumenal side of the circular
muscle layer.
These plexuses are interconnected and their ganglion cells receive preganglionic
parasympathetic fibres from the vagus.

4. • These are mostly cholinergic and excitatory, although a few are inhibitory.
• The neurons within the plexuses constitute the enteric nervous system and secrete not
only acetylcholine and noradrenaline (norepinephrine), but also 5-hydroxytryptamine
(5-HT), purines, nitric oxide and a variety of pharmacologically active peptides .
• The enteric plexus also contains sensory neurons, which respond to mechanical and
chemical stimuli.

5. HORMONAL CONTROL
The hormones of then gastrointestinal tract include both endocrine and paracrine
secretions.
 The endocrine secretions : peptides synthesized by endocrine cells in the mucosa. Eg:
gastrin and cholecystokinin.
 The paracrine secretions : many regulatory peptides released from special cells found
in the wall of the tract. These hormones act on nearby cells, and in the stomach the Eg:
histamine.
Some of these paracrine factors also function as neurotransmitters.
 Orally administered drugs are absorbed during their passage through the GIT.
 Other functions of the gastrointestinal tract that are important from the viewpoint of
pharmacological intervention are:
• gastric secretion
• vomiting (emesis) and nausea
• gut motility and defecation
• the formation and excretion of bile.

6. GASTRIC SECRETION
 The stomach secretes about 2.5 liters of gastric juice daily.
 The principal exocrine components are proenzymes such as prorennin and pepsinogen
elaborated by the chief or peptic cells, and HCl and intrinsic factor secreted by the
parietal or oxyntic cells.
 The production of acid is important for promoting proteolytic digestion of foodstuffs,
iron absorption and killing pathogens.
 Mucus-secreting cells also abound in the gastric mucosa.
 Bicarbonate ions are secreted in the mucus, creating a gel-like protective barrier that
maintains the mucosal surface at a pH of 6–7.
 Alcohol and bile can disrupt this protective layer. Locally produced ‘cytoprotective’
prostaglandins stimulate the secretion of both mucus and bicarbonate.
 Disturbances in these secretory and protective mechanisms are thought to be
involved in the pathogenesis of peptic ulcer, and indeed in other types of gastric
damage such as gastro-oesophageal reflux disease (GORD) and injury caused by
NSAIDs.

7. THE REGULATION OF ACID SECERETION BY PARIETAL CELLS
 The secretion of the parietal cells is an isotonic solution of HCl (150 mmol/l) with a pH
less than 1, the concentration of hydrogen ions being more than a million times higher
than that of the plasma.
 To produce this Cl− is actively transported into canaliculi in the cells that communicate
with the lumen of the gastric glands and thus with the stomach itself.
 This is accompanied by K+ secretion, which is then exchanged for H+ from within the
cell by a K+-H+-ATPase
 Within the cell, carbonic anhydrase catalyses the combination of carbon dioxide and
water to give carbonic acid, which dissociates into H+ and bicarbonate ions.
 The latter exchanges across the basal membrane of the parietal cell for Cl−.
 The principal mediators that directly – or indirectly – control parietal cell acid output
are:
• histamine (a stimulatory local hormone)
• gastrin (a stimulatory peptide hormone)
• acetylcholine (a stimulatory neurotransmitter)
• prostaglandins E2 and I2 (local hormones that inhibit acid secretion)
• somatostatin (an inhibitory peptide hormone).

8. HISTAMINE
 Neuroendocrine cells abound in the stomach and the dominant type are the ECL cells
(enterochromaffin-like cells).
 These are histamine-containing cells similar to mast cells, which lie close to the
parietal cells.
 They sustain a steady basal release of histamine, which is further increased by gastrin
and acetylcholine.
 Histamine acts in a H1 receptors, increasing intracellular cAMP.
 These cells are responsive to histamine concentrations that are below the threshold
required for vascular H2 receptor activation.
ACETYLCHOLINE
 Acetylcholine released from postganglionic cholinergic neurons, stimulates specific
muscarinic M3 receptors on the surface of the parietal cells ,thereby elevating
intracellular Ca2+ and stimulating the release of protons.
 It also has complex effects on other cell types; by inhibiting somatostatin release from
D cells, it potentiates its action on parietal cell acid secretion.

