Dianne B. Williams and Marie A. Chisholm-Burns
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Explain the underlying causes of gastroesophageal reflux disease (GERD).
2. Differentiate among typical, atypical, and complicated symptoms of GERD.
3. Determine which diagnostic test should be recommended based on the patient’s clinical presentation.
4. Identify the desired therapeutic outcomes for patients with GERD.
5. Recommend appropriate lifestyle modifications and pharmacotherapy interventions for patients with GERD.
6. Discuss other nonpharmacologic interventions that may be appropriate for patients with GERD.
7. Formulate a monitoring plan to assess the effectiveness and safety of pharmacotherapy for GERD.
8. Educate patients on appropriate lifestyle modifications and drug therapy issues, including compliance, adverse effects, and drug interactions.
KEY CONCEPTS
Esophageal gastroesophageal reflux disease (GERD) syndromes can be divided into two distinct categories: (a) symptomatic esophageal syndromes and (b) syndromes associated with esophageal tissue injury.
Patients with GERD may display symptoms described as: (a) typical, (b) atypical, or (c) complicated.
Patients presenting with uncomplicated, typical symptoms of reflux (heartburn and regurgitation) do not usually require invasive esophageal evaluation.
The goals of treatment of GERD are to alleviate symptoms, decrease the frequency of recurrent disease, promote healing of mucosal injury, and prevent complications.
Treatment for GERD involves one or more of the following modalities: (a) patient-specific lifestyle changes and patient-directed therapy; (b) pharmacologic intervention primarily with acid-suppressing agents; (c) antireflux surgery, or (d) endoscopic therapies.
Acid-suppressing therapy is the mainstay of GERD treatment and should be considered for anyone not responding to lifestyle changes and patient-directed therapy after 2 weeks.
Antireflux surgery or endoscopic therapies offer an alternative treatment for refractory GERD or when pharmacologic management is undesirable.
Many patients with GERD experience relapse if medication is withdrawn, and long-term maintenance treatment is required in such patients.
Patient medication profiles should be reviewed for drugs that may aggravate GERD.
INTRODUCTION
Previously, gastroesophageal reflux disease (GERD) was defined as symptoms or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus.1 In late 2008, the American College of Gastroenterology redefined GERD as troublesome symptoms and/or complications caused by refluxing the stomach contents into the esophagus.2 The key is that these troublesome symptoms adversely affect the well-being of the patient.2 Esophageal GERD syndromes can be divided into two distinct categories: (a) symptomatic (or “symptom-based”) esophageal syndromes and (b) syndromes associated with esophageal tissue injury.2 Symptomatic esophageal syndrome is associated with severe reflux symptoms with normal endoscopic findings. Erosive esophagitis, a syndrome associated with esophageal tissue injury, occurs when the esophagus is repeatedly exposed to refluxed material for prolonged periods (Fig. 17–1). The inflammation that occurs progresses to erosions of the squamous epithelium. Barrett’s esophagus is a complication of GERD, characterized by replacement of the normal squamous epithelial lining of the esophagus by specialized columnar-type epithelium. Barrett’s esophagus is more likely to occur in patients with a long history (years) of symptomatic reflux and may be a risk factor for developing adenocarcinoma of the esophagus.
FIGURE 17–1. Endoscopic images of the esophagus. Left: Image taken during an endoscopy of the esophagus revealing normal smooth squamous cell lining. Right: Narrowed esophageal lumen (stricture) due to chronic GERD with inflammation and scarring. The surrounding esophageal lining has ulcerations and erosions from chronic acid injury. (From Barrett’s esophagus website: http://www.barrettsinfo.com)
EPIDEMIOLOGY AND ETIOLOGY
GERD is prevalent in patients of all ages and appears to be increasing in both adults and children. The prevalence of GERD in Western countries is approximately 10% to 20%.3 Although mortality associated with GERD is rare, symptoms can significantly decrease quality of life. The true prevalence and incidence of GERD are unknown because: (a) many patients do not seek medical treatment, (b) symptoms do not always correlate well with disease severity, and (c) there is no gold standard for diagnosing the disease. The prevalence of erosive esophagitis increases in adults older than 40 years. There does not appear to be a major gender difference in incidence except for its association with pregnancy. Gender is an important factor in the development of Barrett’s esophagus that occurs more frequently in males.
