Management of GERD

A continuing Education session for pharmacists

1. Management of GERD: A patient outcome/education-driven session Dalia A. Hamdy , BPSc , MSc, PhD, RP(ACP ), MRSC Nahla H. Kandil BPSc , MSc, BCPS

2. Putting issues in perspective: why are we here? GERD (DH/NK-April 2015) 2

3. Learning Objectives Define GERD and recognize its triggers and pathophysiology Identify GERD symptoms and red flags Describe the non pharmacological treatment options for your patient Choose the most appropriate therapeutic agent for your patient Identify the possible drug-drug interactions Set the appropriate monitoring plan for your patient GERD (DH/NK-April 2015) 3

4. Session outline GERD pathophysiology, triggers and exacerbating factors GERD goals of therapy GERD symptoms and red flags GERD non pharmacological treatment GERD therapy algorithms and drug interactions GERD (DH/NK-April 2015) 4

5. References Thomson P., Pham Q.D. Patient Self-Care. 2 nd Edition. Canadian Pharmacists Association; 2010. Chapter Shaffer E.A. Therapeutic Choices. 6 th Edition. Canadian Pharmacists Association ; 2011. Chapter 60 Kinnear M. Clinical Pharmacy and Therapeutics, 5 th Edition. Elservier ; 2012. Chapter 12. Kaiser T.E. Gastrointestinal disorders. ACCP Updates in Therapeutics; 2014 . rxPassport . Antacids, H2RA or PPI? Am I Choosing the Best Option for my Patient? Heartburn series; 2015 http:// www.rxbriefcase.com/passportdefault.aspx GERD (DH/NK-April 2015) 5

6. GERD: pathopysiology Gastroesophageal Reflux Disease “Refers to troublesome symptoms ( heart burn & regurgitation ) and/or complications that result from an excessive reflux of stomach contents into esophagus” Therapeutic Choices 2011 GERD (DH/NK-April 2015) 6 NERD non erosive reflux disease

7. GERD: pathophysiology , triggers ad Exacerbating factors Physiologic : -Transient relaxation of the lower esophageal sphincter (LES), -hypotensive LES -anatomic disruption of the junction; often caused by hiatal hernia 2. Drugs inducing LES relaxation : anticholinergics , aminophyllines , β- adrenergic agonists, benzodiazepines, and nitroglycerines, B-blockers, -blockers, calcium channel blockers, narcotics, nicotine, theophylline. 3. Life style : obesity , smoking, diet (fatty food, chocolate, coffee, alcohol, carbonated drinks) 4. Pregnancy 5. Stress and anxiety 6. Age >65 years GERD (DH/NK-April 2015) 7

8. GERD: goals of therapy Relief symptoms & improve quality of life Promote healing of esophagitis Prevent complications Prevent recurrences GERD (DH/NK-April 2015) 8

9. GERD: Visit your patient Mrs Hoda , a 75-year-old woman, showed up in your pharmacy. She is suffering from heart burn and acidic taste. Two days ago, she had a coffee ground color vomit. Her past medical history included osteoarthritis, gout, hypertension, and resting tremor secondary to anxiety. She had no known drug allergies and was taking the following prescription drugs: GERD (DH/NK-April 2015) 9 Propranolol 40 mg tid prn Indometacin 25 mg tid Diclofenac 50 mg qd Allopurinol 100 mg qd Ramipril 10 mg qd Simvastatin 40 mg qn

10. GERD: Questions for your patient GERD (DH/NK-April 2015) 10 Rxpassport , Heartburn series, 2015

11. GERD: Red Flags! Alarming symptoms Description Chest pain Resembling cardiac pain Chocking Sensation of acid refluxing into the windpipe causing shortness of breath, coughing or hoarsness Dysphagia Difficulty swallowing GIT bleeding Vomiting blood or having tarry or black bowl movement odynophagia Pain upon swallowing Unintentional weight loss (>3kg in past 6 months) Anemia Persistent vomiting Severe abdominal pain GERD (DH/NK-April 2015) 11 Refer to a Doctor! Therapeutic Choices . 2011 Patient Self-Care, 2010

12. GERD: non-pharmacological treatment Life style modification: Avoid foods that ppts events Avoid lying down right after meals Obtain ideal body weight Reduce alcohol intake! Reduce caffeine intake (2-3 cups/day) Smaller more frequent meals GERD (DH/NK-April 2015) 12

