1 Gastroenterology: Gastroesophageal Reflux DiseaseCourses in Therapeutics and Disease State Management

2 Learning Objectives Define GERD and describe the various stages of disease severity Describe the etiology of GERD and risk factors associated with the disease Discuss typical symptoms, atypical symptoms, alarm symptoms, aggravating factors and complications associated with GERD Describe how GERD is diagnosed and the role of endoscopy Discuss the various pharmacologic approaches for the treatment of GERD

3 Learning Objectives Review the roles of the H2-antagonists and proton pump inhibitors in the treatment of GERD and prevention of its recurrence Describe non-pharmacologic and lifestyle measures that may be beneficial in the reduction of symptoms of reflux disease Given a GERD patient history, be able to recommend appropriate pharmacologic and nonpharmacologic therapies and explain the rationale behind your decision Discuss drug adverse effects and monitoring parameters for drugs and GERD

4 Required and Recommended ReadingMay D, Thiman M, Rao SC. Gastroesophageal Reflux Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; 2017. Each one of the following patients is presenting with the same signs and symptoms consistent an infection.

5 GERD Definitions GERD (Gastroesophageal Reflux Disease)A condition that occurs when refluxed stomach contents lead to troublesome symptoms and/or complications Episodic pyrosis (heartburn) that is not frequent enough or painful enough to be considered bothersome by the patient is not included in the above consensus GERD definition Pyrosis frequency of more than 2 times per week is sometimes used as a criteria for GERD Chronic symptoms or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus. Symptoms of GERD vary in severity, duration, and frequency. When the esophagus is repeatedly exposed to refluxed material for prolonged periods of time, inflammation of the esophagus (esophagitis) occurs, and in some cases it can progress to erosion of the squamous epithelium of the esophagus (erosive esophagitis) and may lead to other complications. If symptoms (e.g. pyrosis) are not frequent or troublesome, it is usually not considered to be gastroesophageal reflux disease (GERD). Many people experience occasional pyrosis (heartburn)

6 Epidemiology Heartburn is the most frequent clinical complaintReported to occur at least once daily in 10% 20% weekly; 44% monthly of U.S. adults $5 billion for OTC/Rx per year Most frequently occurs in adults over 40 years of age Incidence in similar between men and women - It can occur in all ages, but most frequently in adults over 40 years old

7 Epidemiology About 50% of pregnant women will experience GERDCan also occur in infants Prevalence depends on geographic region but is highest in Western countries Pregnancy causes an increase in intra-abdominal pressure particularly in the 3rd trimester Infants have lesser developed lower esophageal sphincters and are frequently in a recumbent position, both of which increase their risk of GERD

8 Risk Factors Obesity (BMI ≥ 30) Alcohol use SmokingExcessive caffeine intake Respiratory diseases Obese patients are 3 times more likely to develop GERD than non-obese patients Ethanol decreases lower esophageal sphincter pressure causing it to relax. Nicotine decreases lower esophageal sphincter pressure causing it to relax. Caffeine decreases lower esophageal sphincter pressure causing it to relax.

9 Key Factors in the Development of GERDA decrease in lower esophageal sphincter (LES) pressure Decreased clearance of gastric contents from the esophagus Decreased mucosal resistance in the esophagus - Decreased clearance can happen due to decreased esophageal peristalsis and/or decreased salivary production. Salivary flow down the esophagus helps to clear gastric contents. Also, saliva contains bicarbonate which helps to buffer gastric contents. - Examples of decreased mucosal resistance include decreased mucous production and decreased bicarbonate secretion

10 Key Factors in the Development of GERDComposition of reflux contents “extra acidic” Gastric fluid that has a pH < 4 is extremely caustic to the esophageal mucosa. Decreased gastric emptying (increased gastric emptying time)  Certain anatomic features Most commonly a hiatal hernia Delayed gastric empyting can occur when there is a high gastric volume and a decreased gastric emptying rate. For example, fatty foods can increase gastric volume and decrease gastric emptying rate. In addition, fatty foods can decrease LES pressure.

