Gastrointestinal Agents

1. Gastrointestinal Agents Subat Turdi Xinjiang Medical University

2. Includes: • Antiulcer -H2- receptor blockers -Inhibitors of proton pump -Antacids -Antimicrobials -Prostaglandins • Antiemetics • Laxatives • Antidiarrhea • Antispasmodics • Appetite Suppressants

3. Pathophysiology of ulcer Gastric Cell Types: 1. parietal - HCl 2. mucus - mucous and bicarbonate 3. chief - pepsin

4. source: www.gerd.com

5. Parietal cell • Receptors • gastrin • muscarinic cholinergic • histamine H-2 • Final common pathway for acid secretion - hydrogen-potassium ATP'ase

6. + + + H H H + + + K K K Acid is released into the stomach by a proton pump vagus nerve parietal cell Stomach MR proton pump HR PGR ECL cell

7. + + + H H H + + + K K K Signaling acid release from parietal cells vagus nerve parietal cell Stomach MR proton pump HR PGR ECL cell Enterochromaffin-like

8. Pepsin • Proteolytic enzyme • pH profile • highest activity at pH 2.5 to 3 • activity severely diminished at pH 4 • unstable above pH 6 • Stored as pepsinogen in chief cell • Activated by acid and pepsin acid pepsin pepsinogen pepsin

9. Mucus • Secreted by goblet • Mucopolysaccharides and other substances suspended in water • Probably plays an important protective role in the stomach

10. Gastrin • several polypeptide hormones secreted into blood • secreted by the “G” cell • stimulatory to acid secretion • may be a trophic hormone for the gut

11. Nerve and Hormone Control Ach Ach histamine gastrin Parietal cell G cell acid inhibition --- ATP’ase Gastric lumen K+ H+

12. Peptic Ulcer • types: gastric and duodenal • incidence - 10 percent • symptoms: epigastric pain, blood excretion, nausea • chronic - high (80% in one year) recurrence rate • causes • Helicobacter pylori infection - main cause • acid and pepsin hypersecretion

13. source: www.gerd.com

14. Antiulcer drugs -H2- receptor blockers -Inhibitors of proton pump -Antacids -Antimicrobials -Prostaglandins

15. H2- receptor blockers • cimetidine (Tagamet) • ranitidine (Zantac) • famotidine (Pepcid) • nizatidine (Axid)

16. Cimetidine • reduces fasting, nocturnal and food-stimulated gastric acid secretion • heals GU and DU in a large percentage (eg. 75-90%) of patients over 8 weeks • effective when full daily dose given hs • reduced dosage for ulcer prophylaxis

17. Cimetidine: side-effects • mental confusion (esp. in elderly) • reversible gynecomastia • headache • inhibition of drug metabolism • warfarin • theophylline • diazepam • phenytoin

18. Cimetidine • short-term and prophylactic treatment • active duodenal • gastric ulcer • hypersecretory states – Zollinger-Ellison syndrome, mastocytosis • GERD therapy • dyspepsia

19. Proton Pump Inhibitor • protonated and activated at the parietal cell canaliculi • inhibits parietal cell H+, K+ ATP'ase • binds irreversibly to the enzyme

20. vagus nerve parietal cell Stomach MR + + + H H H proton pump HR + + + K K K PGR ECL cell Omeprazole and pantoprazole • Mechanism: Proton pump inhibitors travel through the blood stream to parietal cells and accumulate in the acidic secretory canaliculi, where they form covalent bonds with cysteine residues of the H+/K+ proton pump.

21. Omeprazole and pantoprazole • Pharmacokinetics:The uptake, activation, and clearance of proton pump inhibitors are complex. • Uptake:Proton pump inhibitors are unstable at low pH. As a result, omeprazole is given in an alkali-soluble gelatin capsule to prevent degradation in the stomach. Pantoprazole can be given i.v. • Activation: proton pump inhibitors require an acid environment to become active, so they are given with food to stimulate acid secretion. They should not be given with acid suppressing agentssuch as H2-receptor antagonists.

22. Ome Ome + + + + + + + + + + + H H H H H H K K K K K proton pump proton pump Importance of acid for the stability and activation of omeprazole antacids food

23. Omeprazole and pantoprazole • Pharmacokinetics: proton pump inhibitors are extensively metabolized in the liver by P450 proteins. Because the drugs bind irreversibly to proton pumps, they are effective for longer periods of time (24-48 hours) than they are present in the bloodstream (1-2 hours). • Not all proton pumps are cross-linked with a single dose of drug. It may take 2-5 days to cross-link the majority of proton pumps.

