1. ANTI ULCER DRUGS Expected learning outcomes:
1. Understand the definition and pathophysiology of ulcer.
2. Compare and contrast Gastric and Duodenal ulcers.
3. Identify the classification of drugs used to treat PUD.
4. Remember prototype drugs used in each classification and their details.
5. Evaluate therapeutic goals for PUD in various clinical situations.
6. Apply pharmaceutical process for the welfare of the clients receiving drug therapy for PUD.
References:
Lippincott's Illustrated Reviews: Pharmacology, 4th Edition.
Melmon and Morrelli's Clinical Pharmacology, 4th Edition
Dr Manikandan,JIPMER, India, Antiulcer Drugs

2. Can you label the parts? 1 2 4 3

3. Overview of Ulcers
Peptic ulcer is an open sore or raw area on the lining of stomach(Gastric ulcer),
Or on the duodenum (Duodenal ulcer).
GASTRIC ULCER
DUODENAL ULCER
Site
In stomach
generally duodenal bulb
Pain
15-30 minutes after meals, relieved by vomiting
relieved by meals
Vomiting
common
uncommon
Pathology
may be benign or malignant
almost never malignant
Gender
More common in women
More common in men

4. Auto regulation of acid secretion
Food stimulates release of gastrin from antral G cells (G).
Gastrin stimulates enterochromaffin-like cells (ECL) to release histamine, which stimulates parietal cells (P) in the gastric corpus to secrete acid.
Acid stimulates release of somatostatin from somatostatin cells (S) in the antrum, inhibiting further gastrin release.
BMJ 2001; 323 : 980 doi: /bmj  (Published 27 October 2001)

5. Misoprostol Ranitidine Gastrin Histamine _ + Proglumide _ _ + + + Ca++
See Animation
PGE2
Gastrin
Histamine _ +
Proglumide
ACh _ _ H2 M3
Adenyl cyclase +
Gastrin receptor
PGE
receptor + +
Ca++
ATP
cAMP
Ca++ + + +
Protein Kinase
(Activated) K+ H+ + K
Parietal cell
Proton pump _
Lumen of stomach
Omeprazole _
Gastric acid
Antacid

6. Can you identify these people ?
Nobel prize Medicine – 2005
Discovery of H.pylori & its role in ulcer
Barry J Marshall
J. Robin Warren

7. Antacids Duration of action : 30 min when taken in empty stomach
Weak bases that neutralise acid
Also inhibit formation of pepsin
(As pepsinogen converted to pepsin at acidic pH)
Present day antacids :
Aluminium Hydroxide
Magnesium Hydroxide
OTC drug for symptomatic relief of dyspepsia
Duration of action :
30 min when taken in empty stomach
2 hrs when taken after a meal
Side effects :
Al3+ antacids – constipation (As they relax gastric smooth muscle & delay gastric emptying)
Mg2+ antacids – Osmotic diarrhoea .
In renal failure Al3+ antacid – Aluminium toxicity & Encephalopathy

8. Antacids – Common additives & Interactions
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
Adsorb drugs and form insoluble complexes that are not absorbed .
Clinical importance :
Interactions can be avoided by taking antacids 2 hrs before or after ingestion of other drugs .

9. Now answer this question
Is it rational to combine aluminum hydroxide and magnesium hydroxide in antacid preparations ?
Combination provides a relatively fast and sustained neutralising capacity .
(Magnesium Hydroxide – Rapidly acting
Aluminium Hydroxide - Slowly acting )
Combination preserves normal bowel function.
(Aluminium Hydroxide – constipation
Magnesium hydroxide – diarrhoea )

10. Histamine H2 Receptor Antagonist
Reversible competitive inhibitors of H2 receptor
Highly selective, No action on H1 or H3 receptors
Very effective in inhibiting nocturnal acid secretion (as it depends largely on Histamine )
Modest impact on meal stimulated acid secretion (As it depends on gastrin, acetyl choline and histamine)
H2 Blockers–Side effects & Interactions
Extremely safe drugs
Cimetidine causes gynecomastia, galactorrhea
(as it is antiandrogenic & increases prolactin level)
Cimetidine inhibits CYP450 & increases conc. of Warfarin, Theophylline, Phenytoin, Ethanol.

11. Now answer this question
Your friend wants to take a H2 antagonist before he takes alcohol to avoid gastric irritation .He consults you .Which H2 antagonist will you ask him to take ?
Answer :
Famotidine
Explanation :
All H2 antagonist except famotidine inhibit gastric first pass metabolism of ethanol and increase its bioavailability .

