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Modified Ppis (A Search for the Better) Hussein Abdel‑Hamid*

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Modified Ppis (A Search for the Better) Hussein Abdel‑Hamid* [Downloaded free from http://www.azmj.eg.net on Sunday, July 31, 2016, IP: 62.193.78.199] 8 Review article Modified PPIs (a search for the better) Hussein Abdel-Hamid* Department of Internal Medicine and ‘Modified PPIs’ is the term given to proton pump inhibitors (PPIs) introduced after the four Gastroenterology, Al-Azhar University, Cairo, conventional PPIs – omeprazole, lansoprazole, pantoprazole, and rabeprazole – all of which have Egypt similar actions and limitations and are produced by similar technologies. Modified PPIs include *Correspondence to Hussein Abdel-Hamid, isomeric PPIs, dual delayed release PPIs, immediate release PPIs, and long half-life PPIs, MD, Department of Internal Medicine and which are manufactured by different technologies to overcome certain limitations of conventional Gastroenterology, Al-Azhar University, Cairo, Egypt PPIs. This modified category includes esomeprazole (Nexium), dexlansoprazol (Dexilent), Tel: +002 01000076290 omeprazole-sodium bicarbonate mixture (Zegred), and S.tenatoprazole. Although some of e-mail: [email protected] these new products have better efficacy, longer duration of action, can be taken with disregard to meals, and have better nocturnal effect, we still lack the ideal PPI. Received 11 November 2015 Accepted 11 December 2015 Al Azhar Assiut Medical Journal Keywords : 2016, 14:8–10 conventional PPIs, ideal PPIs, modified PPIs Al Azhar Assiut Medical Journal 14:8-10 © 2016 Al Azhar Assiut Medical Journal 1687-1693 Advantages of conventional PPIs population is irreversibly inhibited by a PPI per day, which means that complete inhibition of the proton Conventional PPIs have a potent antisecretory effect pump is delayed for 4–5 days. Therefore, we should not that is 10 times more potent than H2RAs and have judge the efficacy of PPIs within the first few days in thus narrowed the clinical scope of both antacids both clinical trials and clinical practice [2]. and H2RAs to a great extent. In addition, they have demonstrated excellent safety in both short and The fact that the duration of action of PPIs does not long term and do not exhibit the phenomenon of cover the whole 24 h is another limitation, causing tachyphylaxis commonly shown by H2RAs after a weak nocturnal effect and inefficiency against administration for several weeks [1]. nocturnal acid break‑through. Prolongation of the PPI effect shall definitely be a step forward [3]. Limitations of conventional PPIs A noticeable limitation of PPIs is the rebound acid hypersection after sudden cessation of the drug due PPIs are prodrugs that are inactive in vitro. They are to accumulated hypergastrinemia during the whole activated in vivo inside parietal cells by stimulated period of therapy. This phenomenon is the cause of PPI gastric acid through a process of ‘hydrogenation’ or dependence or ‘addiction’ [3]. ‘protonation’. The best natural stimulus to gastric acid secretion is a ‘meal’. For this reason, a PPI should be The rebound hypersection, however, is not a serious given at least 1 h before a meal, preferably breakfast. limitation as it can be avoided by a gradual decrease in If taken with disregard to meals, it remains inactive PPI dose before complete stoppage (decreasing a 40 to in vivo. This strict relation to food requires a high 20 mg dose) or by switching to H2RAs for some weeks degree of patient compliance, which I consider the before complete withdrawal [4]. biggest drawback of PPIs as a class, as it requires strict adherence to the timing of drug and food intake. An important limitation of PPIs is their short plasma Therefore, the discovery of a new PPI that can be taken half‑lives that range from 30 to 90 min. This is an index with disregard to meals will be big achievement [2]. of the time the drug remains in the circulation and is unrelated to the duration of action of PPIs, which depends Other important limitations are the delayed onset of on irreversible inhibition of the proton pumps [5]. action and the delayed peak of action. A single dose of a PPI begins its effect 1–2 h after intake, which is the time A short plasma half‑life means a weak nocturnal taken for the drug to be absorbed into the duodenum effect and inadequate control of the nocturnal acid and activated after absorption in the parietal cells. For This is an open access article distributed under the terms of the Creative this reason, PPIs are not effective for immediate relief Commons Attribution‑NonCommercial‑ShareAlike 3.0 License, which allows from heartburn. If the patient is scheduled to be put others to remix, tweak, and build upon the work non‑commercially, as on a course of PPI therapy, the peak effect is delayed long as the author is credited and the new creations are licensed under for 4–5 days because only 20–25% of the