. B.Pharm Hon, MSc in Pharm Pharmacology Faculty of Pharmacy Mahasarakham University

1. ?.???????? ?????????? B.Pharm (Hon), MSc in Pharm (Pharmacology) Faculty of Pharmacy Mahasarakham University

2. ???????????????????????????? mucosa ??????????????????????????????????????????????????? duodenum ?????????????????????? mucosal protecting mechanism ??? mucosal damaging mechanism

4. ????????????????????????????????????????????????????? ?????????????? ??????????????? ??????? ?????????????????? ????????????????

5. 1. ???????????????????????? ????????????????? - ???????????????????? ????????????????? ?????????????????? - ???????????????? - ??????????? - ???????????? - ?????????????????????? 2. ????????????????????????????? ??????? - ??: aspirin,NSAIDs, steriods - ?????????????????? ?????????????????????????? - ???????????????? 3. ????????????????????? Helicobacter pylori

6. Constituents of gastric mucosa

7. Acid secretion ??? (HCl) ?????????? parietal cell ??????????????????? K+/H+ ATPase ????????????????????????????????? Ach (M3) Gastrin Histamine (H2) The parietal cell contains receptors for gastrin, histamine (H2), and acetylcholine (muscarinic, M3) (Figure 63�1). When acetylcholine or gastrin bind to the parietal cell receptors, they cause an increase in cytosolic calcium, which in turn stimulates protein kinases that stimulate acid secretion from a H+/K+ ATPase (the proton pump) on the canalicular surface. The parietal cell contains receptors for gastrin, histamine (H2), and acetylcholine (muscarinic, M3) (Figure 63�1). When acetylcholine or gastrin bind to the parietal cell receptors, they cause an increase in cytosolic calcium, which in turn stimulates protein kinases that stimulate acid secretion from a H+/K+ ATPase (the proton pump) on the canalicular surface.

8. In close proximity to the parietal cells are gut endocrine cells called enterochromaffin-like (ECL) cells. ECL cells have receptors for gastrin and acetylcholine and are the major source for histamine release. Histamine binds to the H2 receptor on the parietal cell, resulting in activation of adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP). cAMP activates protein kinases that stimulate acid secretion by the H+/K+ ATPase. In humans, it is believed that the major effect of gastrin upon acid secretion is mediated indirectly through the release of histamine from ECL cells rather than through direct parietal cell stimulation. In close proximity to the parietal cells are gut endocrine cells called enterochromaffin-like (ECL) cells. ECL cells have receptors for gastrin and acetylcholine and are the major source for histamine release. Histamine binds to the H2 receptor on the parietal cell, resulting in activation of adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP). cAMP activates protein kinases that stimulate acid secretion by the H+/K+ ATPase. In humans, it is believed that the major effect of gastrin upon acid secretion is mediated indirectly through the release of histamine from ECL cells rather than through direct parietal cell stimulation.

9. Somatostatin is a tetradecapeptide (SS-14) initially isolated from the hypothalamus that is also found in D cells of the stomach and pancreas. Somatostatin is a tetradecapeptide (SS-14) initially isolated from the hypothalamus that is also found in D cells of the stomach and pancreas.

11. 1. antisecretory drugs ***H2 receptor antgonist ???? cimetidine, ranitidine, nizatidine, famotidine ***Proton pump inhibitors ???? omeprazole ***Muscarinic antagonists ???? pirenzepine 2. Antacid 3. cytoprotective 4. antisecretory agents that enhance mucosal defenses ???? prostaglandin analogs ???? misoprostol 5. Antibiotic ???? metronidazole, tetracycline, amoxicillin

12. 1. H2 receptor antagonists 2. proton pump inhibitors 3. anticholinergic drugs (Antimuscarinic drugs) 4. Antacid

13. cimetidine (Tagamet?) ranitidine(Zantac?) famotidine(Pepcid?) nizatidine(Axid?) famotidine ??????? 20-100 ??????? cimetidine, ranitidine ??????? 5 ??????? cimetidine ????????????????????????????? famotidine ??? ranitidine ???????cimetidine ???????? famotidine ??? ranitidine????????????????????????????????? cimetidine famotidine ??????? 20-100 ??????? cimetidine, ranitidine ??????? 5 ??????? cimetidine ????????????????????????????? famotidine ??? ranitidine ???????cimetidine ???????? famotidine ??? ranitidine????????????????????????????????? cimetidine

14. ?????????? ?? 2550 14

15. Competitive inhibition at the parietal cell H2 receptor ?????????????????????????? basal and meal-stimulated acid secretion ??? linear, dose-dependent manner

16. ?????????? ?? 2550 16 Pharmacokinetics Absorption: rapidly absorbed from the intestine. Cimetidine, ranitidine, and famotidine: first-pass hepatic metabolism (BA=50%) Nizatidine bioavailability of almost 100%. T1/2= 1.1�4 h. Metabolism: hepatic metabolism Elimination: glomerular filtration, and renal tubular secretion

17. ADR Central Nervous System Mental status changes (confusion, hallucinations, agitation) = iv, common with cimetidine Endocrine Effects (only Cimetidine) inhibits binding of dihydrotestosterone to androgen receptors inhibits metabolism of estradiol increases serum prolactin levels gynecomastia or impotence in men and galactorrhea in women (long-term or in high doses) Other Effects headache, dizziness, nausea, myalgia, skin rashes, itching somnolence, confusion RARE!! blood dyscrasias bradycardia abnormalities in liver chemistry

18. ??????????????? cimetidine ??????????????????????? CYP 450 ???? CYP 3A4 (CYP3A4 inhibitor) ?? ranitidine, famotidine, nizatidine ??????????????????????? CYP 450 antacid ???????????????????? H2-Receptor antagonist ????????????????????????????????????????????? 2 ???????

