Drugs used to treat peptic ulcer disease

Lecture presentation for BSc Nursing

1. Drugs Used to treat Peptic Ulcer Disease Dr. Pravin Prasad M.B.B.S., MD Clinical Pharmacology Assistant Professor, Maharajgunj MedicalCampus 21 june 2020 (7 asar 2077), Sunday

2. By the end of this class, BSN 1 st year students will be able to: Classify drugs used in Peptic Ulcer Disease (PUD) Explain the pharmacological basis of use of different drugs for the treatment of PUD List the specific adverse drug reactions of different drugs for the treatment of PUD 2

3. Relevant Physiology: Gastric acid secretion 3

4. Drugs Used in PUD: Classification Reduction of gastric acid secretion Neutralization of gastric acids Ulcer protectives Anti H pylori drugs 4

5. Drugs Used in PUD: Classification Reduction of gastric acid secretion Neutralization of gastric acids Ulcer protectives Anti H pylori drugs H 2 anti histamines : Cimetidine, Ranitidine, Famotidine Proton pump inhibitors : Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole Anticholinergic drugs : Pirenzepine, propantheline Prostaglandin analogues : Misoprostol 5

6. Drugs Used in PUD: Classification Reduction of gastric acid secretion Neutralization of gastric acids Ulcer protectives Anti H pylori drugs Systemic : Sodium bicarbonate, sodium citrate Non Systemic : Calcium carbonate, Magnesium hydroxide, Magnesium trisilicate, Aluminium hydroxide gel, Magaldrate 6

7. Drugs Used in PUD: Classification Reduction of gastric acid secretion Neutralization of gastric acids Ulcer protectives Anti H pylori drugs Sucralfate Colloidal bismuth subcitrate 7

8. Drugs Used in PUD: Classification Reduction of gastric acid secretion Neutralization of gastric acids Ulcer protectives Anti H pylori drugs Amoxicillin Clarithromycin Metronidazole, Tinidazole Tetracycline 8

9. Anticholinergics for PUD Nonselective: Atropine, Propantheline, Oxyphenonium Selective: Pirenzepine (M 1 ) Cholinergic receptors: Muscuranic Nicotinic Muscuarnic receptors: M 1 receptors: Stimulatory Gastric glands: increased secretion 9

10. Anticholinergics for PUD Acts by reducing the gastric secretion volume Nonselective anticholinergics: High doses required Intolerable side effects Not used these days Selective anticholinergics: Reduces gastric secretion by 50% Less side effects at effective doses Not commonly used 10

11. Antihistamines in PUD H 2 antihistamines are used: Competitive blockers: Cimetidine, Ranitidine, Roxatidine Non-competitive blockers: Famotidine Acts by decreasing gastric acid secretion Basal, psychic, neurogenic, gastric phases decreased 60-70% inhibition of acid output 11

12. Antihistamines in PUD Uses Promote healing of gastric and duodenal ulcers Heal uncomplicated GERD Prevent occurrence of stress ulcers Gastrinoma Famotidine: Zollinger Ellison syndrome, prevention of aspiration pneumonia PPIs preferred due to higher efficacy and equally good tolerability 12

13. Antihistamines in PUD Adverse Drug Reactions Well tolerated, low incidence of side effects Diarrhoea , headache, drowsiness, fatigue, muscular pain, constipation CNS side effets (confusion, delirium, hallucinations, slurred speech) Cimetidine: Galactorrhoea in females and gynaecomastia Reduced sperm count and impotence in males- rare 13

14. Proton pump inhibitors in PUD Inhibits common final steps in gastric secretion Dose-dependent action Can totally abolish HCl secretion Mechanism of action: Gets activated at pH < 5 (gastric pH) Reacts co- valently with H + K + ATPase pump (proton pump) and inhibits irreversibly: Hit and Run Drugs Acid secretion resumes only after synthesis of new pump molecules (~ 18 hrs ) 14

15. Proton pump inhibitors in PUD Pharmacokinetics Administered orally in enteric coated ( e.c. ) form Do not be break or crush the tablets Oral bioavailability (omeprazole): ~50% Bioavailability reduced by food: should be taken in empty stomach, followed 1 hour later by a meal Omeprazole is highly plasma protein bound Rapidly metabolized in liver by CYP2C19 and CYP3A4 (plasma t½ ~1 hr ) Excreted in urine Inhibition of HCl secretion occurs within 1 hr , reaches maximum at 2 hrs , is still half maximal at 24 hrs and lasts for 2–3 days At steady state all PPIs produce 80–98% suppression of 24 hour acid output with conventional doses Secretion resumes gradually over 3–5 days of stopping the drug 15

16. Proton pump inhibitors in PUD Uses Promote healing of gastric and duodenal ulcer Bleeding peptic ulcer Stress ulcers Gastro-esophageal reflex disorder Erosive esophagitis Zollinger Ellison Syndrome Prevention of recurrence of NSAIDs induced ulcer 16