11 Pathophysiology of GERD (Role of the Lower Esophageal Sphincter)Link: Figure of comparison of esophageal high-resolution manometry Link: Figure of pathophysiology of esophageal reflux disease (LES, lower esophageal sphincter)

12 Hiatal Hernia A hiatal hernia occurs when a portion of the stomach protrudes through the diaphragm into the chest Causes a disruption in the normal anatomic barriers between the stomach and the esophagus Link: Figure of radiographic anatomy of the gastroesophageal junction

13 GERD Symptoms GERD symptoms are often grouped in 3 categoriesTypical or “classic” esophageal symptoms Alarm or complicated symptoms May be indicative of GERD complications Atypical or extraesophageal symptoms GERD is often described and classified in multiple ways. First is by symptoms, which is discussed in the next several slides. GERD is also described if tissue injury is present (erosive disease) or absent (non-erosive disease). This is also discussed in later slides.

14 Typical or “Classic” SymptomsPyrosis (heartburn) Hallmark symptom A substernal feeling of warmth or burning rising up from the abdomen that may radiate to the neck Regurgitation/Belching Acid brash/Hypersalivation Chest pain (non cardiac in nature) If a patient gets occasional pyrosis, they do not necessarily have GERD. Many people get heartburn occasionally.

15 Alarm (Complicated) SymptomsAny of these symptoms warrant immediate referral for testing Dysphagia Odynophagia Bleeding Unexplained weight loss Choking Chest pain (if could be cardiac in nature)

16 Extraesophageal Symptoms/Manifestations (Atypical Symptoms)These symptoms have an association with GERD but causality should only be considered if a concomitant esophageal symptoms are present Chronic cough Asthma-like symptoms About 50% of those with asthma have GERD Laryngitis/Hoarseness Recurrent sore throat Dental enamel erosion

17 GERD GERD is often described on either esophageal symptoms or esophageal tissue injury Symptom-based GERD syndromes (with or without esophageal tissue injury) Tissue injury-based GERD syndromes (with or without esophageal symptoms) Extraesophageal GERD syndromes may also occur GERD is also sometimes described in terms of the absence or presence of esophageal erosions Non-erosive reflux disease (NERD) Erosive reflux disease (ERD)

18 Symptom-Based GERD SyndromesMay or may not have esophageal tissue injury Have typical or “classic” esophageal symptoms May have alarm symptoms particularly if GERD complications (see next section) are present

19 Tissue-Injury Based GERD SyndromesExamples of esophageal tissue injury include the presence of any of the following: Esophagitis (inflammation of the esophagus) Erosions (erosion of the squamous epithelium of the esophagus) Strictures Barrett’s esophagus Esophageal adenocarcinoma May present with alarm symptoms particularly if have GERD complications May or may not have typical or classic symptoms - Not everyone with tissue injury from reflux will present with the “classic” symptoms such as pyrosis.

20 Extraesophageal GERD SyndromesPresent with extraesophageal or atypical symptoms May or may not have typical esophageal symptoms Extraesophageal symptoms have an association with GERD, but causality should only be considered if a concomitant esophageal GERD syndrome is also present Extraesophageal manifestations of GERD are being recognized with increasing frequency. GERD may be either a causative or exacerbating factor in up to 50% of patients who experience these symptoms.

21 Aggravating Factors Recumbency Increased intra-abdominal pressureReduced gastric motility Decreased LES tone or pressure Direct mucosal irritation There are many situations that can aggravate GERD symptoms. Avoiding situations, medications, food, etc. that exacerbate symptoms is common and important strategy in GERD management. Common things that can increase intra-abdominal pressure include obesity, pregnancy, tight clothing, belts, bending over) There are multiple foods and medications that can decrease LES tone or pressure There are multiple foods and medications that are direct irritants to the esophageal mucosa

22 Decrease in LES PressureExamples of foods that decrease LES pressure Fatty foods, peppermint, spearmint, chocolate, coffee, cola, tea, garlic, onions, chili peppers Examples of medications that decrease LES pressure Anticholinergics, barbiturates, benzodiazepines, caffeine, dihydropyridine calcium channel blockers, dopamine, estrogen, ethanol, narcotics, nicotine, nitrates, progesterone, theophylline - There are a variety of foods and medications that can decrease LES pressure and hence aggravate or exacerbate GERD symptoms such as pyrosis.