19. ?????????? ?? 2550 19 ??????????????? Drug Interaction ??? cimetidine Anitplatelet drugs ???? warfarin ???????????????????????? anticoagulant Antifungal drugs ???? ketoconazole, itraconazole, fluconazole Antiasthma drugs ???? theophyline, aminophyline ???????????? H2-Receptor antagonist ???????????????????????????????? theophyline CVS drugs ???? nifedipine, quinidine, procanamine

20. Duodenal Ulcer and Gastric Ulcer Non-ulcer Dyspepsia Gastroesophageal Reflux Prevention NSAID-Induced Gastric Ulcer Zollinger-Ellison Syndrome  Patients with infrequent heartburn or dyspepsia (fewer than 3 times per week) may take either antacids or intermittent H2 antagonists. Because antacids provide rapid acid neutralization, they afford faster symptom relief than H2 antagonists. However, the effect of antacids is short-lived (1�2 hours) compared with H2 antagonists (6�10 hours). H2 antagonists may be taken prophylactically before meals in an effort to reduce the likelihood of heartburn. Frequent heartburn is better treated with twice daily H2 antagonists; this regimen provides effective symptom control in 50�75% of people (Table 63�1). In patients with erosive esophagitis (approximately half of patients with GERD), H2 antagonists afford healing in less than 50% of patients. Although higher doses of H2 antagonists increase healing rates, proton pump inhibitors are preferred. Peptic Ulcer Disease Proton pump inhibitors have largely replaced H2 antagonists in the treatment of peptic ulcer disease. Nocturnal acid suppression affords effective ulcer healing in the majority of patients with uncomplicated gastric and duodenal ulcers. Hence, all the agents may be administered once daily at bedtime for acute, uncomplicated ulcers, resulting in ulcer healing rates greater than 80�90% after 6�8 weeks of therapy. For patients with acute peptic ulcers caused by H pylori, H2 antagonists no longer play a significant therapeutic role. For the minority of patients in whom H pylori cannot be successfully eradicated, H2 antagonists may be given daily at bedtime in half of the usual ulcer therapeutic dose in order to prevent ulcer recurrence (eg, ranitidine 150 mg, famotidine 20 mg). For patients with ulcers caused by aspirin or other NSAIDs, H2 antagonists provide rapid ulcer healing so long as the NSAID is discontinued. If the NSAID must be continued for clinical reasons despite active ulceration, a proton pump inhibitor should be given to promote ulcer healing. Nonulcer Dyspepsia H2 antagonists are commonly used as over-the-counter agents and prescription agents for treatment of intermittent dyspepsia not caused by peptic ulcer. However, benefit compared with placebo has never been convincingly demonstrated. Prevention of Bleeding from Stress-Related Gastritis H2-receptor antagonists significantly reduce the incidence of bleeding from stress-related gastritis in seriously ill patients in the intensive care unit. H2 antagonists are given intravenously, either as intermittent injections or continuous infusions. For maximal efficacy, the pH of gastric aspirates should be measured and the doses titrated to achieve a gastric pH 4. Patients with infrequent heartburn or dyspepsia (fewer than 3 times per week) may take either antacids or intermittent H2 antagonists. Because antacids provide rapid acid neutralization, they afford faster symptom relief than H2 antagonists. However, the effect of antacids is short-lived (1�2 hours) compared with H2 antagonists (6�10 hours). H2 antagonists may be taken prophylactically before meals in an effort to reduce the likelihood of heartburn. Frequent heartburn is better treated with twice daily H2 antagonists; this regimen provides effective symptom control in 50�75% of people (Table 63�1). In patients with erosive esophagitis (approximately half of patients with GERD), H2 antagonists afford healing in less than 50% of patients. Although higher doses of H2 antagonists increase healing rates, proton pump inhibitors are preferred. Peptic Ulcer Disease Proton pump inhibitors have largely replaced H2 antagonists in the treatment of peptic ulcer disease. Nocturnal acid suppression affords effective ulcer healing in the majority of patients with uncomplicated gastric and duodenal ulcers. Hence, all the agents may be administered once daily at bedtime for acute, uncomplicated ulcers, resulting in ulcer healing rates greater than 80�90% after 6�8 weeks of therapy. For patients with acute peptic ulcers caused by H pylori, H2 antagonists no longer play a significant therapeutic role. For the minority of patients in whom H pylori cannot be successfully eradicated, H2 antagonists may be given daily at bedtime in half of the usual ulcer therapeutic dose in order to prevent ulcer recurrence (eg, ranitidine 150 mg, famotidine 20 mg). For patients with ulcers caused by aspirin or other NSAIDs, H2 antagonists provide rapid ulcer healing so long as the NSAID is discontinued. If the NSAID must be continued for clinical reasons despite active ulceration, a proton pump inhibitor should be given to promote ulcer healing. Nonulcer Dyspepsia H2 antagonists are commonly used as over-the-counter agents and prescription agents for treatment of intermittent dyspepsia not caused by peptic ulcer. However, benefit compared with placebo has never been convincingly demonstrated. Prevention of Bleeding from Stress-Related Gastritis H2-receptor antagonists significantly reduce the incidence of bleeding from stress-related gastritis in seriously ill patients in the intensive care unit. H2 antagonists are given intravenously, either as intermittent injections or continuous infusions. For maximal efficacy, the pH of gastric aspirates should be measured and the doses titrated to achieve a gastric pH 4.

21. Clinical Comparisons of H2 Receptor Blockers

22. ?????????? ?? 2550 22 Proton Pump Inhibitors (PPI) Omeprazole (prilosec?, losec?) lansoprazole(prevacid?) Esomeprazole (nexium ?) rabeprazole Pantoprazole administered as inactive prodrugs formulated as acid-resistant enteric-coated microgranules from rapid destruction within the gastric lumen, they are formulated as acid-resistant enteric-coated microgranules mixed with apple juice or applesauce. After passing through the stomach into the alkaline intestinal lumen, the enteric coatings dissolve and the prodrug is absorbed. These prodrugs are lipophilic weak bases (pKa 4�5) and therefore diffuse readily across lipid membranes into acidified compartments (such as the parietal cell canaliculus). Within the acidified compartment the prodrug rapidly becomes protonated and is concentrated > 1000-fold within the parietal cell canaliculus. There, it rapidly undergoes a molecular conversion to the active, reactive thiophilic sulfonamide cation. The sulfonamide reacts with the H+/K+ ATPase, forms a covalent disulfide linkage, and irreversibly inactivates the enzyme. The pharmacokinetics of available proton pump inhibitors are from rapid destruction within the gastric lumen, they are formulated as acid-resistant enteric-coated microgranules mixed with apple juice or applesauce. After passing through the stomach into the alkaline intestinal lumen, the enteric coatings dissolve and the prodrug is absorbed. These prodrugs are lipophilic weak bases (pKa 4�5) and therefore diffuse readily across lipid membranes into acidified compartments (such as the parietal cell canaliculus). Within the acidified compartment the prodrug rapidly becomes protonated and is concentrated > 1000-fold within the parietal cell canaliculus. There, it rapidly undergoes a molecular conversion to the active, reactive thiophilic sulfonamide cation. The sulfonamide reacts with the H+/K+ ATPase, forms a covalent disulfide linkage, and irreversibly inactivates the enzyme. The pharmacokinetics of available proton pump inhibitors are

