pharmacology of drugs

1. Drugs for Peptic Ulcer & GERD
Dr. K.R.Prabhakar
Asst.Professor

2. Introduction
• Peptic ulcer- localized loss of gastric as well as
duodenal mucosa.
• Peptic ulcer- both gastric & duodenal ulcer.
• Imbalance primarily between Aggressive factors and
Defensive factors:
Aggressive factors,
e,g, acid, pepsin,
NSAID, H.Pylori etc
Defensive factors-
mucus, mucosal
blood flow, HCo3-
& PGE2

3. • Ulcers occur 5 times more common in duodenum.
• 95% occur in duodenal bulb or pylorus.
• Benign gastric ulcers- 60% in antrum.
• 25% at the junction of antrum & fundus of lesser
curvature.
• Presents as gnawing dull hunger like pain in
epigastric region.
• Barium meal X-ray- ulcer crater.

4. Physiology of acid secretion

5. Drug treatment of peptic ulcer
Goals of antiulcer therapy
• Relief from pain.
• Promotion of ulcer healing.
• Prevention of complications.
• Prevention of relapse.

6. Drugs which neutralize gastric acid
• Systemic antacids: Sodium bicarbonate
• Non systemic antacids:
1. Buffer type: Aluminium hydroxide,
Magnesium trisilicate, Magaldrate.
2. Non Buffer type: Magnesium hydroxide,
Calcium carbonate.
3. Miscellaneous: Alginates, Simethicone

7. Drugs which reduce Gastric acid secretion
H2 receptor Antagonist
• Cimetidine
• Ranitidine
• Famotidine
• Nizatidine
• Roxatidine
• Loxatidine
PG analogues
• Misoprostol
• Enprostil, Rioprostil
Proton pump inhibitors
• Omeprazole
• Lansoprazole
• Pantoprazole
• Rabeprazole
• Esomeprazole
Anticholinergics
• Propanthaline,
• Oxyphenonium,
• Pirenzipine, Telenzepine

8. Mucosal protective drugs
• Sucralfate
• Colloidal bismuth
subcitrate
• Ranitidine bismuth
citrate
Ulcer healing drugs
• carbenoxolone
Anti-Helicobacter pylori
drugs
• Amoxicillin
• Clarithromycin
• Tetracycline
• Metronidazole
• Ranitidine bismuth
citrate
• Bismuth subsalicylate
• Proton pump inhibitors

9. Antacids
• Antacids are weak bases that neutralize gastric HCl.
• Raises pH of the stomach and ↓ pepsin activity.
• Promotes mucosal defense by stimulation of PGs.
• Forms protective layer over gastric mucosa.
• Administered b/w meals & at bed time.
• Food prolongs neutralizing capacity.
• Potency expressed in terms of its acid neutralizing
capacity.

10. Systemic antacids
• Sodium bicarbonate- acts rapidly, has brief duration
of action, raises gastric pH to about 7.4.
• It has several demerits:
1. Absorbed systemically: large doses will induce
alkalosis
2. Produces Co2 in stomach→ distension, discomfort,
belching, risk of ulcer perforation.
3. Acid rebound occurs, but is usually short lasting.
4. Increases Na+ load: may worsen edema and CHF.

11. Uses:
• Restricted to casual treatment of heartburn provides
quick symptomatic relief
• Other uses are to alkalinize urine and to treat
acidosis.

12. Non systemic antacids
• Poorly absorbed from GI tract.
• Do not disturb systemic acid base balance.
• Do not elevate urinary pH.
Buffer type
• Aluminium hydroxide,
• Magnesium trisilicate,
• Magaldrate

13. • These have slow onset but longer duration of action.
• Raises gastric pH to 3.5-4.
• Rebound acidity is not a problem.
Aluminium hydroxide & Mg.trisilicate

14. • Al(OH)3 causes constipation because of –
1. Formation of aluminium phosphate.
2. SMR action of Al3+
3. Mucosal astringent action of aluminium salts.
• Binds to PO4
3- in intestine & prevents absorption.
• Hypophosphataemia may occur.
• Al(OH)3 can also be used to treat
Hyperphosphataemia & phosphate stones.

15. Magnesium trisilicate
• Does not disturb acid base balance.
• SiO2 forms a gelatinous coating over gastric mucosa.
• MgCl2 & MgCO3 cause diarrhea.
• Mg salts & Al salts are commonly administered
together to minimize effect on bowel movement.
Magaldrate
• Hydrated complex of Al-Mg hydroxide sulfate.
• Reacts with HCl & releases Al(OH)3 & Mg(OH)3.