13. GERD: non-pharmacological treatment II. Patient recommendations Reassure patient about the benign nature of disease Stress reduction Avoid exercising or bending on full stomach Avoid exacerbating foods Avoid lying down after meals Avoid tight fitting cloths around the waist Raise head of bed around 10 cm Limit nicotine consumption Obtain ideal body weight GERD (DH/NK-April 2015) 13

14. GERD: revisit your patient Patient information: Question is: Guidelines and references states……………. Patient recommendation is……………….. Monitoring plan is…………………… GERD (DH/NK-April 2015) 14

15. GERD: therapeutic algorithms The choice of agent should be based on: Severity of GERD symptoms Impact of symptoms on the patient’s daily life Previous experience with GERD pharmacotherapy Current medications, adverse effects and potential drug interactions Cost GERD (DH/NK-April 2015) 15

16. GERD: therapeutic algorithms A 43-year-old man with type 2 diabetes mellitus and hypertension presents with a 6-week history of intermittent regurgitation occurring about every other day and an acidic taste in his mouth. He takes metoprolol 100 mg once daily and states that his diabetes is controlled by diet. He avoids chocolate and spicy foods, sleeps with his head elevated on a wedge pillow, and uses OTC famotidine 10 mg when symptoms intensify and when he remembers. He admits that he rarely takes it before eating; instead, he usually takes it only once the symptoms are present and do not dissipate. The symptoms have been so significant that he has not slept and has missed 2 days of work recently. Which is the best course of action to address his symptoms ? A. Administer metoclopramide 10 mg four times daily. B. Administer esomeprazole 20 mg/day. C. Continue famotidine 10 mg, but take on a scheduled frequency of three or four times daily. D. Continue famotidine, but increase dose to 20 mg, scheduled three or four times daily. GERD (DH/NK-April 2015) 16

17. GERD: therapeutic algorithms GERD (DH/NK-April 2015) 17 Pharmacological Group Choice Rxpassport , Heartburn series, 2015

18. GERD: therapeutic algorithms GERD (DH/NK-April 2015) 18

19. GERD: therapeutic algorithms GERD (DH/NK-April 2015) 19

20. GERD: therapeutic algorithms A 43-year-old man with type 2 diabetes mellitus and hypertension presents with a 6-week history of intermittent regurgitation occurring about every other day and an acidic taste in his mouth. He takes metoprolol 100 mg once daily and states that his diabetes is controlled by diet. He avoids chocolate and spicy foods, sleeps with his head elevated on a wedge pillow, and uses OTC famotidine 10 mg when symptoms intensify and when he remembers. He admits that he rarely takes it before eating; instead, he usually takes it only once the symptoms are present and do not dissipate. The symptoms have been so significant that he has not slept and has missed 2 days of work recently. Which is the best course of action to address his symptoms ? A. Administer metoclopramide 10 mg four times daily. B. Administer esomeprazole 20 mg/day. C. Continue famotidine 10 mg, but take on a scheduled frequency of three or four times daily. D. Continue famotidine, but increase dose to 20 mg, scheduled three or four times daily. GERD (DH/NK-April 2015) 20

21. GERD: therapeutic algorithms Prokinetics Prokinetics are not widely used to treat GERD because they are not as effective as other treatments and are associated with numerous side effects (sedation, anxiety, extrapyramidal symptoms , etc .). Prokinetics are reserved for patients who are refractory to other available treatment options or who have delayed gastric emptying GERD (DH/NK-April 2015) 21

22. Which of the following is inappropriate monotherapy for mild, intermittent GERD ? Omeprazole Metoclopramide Famotidine Calcium carbonate GERD (DH/NK-April 2015) 22 GERD: therapeutic algorithms

23. GERD (DH/NK-April 2015) 23 GERD: therapeutic algorithms

24. L.F. is a 48-year-old woman who presents to her primary-care provider complaining of recurrent heartburn occurring daily for the past 6 weeks. She states that the heartburn occurs frequently after meals and often wakens her at night. Lately, she has been experiencing difficulty swallowing solid foods. L.F. currently smokes two packs of cigarettes per day and likes to have two glasses of wine each night with her dinner. She states that she occasionally uses OTC ranitidine 150 mg orally up to twice daily, which temporarily relieves her symptoms. Which medication do you suggest ? GERD (DH/NK-April 2015) 24 GERD: therapeutic algorithms

25. GERD: therapeutic algorithms a) It should be taken 30 minutes prior to a meal b) It takes 1-3 days for a clinical response c) It is associated with a therapeutic effect that last for more than the 14 days of treatment d) All of the above GERD (DH/NK-April 2015) 25 Which of the following statements should be used when counselling a patient taking non-prescription PPI therapy?