24. irreversible inhibition ??? H+/K+ ATPase (proton pump) ??? parietal cell ?????????? final common pathway ?????????????? ???? prodrugs ?????????????????????? sulfenamides ???????????? covalent ??? sulfhydryl group ??? proton pump

25. After passing through the stomach into the alkaline intestinal lumen, the enteric coatings dissolve and the prodrug is absorbed. These prodrugs are lipophilic weak bases (pKa 4�5) and therefore diffuse readily across lipid membranes into acidified compartments (such as the parietal cell canaliculus). Within the acidified compartment the prodrug rapidly becomes protonated and is concentrated > 1000-fold within the parietal cell canaliculus. There, it rapidly undergoes a molecular conversion to the active, reactive thiophilic sulfonamide cation. The sulfonamide reacts with the H+/K+ ATPase, forms a covalent disulfide linkage, and irreversibly inactivates the enzyme. After passing through the stomach into the alkaline intestinal lumen, the enteric coatings dissolve and the prodrug is absorbed. These prodrugs are lipophilic weak bases (pKa 4�5) and therefore diffuse readily across lipid membranes into acidified compartments (such as the parietal cell canaliculus). Within the acidified compartment the prodrug rapidly becomes protonated and is concentrated > 1000-fold within the parietal cell canaliculus. There, it rapidly undergoes a molecular conversion to the active, reactive thiophilic sulfonamide cation. The sulfonamide reacts with the H+/K+ ATPase, forms a covalent disulfide linkage, and irreversibly inactivates the enzyme.

27. Pharmacokinetics bioavailability ?????????? 50% ?????????????????? ??????????????????? ???? 1 ????????????????????????? ????????????????????????????????????????? ?????? 24 ??????? (irreversible inactivation proton pump) ???????????????????????????? ??????????????? 3-4 ??? ????????????????????????? 3-4 ??? ?????? first-pass metabolism ???????????? metabolized ??? hepatic P450 cytochromes (CYP2C19, CYP3A4) ?????????????? At least 18 hours are required for synthesis of new H+/K+ ATPase pump molecules Because not all proton pumps are inactivated with the first dose of medication, up to 3�4 days of daily medication are required before the full acid-inhibiting potential is reached. At least 18 hours are required for synthesis of new H+/K+ ATPase pump molecules Because not all proton pumps are inactivated with the first dose of medication, up to 3�4 days of daily medication are required before the full acid-inhibiting potential is reached.

28. ?????????? ?? 2550 28 ??????????????????? PPI (ideal drugs) short serum half-life concentrated and activated near their site of action long duration of action inhibit 90�98% of 24-hour acid secretion

