ok

1. Pharmacotherapy of
Peptic ulcer

2. Objectives
 Regulation of Gastric acid secretion
 Classification of drugs used in peptic
ulcer
 Mechanism of action, Uses & Adverse
effects, drug interactions of
 H2 Blockers
 Proton pump inhibitors
 Antacids
 Ulcer protectives
 Drugs for eradication of H.pylori

3. Stomach Lining Basics

4. Gastric Gland

5. Gastric Mucosal Barrier
•Surface mucosa cells in the pyloric region secrete a thick, alkaline-rich mucus that protects the
epithelium of the stomach and duodenum from harsh acid conditions of the lumen.
•This is known as the gastric mucosal barrier.
•These cells are stimulated by mechanical and chemical irritation and parasympathetic inputs.
•This protective mucus barrier can be damaged by bacterial and viral infection, certain drugs,
and aspirin.

6. Formation of HCL

7. GASTRIC SECRETION:-
• The stomach secretes about 2.5 litres of gastric juice daily.
• The principal exocrine secretions are proenzymes such as
• Prorennin and Pepsinogen from chief or peptic cells, and
•hydrochloric acid (HCl) and intrinsic factor secreted by the parietal or oxyntic cells.
•Mucus-secreting cells abound among the surface cells of the gastric mucosa.
•Bicarbonate ions are also secreted and are trapped in the mucus, creating a gel-like
protective barrier that maintains the mucosal surface at a pH of 6-7 in the face of a
much more acidic environment (pH 1-2) in the lumen.
•Alcohol and bile can disrupt this 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 the therapy of this condition includes drugs that
modify each of these factors.

8. THE REGULATION OFACID SECRETION BY PARIETAL CELLS :-
• The secretion of the parietal cells is an isotonic solution of HCl (150 mmol/l) with a pH < 1,
•The concentration of hydrogen ions being more than a million times higher than that of the
plasma.
•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-.

10. •The principal stimuli acting on the parietal cells are:
•Gastrin (a stimulatory hormone)
•Acetylcholine (a stimulatory neurotransmitter)
•Histamine (a stimulatory local hormone)
•Prostaglandins E2 and I2 (local hormones that inhibit acid
secretion

11. Gastrin :-
Gastrin is a peptide hormone synthesised in endocrine cells of the mucosa of the
gastric antrum and duodenum, and secreted into the portal blood.
Its main action is stimulation of the secretion of acid by the parietal cells, but
there is controversy about the precise mechanism of stimulatory action.
Gastrin also indirectly increases pepsinogen secretion, stimulates blood flow
and increases gastric motility.
Release of this hormone is controlled both by neuronal transmitters and blood-
borne mediators, as well as the chemistry of the stomach contents.
Gastrin secreation is inhibited when PH of the gastric content falls to2.5 or
lower.

12. Acetylcholine:
It is released from (e.g. vagal) neurons and stimulates specific muscarinic
receptors on the surface of the parietal cells and on the surface of histamine-
containing cells.
Histamine:
•Histamine play important role in gastric secretion.
•Within the stomach, mast cells (or histamine-containing cells similar to
mast cells) lying close to the parietal cell release a steady basal release of
histamine, which is further increased by gastrin and acetylcholine.
•The hormone acts on parietal cell H2 receptors, which are responsive to
histamine concentrations that are below the threshold required for vascular
H2 receptor activation

13. Regulation of gastric acid secretion

14. What is 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
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)

15. 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
through stomach wall

16. Gastroesophageal Reflux Disease
(GERD)
• Common and is a GIT motility disorder
• Acidity of Gastric contents – most common factor Acid
contents reflux back into esophagus
• Intense burning, sometimes belching
• Can lead to esophagitis, esophageal ulcers, and
strictures
• Commonly associated with obesity
Improves with lifestyle management

17. Why Ulceration Occurs?
•
•
High pH (2 to 3) in the gastric lumen – Pepsin is
active
Require defense mechanisms to protect oesophagus
and stomach
➢Oesophagus – protected by LES
– Stomach: a number of mechanisms
• Mucus secretion
• Prostaglandins: I2 and E2 (alcohol, aspirin, and other drugs)
• Bicabonate ions
• High Blood Flow (nitric oxide mediated)

