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. Gastric acidity and GERD affects people of all ages, races, and gender
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
3 NH3 + CO2
H20
Urea

10. H. pylori
Secret proteins and toxins that interact with the stomach’s 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
Barrett’s Esophagus
Precursor to Esophageal Cancer

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

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

16. Medications Anticholinergics (urinary tract disorders)
Beta Adrenergic Agonists (asthma)
Dopamine (Parkinson’s 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, H2
Acetylcholine activates the cholinergic receptors
Gastrin is released when food is present in the stomach

22. Treatments Antacids Alginates Sucralfate Proton Pump Inhibitors
Histamine H2-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 AlCl3 + 3 H2O

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

25. Antacids
Tums
CaCO3 (calcium carbonate)

26. Antacids
Pepto-Bismol
C7H5BiO4 (bismuth subsalicylate)

27. Antacids
Alka-Seltzer
NaHCO3 (sodium bicarbonate)

28. Alginates Alginates Usually combined with an antacid
Forms protective barrier on top of gastric contents
Gaviscon
Sodium Alginate, Sodium Bicarbonate, and Calcium Carbonate
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. Lansoprazole (Prevacid)
PPIs
Lansoprazole (Prevacid)

39. Esomeprazole (Nexium)
PPIs
Esomeprazole (Nexium)

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

41. Pantoprazole (Protonix)
PPIs
Pantoprazole (Protonix)

42. Treatments Histamine H2-recptor antagonists (H2RAs)
The hormone, histamine stimulates the release of acid by interacting with the histamine receptor, or H2 receptor.
Inhibit acid secretion by competitively and reversibly blocking parietal cell H2-receptors
Less potent then PPI’s

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. H2RAs
Cimetidine (Tagamet)

47. H2RAs
Nizatidine (Axid)

48. Ranitidine HCl (Zantac)
Other H2RAs
Famotidine (Pepcid)
Ranitidine HCl (Zantac)

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

50. Metoclopramide (Reglan, Degan)
Prokinetics
Metoclopramide (Reglan, Degan)

51. Domperidone (Motilium, Costi)
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 Cholecystokinin2 receptor antagonists (CCK2)
Potassium competitive acid blockers (P-CABs)

55. Treatments Cholecystokinin2 receptor antagonists (CCK2)
Block the CCK2 receptors inhibiting acid secretion
Still in clinical trials
Best use in combination with PPI’s

56. CCK2
Itriglumide

57. CCK2
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,

63. Homework Questions
What is an antagonist and how do the H2RAs (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 PPI’s 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,
Pettit, M. Treatment of Gastroesophageal Reflux Disease. Pharm World Sci (2005) 27,
Vakil, N., New Pharmacological Agents for the Treatment of Gastroesophageal Reflux Disease. AP&T (2006), 19,
Vesper, J.B. et all, Gastroesophageal Reflux Diesease, Is there More to the Story?, ChemMedChem (2008), 3,
Goodman and Gilman pg
Patrick pg