29. General (?????????????) Diarrhea, headache, and abdominal pain Nutrition ??????????? vitamin B12 and some mineral Enteric Infections eg,salmonella, shigella Potential Problems Due to Increased Serum Gastrin ???????????? gastric carcinoids Proton pump inhibitors are extremely safe. Adverse Effects General Proton pump inhibitors are extremely safe. Diarrhea, headache, and abdominal pain are reported in 1�5% of patients, although the frequency of these events is only slightly increased compared with placebo. Proton pump inhibitors do not have teratogenicity in animal models; however, safety during pregnancy has not been established. Nutrition Acid is important in releasing vitamin B12 from food. A minor reduction in oral cyanocobalamin absorption occurs during proton pump inhibition, potentially leading to subnormal B12 levels with prolonged therapy. Acid also promotes absorption of food-bound minerals (iron, calcium, zinc); however, no mineral deficiencies have been reported with proton pump inhibitor therapy. Enteric Infections Gastric acid is an important barrier to colonization and infection of the stomach and intestine from ingested bacteria. Hypochlorhydria from any cause increases the risk for enteric infections (eg, salmonella, shigella). A small increased risk of enteric infections may exist in patients taking proton pump inhibitors, especially when traveling in underdeveloped countries. Potential Problems Due to Increased Serum Gastrin Gastrin levels are regulated by a feedback loop. During meals, intraluminal food proteins stimulate gastrin release from antral G-cells. The rise in serum gastrin stimulates parietal cell acid secretion. Increased intragastric acidity stimulates antral D-cells to release somatostatin, which binds to receptors on adjacent antral G-cells, turning off further gastrin release. Acid suppression alters this feedback inhibition so that gastrin levels rise two- to four-fold in patients taking proton pump inhibitors. In approximately 3%, gastrin levels exceed 500 pg/mL (normal < 100 pg/mL). Upon stopping the drug, the levels normalize. The rise in serum gastrin levels in patients receiving long-term therapy with proton pump inhibitors has raised two theoretical concerns. First, gastrin is a trophic hormone that stimulates hyperplasia of ECL cells. Hypergastrinemia due to gastrinoma (Zollinger-Ellison syndrome) or atrophic gastritis is associated with the development of gastric carcinoids in up to 3% of patients. In female rats given proton pump inhibitors for prolonged periods, gastric carcinoid tumors developed in areas of ECL hyperplasia. Although humans who take proton pump inhibitors for a long time may exhibit ECL hyperplasia in response to hypergastrinemia, carcinoid tumor formation has not been documented. Second, hypergastrinemia increases the proliferative rate of colonic mucosa, potentially promoting carcinogenesis. In humans, hypergastrinemia caused by vagotomy, atrophic gastritis, or Zollinger- Ellison syndrome has not been associated with increased colon cancer risk. At present, routine monitoring of serum gastrin levels is not recommended in patients receiving prolonged proton pump inhibitor therapy. Potential Problems Due to Decreased Gastric Acidity As noted above, gastric acid serves as an important barrier to bacterial colonization of the stomach and small intestine. Increases in gastric bacterial concentrations are detected in patients taking proton pump inhibitors. An increase in nitrate-reductase positive strains could theoretically increase carcinogenic nitrites and N-nitrosamines. However, most studies do not demonstrate this. Among patients infected with H pylori, long-term acid suppression leads to increased chronic inflammation in the gastric body and decreased inflammation in the antrum. Concerns have been raised that increased gastric inflammation may accelerate gastric gland atrophy (atrophic gastritis) and intestinal metaplasia�known risk factors for gastric adenocarcinoma. A special US Food and Drug Administration Gastrointestinal Advisory Committee concluded that there is no evidence that prolonged proton pump inhibitor therapy produces the kind of atrophic gastritis (multifocal atrophic gastritis) or intestinal metaplasia that is associated with increased risk of adenocarcinoma. Routine testing for H pylori is no longer recommended in patients who require long-term proton pump inhibitor therapy. Proton pump inhibitors are extremely safe. Adverse Effects General Proton pump inhibitors are extremely safe. Diarrhea, headache, and abdominal pain are reported in 1�5% of patients, although the frequency of these events is only slightly increased compared with placebo. Proton pump inhibitors do not have teratogenicity in animal models; however, safety during pregnancy has not been established. Nutrition Acid is important in releasing vitamin B12 from food. A minor reduction in oral cyanocobalamin absorption occurs during proton pump inhibition, potentially leading to subnormal B12 levels with prolonged therapy. Acid also promotes absorption of food-bound minerals (iron, calcium, zinc); however, no mineral deficiencies have been reported with proton pump inhibitor therapy. Enteric Infections Gastric acid is an important barrier to colonization and infection of the stomach and intestine from ingested bacteria. Hypochlorhydria from any cause increases the risk for enteric infections (eg, salmonella, shigella). A small increased risk of enteric infections may exist in patients taking proton pump inhibitors, especially when traveling in underdeveloped countries. Potential Problems Due to Increased Serum Gastrin Gastrin levels are regulated by a feedback loop. During meals, intraluminal food proteins stimulate gastrin release from antral G-cells. The rise in serum gastrin stimulates parietal cell acid secretion. Increased intragastric acidity stimulates antral D-cells to release somatostatin, which binds to receptors on adjacent antral G-cells, turning off further gastrin release. Acid suppression alters this feedback inhibition so that gastrin levels rise two- to four-fold in patients taking proton pump inhibitors. In approximately 3%, gastrin levels exceed 500 pg/mL (normal < 100 pg/mL). Upon stopping the drug, the levels normalize. The rise in serum gastrin levels in patients receiving long-term therapy with proton pump inhibitors has raised two theoretical concerns. First, gastrin is a trophic hormone that stimulates hyperplasia of ECL cells. Hypergastrinemia due to gastrinoma (Zollinger-Ellison syndrome) or atrophic gastritis is associated with the development of gastric carcinoids in up to 3% of patients. In female rats given proton pump inhibitors for prolonged periods, gastric carcinoid tumors developed in areas of ECL hyperplasia. Although humans who take proton pump inhibitors for a long time may exhibit ECL hyperplasia in response to hypergastrinemia, carcinoid tumor formation has not been documented. Second, hypergastrinemia increases the proliferative rate of colonic mucosa, potentially promoting carcinogenesis. In humans, hypergastrinemia caused by vagotomy, atrophic gastritis, or Zollinger- Ellison syndrome has not been associated with increased colon cancer risk. At present, routine monitoring of serum gastrin levels is not recommended in patients receiving prolonged proton pump inhibitor therapy. Potential Problems Due to Decreased Gastric Acidity As noted above, gastric acid serves as an important barrier to bacterial colonization of the stomach and small intestine. Increases in gastric bacterial concentrations are detected in patients taking proton pump inhibitors. An increase in nitrate-reductase positive strains could theoretically increase carcinogenic nitrites and N-nitrosamines. However, most studies do not demonstrate this. Among patients infected with H pylori, long-term acid suppression leads to increased chronic inflammation in the gastric body and decreased inflammation in the antrum. Concerns have been raised that increased gastric inflammation may accelerate gastric gland atrophy (atrophic gastritis) and intestinal metaplasia�known risk factors for gastric adenocarcinoma. A special US Food and Drug Administration Gastrointestinal Advisory Committee concluded that there is no evidence that prolonged proton pump inhibitor therapy produces the kind of atrophic gastritis (multifocal atrophic gastritis) or intestinal metaplasia that is associated with increased risk of adenocarcinoma. Routine testing for H pylori is no longer recommended in patients who require long-term proton pump inhibitor therapy.

30. ??????????????????????????????????????????????????????????????????????????? ketoconazole and digoxin Omeprazole ????? metabolism ????? coumadin, diazepam, and phenytoin. Esomeprazole ?? metabolism ????? diazepam Lansoprazole ?????????????????? theophylline Rabeprazole ??? pantoprazole ???????? drug interaction