18. Why Peptic ulcer occurs
 Imbalance primarily between Aggressive
factors and Defensive factors

19. What may contribute imbalance ?
• Helicobacter pylori
• NSAIDs
• Ethanol
• Tobacco
•Severe physiologic
stress (Burns, CNS trauma,
Surgery, Severe medical illness)
• Steroids

20. H. pylori
•
•
•
•
•
•
•
Gram (-) rod with flagella
H pylori is most common cause of
PUD
Transmission route fecal-oral
Secretes urease → convert urea to
ammonia
Produces alkaline environment
enabling survival in stomach
Almost all duodenal and 2/3 gastric
ulcer pt’s infected with HP
Considered class 1 carcinogen →
gastric cancer

21. Classification of drugs
used in peptic ulcer
1. Drugs that inhibit gastric
acid secretion
2. Drugs that neutralize
gastric acid (Antacids)
3. Ulcer protectives
4. Anti H. pylori drugs

22. Classification (Contd.)
 Drugs that inhibit gastric acid
secretion
 H2 receptor blockers: Cimetidine,
Ranitidine, Famotidine
 Proton pump inhibitors: Omeprazole,
Pantoprazole, esomeprazole
 Anticholinergics : Pirenzepine
 Prostaglandin analogues: Misoprostol

23. Classification (Contd..)
 Drugs that neutralize gastric acid
(Antacids)
 Systemic:
• Sodium bicarbonate, sodium citrate
 Non systemic:
• Magnesium hydroxide, Mag. Trisilicate,
Aluminium hydroxide gel, Magaldrate

24. Classification (Contd..)
 Ulcer protectives
 Sucralfate
 Colloidal Bismuth Sulfate (CBS)
 Anti H. pylori drugs
 Amoxicillin, Clarithromycin,
Metronidazole, Tinidazole, Tetracycline

25. H2 ANTAGONISTS

26. Mechanism of action
 Competitively block H2 receptors on parietal
cell & inhibit gastric acid production
 Supress secretion of acid in all phases but mainly
nocturnal acid secretion
 Also reduce acid secretion stimulated by Ach,
gastrin, food, etc.

27. Pharmacokinetics
 Absorption is not interfered by food
 Can cross placental barrier and reaches
milk, Poor CNS penetration
 The serum half-lives range from 2
to 3hours;
 Cleared by a combination of hepatic
metabolism, glomerular filtration, and
renal tubular secretion.
 Dose reduction needed in moderate to
severe renal insufficiency

28. Cimetidine Ranitidine Famotidine Nizatidine
Bioavailability 80 50 40 >90
Relative Potency 1 5 -10 32 5 -10
Half life (hrs) 2 - 3 2 - 3 2.5 – 3.5 1.1 -1.6
DOA (hrs) 6 8 12 8
Inhibition of 1 0.1 0 0
CYP 450
Dose mg (bd) 400 150 20 150
Comparison of H2 antagonists

29. 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

30. Adverse effects
 Headache, dizziness, bowel upset, dry
mouth
 CNS: Confusion, restlessness
 Bolus IV – release histamine – bradycardia,
arrhythmia, cardiac arrest
 Cimetidine has antiandrogenic actions

31. 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

32. Proton Pump Inhibitors
 Most effective drugs in antiulcer therapy
 Prodrugs requiring activation in acid
environment
 Activated forms binds irreversibly to
H+K+ATPase and inhibit it
Omeprazole
Pantoprazole
Lansoprazole
Esomeprazole

33. Mechanism of Action
 Prodrugs inactive at neutral pH
 At pH < 5 rearranges to two charged cationic
forms (sulfenamide + sulphenic acid) that bind
covalently with SH groups of H⁺K⁺ ATPase and
inactivate it irreversibly
 Also inhibits gastric mucosal carbonic anhydrase

35. Pharmacokinetics - PPI
 Available as enteric coated tablets
 They should be given 30 minutes to 1 hour
before food intake
 half life is very short and only 1-2 Hrs
 Still the action persists for 24 Hrs to 48 hrs after a
single dose
 Action lasts for 3-4days even after stoppage of
the drug