proton pump the identical terms. © 2016 Al Azhar Assiut Medical Journal | Published by Wolters Kluwer - Medknow DOI: 10.4103/1687-1693.180455 [Downloaded free from http://www.azmj.eg.net on Sunday, July 31, 2016, IP: 62.193.78.199] Modified proton pump inhibitors Abdel-Hamid 9 break‑through, because by the time a nocturnal acid all conventional PPIs. The other set is designed to be attack occurs, usually after several hours, the drug has released and absorbed into the jejunum more distally. It already left the circulation. Surprisingly the H2RAs follows that the double absorption sites lead to double that are weaker antisecretory agents are more effective plasma peaks. The PPI action is thus prolonged to in control of acid nocturnal break‑through because of cover 24 h and gives better nocturnal effect. Furthermore, their long half‑lives (8–12 h) [6]. the PPI could be taken with disregard to meals, which I consider a major advancement for both compliant and noncompliant patients. Only the first dose has to be given 1 h before breakfast to be activated as usual Modified PPIs by the gastric acid, but because the capsule contains So far this term includes four distinct groups: isomeric a double dose of PPI (30/60 mg instead of 15/30 mg PPIs, delayed dual release PPI, immediate release PPIs, lansoprazole) and because no more than 20–25% of and long half‑life PPIs [7]. proton pumps are blocked per day, a good amount of PPI shall remain active in the parietal cells to react with the Isomeric PPIs following doses irrespective of meals. This phenomenon is known as ‘residence time in the parietal cells’ and is All of the conventional PPIs and all drugs until recently unrelated to the plasma half‑life [11]. were racemic compounds, meaning that they consist of two isomers that are chemically identical but differ in Lansoprazole was the second conventional PPI the arrangements of their ions within the molecules in to be isomerized and the first to be manufactured a way that makes them mirror images. The two isomers following the delayed dual release technology. The occur in equimolar amounts in racemic compounds. They modified lansoprazole is known as dexlansoprazol or have identical chemical reactions in vitro but different R‑lansoprazole (Dexilent) [12]. pharmacological reactions in vivo. They are referred to as ‘S’ and ‘R’ isomers. The difference is attributed to the fact that human cell receptors accept only one Immediate release PPI isomer, called the ‘favorable isomer’, and do not accept Immediate release refers to rapid release of the capsule its twin isomer, which is called the ‘unfavorable isomer. contents in the stomach rather than in the duodenum The favorable isomer can be S or R according to the as with conventional PPIs because the capsule is compound. The unfavorable isomer may remain inert, nonenteric and cannot resist the acid. The capsule decrease the potency of the favorable isomer, or produce contains a mixture of 20–40 mg omeprazole powder side effects that may be serious. Drug isomers became a plus 1100 mg sodium bicarbonate powder, and thus focus of attention because of the congenital mutilations when it opens both contents are released free into the seen in newborns that swept Europe in the 1960s due to gastric lumen. If not for the sodium bicarbonate, the the wide intake of thalidomide as an antiemetic during released omeprazole would be completely destroyed by pregnancy. Later when the unfavorable isomer was the gastric acid as its powder is nonenteric coated. The isolated by isomeric technology, thalidomide became bicarbonate raises the pH of the stomach and creates safe and is still in use [8]. a chemical umbrella that protects the omeprazole powder and allows it to pass safely to the duodenum In 1992 and 1993 both the FDA and European Union where it is absorbed. The chemical umbrella thus issued two separate nonobligatory recommendations produced is more productive than the mechanical for pharmaceutical companies to produce all their umbrella in the enteric‑coated pellets, and it increases products in the future in the form of favorable absorption because a larger amount of omeprazole isomers and not as racemic compounds to increase reaches the duodenum. This simple manufacturing potency and lessen the side effect. The first PPI to be technology increases the bioavailability of omeprazole. isomerized is omeprazole from Astra under the name In addition, the presence of sodium bicarbonate of Nexium (osemeprazole or S‑omeprazole) [9]. powder in the stomach immediately counteracts acid‑related symptoms such as heartburn. However, this preparation should be used with caution in cases Delayed dual release PPIs of heart disease and generalized edema because of its The term ‘delayed dual release’ is related to the sodium content. This product is termed ome/Na bicarb manufacturing technology of this category [10]. PPI mixture (Zegred) [13]. It may also be referred to as MR technology.
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