1. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Antacids and Acid-Controlling Agents Antacids H 2 Antagonists Proton Pump Inhibitors

2. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Acid-Related Pathophysiology The stomach secretes: Hydrochloric acid (HCl)Hydrochloric acid (HCl) BicarbonateBicarbonate PepsinogenPepsinogen Intrinsic factorIntrinsic factor MucusMucus ProstaglandinsProstaglandins

3. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Glands of the Stomach CardiacCardiac PyloricPyloric Gastric*Gastric* *The gastric glands are the largest in number

4. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Cells of the Gastric Gland ParietalParietal ChiefChief MucoidMucoid

5. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Cells of the Gastric Gland Parietal Cells Produce and secrete HClProduce and secrete HCl Primary site of action for many acid-controller drugsPrimary site of action for many acid-controller drugs

6. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Cells of the Gastric Gland Chief Cells Secrete pepsinogen, a proenzymeSecrete pepsinogen, a proenzyme Pepsinogen becomes PEPSIN when activated by exposure to acidPepsinogen becomes PEPSIN when activated by exposure to acid Pepsin breaks down proteins (proteolytic)Pepsin breaks down proteins (proteolytic)

7. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Cells of the Gastric Gland Mucoid Cells Mucus-secreting cells (surface epithelial cells)Mucus-secreting cells (surface epithelial cells) Provide a protective mucous coatProvide a protective mucous coat Protects against self-digestion by HClProtects against self-digestion by HCl

8. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Hydrochloric Acid Secreted by the parietal cellsSecreted by the parietal cells Maintains stomach at a pH of 1 to 4Maintains stomach at a pH of 1 to 4 Secretion stimulated by:Secretion stimulated by: –Large, fatty meals –Excessive amounts of alcohol –Emotional stress

9. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Acid-Related Diseases Caused by imbalance of the three cells of the gastric gland and their secretionsCaused by imbalance of the three cells of the gastric gland and their secretions Most common:HyperacidityMost common:Hyperacidity Most harmful:Peptic ulcer disease (PUD)Most harmful:Peptic ulcer disease (PUD) Lay terms for overproduction of HCl by the parietal cells: indigestion, sour stomach, heartburn, acid stomachLay terms for overproduction of HCl by the parietal cells: indigestion, sour stomach, heartburn, acid stomach

10. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Antacids: Mechanism of Action Promote the gastric mucosal defense mechanisms Secretion of:Secretion of: –Mucus: Protective barrier against HCl –Bicarbonate: Helps buffer acidic properties of HCl –Prostaglandins: Prevent activation of proton pump

11. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Antacids: Mechanism of Action Antacids DO NOT prevent the overproduction of acid.Antacids DO NOT prevent the overproduction of acid. Acids DO neutralize the acid once it’s in the stomach.Acids DO neutralize the acid once it’s in the stomach.

12. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Antacids: Drug Effects Reduction of pain associated with acid-related disorders Raising gastric pH from 1.3 to 1.6 neutralizes 50% of the gastric acid.Raising gastric pH from 1.3 to 1.6 neutralizes 50% of the gastric acid. Raising gastric pH 1 point (1.3 to 2.3) neutralizes 90% of the gastric acid.Raising gastric pH 1 point (1.3 to 2.3) neutralizes 90% of the gastric acid.

13. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Antacids OTC formulations available as:OTC formulations available as: Capsules and tabletsPowders Chewable tabletsSuspensions Effervescent granules and tablets

14. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Antacids Aluminum saltsAluminum salts Magnesium saltsMagnesium salts Calcium saltsCalcium salts Sodium bicarbonateSodium bicarbonate Used alone or in combination

15. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Antacids Aluminum Salts Forms: carbonate, hydroxide, phosphateForms: carbonate, hydroxide, phosphate Have constipating effectsHave constipating effects Often used with magnesium to counteract constipationOften used with magnesium to counteract constipation Example: aluminum carbonate (Basaljel)

16. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Antacids Magnesium Salts Forms: carbonate, hydroxide, oxide, trisilicateForms: carbonate, hydroxide, oxide, trisilicate Commonly cause a laxative effectCommonly cause a laxative effect Usually used with other agents to counteract this effectUsually used with other agents to counteract this effect Dangerous when used with renal failure—the failing kidney cannot excrete extra magnesium, resulting in accumulationDangerous when used with renal failure—the failing kidney cannot excrete extra magnesium, resulting in accumulation Examples: magnesium hydroxide (MOM); combination products such as Maalox, Mylanta (aluminum and magnesium)

17. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Antacids Calcium Salts Forms: many, but carbonate is most commonForms: many, but carbonate is most common May cause constipationMay cause constipation Their use may result in kidney stonesTheir use may result in kidney stones Long duration of acid action may cause increased gastric acid secretion (hyperacidity rebound)Long duration of acid action may cause increased gastric acid secretion (hyperacidity rebound) Often advertised as an extra source of dietary calciumOften advertised as an extra source of dietary calcium Example: Tums (calcium carbonate)

18. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Antacids Sodium Bicarbonate Highly solubleHighly soluble Quick onset, but short durationQuick onset, but short duration May cause metabolic alkalosisMay cause metabolic alkalosis Sodium content may cause problems in patients with CHF, hypertension, or renal insufficiencySodium content may cause problems in patients with CHF, hypertension, or renal insufficiency

19. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Antacids and Antiflatulents Antiflatulents: used to relieve the painful symptoms associated with gasAntiflatulents: used to relieve the painful symptoms associated with gas Several agents are used to bind or alter intestinal gas, and are often added to antacid combination products.Several agents are used to bind or alter intestinal gas, and are often added to antacid combination products.

20. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Antacids and Antiflatulents OTC Antiflatulents activated charcoalactivated charcoal simethiconesimethicone –Alters elasticity of mucus-coated bubbles, causing them to break. –Used often, but there are limited data to support effectiveness.

21. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Antacids: Side Effects Minimal, and depend on the compound used Aluminum and calciumAluminum and calcium –Constipation MagnesiumMagnesium –Diarrhea Calcium carbonateCalcium carbonate –Produces gas and belching; often combined with simethicone

22. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Antacids: Drug Interactions ChelationChelation –Chemical binding, or inactivation, of another drug Chemical inactivationChemical inactivation –Produces insoluble complexes Result: reduced drug absorptionResult: reduced drug absorption

23. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Antacids: Drug Interactions Increased stomach pH Increased absorption of basic drugsIncreased absorption of basic drugs Decreased absorption of acidic drugsDecreased absorption of acidic drugs Increased urinary pH Increased excretion of acidic drugsIncreased excretion of acidic drugs Decreased excretion of basic drugsDecreased excretion of basic drugs

24. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Histamine Type 2 (H 2 ) Antagonists

25. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. H 2 Antagonists Reduce acid secretionReduce acid secretion All available OTCAll available OTC Most popular drugs for treatment of acid- related disordersMost popular drugs for treatment of acid- related disorders cimetidine (Tagamet)famotidine (Pepcid) nizatidine (Axid)ranitidine (Zantac)

26. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. H 2 Antagonists: Mechanism of Action Block histamine (H 2 ) at the receptors of acid- producing parietal cellsBlock histamine (H 2 ) at the receptors of acid- producing parietal cells Production of hydrogen ions is reduced, resulting in decreased production of HClProduction of hydrogen ions is reduced, resulting in decreased production of HCl

27. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. H 2 Antagonists: Drug Effect Suppressed acid secretion in the stomachSuppressed acid secretion in the stomach

28. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. H 2 Antagonists: Therapeutic Uses Shown to be effective for:Shown to be effective for: Gastric ulcerGastroesophageal reflux disease (GERD) Upper GI Duodenal ulcer (with or bleeding without H. pylori) May be effective for:May be effective for: –Stress ulcersPeptic esophagitis –Prevention and management of allergic conditions, when used with H 1 blockers

29. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. H 2 Antagonists: Side Effects Overall, less than 3% incidence of side effectsOverall, less than 3% incidence of side effects Cimetidine may induce impotence and gynecomastiaCimetidine may induce impotence and gynecomastia

30. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. H 2 Antagonists: Drug Interactions CimetidineCimetidine –Binds with P-450 microsomal oxidase system in the liver, resulting in inhibited oxidation of many drugs and increased drug levels –All H 2 antagonists may inhibit the absorption of drugs that require an acidic GI environment for absorption.

31. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. H 2 Antagonists: Drug Interactions SMOKING has been shown to decrease the effectiveness of H 2 blockersSMOKING has been shown to decrease the effectiveness of H 2 blockers

32. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Proton Pump Inhibitors

33. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Proton Pump Inhibitors The parietal cells release positive hydrogen ions (protons) during HCl production.The parietal cells release positive hydrogen ions (protons) during HCl production. This process is called the “proton pump.”This process is called the “proton pump.” H 2 blockers and antihistamines do not stop the action of this pump.H 2 blockers and antihistamines do not stop the action of this pump.

34. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved.

35. Proton Pump Inhibitors: Mechanism of Action Irreversibly bind to H+/K+ ATPase enzyme. This bond prevents the movement of hydrogen ions from the parietal cell into the stomach.This bond prevents the movement of hydrogen ions from the parietal cell into the stomach. Result: Achlorhydria—ALL gastric acid secretion is blocked.Result: Achlorhydria—ALL gastric acid secretion is blocked. –In order to return to normal acid secretion, the parietal cell must synthesize new H+/K+ ATPase.

36. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Proton Pump Inhibitors: Drug Effect Total inhibition of gastric acid secretionTotal inhibition of gastric acid secretion lansoprazole (Prevacid)omeprazole (Prilosec) rabeprazole (Aciphex)pantoprazole (Protonix) esomeprazole (Nexium)

37. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Proton Pump Inhibitors: Therapeutic Uses GERD maintenance therapyGERD maintenance therapy Erosive esophagitisErosive esophagitis Short-term treatment of active duodenal and benign gastric ulcersShort-term treatment of active duodenal and benign gastric ulcers Zollinger-Ellison syndromeZollinger-Ellison syndrome Treatment of H. pylori-induced ulcersTreatment of H. pylori-induced ulcers

38. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Proton Pump Inhibitors: Side Effects Safe for short-term therapySafe for short-term therapy Incidence low and uncommonIncidence low and uncommon

39. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Other Drugs sucralfate (Carafate)sucralfate (Carafate) misoprostol (Cytotec)misoprostol (Cytotec)

40. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Sucralfate (Carafate) Cytoprotective agentCytoprotective agent Used for stress ulcers, erosions, PUDUsed for stress ulcers, erosions, PUD Attracted to and binds to the base of ulcers and erosions, forming a protective barrier over these areasAttracted to and binds to the base of ulcers and erosions, forming a protective barrier over these areas Protects these areas from pepsin, which normally breaks down proteins (making ulcers worse)Protects these areas from pepsin, which normally breaks down proteins (making ulcers worse)

41. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Sucralfate (Carafate) Little absorption from the gutLittle absorption from the gut May cause constipation, nausea, and dry mouthMay cause constipation, nausea, and dry mouth May impair absorption of other drugs, especially tetracyclineMay impair absorption of other drugs, especially tetracycline Binds with phosphate; may be used in chronic renal failure to reduce phosphate levelsBinds with phosphate; may be used in chronic renal failure to reduce phosphate levels Do not administer with other medicationsDo not administer with other medications

42. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. misoprostol (Cytotec) Synthetic prostaglandin analogueSynthetic prostaglandin analogue Prostaglandins have cytoprotective activity:Prostaglandins have cytoprotective activity: –Protect gastric mucosa from injury by enhancing local production of mucus or bicarbonate –Promote local cell regeneration –Help to maintain mucosal blood flow

43. Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. misoprostol (Cytotec) Used for prevention of NSAID-induced gastric ulcersUsed for prevention of NSAID-induced gastric ulcers Doses that are therapeutic enough to treat duodenal ulcers often produce abdominal cramps, diarrheaDoses that are therapeutic enough to treat duodenal ulcers often produce abdominal cramps, diarrhea