17. Proton pump inhibitors in PUD Adverse effects: Rare, well tolerated Nausea, loose stools, headache, abdominal pain, muscle and joint pain, dizziness (3-5%) Rashes, leucopenia, hepatic dysfunction Atrophic gastritis on prolonged use Accelerated osteoporosis among elderly patients: high dose and long term use Omeprazole (prolonged use): gynecomastia, erectile dysfunction Subacute myopathy, arthralgias, headache and skin rashes have been reported 17

18. Ulcer Protectives: Sucralfate Basic aluminum salt of sulfated sucrose Mechanism of action: Polymerizes at pH < 4 by cross linking of molecules, assuming a sticky gel-like consistency Preferentially and strongly adheres to ulcer base, especially duodenal ulcer Surface proteins at ulcer base are precipitated Acts as a physical barrier Dietary proteins get deposited on this coat 18

19. Ulcer protectives: Sucralfate Minimally absorbed after oral administration Should not be given with antacids Infrequently used now because of need for 4 large well-timed daily doses and the availability of simpler and more effective H 2 blockers/PPIs. Indications : Ulcer healing (duodenal, gastric) Bile reflux Gastritis Prophylaxis of stress ulcers Topical: burns, bedsores, diabetic/ radiation ulcers, excoriated skin 19

20. Ulcer Protectives: Sucralfate Adverse drug reaction Constipation Hypophosphatemia Dry mouth and nausea 20

21. Ulcer Protectives: Colloidal Bismuth Subcitrate It is a colloidal bismuth compound; water soluble but precipitates at pH < 5 Mechanism of action (possibilities): May increase gastric mucosal PGE2, mucus and HCO3 ¯ production May precipitate mucus glycoproteins and coat the ulcer base May detach and inhibit H.pylori directly Milk and antacids should not be taken concomitantly 21

22. Ulcer Protectives: Colloidal Bismuth Subcitrate Majority eliminated unchanged in faeces Small amounts absorbed are excreted in urine Adverse drug reactions: Diarrhoea , headache and dizziness Poor patient acceptance of CBS Blackening of tongue, dentures and stools Inconvenient dosing schedule Indication: Add on drug for triple drug Anti- H. pylori therapy 22

23. Introduction Basic substances which neutralize gastric acid and raise pH of gastric contents Includes: Aluminum Hydroxide, Magnesium Carbonate, And Magnesium Trisilicate Are Available As Tablets And Liquids May be combined with: Simethicone: reduces flatulence Alginates: protects the lining of the esophagus (gullet) from stomach acid Sodium Alginate And Alginic Acid 23

24. Antacids: Mechanism of Action Neutralises the gastric acid Acid Neutralising Capacity: number of mEq of 1N HCl that are brought to pH 3.5 in 15 min (or 60 min in some tests) by a unit dose of the antacid preparation Leads to: Decrease in pain Allow the ulcers to heal Decreases the activity of pepsin Secreted as an inactive form, gets activated in pH < 4 May lead to rebound acidity 24

25. Non systemic antacids Insoluble and poorly absorbed basic compounds react in stomach to form the corresponding chloride salt Chloride salt again reacts with the intestinal bicarbonate so that HCO 3 ¯ is not spared for absorption—no acid-base disturbance occurs However, small amounts that are absorbed have the same alkalinizing effect as NaHCO 3 25

26. Non systemic antacids Mag. Hydroxide: low water solubility: its aqueous suspension (milk of magnesia) has low concentration of OH¯ ions and thus low alkalinity Reacts with HCl promptly and is an efficacious antacid (1 g → 30 mEq HCl) Rebound acidity is mild and brief 26

27. Non systemic antacids Magnesium trisilicate Low solubility and reactivity 1 g can react with 10 mEq acid, but in clinical use only about 1 mEq is neutralized About 5% of administered Mg is absorbed systemically—may cause problem if renal function is inadequate All Mg salts have a laxative action by generating osmotically active MgCl 2 in the stomach and through Mg 2+ ion induced cholecystokinin release 27

28. Non systemic antacids Aluminium hydroxide gel bland, weak and slowly reacting antacid Little acid neutralization obtained at conventional doses The Al 3+ ions relax smooth muscle: delays gastric emptying (constipation) Binds phosphate in the intestine and prevents its absorption—hypophosphatemia occurs on regular use leading to: osteomalacia Be used as therapeutically in hyperphosphatemia and phosphate stones. Small amount of Al 3+ that is absorbed is excreted by kidney Aluminium toxicity (encephalopathy, osteoporosis) in renal failure 28

29. Non systemic antacids Magaldrate hydrated complex of hydroxymagnesium aluminate that initially reacts rapidly with acid and releases alum. hydrox . which then reacts more slowly The freshly released alum. hydrox . is in the unpolymerized more reactive form Thus, magaldrate cannot be equated to a physical mixture of mag. and alum. Hydroxides It is a good antacid with prompt and sustained neutralizing action. Its ANC is estimated to be 28 mEq HCl/g 29