GASTROESOPHAGEAL REFLUX DISEASE (GERD) • Gastroesophageal reflux disease (GERD) refers to symptoms or mucosal damage resulting from the abnormal retrograde movement of gastric contents from the stomach into the esophagus. . It is primarily the result of transient relaxation of the LES. •When the esophagus is repeatedly exposed to refluxed material for prolonged periods, inflammation of the esophagus (reflux esophagitis) can occur and in some cases it progresses to erosion of the squamous epithelium (erosive esophagitis). •Severe reflux symptoms associated with normal endoscopic findings are referred to as “symptomatic GERD,” non erosive reflux disease, or endoscopy- negative reflux disease. Protective mechanisms such as esophageal peristalsis and bicarbonate-rich saliva quickly return the acidic pH to normal. GERD develops when alterations in reflux result in symptoms, mucosal injury, or both. Esophageal injury occurs with continued exposure of the mucosa to gastric acid and results in inflammation that can progress to ulceration (erosive esophagitis). Epidemiology GERD is a chronic disease that affects patients across all age groups with equal distribution between men and women. The prevalence of GERD appears to be greater in the Western population with patients presenting with more clinically important disease and complications than in Eastern countries (especially Asian populations) where GERD is uncommon. When considering the symptoms of GERD, such as heartburn and acid regurgitation, the overall prevalence in the United States is approximately 45%. In Western populations, 25% of patients report heartburn monthly, 12% weekly, and 5% describe daily symptoms. It has also been estimated that 7% of the U.S. population have complicated GERD associated with erosive esophagitis Up to 75% of patients who undergo endoscopic procedures due to symptoms associated with GERD have normal esophageal findings. These patients are identified as having functional heartburn, nonerosive reflux disease (NERD), or endoscopy-negative reflux disease (ENRD). Other patients with GERD have symptoms that occur outside of the esophagus which are considered atypical or extraesophageal manifestations of GERD. Extraesophageal manifestations may be present with or without accompanying typical symptoms (e.g., heartburn). Extraesophageal manifestations have been estimated to occur in about 80% of patients with at least weekly symptoms of GERD. Extraesophageal disorders in GERD Noncardiac chest pain laryngeal diseases Laryngitis pulmonary diseases Asthma chronic cough recurrent bronchitis sleep apnea pulmonary fibrosis subglottic stenosis laryngeal cancer other ENT (ear, nose, throat) disorders Sinusitis Otitis media Pharyngitis dental erosion Etiology and Risk Factors Increased contact of the acidic refluxate with the esophageal mucosa. Dietary and lifestyle factors, drugs, and certain medical and surgical conditions. Lowering the LES pressure (e.g., nitrates, progesterone, foods high in fat, mint, chocolate) or having a direct irritating effect on the esophageal mucosa (e.g., citrus, tomatoes, bisphosphonates). Increased intra-abdominal pressure has been associated with overeating, coughing, and bending or straining to lift heavy objects as well as tight-fitting clothing. Life style Smoking – Inhibits saliva, may also increase acid production & weaken the LES. Certain exercising & bending – that may increase the abdominal pressure. Wearing of tight clothing – increases the abdominal pressure. Lying flat after a meal – relaxes the muscles making susceptibility for reflux. Diet Fatty, greasy foods - take longer to digest keeping food in the stomach longer. Peppermint, spearmint, and chocolate weaken the LES. Carbonated and alcoholic beverages increase the acidity in the stomach. Large meal portions – produce large acid levels. Citrus, onions, and acid from tomatoes can be irritating to the esophagus. “Medications that relax the LES” Benzodiazepines Anticholinergics Theophylline Potassium supplements Narcotics containing codeine. Calium channel Blockers Nitroglycerine Iron supplements NSAIDS Fosamax Erythromycin Childhood GERD appears to continue into adolescence and adulthood. Although most infants develop physiological regurgitation, or spitting up, the majority (95%) will have abatement of symptoms by 1.0 to 1.5 years of age. However, infants with persisting symptoms beyond 2 years of age are at risk of developing complicated GERD. Pregnancy has also been associated with an increased incidence of GERD with 30% to 50% of pregnant women complaining of heartburn; however, in patients without a previous diagnosis of GERD, the symptoms resolve when the child is born. The