2. Peptic ulcer
• A peptic ulcer disease or PUD is an ulcer defined as mucosal erosions
equal to or greater than 0.5 cm of an area of the gastrointestinal tract
exposed to the acid and pepsin secretion.
• Stomach Lining Basics
4. Regulation of gastric acid secretion
• The terminal enzyme H+K+ATPase (proton pump) which secretes H+
ions in the apical canaliculi of parietal cells can be activated by
histamine, ACh and gastrin acting via their receptors located on the
basolateral membrane of these cells.
• Histamine acting through H2 receptors
• ACh acts partly directly and to a greater extent indirectly by releasing
histamine from paracrine enterochromaffin-like (ECL) cells called
“histaminocytes” located in the oxyntic glands.
• Gastrin is secreted from the antrum in response to a rise in antral pH,
food constituents, especially peptides, and vagally mediated reflexes
involving ganglion cells of the enteric nervous system (ENS).
5. • H2 receptors activate H+K+ATPase by generating cAMP, muscarinic and
gastrin/ cholecystokinin (CCK2) receptors appear to function through the
phospholipase C → IP3–DAG pathway that mobilizes intracellular Ca2+
• The secretomotor response to gastrin and cholinergic agonists is expressed
fully only in the presence of cAMP generated by H2 activation.
• Histamine participates in the acid response to gastrin and ACh at more than
one level, and H2 antagonists suppress not only histamine but also ACh,
pentagastrin and any gastric acid secretory stimulus.
• Prostaglandins have been ascribed a “cytoprotective” role in the gastric
mucosa by augmenting mucus and bicarbonate secretion from gastric
mucosal epithelial cells as well as other actions.
6. • The gastric mucus transforms into an adherent gell-like film over the
mucosa which traps the secreted HCO3¯ ions and prevents their
neutralization by creating a barrier for the H+ ions in the juice and
also shields the mucosa from attack by pepsin.
• PGE2 produced by gastric mucosa, inhibits acid secretion by
opposing cAMP generation (in parietal cells) and gastrin release
(from antral G cells).
•The secretion of the parietal cells is an isotonic solution of HCl (150
mmol/l) with a pH < 1, about 2.5 litres of gastric juice daily
•The concentration of hydrogen ions is more than a million times
higher than that of the plasma.
7. • The 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 Cl- secretion is accompanied by K+, which is then exchanged for H+ from within
the cell by a K+/H+ ATPase+ and bicarbonate ions. The latter exchanges across the basal
membrane of the parietal cell for Cl-. at of the plasma.
8. Secretion of HCl by
gastric parietal cell and
its regulation
C.Ase.—Carbonic
anhydrase; Hist.—
Histamine; ACh.—
Acetylcholine; CCK2—
Gastrin cholecystokinin
receptor; M.—
Muscarinic receptor; N—
Nicotinic receptor; H2—
Histamine H2 receptor;
EP3—Prostaglandin
receptor; ENS—Enteric
nervous system; ECL
cell—Enterochromaffin-
like cell; GRP—Gastrin
releasing peptide; +
Stimulation; – Inhibition
9.
10. • The goals of antiulcer therapy are:
• Relief of pain
• Ulcer healing
• Prevention of complications (bleeding, perforation)
• Prevention of relapse.
• Gastritis is the precursor to PUD and it is clinically difficult to differentiate the
two
• Stomach (called gastric ulcer)
• Duodenum (called duodenal ulcer)
• Esophagus (called Esophageal ulcer)
• Meckel's Diverticulum (called Meckel's Diverticulum ulcer)
11. Duodenal Vs Gastric Ulcers
Duodenal
• Age: 25-75 years
• Gnawing or burning upper
abdomen pain relieved by food
but reappears 1-3 hrs after meals
• Worsening pain when stomach
empty
• Bleeding occurs with deep
erosion
– Haematemesis
– Maelena
Gastric
• Age: 55-65 years
• Relieved by food but pain may
persist even after eating
• Anorexia, wt loss, vomiting
Infrequent or absent remissions
• Small % become cancerous
• Severe ulcers may erode (Slowly)
through the stomach wall weight
12. • Common and is a GIT motility disorder
• The most common factor is Acid content reflux back into the oesophagus
• Intense burning, sometimes belching
• Can lead to esophagitis, oesophagal ulcers, and strictures
• Commonly associated with obesity
• Improves with lifestyle management oesophagus
Gastroesophageal Reflux Disease (GERD)