PATHOPHYSIOLOGY
The retrograde movement of acid or other noxious substances from the stomach into the esophagus is a major factor in the development of GERD.4 Commonly, gastroesophageal reflux is associated with defective lower esophageal sphincter (LES) pressure or function. Problems with other normal mucosal defense mechanisms such as anatomic factors, esophageal clearance, mucosal resistance, gastric emptying, epidermal growth factor, and salivary buffering may also contribute to the development of GERD. Other factors that may promote esophageal damage upon reflux into the esophagus include gastric acid, pepsin, bile acids, and pancreatic enzymes. Therapeutic regimens for GERD are designed to maximize normal mucosal defense mechanisms and attenuate these other factors that contribute to the disease.
LES Pressure
The LES is a manometrically defined zone of the distal esophagus with an elevated basal resting pressure. The sphincter is normally in a tonic, contracted state, preventing the reflux of gastric material from the stomach. It relaxes on swallowing to permit the free passage of food into the stomach.
Mechanisms by which defective LES pressure may cause gastroesophageal reflux are threefold. First, and probably most important, reflux may occur after spontaneous transient LES relaxations that are not associated with swallowing.5 Esophageal distention, vomiting, belching, and retching can cause relaxation of the LES. These transient relaxations may play an important role in intermittent nonerosive reflux.6Transient decreases in sphincter pressure are responsible for approximately 65% of the reflux episodes in patients with GERD.
Second, reflux may occur after transient increases in intra-abdominal pressure (stress reflux).4 An increase in intra-abdominal pressure such as that occurring during straining, bending over, or a Valsalva maneuver may overcome a weak LES, and thus may lead to reflux.
Third, the LES may be atonic, thus permitting free reflux. Although transient relaxations are more likely to occur when there is normal LES pressure, the latter two mechanisms are more likely when the LES pressure is decreased by such factors as fatty foods, gastric distention, or smoking.4 Certain foods and medications may worsen esophageal reflux by decreasing LES pressure or by irritating the esophageal mucosa (Table 17–1.7
Anatomic Factors
Disruption of the normal anatomic barriers by a hiatal hernia was once thought to be a primary etiology of gastroesophageal reflux and esophagitis. Currently, the presence of a hiatal hernia is generally considered to be a separate entity that may or may not be associated with reflux.
Esophageal Clearance
Many patients with GERD produce normal amounts of acid, but the acid produced spends too much time in contact with the esophageal mucosa. The contact time is dependent on the rate at which the esophagus clears the noxious material, as well as the frequency of reflux. The esophagus is cleared by primary peristalsis in response to swallowing, or by secondary peristalsis in response to esophageal distention and gravitational effects.
Table 17–1 Foods and Medications That May Worsen GERD Symptoms
Swallowing contributes to esophageal clearance by increasing salivary flow. Saliva contains bicarbonate that buffers the residual gastric material on the surface of the esophagus. The production of saliva decreases with increasing age, making it more difficult to maintain a neutral intraesophageal pH. Therefore, esophageal damage due to reflux occurs more often in the elderly and patients with Sjögren’s syndrome or xerostomia. Swallowing is also decreased during sleep, which contributes to nocturnal GERD in some patients.
Mucosal Resistance
The esophageal mucosa and submucosa consist of mucus-secreting glands that contain bicarbonate. Bicarbonate moving from the blood to the lumen can neutralize acidic refluxate in the esophagus. A decrease in this normal defense mechanism can potentially lead to erosions in the esophagus. When the mucosa is repeatedly exposed to the refluxate in GERD, or if there is a defect in the normal mucosal defenses, hydrogenions diffuse into the mucosa, leading to the cellular acidification and necrosis that ultimately cause esophagitis.4
Gastric Emptying
Gastric volume is related to the amount of material ingested, rate of gastric secretion, rate of gastric emptying, and amount and frequency of duodenal reflux into the stomach. Delayed gastric emptying can lead to increased gastric volume and can contribute to reflux. Factors that increase gastric volume and/or decrease gastric emptying, such as smoking and high-fat meals, are often associated with gastroesophageal reflux. This partially explains the prevalence of postprandial gastroesophageal reflux.
Composition of Refluxate
The composition, pH, and volume of the refluxate are other factors associated with gastroesophageal reflux. Duodeno-gastric reflux esophagitis or “alkaline esophagitis” refers to esophagitis induced by the reflux of bilious and pancreatic fluid. Although bile acids have both a direct irritant effect on the esophageal mucosa and an indirect effect of increasing hydrogen ion permeability of the mucosa, symptoms are more often related to acid reflux than to bile reflux. The percentage of time that esophageal pH is below 4 is greater for patients with severe disease than for those with mild disease.
The pathophysiology of GERD is a complex process. It is difficult to determine which occurs first: gastroesophageal reflux leading to defective peristalsis with delayed clearing or an incompetent LES pressure leading to gastroesophageal reflux. Understanding factors associated with the development of GERD is essential to providing effective treatment (Fig. 17–2).