mechanisms for GERD in pregnancy are related to a) the hormonal effects of progesterone and estrogen, which lower LES pressure, and b) increasing intra-abdominal pressure Certain medical and surgical conditions such as Gastroparesis,(A condition that affects the stomach muscles and prevent proper stomach emptying) Scleroderma, (Chronic hardening and tightening of the skin and connective tissues) Long-term placement of nasogastric tubes may also be associated with GERD. The eradication of H. pylori infection may increase the risk of GERD symptoms and esophagitis. Quality Of Life (QOL) Patients with GERD may have a decrease in quality of life. When comparing quality of life in patients with GERD to those with other chronic medical diseases, the quality of life in GERD patients was between patients with psychiatric disorders and patients with mild heart failure. Pathophysiology The pathophysiology of GERD is associated with Defects in transient relaxations of the LES, Esophageal acid clearance and buffering capabilities, Anatomy, Gastric emptying, Mucosal resistance and with exposure of the esophageal mucosa to aggressive factors (gastric acid, pepsin, and bile salts) leading to esophageal damage. Transient Relaxations of the Lower Esophageal Sphincter The LES, when in a resting state, remains at a high pressure (10–30 mmHg) to prevent the gastric contents from entering into the esophagus. Pressures are lowest during the day and with meals and highest at night. Transient relaxations of the LES are short periods of sphincter relaxation that are different from those that occur with swallowing or peristalsis. They occur due to vagal stimulation in response to gastric distension from meals (most common), gas, stress, vomiting, or coughing and can persist >10 seconds. A small percentage of patients may also have a continuously weak and hypotensive LES (decreased LES resting tone). Stress reflux increases intra-abdominal pressure and may blow open the hypotensive LES. When LES pressures remain constantly low, the risk for serious complications (e.g., erosive esophagitis) increase dramatically. Scleroderma, which is related to fibrosis of smooth muscle, may reduce LES tone and increase the potential for GERD. Esophageal Acid Clearance and Buffering Capabilities Although the number of reflux events and quantity of refluxate are notable, it is the duration of time the mucosa is in contact with these noxious substances that determines esophageal damage and complications. More than 50% of patients diagnosed with severe esophagitis have decreased acid clearance from the esophagus. Peristalsis is the primary mechanism by which acid refluxate is removed from the esophagus. Other mechanisms include swallowing, esophageal distension in response to refluxate, and gravity (which is only effective when the patient is in an upright position). Saliva plays an important role in the neutralization of gastric acid within the esophagus. Its bicarbonate-rich content buffers the residual acid that remains in the esophagus after peristalsis. However, saliva is only effective on small amounts of gastric acid, as patients with larger volumes of acid refluxate may not have the neutralizing capacity in saliva necessary to protect the esophagus. Swallowing increases the rate of saliva production and esophageal acid clearance. The reduction of swallowing that occurs during sleep is associated with nocturnal GERD. Patients with decreased saliva production (e.g., elderly, patients taking medication with anticholinergic effects, and those with certain medication conditions such as xerostomia or Sjogren's syndrome) may also be at increased risk of developing GERD. Anatomic Abnormalities Hiatal hernia (protrusion of the upper portion of the stomach into the thoracic cavity due to weakening in the diaphragmatic muscles) is frequently described as a cause of GERD, but its causal relationship remains uncertain. Although hiatal hernia is associated with a greater degree of esophagitis, strictures, and Barrett's metaplasia, not all patients with hiatal hernia develop symptoms or complications. This may be related to the size of the hiatal hernia and its effect on LES pressure. Hypotensive LES in combination with hiatal hernia increases the likelihood of reflux and complicated disease Gastric Emptying Delayed gastric emptying increases the volume of gastric fluid remaining within the stomach that is available for reflux and is associated with gastric distension. Although delayed gastric emptying is present in up to 15% of patients with GERD, a causal relationship has not been established. Because some patients such as those with diabetic gastroparesis also have GERD, the