Year : 2016 | Volume
: 14 | Issue : 1 | Page : 8--10
Modified PPIs (a search for the better)
Department of Internal Medicine and Gastroenterology, Al-Azhar University, Cairo, Egypt
Department of Internal Medicine and Gastroenterology, Al-Azhar University, Cairo
'Modified PPIs' is the term given to proton pump inhibitors (PPIs) introduced after the four conventional PPIs – omeprazole, lansoprazole, pantoprazole, and rabeprazole – all of which have similar actions and limitations and are produced by similar technologies. Modified PPIs include isomeric PPIs, dual delayed release PPIs, immediate release PPIs, and long half-life PPIs, which are manufactured by different technologies to overcome certain limitations of conventional PPIs. This modified category includes esomeprazole (Nexium), dexlansoprazol (Dexilent), omeprazole-sodium bicarbonate mixture (Zegred), and S.tenatoprazole. Although some of 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.
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Abdel-Hamid H. Modified PPIs (a search for the better).Al-Azhar Assiut Med J 2016;14:8-10
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Abdel-Hamid H. Modified PPIs (a search for the better). Al-Azhar Assiut Med J [serial online] 2016 [cited 2020 Oct 25 ];14:8-10
Available from: http://www.azmj.eg.net/text.asp?2016/14/1/8/180455
Advantages of Conventional PPIs
Conventional PPIs have a potent antisecretory effect that is 10 times more potent than H2RAs and have thus narrowed the clinical scope of both antacids and H2RAs to a great extent. In addition, they have demonstrated excellent safety in both short and long term and do not exhibit the phenomenon of tachyphylaxis commonly shown by H2RAs after administration for several weeks .
Limitations of Conventional PPIs
PPIs are prodrugs that are inactive in vitro. They are activated in vivo inside parietal cells by stimulated gastric acid through a process of 'hydrogenation' or 'protonation'. The best natural stimulus to gastric acid secretion is a 'meal'. For this reason, a PPI should be given at least 1 h before a meal, preferably breakfast. If taken with disregard to meals, it remains inactive in vivo. This strict relation to food requires a high degree of patient compliance, which I consider the biggest drawback of PPIs as a class, as it requires strict adherence to the timing of drug and food intake. Therefore, the discovery of a new PPI that can be taken with disregard to meals will be big achievement .
Other important limitations are the delayed onset of 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 taken for the drug to be absorbed into the duodenum and activated after absorption in the parietal cells. For this reason, PPIs are not effective for immediate relief from heartburn. If the patient is scheduled to be put on a course of PPI therapy, the peak effect is delayed for 4–5 days because only 20–25% of the proton pump population is irreversibly inhibited by a PPI per day, which means that complete inhibition of the proton pump is delayed for 4–5 days. Therefore, we should not judge the efficacy of PPIs within the first few days in both clinical trials and clinical practice .
The fact that the duration of action of PPIs does not cover the whole 24 h is another limitation, causing a weak nocturnal effect and inefficiency against nocturnal acid break-through. Prolongation of the PPI effect shall definitely be a step forward .
A noticeable limitation of PPIs is the rebound acid hypersection after sudden cessation of the drug due to accumulated hypergastrinemia during the whole period of therapy. This phenomenon is the cause of PPI dependence or 'addiction' .
The rebound hypersection, however, is not a serious limitation as it can be avoided by a gradual decrease in PPI dose before complete stoppage (decreasing a 40 to 20 mg dose) or by switching to H2RAs for some weeks before complete withdrawal .
An important limitation of PPIs is their short plasma half-lives that range from 30 to 90 min. This is an index of the time the drug remains in the circulation and is unrelated to the duration of action of PPIs, which depends on irreversible inhibition of the proton pumps .
A short plasma half-life means a weak nocturnal effect and inadequate control of the nocturnal acid break-through, because by the time a nocturnal acid attack occurs, usually after several hours, the drug has already left the circulation. Surprisingly the H2RAs that are weaker antisecretory agents are more effective in control of acid nocturnal break-through because of their long half-lives (8–12 h) .