9. GASTRIN
 Gastrin is a polypeptide synthesized by G cells in the gastric antrum and secreted into
the portal blood (i.e. it acts in an endocrine fashion).
 Its main action is stimulation of acid secretion by ECL cells through its action at
gastrin/cholecystokinin (CCK) receptors, which elevate intracellular Ca2+.
 Gastrin also stimulates histamine synthesis by ECL cells and indirectly increases
pepsinogen secretion, stimulates blood flow and increases gastric motility.
 Release of this hormone is controlled by both neuronal transmitters and blood-borne
mediators, as well as by the chemistry of the stomach contents.
 Amino acids and small peptides directly stimulate the gastrin-secreting cells, as do
milk and solutions of calcium salts, explaining why it is inappropriate to use calcium-
containing salts as antacids.

10. PROSTAGLANDINS
 Most cells of the gastrointestinal tract produce prostaglandins ,the most important
being PGE2 and I2.
 Prostaglandins exert ‘cytoprotective’ effects on many aspects of gastric function
including increasing bicarbonate secretion ,increasing the release of protective mucin
reducing gastric acid output probably by acting on EP2/3 receptors on ECL cells and
preventing the vasoconstriction that follows injury.
SOMATOSTATIN
 This peptide hormone is released from D cells at several locations within the stomach.
 By acting at its somatostatin (SST) receptor, it exerts paracrine inhibitory actions on
gastrin release from G cells, histamine release from ECL cells, as well as directly on
parietal cell acid output.

13. PATHOPHYSIOLOGY
 A physiologic imbalance between aggressive factors (gastric acid and pepsin) and
protective factors (mucosal defense and repair) remain important issues in the
pathophysiology of gastric and duodenal ulcers.
 Acid secretion is expressed as the amount of acid secreted under basal or fasting
conditions, basal acid output (BAO); after maximal stimulation, maximal acid output
(MAO); or in response to a meal.
 Pepsin is an important cofactor that plays a role in the proteolytic activity involved in
ulcer formation.
 Pepsinogen, the inactive precursor of pepsin, is secreted by the chief cells located in
the gastric fundus .
 Pepsin is activated by acid pH (optimal pH of1.8 to 3.5), inactivated reversibly at pH 4,
and irreversibly destroyed at pH 7.

14.  Mucosal defense and repair mechanisms protect the gastro duodenal mucosa from
noxious endogenous and exogenous substances.
 The viscous nature and near-neutral pH of the mucus-bicarbonate barrier protect the
stomach from the acidic contents in the gastric lumen.
 The maintenance of mucosal integrity and repair is mediated by the production of
endogenous prostaglandins.
 The term cytoprotection is often used to describe this process, but mucosal defense and
mucosal protection are more accurate terms, as prostaglandins prevent deep mucosal
injury and not superficial damage to individual cells.
 This phenomenon enables the stomach to initially withstand the damaging effects of
irritants.
 Alterations in mucosal defense that are induced by H. pylori or NSAIDs are the most
important cofactors in the formation of peptic ulcers.

15. HELICOBACTER PYLORI
 H. pylori is a spiral-shaped, pH-sensitive, gram-negative bacterium that resides
between the mucus layer and surface epithelial cells in the stomach
 spiral shape and flagellum permits it to move from the lumen of the stomach, where
the pH is low, to the mucus layer, where the local pH is neutral.
 The acute infection is accompanied by transient hypo chlorhydria, which permits the
organism to survive in the acidic gastric juice.
 The exact method by which H. pylori initially induces hypochlorhydria is unclear.
 One theory is that H. pylori produces large amounts of urease, which hydrolyzes urea
in the gastric juice and converts it to ammonia and carbon dioxide.
 The local buffering effect of ammonia creates a neutral microenvironment within and
surrounding the bacterium, which protects it from the lethal effect of acid.