CLINICAL PRESENTATION AND DIAGNOSIS
Patients with GERD may display symptoms described as: (a) typical, (b) atypical, or (c) complicated (see Clinical Presentation box).8
Diagnosis of GERD
The most useful tool in the diagnosis of GERD is the clinical history, including both the presenting symptoms and associated risk factors. Patients presenting with uncomplicated, typical symptoms of reflux (heartburn and regurgitation) do not usually require invasive esophageal evaluation. These patients generally benefit from a trial of patient-specific lifestyle modifications and empiric acid-suppressing therapy.1 A clinical diagnosis of GERD is assumed in those responding to appropriate therapy.
Endoscopy with biopsy is the preferred diagnostic test for assessing the mucosa for esophagitis and Barrett’s esophagus. It should also be performed in patients with troublesome dysphagia, weight loss, or epigastric mass and in patients with esophageal GERD syndrome who have not responded to an empiric trial of twice-daily proton pump inhibitor (PPI) therapy.2 While controversial, some feel that screening for Barrett’s esophagus should be performed in patients more than 50 years of age and those with longstanding heartburn.
FIGURE 17–2. Therapeutic interventions in the management of gastroesophageal reflux disease. Pharmacologic interventions are targeted at improving defense mechanisms or decreasing aggressive factors. LES, lower esophageal sphincter. (Adapted with permission from Williams DB, Schade RR. Gastroesophageal reflux disease. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill 2008: 559.)
Clinical Presentation of GERD
• Heartburn is the hallmark symptom of GERD and is described as a substernal sensation of warmth or burning rising up from the abdomen that may radiate to the neck. It may be waxing and waning in character.
• Regurgitation is common.
• Symptoms may be worse after a fatty meal, when bending over, or when lying in a recumbent position.1
• Hypersalivation and belching.
Atypical Symptoms
• Asthma, chronic cough, hoarseness, pharyngitis, chest pain, and dental erosions.
• It is important to distinguish GERD symptoms from those of other diseases, especially when chest pain or pulmonary symptoms are present.
Complicated Symptoms
• Continual pain, dysphagia (difficulty swallowing), odynophagia (painful swallowing), bleeding, unexplained weight loss, unexplained anemia, and choking.
• These symptoms may be indicative of complications of GERD such as Barrett’s esophagus, esophageal strictures (Fig. 17–1), or esophageal cancer.
Patient Encounter, Part 1
A 42-year-old man with a history of diabetes and hypertension presents complaining of “heartburn.” He reports a burning sensation in his upper chest and some regurgitation of sour-tasting material into his throat. The symptoms began about 1 month ago, occur about twice a week, and are associated with heavy meals and lying down after eating. He says that he smokes about one pack of cigarettes per day and drinks coffee and alcohol-containing beverages on most days. His weight is 116 kg (255 1b).
What information is suggestive of GERD?
Does he have any factors contributing to GERD?
What additional information do you need before creating a treatment plan for this patient?
Newer technology involves a camera-containing capsule swallowed by the patient, which can perform noninvasive endoscopy but cannot adequately assess for Barrett’s esophagus. The procedure can be performed in the practitioner’s office in approximately 15 minutes.
Patients with esophageal GERD syndromes who have failed twice-daily PPI therapy and have normal findings on endoscopy may benefit from manometry. Manometry helps to localize the LES for ambulatory pH monitoring, evaluates peristaltic function in patients considering surgery, and identifies possible motor disorders.2
Ambulatory pH monitoring objectively proves that symptoms are reflux related in patients with esophageal GERD syndromes not responding to twice-daily PPI therapy. Impedance monitoring allows reflux episodes to be characterized as acid or nonacid.9 This method may be useful in patients with refractory symptoms. Duodenogastroesophageal reflux monitoring may be useful in identifying nonacid reflux (e.g., bile reflux), especially in patients not responding to twice-daily PPI therapy. It is preferable that PPI therapy be held for 7 days prior to ambulatory impedance pH, catheter pH, or wireless pH monitoring for best results.2
TREATMENT
Desired Outcomes
The goals of treatment of GERD are to alleviate symptoms, decrease the frequency of recurrent disease, promote healing of mucosal injury, and prevent complications. Inadequate treatment and consequent long-term acid exposure may lead to complications such as Barrett’s esophagus, which may be an independent risk factor for esophageal adenocarcinoma.10
Patient Encounter, Part 2: Medical History, Physical Exam, and Diagnostic Tests
PMH: Type-2 diabetes mellitus since age 36, it is often not well controlled because of poor patient compliance; hypertension × 3 years, currently controlled; history of hepatitis B
FH: Father died of Ml at the age of 68, mother is still alive with history of colon cancer and diabetes
SH: Works as a laborer in a warehouse, drinks alcohol most days but denies any alcohol-related problems
Meds: Metformin 1,000 mg orally twice daily; hydrochlorothiazide 25 mg orally once daily; nifedipine XL 60 mg orally once daily; regular insulin 4 units subcutaneously 3 times daily with meals; insulin glargine 20 units subcutaneously at bedtime
ROS: (+) Heartburn, regurgitation; (-) chest pain, nausea, vomiting, diarrhea, weight loss, change in appetite, shortness of breath or cough, difficulty or painful swallowing
PE:
VS: BP 134/84 mm Hg, P 82 bpm, RR 16 per minute, T 37°C (98.6°F)
CV: RRR, normal S17 S2; no murmurs, rubs, or gallops
Abd: Soft, nontender, nondistended; (+) bowel sounds, (−) hepatosplenomegaly, heme (−) stool
Given this additional information, what findings are consistent with a diagnosis of GERD?
