management of uncomplicated gerd in adult patients

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Objective:At the conclusion of this knowledge-based activity, the pharmacist will be able to:• Review the pathophysiology and common clinical

presentation of gastroesophageal reflux disease (GERD).

• Evaluate diagnostic criteria for GERD for adult patients and describe current treatment guidelines from the American College of Gastroenterology (ACG).

• Compare and contrast treatment modalities avail-able for the management of uncomplicated GERD in adult patients.

• Recognize the role of the pharmacist in managing uncomplicated GERD in adults.

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Management of Uncomplicated GERD in Adult PatientsACPE UAN: 0171-9999-15-037-H01-P Kayce Shealy, PharmD, BCPS, BCACP, CDE, Assistant Professor, Department of Pharmacy PracticeDirector, Center for Entrepreneurial Development, Presbyterian College School of Pharmacy

Jennifer N. Clements, PharmD, BCPS, CDE, BCACP, Interim Chair and Associate Professor Department of Pharmacy Practice, Presbyterian College School of Pharmacy

Objective: To review the treatment of uncomplicated gastroesophageal reflux disease (GERD) in adult patients.Data sources: PubMed using search terms gastroesophageal reflux disease, diagnosis, erosive esophagitis, antacids, histamine-2 receptor antagonists, proton pump inhibitors, and current treatment guidelines.Data synthesis: Gastroesophageal reflux disease is a common gastrointestinal disorder for both pediatrics and adults. The backflow of contents from the stomach into the esophagus can lead to common symptoms such as heartburn, regurgitation, and acidic taste. Gastroesophageal reflux disease is divided into esophageal or extraesophageal syndromes, and then further depending on the presence of esophageal injury. Many exacerbating factors have been identified, including certain foods, pregnancy, being overweight or obese, and some medications. There are many treatment options available for use in the medical management of GERD in adult patients. These

options include antacids, histamine-2 receptor antagonists (H2RAs), and proton pump inhibitors (PPIs). Guidelines for both adult and pediatric patients have recently been published to provide guidance on the treatment of GERD in these populations. For adult patients, the preferred treatment strategy includes PPI therapy in conjunction with lifestyle modifications. Conclusion: Pharmacists, regardless of setting, are likely to encounter patients who suffer from GERD. It is important to be aware of the updated treatment guidelines, as well as the different medications available, in order to ensure optimal patient care is provided.

Keywords: gastroesophageal reflux symptoms, gastroesophageal reflux diseaseIntroduction.

Gastroesophageal reflux disease (GERD) is a relatively common gastrointestinal disorder.1 In 2009, there were approximately 9 million outpatient visits for GERD in the United States (US) alone.1,2 Gastroesophageal reflux disease is caused by the backwards flow of stomach contents, or acid reflux, into the esophagus, leading to symptoms such as heartburn and potentially esophageal damage.3 Gastroesophageal reflux symptoms (GERS) such as heartburn or reflux may occur without being classified as GERD. According to the Montreal definition, GERD develops once these symptoms become troublesome and affect the patient’s quality of life.4 It is categorized into esophageal or extraesophageal syndromes, and then further divided based upon the presence of esophageal damage.4

The reflux of contents back into the esophagus may be due to many factors, including dysfunction in the lower esophageal sphincter (LES).5 The LES is an area of smooth muscle at the end of the esophagus that protects contents from the stomach, including gastrin

30 Palmetto Pharmacist • Volume 55 Number 4

and pepsin, from flowing into the esophagus. Back flow of these acidic enzymes can lead to damaged tissue in the esophagus or aspiration. During periods of eating and swallowing, the LES also acts as a one-way valve to prevent the passage of food or other stomach contents back into the esophagus. The LES does, however, have transient episodes of relaxation in healthy adults where the backflow of stomach contents may occur, but these episodes are usually symptom-free.2

Changes in the gastroesophageal pressure gradient may also lead to the inappropriate relaxation of the LES.5 This may be the result of either increased intra-abdominal pressure or reduction in pressure at the LES. Increased pressure is present during pregnancy and among overweight or obese people.1 Changes in anatomy, such as presence of hiatal hernia, may also contribute to the development of GERD. Hiatal hernias may lead to the presence of an acid pocket much closer to the esophagus than normal, allowing more reflux to occur. Delayed gastric emptying has also been linked to the development of GERD and related symptoms. Factors that delay or prolong gastric emptying may contribute to or exacerbate symptoms.5 The presence of Helicobacter pylori (H. pylori), though, has no effect on the development or severity of GERD.1,5 Factors that may exacerbate symptoms related to GERD are presented in Table 1.

The true prevalence of GERD worldwide is not completely clear, although it appears to be higher in Europe and North America.3 It has been reported that the prevalence of GERD in patients of all ages in these areas is anywhere from 10-30%, while approximately 5-6% of the Asian population may have GERD.3

Clinical Presentation When encountering a patient with possible GERD, it is important to thoroughly assess the patient’s symptoms. Based on an individual’s symptoms, GERD can be divided into two main categories - esophageal or extraesophageal conditions. Esophageal conditions can be further categorized as symptomatic syndromes (i.e. typical reflux, reflux chest pain syndrome) or esophageal injury (i.e. Barrett’s esophagus, adenocarcinoma). Barrett’s esophagus is a long-term complication of GERD and is associated with an increased risk of esophageal cancer. Extraesophageal conditions may have proposed associations with other problems, such as sinusitis and pharyngitis. Extraesophageal conditions can also have established associations, such as asthma with reflux.1,4,6,7

A pharmacist would most likely encounter a patient when he/she has experienced troublesome symptoms. Troublesome symptoms may interfere and affect the patient’s normal activities and/or quality of life. There are three classic symptoms of GERD – heartburn, regurgitation, and acidic taste – which are defined in Box 1.6,7 In addition to esophageal symptoms, a patient should be assessed for possible extraesophageal symptoms. Questions may include do you have a chronic cough? Have you noticed or experienced asthma-like symptoms? Have you experienced other symptoms, such as recurrent sore throat, laryngitis, or hoarseness?

