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Agents to Treat Gastric Acidity and Gastroesophageal Reflux Disease (GERD) Presented by Abby Roth.

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Presentation on theme: "Agents to Treat Gastric Acidity and Gastroesophageal Reflux Disease (GERD) Presented by Abby Roth."— Presentation transcript:

1 Agents to Treat Gastric Acidity and Gastroesophageal Reflux Disease (GERD) Presented by Abby Roth

2 Overview Introduction – Symptoms Causes – Peptic Ulcer Disease H. pylori NSAIDs – GERD Treatments

3 Who is Affected? Gastric acidity and GERD affects people of all ages, races, and gender

4 Symptoms Heartburn Acid Indigestion Regurgitation Nausea

5 Symptoms Continued Hoarseness Sore Throat Chest Pain Bad Breath Dry Cough Asthma*

6 Symptoms in Children Vomiting Coughing Breathing Problems

7 Acid-Peptic Disorders Peptic Ulcer Disease – Occurs when there is an imbalance between the mucosal defense factors and the acid and pepsin.

8 Helicobacter pylori Infection Causes 80% of peptic ulcers Survives the acid environment by attaching to the sugar molecules that line the stomach wall Uses the mucus layer as protection

9 H. pylori Produce large amounts of urease Urease H20H20 3 NH 3 + CO 2 Urea

10 H. pylori Secret proteins and toxins that interact with the stomachs epithelial cells Leads to inflammation and damage

11 NSAIDs Aspirin, Ibuprofen, Naproxen Can have an affect at very low doses Suppresses cylooxygenase-1 Decrease production of prostaglandins

12 What is GERD? Condition where the stomach acid/content is pushed back or refluxed into the esophagus Affects 10 million Americans Approximately 7% have daily symptoms Link

13 GERD vs. NERD Patients suffering symptoms are placed in two groups – Non-erosive reflux disease, or NERD – Erosive esophagitis Erosive esophagitis is characterized by swelling and Inflammation – Barretts Esophagus – Precursor to Esophageal Cancer

14 Causes of GERD Abnormalities with the Lower Esophageal Sphincter, or LES Stomach Abnormalities – Hiatal hernia – Link Link

15 Causes Medications – NSAIDs – Calcium Channel Blockers (high blood pressure, angina)

16 Medications – Anticholinergics (urinary tract disorders) – Beta Adrenergic Agonists (asthma) – Dopamine (Parkinsons disease)

17 Causes Food and Drinks – Carbonated beverages – Chocolate – Alcohol – Citrus Fruits – Coffee or Tea – Fatty foods – Containing tomatoes – Mint – Spicy Food

18 Causes Smoking – Damages mucus membranes – Impairs muscle reflexes in the throat – Increases acid secretion – Reduces LES function and salivation

19 Causes Obesity Laying down after a large meal Eating close to bed time Exercise

20 Release of Gastric Acid

21 Release of Gastric acid Histamine stimulates acid release by interacting with the histamine receptor, H 2 Acetylcholine activates the cholinergic receptors Gastrin is released when food is present in the stomach

22 Treatments Antacids Alginates Sucralfate Proton Pump Inhibitors Histamine H 2 -Recptor Antagonists Prokinetics New Treatments

23 Antacids Quick but short term Buffer gastric acid, increasing the pH Neutralize acid by the following reaction Al(OH) 3 + 3 HCl AlCl 3 + 3 H 2 O

24 Antacids – Maalox Al(OH) 3 (aluminum hydroxide), Mg(OH) 2 (magnesium hydroxide)

25 Antacids Tums CaCO 3 (calcium carbonate)

26 Antacids – Pepto-Bismol C 7 H 5 BiO 4 (bismuth subsalicylate)

27 Antacids – Alka-Seltzer NaHCO 3 (sodium bicarbonate)

28 Alginates – Usually combined with an antacid – Forms protective barrier on top of gastric contents – Gaviscon Sodium Alginate, Sodium Bicarbonate, and Calcium Carbonate – Link Link

29 Alginates Polysaccharide found in the cell walls of brown algae Sodium alginate is the sodium salt of alginic acid

30 Alginic Acid

31 Sucralfate Reacts with stomach acid to from a cross linked viscous polymer that acts as an acid buffer Can bind to proteins on the surface of an ulcer to prevent further acid damage Has been shown to aid in healing by promoting epidermal growth factors and prostaglandins