24. Omeprazole :Properties • inhibits gastric secretion regardless of stimulus • more efficacious than H-2 blockers • prolonged duration of action (eg. days) • no correlation between plasma half life (1 hour) and effect

25. Omeprazole 1.pathological hypersecretory states 2. acute or chronic duodenal ulcers 3. esophagitis

26. Antacids 1.still important 2. differ widely acid neutralizing capacity taste cost 3. liquids better than tablets 4. increase healing 5. some contain excessive sodium ion.

27. Antacids Ingredient: Al(OH)3, Mg(OH) 3or both Side effects: 1.Sodium bicarbonate - sodium over load, systemic alkalosis 2. Magnesium - diarrhea 3. Aluminum - constipation, phosphate depletion, bone resorption; 4. Calcium - constipation, milk-alkali syndrome 5. Binds certain drugs in the GI tract - tetracycline, ciprofloxacin, captopril, H2 blockers

28. Antimicrobials • Helicobacter pylori 1.H. pylori decreases somatostatin production 2. populates 90% of DU and 70% of GU patients 3. rationale of eradication • heals ulcers • prevents recurrence 4.may be a factor in gastric cancer • Combination of drugs bismuth subsalicylate，metronidazole and tetracycline or combines ranitidine , bismuth citrate and clarithromycin

29. Prostaglandins • PGE2 and I2,produced by gastric mucosa, secretion of HCl  secretion of bicarbonate Deficiency of PG is involved in the occurrence of peptic ulcer • Misoprostol (Cytotec) -methyl ester analog of PGE-1 -inhibits gastric acid secretion -cytoprotective actions - protects gastric mucosa from certain damaging agents (eg. ethanol, etc.)

30. Misoprostol: • Indication: prevention of gastric ulcers in patients taking NSAIDs • Contraindication: Pregnancy • Side-effects : nausea vomiting diarrhea others - mainly gynecological (cramps, hypermenorrhea, menstrual disorders)

31. Chemotherapy Induced Emesis higher centers Central emetic apparatus ondansetron metoclopramide?? anticancer drugs emesis 5HT3 receptors GUT release 5HT

32. Antiemetics Include: 1. H1 receptor blokers:diphenhydramine, promethazine,etc 2.M receptor blockers: hyoscine 3. Dopamine receptor blockers: metoclopramide, domperidone,chloropromazine, etc 4. 5-HT3 receptor blokers: ondansetron, graniseton treatment: 1.metoclopramide alone 2. metoclopramide combined with dexamethazone diphenhydramine lorazepam 3. ondansetron or granisetron

33. Laxatives • Classes: bulk osmotic stimulants softeners

34. Bulk laxatives • fiber - bran or other indigestible parts of fruits, vegetables and seeds • synthetic and semi-synthetic cellulose • psyllium (Metamucil) - from Plantago seed • attract water molecules • some bind bile salts • bile salts inhibit water and electrolyte absorption in the colon • metabolized by bacteria into smaller, osmotically active molecules • may exert osmotic pressure in the colon

35. Bulk laxatives • additional uses: • diverticular disease • irritable bowel syndrome • serum cholesterol lowering • onset: 12-24 hours

36. Osmotic laxatives • magnesium salts • sulfate (Epsom salt) • hydroxide • citrate • sodium phosphate (Fleets) • lactulose (Cephulac) • Sorbitol • relatively non-absorbed • an osmotic equivalent of water remains in the bowel • adverse effects • sodium overload • magnesium toxicity in patients with poor renal function • special uses: treatment of toxic ingestion • onset: 3-6 hours

37. Stimulants • castor oil • cascara and senna compounds • bisacodyl (Dulcolax)

38. Castor oil • triglyceride of ricinoleic acid • ricinoleic acid • long chain hydrox fatty acid • inhibits net water absorption in the intestine • enhances intestinal propulsion • mechanism: inhibition of intestinal water and electrolyte absorption • onset: 3 hours

39. Softeners 1.docusates calcium (Surfak) sodium (Colace) potassium (Kasof) 2. mineral oil (liquid petrolatum)