23 Direct Mucosal IrritationExamples of foods that are direct irritants to the esophageal mucosa Spicy foods, orange juice, tomato juice, coffee Examples of medications that are direct irritants to the esophageal mucosa Oral bisphosphonates, aspirin, iron, NSAIDs, quinidine, potassium - There are foods and medications that are very irritating to the esophageal mucosa and hence can exacerbate pyrosis

24 Foods and Medications that May Worsen GERD SymptomsFoods/Beverages Medications Decreased Lower Esophageal Sphincter Pressure Fatty meal Anticholinergics Carminatives (peppermint, spearmint) Barbiturates Chocolate Caffeine Coffee, cola, tea Dihydropyridine calcium channel blockers Garlic Dopamine Onionsz Estrogen Chili peppers Nicotine Alcohol (wine) Nitrates Progesterone Tetracycline Theophylline Direct Irritants to the Esophageal Mucosa Spicy foods Aspirin Orange juice Bisphosphonates Tomato juice Nonsteroidal antiinflammatory drugs (NSAIDs) Coffee Iron Tobacco Quinidine Potassium chloride From AccessPharmacy: accesspharmacy.mhmedical.com, Copyright© McGraw-Hill Education. All rights reserved. Chapter 19. Antimicrobial Regimen Selection, Table 19-1 Foods and Medications that May Worsen GERD Symptoms Pharmacotherapy: A Pathophysiologic Approach, 9e, 2014 Joseph T. DiPiro, Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael Posey

25 Complications of GERD EsophagitisLink: Figure of EGD demonstrating linear red streaks with a central white streak extended up the esophagus in peptic regurgitant esophagitis Erosions and ulceration of the esophageal mucosa Strictures of the esophagus Secondary to fibrous tissue deposition after long standing erosion Barrett’s esophagus Present in about 10% of those with GERD Most prevalent in white males in Western countries Esophageal adenocarcinoma Erosions and ulcerations may have bleeding. The blood loss is usually low grade and chronic in nature and may lead to anemia Strictures of the esophagus are most common in the distal esophagus. They are usually 1 to 2 cm in length.

26 Barrett’s Esophagus Barrett’s esophagus occurs when the normal squamous cell epithelium in the esophagus converts to a columnar cell epithelium (intestinal-type epithelium) More common in men than women Barrett’s esophagus does not cause specific symptoms but the reflux does Barrett’s esophagus may occur after long-standing disease About 1/3 of those with Barrett’s esophagus have minimal or no symptoms

27 Barrett’s Esophagus Those with Barrett’s esophagus develop adenocarcinoma of the esophagus at a rate of 0.12% per year Gender ratio for esophageal adenocarcinoma is 8:1 (male:female) Patients must be monitored via endoscopy to evaluate changes in cell type and conversion to adenocarcinoma - The frequency of endoscopy depends on biopsy results.

28 Complications of GERD Link: Photos of endoscopic appearance of peptic esophagitis, a peptic stricture, Barrett’s metaplasia, and adenocarcinoma

29 GERD Diagnosis/Diagnostic TestsClinical History Patient’s description of typical or classic GERD symptoms such as pyrosis, is often enough to consider GERD as an initial diagnosis (uncomplicated GERD) Empiric trial of proton pump inhibitor (PPI) therapy ACG (American College of Gastroenterology) guidelines state that it is reasonable to assume a GERD diagnosis in patients who respond to appropriate therapy - Invasive testing such as endoscopy is not necessary in these circumstances

30 GERD Diagnosis/Diagnostic TestsEndoscopy Endoscopy is the technique of choice to identify complications of GERD such as ulcerations, erosions, Barrett’s esophagus, etc. Biopsy of the esophageal tissue is needed to identify and diagnose Barrett’s esophagus and esophageal adenocarcinoma Many patients with GERD (presenting with typical or atypical symptoms) will have normal appearing esophageal mucosa on endoscopy Usually not part of the work-up except in certain subsets of patients (alarm symptoms, those refractory to treatment, etc.) - Many patients with GERD (presenting with typical or atypical symptoms) will have normal appearing esophageal mucosa on endoscopy. That doesn’t mean they don’t have GERD. It means at that point in time they do not have any esophageal tissue injury present.