26. Maintenance Therapy L.F .’s symptoms resolved in about 2 weeks after starting PPI therapy, and she remained asymptomatic after 8 weeks. She then underwent endoscopy, which revealed that the esophagus had healed completely. Her primary-care physician then stopped the PPI. Now , 2 weeks later, she is experiencing mild heartburn. Is L.F . a candidate for long-term maintenance therapy? GERD (DH/NK-April 2015) 26 GERD: therapeutic algorithms

27. Stepping down treatment if patient responds adequately It includes: 1- Discontinuing PPI Therapy 2- Switching To Symptom-driven Therapy 3- Reducing dose of daily PPI GERD (DH/NK-April 2015) 27 GERD: therapeutic algorithms

28. GERD: therapeutic algorithms GERD (DH/NK-April 2015) 28

29. GERD: therapeutic algorithms Key Points on Non-Prescription PPI Most patients will respond to PPI therapy within 1-3 days of treatment .  Maximum acid suppression with PPIs is seen after 3-5 days of treatment . Patients should be instructed to take their full course of therapy and to not discontinue it when the symptoms start to improve . This medication is NOT recommended for PRN use like antacids or H2-receptor antagonists . It should not be taken more frequently than every 4 months Bottom Line:  A 14-day course of non-prescription omeprazole is the first-line treatment of choice for patients with heartburn symptoms occurring on 2 or more days per week. This course will most often resolve the condition.  GERD (DH/NK-April 2015) 29

30. GERD: therapeutic algorithms Rebound Acid Secretion Antacids can be prescribed as “rescue” medication for rebound acid secretion Medicines that contain both an antacid and an anti-foaming agent are likely to be the most effective treatment for rebound acid secretion.  GERD (DH/NK-April 2015) 30

31. • Rapidly neutralize esophageal acid within 15-30 minutes and will typically provide modest relief for up to 90 minutes. • Alginic acid does not neutralize acid but acts as a physical barrier. Currently combined with an antacid, as it offers limited benefit when administered alone. • Generally well tolerated but can lead to constipation (calcium, aluminum) or diarrhea (magnesium ).   • Interact with many medications • Caution in older patients and those with renal disease   • Alginic acid contains a large amount of sodium and could be an issue in patients with congestive heart failure or renal disease Bottom Line:  Inexpensive and rapid relief. The major limitation is the short duration of action. Guidelines recommend considering it for episodic (≤1 day/week) and/or mild symptoms. GERD (DH/NK-April 2015) 31 GERD: therapeutic algorithms Key Points on Antacids

32. Which of the following disorders is an adverse event associated with aluminum hydroxide? Tinnitus Diarrhea Constipation Hyperkalemia GERD (DH/NK-April 2015) 32 GERD: therapeutic algorithms

33. Antacid component Adverse effects Drug interactions Notes Calcium salts Magnesium salts Aluminum salts Magnesium/aluminum antacids Alginic acid Aluminum : Constipation Accumulation in patients with renal failure Hypophosphatemia Calcium : Constipation Rebound hyperacidity Magnesium: Diarrhea Accumulation in patients with renal impairment Magnesium/aluminum combo Minor changes in bowel habits Alginic Acid Flatulence , belching Allopurinol Bisphosphonates Iron salts Quinolones Tetracyclines Digoxin Rosuvastatin To minimize the interaction with these products patients should separate antacid dosing by 1-2 hours Dosing should be taken within 20-60 minutes and/or after a meal at bedtime as needed Relieves symptoms but unlikely to heal inflamed esophagus Dosing for magnesium/aluminum antacids is 10-30 mL PC and HS GERD (DH/NK-April 2015) 33