16. Non Buffer type
Calcium carbonate
• Powerful antacids with fast action.
• Raises gastric pH above 7.
• Causes belching due to release of CO2.
• Excessive doses with milk causes hypercalcemia,
renal insufficiency & metabolic alkalosis called
milk-alkali syndrome.
• Acid rebound is marked as CaCl2 itself is gastrin
stimulant.
• Causes constipation due to Ca stereate.

17. Magnesium hydroxide
• Efficacious, neutralizes HCl promptly.
• Elevates gastric pH up to 7.
• Acid rebound is mild & brief.
• MgCO3 causes diarrhea.
• Belching does not occur as CO2 is not generated.
• Given along with Al(OH)3.

18. Drug interactions
• AL, Ca & Mg salts forms inert complexes and ↓
absorption & BA of
1. Tetracyclines
2. Fluroquinolones
3. Itraconazole
4. Digoxin
5. Iron salts & phosphates.
• ↓ absorption of acidic drugs like barbiturates,
phenytoin & NSAID’s

19. Miscellaneous adjuants to antacids
Simethicone (Dimethyl polysiloxane)
• Silicon polymer with water repellent properties.
• Acts as antifoaming agent & ↓ flatulence.
• Aids proper dispersion of antacid in gastric contents.
• Coats ulcer surface, prevents hiccups.
• Pharmacologically inert, not absorbed from GIT.
• Also used in topical skin preparations to prevent bed
sores.

20. Sodium alginate
• Hydrophilic colloidal carbohydrate derivatives.
• Extracted from brown sea weeds.
• Used along with antacids/H2 blockers.
• Reacts with gastric acid to form a viscous gel (raft).
• Acts a mechanical barrier to ↓ heartburn & GERD.

21. H2- Receptor antagonists
Mechanism of action:
• Competitively inhibit H2 receptors on parietal cells.
• Suppresses basal & food induced acid secretion.
• Specific for H2, don’t inhibit H1 & H3 receptors.
• Blocks the action of histamine released from ECL
through gastric & vagal stimulation.
• Secretory responses to other stimuli (ACh, gastrin,
insulin, alcohol, food) are also attenuated.
• Markedly↓ gastric acid secretion for longer duration
& pepsin for shorter period.

22. • Blocks >90% of nocturnal acid & 60-70% of day time
food stimulated acid secretion.
• Therapeutic doses maintain 50% of inhibition for up
to 10hrs, hence given twice daily.
• Cimetidine is a prototype drug others are-
• Ranitidine
• Famotidine
• Nizatidine
• Roxatidine
• Loxatidine

23. Clinical uses
• GERD (Gastro Esophageal Reflux Disease).
• Peptic ulcer (gastric & duodenal ulcer)disease.
• NSAID’S induced ulcer (PPI are preferred).
• Prevention of stress related gastric bleeding.
• Prevention of ulcer recurrence.
• Zollinger-Ellison syndrome (PPI are preferred).
• Chronic urticaria as they ↑ efficacy of H1 blockers.

24. Definitive treatment
of ZES is surgery

25. Adverse effects
• Extremely safe drugs.
• Headache, fatigue, myalgia & constipation- rarely.
• Cimetidine –
1. Mental status changes may occur with I.V adm.
2. Impotence in males
3. Gynaecomastia in males, galactorrhoea in females.
• ↓ IF but Vit B12 deficiency do not occur.
• Should be avoided in pregnancy & lactation.

26. Drug interactions
• Antacids ↓ absorption of H2 blockers.
• Cimetidine is potent inhibitor of CYP1A2, CYP2C9,
CYP2D6, CYP3A4.
• Hence effects plasma half lives of-
• Warfarin TCA
• Theophylline Benzodiazipines
• Phenytoin CCB
• Quinidine OHA
• Beta-blockers Metronidazole

27. H2 blockers

28. Proton pump inhibitors
• Most widely used drugs for peptic ulcer.
• Safe & efficacious.
• Omeprazole is the prototype.
• Esomeprazole
• Lansoprazole
• Pantoprazole
• Rabeprazole
• All are given orally, pantaprazole I.V also.
• Available as enteric coated formulations.

29. Mechanism of action
• All PPIs are prodrugs. These are weak bases.
• Active entity is sulfenamide cation formed in parietal
cell.
• Enteric coating dissolves in alkaline intestinal lumen.
• Prodrug gets absorbed in the intestine.
• In parietal cell canaliculus they gets trapped due to
acidic pH.
• Undergoes molecular rearrangement to form
sulfenamide cation.