association between delayed gastric emptying and GERD cannot be overlooked. Mucosal Resistance The capability of the esophageal mucosa to endure contact with and withstand injury from gastric refluxate (acid and pepsin) is a substantial determinate for the development of GERD. When considering the mucosal resistance within the esophagus compared with that of the stomach and duodenum, the esophagus is less resistant to damage from gastric acid. However, mucosal resistance in the esophagus is composed of many defensive factors working in tandem to prevent esophageal injury. The esophagus also secretes a protective mucous layer and bicarbonate. This creates an environment in the esophagus of a higher pH than that of the stomach. The pH in the esophagus is normally about 7-8, whereas the pH in the stomach is generally 2-4. Enhanced blood flow in response to an acidic environment within the esophagus improves tissue oxygenation, provides nutrients, and helps to maintain a normal acid–base balance. Esophageal injury also occurs when the concentration of acid and pepsin exceed the protection afforded by mucosal resistance mechanisms. Aggressive Factors Associated With Esophageal Damage The gastric refluxate, which is composed primarily of gastric acid and pepsin, is the primary aggressive factor associated with GERD. The development and degree of mucosal damage is dependent on the pH and contents of the refluxate as well as the total exposure time of refluxate with the esophageal mucosa. A pH <4 is usually required to produce injury to the esophageal mucosa, but as the refluxate becomes more acidic, the mucosal damage is accelerated. The addition of pepsin (which is converted from secreted pepsinogen in an acidic pH) to the acidic refluxate will markedly increase the propensity of the refluxate to compromise mucosal resistance and increases the potential for esophageal bleeding. Duodenogastric reflux or alkaline reflux containing bile acids and pancreatic juices may also contribute to esophagitis. Because gastric and duodenogastric reflux are often concomitantly present, their actions may be additive in causing esophageal damage. The duration of total exposure time of the esophagus to the refluxate is the primary mechanism involved in the development of GERD and its complications. The longer the duration of exposure time, the greater the possibility of severe disease, including progression to Barrett's metaplasia. Eradication of Helicobacter pylori The relationship between H. pylori infection and GERD remains controversial. Early studies suggest that H. pylori eradication is associated with increased gastric acidity and subsequent development of erosive esophagitis. In contrast, it appears that H. pylori may be protective against GERD symptoms and related complications. This is presumably due to the microorganisms ability to decrease the acidity of the refluxate, as it does not appear to affect the functional defense mechanisms of the esophagus. Although H. pylori testing in patients with GERD is not standard practice, if the patient is tested and found to be H. pylori positive, eradication is recommended The 3 mechanisms of the lower esophageal sphincter (LES) which prevent backflow are: Pressure in the LES is greater than that of the stomach. High levels of Acetylcholine, a neurotransmitter increases constriction of the LES. Gastrin, a hormone also increases constriction of the LES. Some conditions that can interfere with the mechanisms of the Lower Esophageal Sphincter (LES): OBESITY - excess weight puts extra pressure on the stomach & diaphragm. Pregnancy – results in greater pressure on the stomach & also has a higher level of progesterone. This hormone relaxes many muscles, including the LES. ASTHMA – it is unsure why, but, is believed that the coughing leads to pressure changes on the diaphragm. HIATAL HERNIA – which is the following topic. There are specialized cells deep in the stomach lining that affect the rate of acid production. The primary cells which contribute to acid production are known as parietal cells. Each gastric parietal cell contains about 1 million acid pumps. The primary function of the activated pumps are to exchange hydrogen ions from the parietal cells to potassium using energy derived from splitting ATP. The stomach produces an average of 2 liters of HCL a day, which in combination with the protein-splitting enzyme pepsin, breaks down chemicals in food. Complications Complications of long-term reflux may include the development of Erosive esophagitis (up to 47%) Strictures (>30%), Barrett’s esophagus (10% to 15% ), or Adenocarcinoma of the esophagus. CLINICAL PRESENTATION • The hallmark symptom of gastroesophageal