UCLA UCLA Previously Published Works Title Novel Approaches to Inhibition of Gastric Acid Secretion Permalink https://escholarship.org/uc/item/6319s54m Journal Current Gastroenterology Reports, 12(6) ISSN 1534-312X Authors Sachs, George Shin, Jai Moo Hunt, Richard Publication Date 2010-12-01 DOI 10.1007/s11894-010-0149-5 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Curr Gastroenterol Rep (2010) 12:437–447 DOI 10.1007/s11894-010-0149-5 Novel Approaches to Inhibition of Gastric Acid Secretion George Sachs & Jai Moo Shin & Richard Hunt Published online: 6 October 2010 # The Author(s) 2010. This article is published with open access at Springerlink.com Abstract The gastric H,K-adenosine triphosphatase and the requirement for acid activation impair their efficacy (ATPase) is the primary target for treatment of acid- in acid suppression, particularly at night. All PPIs give related diseases. Proton pump inhibitors (PPIs) are weak excellent healing of peptic ulcer and produce good, but less bases composed of two moieties, a substituted pyridine than satisfactory, results in reflux esophagitis. PPIs combined with a primary pKa of about 4.0 that allows selective with antibiotics eradicate Helicobacter pylori, but success has accumulation in the secretory canaliculus of the parietal fallen to less than 80%. Longer dwell-time PPIs promise to cell, and a benzimidazole with a second pKa of about 1.0. improve acid suppression and hence clinical outcome. Protonation of this benzimidazole activates these prodrugs, Potassium-competitive acid blockers (P-CABs) are another converting them to sulfenic acids and/or sulfenamides that class of ATPase inhibitors, and at least one is in develop- react covalently with one or more cysteines accessible from ment. The P-CAB under development has a long duration of the luminal surface of the ATPase. The maximal pharma- action even though its binding is not covalent. PPIs with a codynamic effect of PPIs as a group relies on cyclic longer dwell time or P-CABs with long duration promise to adenosine monophosphate–driven H,K-ATPase transloca- address unmet clinical needs arising from an inability to tion from the cytoplasm to the canalicular membrane of the inhibit nighttime acid secretion, with continued symptoms, parietal cell. At present, this effect can only be achieved delayed healing, and growth suppression of H. pylori with protein meal stimulation. Because of covalent binding, reducing susceptibility to clarithromycin and amoxicillin. inhibitory effects last much longer than their plasma half- Thus, novel and more effective suppression of acid secretion life. However, the short dwell-time of the drug in the blood would benefit those who suffer from acid-related morbidity, continuing esophageal damage and pain, nonsteroidal anti- inflammatory drug–induced ulcers, and nonresponders to H. pylori eradication. G. Sachs (*) : J. M. Shin Department of Physiology and Medicine, David Geffen School Keywords Proton pump inhibitor . Gastric H,K-ATPase . of Medicine, University of California at Los Angeles, and VA Greater Los Angeles Healthcare System, Ulcer . Gastroesophageal reflux disease Room 324, Building 113, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA e-mail: [email protected] Introduction J. M. Shin e-mail: [email protected] The two major types of acid-related disorders are peptic R. Hunt ulcer disease (PUD) and gastroesophageal reflux disease Farncombe Family Digestive Disease Research Institute, (GERD), although other extra-esophageal disorders are Division of Gastroenterology, McMaster University Health ascribed to gastric acid reflux (eg, reflux laryngitis). The Sciences Centre, target for treatment was and still is reduction of gastric 1200 Main Street West, Room 4W8A, Hamilton, ON L8N 3Z5, Canada acidity. However, despite clinical and commercial success, e-mail: [email protected] histamine-2 receptor antagonists (H2-RAs) have several 438 Curr Gastroenterol Rep (2010) 12:437–447 pharmacologic limitations that are increasingly apparent in Ranitidine, 300 mg, at 8 PM the clinical setting. The H -RAs are less effective for the Median intragastric pH profiles 2 7 management of GERD and gastrointestinal (GI) bleeding Control Day 1 6 than for healing of PUD, and the rapid development of Day 7 tachyphylaxis limits their usefulness for long-term maintenance Day 28 5 treatment or high-dose intravenous use. The H2-RAs have been largely supplanted by the proton pump inhibitors (PPIs) because 4 of greater efficacy and lack of pharmacologic tolerance. The pH 3 PPIs were found to be very effective for the management of patients with erosive esophagitis, and a meta-analysis in 1997 2 confirmed their superiority to H2-RAs for the treatment of 1 GERD, particularly erosive esophagitis [1]. ← ← ← Dinner Breakfast Lunch PPIs have also found a place in treatment of a wide 0 range of acid-related disorders, including nonerosive reflux 8 PM Midnight 4 AM 8 AM 12 Noon 4 PM disease (NERD) and PUD, especially as treatment or Time of day prophylaxis of GI injury caused by nonsteroidal anti- inflammatory drugs (NSAID). PPIs have became established Fig. 1 The effect of nighttime administration of ranitidine, 300 mg, as combination antisecretory treatment, together with antibiotic on intragastric pH therapy, for the eradication of Helicobacter pylori infection. Furthermore, PPIs have become the standard of care in improved GERD symptoms, because the tolerization to patients with nonvariceal upper GI bleeding or for the ranitidine shown in Figure 1 is shared by all H2-RAs. prevention of stress-related mucosalbleedinginintensive The discovery that PUD was largely the result of care units. infection with H. pylori revolutionized the treatment of PUD, namely eradication of the infection either with triple or quadruple therapy. Hence, H2-RAs are used to treat H2-Histamine Receptor Antagonists and PPIs symptomatic GERD, but are not used alone for PUD. NSAID-induced PUD requires better acid inhibition for The launch in 1979 of cimetidine (Tagamet; GlaxoSmithKline, treatment, and hence H2-RAs are not indicated with Philadelphia, PA) revolutionized medical treatment of PUD and concomitant NSAID use. GERD, for the first time providing relatively long-lasting The synthesis of a novel secretory inhibitor, omeprazole reduction of gastric acid secretion with healing of both gastric (Prilosec; AstraZeneca, Wilmington, DE), in 1978 and its and duodenal ulcers and some remission of the symptoms of launch in 1989 in the United States further revolutionized GERD. Cimetidine was followed by ranitidine (Zantac; treatment of acid-related diseases. Omeprazole was the first Boehringer Ingelheim, Ingelheim, Germany), famotidine drug of the PPI class. Four more such PPIs are now on the (Pepcid; Johnson & Johnson, New Brunswick, NJ), and market: lansoprazole (Prevacid; Takeda Pharmaceuticals, nizatidine (Axid; Eli Lilly Indianapolis, IN)—all of which Osaka, Japan), pantoprazole (Protonix; Wyeth-Ayerst have an identical mechanism of action, namely reversible Laboratories, Madison, NJ), rabeprazole (Aciphex; Eisai, inhibition of the histamine (H2) receptor on the acid-secreting Tokyo, Japan), and esomeprazole (Nexium; AstraZeneca, parietal cell of the stomach. These drugs have very similar Wilmington, DE). Their mechanism of action is unique mechanisms of action. Famotidine is the most potent and their target is the active gastric proton pump, the H, commonly prescribed H2-RA, with about a 20-fold increase K-ATPase. They are weak-base prodrugs and accumulate in potency. H2-RAs result in short-lived inhibition of acid in the unique, highly acidic canalicular space of the secretion; the onset of inhibition occurs after about 4 h and active parietal cell, where the pH is less than 2.0. At this maximal inhibition after about 8 h, with return of acid pH, they are converted to the active form of the drug, secretion after about 12 h, therefore requiring at least twice- which then covalently binds to one or more cysteines daily administration. Moreover, all these drugs exhibit that are accessed from the luminal surface of the pump. tolerance such that they lose about 50% of their efficacy over Thus the inhibition is long-lasting and no tolerance has a 7-day period (Fig. 1). been observed with this class of drug. However, they Figure 1 shows the effect of ranitidine given at night to require the presence of acid secretion for accumulation reduce nighttime GERD symptoms on days 1, 7, and 28; and activation, hence their action is meal-dependent. intragastric pH is raised to greater than 5.0 by nighttime of Moreover, they have a relatively short plasma half-life of day 1, but reaches a level between 2.0 and 3.0 by day 28 about 2 h. Given this mechanism of action, the effect on [2]. Hence, this class of drug offers little likelihood of acid secretion is cumulative, increasing to steady state Curr Gastroenterol Rep (2010) 12:437–447 439 after 3 to 5 days of administration, because pumps that Level and duration of intragastric pH elevation are nonsecreting will not be inhibited whereas inhibited achieved for optimal treatment of: pumps will stay inhibited. A typical intragastric pH 24 profile is shown for pantoprazole in Fig. 2. Untreated BID H2 antagonist OD acid pump inhibitor The ability to progressively increase intragastric pH with Duodenal ulcer Reflux disease H2-RAs and PPIs resulted in a comprehensive meta- analysis of the relationship between intragastric pH, healing h/d 16 P of duodenal and gastric ulcers, and treatment of GERD P immediately after the launch of omeprazole. This analysis R predicted that a pH greater than 4.0 for 16 h per day was 8 optimum for healing of GERD and a pH greater than 3.0 pH > 3, 4, or 5, R was optimum for healing of duodenal ulcers (Fig. 3). C C The gastric H,K-ATPase has a half-life of 50 h, hence 0 about 25% of pumps are synthesized per day, at a rate of pH > 3 pH > 4 about 1% per hour [3].