31. ?????????????????? GU, DU which resistance to H2 receptor antagonist Gastroesophageal Reflux Disease (GERD) H Pylori�Associated Ulcers NSAID-Associated Ulcers Prevention of Rebleeding from Peptic Ulcers Non-ulcer Dyspepsia Prevention of Stress Gastritis Gastrinoma and Other Hypersecretory Conditions Zollinger-Ellison syndrome (treatment of choice) Clinical Uses Gastroesophageal Reflux Disease (GERD) Proton pump inhibitors are the most effective agents for the treatment of nonerosive and erosive reflux disease, esophageal complications of reflux disease (peptic stricture or Barrett's esophagus), and extraesophageal manifestations of reflux disease. Once-daily dosing provides effective symptom relief and tissue healing in 85�90% of patients; up to 15% of patients require twice daily dosing. Symptoms of erosive esophagitis recur in over 80% of patients within 6 months after discontinuation of a proton pump inhibitor. For this reason, long-term daily maintenance therapy with a full-dose or half-dose proton pump inhibitor often is needed, particularly for patients with erosive esophagitis or esophageal complications. In current clinical practice, many patients with symptomatic gastroesophageal reflux are treated empirically with medications without prior endoscopy, ie, without knowledge of whether the patient has erosive or nonerosive reflux disease. Empiric treatment with proton pump inhibitors provides sustained symptomatic relief in 70�80% of patients, compared with 50�60% with H2 antagonists. Due to recent cost reductions, proton pump inhibitors are increasingly being used as first-line therapy for patients with symptomatic GERD. Sustained acid suppression with twice-daily proton pump inhibitors for at least 3 months is used to treat extraesophageal complications of reflux disease (asthma, chronic cough, laryngitis, and noncardiac chest pain). Peptic Ulcer Disease Compared with H2 antagonists, proton pump inhibitors afford more rapid symptom relief and faster ulcer healing for duodenal ulcers and, to a lesser extent, gastric ulcers. All of the pump inhibitors heal more than 90% of duodenal ulcers within 4 weeks and a similar percentage of gastric ulcers within 6�8 weeks. H Pylori�Associated Ulcers For H pylori�associated ulcers, there are two therapeutic goals: heal the ulcer and eradicate the organism. The most effective regimens for H pylori eradication are combinations of two antibiotics and a proton pump inhibitor. Proton pump inhibitors promote eradication of H pylori through several mechanisms: direct antimicrobial properties (minor) and�by raising intragastric pH� lowering the minimal inhibitory concentrations of antibiotics against H pylori. The best treatment regimen consists of a 10�14 day regimen of "triple therapy": a proton pump inhibitor twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily. For patients who are allergic to penicillin, metronidazole 500 mg twice daily should be substituted for amoxicillin. After completion of triple therapy, the proton pump inhibitor should be continued once daily for a total of 4�6 weeks to ensure complete ulcer healing. NSAID-Associated Ulcers For patients with ulcers caused by aspirin or other NSAIDs, either H2 antagonists or proton pump inhibitors provide rapid ulcer healing so long as the NSAID is discontinued; continued use of the NSAID impairs ulcer healing. Treatment with a once daily proton pump inhibitor promotes ulcer healing despite continued NSAID therapy. Proton pump inhibitors are also given to prevent ulcer complications from NSAIDs. Asymptomatic peptic ulceration develops in 10�20% of people taking frequent NSAIDs, and ulcer-related complications (bleeding, perforation) develop in 1�2% of persons per year. Proton pump inhibitors taken once daily are effective in reducing the incidence of ulcers and ulcer complications in patients taking aspirin or other NSAIDs. Prevention of Rebleeding from Peptic Ulcers In patients with acute gastrointestinal bleeding due to peptic ulcers, the risk of rebleeding from ulcers that have a visible vessel or adherent clot is increased. Ulcer rebleeding is reduced significantly with use of proton pump inhibitors administered for 3�5 days either as high-dose oral therapy (eg, omeprazole 40 mg orally twice daily) or as a continuous intravenous infusion. The optimal dosing for intravenous pantoprazole is under investigation. Nonulcer Dyspepsia Proton pump inhibitors have modest efficacy for treatment of nonulcer dyspepsia, benefiting 10� 20% more patients than placebo. Despite their increasing use for this indication, superiority to H2 antagonists (or even placebo) has not been conclusively demonstrated. Prevention of Stress Gastritis Intravenous proton pump inhibitors increasingly are being used in critically ill patients to reduce the incidence of stress-related mucosal bleeding despite a lack of any controlled trials demonstrating their efficacy. In the absence of trials that establish efficacy and optimal dosing for proton pump Clinical Uses Gastroesophageal Reflux Disease (GERD) Proton pump inhibitors are the most effective agents for the treatment of nonerosive and erosive reflux disease, esophageal complications of reflux disease (peptic stricture or Barrett's esophagus), and extraesophageal manifestations of reflux disease. Once-daily dosing provides effective symptom relief and tissue healing in 85�90% of patients; up to 15% of patients require twice daily dosing. Symptoms of erosive esophagitis recur in over 80% of patients within 6 months after discontinuation of a proton pump inhibitor. For this reason, long-term daily maintenance therapy with a full-dose or half-dose proton pump inhibitor often is needed, particularly for patients with erosive esophagitis or esophageal complications. In current clinical practice, many patients with symptomatic gastroesophageal reflux are treated empirically with medications without prior endoscopy, ie, without knowledge of whether the patient has erosive or nonerosive reflux disease. Empiric treatment with proton pump inhibitors provides sustained symptomatic relief in 70�80% of patients, compared with 50�60% with H2 antagonists. Due to recent cost reductions, proton pump inhibitors are increasingly being used as first-line therapy for patients with symptomatic GERD. Sustained acid suppression with twice-daily proton pump inhibitors for at least 3 months is used to treat extraesophageal complications of reflux disease (asthma, chronic cough, laryngitis, and noncardiac chest pain). Peptic Ulcer Disease Compared with H2 antagonists, proton pump inhibitors afford more rapid symptom relief and faster ulcer healing for duodenal ulcers and, to a lesser extent, gastric ulcers. All of the pump inhibitors heal more than 90% of duodenal ulcers within 4 weeks and a similar percentage of gastric ulcers within 6�8 weeks. H Pylori�Associated Ulcers For H pylori�associated ulcers, there are two therapeutic goals: heal the ulcer and eradicate the organism. The most effective regimens for H pylori eradication are combinations of two antibiotics and a proton pump inhibitor. Proton pump inhibitors promote eradication of H pylori through several mechanisms: direct antimicrobial properties (minor) and�by raising intragastric pH� lowering the minimal inhibitory concentrations of antibiotics against H pylori. The best treatment regimen consists of a 10�14 day regimen of "triple therapy": a proton pump inhibitor twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1 g twice daily. For patients who are allergic to penicillin, metronidazole 500 mg twice daily should be substituted for amoxicillin. After completion of triple therapy, the proton pump inhibitor should be continued once daily for a total of 4�6 weeks to ensure complete ulcer healing. NSAID-Associated Ulcers For patients with ulcers caused by aspirin or other NSAIDs, either H2 antagonists or proton pump inhibitors provide rapid ulcer healing so long as the NSAID is discontinued; continued use of the NSAID impairs ulcer healing. Treatment with a once daily proton pump inhibitor promotes ulcer healing despite continued NSAID therapy. Proton pump inhibitors are also given to prevent ulcer complications from NSAIDs. Asymptomatic peptic ulceration develops in 10�20% of people taking frequent NSAIDs, and ulcer-related complications (bleeding, perforation) develop in 1�2% of persons per year. Proton pump inhibitors taken once daily are effective in reducing the incidence of ulcers and ulcer complications in patients taking aspirin or other NSAIDs. Prevention of Rebleeding from Peptic Ulcers In patients with acute gastrointestinal bleeding due to peptic ulcers, the risk of rebleeding from ulcers that have a visible vessel or adherent clot is increased. Ulcer rebleeding is reduced significantly with use of proton pump inhibitors administered for 3�5 days either as high-dose oral therapy (eg, omeprazole 40 mg orally twice daily) or as a continuous intravenous infusion. The optimal dosing for intravenous pantoprazole is under investigation. Nonulcer Dyspepsia Proton pump inhibitors have modest efficacy for treatment of nonulcer dyspepsia, benefiting 10� 20% more patients than placebo. Despite their increasing use for this indication, superiority to H2 antagonists (or even placebo) has not been conclusively demonstrated. Prevention of Stress Gastritis Intravenous proton pump inhibitors increasingly are being used in critically ill patients to reduce the incidence of stress-related mucosal bleeding despite a lack of any controlled trials demonstrating their efficacy. In the absence of trials that establish efficacy and optimal dosing for proton pump

