pharmacotherapy of peptic ulcer , antiulcer drugs

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

4. Formation of HCL

5. Regulation of gastric acid
secretion

6. 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

7. 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

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

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

10. H2 ANTAGONISTS

11. 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.

12. Pharmacokinetics
 Absorption is not interfered by food
 Can cross placental barrier and reaches milk,
Poor CNS penetration
 The serum half-lives range from 1.1 to 4
hours;
 Cleared by a combination of hepatic
metabolism, glomerular filtration, and renal
tubular secretion.
 Dose reduction needed in moderate to severe
renal insufficiency

13. Bioavailability 80 50 40 >90
Relative Potency 1 5 -10 32 5 -10
Half life (hrs) 1.5 - 2.3 1.6 - 2.4 2.5 - 4 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
Cimetidine Ranitidine Famotidine Nizatidine
Comparison of H2
antagonists

14. 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
 Zollinger-Ellison syndrome
 Prophylaxis of aspiration pneumonia

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

16. 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

17. 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

18. 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

20. 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

22. 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

23. Comparative success of therapy
with PPI and H2 antagonist

24. 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

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

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

27. 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.

28. 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)

29. 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)

30. 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)

31. 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)

32. 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

33. 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

34. 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)

35. 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 (As they relax gastric
smooth muscle & delay gastric emptying) – also
hypophosphatemia and osteomalcia
 Mg2+ antacids – Osmotic diarrhoea
 In renal failure Al3+ antacid – Aluminium toxicity
& Encephalopathy

36. Miscellaneous drugs
 Simethicone: Decrease surface
tension thereby reduce bubble
formation - added to prevent reflux
 Alginates: Form a layer of foam on
top of gastric contents & reduce
reflux
 Oxethazaine: Surface anaesthetic

37. Chemical reactions of
antacids with HCl in the
stomach

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

39. 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

40. 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

41. 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

42. 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

43. Eradication of H.pylori
No acid
No ulcer
OLD TESTAMENT
No HP No ulcer
NEW TESTAMENT

44. 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
 Higher prevalence in Low SES

45. Who are they ?
Barry J Marshall J. Robin Warren
Nobel Laureates
of Medicine –
2005
Discovery of
H. pylori & its
role in peptic
ulcer

46. Triple Therapy
The BEST among all the Triple therapy regimen is:
Omeprazole / Lansoprazole - 20 / 30 mg bd
Clarithromycin - 500 mg bd
Amoxycillin / Metronidazole - 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

47. 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

48. Thank You