DRUG PROFILE Esomeprazole: a new proton pump inhibitor for NSAID-associated peptic ulcers and dyspepsia Grace Lai-Hung Wong Ulcer and ulcer symptoms related to the use of non-steroidal anti-inflammatory drugs & Joseph JY Sung† (NSAIDs) and aspirin constitute a major global health issue. Despite various attempts to †Author for correspondence prevent and heal injuries inflicted by NSAIDs and aspirin, acid suppression remains one of The Prince of Wales Hospital, Department of Medicine and the cornerstones in the management of NSAID-associated ulcers. Esomeprazole, the Therapeutics, 9/F, S-optical isomer (enantiomer) of omeprazole, suppresses gastric acid secretion by 30–32 Ngan Shing Road, inhibiting the parietal cell membrane enzyme H+/K+-ATPase. With improved bioavailability, Shatin, NT, Hong Kong SAR due to reduced first-pass metabolism in the liver, esomeprazole promises to be more Tel.: +852 2632 3132 potent in acid suppression in the stomach. Similar to omeprazole, the safety profile of Fax: +852 2645 1699 esomeprazole has been well established. Clinical studies comparing esomeprazole with [email protected] other proton pump inhibitors (PPIs) in the healing of NSAID-related ulcer are few. Recent multicenter randomized studies demonstrated that esomeprazole significantly improves dyspeptic symptoms in patients taking nonselective NSAIDs and specific cyclooxygenase-2 inhibitors. Esomeprazole also protects the stomach from aspirin-induced ulcer bleeding. Safety profiles of esomeprazole appear promising. Non-steroidal anti-inflammatory drugs both basal and stimulated acid secretion. PPIs are (NSAIDs) are the most commonly used medica- most effective against meal-induced gastric acid tions for chronic pain and arthritis due to their secretion [3]. Omeprazole, the first drug in this efficacy in pain control. However, it is well rec- class, was introduced in 1988. Since then, three ognized that NSAIDs cause various gastrointes- other PPIs have been introduced: lansoprazole tinal (GI) conditions including dyspepsia, (1995), rabeprazole (1999) and pantoprazole peptic ulcer disease and its complications (2000). In 2001, esomeprazole was introduced as (bleeding and perforation), and small bowel the S-optical isomer of the racemic molecule of stricture. These complications have a huge omeprazole. All PPIs share a common structural impact on healthcare system around the world. motif but vary in their substitutions. PPIs have In the USA alone, the use of NSAIDs causes revolutionized the management of acute upper more than 100,000 hospitalizations and 17,000 gastrointestinal bleeding (GIB), as adequate acid deaths annually [1]. The risk is substantially suppression improves the success of endoscopic higher among the elderly population and those hemostasis, and reduces the need of surgery [4]. with concomitant medical illnesses. This article focuses on the existing literature of As mucosal injury induced by NSAIDs is an esomeprazole and it’s effects in preventing and acid-dependent process, effective acid suppres- healing of NSAID-induced GI mucosal injury. sion is one of the ways to prevent NSAID-associ- ated ulcer formation and complications. Proton Chemistry pump inhibitors (PPIs) are a group of acid-sup- Omeprazole is a racemate with a sulfur atom pressing agents that act by binding covalently to which acts as a chiral center for the compound. Keywords: aspirin, duodenal the amino acid cysteine 813 residue present at It contains two optical isomers, S- and R-ome- ulcer, esomeprazole, gastric their primary binding site on the H+/K+-ATPase, prazole. Conversion of the two enantiomers to ulcer, gastrointestinal also known as the ‘proton pump’, on the luminal the active form, the achiral sulfenamide, occurs bleeding, Helicobacter pylori, histamine-2 receptor surface of gastric parietal cells [2]. This results in via an acid-dependent chemical reaction at the antagonists, NSAID, peptic irreversible inhibition of acid secretion by the gas- luminal surface of the parietal cells and at the ulcer disease, proton pump tric H+/K+-ATPase. Only after recruiting newly same rate for both enantiomers. inhibitors synthesized proton pump molecules from the Esomeprazole is the S-isomer (enantiomer) of Golgi apparatus of the cell will acid secretion omeprazole, and the first PPI to be developed as gradually resume [3]. As PPIs block the final step an optical isomer. Similar to other PPIs, esome- in the pathway to gastric acid secretion arising prazole suppresses gastric acid secretion by inhib- Future Drugs Ltd from various stimuli, they are effective against iting the parietal cell membrane enzyme 10.1586/14750708.3.2.227 © 2006 Future Drugs Ltd ISSN 1475-0708 Therapy (2006) 3(2), 227–236 227 DRUG PROFILE – Wong & Sung Figure 1. Molecular