32. ?????? pirenzepine, telenzepine Competitively inhibition of M3receptor ?????????? first line drug ????????????????????????? H2 antagonist ??????????????????? Anticholinergic side effects

33. 2. ??????? (antacid) weak bases react with gastric hydrochloric acid to form a salt and water principle mechanism of action: reduction of intragastric acidity stimulation of mucosal prostaglandin production After a meal, approximately 45 meq/h of hydrochloric acid is secreted. A single dose of 156 meq of antacid given 1 hour after a meal effectively neutralizes gastric acid for up to 2 hours. After a meal, approximately 45 meq/h of hydrochloric acid is secreted. A single dose of 156 meq of antacid given 1 hour after a meal effectively neutralizes gastric acid for up to 2 hours.

35. ????????????????????????? 1N HCl ?? pH ????????????? 3.5 ????? 15 ???? ???????????????????????? 

36. Antacid Al(OH)3 +3HCl AlCl3 + 3H2O Mg(OH)2 + 2 HCl MgCl2 + 2H2O CaCO3 + 2 HCl CaCl2 + H2O+CO2 NaHCO3 + HCl NaCl + H2O+ CO2

37. ?????????? ?? 2550 37 Factor affecting capacity rate of dissolution (tablet versus liquid) water solubility rate of reaction with acid rate of gastric emptying

38. Depend on constituents of antacid 1. Systemic antacid NaHCO3 (baking soda, Alka Seltzer) ??????????????? ???? CO2 + NaCl ADR systemic alkalosis ????????? Na+ ?????????????? CHF rebound hypersecretion Milk alkaline syndrome ??????????????? ?????????? Ca2+ Sodium bicarbonate (eg, baking soda, Alka Seltzer) reacts rapidly with HCl to produce carbon dioxide and NaCl. Formation of carbon dioxide results in gastric distention and belching. Unreacted alkali is readily absorbed, potentially causing metabolic alkalosis when given in high doses or to patients with renal insufficiency. Sodium chloride absorption may exacerbate fluid retention in patients with heart failure, hypertension, and renal insufficiency. Milk-alkaline syndrome ???????????????????????????????????? sodium bicarbonte ????????????????????????????? ?????????????????????????????? ???????????????????????????????????? ???????????????????????? ???????? ?????? ??????????????????????????????????????? ?????????????????????????? ?????? ??????????????????????? ??????????????????????????????????????????????????? alkalosis ??? azotemia ???????? ??????????????????????????????????????????? ???????????????????????????????????????????????????????????????????????????Sodium bicarbonate (eg, baking soda, Alka Seltzer) reacts rapidly with HCl to produce carbon dioxide and NaCl. Formation of carbon dioxide results in gastric distention and belching. Unreacted alkali is readily absorbed, potentially causing metabolic alkalosis when given in high doses or to patients with renal insufficiency. Sodium chloride absorption may exacerbate fluid retention in patients with heart failure, hypertension, and renal insufficiency. Milk-alkaline syndrome ???????????????????????????????????? sodium bicarbonte ????????????????????????????? ?????????????????????????????? ???????????????????????????????????? ???????????????????????? ???????? ?????? ??????????????????????????????????????? ?????????????????????????? ?????? ??????????????????????? ??????????????????????????????????????????????????? alkalosis ??? azotemia ???????? ??????????????????????????????????????????? ???????????????????????????????????????????????????????????????????????????

39. 2. Non systemic antacids Al salt Mg salt Ca salt

40. Al salt Al(OH)3 , Al phosphate ??????????????????????????????? ???????? Al(Cl)3 ?????? ???????????? rebound hypersecretory ???????????????????? ?????? Gel,tablet ADR ??????? ???????? PO43- ????????? osteomalacia ??????? Metabolic alkalosis ???? Formulations containing magnesium hydroxide or aluminum hydroxide react slowly with HCl to form magnesium chloride or aluminum chloride and water. Because no gas is generated, belching does not occur. Metabolic alkalosis is also uncommon because of the efficiency of the neutralization reaction. Because unabsorbed magnesium salts may cause an osmotic diarrhea and aluminum salts may cause constipation, these agents are commonly administered together in proprietary formulations (eg, Gelusil, Maalox, Mylanta) to minimize the impact upon bowel function. Both magnesium and aluminum are absorbed and excreted by the kidneys. Hence, patients with renal insufficiency should not take these agents long-term. Formulations containing magnesium hydroxide or aluminum hydroxide react slowly with HCl to form magnesium chloride or aluminum chloride and water. Because no gas is generated, belching does not occur. Metabolic alkalosis is also uncommon because of the efficiency of the neutralization reaction. Because unabsorbed magnesium salts may cause an osmotic diarrhea and aluminum salts may cause constipation, these agents are commonly administered together in proprietary formulations (eg, Gelusil, Maalox, Mylanta) to minimize the impact upon bowel function. Both magnesium and aluminum are absorbed and excreted by the kidneys. Hence, patients with renal insufficiency should not take these agents long-term.