In the updated American College of Gastroenterology (ACG) guidelines, troublesome dysphagia - formerly referred to as alarming symptoms - should be determined.7 These symptoms include dysphagia, odynophagia (i.e. painful swallowing with or without dysphagia), bleeding, weight loss, choking, chest pain, and epigastric mass. If a pharmacist encounters a patient with these troublesome symptoms, then the patient should be instructed to seek immediate medical attention with a referral for invasive testing. For example, a patient complaining of possible GERD-related chest pain may be experiencing angina pectoris (i.e. squeezing sensation in sternal area). In addition, odynophagia is a rare symptom of GERD, but may indicate the presence of an esophageal ulcer.7

A patient should be encouraged to identify aggravating factors, leading to current GERD symptoms. For example, increased intra-abdominal pressure (i.e. tight-fitting clothes, pregnancy) could cause the classic symptoms of GERD. Certain types of food (i.e. chocolate or peppermint) can reduce the lower esophageal sphincter tone. Other aggravating factors could be recumbency or gravity, reduced gastric motility, and direct mucosal irritation. A patient should be given a diagnosis of GERD in a timely manner in order to begin treatment and prevent long-term complications, such as erosion, strictures, obstruction, and Barrett esophagus.7

After a thorough patient interview has been completed, the frequency and severity of a patient’s GERD symptoms should be assessed in order to classify the patient’s condition. In addition, the presence of erosive esophagitis on upper endoscopy may need to be determined before initiating treatment. The mild and/or intermittent classification is defined as symptoms occurring less than two times (or episodes) per week and no evidence of erosive esophagitis.1,4,7 If a patient has mild or intermittent GERD, then the individual may experience symptoms following meals. The severe and/or frequent classification is defined

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as symptoms occurring more than two times (or episodes) per week and there is presence of erosive esophagitis.1,4,7 A patient with severe or frequent GERD may experience the classic symptoms following meals, during the day and/or at bedtime. Refractory GERD is continual symptoms despite adequate trial of once-daily PPI therapy. A patient with refractory GERD should be referred to a gastroenterologist.1,4,7

Diagnostic CriteriaTable 2 lists possible diagnostic tests for

adults and pediatric patients, along with the purpose of each test. For more details, please refer to the specific guidelines for GERD in these patient populations.2,6,7

Based on the ACG guidelines, there are specific diagnostic tests recommended to confirm GERD. Any patient with symptoms resembling troublesome dysphagia (see Box 1) should be referred for an endoscopy due to the possibility of complications, such as Barrett’s esophagus. An esophageal reflux monitoring test is another diagnostic test and can be completed if (1) non-erosive GERD is suspected, (2) patient has refractory GERD after an adequate trial of proton pump inhibitors, or (3) there is an uncertain diagnosis. If a patient has refractory GERD and surgery is an option, then manometry should be completed prior to the procedure. However, this test is not useful in confirming the diagnosis of GERD. The ACG guidelines do not recommend barium testing, biopsies, or screening for Helicobacter pylori to determine and/or confirm the diagnosis of GERD.6,7 A clinical diagnosis of GERD can be made if the patient presents with the classic symptoms, in which empiric therapy can be initiated. The patient may also be evaluated for non-cardiac causes of GERD. A differential diagnosis should be considered, evaluating any cardiac cause first, then gastrointestinal cause.6,7

Treatment Recommendations:For adult patients, the primary set of guidelines is published by the ACG. In 2008, the ACG guidelines provided recommendations and additional information on 12 broad questions based on clinical practice and scenarios.6 These questions ranged from diagnosis to pharmacologic therapy to surgical options for patients with GERD.6 In 2013, the ACG guidelines were updated to provide strong or conditional recommendations based on the level of evidence (i.e. high, moderate, or low).7 In comparison, the 2013 guidelines provide clarity to the

diagnosis of GERD. This set of guidelines had similar recommendations for the nonpharmacologic interventions and pharmacologic therapy, but provide a specific duration for proton pump inhibitor (PPI) administration (i.e. 8 weeks). Due to recent evidence, the 2013 ACG guidelines elaborated on the long-term management of GERD with proton pump inhibitors (PPIs).7

Nonpharmacologic Interventions Lifestyle modifications should be included in the treatment for GERD. The 2013 ACG guidelines recommend weight loss to ameliorate symptoms, especially among patients who are overweight, obese or have experienced recent weight gain.7 In addition, elevating the head of the bed can be recommended, as lying down can precipitate GERD symptoms.7 If patients are experiencing symptoms later in the evening or during the night, the ACG guidelines recommend avoiding meals within 2-3 hours of bedtime.7 These recommendations are based on low to moderate evidence because these interventions have been investigated in mostly case-control studies, and only bed elevation has been investigated in a randomized, controlled trial.7 While avoiding food triggers and reducing consumption of tobacco and alcohol is commonly encouraged by health care providers, there is little literature to support the notion that these dietary restrictions may actually improve GERD symptoms. Several trials are available that demonstrate an effect on LES pressure for some of these foods or products, including tobacco, chocolate, and carbonated beverages, but there are also several trials that suggest consuming these had no effect. Likewise, there are a handful of trials that show avoiding or reducing the consumption of these common dietary and lifestyle triggers has no effect on symptoms, LES pressure, or esophageal pH.7 For this reason, routine elimination or avoidance of certain foods such as chocolate, spicy foods, caffeine, or alcohol are not recommended as part of the patient care plan.