34. W.J . is a 39-year-old, 130-kg, 170-cm-tall man who presents with complaints of indigestion. He describes a burning sensation behind his breastbone and some belching that is often associated with an acid taste in the back of his mouth . He indicates that his symptoms began a few months ago , and they only occur a few times a month, especially after eating large or spicy meals. Also, if he eats too close to his bedtime, the burning keeps him up at night. He has used liquid antacids in the past for these symptoms and states they work fairly well, but he has to take frequent doses, as the symptoms return quickly . He does not take any other medications . Which medication do you suggest? GERD (DH/NK-April 2015) 34 GERD: therapeutic algorithms

35. M ild symptoms and occur infrequently, and no alarm symptoms . T o specifically “prevent ” meal-related symptoms, he should take an H2RA 30 to 60 minutes before eating or drinking. If symptoms remain infrequent but are unrelated to meals, the use of an OTC H2RA as needed for symptoms may be required . GERD (DH/NK-April 2015) 35 GERD: therapeutic algorithms

36. a) Famotidine is usually superior to ranitidine at equivalent doses b) Tachyphylaxis commonly develops with these medications c) They provide symptom relief in approximately 50% of patients d) Most drug interactions with these medications are clinically significant GERD (DH/NK-April 2015) 36 You start to discuss H2-receptor antagonists with the patient. Which one of the following statements is TRUE? GERD: therapeutic algorithms

37. The H2RA associated with the most significant drug interactions due to inhibition of CYP450 enzymes is ranitidine b ) cimetidine c ) Nizatidine d) famotidin GERD (DH/NK-April 2015) 37 GERD: therapeutic algorithms Drug Metabolism!! Stay Tuned!

38. • Bind to the H 2 -receptors on the gastric parietal cells to reduce gastric acid secretion. • They start to reduce gastric acid within 1 to 2 hours of dosing and the effects last up to 9 hours .   • In equivalent doses, ranitidine and famotidine are equally effective for mild symptoms but are generally not effective for more frequent or severe symptoms .   • Provide complete symptom relief in only 15% of GERD patients .   • Tachyphylaxis (decrease in acid-lowering response over time) commonly develops and has been reported within a few doses with these medications; this can limit their use beyond the on-demand treatment of mild heartburn. • H2RAs are generally very well tolerated and adverse effects are infrequent.  Bottom Line:  Slower onset but longer duration of action compared to antacids. Guidelines recommend their use for mild and episodic (≤1 episode per week) heartburn or occasional meal-provoked heartburn. GERD (DH/NK-April 2015) 38 GERD: therapeutic algorithms Key Points on H2 Receptor Antagonists

39. BACK TO PPIs! The pharmacology of proton pump inhibitors GERD (DH/NK-April 2015) 39 GERD: therapeutic algorithms

40. The gastrointestinal adverse effects of PPIs can be mistaken for symptoms of GORD, sometimes resulting in increased doses of PPI being prescribed. GERD (DH/NK-April 2015) 40 PPIs A dverse Effects GERD: therapeutic algorithms

41. Which adverse event can occur in a patient receiving chronic PPI therapy? Gynecomastia Increased infection risk Extrapyramidal side effects Altered calcium and vitamin D levels GERD (DH/NK-April 2015) 41 GERD: therapeutic algorithms

42. Adverse effects due to chronic use May 2010 - Decreased calcium absorption, leading to increased risk of fracture March 2011- may cause low hypomagnesium if taken for prolonged periods (in most cases , greater than 1 year). Gastric acid suppression with PPIs increases the risk of infection with gastrointestinal ( C.difficile ) or respiratory pathogens, although the absolute risk to most patients remains low. GERD (DH/NK-April 2015) 42 GERD: therapeutic algorithms

43. GERD: therapeutic algorithms PPI-Drug interactions GERD (DH/NK-April 2015) 43 Drug Metabolism Phase 1: Functionalization reactions (introduction of a functional group ) Phase 2: Conjugative reactions (Conjugation with endogenous compounds) Drug AND /OR

44. PPI-Drug interactions Phase 1 metabolism By introducing or unmasking more polar a functional group more readily eliminated GERD (DH/NK-April 2015) 44 Chemical reactions Oxidation Reduction Hydrolysis Hydration Isomerization Dethioacetylation GERD: therapeutic algorithms

45. PPI-Drug interactions Phase 2 metabolism By conjugation with an more polar and water soluble endogenous substance more readily excretable in urine or bile GERD (DH/NK-April 2015) 45 Chemical reactions Glucuronidation/ glycosidation Sulfation Methylation Acetylation Amino acid conjugation Fatty acid conjugation GERD: therapeutic algorithms

