Gastroesophageal Reflux Disease Pharmacotherapy

Definition
"a condition that occurs when the refluxed stomach contents lead to troublesome symptoms and/or complications. Episodic heartburn that is not frequent enough or painful enough to be considered bothersome by the patient is not included in this definition of GERD Gastroesophageal reflux symptoms associated with disease processes in organs other than the esophagus are referred to as extraesophageal reflux syndromes. Patients with extraesophageal reflux syndromes may present with reflux chest pain syndrome, laryngitis, or asthma

Clasification
Esophageal GERD syndromes are classified as either symptombased or tissue injury based depending on how the patient presents. Symptom-based esophageal GERD syndromes may exist with or without esophageal injury and most commonly present as heartburn, regurgitation or dysphagia. Less commonly, odynophagia (painful swallowing) or hypersalivation may occur Tissue injurybased syndromes may exist with or without symptoms. The spectrum of injury includes esophagitis (inflammation of the lining of the esophagus), Barrett esophagus (when tissue lining the esophagus is replaced by tissue similar to the lining of the intestine), strictures, and esophageal adenocarcinoma

Epidemiology
Gastroesophageal reflux disease occurs in people of all ages but is most common in those older than age 40 years The true prevalence and incidence of GERD is difficult to assess because many patients do not seek medical treatment, symptoms do not always correlate well with the severity of the disease, and there is no standardized definition or universal gold standard method for diagnosing the disease 10% to 20% of adults in Western countries suffer from GERD symptoms on a weekly basis. The prevalence of GERD varies depending on the geographic region but appears highest in Western countries does not appear to be a major difference in incidence between men and women. Although gender does not generally play a major role in the development of GERD, it is an important factor in the development of Barrett esophagus. Barrett esophagus is most prevalent in white adult males in Western countries and may increase the risk for adenocarcinoma of the esophagus especially in white males Other risk factors and comorbidities that may contribute to the development or worsening of GERD symptoms include family history, obesity, smoking, alcohol consumption, certain medications and foods, respiratory diseases, and reflux chest pain syndrome.

Pathophysiology
The key factor in the development of GERD is the abnormal reflux of gastric contents from the stomach into the esophagus gastroesophageal reflux is associated with defective lower esophageal sphincter (LES) pressure or function Problems with other normal mucosal defense mechanisms, such as abnormal esophageal anatomy, improper esophageal clearance of gastric fluids, reduced mucosal resistance to acid, delayed or ineffective gastric emptying, inadequate production of epidermal growth factor, and reduced salivary buffering of acid, may also contribute to the development of GERD Substances that may promote esophageal damage upon reflux into the esophagus include gastric acid, pepsin, bile acids, and pancreatic enzymes. Thus the composition and volume of the refluxate, as well as duration of exposure, are important aggressive factors in determining the consequences of gastroesophageal reflux. Rational therapeutic regimens in the treatment of gastroesophageal reflux are designed to maximize normal mucosal defense mechanisms and attenuate the aggressive factors.

Pathophysiology
1. Lower Esophageal Sphincter Pressure The sphincter is normally in a tonic, contracted state, preventing the reflux of gastric material from the stomach but relaxes on swallowing to permit the free passage of food into the stomach Although the exact mechanism is unknown, esophageal distension, vomiting, belching, and retching cause relaxation of the LES decreases in LES pressure is probably dependent on numerous factors, including the degree of sphincter relaxation, efficacy of esophageal clearance, patient position (more common in recumbent position), gastric volume, and intragastric pressure. Second, reflux may occur following transient increases in intraabdominal pressure (stress reflux). An increase in intraabdominal pressure such as that occurring during straining, bending over, coughing, eating, 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 as seen in patients with scleroderma Although transient relaxations are more likely to occur when there is normal LES pressure, the latter two mechanisms are more likely to occur when the LES pressure is decreased by such factors as fatty foods, gastric distension, smoking, or certain medications Various foods aggravate esophageal reflux by decreasing LES pressure or by precipitating symptomatic reflux by direct mucosal irritation (e.g., spicy foods, orange juice, tomato juice, and coffee).