Surgery may be an effective option for patients needing long-term management. The ACG suggests surgery be considered for patients who wish to discontinue medications or who are nonadherent, experience undesirable adverse effects, or have GERD or esophagitis that is refractory to medical management.7 However, it should not be considered for symptom-relief only in patients who have had no response to PPI treatment.7,9 Surgery has been shown to be more successful and effective long-term in patients with typical

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GERD-like symptoms and also have responded well to PPI treatment. If patients’ symptoms fail to respond to PPI therapy, including high-dose, they are less likely to experience symptomatic relief with surgery. Before considering surgery for these non-responding patients, other causes of these symptoms should be evaluated by ear, nose, and throat (ENT) specialists, as well as pulmonary and allergy specialists. Obese patients may benefit from bariatric surgery, especially gastric bypass.7

Pharmacologic InterventionsThere are several options available for the medical management of GERD. These include antacids, histamine receptor antagonists (H2RAs), and PPIs. Proton pump inhibitors are the preferred treatment for patients who suffer from GERD with erosive esophagitis. A Cochrane review published in 2013 found that PPI therapy was superior to H2RAs and other agents for the relief of GERD-like symptoms.10 Acid suppression should be the target of therapy for patients with GERD unless there has been more in-depth diagnostic testing. The recommended dosing and duration for PPI therapy per the ACG guidelines is once daily for approximately 8 weeks.7 For patients who have a partial response after 8 weeks, the dosing frequency can be increased to twice daily in order to achieve optimal symptom relief. Patients who have no response after 8 weeks should be referred to a gastroenterologist for further evaluation.7 Long-term therapy should be reserved for patients whose symptoms return once the PPI therapy is stopped, or if there are complications such as Barrett’s esophagus or erosive esophagitis.7 Histamine receptor antagonists may be considered in lieu of PPIs if there is no presence of complications. Also, the addition of a nighttime dose of an H2RA to the daytime regimen of a PPI may be considered if the patient experiences nocturnal symptoms. However, this may lead to tolerance after several weeks of therapy.7,11 Although the ACG guidelines do not specifically address the use of antacids, these agents can be used for immediate relief of GERD symptoms, especially if the symptoms occur after eating.1 The ACG recommends against the use of non-acid suppression therapy such as with metoclopramide or baclofen (i.e. prokinetic agents) in adults without further diagnostic evaluation.7 These agents have not been shown to improve symptoms for patients without underlying factors.12 Likewise, sucralfate (i.e. surface agent) is not recommended for use in non-pregnant patients for the management of GERD symptoms.7

General Management The step-up or step-down approach may be recommended for an adult patient with GERD. There are advantages and disadvantages to either management strategy. In the step-up approach, antacids and H2RAs would be tried first and the potency of therapy would increase until the patient achieved symptom control. Therefore, PPIs could be avoided and would save the patient medication costs along with limiting exposure to safety issues. However, it could take a longer period of time to achieve symptom control, if antacids and H2RAs are ineffective. In a step-down approach, the most potent agents - the PPIs - are initiated first, which can provide fast relief. However, PPIs are most often the most expensive antisecretory agents available over-the-counter or as a prescription. Depending on the PPI, a prior authorization of previous agents may be needed for insurance coverage. Treatment with a PPI can be tapered down until the patient’s treatment is guided with antacids by the presence of breakthrough symptoms. Approximately 2 to 4 weeks is adequate time to taper a PPI; however, the higher the dose of a PPI, then the taper period will be longer.13 If the patient is tolerant to a lower dose, then step-down therapy may include H2RA once-daily or as-needed antacids. If the patient is intolerant to a lower dose of PPI, then the previous dose should be resumed.13 Table 3 provides a general approach and management strategies for an adult patient with GERD.

Proton Pump InhibitorsProton pump inhibitors have become the preferred agents in persistent or moderate GERD management. As mentioned before, a recent Cochrane review found that short-term use of PPIs were more effective than H2RAs and prokinetic agents at reducing heartburn and GERD-related symptoms.10 Proton pump inhibitors reduce gastric acid by inhibiting the hydrogen-potassium adenosine triphosphatase (ATPase) in gastric parietal cells.14 This enzyme is the last step during the acid secretion process in the stomach. There are many PPIs now available, both by prescription only and over-the-counter. Table 4 outlines the options available.

These agents are metabolized by the cytochrome P450 (CYP) system in the liver. This may lead to some drug interactions, although major interactions are rare. The most common enzyme affected during the metabolism of PPIs is CYP2C19, although inhibition is to varying degrees. The strongest PPI inhibitor of CYP2C19 is omeprazole and its use should be avoided when use of this enzyme is critical, such as with clopidogrel, according to the manufacturer and the Food and Drug Administration.15 Clopidogrel is a pro-drug that is activated by CYP2C19, so its therapeutic effects may be

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lessened by concomitant administration with strong enzyme inhibitors.16 However, the ACG contends that there is no need to change a patient’s PPI therapy solely due to concomitant use of clopidogrel due to the lack of evidence in regards to clinical cardiovascular outcomes in these patients.7

Patients should be counseled on proper administration of PPIs. The older agents, such as omeprazole, esomeprazole, and lansoprazole, should be taken prior to eating in order to achieve maximal acid suppression.17 Typically, PPIs should be taken 30-60 minutes before breakfast or at least the largest meal of the day. The newer PPIs, including dexlansoprazole, pantoprazole, and rabeprazole, can be administered without regard to meals.17 However, premeal administration is recommended if there is no relief once taken after eating.