16.  H. pylori also produces acid-inhibitory proteins, which allows it to adapt to the low-
pH environment of the stomach.
 Organisms colonize gastric metaplastic tissue in the duodenal bulb, leading to
duodenal ulcer .
Pathogenic mechanisms include :
(a) Direct mucosal damage,
(b) Alterations in the host immune/ inflammatory response, and
(c) Hypergastrinemia leading to increased acid secretion.
(d) In addition, H.pylori enhances the carcinogenic conversion of susceptible gastric
epithelial cells.
(e) Direct mucosal damage is produced by virulence factors (vacuolating cytotoxin,
cytotoxin-associated gene protein, and growth-inhibitory factor), elaborating
bacterial enzymes (lipases, proteases, and urease), and adherence.

17. NON STEROIDAL ANTIINFLAMMATORY DRUGS
Nonselective NSAIDs, including aspirin cause gastric mucosal damage by two important
mechanisms:
(a) direct or topical irritation of the gastric epithelium and injury is initiated topically by
the acidic properties of many of the NSAIDs,
(b) systemic inhibition of endogenous mucosal prostaglandin synthesis.
systemic inhibition of the protective prostaglandins plays the predominant role in the
development of gastric ulcer.
 Cyclooxygenase (COX) is the rate-limiting enzyme in the conversion of arachidonic
acid to prostaglandins and is inhibited by NSAIDs
 Two similar COX isoforms have been identified:
 COX-1 : found in most body tissue, including the stomach, kidney, intestine, and
platelets;
 COX-2 : is undetectable inmost tissues under normal physiologic conditions, but its
expression can be induced during acute inflammation and arthritis
 COX-1 produces protective prostaglandins that regulate physiologic processes such as
GI mucosal integrity, platelet homeostasis, and renal function.

18.  COX-2 is induced by inflammatory stimuli such as cytokines, and produces
prostaglandins involved with inflammation , fever , and pain.
 COX-2 is also constitutionally expressed in organs such as the brain, kidney, and
reproductive tract.
 Adverse effects (e.g., GI or renal toxicity) of NSAIDs are primarily associated with
the inhibition of COX-1, whereas anti inflammatory actions result primarily from
NSAID inhibition of COX-2.
 Nonselective NSAIDs , including aspirin inhibit both COX-1 and COX-2 to varying
degrees resulting in decreased platelet aggregation and prolonged bleeding times ,
thereby increasing the potential for upper and lower GI bleeding .
Other mechanisms may also contribute to the development of NSAID-related mucosal
injury .
 Topical irritant properties are predominantly associated with acidic NSAIDs (e.g.,
aspirin) and their ability to decrease the hydrophobicity of the mucous gel layer in
the gastric mucosa.

20. Imbalance (Aggressive/Defensive Factors)
Aggressive Factors
* H. pylori
* Acid Secretion
* Pepsinogen Secretion
* NSAIDS
* Cigarette smoking
* Corticosteroid use
Defensive Factors
* Mucus Production
* Bicarbonate Production
* Mucosal blood flow - more important in the development of stress ulcer
* High epithelial cell turnover
* Prostaglandins (PGE2) - stimulate mucus and bicarbonate production, and blood
flow

21. TABLE 35-5 Presentation of Peptic Ulcer Disease
General
• Mild epigastric pain or acute life-threatening upper gastrointestinal complications
Symptoms
• Abdominal pain ,burning, abdominal fullness, or cramping
• Nocturnal pain that awakens the patient from sleep (between 12 AM and 3AM)
• Heartburn, belching, and bloating often accompany the pain
• Nausea, vomiting, and anorexia, are more common in patients with gastric ulcer than
with duodenal ulcer, but may also be signs of an ulcer-related complication
Signs
• Weight loss , vomiting, and anorexia
• Complications, including ulcer bleeding, perforation, penetration, or obstruction