Could any of the medications listed aggravate GERD symptoms in this patient?
Identify your treatment goals for this patient.
What nonpharmacologic and pharmacologic options are feasible for this patient?
General Approach to Treatment
Treatment for GERD involves one or more of the following modalities: (a) lifestyle changes and patient-directed therapy; (b) pharmacologic intervention primarily with acid-suppressing agents; (c) antireflux surgery; or (d) endoscopic therapies. The first therapeutic option used depends upon the patient’s condition (i.e., frequency of symptoms, degree of esophagitis, and presence of complications; Table 17–2).
Acid-suppressing therapy is the mainstay of GERD treatment and should be considered for anyone not responding to patient-specific lifestyle changes and patient-directed therapy after 2 weeks. The PPIs provide the greatest relief of symptoms and highest rates of healing, especially in patients with erosive disease or moderate to severe symptoms.
Maintenance therapy is generally necessary to control symptoms and prevent complications. GERD that is refractory to adequate acid suppression is rare. In these cases, the diagnosis should be confirmed through further diagnostic tests before long-term, high-dose therapy or antireflux surgery or endoscopic therapies are considered.1
Nonpharmacologic Therapy
Nonpharmacologic treatment of GERD includes patient-specific lifestyle modifications, antireflux surgery, or endoscopic therapies.
Lifestyle Modifications
Although most patients do not respond to lifestyle changes alone, the importance of maintaining these lifestyle changes throughout the course of GERD therapy should be stressed to selected patients on a routine basis. The most common lifestyle changes that a patient should be educated about include: (a) losing weight and (b) elevating the head of the bed if symptoms are worse when recumbent. Elevating the head of the bed about 6 to 10 in. (15–25 cm) with an undermattress foam wedge (not just elevating the head with pillows) decreases nocturnal esophageal acid contact time and should be recommended.4
Other lifestyle modifications should be considered based on the circumstances of the individual patient. These include: (a) eating smaller meals and avoiding meals 3 hours before sleeping, (b) avoiding foods or medications that exacerbate GERD, (c) smoking cessation, and (d) avoiding alcohol.
Patient medications and food histories should be evaluated to identify potential factors that may exacerbate GERD symptoms (see Table 17–1).7,11,12 Patients should be monitored closely for symptoms when medications known to worsen GERD are started.
Antireflux Surgery and Endoscopic Therapies
Antireflux surgery or endoscopic therapies offer alternative treatments for refractory GERD or when pharmacologic management is undesirable.
Antireflux Surgery
Surgical intervention is a viable alternative for selected patients with well-documented GERD.1 The goal of surgery is to re-establish the antireflux barrier, to position the LES within the abdomen where it is under positive (intra-abdominal) pressure, and to close any associated hiatal defect.13 It should be considered in patients who: (a) fail to respond to pharmacologic treatment; (b) opt for surgery despite successful treatment because of lifestyle considerations including age, time, or expense of medications; (c) have complications of GERD (Barrett’s esophagus or strictures); or (d) have atypical symptoms and reflux documented on 24-hour ambulatory pH monitoring.13 In the latter situation, the benefits of surgery must be carefully weighed against the risks including flatulence, inability to belch, and postsurgery bowel symptoms.2
Table 17–2 Therapeutic Approach to GERD in Adults
Unfortunately, up to 60% of patients still require use of antireflux medications approximately 10 years postsurgery, and surgery is not superior to PPIs in terms of esophagitis grade, complications, or quality of life with long-term follow-up.14
Endoscopic Therapies
Three endoscopic approaches to the management of GERD are available.15 They include: (a) application of radiofrequency energy to the LES area (Stretta procedure), (b) endoscopic suturing to produce a plication (Endocinch),and (c) endoscopic injection of a biopolymer at the gastroesophageal junction.1 More studies and experience are needed to determine their exact role in the management of GERD. They cannot currently be recommended for routine use in patients with esophageal GERD syndromes.2
Pharmacologic Therapy
Antacids and Antacid-Alginic Acid Products
Antacids are an appropriate component of treating mild GERD as they are clearly effective for immediate, symptomatic relief. They are often used concurrently with other acid-suppressing therapies.