reflux and esophagitis is heartburn, or pyrosis. It is classically described as a substernal sensation of warmth or burning that may radiate to the neck. It is waxing and waning in character and is often aggravated by activities that worsen gastroesophageal reflux (e.g., recumbent position, bending over, eating a high-fat meal). Other symptoms include water brash (hypersalivation), belching, and regurgitation. • Atypical symptoms include nonallergic asthma, chronic cough, hoarseness, pharyngitis, dental erosions, and chest pain that mimics angina. • Inadequately treated GERD may lead to complications from long-term acid exposure such as continual pain, dysphagia, and odynophagia. Other severe complications include esophageal strictures, hemorrhage, Barrett’s esophagus, and esophageal adenocarcinoma. Clinical Presentation A normal upper esophagoscopy The Los Angeles Classification System for the endoscopic assessment of reflux oesophagitis GRADE A: One or more mucosal breaks no longer than 5 mm, non of which extends between the tops of the mucosal folds The Los Angeles Classification System for the endoscopic assessment of reflux oesophagitis GRADE B: One or more mucosal breaks more than 5 mm long, none of which extends between the tops of two mucosal folds The Los Angeles Classification System for the endoscopic assessment of reflux oesophagitis GRADE C: Mucosal breaks that extend between the tops of two or more mucosal folds, but which involve less than 75% of the oesophageal circumference The Los Angeles Classification System for the endoscopic assessment of reflux oesophagitis GRADE D: Mucosal breaks which involve at least 75% of the oesophageal circumference Endoscopic view of GERD complications Treatment Therapeutic Goals to alleviate symptoms, promote esophageal healing, prevent recurrence, provide cost-effective pharmacotherapy, and avoid long-term complications. One long-term consequence is Barrett's esophagus, or Barrett's metaplasia, which is identified in 10% to 15% of GERD patients on endoscopic evaluation. This premalignant condition may predispose the patient to esophageal adenocarcinoma. Patients with Barrett's esophagus have a 30- to 125-fold greater risk of developing esophageal cancer than an age-matched population. Nonpharmacologic Measures and SelfDirected Treatment Lifestyle and dietary modifications comprise the initial step in managing patients with GERD Lifestyle modifications are aimed at reducing acid exposure within the esophagus by increasing LES pressure, decreasing intragastric pressure, improving esophageal acid clearance, and avoiding specific agents that irritate the esophageal mucosa. There is evidence to support several modifications that reduce esophageal gastric acid exposure and symptoms.These include raising the head of the bed 6 to 8 inches by using blocks sleeping in a left lateral decubitus position; and weight loss, which also decreases intra-gastric pressure. Avoiding large meals within 3 hours of bedtime or lying down in the supine position may also decrease symptoms. Pharmacotherapy Antacids Antacids are useful only in the relief of mild symptoms associated with GERD. Because of their short duration of action and inability to heal erosive esophagitis, they are not an option for treating moderate to severe GERD. H2-Receptor Antagonists The H2RAs are effective in treating patients with mild to moderate GERD, but response rates vary with the severity of disease, the dose of the drug, and the duration of therapy. The H2RAs are considered equally effective when used in equipotent doses for symptomatic relief and esophageal healing. They are effective in reducing nocturnal symptoms but only modestly effective in relieving meal-related symptoms, as they only block one mechanism of parietal cell activation (the H2 receptor). The H2RAs relieve symptoms in about 50% to 60% of patients treated after 12 weeks of continuous therapy and are superior to placebo. Increasing the H2RA dose may not improve symptoms in some patients. Esophageal healing requires higher doses Esophageal healing rates with the H2RAs are reported to be about 50% after 8 to 12 weeks of treatment, but rates will vary depending on the degree of esophagitis. For example, endoscopic healing rates in trials with high-dose H2RAs were approximately 60% to 90% in patients with grades I and II esophagitis but were only 30% to 50% in patients with more severe disease (grades III and IV esophagitis). When a H2RA is used to heal the esophagus, higher daily dosages and prolonged treatment (8–12 weeks) are required. Proton Pump Inhibitors The PPIs are the drugs of choice for patients with frequent moderate to severe GERD symptoms and