22. Laboratory tests
• Gastric acid secretory studies
• Fasting serum gastrin concentrations are only recommended for patients who are
unresponsive to therapy, or for those in whom hyper secretory diseases are suspected
• The hematocrit and hemoglobin are low with bleeding, and stool hemoccult tests are
positive
• Tests for Helicobacter pylori
Other diagnostic tests
• Fiberoptic upper endoscopy (esophagogastroduodenoscopy)
• Routine single-barium contrast techniques detect 30% of peptic ulcers; optimal double-
contrast radiography detects 60% to 80% of ulcers

23. 1. Reduction of gastric acid secretion
(a) H2 antihistamines: Cimetidine,
Ranitidine, Famotidine,
Roxatidine
(b) Proton pump inhibitors:
Omeprazole, Lansoprazole,
Pantoprazole, Rabeprazole,
Esomeprazole
(c) Anticholinergics: Pirenzepine,
Propantheline,
Oxyphenonium
(d) Prostaglandin analogue:
Misoprostol
Approaches for the treatment of peptic ulcer are:
2. Neutralization of gastric acid (Antacids)
(a) Systemic: Sodium bicarbonate, Sod.citrate
(b) Nonsystemic: Magnesium hydroxide,
Mag. trisilicate, Aluminium hydroxide gel,
Magaldrate, Calcium carbonate
3. Ulcer protectives:
Sucralfate, Colloidal bismuth subcitrate(CBS)
4. Anti-H. pylori drugs:
Amoxicillin, Clarithromycin, Metronidazole,
Tinidazole, Tetracycline

24. H2 ANTAGONISTS
These are the first class of highly effective drugs for acid peptic disease.
Cimetidine was the first H2 blocker to be introduced clinically and is described as the
prototype, though otherH2 blockers are more commonly used now.
PHARMACOLOGICAL ACTIONS
1. H2 blockade
 Cimetidine and all other H2antagonists block histamine-induced
 gastric secretion,
 cardiac stimulation ,
 uterine relaxation and
 bronchial relaxation (H2 blockers potentiate histamine induced bronchospasm).
 They attenuate fall in BP due to histamine
They are highly selective: have no effect on H1 mediated responses
2. Gastric secretion
 The only significant invivo action of H2 blockers is marked inhibition of gastric
secretion.
 Secretory responses to not only histamine but all other stimuli are attenuated.

25. PHARMACOKINETICS
Cimetidine is adequately absorbed orally,
Absorption is not interfered by presence of food in stomach.
About 2/3 of a dose is excreted unchanged in urine and bile, the rest as oxidized
metabolites.
The elimination t½is 2–3 hr.
Dose reduction is needed in renal failure.
ADVERSE EFFECTS
• Headache, dizziness, bowel upset, dry mouth,rashes.
• CNS effects like confusional state, restlessness , convulsions and coma in elderly
patients , in those with renal impairment,
• Bolus i.v. injection can release histamine—has caused bradycardia, arrhythmias and
cardiac arrest: it should always be given by slow infusion.

26. USES
1. Duodenal ulcer H2 blockers produce rapid and marked pain relief (within 2–3 days);
2. Gastric ulcer Healing rates obtained in gastric ulcer are somewhat lower (50–75% at 8
weeks).
3. Stress ulcers and gastritis
4. Zollinger-Ellison syndrome It is a gastric hyper secretory state due to a rare tumor
secreting gastrin.
5. Gastroesophageal reflux disease (GERD)
6. Prophylaxis of aspiration pneumonia H2 blockers given reduce the risk of aspiration of
acidic gastric contents during anesthesia and surgery.
7. Other uses H2 blockers have adjuvant beneficial action in certain cases of urticaria