Pathophysiology
2. Anatomic Factors Disruption of the normal anatomic barriers by a hiatal hernia (when a portion of the stomach protrudes through the diaphragm into the chest) was once thought to be a primary etiology of gastroesophageal reflux and esophagitis 3. Esophageal Clearance In many patients with GERD, the problem is not that they produce too much acid but that the acid produced spends too much time in contact with the esophageal mucosa The esophagus is cleared by primary peristalsis in response to swallowing, or by secondary peristalsis in response to esophageal distension and gravitational effects. esophageal damage caused by reflux occurs more often in the elderly and similarly for patients with Sjgren syndrome or xerostomia Swallowing is also decreased during sleep, making nocturnal GERD a problem in many patients

Pathophysiology
4. Mucosal Resistance Within the esophageal mucosa and submucosa there are mucussecreting glands that may contribute to the protection of the esophagus Bicarbonate moving from the blood to the lumen can neutralize acidic refluxate in the esophagus Saliva is also rich in epidermal growth factor, stimulating cell renewal 5. Gastric Emptying An increase in gastric volume may increase both the frequency of reflux and the amount of gastric fluid available to be refluxed Factors that increase gastric volume and/or decrease gastric emptying, such as smoking and high-fat meals, are often associated with gastroesophageal reflux The delay in emptying may promote regurgitation of feedings, which might, in turn, contribute to two common complications of GERD in infants (e.g., failure to thrive and pulmonary aspiration)

Pathophysiology
6. Composition of Refluxate The composition, pH, and volume of the refluxate are important aggressive factors in determining the consequences of gastroesophageal reflux First, if the pH of the refluxate is less than 2, esophagitis may develop secondary to protein denaturation. In addition, pepsinogen is activated to pepsin at this pH and may also cause esophagitis. Duodenogastric reflux esophagitis, or "alkaline esophagitis," refers to esophagitis induced by the reflux of bilious and pancreatic fluid An increase in gastric bile concentrations may be caused by duodenogastric reflux as a result of a generalized motility disorder, slower clearance of the refluxate, or after surgery the percentage of time that the esophageal pH is <4 is greater for patients with severe disease as compared with those with mild disease

Clinical Presentation

Symptom-based esophageal GERD syndromes (with or without esophageal tissue injury) Typical symptoms (May be aggravated by activities that worsen gastroesophageal reflux such as recumbent position, bending over, or eating a meal high in fat.) Heartburn (hallmark symptom described as a substernal sensation of warmth or burning rising up from the abdomen that may radiate to the neck. May be waxing and waning in character. Water brash (hypersalivation) Belching Regurgitation Alarm symptoms (These symptoms may be indicative of complications of GERD such as Barrett esophagus, esophageal strictures, or esophageal adenocarcinoma.) Dysphagia Odynophagia

Clinical Presentation

Tissue injurybased esophageal GERD syndromes (with or without esophageal symptoms) Symptoms (May present with alarm symptoms such as dysphagia, odynophagia or unexplained weight loss.) Esophagitis Strictures Barrett esophagus Esophageal adenocarcinoma Extraesophageal GERD syndromes Symptoms (These symptoms have an association with GERD, but causality should only be considered if a concomitant esophageal GERD syndrome is also present.) Chronic cough Laryngitis Asthma Dental enamel erosion

Diagnostic tests for GERD

Clinical history Generally sufficient to clinically diagnose GERD for patients with typical symptoms. Endoscopy Preferred for assessing the mucosa for esophagitis, identifying Barrett esophagus and diagnosing complications. Non-inflammatory GERD and major motor disorders may be missed by endoscopy. If no erosions, does not definitively show symptoms are GERD-related. Ambulatory pH monitoring Identifies patients with excessive esophageal acid exposure and helps determine if symptoms are acid related. Useful for patients not responding to acid-suppression therapy. Documents the percentage of time the intraesophageal pH is <4 and determines the frequency and severity of reflux. Measures only acid reflux (not nonacid reflux). Combined impedancepH monitoring Measures both acid and nonacid reflux. Manometry Ensure proper placement of esophageal pH probes (The recent advancement of the tubeless pH monitoring system using endoscopic landmarks for placement may negate the need for manometry for ensuring proper placement of esophageal pH probes.) Evaluate esophageal peristalsis and motility prior to antireflux surgery Empiric trial of a proton pump inhibitor as a diagnostic test for GERD Less expensive and more convenient than ambulatory pH monitoring but lack standardized dosing regimen and duration of the diagnostic trial. Barium radiography Not routinely used to diagnose GERD because lacks sensitivity and specificity; cannot identify Barrett esophagus.

Treatment
Desired Outcomes (1) alleviate or eliminate the patient's symptoms, (2) decrease the frequency or recurrence and duration of gastroesophageal reflux, (3) promote healing of the injured mucosa, and (4) prevent the development of complications

Treatment
Therapy is directed at (1) decreasing the acidity of the refluxate, (2) decreasing the gastric volume available to be refluxed, (3) improving gastric emptying, (4) increasing LES pressure, (5) enhancing esophageal acid clearance, and (6) protecting the esophageal mucosa.

Evidence Base Medicine

Non Pharmacologic therapy

Pharmacologic therapy

Pharmacologic therapy

Pharmacologic therapy