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Drugs used in the treatment of peptic ulcer

Drugs used in the treatment of peptic ulcer. Mechanism of HCl secretion. ACh. PGE 2. _. +. +. +. +. +. +. +. Gastrin. Histamine. PGE receptor. H 2. M 3. Adenyl cyclase. Gastrin receptor. Ca ++. ATP. cAMP. Ca ++. Protein Kinase (Activated). K +. H +. Parietal cell.

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Drugs used in the treatment of peptic ulcer

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  1. Drugs used in the treatment of peptic ulcer

  2. Mechanism of HCl secretion

  3. ACh PGE2 _ + + + + + + + Gastrin Histamine PGE receptor H2 M3 Adenyl cyclase Gastrin receptor Ca++ ATP cAMP Ca++ Protein Kinase (Activated) K+ H+ Parietal cell Proton pump Lumen of stomach Gastric acid

  4. ACh PGE2 _ + + + + + + + Gastrin Histamine 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 Gastric acid

  5. Types of gastric HCl secretion 1- Nocturnal (basal) acid secretion: depend on histamine 2- Meal stimulated acid secretion: stimulated by: • Gastrin • Acetylcholine • Histamine

  6. Phases of gastric secretion 1) Cephalic Phase 2) Gastric Phase 3) Intestinal Phase

  7. Phases of gastric secretion

  8. Regulatory molecules that stimulate acid secretion

  9. Steps of gastric acid secretion by parietal cells * Chloride (Cl¯) and hydrogen ions are secreted actively from the cytoplasm of parietal cells into the lumen of the canaliculus where and they combine into HCl then secreted into the lumen of the stomach * Hydrogen ions are produced in the parietal cells by the action of the enzyme carbonic anhydrase which catalyses the reaction between carbon dioxide and water, in which carbonic acid is produced. This acid immediately dissociates into hydrogen ions and carbonate ions. Hydrogen ions leave the cell by the aid of H+/K+ATPase pump. * Chloride ions are transported across the basolateral membrane of the parietal cells into the parietal cells in exchange with bicarbonates

  10. Gastric Defenses Against Acid 1-Esophageal defense: the lower esophageal sphincter, which prevents reflux of acidic gastric contents into the esophagus. 2- Stomach defense: (require adequate mucosal blood flow because of the high metabolic activity and oxygen requirements of the gastric mucosa) a) Secretion of a mucus layer that protects gastric epithelial cells. Mucus production is stimulated by prostaglandins E2 and I2, which also directly inhibit gastric acid secretion by parietal cells. Drugs that inhibit prostaglandin formation (as alcohol and NSAIDs) decrease mucus secretion and predispose to the development of acid-peptic disease. b) Secretion of bicarbonate ions by superficial gastric epithelial cells. Bicarbonate neutralizes HCl.

  11. I- Agents that reduce gastric acidity • Proton pump inhibitors • H2 receptor antagonists • Muscarine receptor antagonists • Antacids II- Mucosal protective agents • Sucralfate • Prostaglandin (PGE1) agonists (misoprostol) • Colloidal bismuth compounds • Carbenoxolone

  12. I- Agents that reduce gastric acidity • Proton pump inhibitors • H2 receptor antagonists • Muscarine receptor antagonists • Antacids

  13. I- Agents that reduce increased gastric acidity 1-Proton pump inhibitors • Proton pump inhibitors are the most potent suppressors of gastric acid secretion • Omprazole • Esomeprazole • Lansoprazole • Rabeprazole • Pantoprazole Action: Inhibit both fasting (basal) and meal-stimulated HCl secretion by irreversible inactivation of the proton pump in the wall of parietal cells

  14. Proton pump inhibitorsPharmacokinetics: Proton pump inhibitors are prodrugs that require activation in an acid environment 1- Oral forms are prepared as acid resistant formulations that release the drug in the intestine (because they are degraded in acid media) 2- After absorption, they are distributed by blood to parietal cells 3-They irreversibly inactivate the proton pump molecule (providing 24- to 48-hour suppression of acid secretion, despite the much shorter plasma half-lives of the parent compounds).

  15. Proton pump inhibitorsPharmacokinetics 4- they should be given on an empty stomach because food affects absorption 5- They should be given 30 minutes to 1 hour before food intake because an acidic pH in the parietal cell acid canaliculi is required for drug activation, and food stimulates acid production (Concomitant use of other drugs that inhibit acid secretion, such as H2-receptor antagonists, might be predicted to lessen the effectiveness of the proton pump inhibitors )

  16. Proton pump inhibitorsPharmacokinetics 6- Maximal effect is reached after 3 to 4 days of administration (the time required to fully inactivate the proton pumps) 7- Their effects persists for 3 to 4 days after stopping the drug (the time required for full recovery of the proton pumps) 8- Metabolized by the liver (dose reduction is necessary in severe liver impairment) 9- Minimal excretion by the kidney ( no dose reduction is necessary in renal impairment)

  17. Proton pump inhibitors Adverse effects Few 1- The most common are GIT troubles in the form of nausea, abdominal pain, constipation, flatulence, and diarrhea 2- Subacute myopathy, arthralgias, headaches, and skin rashes 3- Prolonged use leads to vitamin B12 deficiency (because HCl is important for releasing vitamin B12 from food). 4-Hypergastrinemia which may predispose to rebound hypersecretion of gastric acid upon discontinuation of therapy and may promote the growth of gastrointestinal tumors (carcinoid tumors )

  18. Proton pump inhibitorsDrug interactions • Metabolized by cytochrome P450 enzymes and may interfere with the metabolism of drugs metabolized with cytochrome P45o as warfarin, diazepam and cyclosporine increasing their levels and producing toxicity

  19. Proton pump inhibitorsTherapeutic uses • Gastroesophageal reflux disease (GERD) • Gastric and duodenal ulcers • Prevention of recurrence of nonsteroidalantiinflammatory drug (NSAID)-associated gastric ulcers in patients who continue NSAID use. • Reducing the risk of duodenal ulcer recurrence associated with H. pylori infections.