27. PROTON PUMP INHIBITORS (PPIs)
Omeprazole It is the prototype member of substituted benzimidazoles which inhibit the
final common step in gastric acid secretion
MOA
 Omeprazole is inactive at neutral pH, but at pH < 5 rearranges to two charged cationic
forms that react covalently with SH groups of the H+K+ATP ase enzyme and
inactivate it irreversibly, especially when two molecules of omeprazole react with one
molecule of the enzyme.
 After diffusing into the parietal cell from blood, it gets concentrated in the acidic pH
of the canaliculi because the charged forms generated there are unable to diffuse back.
 Moreover, it gets tightly bound to the enzyme. These features and the specific
localization of H+K+ATP ase to the apical membrane of the parietal cells confer high
degree of selectivity of action to omeprazole.
 Acid secretion resumes only when new H+K+ATP ase molecules are synthesized.
 It also inhibits gastric mucosal carbonic anhydrase.

28. PHARMACOKINETICS
Omeprazole is highly plasma protein bound, rapidly metabolized in liver by CYP2C19
and CYP3A4 (plasma t½ ~1 hr.) and metabolites are excreted in urine
inhibition of HCl secretion occurs within1 hr., reaches maximum at 2 hr., is still half
maximal at 24 hr. and lasts for 3 days.
Uses
1. Peptic ulcer
2. Bleeding peptic ulcer: Acid enhances clot dissolution promoting ulcer bleed. Suppression
of gastric acid has been found to facilitate clot formation reducing blood loss and rebleed.
3. Stress ulcers: Intravenous pantoprazole is as effective prophylactic (if not more) for
stress ulcers as i.v. H2 blockers.
4. Gastroesophageal reflux disease (GERD)
5. Zollinger-Ellison syndrome

29. ANTICHOLINERGICS
Atropinic drugs reduce the volume of gastric juice without raising its pH unless there is
food in stomach to dilute the secreted acid.
Effective doses of nonselective anti muscarinics (atropine, propantheline,
oxyphenonium) invariably produce intolerable side effects.
Introduction of H2 blockers and PPIs has sent them into oblivion.
 Pirenzepine It is a selective M1 anticholinergic that has been used in Europe for peptic
ulcer.
Gastric secretion is reduced by 40–50% without producing intolerable side effects, but
side effects occur with slight excess.
It has not been used in India and USA.

30. PROSTAGLANDIN ANALOGUE
PGE2 and PGI2 are produced in the gastric mucosa and appear to serve a protective
role by inhibiting acid secretion and promoting mucus HCO3 ¯ secretion
In addition, PGs inhibit gastrin production, increase mucosal blood flow and probably
have an ill-defined “cyto protective” action.
ADR
 diarrhoea,
 abdominal cramps,
 uterine bleeding,
 abortion, and need for multiple daily doses.
 Patient acceptability is poor.
USE
prevention and treatment of NSAID associated gastrointestinal injury and blood loss.
However, PPIs are more effective, more convenient, better tolerated and cheaper.

31. ANTACIDS
These are basic substances which neutralize gastric acid and raise pH of gastric
contents.
Peptic activity is indirectly reduced if the pH rises above 4, because pepsin is secreted
as a complex with an inhibitory terminal moiety that dissociates below pH 5: optimum
peptic activity is exerted between pH 2 to 4.
Antacids do not decrease acid production ;
The potency of an antacid is generally expressed in terms of its acid neutralizing
capacity(ANC), which is defined as number of m Eq of 1N HCl that are brought to pH
3.5 in 15 min by a unit dose of the antacid preparation.

32. SYSTEMIC ANTACIDS
Sodium bicarbonate It is water soluble, acts instantaneously, but the duration of action is
short. It is a potent neutralizer (1 g → 12 mEq HCl), pH may rise above 7.
However, it has several demerits:
(a) Absorbed systemically: large doses will induce alkalosis.
(b) Produces CO2 in stomach →distention, discomfort, belching, risk of ulcer
perforation.
(c) Acid rebound occurs, but is usually short lasting.
(d) Increases Na+ load: may worsen edema and CHF.
NONSYSTEMIC ANTACIDS
 These are insoluble and poorly absorbed basic compounds; react in stomach to form
the corresponding chloride salt.
 The chloride salt again reacts with the intestinal bicarbonate so that HCO3¯ is not
spared for absorption—no acid-base disturbance occurs
—may cause problem if renal function is inadequate

33. ADR
 Antacids are no longer used for healing peptic ulcer because
 needed in large
 frequent doses,
 inconvenient,
 cause acid rebound and bowel upset,
 poor patient acceptability.