14. What may contribute to imbalance?
• Helicobacter pylori
• NSAIDs
• Ethanol
• Tobacco
•Severe physiologic stress (Burns, CNS
trauma, Surgery, Severe medical illness)
• Steroids
15. • Gram (-) rod with flagella
• H pylori is the most common cause of PUD
• Transmission route faecal-oral
• Secretes urease → convert urea to ammonia
• Produces an alkaline environment enabling survival in the stomach
• Almost all duodenal and 2/3 gastric ulcer patients are infected with HP
• Considered class 1 carcinogen → gastric cancer faecal-oral faecal-oral
H. pylori
16.
17. • H2 antagonists-
• These are the first class of highly effective drugs for acid-peptic disease but
have now been surpassed by proton pump inhibitors.
• H2 blockers are competitive antagonists of histamine at the H2 receptors,
but with famotidine, the antagonism is partly noncompetitive due to
stronger binding to the H2 receptors.
• These drugs block, histamine-induced gastric secretion, cardiac
stimulation uterine relaxation and bronchial relaxation
• Human bronchial muscles express both contractile H1 and relaxant H2
receptors.
• Normally the H1 response predominates, but H2 mediated relaxation can be
demonstrated after H1 blockade. As such, H2 blockers can potentiate
histamine-induced bronchospasm.
• H2 blockers attenuate fall in BP due to histamine, This is due to the
blockade of relaxant H2 receptors located directly on vascular smooth muscle.
18. Gastric secretion
• The action of H2 blockers is marked inhibition of gastric secretion.
• All phases (basal, psychic, neurogenic, gastric) of secretion are
suppressed dose-dependently, but the basal nocturnal acid secretion is
suppressed more completely.
• Secretory response to not only histamine but all other stimuli (ACh,
gastrin, insulin, alcohol, food) is attenuated.
• The volume of gastric juice, pepsin content and intrinsic factor
secretion are all reduced, but the most marked effect is on acid secretion.
• The usual ulcer healing doses produce 60–70% inhibition of 24-hour acid
output.
• Gastric ulceration due to stress and drugs (NSAIDs, cholinergic,
histaminergic) is prevented
• H2 blockers have no direct effect on gastric or oesophagal motility or
lower oesophagal sphincter (LES) tone.
19. • Pharmacokinetics
• After oral administration, the H2 antagonists distribute widely
throughout the body (including into breast milk and across the placenta)
and are excreted mainly in urine.
• Cimetidine, ranitidine, and famotidine are also available in intravenous
formulations.
• The half-life of all of these agents may be increased in patients with renal
dysfunction, and dosage adjustments are needed.
21. H2 antagonists - Uses
• Promote the healing of gastric and duodenal ulcers
• Duodenal ulcer – 70 to 90% at 8 weeks
• Gastric Ulcer – 50 to 75%
• NSAID ulcers induced ulcers
• Stress ulcer and gastritis
• GERD in mild cases
• Zollinger-Ellison syndrome
• Prophylaxis of aspiration pneumonia
22. • Headache, dizziness, bowel upset, dry mouth
• CNS: Confusion, restlessness
• Bolus IV – release histamine – bradycardia, arrhythmia, cardiac
arrest
• Cimetidine has antiandrogenic actions
• Increases plasma prolactin and inhibits degradation of estradiol by liver
• High doses given for long periods have produced gynaecomastia, loss
of libido, impotence and short-lasting decrease in sperm count.
Adverse effects
23. Drug interactions
• Cimetidine inhibits several CYP-450 isoenzymes and reduces hepatic
blood flow, so inhibits metabolism of many drugs like theophylline,
metronidazole, phenytoin, imipramine etc.
• Antacids reduce the absorption of all H2 blockers
24. PROTON PUMP INHIBITORS (PPIs)
• The membrane-bound proton pump is the final step in the secretion
of gastric acid.
• The PPIs bind to the H+/K+-ATPase enzyme system (proton pump)
and suppress the secretion of hydrogen ions into the gastric lumen.
• The available PPIs include dexlansoprazole, esomeprazole, lansoprazole,
omeprazole, pantoprazole and rabeprazole.
• Omeprazole, esomeprazole, and lansoprazole are available over-the
counter for short-term treatment of GERD.