12. Proton Pump Inhibitors
Most effective drugs in antiulcer therapy
Irreversible inhibitor of H+ K+ ATPase
Prodrugs requiring activation in acid environment
Weakly basic drugs & so accumulate in canaliculi of parietal cell
Activated in canaliculi & binds covalently to extracellular domain of H+ K+ ATPase
Acid secretion resumes only after synthesis of new molecules
Half life is about 1.5 hrs

13. Proton Pump Inhibitors
Omeprazole mg o.d.
Esomeprazole mg o.d.
Lansoprazole mg o.d.
Pantoprazole mg o.d.
Rabeprazole mg o.d.
Now answer this question
It is given in the previous slides that the half life of proton pump inhibitors is 1.5 hours only and these drugs are generally given once daily. How this can be justified ?
Answer :
P.P.I - Irreversible inhibitors of H+K+ATPase
(Hit and run drugs)

14. Proton Pump Inhibitors – Kinetics
Given as enteric coated granules in capsule or enteric coated tablets
Pantoprazole also given intravenously
Half life – 1.5 hrs
Since it requires acid for activation - given 1 hr before meals
Other acid suppressing agents not coadministered

15. P.P.I. – Side effects & Interactions
Extremely safe drugs
Causes hypergastrinemia which leads to carcinod tumor in rats
But no evidence of such tumors in man
Inhibit CYP 450 & hence metabolsim of warfarin, phenytoin, etc
Pantoprazole & Rabeprazole have no significant interactions

16. Now Answer this Question
A patient comes to your clinic at midnight complaining of heart burn. You want to relieve his pain immediately. What drug will you choose?
Answer :
Antacids
Explanation :
Antacids neutralise the already secreted acid in the stomach. All other drugs act by stopping acid secretion and so may not relieve symptoms atleast for 45 min.

17. Mucosal Protective Agents
Sucralfate
Salt of sucrose complexed to sulfated aluminium hydroxide
In acidic pH polymerises to viscous gel that adheres to ulcer crater
Taken on empty stomach 1 hr. before meals
Concurrent antacids, H2 antagonist avoided
( as it needs acid for activation )
Sucralfate
Misoprostol
Colloidal Bismuth compounds

18. Mucosal Protective Agents Colloidal Bismuth Compounds
Misoprostol
PGE1 analogue
Modest acid inhibition
Stimulate mucus & bicarbonate secretion
Enhance mucusal blood flow
Approved for prevention of NSAID induced ulcer
Diarrhoea & cramping abd. pain – 20 %
Not so popular as P.P.I are more effective & better tolerated
Colloidal Bismuth Compounds
Coats ulcer, stimulates mucus & bicarbonate secretion
Direct antimicrobial activity against H.pylori
May cause blackening of stools & tongue
Not used for long periods – bismuth toxicity

19. Now answer this question
A pregnant lady (first trimester) comes to you with peptic ulcer disease. Which drug will you prescribe for her ?
Answer :
Antacids or Sucralfate
Explanation ;
H2 antagonists cross placenta and are also secreted in breast milk. Safety of Proton pump inhibitors not established in pregnancy. Misoprostol causes abortion .

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

21. Triple Therapy vs Sequential Therapy
The BEST Triple therapy regimen
Omeprazole / Lansoprazole / 30 mg bd
Clarithromycin mg bd
Amoxycillin / Metronidazole- 1gm / 500 mg bd
Recent Meta analysis:
25% of patients are resistant
Sequential Therapy:
PPI+Amoxycillin for first 5 Days
AND
PPI+Clarithromycin+Tinidazole/Metronidazole for next 5 Days
Recent Meta analysis:
Sequential therapy is better than Triple therapy.
Nadim S. Jafri Ann Intern Med. 2008;148:

22. Quadruple Therapy Given when Triple Therapy fails
Omeprazole / Lansoprazole / 30 mg bd
Bismuth subsalycilate tabs qid
Metronidazole mg qid
Tetracycline mg qid

23. Now you have learnt about drugs used for treating peptic ulcer
Now you have learnt about drugs used for treating peptic ulcer ? Are there any drugs that can cause peptic ulcer ?
Drugs causing peptic ulcer
Non Steroidal Anti Inflammatory Drugs (NSAIDs)
Glucocorticoids
Cytotoxic agents