30. • Sulfenamide forms covalent disulfide bond with SH
group of proton pump.
• Inactivates Proton pump irreversibly & shuts off acid
secretion.
• PPIs also inhibit gastric mucosal CA, ↓HCO3
-
• Tenatoprazole: longer half life than other PPIs.
• Inhibits nocturnal acid secretion effectively.
• Potassium competitive acid pump blockers (P-CABs).
• Newer class of drugs under development.

31. Pharmacokinetics
• Food decreases BA significantly.
• Should be taken in empty stomach, followed 1 hour
later by a meal to activate the H+K+ ATPase and
make it more susceptible to the PPI.
• Short t1/2 but longer duration of action up to 24hrs.
• Inhibits proton pump irreversibly.
• There is a biological lag of 3-4 days for full inhibition.
• Produce 80-98% suppression of 24 hour acid output.

32. • Secretion resumes gradually over 3-5 days of
stopping the drug.
• PPI undergoes rapid first pass & metabolized by liver.
• Dose reduction needed only in severe liver
impairment.
• I.V pantaprazole should be given as 24hrs continuous
infusion.
• Compensatory hypergastrinemia has been observed
on long term use.

33. Clinical uses
• PPIs inhibit fasting & food stimulated acid secretion.
• Duodenal & gastric ulcer disease.
• GERD.
• NSAIDs induced ulceration.
• Prevention of ulcer recurrence.
• ZES.
• H.pylori assosiated ulcers. 2antibiotics+ PPI BD. PPI
continued OD for 4-6 wks to promote ulcer healing.
• Aspiration pneumonia.

35. Adverse effects
• These are minimal:
• Nausea, Loose stools, headache, abdominal pain,
muscle & joint pain, dizziness (3-5%).
• Rashes (1.5% incidence)
• leucopenia and hepatic dysfunction are infrequent.
• On prolonged treatment atrophic gastritis has been
reported occasionally.
• Compensatory hypergastrenemia.

36. Drug interactions
• ↓absorption of ketoconazole & digoxin.
• Omeprazole esomeprazole & lansoprazole inhibit
CYP2C19,& CYP3A4 – May enhance the effect of -
warfarin, phenytoin, carbamazepine & BZD.
• Lansoprazole enhance elimination of theophylline.
• Rabeprazole & pantoprazole exhibit no significant
drug interaction.

37. Anticholinergics
• Propantheline & Oxyphenonium are preferred as
they don’t cross BBB.
• Blocks basal secretions more effectively.
• ↑gastric emptying time and prolongs exposure of
ulcer bed to gastric acid. Relaxes LES.
• These disadvantages make them unsuitable for
peptic ulcer & GERD.
• Nonselective retains anticholinergic side effects.

38. Pirenzepine & Telenzepine
• Selective M1 receptor blockers used in Canada &
Europe for Rx of peptic ulcer.
• Effectively heal as well as prevent recurrence.
• At usual doses side effects are low.

39. PG analogues
Misoprostol (PGE1)
• 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)

40. • Doses: 200 mcg 4 times a day
• ADRs:
– Diarrhoea and abdominal cramps
– Uterine bleeding
– Abortion
– Exacerbation of inflammatory bowel disease.
Contraindications:
1. Inflammatory bowel disease
2. Pregnancy (may cause abortion)

41. 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 - acts as acid resistant
physical barrier.
– Dietary proteins get deposited on this layer
forming another coat.
– May stimulate PGE2 synthesis & HCO3- secretion.

42. • Bind epithelial & fibroblast growth factors which
promotes mucosal repair.
• SE: hypophosphataemia may occur.
• Concurrent antacids avoided.
• 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 .

43. 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

44. • Dose: 120 mg 4 times a day
• Adverse effects
– blackening of tongue, stools, dentures
– Prolonged use may cause osteodystrophy and
encephalopathy
– Diarrhoea, headache, dizziness

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

46. H.Pylori
• Gram (-) rod.
• Associated with gastritis, gastric & duodenal ulcers,
gastric adenocarcinoma, gastric lymphoma.
• Transmission route fecal-oral
• Secretes urease → convert urea to ammonia.
• Produces alkaline environment enabling survival in
stomach.
• Present in 90% of peptic ulcer cases.
• Higher prevalence in Low SES

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

51. THANK YOU