37. PPI – contd.
 Therapeutic uses:
1. Gastroesophageal reflux disease (GERD)
2. Peptic Ulcer - Gastric and duodenal ulcers
3. Bleeding peptic Ulcer
4. Zollinger Ellison Syndrome
5. Prevention of recurrence of nonsteroidal
antiinflammatory drug (NSAID) - associated
gastric ulcers in patients who continue NSAID use.
6. Reducing the risk of duodenal ulcer recurrence
associated with H. pylori infections
7. Aspiration Pneumonia

38. Comparative success of therapy
with PPI and H2 antagonist

39. 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
 Hypergastrinemia

40. Drug interactions
 Omeprazole inhibits the metabolism
of warfarin, phenytoin, diazepam,
and cyclosporine.
 However, drug interactions are not a
problem with the other PPIs.

41. PPI – Dosage schedule
 Omeprazole
 Lansoprazole
 Pantoprazole
 Rabeprazole
 Esomeprazole
20 mg o.d.
30 mg o.d.
40 mg o.d.
20 mg o.d.
20-40 mg o.d

42. Proton Pump Inhibitors
 Lansoprazole :
 Partly reversible, more potent, slightly more against
H pylori, Higher BA, rapid onset.
 Pantoprazole:
 More acid stable, I.V, CYP450 less affinity
 Rabeprazole: claimed to most rapid
 Es-omeprazole
 Better intragastric pH , higher healing rates.

43. 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)

44. 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)

45. Misoprostol
 Doses: 200 mcg 4 times a day
 ADRs:
 Diarrhoea and abdominal cramps
 Uterine bleeding
 Abortion
 Exacerbation of inflammatory bowel disease and
should be avoided in patients with this disorder
Contraindications:
1. Inflammatory bowel disease
2. Pregnancy (may cause abortion)

46. 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
unit dose of a preparation (1 gm)

47. Systemic antacids
 Sodium Bicarbonate:
 Potent neutralizing capacity and acts instantly
 ANC: 1 gm = 12 mEq
 DEMERITS:
 Systemic alkalosis
 Distension, discomfort and belching – CO2
 Rebound acidity
 Sodium overload

48. 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)

49. 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

50. 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

51. Chemical reactions of
antacids with HCl in the
stomach

52. Drug interactions
 By raising gastric pH & forming insoluble
complexes ↓ absorption of many drugs
 Tetracyclines, iron salts, H2 Blockers, diazepam,
phenytoin, isoniazid, ethambutol

53. Sucralfate – ulcer
protective
 Aluminium salt of sulfated sucrose
 MOA:
 In acidic environment ( pH <4) it polymerises by cross
linking molecules to form sticky viscous gel that
adheres to ulcer crater - more on duodenal ulcer
 Astringent action and acts as physical barrier
 Dietary proteins get deposited on this layer
forming another coat

54. 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 1 Hr before 3 major meals and at bed time
for 4-8 weeks
 ADRs: Constipation, hypophosphatemia
 Drug interactions : adsorbs many drugs and
interferes with their absorption

55. 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 surface of mucosa and
directly kills them

56. 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

57. Eradication of H.pylori
Noacid
Noulcer
OLD TESTAMENT
No HP No ulcer
NEW TESTAMENT

58. H. pylori
 Gram (-) rod
 Associated with gastritis,
gastric & duodenal ulcers,
gastric adenocarcinoma
 Transmission route fecal-oral
 Secretes urease → convert
urea to ammonia
 Produces alkaline
environment enabling survival
in stomach

59. Triple Therapy
The BEST among all the Triple therapy regimen is:
Omeprazole / Lansoprazole
Clarithromycin
Amoxycillin / Metronidazole
- 20 / 30 mg bd
- 500 mg bd
- 1gm / 500 mg bd
Given for 14 days followed by P.P.I for 4 – 6 weeks
Short regimens for 7 – 10 days not very effective

60. Other 2 weeks regimen(mg)
 Amoxicillin 750/ + Tinidazole 500
+omeprazole 20 mg/ lansoprazole 30
mg BD
 clarithromycin 250 + Tinidazole
500/amoxicillin 1000 + lansoprazole
30 mg BD

61. Thank You