An antacid product combined with alginic acid (Gaviscon) is not a potent neutralizing agent but forms a highly viscous solution that floats on the surface of the gastric contents. This viscous solution serves as a protective barrier for the esophagus against reflux of gastric contents. It also reduces the frequency of the reflux episodes.16
Dosage recommendations for antacids vary and range from hourly dosing to administration on an as-needed basis. In general, antacids have a short duration of action, which requires frequent administration throughout the day to provide continuous acid neutralization.
Antacids also have clinically significant drug interactions with ferrous sulfate, isoniazid, sulfonylureas, and quinolone antibiotics. Antacid-drug interactions are influenced by antacid composition, dose, dosage schedule, and formulation.
Histamine2-Receptor Antagonists
The histamine2-receptor antagonists (H2RAs)—cimetidine, famotidine, nizatidine, and ranitidine—decrease acid secretion by inhibiting the histamine2-receptors in gastric parietal cells. When given in divided doses, they are effective for patients with mild to moderate GERD.1 Standard doses provide symptomatic improvement in about 60% of patients after 12 weeks of therapy.1 Healing rates per endoscopy tend to be lower (50%).1 Response to the H2RAs is dependent on: (a) the severity of disease, (b) the dosage regimen used, and (c) the duration of therapy.
For symptomatic relief of mild GERD, low-dose, nonprescription H2RAs may be beneficial. For patients not responding to patient-directed therapy with over-the-counter agents after 2 weeks, standard-dose acid-suppressing therapy is warranted. Although higher doses of H2RAs may provide greater symptomatic and endoscopic healing rates, limited information exists regarding the safety of these regimens and they can be less effective and more costly than once-daily PPIs.
Because all H2RAs have similar efficacy, selection of the specific agent should be based on factors such as differences in dosage regimen, safety profile, and cost. In general, H2RAs are well tolerated. Patients should be monitored for adverse effects and potential drug interactions. Cimetidine may inhibit the metabolism of certain medications such as theophylline, warfarin, or phenytoin. An alternate H2RA should be selected if the patient is taking any of these medications.
Proton Pump Inhibitors
The PPIs—esomeprazole, lansoprazole, omeprazole, panto-prazole, rabeprazole, and dexlansoprazole—block gastric acid secretion by inhibiting gastric H+/K+-adenosine triphosphatase in gastric parietal cells.17 This produces a profound, long-lasting antisecretory effect capable of maintaining the gastric pH above 4, even during acid surges seen postprandially.4,6
The PPIs are superior to H2RAs in patients with moderate-to-severe GERD. This includes not only patients with erosive esophagitis or complicated symptoms (Barrett’s esophagus or strictures) but also those with symptomatic esophageal syndromes. Symptomatic relief is seen in approximately 83% of patients, and healing rates at 8 weeks as judged by endoscopy are 78%.1
A PPI should be given empirically to patients with troublesome symptoms of GERD. If the standard once-daily course of therapy is not effective in eliminating symptoms, then empiric therapy with twice-daily dosing should be given. Patients not responding to twice-daily PPI therapy should be considered treatment failures and further diagnostic evaluation should be performed.2
Whether PPIs can reverse Barrett’s esophagus remains a topic for debate. The use of high-dose omeprazole (40 mg twice daily) caused partial regression of Barrett’s esophagitis, but no change was noted in patients receiving ranitidine 150 mg twice daily.17 Others propose that islands of normal squamous cells that appear in patients with Barrett’s esophagus after high-dose PPIs may be covering gastric mucosa and may mask the development of cancerous changes in the mucosa.18 It is unknown whether regression of Barrett’s esophagus reduces the risk of adenocarcinoma, but aggressive therapy to suppress acid reflux early in the disease may help prevent Barrett’s esophagus.
Comparable daily doses of PPIs are omeprazole 20 mg = esomeprazole 20 mg = lansoprazole 30 mg = dexlansoprazole 30 mg = rabeprazole 20 mg = pantoprazole 40 mg. The PPIs degrade in acidic environments and are therefore formulated in delayed-release capsules or tablets.19 Lansoprazole, esomeprazole, and omeprazole contain enteric-coated (pH-sensitive) granules in a capsule form. For patients unable to swallow the capsule or in pediatric patients, the contents of the capsule can be mixed in applesauce or placed in orange juice. Lansoprazole is also available in a packet for oral suspension and a delayed-release orally disintegrating tablet. Patients taking pantoprazole or rabeprazole should be instructed not to crush, chew, or split the delayed-release tablets.