31 GERD Diagnosis/Diagnostic TestsAmbulatory pH Monitoring Identifies patients with excessive esophageal acid exposure and helps determine if symptoms are acid related Useful in patients not responding to acid-suppression therapy Barium Radiography Not routinely used to diagnose GERD due to a lack of sensitivity and specificity Can detect hiatal hernia

32 GERD Diagnosis/Diagnostic TestsPatients presenting with extraesophageal or atypical symptoms should be reviewed on a case-by-case basis to be considered for testing Alarm symptoms always warrant further testing

33 Therapeutic Approach to GERDThe initial treatment used is determined by the patient’s condition: Frequency of symptoms Degree of symptoms Presence and/or degree of esophagitis Presence of complications

34 Goals of Treatment Alleviate or eliminate acute symptomsDecrease frequency of recurrence Promote healing if esophageal tissue injury is present Prevent complications

35 General Treatment ApproachInitial therapy in patients who present with typical GERD symptoms should include patient-directed (self-care) therapy (antacids, OTC H2-antagonist, or OTC PPIs) and lifestyle modifications Those who do not respond to patient-directed therapy and lifestyle modifications after 2 weeks should seek medical attention and are usually started on empiric therapy consisting of an acid suppression agent such as a proton pump inhibitor (PPI) Those who do not respond to empiric acid suppression therapy or have alarm symptoms should undergo testing such as an endoscopy - OTC = over the counter or nonprescription medications

36 Nonpharmacologic TherapiesLifestyle modifications Should be incorporated into the management of GERD regardless of the severity of disease Lifestyle modifications should be tailored to an each individual patient’s needs Anti-reflux surgery Used as a last resort option in select patients When long-term pharmacologic therapy is undesirable Who have refractory GERD Have complications Endoscopic therapies Results have been disappointing and hence are not usually recommended Endoscopic therapies include endoscopic sewing devices, the Stretta procedure, and the LINX system.

37 Lifestyle ModificationsWeight loss (if the patient is overweight or obese) Elevation of the head of the bed 6 to 8 inches Eat smaller, more frequent meals (as opposed to larger meals less frequently) Include protein-rich meals in diet (increases LES pressure) - To elevate the head of the bed, it is preferable to place a wedge or blocks between the mattress and the box spring as opposed to stacking pillows under the patient’s head

38 Lifestyle ModificationsAvoid eating 3 hours prior to sleeping or lying down Avoid foods or medications that exacerbate GERD Avoid alcohol Tobacco cessation - Remember both alcohol and nicotine decrease LES pressure and can exacerbate symptoms

39 Endoscopic InterventionsStretta Procedure Stretta is an endoscopically guided radiofrequency (RF) energy delivery system. The device is guided down the esophagus and RF energy is delivered to tissues via catheters/needles. RF energy is thought to improve GERD symptoms by increasing collagen deposition at the LES, increasing muscle wall thickness and reconstituting the barrier to the reflux of gastric contents.  LINX Reflux Management System (FDA approved March 2012) A series of titanium beads each with a magnetic core connected together with a wire to form a ring shape. Implanted in the LES The force of the magnetic beads provides additional strength to a keep a weak LES closed.