32 Sucralfate (Carafate)

33 Proton Pump Inhibitors Proton pump inhibitors (PPIs) – Inhibits the gastric acid pump, H + /K + ATPase – Are prodrugs

34 PPIs Diffuse into the parietal cells of the stomach and accumulates Activated by proton-catalyzed formation of sulfenic acid This prevents the drug from diffusing out Activated form then irreversibly binds at the sulfhydryl groups of the cysteins of the H + /K + ATPase Link

35 Cysteine


37 PPIs Rabeprazol (Acipex)

38 PPIs Lansoprazole (Prevacid)

39 PPIs Esomeprazole (Nexium)

40 PPIs Omeprazole (Prilosec) Omeprazole/sodium bicarbonate (Zegerid)

41 PPIs Pantoprazole (Protonix)

42 Treatments Histamine H 2 -recptor antagonists (H 2 RAs) The hormone, histamine stimulates the release of acid by interacting with the histamine receptor, or H 2 receptor. Inhibit acid secretion by competitively and reversibly blocking parietal cell H 2 - receptors Less potent then PPIs

43 Agonist vs. Antagonist An agonist is a drug that produces the same response at a receptor as the natural messenger An antagonist is a drug which binds to a receptor without activating it, prevent an agonist or natural messenger from binding

44 Histamine


46 H 2 RAs Cimetidine (Tagamet)

47 H 2 RAs Nizatidine (Axid)

48 Other H 2 RAs Ranitidine HCl (Zantac) Famotidine (Pepcid)

49 Treatments Prokinetics – Increase LES function – Release stomach contents by Activating serotonin receptors Acting on dopaminergic receptors

50 Prokinetics Metoclopramide (Reglan, Degan)

51 Prokinetics Domperidone (Motilium, Costi)

52 Prokinetics Cisapride (Prepulsid, Propulsid)

53 Prokinetics Rarely used because of severe side effects – Fatigue – Tremors – Parkinsonism – Tardive Dyskinesia – Severe cardiac events

54 New Treatments Cholecystokinin 2 receptor antagonists (CCK 2 ) Potassium competitive acid blockers (P-CABs)

55 Treatments Cholecystokinin 2 receptor antagonists (CCK 2 ) – Block the CCK 2 receptors inhibiting acid secretion – Still in clinical trials – Best use in combination with PPIs

56 CCK 2 Itriglumide

57 CCK 2 Z-360

58 Treatments Potassium competitive acid blockers (P-CABs) – Target H + /K + ATPase – Ionically binds to the proton pump – Specific for the K + binding region and prevents acid secretion – Binds reversibly – Still in clinical trials

59 P-CABs Revaprazan

60 P-CABs Soraprazan

61 Treatment for H. pylori Amoxicillin + clarithromycin + proton pump inhibitor Metronidazole + clarithromycin + proton pump inhibitor Bismuth subsalicylate + metronidazole + tetracycline + proton pump inhibitor

62 Assigned Reading Vesper, J.B. et all, Gastroesophageal Reflux Diesease, Is there More to the Story?, ChemMedChem (2008), 3, 552-559.

63 Homework Questions What is an antagonist and how do the H 2 RAs (histamine receptor antagonists) act as one? Explain the precise biological mechanism whereby prokinetics achieve their effect, including the receptors they act upon. Are they agonists or antagonists? Of which chemical messenger? What is a prodrug? What causes the PPIs to become an active drug? Bacteria in the upper GI tract may play a role in GERD. Explain.

64 References Bak, Young-Tae. Management Strategies for Gastroesophageal Reflux Disease. Journal of Gastroenterology and Hepatology (2004), 19, S49-S53. Horn, J. Understanding the Pharmacodynamic and Pharmacokinetic Differences between proton pump inhibitors- focus on pKa and metabolism. AP&T (2006), 2, 340-350. Pettit, M. Treatment of Gastroesophageal Reflux Disease. Pharm World Sci (2005) 27, 432-435. Vakil, N., New Pharmacological Agents for the Treatment of Gastroesophageal Reflux Disease. AP&T (2006), 19, 1041-1049. Vesper, J.B. et all, Gastroesophageal Reflux Diesease, Is there More to the Story?, ChemMedChem (2008), 3, 552-559. Goodman and Gilman pg 967-980. Patrick pg 643-671.

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