While PPIs are generally well tolerated, there are a few adverse effects that should be noted when counseling a patient. The most common adverse effects include diarrhea, nausea or vomiting, abdominal pain, and headache.18 Chronic or long-term use of PPIs is linked to more serious adverse effects, including Clostridium dificile-associated diarrhea and osteoporosis-related fractures, while short-term use has also been linked to an increased risk of community-acquired pneumonia.7 Chronic use may also cause hypomagnesemia, particularly in patients who take other therapies that are also linked to reduced magnesium levels, such as digoxin or diuretics. Vitamin B12 deficiency has been linked to long-term PPI use, especially in patients who take PPIs twice daily for at least 2 years.19 Also, rebound hypersecretion of acid is possible if PPIs are stopped abruptly, rather than tapering down doses when therapy is completed.

Most of the PPIs are pregnancy category B, and are considered safe to use during pregnancy. Omeprazole and esomeprazole are labeled as a pregnancy category C, but are considered to have a low risk for negative effects on the fetus.20 Proton pump inhibitors do not require dosage adjustments in renal impairment, but may in the presence of severe hepatic impairment.

Histamine Receptor AntagonistsHistamine-2 receptor antagonists are commonly used for treatment of GERD symptoms. These agents inhibit

the binding of histamine at receptors on the gastric parietal cell, thereby inhibiting gastric acid secretion.26,27 Like PPIs, there are many options available, both by prescription only and over-the-counter. Table 4 details the available options. Like PPIs, H2RAs are generally well tolerated. The most common side effects for these agents include headache, dizziness, constipation, and diarrhea.26-30 Similar to PPI therapy, long-term use of H2RAs has also been linked to vitamin B12 deficiency, particularly in patients who take these medications for at least 2 years.19

Since the H2RAs are eliminated by the kidneys, it is important to monitor renal function during therapy. Once the estimated creatinine clearance is reduced to less than 50 ml/min, the dose of these agents should be cut in half. In clinical practice, this dose adjustment is typically done by reducing the dosing frequency from twice daily to once daily. Failure to reduce the dose in renal insufficiency may lead to confusion in patients due to decreased clearance of the medication. Histamine receptor antagonists are labeled as a pregnancy category B, and may be used if clinically indicated.26-30

AntacidsAntacids are readily available over the counter and may be sought by patients for quick relief. Antacids such as calcium salts are useful for mild or intermittent GERD symptoms; these agents can also be used as adjuvant therapy with H2RAs or PPIs. Antacids are not useful as chronic therapy and do not heal esophagitis. These agents neutralize gastric acidity as well as improve the lower esophageal sphincter tone and are intended to be taken on an as needed basis.1,6,7

There are several antacids preparations - aluminum, calcium, and magnesium salts. Each salt has a quick onset and short duration of action, which may require frequent administration during the day (i.e. three to four times per day). Antacids are well tolerated, but a patient should be counseled on the most common adverse events. These may vary depending on the salt. Constipation may occur with aluminum and calcium-based formulation, whereas a patient may experience diarrhea with a magnesium-based formulation. In general, antacids have a chalky taste and could cause abdominal pain. A thorough medical history should be obtained prior to recommending antacids as caution should be utilized among patients with renal dysfunction because accumulation may occur. In addition, antacids may bind to certain medications, such as

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fluoroquinolones, making the bound drugs ineffective. A thorough review of the patient’s medication profile is warranted when recommending antacid therapy, and the patient may be required to separate the administration of the interacting medication by several hours.

OtherOther options that may be considered in the management of GERD symptoms include prokinetic and surface agents. Metoclopramide is a prokinetic agent with antidopaminergic properties that increases the pressure at the LES and facilitates gastric emptying.8 The most common adverse effects include extrapyradimal side effects, including tardive dyskinesia.31 Other common adverse effects include lethargy and irritably. Other prokinetic agents that may also be used in refractory cases include erythromycin, bethanechol, and baclofen. Sucralfate is a surface agent that is not routinely recommended for management in GERD, nor is it FDA-approved. It is more commonly used in the presence of erosive esophagitis or an ulcer, in addition to acid suppression therapy.32,33 Sucralfate forms a complex over the injured tissue in the stomach, protecting it from further injury by acid. It has also been shown to inhibit pepsin activity in gastric juices by almost 30%.32 Constipation is the most common adverse event associated with use.32,33

Role of the Pharmacist It is very likely that a pharmacist will encounter patients suffering from GERD regardless of setting, and pharmacists may serve various roles. A pharmacist can help assess and identify the potential problem to recommend appropriate treatment or refer the patient for immediate attention. Based on the patient’s complaints and risk factors for GERD, nonpharmacologic interventions can be reviewed and recommended as initial and/or adjunctive treatment for the individual. Patients who have mild symptoms may be appropriate candidates to practice self care. The pharmacist can discuss the general approach, design an individualized plan from the evidence-based guidelines, and recommend a specific agent, based on the symptom frequency, duration, and/or severity. For patients with more severe or prolonged symptoms, the pharmacist should make a referral to a primary care provider. In these scenarios, the pharmacy may suggest treatment recommendations to the medical provider. Once a

specific agent is selected and recommended, the pharmacist can screen for drug interactions, review the role of the agent and timing of onset, and provide education on the appropriate dosing and potential adverse events. For a pregnant woman, it is important to evaluate and determine the most appropriate agent based on the pregnancy category rating. The pharmacist can help make cost-effective selections for therapy, as well as recommend alternatives if there is a shortage.