40 Therapeutic Interventions in the Management of GERDLink: Figure of therapeutic interventions in the management of gastroesophageal reflux disease

41 Pharmacologic Agents Used in the Treatment of GERDAntacids and alginic acid products H2-receptor antagonists (HRA) Proton pump inhibitors (PPIs) Promotility agents

42 Antacids MOA Agents Adverse effectsNeutralize hydrochloric acid in the stomach, which results in an increase in gastric pH Agents Magnesium hydroxide Aluminum hydroxide Calcium carbonate Adverse effects Diarrhea (magnesium hydroxide) Constipation (aluminum hydroxide and calcium carbonate) Alterations in mineral metabolism Acid-base disturbances

43 Antacids Monitoring Patient counselingPeriodic calcium and phosphate levels if on chronic antacid therapy Patient counseling Antacids can decrease the levels of numerous other drugs including tetracyclines, digoxin, iron supplements, fluroquinolones, and ketoconazole. Patients should separate antacids and other medications by at least 2 hours Patients with renal impairment should not use aluminum or magnesium containing antacids unless directed by their physician Onset of relief is less than 5 minutes and duration of relief is 20 to 30 minutes - Antacids can interact and decrease the effectiveness of other medications through a various mechanisms including increasing gastric pH with resulting decreased absorption of some medications, increasing urinary pH, adsorbing other medications, acting as a physical barrier to the absorption of other medications, forming insoluble complexes with some medications.

44 Composition and Acid Neutralizing Capacities of Popular Antacid PreparationsPRODUCT Al(OH)3a Mg(OH)2a CaCO3a SIMETHICONEa ACID NEUTRALIZING CAPACITYb Tablets Gelusil 200 25 10.5 Maalox Quick Dissolve 600 12 Mylanta Double Strength 400 40 23 Riopan Plus Double Strength Magaldrate, 1080 20 30 Calcium Rich Rolaids 80 412 11 Tums EX 750 15 Liquids Maalox TC 300 28 Milk of Magnesia 14 Mylanta Maximum Strength Riopan Magaldrate, 540 From AccessPharmacy: accesspharmacy.mhmedical.com, Copyright© McGraw-Hill Education. All rights reserved. Chapter 45: Pharmacotherapy of Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease  Table 45-2Composition and Acid Neutralizing Capacities of Popular Antacid Preparations Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e, Copyright © 2011 Laurence L. Brunton, Bruce A. Chabner, Björn C. Knollmann aContents, milligrams per tablet or per 5 ml. bAcid neutralizing capacity, milliequivalents per tablet or per 5 ml. The U.S. marketplace for antacids is fluid. The current trend of "reusing" well-known brand names to introduce new products that contain an active ingredient different from expected is a source of confusion that can present a danger to patients. Medication safety experts encourage clinical practitioners to refer to the active ingredient(s) in conjunction with the proprietary (brand) name when selecting OTC products.

45 Antacid-Alginic Acid CombinationMOA The antacid neutralizes stomach acid and the alginic acid is a foaming agent that creates a viscous solution that floats on top of the stomach contents and may be protect the esophagus from refluxed stomach acid Agents Aluminum hydroxide/Magnesium carbonate/Alginic acid (Gaviscon)

46 H2-Receptor AntagonistsMOA Competitive inhibition of histamine at H2 receptors of gastric parietal cells which inhibits gastric acid secretion Agents Cimetidine (Tagamet) Famotidine (Pepcid) Nizatidine (Axid) Ranitidine (Zantac)

47 H2-Receptor AntagonistsAdverse effects Headache, somnolence, fatigue, dizziness, constipation, diarrhea Monitoring Monitor for CNS effects (rare) in those over 50 years old or in those with renal or hepatic impairment Patient counseling If taking once a day, it is preferable to take the dose at bedtime Onset of relief is 30 to 45 minutes and duration of relief is 4 to 10 hours

48 Proton Pump Inhibitors (PPIs)MOA Blocks acid secretion by inhibiting gastric H+/K+ adenosine triphosphatase found on the secretory surface of gastric parietal cells Results in a long-lasting anti-secretory effect that can maintain gastric pH levels above 4 Agents Dexlansoprazole (Dexilant) Esomeprazole (Nexium) Lansoprazole (Prevacid) Omeprazole (Prilosec) Omeprazole/sodium bicarbonate (Zegerid) Pantoprazole (Protonix) Rabeprazole (Aciphex) - There is a correlation between the percentage of time that the gastric pH remains above 4 and healing of erosive esophagitis.