Omeprazole is also available in an immediate-release formulation combined with sodium bicarbonate (Zegerid). The proposed benefit of this combination product is fast onset of action and increase in pH by the sodium bicarbonate, which helps prevent degradation of omeprazole in the stomach. Sodium bicarbonate may also stimulate gastrin production, which may activate the proton pumps and optimize the effectiveness of omeprazole.
Pantoprazole and esomeprazole are available in IV formulations that offer an alternative route for patients unable to take oral medications. The IV product is not more effective than the oral forms and is significantly more expensive.
Patients should be instructed to take their PPI in the morning, 15 to 30 minutes before breakfast to maximize efficacy, because these agents inhibit only actively secreting proton pumps.6,20 While usually given prior to breakfast, patients with night-time symptoms may benefit from taking their PPI prior to the evening meal.1 If a second dose is needed, it should be administered before the evening meal and not at bedtime.1 Regardless of the time of day, PPIs should be given prior to a meal to gain the most benefit. The exception to this is the immediate-release omeprazole-sodium bicarbonate combination product, which can be given at bedtime.
The PPIs are generally well tolerated, and the choice of a particular agent is often based on cost and tolerability. The most common side effects are headache, diarrhea, constipation, and abdominal pain. All PPIs can decrease the absorption of drugs (e.g., ketoconazole) that require an acidic environment to be absorbed. All PPIs are metabolized by the cytochrome P-450 system to some extent. Omeprazole and lansoprazole are metabolizedbyCYP2C19 enzymes. Concerns have been raised in patients taking PPIs concurrently with clopidogrel, a prodrug, that must be converted to its active form by CYP2C19. Inhibition of CYP2C19 by PPIs has been suggested to decrease the effectiveness of clopidogrel and increase the risk of cardiac events. More study is needed to determine this effect. No interactions with lansoprazole, pantoprazole, or rabeprazole have been seen with CYP2C19 substrates such as diazepam, warfarin, or phenytoin.21 Esomeprazole does not appear to interact with warfarin or phenytoin. Pantoprazole is metabolized by a cytosolic sulfotransferase and is therefore less likely to have significant drug interactions than other PPIs.20
While generally not of major concern, omeprazole may inhibit the metabolism of warfarin, diazepam, and phenytoin; lansoprazole may decrease theophylline concentrations. Drug interactions with omeprazole are of particular concern in patients who are considered “slow metabolizers,” as are approximately 3% of the Caucasian population. Unfortunately, it is unclear which patients have the polymorphic gene variation that makes them slow metabolizers.20 Alternatively, patients who are considered rapid metabolizers, which is most common in the Asian population (12–20%), may not respond as well as those who are considered slow metabolizers.22,23 This genetic variation among patients may alter the effect of PPIs due to the ability of their enzyme system to metabolize the drug.22 Esomeprazole is metabolized more by CYP3A4 enzymes and maybe affected less by the patient’s genotype.24Patients on potentially interacting drugs should be monitored for development of drug-related problems.
Other potential concerns with PPIs include hypergastrinemia, vitamin B12 deficiency, and risk for enteric infections or fractures. Prolonged hypergastrinemia leading to the development of colonic polyps and potentially adenocarcinoma in rats was a concern that has proven to be unfounded with long-term use in humans.25 The FDA has stated that there is insufficient evidence linking PPI use to atrophic gastritis, intestinal metaplasia, or gastric cancer.26 PPIs may inhibit the secretion of intrinsic factor by the parietal cells, which may lead to decreased absorption of vitamin B12 with subsequent deficiency. Patients receiving long-term PPI therapy should have periodic complete blood counts performed to detect signs of vitamin B12 deficiency. More recently, concerns include risk of enteric infections and risk of fractures with long-term use of PPIs. Although the incidence is low, further evaluation is needed to adequately quantify the risk of developing these effects. Routine bone density studies or calcium supplementation is not warranted based on PPI use alone.2
Prokinetic Agents
The prokinetic agents include cisapride, metoclopramide, andbethanechol. The inferior efficacy and side-effect profiles of metoclopramide and bethanechol limit their use in the treatment of GERD, and they are not recommended.
Mucosa I Protect ants
Sucralfate, a nonabsorbable aluminum salt of sucrose octasulfate, has very limited value in the treatment of GERD and is not recommended.