41. MgO, MgOH, Mg trisilicate, MaCo3 ???????? Mg2Cl ?????? ?????????????? ?????????????????????????? ???????????????????? ??????? Metabolic alkalosis ???? ADR ???????? ???????????????????????????? neurological syndrome

42. CaCO3 ???????????? ????????????? (15%) ???? CaCl2+CO2 ???? rebound hypersecretory ??? ADR ???????? CO2 ????????????????????? (belching) metabolic alkalosis&calcinosis hypercalcemia nephrolethiasis milk-alkaline syndrome Calcium carbonate(eg, Tums, Os-Cal) is less soluble and reacts more slowly than sodium bicarbonate with HCl to form carbon dioxide and CaCl2. Like sodium bicarbonate, calcium carbonate may cause belching or metabolic alkalosis. Calcium carbonate is used for a number of other indications apart from its antacid properties (see Chapter 42: Agents That Affect Bone Mineral Homeostasis). Excessive doses of either sodium bicarbonate or calcium carbonate with calcium-containing dairy products can lead to hypercalcemia, renal insufficiency, and metabolic alkalosis (milk-alkali syndrome). Calcium carbonate(eg, Tums, Os-Cal) is less soluble and reacts more slowly than sodium bicarbonate with HCl to form carbon dioxide and CaCl2. Like sodium bicarbonate, calcium carbonate may cause belching or metabolic alkalosis. Calcium carbonate is used for a number of other indications apart from its antacid properties (see Chapter 42: Agents That Affect Bone Mineral Homeostasis). Excessive doses of either sodium bicarbonate or calcium carbonate with calcium-containing dairy products can lead to hypercalcemia, renal insufficiency, and metabolic alkalosis (milk-alkali syndrome).

43. ?????????????? ????????? ?????????????? ???? tetracyclines, fluoroquinolones, itraconazole, and iron,iron, theophylline, quinolone,, isoniazid, ketoconazone ?? bioavailability?????????????? ????????????????????????????????? 2 ???????

44. ????????????? peptic ulcer �DU>GU 2. Relief of Gastroesophageal reflux 3. acid indigestion, heartburn, dyspepsia 4. ?????????????? aspiration ????????????? (anesthesia), coma, cesarean section 5. management of hyperphosphatemia (Al, Ca)

45. ?????? antacid ????? ??????? ????????????????????????? ??????? ???????????????????????? ????????????????????????????

46. ?????????? ?? 2550 46 Mucosal Protective Agents Cytoprotective antisecretory agents that enhance mucosal defenses

47. 1. ???????????????????????????????????? (cytoprotective) sucralfate carbenoxolone colloidal bismuth compound octreotide

48. 1.1 Sucralfate salt of sucrose complexed to sulfated aluminum hydroxide

50. ?????????? ?? 2550 50 Pharmacodynamics ?????????????????????????????????? ????????????????????????????????????? 6 ??. negatively charged binds to positively charged proteins in the base of ulcers ??????????????? mucosal prostaglandin ???bicarbonate secretion. mucosal repair (epithelial growth factor and fibroblast growth factor) In water or acidic solutions it forms a viscous, tenacious paste that binds selectively to ulcers or erosions for up to 6 hours. Sucralfate has limited solubility, breaking down into sucrose sulfate (strongly negatively charged) and an aluminum salt. Less than 3% of intact drug and 0.01% of In water or acidic solutions it forms a viscous, tenacious paste that binds selectively to ulcers or erosions for up to 6 hours. Sucralfate has limited solubility, breaking down into sucrose sulfate (strongly negatively charged) and an aluminum salt. Less than 3% of intact drug and 0.01% of

51. ?????????? ?? 2550 51 Dosage and administration 1 g 4 times daily on an empty stomach (at least 1 hour before meals)

52. ????????? systemic ADR: (not absorb) Constipation (aluminum salt) Because it is not absorbed, sucralfate is virtually devoid of systemic side effects. Because a small amount of aluminum is absorbed, it should not be used for prolonged periods in patients with renal insufficiency. Because it is not absorbed, sucralfate is virtually devoid of systemic side effects. Because a small amount of aluminum is absorbed, it should not be used for prolonged periods in patients with renal insufficiency.

53. Antacid ?? bioavailability ??? tetracycline, phenytoin, digoxin, cimetidine, ketoconazole, fluoroquinolone

54. ???????? healing of duodenal ulcers (??????????????? PPI ???????) 2. prevention of bleeding from stress-related gastritis Sucralfate is administered in a dosage of 1 g four times daily on an empty stomach (at least 1 hour before meals). At present, its clinical uses are limited. It has been shown to be effective for the healing of duodenal ulcers, but with the advent of more effective agents (proton pump inhibitors), it is seldom used for this indication. In critically ill patients hospitalized in the intensive care unit, sucralfate is effective for the prevention of bleeding from stress-related gastritis. It is still unclear which is the preferred agent for this indication: sucralfate (administered as a slurry through a nasogastric tube), intravenous H2 antagonists, or intravenous proton pump inhibitors. Some clinicians administer sucralfate to patients taking NSAIDs who are experiencing dyspepsia. It is not an effective agent in preventing or healing NSAID-induced ulcers. Sucralfate is administered in a dosage of 1 g four times daily on an empty stomach (at least 1 hour before meals). At present, its clinical uses are limited. It has been shown to be effective for the healing of duodenal ulcers, but with the advent of more effective agents (proton pump inhibitors), it is seldom used for this indication. In critically ill patients hospitalized in the intensive care unit, sucralfate is effective for the prevention of bleeding from stress-related gastritis. It is still unclear which is the preferred agent for this indication: sucralfate (administered as a slurry through a nasogastric tube), intravenous H2 antagonists, or intravenous proton pump inhibitors. Some clinicians administer sucralfate to patients taking NSAIDs who are experiencing dyspepsia. It is not an effective agent in preventing or healing NSAID-induced ulcers.