ConclusionGastroesophageal reflux disease is a common condition that will be encountered by pharmacists in any practice setting - community, ambulatory care, and hospital. This disease requires an effective and patient-centered therapeutic plan to achieve symptom control, prevent complications, and improve quality of life. Guidelines have been published for pediatric and adult patients to guide diagnosis and therapeutic plans. These guidelines supplement clinical judgment. Nonpharmacologic interventions should be specific for each patient. Pharmacotherapy is effective in symptom control based on the frequency and severity of a patient’s clinical features. Further diagnostic tests or referral to a gastroenterologist may be necessary in patients unable to achieve control with specific agents or have refractory GERD.

References1. Bredenoord AJ, Pandolfino JE, Smout AJ. Gastro-oesophageal reflux disease. Lancet 2013;381:1933-1942.

2. Lightdale JR, Gremse DA, and Section on Gastroenterology, Hepatology, and Nutrition. Gastroesophageal reflux: Management guides for the pediatrician. Pediatrics 2013;131:1684-95.

3. Ronkainen J and Agreus L. Epidemiology of reflux symptoms and GORD. Best Pract Res Clin Gastroenterol 2013;27:325-337.

4. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal defini-tion and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101:1900-20.

5. Lee YY and McColl KEL. Pathophysiology of gastroesophageal reflux disease. Best Pract Res Clin Gastroenterol 2013;27:339-351.

6. Kahrilas PJ, Shaheen NJ, Vaezi MF. American Gastroentero-logic Association Medical Position Statement on the Management of Gastroesphageal Reflux Disease. Gastroenterology 2008;135:1383-1391.

7. Katz PO, Gerson LB, and Vela MF. Diagnosis and manage-ment of gastroesophageal reflux disease. Am J Gastroenterol 2013;108:308-28.

8. Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gas-troesophageal reflux clinical practice guidelines: joint recommenda-tions of the North American Society for Pediatric Gastroenterology,

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Hepatology, and Nutrition (NASPGHAN) and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESP-GHAN). J Pediatr Gastroenterol Nutr 2009;49:498-547.

9. Oelschlager BK, Quiroga E, Parra JD, et al. Long-term out-comes after laparoscopic antireflux surgery. Am J Gastroenterol 2008;103:280-7.

10. Sigterman KE, van Pinxteren B, Bonis PA, Lau J, Numans ME. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Data-base of Systematic Reviews 2013; Issue 5. Art. No.: CD002095. DOI: 10.1002/14651858.CD002095.pub5.

11. Fackler WK, Ours TM, Vaezi MF, Richter JE. Long-term effect of H2RA therapy on nocturnal gastric acid breakthrough. Gastroenterol 2002;122:625-32.

12. Ren LH, Chen WX, Qian LJ, et al. Addition of prokinetics to PPI therapy in gastroesophageal reflux disease: a meta-analysis. World J Gastroenterol 2014; 20(9): 2412-9.

13. Bundeff AW, Zaiken K. Impact of clinical pharmacists’ recom-mendations on a proton pump inhibitor taper protocol in an ambula-tory care practice. J Manag Care Pharm 2013;19:325-33.

14. Kierkus J, Oracz G, Korczowski B, et al. Comparative safety and efficacy of proton pump inhibitors in paediatric gastroesophageal reflux disease. Drug Saf 2014;37:309-16.

15. Prilosec (omeprazole and omeprazole magnesium) delayed-re-lease capsules and oral suspension [product information]. Wilming-ton, DE: AstraZeneca LP, March 2014.

16. Gilard M, Arnaud B, Le Gal G, Abgrall JF, Boschat J. Influence of omeprazole on the antiplatelet action of clopidgrel associated to aspirin. J Thromb Haemost 2006;4(11):2508-2509.

17. Solem C, Mody R, Stephens J, Macahilig C, Gao X. Mealtime-related dosing directions for proton-pump inhibitors in gastroesopha-geal reflux disease: physician knowledge, patient adherence. J Am Pharm Assoc 2014;54:144-53.

18. Ip S, Chung M, Moorthy D, Yu WW, Lee J, Chan JA, Bonis PA, Lau J. Comparative Effectiveness of Management Strategies for Gastroesophageal Reflux Disease: Update. Comparative Effective-ness Review No. 29. (Prepared by Tufts Medical Center Evidence-based Practice Center under Contract No. HHSA 290-2007-10055-I.) AHRQ Publication No. 11-EHC049-EF. Rockville, MD: Agency for Healthcare Research and Quality. September 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

19. Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA 2013;310(22):2435-42.

20. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation, 9th edition [medical app] DxPregLac9; version 14.0.5/2012.02.06 May 2013 Lippincott Williams & Wilkins; 2011.

21. Aciphex (rabeprazole sodium) delayed-release tablets and cap-sules [product information]. Woodcliff Lake, NJ: Eisai Inc, Novem-ber 2013.

22. Dexilant (dexlansoprazole) delayed-release capsules [product information]. Deerfield, IL: Takeda Pharmaceuticals America Inc, August 2013.