Combination Therapy
Two agents of different therapeutic classes should not be used routinely. Only modest improvements have been shown when a prokinetic agent is combined with a standard dose of an H2RA. Therefore, patients not responding to standard H2RA doses should be switched to a PPI instead of adding a prokinetic agent. Monotherapy with a PPI is not only more effective, but it also improves compliance with once-daily dosing and is ultimately more cost effective.
The addition of an H2RA at bedtime to PPI therapy has been suggested to decrease nocturnal acid breakthrough. While there may be an immediate effect to control symptoms and keep the pH greater than 4, tachyphylaxis may develop within 1 week. If H2RAs are used at night, it maybe preferable to only use them as needed to provide a “drug holiday” that may lessen the occurrence of tachyphylaxis.27Immediate-release omeprazole-sodium bicarbonate has been shown to decrease nocturnal acid exposure compared with pantoprazole administered daily with the evening meal and lansoprazole administered at bedtime. Although more studies are needed, immediate-release omeprazole may offer an effective option for controlling nocturnal acid exposure and symptoms.
Maintenance Therapy
Many patients with GERD experience relapse if medication is withdrawn, and long-term maintenance treatment is required in such patients.1 Candidates for maintenance therapy include patients whose symptoms return once therapy is discontinued or decreased, patients with a history of esophagitis healed by PPIs, patients with complications such as Barrett’s esophagus or strictures, and perhaps patients with atypical symptoms. In some patients, the dose of acid-suppressing therapy may be titrated to the lowest dose that controls symptoms.2
The goal of maintenance therapy is to improve quality of life by controlling symptoms and preventing complications. These goals cannot generally be achieved by decreasing the dose or switching to a less potent acid-suppressing agent. Most patients require standard doses to prevent relapses.28 Patients should be counseled on the importance of complying with patient-specific lifestyle changes and long-term maintenance therapy to prevent recurrence or worsening of disease.
The H2RAs may be effective maintenance therapy for patients with mild disease.6 The PPIs are first choice for maintenance treatment of moderate-to-severe GERD.29 A short course of “on-demand” therapy maybe appropriate in patients with symptomatic esophageal syndromes without esophagitis when symptom control is the primary outcome of interest.2 With on-demand therapy, patients take the medication only when symptoms occur. Antacids have the fastest onset and may be used in combination with an H2RA or PPI for “on-demand” symptom relief. However, patients with a history of esophagitis and/or complications should be maintained on standard daily doses of PPIs for maximum benefit. PPIs significantly decrease the incidence of dysplasia in patients with Barrett’s esophagus for over 20 years.30
Long-term use of higher PPI doses is not indicated unless the patient has complicated symptoms, has erosive esophagitis per endoscopy, or has had further diagnostic evaluation to determine degree and frequency of acid exposure. Antireflux surgery and endoscopic therapies may be viable alternatives to long-term drug use for maintenance therapy in selected patients.
Special Population Considerations
Patients With Atypical GERD
In patients presenting with extraesophageal GERD syndromes such as laryngitis or asthma, treatment with twice-daily PPI therapy for 2 months is probably warranted when there is a concomitant esophageal GERD syndrome.2Patients with suspected reflux chest pain syndrome should receive twice-daily PPI therapy after cardiac causes have been excluded. Manometry and pH or impedance pH monitoring should be considered in patients who do not respond to PPI therapy.2
Maintenance therapy is generally indicated in patients with extraesophageal GERD syndromes and concomitant esophageal GERD syndromes but not with reflux chest pain syndrome alone.2 Stepdown therapy can be attempted based on symptom control.
Pediatric Patients With GERD
Gastroesophageal reflux occurs in approximately 18% of infants. As in adults, transient LES relaxations appear to be the most common cause.31 This is due to developmental immaturity of the LES.32 Other causes include impaired luminal clearance of gastric acid, neurologic impairment, and type of infant formula. Most infants with gastroesophageal reflux have physiologic reflux with no clinical consequence.31
Uncomplicated GERD usually resolves by 12 to 18 months of life and responds to supportive therapy, including dietary adjustments such as smaller meals, more frequent feedings, or thickened infant formula. Postural management (e.g., positioning the infant in an upright position, especially after meals) may also be helpful.32 Medical therapy may be indicated if there is no improvement.
The combination of a prokinetic agent and acid-suppressing drug is used commonly in pediatric patients with GERD.32 Monotherapy with an H2RA is also used frequently; ranitidine 2 to 4 mg/kg/day IV (or 4–6 mg/kg/day orally) is effective in neonates and pediatric patients.