esophagitis because they provide more rapid relief of symptoms and esophageal healing than do the H2RAs. Act by Inhibits the gastric acid pump, H+/K+ ATPase & are prodrugs When used in recommended dosages, all of the PPIs provide similar rates of symptom relief and esophageal healing. Their superior efficacy, when compared with the H2RAs, is related to their ability to maintain an intragrastric pH >4 for a long duration time (up to 24 hours/day vs. up to 10 hours with a H2RA). Typically, PPIs are taken once daily 30 to 60 minutes before breakfast, but if a second dose is required, it should be taken prior to the evening meal. A large meta-analysis of 16 trials confirms that PPIs are superior to the H2RAs for achieving rapid and complete relief of GERD symptoms. Complete symptom relief (within 4–12 weeks) was achieved in 77.4% of patients taking a PPI versus 47.6% of those taking and H2RA (p <0.0001). Healing also occurred more quickly with PPI therapy in that by week two, 63.4% of patients had healed with the PPI, while it took 12 weeks with the H2RAs for 60.2% of patients to heal. Another large meta-analysis, which evaluated over 33 randomized trials, demonstrated similar results with 81.7% of patients healed at 8 weeks with a PPI versus 52.0% with a H2RA. Esophageal healing among the five PPIs appears to be equivalent, as about 85% to 90% of patients achieve complete healing at 8 weeks in numerous head-to-head trials with equivalent doses. One meta-analysis, which compared esophageal healing rates among omeprazole 20 mg, lansoprazole 30 mg, pantoprazole 40 mg, and rabeprazole 20 mg (each given once daily), reported no statistical difference. However, all of the PPIs were superior to ranitidine 300 to 600 mg/day. The ability of a high-dose PPI to reverse Barrett's metaplasia remains controversial. Although studies have demonstrated islands of normal squamous epithelium returning, no data have determined that this is associated with a risk reduction in adenocarcinoma. In fact, others have suggested that this return of normal mucosa may actually mask carcinogenic changes occurring deeper in the gastric mucosa. Improvement of quality of life has also been evaluated in patients receiving PPI therapy in the management of GERD. A recent study comparing esomeprazole with ranitidine over a period of 6 months showed a significant improvement in both physical functioning and sleep with the PPI therapy. Prokinetic Agents Two prokinetic agents, metoclopramide and bethanechol, may be effective in the management of GERD. Both drugs stimulate the motility of the upper GI tract without altering gastric acid secretion and increase LES pressure. Although these drugs may provide relief of symptoms, they are ineffective in healing erosive esophagitis unless they are combined with a H2RA or PPI. Prokinetics are not widely used to treat GERD, because they are not as effective as other treatments and are associated with numerous side effects. Prokinetics are reserved for patients who are refractory to other available treatment options or who have delayed gastric emptying. Sucralfate Sucralfate appears to be effective in treating mild cases of GERD and possibly mild esophagitis but is not effective in the management of severe disease. Given better options at this time, sucralfate is rarely used in the management of GERD. The PPIs are considered the drugs of choice for patients with frequent or severe GERD symptoms, or who have complicated disease, because of their potent inhibition of gastric acid secretion. Maintenance Therapy GERD is chronic disease. Up to 80% of patients with severe esophagitis and 15% to 30% with less severe disease have a symptomatic relapse within 6 months after discontinuing treatment. The goal of maintenance therapy is to keep the patient symptom-free and prevent potentially life-threatening complications. Continuous maintenance therapy with a daily PPI is more effective than a H2RA, with reported relapse rates of 25% and 50%, respectively. Thus, PPIs are the drugs of choice for maintaining remission in patients with healed esophagitis. On-Demand Pharmacotherapy The use of intermittent (on-demand) courses of PPI therapy (2–4 weeks) have been suggested as being potentially beneficial in patients with GERD. One trial, which compared continuous maintenance therapy with esomeprazole 20 mg daily versus on-demand therapy with the same drug and dose in patients with healed erosive esophagitis, reported that continuous therapy was superior to on-demand therapy (81% vs. 58%, respectively) in maintaining endoscopic remission at 6 months. Although numerous studies with a variety of PPIs have demonstrated patient satisfaction with on-demand