23. Nexium (esomeprazole magnesium) delayed-release capsules and oral suspension [product information]. Wilmington, DE: AstraZen-eca LP, March 2014.

24. Prevacid (lansoprazole) delayed-release capsules and orally disintegrating tablets [product information]. Deerfield, IL: Takeda Pharmaceuticals Inc, September 2012.

25. Protonix (pantoprazole sodium) delayed-release tablets and oral suspension [product information]. Philadelphia, PA: Wyeth Pharma-ceuticals Inc, May 2012.

26. Axid (nizatidine USP) capsules [product information]. Liberty Corner, NJ: Reliant Pharmaceuticals, Inc, March 2005.

27. Axid (nizatidine USP) oral solution [product information]. Lib-erty Corner, NJ: Reliant Pharmaceuticals Inc, August 2004.

28. Pepcid (famotidine) tablets and oral suspension [product infor-mation]. Whitehouse Station, NJ: Merck & Co Inc, October 2006.

29. Tagamet (cimetidine) tablets [product information]. Boronia, Victoria: GlaxoSmithKline Australia Pty Ltd, March 2008.

30. Zantac (ranitidine hydrochloride) tablets, EFFERdose tablets, and syrup [product information]. Research Triangle Park, NC: GlaxoSmithKline, April 2009.

31. Reglan (metoclopramide) tablets [product information]. Mari-etta, GA: Alaven Pharmaceutical LLC, November 2010.

32. Carafate (sucralfate) suspension [product information]. Bridge-water, NJ: Aptalis Pharma US Inc, March 2013.

33. Carafate (sucralfate) tablets [product information]. Mont St Hilaire, Quebec: Aptalis Pharma Canada Inc, September 2013.

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Table 1. Exacerbating Factors Pathophysiologic Changes Decreased saliva

Slowed gastric emptyingImpaired esophageal peristalsis

Medical Conditions Zollinger-Ellison SyndromeObesityPregnancyGastroparesisHiatal hernia

Medications Anticholinergic agentsProgesteroneBeta-adrenergic antagonistsCalcium channel blockersNitrates

Dietary Substances Fatty foodsChocolatePeppermintEthanol Acidic foodsSpicy foods

Adapted from: Kahrilas PJ. Diagnosis of symptomatic gastroesophageal reflux disease. Am J Gastroenterol 2003;98:S15-23.

Box 1. Definitions of Symptoms Related to Gastroesophageal Reflux DiseaseHeartburn is a common symptom that occurs after a meal and is generally a burning sensation in the retrosternal area.

• Regurgitation is a mixture of acidic material and undigested food. It is described as the back flow of gastric contents into the mouth and/or pharynx.

• Dysphagia is difficulty with swallowing and occurs from longstanding or recurring heartburn.

Adapted from: Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101:1900-20.

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Table 2. List of Diagnostic Tests for Gastroesophageal Reflux DiseaseDiagnostic Test Purpose When It should be UsedEndoscopy • Observation of epithe-

lium lining and identifica-tion of Barrett’s esopha-gus and complications of GERD

• Any patient older than 45 years• Patients with alarming symptoms• Patients with refractory GERD

Manometry • Evaluation of peristaltic function of the esopha-gus in patients with nor-mal endoscopic findings prior to pH testing

• Patients with a suspected a motility problem with esophagus

pH Testing • Determination of percent time pH is less than 4 in a 24-hour period

• Patients with mucosal changes on endoscopy• Patients with normal manometry who have symptoms• Patients with refractory GERD• Patients with continued symptoms despite therapy

• Evaluation of postprandi-al reflux and assessment of gastric emptying

• Pediatric patients with suspected GERD

Adapted from: Kahrilas PJ, Shaheen NJ, Vaezi MF. American Gastroenterologic Association Medical Position Statement on the Management of Gastroesphageal Reflux Disease. Gastroenterology 2008;135:1383-1391; Katz PO, Gerson LB, and Vela MF. Diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2013;108:308-28.

Table 3. General Pharmacologic Management of Gastroesophageal Reflux DiseaseAdultsClassification Initial Therapy Other Options CommentsMild and/or

intermittent

symptoms

- Antacids as needed - Low-dose H2RA as needed

- Standard-dose H2RA twice

daily

- High-dose H2RA

- Different H2RA

- Doses can be adjusted every 2 to 4 weeks.

- If symptom control is not achieved, then con-sider PPIs for at least 8 weeks.

Severe and/

or frequent

symptoms

- Standard-dose PPI

once daily

- Low-dose PPI

- Standard-dose or low-dose

H2RA

- Antacids, as needed

- If symptom control is achieved after 8 weeks, then treatment can be decreased.

- If symptoms control is not achieved after 8 weeks, then consider additional options for refractory GERD.

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Refractory

symptoms

- Standard-dose PPI

twice daily

- Different PPI

- Antireflux surgery

- Twice-daily PPI can be administered prior to the morning and eve-ning meals.

- A standard-dose H2RA at bedtime could be given with twice-daily PPI.

- Metoclopramide is not recommended for this classification.

- Abbreviations: H2RA = histamine-2 receptor antagonist; PPI = proton pump inhibitor

Adapted from: Lightdale JR, Gremse DA, and Section on Gastroenterology, Hepatology, and Nutrition. Gastroesophageal reflux: Management guides for the pediatrician. Pediatrics 2013;131:1684-95; Kahrilas PJ, Shaheen NJ, Vaezi MF. American Gastroenterologic Association Medical Position Statement on the Management of Gastroesphageal Reflux Disease. Gastroenterology 2008;135:1383-1391; Katz PO, Gerson LB, and Vela MF. Diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2013;108:308-28.