34. ULCER PROTECTIVES
 Sucralfate It is a basic aluminium salt of sulfated sucrose; a drug of its own kind.
 Sucralfate polymerizes at pH < 4 by cross linking of molecules, assuming a sticky gel-
like consistency.
 It preferentially and strongly adheres to ulcer base, especially duodenal ulcer;
 It precipitates surface proteins at ulcer base and acts as a physical barrier preventing
acid, pepsin and bile from coming in contact with the ulcer base.
Side effects are few;
 constipation is reported by 2% patients.
 It has potential for inducing hypophosphatemia by binding phosphate ions in the
intestine.
 Dry mouth, nausea are infrequent.
Interactions Sucralfate
adsorbs many drugs and interferes with the absorption of tetracyclines, fluoroquinolones
cimetidine, phenytoin and digoxin.

35. Colloidal bismuth sub citrate (CBS; Tri potassium di citrato bismuthate)
 It is a colloidal bismuth compound; water soluble
 The mechanism of action of CBS is not clear;
Probabilities are:
(i) Increased secretion of mucus and bicarbonate through stimulation of mucosal PGE2
production.
(ii) CBS and mucus form a glycoprotein-Bi complex which coats the ulcer and acts as a
diffusion barrier to HCl.
(iii) Detaches H. pylori from the surface of mucosa and directly kills this organism
involved in causation of ulcers and relapses. Gastritis and nonulcer dyspepsia associated
with H. pylori are also improved by CBS.

36. ANTI-HELICOBACTER PYLORI DRUGS
 Antimicrobials that have been found clinically effective against H. pylori are:
amoxicillin, clarithromycin, tetracycline and metronidazole/tinidazole.
 However, any single drug is relatively ineffective. Resistance develops rapidly,
especially to metronidazole/tinidazole.
 Since bismuth (CBS) is active against H. pylori and resistance does not develop to it,
early combination regimens included bismuth, but had poor patient acceptability; are
infrequently used now.
 Rise in intra gastric pH enhances the anti-H. pylori action of the antibiotics

37. Two week regimens (mg)
1. Amoxicillin 750 + Tinidazole 500 +Omeprazole 20 all BD
2. Amoxicillin 750 + Tinidazole 500 +Lansoprazole 30 all BD
3. Clarithromycin 250 + Tinidazole 500 +Lansoprazole 30 all BD
4. Clarithromycin 500 + Amoxicillin 1000 +Lansoprazole 30 all BD
5. Clarithromycin 500 BD/Amoxicillin750 BD + Omeprazole 20 BD
6. Amoxicillin 500 TDS/Tetracycline500 QID + Metronidazole 400 QID/Tinidazole 500
BD + Bismuth 120 QID
7. Amoxicillin 750 TDS + Metronidazole500 TDS + Ranitidine 300 OD
8. Amoxicillin 750 BD + Clarithromycin250 BD + Lansoprazole 30 BD
Some of the 2 week regimens are:

38. The US-FDA approved regimen is:
lansoprazole30 mg + amoxicillin 1000 mg + clarithromycin 500 mg all
given twice daily for 2 weeks.
It has achieved 86–92% eradication rate.* High prevalence of in vitro nitro
imidazole resistance among H. pylori now being detected, especially in
tropical regions, and better tolerability of regimens which exclude the
nitro imidazole, favour the triple drug regimen of a PPI + amoxicillin
+clarithromycin. The 2 week treatment is considered more appropriate,
because higher relapse