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1 Peptic ulcer Gastric and duodenal mucosa are eroded by acid , pepsin or HP,which cause mucosa injure. 2 When does peptic ulcer happen? aggressive factors > defensive factors 3 Defensive factors ①mucus ②bicarbonate ③blood ④prostaglandins Aggressive factors ①acid(Ach gastin、 histamin) ②pepsin ③HP. ④smoking,drugs 4 Anti-Peptic Ulcer Drugs 1. Antacids 2. Gastric acid secretion inhibitors • H2-receptor antagonists proton pump inhibitors • M1 muscarinic receptor antagonists • Cholecystokinin receptor 2 (CCK2) antagonist 3. Agents that enhance mucosal defense 4. anti- H. pylori drugs: 5 1. Drugs that Reduce intragastric acidity Include two classes: Antacids and inhibiting secretary drugs 6 Antacids Principle Base + acid (-OH) salt + water (HCl) 7 Tipycal drugs Magnesium Hydroxide and Aluminum Hydroxide + Hcl Al(OH)3 + Hcl Mg(OH)2 Mgcl2 + H2O Alcl3 + H2O 8 Adverse effects Mgcl2 cannot be absorbed ,it produces osmotic diarrhea. Alcl3 can produce constipation. So these drugs are commonly administered together to minimize the impact upon bowel function. 9 Calcium carbonate CaCO3 + Hcl Cacl2 + H2O+ CO2 Adverse effects Metabolic alkalosis hypercalcemia belching 10 Sodium Bicarbonate NaHCO3 + Hcl Nacl + H2O+ CO2 Adverse effects Metabolic alkalosis distention belching 11 comparison of some commonly used antacid preparations). NaHCO3 MgSiO3 Al(OH)3 Mg(OH)2 CaCO3 Strengh Onset time strong fastest weak faster moderate strong slower longer longer moderate faster faster duration short longer astringency - - CO2 alkalemia + + - - - - - - + - protection - + + ± - diachoresis - diarrhea + constipation - longer + dia. Cons. 12 Acid secretion inhibitor H2-receptor antagonists Proton pump inhibitors (PPI) Antimuscarinic drugs(M-R inhibitors) Antagonist of gastrin receptor 13 14 Proton pump CCK2 CCK2 (-) Drug 15 H2-receptor antagonists • Mechanism It can exhibit competitive inhibition at the parietal cell H2 receptor,and suppress acid secretion. • Typical drugs • cimetidine (TAGAMET), ranitidine (ZANTAC), famotidine (PEPCID), and nizatidine (AXID). 16 • The H2-receptor antagonists inhibit acid production by reversibly competing with histamine for binding to H2 receptors on the basolateral membrane of parietal cells. • These drugs are less potent than proton pump inhibitors but still suppress 24-hour gastric acid secretion by about 70%. The H2receptor antagonists predominantly inhibit basal acid secretion, which accounts for their efficacy in suppressing nocturnal acid secretion. • Because the most important determinant of duodenal ulcer healing is the level of nocturnal acidity, evening dosing of H2receptor antagonists is adequate therapy in most instances. • Ranitidine and nizatidine also may stimulate GI motility, but the clinical importance of this effect is unknown. 17 Adverse Reactions • with a low (3%) incidence of adverse effects. • are minor and include diarrhea, headache, drowsiness, fatigue, muscular pain, and constipation. • cause galactorrhea in women and gynecomastia, reduced sperm count, and impotence in men. • Famotidine and nizatidine are even safer in this regard, with no significant drug interactions mediated by inhibiting hepatic CYPs. 18 Proton pump inhibitors (PPI) It is the main drug for the treatment of acidpeptic disorders. Five proton pump inhibitors are available for clinical use: omeprazole (PRILOSEC, RAPINEX, ZEGERID) and its S-isomer, esomeprazole (NEXIUM), lansoprazole (PREVACID), rabeprazole (ACIPHEX), and pantoprazole (PROTONIX). 19 Omeprazole Parmacodynamics It blocks the final common pathway of acid secretion,the proton pump. In standard doses,it inhibit 90%-98% of 24-hours acid secretion. 20 Pharmacokinetics Serum half-life : 1 hour Duration of acid inhibition : 24 hours Metabolism : hepar 21 Adverse effects It is extremely safe. Diarrhea headache abdominal pain 15% 22 Clinical use Gastroesophafeal Reflux Disease Peptic Ulcer Disease Prevention of stress gastritis In children, omeprazole is safe and effective for treatment of erosive esophagitis and (gastroesophageal reflux disease) GERD. 23 Antimuscarinic drugs (M-R inhibitors) Typical drug : Pirenzepine It has dramatic inhibition on motility and some of the secretory functions of the gut. The ACh receptor on the parietal cell itself is of the M3 subtype, and these drugs are believed to suppress neural stimulation of acid production via actions on M1 receptors of intramural ganglia. Because of their relatively poor efficacy, significant and undesirable anticholinergic side effects, and risk of blood disorders (pirenzepine), they rarely are used today. 24 Antagonist of gastrin receptor Typical drug : Proglumide Mechanism It can exhibit competitive inhibition at the parietal cell gastrinreceptor ,and suppress acid secretion. CCK2 CCK2 25 2. Mucosal protective agents • Typical drugs : misoprostol • sucralfate 26 Cavity Cl- H+ H+ Gastric juice Cl- pepsin pH2 NaCl H2O+CO2 NaHCO3mucous layer PGE2R PGI2R pH7 PG mucosa parietal cells The protection of mucous layer 27 misoprostol A methyl analog of PGE1 Administration : oral Serum half-life : less than 30 min Pharmacological action: acid inhibitory stimulating mucus and bicarbonate secretion enhance mucosal blood flow 28 Adverse effects Diarrhea, with or without abdominal pain and cramps, occurs in up to 30% of patients who take misoprostol. Apparently dose-related, it typically begins within the first 2 weeks after therapy is initiated and often resolves spontaneously within a week; more severe or protracted cases may necessitate drug discontinuation. Misoprostol can cause clinical exacerbations of inflammatory bowel disease and should be avoided in patients with this disorder. Misoprostol is contraindicated during pregnancy because it can increase uterine contractility. 29 Therapeutic Use. • Misoprostol is FDA approved to prevent NSAID-induced mucosal injury. However, it rarely is used because of its adverse effects and the inconvenience of four-times-daily dosing. The proton pump inhibitors and H2receptor antagonists also are used to diminish the gastrointestinal side effects of NSAIDs, but only lansoprazole holds an FDA approved indication for this purpose. 30 sucralfate It is a salt of sucrose complexed to sulfated aluminum hydroxide. Mechanism In water or acidic(ph<4) solution it form a paste that bind to ulcer. It stimulates mucosal prostaglandin and bicarbonate secretion. It binds epithelial growth factor and fibroblast growth factor ,enhence mucosal repair. 31 Adverse The most common side effect of sucralfate is constipation (about 2%). renal failure---should be avoided Sucralfate forms a viscous layer in the stomach that may inhibit absorption of other drugs, including phenytoin, digoxin, cimetidine, ketoconazole, and fluoroquinolone antibiotics. Sucralfate therefore should be taken at least 2 hours after the administration of other drugs. 32 Drugs against H pylori Treatment regimen “Triple therapy”------10-14days Proton pump inhibitors(omeprazole) + clarithromycin + amoxicillin(metronidazole) They are all twice daily,and then omeprazole should be continued once daily for 4-6 weeks to ensure complete ulcer healing. 33 3. Hp Also called helicobacter pylori It is a kind of bacterium ,living in the mucosa and it can induce mucosa injure ,which discovered by scientists recently. 34