Table 4. Available Treatment Options for Gastroesophageal Reflux DiseaseDrug Dose (Adults) Dosage Forms

available

Comment Drug Interactions

Proton Pump InhibitorsDexlansoprazole

(Dexilant)

NERD: 30 mg once daily

EE: 60 mg once daily

Delayed- release

capsules (30, 60

mg)

•Approved for use

up to 4 weeks for

NERD

•No generic avail-

able

Atazanavir

Methotrexate

Tacrolimus

Warfarin

Esomeprazole

(Nexium)

20-40 mg once daily Delayed-release

capsules (20, 40

mg) and oral pow-

der for suspension

(2.5, 5, 10, 20,

and 40 mg)

Available OTC: 20 mg

Infant dose approved for

up to 6 weeks; all other

approved up to 8 weeks

Atazanavir

Cilostazol

Clopidogrel

Methotrexate

Nelfinavir

Saquinavir

TacrolimusLansoprazole

(Prevacid)

15-30 mg once daily Delayed-release

capsules and

orally disintegrat-

ing tablets (15 mg,

30 mg)

Available OTC: 15 mg Atazanavir

Methotrexate

Tacrolimus

Theophylline

Warfarin

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Omeprazole

(Prilosec)

20 mg once daily Delayed-release

capsules (10, 20,

40 mg) and oral

suspension (2.5,

10 mg)

Available OTC: 20 mg

and in combination with

sodium bicarbonate (Ze-

gerid OTC)

Atazanavir

Cilostazol

Clopidogrel

Methotrexate

Nelfinavir

Saquinavir

TacrolimusPantoprazole

(Protonix)


tablets (20, 40

mg) and oral pow-

der for suspension

(40 mg)

Approved for erosive

esophagitis associ-

ated with GERD (up to 8

weeks)

Atazanavir,

Nelfinavir

Methotrexate

Warfarin

Rabeprazole

(Aciphex)


tablets (20 mg)

and capsules (5,

10 mg)

No generic available Atazanavir

Cyclosporine

Methotrexate

WarfarinHistamine-2 Receptor Antagonists

Cimetidine (Ta-

gamet)

800 mg per day in one

or up to 4 divided doses

Tablets (200, 400

mg)

Available OTC Numerous; inhib-

its CYP1A2, 2C9,

2C18, 2D6, 3A3,

3A4Famotidine (Pep-

cid)

NERD: 20 mg twice

daily

EE: 20-40 mg twice

daily

Tablets (20, 40

mg)

Oral suspension

(40 mg/5 ml)

Available OTC alone and

with antacids

None

Nizatidine (Axid)

(pulvules)

(solution)

150 mg twice daily Pulvules (150, 300

mg)

Oral solution (15

mg/ml)

Available OTC: 75 mg;

solution only approved

for pediatrics > 12 years

old

None

Ranitidine

(Zantac)

150 mg twice daily Tablets (150, 300

mg)

Effervescent tab-

lets (25 mg)

Syrup (15 mg/ml)

Available OTC Atazanavir

Glipizide

Ketoconazole

Triazolam

Warfarin

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Aluminum Hy-

droxide

Varies by product Chewable tablets,

suspension, etc

Doses three to four times

per day

Take 1 to 3 hours after

meals and other medica-

tions

Varies by the

product, but chela-

tion or increases /

decreased absorp-

tion may occurCalcium Carbon-

ateMagnesium Hy-

droxideSodium Bicar-

bonateOther Options

Metoclopramide

(Reglan)

10-15 mg up to four

times daily before meals

and at bedtime

Tablets (5, 10 mg)

Dispersible tablet

(5 mg)

Solution (1 mg/ml,

5 mg/ml)

Not approved for use in

children

Anticholinergic

agents

CNS depressants

Sucralfate (Cara-

fate)

1 gm four times daily Tablet (1 gm)

Suspension (1

gm/ml)

•Generic not avail-

able for suspen-

sion

•Not approved for

use in children

Cimetidine

Fluoroquinolones

Digoxin

Levothyroxine

Phenytoin

Ranitidine

Theophylline

Tetracycline Abbreviations: CNS = central nervous system; CYP = cytochrome; EE = erosive esophagitis; GERD = gastroesophageal reflux disease; gm = gram; mg = milligram; ml = milliliter; NERD = nonerosive reflux disease; OTC = over the counter

Adapted from: Aciphex (rabeprazole sodium) delayed-release tablets and capsules [product information]. Woodcliff Lake, NJ: Eisai Inc, November 2013; Axid (nizatidine USP) capsules [product information]. Liberty Corner, NJ: Reliant Pharmaceuticals, Inc, March 2005; Axid (nizatidine USP) oral solution [product information]. Liberty Corner, NJ: Reliant Pharmaceuticals Inc, August 2004; Carafate (sucralfate) suspension [product information]. Bridgewater, NJ: Aptalis Pharma US Inc, March 2013; Carafate (sucralfate) tablets [product information]. Mont St Hilaire, Quebec: Aptalis Pharma Canada Inc, September 2013; Dexilant (dexlansoprazole) delayed-release capsules [product information]. Deerfield, IL: Takeda Pharmaceuticals America Inc, August 2013; Nexium (esomeprazole magnesium) delayed-release capsules and oral suspension [product information]. Wilmington, DE: AstraZeneca LP, March 2014; Pepcid (famotidine) tablets and oral suspension [product information]. Whitehouse Station, NJ: Merck & Co Inc, October 2006; Prevacid (lansoprazole) delayed-release capsules and orally disintegrating tablets [product information]. Deerfield, IL: Takeda Pharmaceuticals Inc, September 2012; Prilosec (omeprazole and omeprazole magnesium) delayed-release capsules and oral suspension [product information]. Wilmington, DE: AstraZeneca LP, March 2014; Protonix (pantoprazole sodium) delayed-release tablets and oral suspension [product information]. Philadelphia, PA: Wyeth Pharmaceuticals Inc, May 2012; Reglan (metoclopramide) tablets [product information]. Marietta, GA: Alaven Pharmaceutical LLC, November 2010; Tagamet (cimetidine) tablets [product information]. Boronia, Victoria: GlaxoSmithKline Australia Pty Ltd, March 2008; Zantac (ranitidine hydrochloride) tablets, EFFERdose tablets, and syrup [product information]. Research Triangle Park, NC: GlaxoSmithKline, April 2009.