25. 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 it rearranges to
two charged cationic forms (a sulphenic acid and a sulphenamide
configurations) that react covalently with SH groups of the
H+K+ATPase enzyme and inactivate it irreversibly.
• When two molecules of omeprazole react with one molecule of the
enzyme.
• After absorption into bloodstream and subsequent diffusion into the parietal
cell, it gets concentrated in the acidic canaliculi because the charged
forms generated at the acidic pH are unable to diffuse back.
26. • It gets tightly bound to the enzyme by covalent bonds.
• These features and the specific localization of H+K+ATPase to the
apical membrane of the parietal cells confer high degree of
selectivity of action to omeprazole and all other PPIs.
• Acid secretion resumes only when new H+K+ATPase molecules are
synthesized (reactivation half time 18 hours).
• It also inhibits gastric mucosal carbonic anhydrase
PPI – contd.
27.
28. • Pharmacokinetics
• All PPIs are administered orally in enteric-coated (e.c.) form to protect
them from the molecular transformation in the acidic gastric juice.
• PPIs should be taken 30 to 60 minutes before breakfast or the largest
meal of the day.
• Esomeprazole, lansoprazole, and pantoprazole are also available in
intravenous formulations.
• The plasma half-life of these agents is only a few hours, they have a long
duration of action due to covalent bonding with the H+/K+- ATPase
enzyme.
• Omeprazole is a high plasma protein bound, rapidly metabolized in the
liver by CYP2C19 and CYP3A4
• Metabolites of these agents are excreted in urine and faeces.
30. PPI – contd.
Therapeutic uses:
• Gastroesophageal reflux disease (GERD)
• Peptic Ulcer - Gastric and duodenal ulcers
• Bleeding peptic Ulcer
• Stress ulcers
• Zollinger Ellison Syndrome
• Prevention of recurrence of nonsteroidal antiinflammatory drug (NSAID) -
associated gastric ulcers in patients who continue NSAID use.
• Reducing the risk of duodenal ulcer recurrence associated with H. pylori
infections
• Aspiration Pneumonia
31. Adverse Effects
• Nausea, loose stools, headache abdominal pain, constipation,
• Muscle & joint pain, dizziness, rashes
• Rare
• Gynaecomastia, erectile dysfunction
• Leucopenia and hepatic dysfunction
• Osteoporosis in elderly on prolonged use
32. Drug interactions
• Omeprazole inhibits the metabolism of warfarin, phenytoin,
diazepam, and cyclosporine.
• It interferes with activation of clopidogrel by inhibiting CYP2C19.
• Reduced gastric acidity decreases absorption of ketoconazole and
iron salts.
• However, drug interactions are not a problem with the other PPIs.
33. Muscarinic antagonists
• Block the M1 class receptors
• Reduce acid production, Abolish gastrointestinal spasm
Pirenzepine and Telenzepine
• Reduce meal stimulated HCl secretion by reversible blockade of
muscarinic (M1) receptors on the cell bodies of the intramural
cholinergic ganglia
• Unpopular as a first choice because of high incidence of
anticholinergic side effects (dry mouth and blurred vision)meal-
stimulated
34. Prostaglandin analogues- Misoprostol
• Inhibit gastric acid secretion
• Enhance local production of mucus or bicarbonate
• Help to maintain mucosal blood
• Therapeutic use:
• Prevention of NSAID-induced mucosal injury (rarely used
because it needs frequent administration – 4 times daily)
35. Misoprostol
• Doses: 200 mcg 4 times a day
• ADRs:
• Diarrhoea and abdominal cramps
• Uterine bleeding
• Abortion
• Contraindications:
• Inflammatory bowel disease
• Pregnancy (may cause abortion)
36. Antacids
• Weak bases that neutralize acid
• Also inhibit formation of pepsin (As pepsinogen converted to pepsin at
acidic pH)
• Acid Neutralizing Capacity:
• Potency of Antacids expressed in terms of Number of mEq of 1N HCl
that are brought down to pH 3.5 in 15 minutes by a unit dose of the
preparation (1 gm)
38. Non systemic Antacids
• Magnesium hydroxide (ANC 30 mEq)
• Aqueos suspension is called Milk of magnesia
• Magnesium trisilicate (ANC 10 mEq)
• Aluminium Hydroxide (ANC 1-2.5mEq/g)
• Magaldrate – hydrated hydroxy magnesium aluminate
39. Non systemic antacids
• Insoluble and poorly absorbed basic compounds
• React in stomach to form corresponding chloride salt
• The chloride salt again reacts with the intestinal HCO3- so that
HCO3- is not spared for absorption.