49 Proton Pump Inhibitors (PPIs)Common adverse effects Headache, dizziness, somnolence, diarrhea, constipation, flatulence, abdominal pain, nausea Serious adverse effects Increased risk of Clostridium difficile infections Increase risk of community-acquired pneumonia Long-term adverse effects (> 1 year) Hypomagnesemia Bone fractures Vitamin B12 deficiency

50 Proton Pump Inhibitors (PPIs)Monitoring Appearance of diarrhea (frequency and type of diarrhea episodes) Periodic magnesium levels (if long-term therapy) Routine bone density studies (DXA scans) If other risk factors for osteoporosis or bone fractures present Patient counseling Preferable to take a PPI 30 to 60 minutes before a meal (mainly breakfast) If a second dose is needed, take prior to the evening meal Onset of relief is 2 to 3 hours and the duration of relief is 12 to 24 hours

51 Evaluate the Risks versus Benefits of Long-Term PPI UseLong-term PPI use has been associated with increased risk of: Fractures Infections such as C. Diff and pneumonia (expand) Hypomagnesemia Vitamin B12 deficiency

52 Evaluate the Risks versus Benefits of Long-Term PPI UseLong-term PPI use MAY BE associated with increased risk of: Dementia Renal disease Cardiovascular disease

53 Promotility Agents Promotility agents, such as metoclopramide and bethanechol, have been used as adjunct therapy to acid suppression agents such as PPIs in patients who have a known motility defect However, they are not generally recommended to be used for GERD treatment due to their limited effectiveness and undesirable adverse effect profiles

54 Pharmacologic TherapyPatient directed therapy (Self-care) is appropriate for intermittent, mild pyrosis and is managed using over-the-counter products such as antacids, OTC H2-receptor antagonists, and OTC proton pump inhibitors (PPIs) Link: Table on Therapeutic Approach to GERD in Adults

55 Pharmacologic TherapySymptomatic relief of uncomplicated GERD is treated with prescription H2-receptor antagonists or prescription PPIs at the following doses and durations: Refer to Link: Table on Therapeutic Approach to GERD in Adults

56 Pharmacologic TreatmentHealing of erosive esophagitis or treatment of patients presenting with moderate to severe symptoms or complications Refer to Link: Table on Therapeutic Approach to GERD in Adults

57 PPIs v. H2-Receptor AntagonistsSymptomatic improvement as well as endoscopic healing rates are higher for the PPIs compared to the H2-receptor antagonists PPIs are therefore preferred over H2-receptor antagonists in patients with erosive disease, moderate to severe symptoms, or with complications

58 Maintenance Therapy What patients should receive maintenance therapy?Those with symptomatic relapse following discontinuation of the drug or a decrease in dose. If NERD/uncomplicated GERD, try to manage with on-demand or intermittent PPI therapy or H2-receptor antagonists

59 Maintenance Therapy What patients should receive maintenance therapy?Those with a history of complications (e.g. Barrett’s esophagus, strictures, hemorrhage, ulcerations, etc.) Long-term maintenance therapy with PPIs at the lowest possible dose Can consider intermittent or on demand PPI therapy in some circumstances

60 PPIs and Rebound Acid SecretionThere have been reports of rebound acid secretion when PPIs are abruptly discontinued. This can happen when PPIs are used for as little as 2 months (and of course when they are used longer) These hyperacidity symptoms include dyspepsia and heartburn Often attributed to a relapse of the disorder (e.g. GERD), but it can even happen in patients who didn’t have these symptoms to start with - Rebound acid secretion following discontinue of a PPI as described could be one reason why some people find it hard to stop a PPI