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Self-assessment questions 1. According to the Montreal definition, gastroesophageal reflux disease (GERD) develops when symptoms are:a. Mildb. Infrequentc. Persistentd. TroublesomeLO#1 (Answer can be found in the Introduction section.)

2. Increased abdominal pressure that leads to inappropriate relaxation of the lower esophageal sphincter (LES) may be present in patients who are _______________________.a. Underweightb. Not pregnantc. Obesed. Normal weightLO#1 (Answer can be found in the Introduction section.)

3. While many people may consume or use this after eating, it may actually exacerbate GERD symptoms.a. Peppermintb. Waterc. Chewing gumd. Skim milk LO#1 (Answer can be found in Table 1 in which exacerbating factors are listed.)

Management of Uncomplicated GERD in Adult Patients Corresponding Course Program Number: 0171-9999-15-037-H01-P1. Complete and mail entire page. SCPhA members can take journal CE for free; $15 for non-members. Check must accompany test. You may also complete the test and submit payment online at www.scrx.org.2. Mail to: Palmetto Pharmacist CE, 1350 Browning Road, Columbia, SC 29210-6309. 3. Continuing Education credits will be uploaded to the CPE Monitor System within six weeks from the submission date for the quiz once the evaluation form and payment are received. Notification will be sent via email if you have not suc-cessfully completed the quiz.

4. Participants scoring 70% or greater and completing the program evaluation form will be issued CE credit. Participants recieving a failing grade on any examination will have the examination returned. The participant will be permitted to retake the examination one time at no extra charge.

South Carolina Pharmacy Association is accredited by the Accreditation Council for Pharmacy Education as provid-ers for continuing education. This article is approved for 1 contact hour of contiuning education credit (ACPE: UAN: 0171-9999-15-037-H01-P). This CE credit begins 06/15/2015 and expires 06/15/2018.

Name _______________________________ License # _________________ Birth Month/Day (MM/DD)___________ Address _________________________________________________________________________________________ NABP eID ______________ Phone _______________ Email ______________________________________________EVALUATION (circle the appropriate response)1. Did the article achieve the stated objects? (Note at all) 1 2 3 4 5 (Completely)

2. Overall evaluation of the article? (Poor) 1 2 3 4 5 (Excellent)

3. Was the information relevent to your practice? (No) 1 2 3 4 5 (Yes)

4. How long did it take you to read the article and complete the exam? _______________CE credit will ONLY be awarded when a submitted test is accompanied by completing the evaluation above or online at www.scrx.org.

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4. Surgery is not a consideration for long-term management of GERD symptoms for patients who have: a. Complete response to famotidineb. Complete response to lansoprazolec. No response to esomeprazoled. Partial response to ranitidine

5. Which one of the following is a classic symptom of GERD for an adult patient?a. Odynophagiab. Hoarsenessc. Regurgitationd. Weight lossLO#1 (Answer can be found in Clinical presentation for an adult patient.)

6. Recommendations for lifestyle modifications to control GERD symptoms may include:a. Routine avoidance of certain foodsb. Eating meals within 2-3 hours of bedtimec. Lowering the head of the bedd. Weight loss if overweight or obeseLO#3 (Answer can be found under Nonpharmacologic interventions for an adult patient.)

7. Which of the following proton pump inhibitors may be taken without regards to meals?a. Dexlansoprazoleb. Esomeprazolec. Lansoprazoled. OmeprazoleLO #3 (Answer can be found within the subsection Proton pump inhibitors under the General management section.)

8. Short-term use of proton pump inhibitors has been linked with an increased risk of:a. Clostridium difficile-associated diarrheab. Community acquired pneumoniac. Hypomagnesemiad. Osteoporosis-related fracturesLO #3 (Answer can be found within the subsection Proton pump inhibitors under the General management section.)

9. A 29-year-old gentleman complains of classic GERD symptoms intermittently in the evening. He wants a product with the quickest “relief”. Which one of the following agents is the best choice for this patient?a. Calcium carbonateb. Cimetidinec. Dexlansoprazoled. MetoclopramideLO#3 (Answer can be found in the subsection Antacids under General Management.)

10. A patient presents to his local community pharmacist and complains of classic GERD symptoms. Which one of the following questions would be the most important question that a pharmacist can ask?a. Do you eat chocolate or drink alcohol often?b. How often are these symptoms occurring?c. Have you called or seen your doctor lately?d. Are you taking a proton pump inhibitor?LO#4 (Answer can be found two sections related to GERD among an adult patient (i.e. Clinical presentation; Role of pharmacist)

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management of uncomplicated gerd in adult patients

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