therapy, systemic review of 17 trials evaluating the use of ondemand therapy indicates that intermittent therapy should only be considered in patients with mild, nonerosive disease. Combination of a Proton Pump Inhibitor and H2-Receptor Antagonists The addition of a H2RA at bedtime to a once or twice daily PPI regimen is sometimes used for patients who continue to have nocturnal symptoms, although the evidence to support this combination remains inconclusive. The rational for this practice is based on evidence that suggests a period of nocturnal acid breakthrough (defined as intragastric pH <4 for longer than 1 hour during the night) in a significant number of patients despite twice-daily PPI therapy, suggesting that histamine release may have an important function in nocturnal acid secretion. One study suggests that the addition of a H2RA to a twice-daily PPI regimen resulted in a statistically significant reduction in nocturnal acid breakthrough during the sleeping hours. This trial, however, evaluated only a single bedtime dose of a H 2RA and did not consider the tachyphylaxis that can occur with continuous use. A more recent trial using a twice-daily PPI regimen with continuous use of a H2RA for 4 weeks demonstrated no difference in nocturnal acid suppression, suggesting that tolerance does play an important role in the use of H2RAs for this indication. Nonerosive Reflux Disease Up to 75% patients with typical GERD symptoms who undergo endoscopy will not have evidence of esophagitis or complicated disease. These patients are described as having functional heartburn, NERD or ENRD and usually undergo 24-hour ambulatory pH monitoring to determine whether abnormal reflux is present despite a negative endoscopy. A trial of a PPI is usually indicated despite no esophageal findings, as many patients will respond to this therapy. Further medical evaluation is usually required if a patient does not respond to PPI therapy despite a doubling of the daily dose. Asthma and Gastroesophageal Reflux Disease GERD may play a role in the pathophysiology of asthma. Reports suggest that concomitant GERD occurs in 34% to 89% of the asthmatic population. Two theoretical mechanisms exist as to how GERD can potentially exacerbate asthma symptoms. The reflex theory proposes that symptoms result from the direct irritation of the vagus nerve when refluxate comes into contact with the esophageal mucosa, resulting in reflex bronchospasm. In contrast, the reflux theory proposes that aspiration of refluxed acid into the lungs causes caustic injury of tissue within the bronchial tree, resulting in asthmatic symptoms. An important meta-analysis of trials that evaluated the effects of antireflux therapy on patients with asthma indicates that asthma symptoms improved in 69% of patients, that the use of asthma medications was reduced by 62%, and that only 26% of the subjects showed improvement in evening peak expiratory flow rate. All other pulmonary function tests (PFTs) showed little or no change with antireflux therapy. However, this meta-analysis only evaluated studies of up to 8 weeks in duration. A recent trial with esomeprazole 40 mg daily for 3 months demonstrated improvements in PFTs and a decreased use of shortacting rescue bronchodilators in asthmatics with GERD compared with asthmatics without GERD. One-third of the patients in the GERD group were also able reduce their dose of inhaled corticosteroid and remained stable. New Treatments Cholecystokinin2 receptor antagonists (CCK2) Potassium competitive acid blockers (P-CABs) Cholecystokinin2 receptor antagonists (CCK2) Block the CCK2 receptors inhibiting acid secretion Still in clinical trials Best use in combination with PPI’s CCK2 Itriglumide Z-360 Potassium competitive acid blockers (P-CABs) Target H+/K+ ATPase Ionically binds to the proton pump Specific for the K+ binding region and prevents acid secretion Binds reversibly Still in clinical trials P-CABs Revaprazan Soraprazan Treatment for H. pylori • Amoxicillin + clarithromycin + proton pump inhibitor • Metronidazole + clarithromycin + proton pump inhibitor • Bismuth subsalicylate + metronidazole + tetracycline + proton pump inhibitor References 1. MARIE A. CHISHOLM-BURNS.PHARMACOTHERAPY PRINCIPLES & PRACTICE. CHISHOLM-BURNS MA, editor: The McGraw-Hill Companies, Inc. ; 2008. 2. Joseph T. DiPiro P, Executive Dean and Professor, South Carolina College of Pharmacy, University of South Carolina. Pharmacotherapy A Pathophysiologic Approach. Seventh Edition ed.: McGraw-Hill; 2008. 3. Koda-Kimble MAY, Lloyd Yee. Applied Therapeutics: The Clinical Use Of Drugs, 9th Edition. Koda-Kimble MAY, Lloyd Yee, editor: Copyright ©2009 Lippincott Williams & Wilkins; 2009.