Because neither the anatomic nor the chemical source of dyspepsia was determined until the late 19th century, therapy before that time was empiric and often quite imaginative. Recommendations included sedum (stonecrop), chewing green tea, and magnesia. For centuries, relief from dyspepsia was provided by chalk, charcoal, and "slop" diets.94 At the turn of the 20th century, proprietary medicines were popular, and were offered not only as cures for heartburn but also for impotence and alopecia.94 Therapy at that time centered on avoidance of acidic foods, otherwise bland diets free of cap-saicin, milk, antacids, and elevation of the head of the bed. In addition to their acid-neutralizing effects, antacids were subsequently demonstrated to increase lower esophageal sphincter pressure and decrease gastroe-sophageal reflux.95,96 Alginic acid, which reacts with saliva to form a viscous coating that protects the esophagus (and stomach) was shown to have effects on reflux symptoms similar to those of antacids.97
The first major medical therapeutic breakthrough came in the 1970s with the identification of two classes of histamine receptors, H1 and H2. After testing >700 histamine derivatives, Black et al.98 identified the first H2 receptor antagonist, burimamide, in 1972. Although intravenous administration led to inhibition of pentagastrin-stimulated acid secretion in humans, it was not active orally. The second antagonist that was developed, metiamide, was tenfold more potent but was found to cause agranulocytosis and was not suitable for clinical use. The introduction of cimetidine for clinical use led to the eventual introduction of a family of H2 receptor antagonists (cimetidine, ranitidine, famotidine, nizatidine) available in both oral and parenteral forms. These compounds reduced basal and stimulated acid production but had no effect on lower esophageal sphincter pressure, esophageal peristalsis, or gastric emptying. They consistently reduced symptoms of heartburn and permitted reduced use of antacids, but significant healing of esophagitis did not reliably occur.99-101 The development of hyperplasia of gastrin-producing cells during chronic administration of H2 receptor antagonists led to initial concerns about the possibility of inducing gastric cancer, but more than two decades of experience has allayed these concerns.102 The H2 receptor antagonists are now available as non-prescription medications.
By the late 1970s it was recognized that low-amplitude lower esophageal sphincter resting pressure, poor distal esophageal motility, and transient relaxations of the lower esophageal sphincter contributed to reflux frequency and severity. This stimulated interest in the use of prokinetic agents in the management of GERD. Several classes of drugs were assessed, including the dopamine antagonists metoclopramide and domperidone, the acetylcholine receptor agonist bethanechol, the serotonin-4 (5-HT4) receptor agonist cisapride, and the motilin agonist erythromycin. Metoclopramide was shown to be effective in reducing symptoms of acid reflux by increasing lower esophageal sphincter pressure and by decreasing gastric emptying time. However, no effect on healing of esophagitis was evident.103,104 Bethanechol was demonstrated to increase resting lower esophageal sphincter pressure resulting in a decrease in acid reflux, and improve esophageal clearance. Some effect on esophageal healing was also identified.105-108 Overall, these agents produced modest improvement in esophageal motility and gastric emptying, and were similar in efficacy to antacids in relieving reflux symptoms. However, side effects produced by most drugs prevented their widespread acceptance. There were great expectations for cisapride, which demonstrated efficacy similar to H2 receptor antagonists in relieving reflux symptoms and in healing mild-to-moderate esophagitis.109-111 Unfortunately,potentially fatal QT interval prolongation and ventricular dys-rhythmias caused by cisapride, first reported publicly in 1995, led to its withdrawal from the United States market in 2000.112 Currently there
MANAGING FAILED ANTI-REFLUX THERAPY
are no prokinetic agents that are proven effective in managing GERD symptoms.113
Intracellular mechanisms of acid production were targeted in the 1980s as therapy for a variety of acid-peptic diseases. Unique to oxyntic cells is gastric hydrogen/potassium adenosine triphosphatase (H+/K+-exchanging ATPase), the gastric proton pump that catalyzes the exchange of K+ for H+ at the canalicular membrane. A compound, omeprazole, was identified that inhibited (H+, K+) ATPase, and was found to inhibit basal and pentagastrin-stimulated acid secretion in humans.114 The new class of proton pump inhibitors (PPIs) was the most potent inhibitor of gastric acid secretion ever identified. Five PPIs are now labeled by the Food and Drug Administration (FDA): omepra-zole, esomeprazole, lansoprazole, rabeprazole, and pantoprazole. The drugs have been associated with relatively few side effects, and are much more effective in controlling symptoms of GERD and in healing esophagitis than any other class of drugs.115-119 Proton pump inhibitors now are the mainstay of medical therapy for severe GERD.
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Gastroesophageal reflux disease is the medical term for what we know as acid reflux. Acid reflux occurs when the stomach releases its liquid back into the esophagus, causing inflammation and damage to the esophageal lining. The regurgitated acid most often consists of a few compoundsbr acid, bile, and pepsin.