61 PPIs and Rebound Acid SecretionTapering strategies for patients experiencing rebound acid secretion (1) Taper PPI over 4 to 6 weeks First lower the dose of the PPI Then extend the PPI dosing interval to every other day then every 3rd day An H2-antagonist or antacid can be used for symptoms on “off days” as needed (2) Suggest a switch to an H2-antagonist with antacids used as needed for several weeks then discontinue - Either of these 2 strategies is appropriate to use to successfully discontinue a PPI in a patient who is experiencing rebound acid secretion symptoms after discontinuing a PPI

62 Patients with Extraesophageal (Atypical) GERDGERD can be considered as a potential co-factor in patients with asthma, chronic cough, or laryngitis Careful evaluation of non-GERD causes should be undertaken in all of these patients Patients with atypical symptoms may need higher doses of acid suppression therapy with longer treatment duration compared to those patients with typical symptoms

63 Patients with Extraesophageal (Atypical) GERDA PPI trial is recommended to treat extraesophageal symptoms in patients who have typical GERD symptoms as well Reflux monitoring should be considered before a PPI trial in patients with extraesophageal symptoms who do not have typical GERD symptoms

64 Pediatric Patients A suspected cause of reflux in infants is a developmentally immature LES Many infants have reflux with little or no clinical consequence This uncomplicated reflux usually manifests as regurgitation or spitting up Usually responds to supportive therapy Chronic vomiting associated with GERD must be carefully evaluated and distinguished from other causes - Supportive therapy includes dietary adjustments, postural management, thickened feedings

65 Pediatric Patients Careful consideration should be given before a medication is recommended When a medication is deemed necessary, ranitidine dosed at 2 to 4mg/kg twice a day is often used PPIs are increasing being used in children older than 1 year Lansoprazole, esomeprazole, and omeprazole are indicated for treating symptomatic and erosive GERD in children > 1 year old See next slide for dosing ranges Omeprazole has been used off-label in children less than 1 year old at a dose of 1mg/kg/day

66 PPIs in Children > 1 year of ageLansoprazole 15mg per day is recommended for children weighing < 30kg 30mg per day is recommended for children weighing > 30kg Esomeprazole Dosed 10 to 20mg a day for children 1 to 11 years old Dosed at 20 to 40mg a day for children 12 to 17 years old Omeprazole 5mg daily in children weighing between 5 and 10kg 10mg daily in children weighing between 10 and 20kg 20mg daily in children weighing ≥ 20kg

67 Elderly Patients Many elderly patients have decreased defense mechanisms such as decreased saliva production PPI therapy may be warranted for those > 60 years of age with symptomatic GERD They have superior efficacy and have once a day dosing Long-term risk of bone fractures is a concern and elderly patients should be monitored appropriately Elderly are at higher risk of being sensitive to possible CNS effects of H2-receptor antagonists

68 Patients with Refractory GERDRefractory GERD should be considered in patients who have not responded to a standard course of twice a day PPI therapy The majority of patients with refractory symptoms experience nocturnal acid breakthrough Switching to a different PPI may be effective in some patients Adding an H2-receptor antagonist at bedtime for nocturnal symptoms is reasonable but the effect may decrease over time due to tachyphylaxis with H2-receptor antagonists

69 References May D, Thiman M, Rao SC. Gastroesophageal Reflux Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; 2017. Mills JC, Stappenbeck TS. Gastrointestinal Disease. In: Hammer GD, McPhee SJ. eds. Pathophysiology of Disease: An Introduction to Clinical Medicine, Seventh Edition. New York, NY: McGraw-Hill; 2013. Kahrilas PJ, Hirano I. Diseases of the Esophagus. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 19e. New York, NY: McGraw-Hill; 2015.

70 References Wallace JL, Sharkey KA. Pharmacotherapy of Gastric Acidity, Peptic Ulcers, and Gastroesophageal Reflux Disease. In: Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill; 2011. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2013; 108: Schoenfeld AJ, Grady D. Adverse effects associated with proton pump inhibitors. JAMA Internal Medicine 2016; 176(2):

71 References Micromedex Solutions.  Truven Health Analytics, Inc. Ann Arbor, MI.  Accessed October 15, 2016. Lexicomp Online®, Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc. Accessed October 15, 2016.