structure of omepraozle: (S)-5-methoxy-2-([(4-methoxy-3,5- dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole and its two optical isomers, the S-isomer (esomeprazole) and the R-isomer of omeprazole. CH3O H3C CH3 N N S O N CH3O Omeprazole S-isomer R-isomer CH3O CH3O H3C CH3 H3C CH3 N N N S N S O O NH NH CH3O CH3O Esomeprazole H+/K+-ATPase. Esomeprazole is rapidly sulfenamide analog, in the acidic environment of degraded in acidic media but is stable under the gastric parietal cell. It effectively blocks acid alkaline conditions just as all other PPIs are. secretion by irreversibly binding to and inhibit- Each capsule of esomeprazole magnesium con- ing the enzyme H+/K+-ATPase that resides on tains enteric-coated granules to prevent the luminal surface of the parietal cell mem- esomeprazole degradation by gastric acidity. brane, resulting in disulfide bond formation Esomeprazole, chemical name: (S)-5-meth- with cysteine 813 located within the α-subunit oxy-2-([(4-methoxy-3,5-dimethyl-2-pyridinyl) of the enzyme (Figure 2). This is the residue that is methyl]sulfinyl)-1H-benzimidazole, (Figure 1) is intimately involved in H+ transport. All PPIs are a weak base. It is converted to its active form, a weak protonatable pyridines, with a pKa 4.0 for 228 Therapy (2006) 3(2) Esomeprazole – DRUG PROFILE Figure 2. Rearrangement of esomeprazole. OCH3 OCH3 OCH3 H3C CH3 H3C CH3 H3C CH3 H+ N N H+/K+- ATPase N Slow S Cys813 S H S O N N N N N S N OCH OCH3 3 OCH3 Esomeprazole Sulfenamide analog Esomeprazole rearranges (in the presence of acid) to a sulfenamide analog, which irreversibly binds to and inhibits the enzyme H+/K+- ATPase that resides on the luminal surface of the parietal cell membrane, resulting in disulfide bond formation with cysteine 813 located within the α-subunit of the enzyme. omeprazole, esomeprazole and lansoprazole, 3.9 by both CYP2C19 (73%) and CYP3A4 (27%). for pantoprazole and 5.0 for rabeprazole. The rate As a result of this difference in liver metabo- of conversion varies among the compounds and is lism of the drug, intrinsic clearance of R-iso- inversely proportional to their pKa: that is, mer is three times faster than the S-isomer, rabeprazole > omeprazole/esomeprazole = lansop- hence a higher plasma concentration of the razole > pantoprazole. As a result, they accumulate later. In contrast, esomeprazole has reduced specifically and selectively in the secretory canalic- first-pass metabolism and slower clearance. ulus, the highly acidic space, of the parietal cell [3]. Pharmacokinetic studies show that esome- Within that space, PPIs undergo an acid catalyzed prazole has a significantly higher area under conversion to become a reactive species, the curve (AUC) value and longer half-life than thiophilic sulfenamide, which are permanent both the R-isomer and racemic omeprazole, cations. resulting in a 10–20% increase in the acid-sup- pressing effect of the drug [6]. The half-life of Pharmacology elimination is 1–1.5 h, and the time to reach Esomeprazole has a different pharmacody- peak plasma drug level after oral administration namic and pharmacokinetic profile from its is 1.5 h. Although altered P450 metabolism parent compound, omeprazole. It is designed appears beneficial as it achieves a higher plasma to improve bioavailability of the drug with levels of esomeprazole, when the CYP2C19 more consistent pharmacokinetics and hence pathway becomes saturated, the isoenzyme may better acid control. After ingestion, both the S- become a major target for interactions with and R-isomers of omeprazole are absorbed other drugs, including warfarin, diazepam and through the intestine and passed through the phenytoin. CYP3A4-mediated metabolism may liver (first-pass metabolism) and transformed also be activated under such conditions and into the active compound which is delivered hence become the principal route of drug elim- back to the stomach as two inactive metabo- ination. Furthermore, induction of CYP450A, lites, the 5-hydroxy and sulfone forms of the another P450 isoenzyme, may occur in compounds [5]. Unlike the R-isomer which is CYP2C19-deficient or saturated individuals, predominantly metabolized by CYP2C19 making them susceptible to interference with (98%), S-isomer (esomeprazole) is metabolized theophylline metabolism [5]. www.future-drugs.com 229 DRUG PROFILE – Wong & Sung Absorption of esomeprazole is decreased by 40 mg was significantly more effective than lan- 43–53% when taken with food. As the amount soprazole 30 mg for controlling intragastric of H+/K+-ATPase present in the parietal cell is acidity, with a difference in percentage of time greatest after prolonged fasting, PPIs are best where gastric pH was above 4 of 5.5% (95% administered before meals. In most individuals, confidence interval