46. PPI-Drug interactions PPI’s Omeprazole Esomeprazole Lansoprazole Pantoprazole (Na or Mg) R abeprazole GERD (DH/NK-April 2015) 46 GERD: therapeutic algorithms All metabolized by CYP P450, 2C19 and 3A Possibility of drug-drug interactions Pantoprazole lower affinity to CYP P450 enzyme system + mostly sulfation Rabeprazole metabolized through non enzymatic pathways Less drug interactions possibilities Clinical Pharmacy and Therapeutics 2012

47. PPI-Drug interactions PPI’s Omeprazole Esomeprazole Lansoprazole Pantoprazole (Na or Mg) R abeprazole GERD (DH/NK-April 2015) 47 GERD: therapeutic algorithms Inhibition of CYP2C9 and CYP2C19 D-D interactions possibility with (Monitoring, sp. With >20 mg/day dose) Phenytoin (2C9) diazepam (2C19) S-Warfarin (2C9) R-Warfarin (2C19) Weak Induction of CYP1A2 D-D interactions possibility with (Monitoring) Theophylline Clinical Pharmacy and Therapeutics 2012

48. Interaction with clopidogrel While there was evidence that PPIs may affect clopidogrel activity ex vivo, the available evidence suggested that this would not translate to clinically significant adverse outcomes. However , if considering prescribing a PPI at the same time as clopidogrel then pantoprazole is the recommended choice. Pantoprazole is known to have less of an inhibitory effect on the CYP2C19 enzyme compared with omeprazole or lansoprazole . GERD (DH/NK-April 2015) 48 GERD: therapeutic algorithms

49. GERD: Visit your patient Mr. Hassan, a 45-year-old man, showed up in your pharmacy. His past medical history included hypertension and . One week ago, he suffered from heart burn and acidic taste and was prescribed omeprazole to alleviate this symptom and was asked to decrease smoking and coffee intake. Yesterday he noticed bruising in his leg and arm. He is coming to ask for heamoclare and wondering if there is better suggested brand. He had no known drug allergies and was taking the following prescription drugs: GERD (DH/NK-April 2015) 49 Omeprazole 40 mg qd Ibuprofen 400 mg prn Warfarin Ramipril 10 mg qd

50. GERD: revisit your patient Patient information: Question is: Guidelines and references states……………. Patient recommendation is……………….. Monitoring plan is…………………… GERD (DH/NK-April 2015) 50

51. GERD (DH/NK-April 2015) 51

52. PPIs dose adjustment GERD (DH/NK-April 2015) 52 GERD: therapeutic algorithms

53. Formulations GERD (DH/NK-April 2015) 53 GERD: therapeutic algorithms

54. Calcium carbonate Aluminium hydroxide Magnesium hydroxide Sodium bicarbonate GERD (DH/NK-April 2015) 54 Which of these antacids is available as a combination product with a proton pump inhibitor (PPI)? GERD: therapeutic algorithms

55. Use a combination or not? GERD (DH/NK-April 2015) 55 GERD: therapeutic algorithms

56. What is the drug of choice for GERD during pregnancy? Between 30 – 50% of pregnant women experience symptoms of GORD and this is considered a normal part of pregnancy Antacids > ranitidine >PPIs GERD (DH/NK-April 2015) 56 GERD: therapeutic algorithms

57. Gastroprotective Therapy A 67-year-old woman with rheumatoid arthritis is taking naproxen 500 mg by mouth daily, metoprolol 25 mg by mouth twice daily, aspirin 81 mg by mouth once daily, and alendronate 70 mcg by mouth weekly . Which gastroprotective therapy is best to recommend ? A . Lansoprazole 30 mg daily. B. No gastroprotective therapy necessary. C. Misoprostol 200 mcg twice daily. D. Esomeprazole 40 mg twice daily. GERD (DH/NK-April 2015) 57 GERD: therapeutic algorithms

58. Gastroprotective Therapy GERD (DH/NK-April 2015) 58 GERD: therapeutic algorithms

59. SUMMARY! Monitoring Plans! GERD (DH/NK-April 2015) 59 Your symptoms should not require more than 2 weeks of continuous medication every 6 months See your doctor if - Red Flags - symptoms persist after treatment - any side effects of the monitored drugs

60. Education & Management of Diabetics (DH/AY/NK/ZG June 6, 2014) 60 Thank You