Use of PPIs is becoming more common in pediatrics. Lansoprazole is FDA approved for treating symptomatic and erosive GERD in patients 1 through 11 years of age. Studies in adolescents (12–17 years old) demonstrated pharmacokinetics similar to those seen in adults.33 The recommended dose is 15 mg once daily for children weighing 30 kg or less and 30 mg once daily for those weighing more than 30 kg. Although omeprazole is not FDA approved for use in children, evidence supports its effectiveness in children with GERD. A common dose for esophagitis is omeprazole 1 mg/kg/day (given once or twice daily).34 Although no major adverse events have been reported in children receiving PPIs for up to 7 years, the safety of prolonged use in children is unknown.34
Elderly Patients With GERD
Older individuals have decreased host defense mechanisms such as slowed gastric emptying and decreased saliva production. These patients often do not seek medical attention because they believe their symptoms are part of the normal aging process. PPIs are the most useful option in this population because they have superior efficacy and are dosed once daily.35 In addition, there are fewer drug-drug and drug-disease state interactions compared with H2RAs and metoclopramide. Elderly patients may be sensitive to the CNS effects of metoclopramide and H2RAs.
Patients With Refractory GERD
Refractory GERD maybe present in patients not responding to 4 to 8 weeks of twice-daily PPI therapy. Compliance should always be assessed prior to deciding that a patient is refractory to acid-suppressing therapy. Endoscopy is indicated to determine if underlying pathology exists. In addition, patients with esophagits may have a genotype that renders the PPIs less effective.22 Patients with normal endoscopy should undergo further testing with ambulatory pH monitoring or impedance monitoring to identify acid and nonacid reflux episodes, respectively.22 Patients not responding to PPI therapy may in fact have nonacid reflux approximately 20% to 30% of the time.9 Consideration should be made to switch a patient to an alternative PPI due to variability of patient responses. As many as 20% of patients on twice-daily PPI therapy with continued symptoms may have nonacid reflux.36,37
Patient Encounter, Part 3: Creating a Care Plan
Based on the information presented, create a care plan for this patient’s GERD. Your plan should include:
A statement of the drug-related needs and/or problems.
The goals of therapy.
A patient-specific, detailed therapeutic plan.
Cultural biases the practitioner should avoid in order to make the best treatment decisions for the patient.
A plan for follow-up to determine whether the goals have been achieved and adverse effects avoided.
OUTCOME EVALUATION
• Monitor for symptom relief and the presence of complicated symptoms, such as difficulty swallowing, painful swallowing, or unexplained weight loss.
• Record the frequency and severity of symptoms by interviewing the patient after 4 to 8 weeks of acid-suppressing therapy. Continued symptoms may indicate the need for long-term maintenance therapy.
• Monitor for adverse drug reactions, drug-drug interactions, and compliance with the therapeutic regimen initially and any time there is a change in symptoms or medications.
• Educate patients about symptoms that suggest the presence of complications requiring immediate medical attention, such as dysphagia or odynophagia.
• Refer patients who present with atypical symptoms such as cough, nonallergic asthma, or chest pain to their physician for further diagnostic evaluation.
• Review patient profiles for drugs that may aggravate GERD.
Patient Care and Monitoring
1. Assess patient symptoms to determine if further diagnostic evaluation is necessary. Does the patient have any GERD-related complications such as difficulty in swallowing or unexplained weight loss?
2. Perform a thorough medication history by evaluating nonprescription, prescription, natural drug products, food, and patient history to determine exacerbating factors.
3. Determine what treatments have been helpful in the past.
4. Instruct the patient to avoid foods that aggravate GERD symptoms.
5. Educate the patient on lifestyle modifications to improve symptoms.
6. Review the results of diagnostic tests such as hemoglobin and hematocrit to rule out unexplained anemia.
7. Recommend appropriate therapy and develop a plan to assess effectiveness. Patients should receive 4 to 8 weeks of empiric acid-suppressing therapy. Patients who fail to respond should be assessed for compliance and proper medication administration. Twice-daily PPI therapy should be considered in patients not responding to once-daily therapy.
8. Evaluate the patient for the presence of adverse drug reactions, drug allergies, and drug interactions.
9. Stress the importance of compliance with the regimen, especially in patients with more severe erosive esophagitis or complicated symptoms.
10. Determine if long-term maintenance treatment is necessary.
11. Assess improvement in quality-of-life measures such as physical, psychological, and social functioning and well-being.
12. Provide patient education on disease, lifestyle modifications, and drug therapy:
• What causes GERD and what are things to avoid?
• What are possible complications of GERD?
• When should medications be taken?
• What potential adverse effects may occur?
• Which drugs may interact with their therapy?
• What warning signs should be reported to the physician?
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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