  20. H2 receptor antagonists -

  21. Muscarine receptor antagonists • Pirenzepine • Telenzepine Mechanism of action: reduce meal stimulated HCl secretion by reversible blockade of muscarinic (M1) receptors on the cell bodies of the intramural cholinergic ganglia ( receptors on parietal cells are M3). Adverse effects: They produce anticholinergic side effects at doses that block HCl secretion Because of poor efficacy, side effects and delay of gastric emptying, they are not used in treating acid peptic disease

  22. I- Agents that reduce increased gastric acidity 4- Antacids Mechanism of action: 1- Reduction of intragastric acidity by reacting with gastric HCl to form salt and water 2- Stimulate mucosal PG production Types: NaHCO31- Sodium bicarbonate CaCO32- Calcium carbonate 3- Al hydroxide Al(OH)3 Mg(OH)24- Magnesium hydroxide

  23. Chemical reactions of antacids with HCl in the stomach

  24. Effects of antacids 1- Neutralize excess HCl in the stomach (by the reacted part) 2- Effect of the unreacted part 3- Effects of the products of the reaction

  25. Effects of antacids1- Sodium bicarbonate 1-Effect of the reacted part: rapid neutralization of the gastric HCL 2- Unreacted sodium bicarbonate could be absorbed causing metabolic alkalosis if given in high doses or in patients with impaired renal function. 3- NaCl produced by the reaction could be absorbed causing fluid retention and aggrevating hypertension 4- CO2 produced causes gastric distention and increased production of gastrin which causes rebound acidity 5- High doses given with dairy products can lead to hypercalcemia and renal insufficiency (milk-alkali syndrome)

  26. Effects of antacids2- Calcium carbonate 1-Effect of the reacted part: less rapid neutralization of the gastric HCL 2- CO2 produced causes gastric distention and increased production of gastrin which causes rebound acidity 3- High doses given with dairy products can lead to hypercalcemia and renal insufficiency (milk-alkali syndrome)

  27. Effects of antacids3- Aluminum hydroxide 1-Effect of the reacted part: slow neutralization of the gastric HCL 2- No metabolic alkalosis 3- Unabsorbed aluminum salts may cause constipation

  28. Effects of antacids4- Magnesium hydroxide 1-Effect of the reacted part: slow neutralization of the gastric HCL 2- No metabolic alkalosis 3- Unabsorbed magnesium salts may cause osmotic diarrhea 4- Magnesium could be absorbed and excreted by the kidney and therefore should not be given to patients with renal insufficiency for a long tine

  29. Mucosal protective agents1- Sucralfate Sucralfate = complex aluminum hydroxide + sulfate + sucrose Mechanism of action: 1- in acidic environment of the stomach, it forms a viscous paste that binds to ulcers or erosions for 6 hours forming a physical barrier against hydrolysis of mucosal proteins by pepsin. 2- stimulates mucosal prostaglandins and bicarbonate production 3- Sucralfate binds bile salts (used to treat individuals with biliary gastritis

  30. Mucosal protective agents1- Sucralfate Therapeutic uses: • Prophylaxis of stress ulcers in critically ill patients (increased pH of the stomach increases the possibility of nosocomial infections. • Conditions associated with mucosal ulceration not due to acid production as aphthous ulcers and by rectal enema solitary rectal ulcers.

  31. Mucosal protective agents1- Sucralfate • Administration: • Since it is activated by acid, sucralfate should be taken on an empty stomach 1 hour before meals. The use of antacids within 30 minutes of a dose of sucralfate should be avoided.

  32. Mucosal protective agents1- Sucralfate • Adverse Effects: Constipation • Precautions: • should be avoided in patients with renal failure (because some aluminium is absorbed). • Should be taken at least 2 hours after the administration of other drugs as phenytoin and digoxin (forms a viscous layer in the stomach that may inhibit absorption of drugs)

  33. Mucosal protective agents 2- Prostaglandin Analogs: (Misoprostol = Synthetic analog of prostaglandin E1) Prostaglandins produced by the gastric mucosa

  34. Mucosal protective agents 2-Misoprostol • Actions: • Inhibit histamine-stimulated gastric acid secretion • Stimulation of mucin and bicarbonate secretion • Increase mucosal blood flow • Therapeutic uses: Prevent ion of NSAID-induced mucosal injury (rarely used because it needs frequent administration – 4 times daily)

  35. Mucosal protective agents 2-Misoprostol • Adverse Effects: • Diarrhea, with or without abdominal pain and • Exacerbations of inflammatory bowel disease and should be avoided in patients with this disorder. Contraindications: • Inflammatory bowel disease • Pregnancy (may cause abortion)

  36. Mucosal protective agents 3- Colloidal bismuth compounds(Bismuth subsalicylate) Pharmacological actions: 1- Undergoes rapid dissolution in the stomach into bismuth and salicylates. 2- Salicylates are absorbed 3- Bismuth coats ulcers and erosions protecting them from acid and pepsin and increases prostaglandin and bicarbonate production Uses: -Treatment of dyspepsia and acute diarrhoea

  37. Mucosal protective agents 4- Cabenooxolone Mechanism of action: not known Adverse reactions: It has aldosterone like action and may cause: 1- sodium retention 2- Hypokalemia 3- Oedema 4- Exacerbates hypertention

  38. Specific acid dyspeptic disorders and therapeutic strategies

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