55. bismuth subsalicylate (Pepto-Bismol?) bismuth subcitrate (De-nol?) ????????? sulcrafate coats ulcers and erosions stimulate prostaglandin, mucus, and bicarbonate secretion 1.2 Colloidal Bismuth Compounds Like sucralfate, bismuth probably coats ulcers and erosions, creating a protective layer against acid and pepsin. It may also stimulate prostaglandin, mucus, and bicarbonate secretion. Bismuth subsalicylate reduces stool frequency and liquidity in acute infectious diarrhea, due to salicylate inhibition of intestinal prostaglandin and chloride secretion. Bismuth has direct antimicrobial effects and binds enterotoxins, accounting for its benefit in preventing and treating traveler's diarrhea. Bismuth compounds have direct antimicrobial activity against H pylori. Like sucralfate, bismuth probably coats ulcers and erosions, creating a protective layer against acid and pepsin. It may also stimulate prostaglandin, mucus, and bicarbonate secretion. Bismuth subsalicylate reduces stool frequency and liquidity in acute infectious diarrhea, due to salicylate inhibition of intestinal prostaglandin and chloride secretion. Bismuth has direct antimicrobial effects and binds enterotoxins, accounting for its benefit in preventing and treating traveler's diarrhea. Bismuth compounds have direct antimicrobial activity against H pylori.

56. ?????????? ?? 2550 56 ADR blackening of the stool darkening of the tongue Prolong use: encephalopathy (ataxia, headaches, confusion, seizures) High dosages: salicylate toxicity

57. ???????? treatment of dyspepsia and acute diarrhea Bismuth subsalicylate: prevention of traveler's diarrhea (30 mL or 2 tablets four times daily) eradication of H pylori infection "triple therapy� regimen bismuth subsalicylate (2 tablets;262 mg each), tetracycline (500 mg), and metronidazole (250 mg), qid 14 days)

58. ???? oleandane derivative ??? glycyrrhizic acid ?????????????????????? (licorice root) ?????????????? steriods ??????????????????????????????????????? mucus ?????????????????? pepsin ??????????????????????? glycoprotein ?????????????????

59. mineralocorticoid side efects ???????? Na+ and fluid retention, hypertension, hypokalemia, impaired glucose tolerance ??????????????? spironolactone ?? fluid retention ??????????????????????????????????????????????

60. ???????? ????? gastric ??? duodenal ulcer

61. ????????????? somatostatin analog ?????????????????? peptide hormone, gastric ??? pancreatic enzyme ?????????????????? ?????????????????????? Zollinger-Ellison syndrome ??????? metastasis ???????????????????? tumor ??? ??????????????????????????????

62. ?????????????????????? (Croton sublyratus Hurz) ??????????????????????????????????????????????? ??????????????? mucus ??? prostaglandin ??????????????? gastrin ????????????????? 80 mg ????? 3 ?????????????? H2 receptor antagonist ???????? peptic ulcer ADR: ?????????????? ????????????????? SGOT ??? SGPT

64. 2. antisecretory agents that enhance mucosal defenses

65. prostaglandin E2 ??? I2 ???????????????????????????????????????????????????? mucus ??? bicarbonate Misoprostol (cytotec?)

66. Misoprostol (cytotec?) a synthetic prostaglandin E1 analog

67. ?????????? ?? 2550 67

68. ?????????? ?? 2550 68 Pharmacodynamic both acid inhibitory and mucosal protective properties stimulate mucus and bicarbonate secretion and enhance mucosal blood flow binds to prostaglandin receptor on parietal cells, reducing histamine-stimulated cAMP production Prostaglandins have a variety of other actions, including stimulation of intestinal electrolyte and fluid secretion, intestinal motility and uterine contractions. Prostaglandins have a variety of other actions, including stimulation of intestinal electrolyte and fluid secretion, intestinal motility and uterine contractions.

69. ?????????? ?? 2550 69 Pharmacokinetics rapidly absorbed metabolized to a metabolically active free acid serum half-life < 30 minutes administered 3�4 times daily

70. ?????????? ?? 2550 70 ADRs Diarrhea and cramping abdominal pain (10-20%) uterine contractions (contraindication in pregnancy woman)

71. ?????????? ?? 2550 71 Clinical Uses NSAID-induced ulcers reduces the incidence of NSAID-induced ulcers to less than 3% and the incidence of ulcer complications by 50%. approved for prevention of NSAID-induced ulcers in high-risk patients (???????? PPI ?????????????????????) however, it has never achieved widespread use due to its high side effect profile and need for multiple daily dosing. As discussed, proton pump inhibitors may be as effective and better tolerated than misoprostol for this indication. however, it has never achieved widespread use due to its high side effect profile and need for multiple daily dosing. As discussed, proton pump inhibitors may be as effective and better tolerated than misoprostol for this indication.

72. H.pylori cause inflammation of the lining of the stomach able to neutralize the acid in the stomach by using a special enzyme called urease (urease enzyme converts urea into ammonia� and CO2) the acid is not able to destroy the H. pylori. Diagnostic: a blood test, x-ray ,endoscopy, A breath test Transmittion: from person to person through contaminated food and water

74. ???? metronidazole, tetracycline, amoxicillin ????????????????????????????? Helicobacter pylori (H. pylori) ???????????????????????????????????? bismuth compound, antisecretory drugs, H2 inhibitor, PPI

75. Regimens to treat H. pylori Antibiotics: metronidazole, tetracycline, clarithromycin,amoxicillin. H2-blockers: cimetidine, ranitidine, famotidine, nizatidine. Proton pump inhibitors: omeprazole, lansoprazole. Stomach-lining protector: bismuth subsalicylate.

76. �triple therapy" 2 antibiotics plus bismuth Two-week triple therapy reduces ulcer symptoms, kills the bacteria, and prevents ulcer recurrence in more than 90 percent of patients. taking as many as 20 pills a day..poor compliance and much ADR

77. ???????????????? HP ???????????????????????? ??????????????????????????????? 80%

78. ?????????? ?? 2550 78

79. ?????????? ?? 2550 79 ???????? anti-secretory ????????????????????????? HP ??????????????????????????????????????? ???????????????????????? anti-secretory ?????? ?????????? ???? complicated ulcer ????? comorbid condition ??????????????? ?????????? anti-secretory ????????? 4-8 ???????

80. ?????????? ?? 2550 80 References 1.Katzung (Text book of Pharmacology) 2. ????????????????????????? ??????? Dyspepsia ?????????????????????????? Helicobacter pylori ???????????, 1999 Thailand Consensus for the Management of Dyspepsia and Helicobacter pylori