41. Non systemic antacids
• Duration of action : 30 min when taken in empty stomach and 2 hrs when taken
after a meal
• Adverse effects:
• Aluminium antacids – constipation
• Mg2+ antacids – Osmotic diarrhoea
• In renal failure Al3+ antacid – Aluminium toxicity & Encephalopathy
1. Fast (Mag. hydroxy) and slow (Alum. hydroxy) acting components yield prompt as
well as sustained effects.
2. Mag. salts are laxative, while alum. Salts are constipating: combination may annul
each other’s action and bowel movement may be least affected.
3. Gastric emptying is least affected; while alum. salts tend to delay it, mag./cal. Salts
tend to hasten it.
4. The dose of individual components is reduced; systemic toxicity (dependent on
fractional absorption) is minimized.
42. DIGENE: Dried alum. hydrox. gel 300 mg, mag. alum. silicate
50 mg, mag. hydrox. 25 mg, methylpolysilox. 10 mg per tab.
DIGENE GEL: Mag. hydrox. 185 mg, alum. hydrox. gel 830
mg, sod. carboxymethyl cellulose 100 mg, methylpolysilox.
25 mg per 10 ml susp.
GELUSIL: Dried alum. hydrox. gel 250 mg, mag. trisilicate
500 mg per tab.
GELUSIL LIQUID: Mag. trisilicate 625 mg, alum. hydrox.
gel 312 mg per 5 ml susp.
MUCAINE: Alum. hydrox. 290 mg, mag. hydrox. 98 mg,
oxethazaine 10 mg per 5 ml susp.
43. Drug interactions
• By raising gastric pH & forming insoluble complexes ↓ absorption
of many drugs
• Tetracyclines, iron salts, H2 Blockers, diazepam, phenytoin,
isoniazid, ethambutol
44. Sucralfate –ulcer protective
• Aluminium salt of sulfated sucrose
• MOA:
• In acidic environment ( pH <4) it polymerises by cross-linking
molecules to form a sticky viscous gel that adheres to the ulcer
crater - more on duodenal ulcer
• Astringent action and acts as a physical barrier
• Dietary proteins get deposited on this layer forming another
coat
45. Sucralfate –contd.
• Concurrent antacids avoided, (as it needs acid for activation)
• Uses:
• Prophylaxis of Stress ulcers
• Bile reflux gastritis
• Topically – burn, bedsore ulcers, excoriated skins
• Dose: 1 gm one Hr before 3 major meals and at bedtime for 4-8
weeks
• ADRs: Constipation, hypophosphatemia
• Drug interactions: Adsorbs many drugs and interferes with their
absorption
46. Colloidal Bismuth Subcitrate (CBS)
• Mechanism of action
• CBS and mucous form glycoprotein bi complex which coats
ulcer crater
• ↑ secretion of mucous and bicarbonate through stimulation of
mucosal PGE production
• Detaches H.pylori from the surface of the mucosa and
directly kills them
47. Colloidal Bismuth subcitrate
• Dose: 120 mg 4 times a day
• Adverse effects
• blackening of tongue, stools, dentures
• Prolonged use may cause osteodystrophy and encephalopathy
• Diarrhoea, headache, dizziness
53. • For large ulcers (> 10 mm in diameter) or those complicated by bleeding/perforation, the
PPI should be continued beyond the 2-week triple-drug regimen till complete
healing occurs.
• Quadruple therapy with CBS 120 mg QID + tetracycline 500 mg QID +
metronidazole 400 mg TDS + omeprazole 20 mg BD is advocated for eradication
failure cases. Another quadruple therapy regimen with PPI + amoxicillin +
clarithromycin + metronidazole all twice daily for 2 weeks has been tested in Europe
with a>90% eradication rate.
• All regimens are complex and expensive, side effects are frequent and compliance is
poor. Higher failure rates (20–40%) have been reported from India. Also, the 5-year
recurrence rate of H. pylori infection is higher.
• long-term benefits of anti-H. pylori therapy includes lowering ulcer disease
prevalence and prevention of gastric carcinoma/lymphoma