So far this term includes four distinct groups: isomeric PPIs, delayed dual release PPI, immediate release PPIs, and long half-life PPIs .
All of the conventional PPIs and all drugs until recently were racemic compounds, meaning that they consist of two isomers that are chemically identical but differ in the arrangements of their ions within the molecules in a way that makes them mirror images. The two isomers occur in equimolar amounts in racemic compounds. They have identical chemical reactions in vitro but different 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 isomer, called the 'favorable isomer', and do not accept its twin isomer, which is called the 'unfavorable isomer. The favorable isomer can be S or R according to the compound. The unfavorable isomer may remain inert, decrease the potency of the favorable isomer, or produce side effects that may be serious. Drug isomers became a focus of attention because of the congenital mutilations seen in newborns that swept Europe in the 1960s due to the wide intake of thalidomide as an antiemetic during pregnancy. Later when the unfavorable isomer was isolated by isomeric technology, thalidomide became safe and is still in use .
In 1992 and 1993 both the FDA and European Union issued two separate nonobligatory recommendations for pharmaceutical companies to produce all their products in the future in the form of favorable isomers and not as racemic compounds to increase potency and lessen the side effect. The first PPI to be isomerized is omeprazole from Astra under the name of Nexium (osemeprazole or S-omeprazole) .
Delayed dual release PPIs
The term 'delayed dual release' is related to the manufacturing technology of this category .
It may also be referred to as MR technology. The category is manufactured in the form of capsules containing two sets of enteric-coated granules or pillets. One set is released and absorbed into the duodenum, similar to all conventional PPIs. The other set is designed to be released and absorbed into the jejunum more distally. It follows that the double absorption sites lead to double plasma peaks. The PPI action is thus prolonged to cover 24 h and gives better nocturnal effect. Furthermore, 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 by the gastric acid, but because the capsule contains a double dose of PPI (30/60 mg instead of 15/30 mg lansoprazole) and because no more than 20–25% of proton pumps are blocked per day, a good amount of PPI shall remain active in the parietal cells to react with the following doses irrespective of meals. This phenomenon is known as 'residence time in the parietal cells' and is unrelated to the plasma half-life .
Lansoprazole was the second conventional PPI to be isomerized and the first to be manufactured following the delayed dual release technology. The modified lansoprazole is known as dexlansoprazol or R-lansoprazole (Dexilent) .
Immediate release PPI
Immediate release refers to rapid release of the capsule contents in the stomach rather than in the duodenum as with conventional PPIs because the capsule is nonenteric and cannot resist the acid. The capsule contains a mixture of 20–40 mg omeprazole powder plus 1100 mg sodium bicarbonate powder, and thus when it opens both contents are released free into the gastric lumen. If not for the sodium bicarbonate, the released omeprazole would be completely destroyed by the gastric acid as its powder is nonenteric coated. The bicarbonate raises the pH of the stomach and creates a chemical umbrella that protects the omeprazole powder and allows it to pass safely to the duodenum where it is absorbed. The chemical umbrella thus produced is more productive than the mechanical umbrella in the enteric-coated pellets, and it increases absorption because a larger amount of omeprazole reaches the duodenum. This simple manufacturing technology increases the bioavailability of omeprazole. In addition, the presence of sodium bicarbonate powder in the stomach immediately counteracts acid-related symptoms such as heartburn. However, this preparation should be used with caution in cases of heart disease and generalized edema because of its sodium content. This product is termed ome/Na bicarb PPI mixture (Zegred) .
PPIs with a long half-life
Prolongation of the plasma half-life of PPIs is achieved only by changing the PPI molecule because the plasma half-life of any product is an innate character of its molecule. This technology was adopted in the production of a Japanese PPI, S.tenatoprazole, which has a plasma half-life of 7–8 h, which is seven to eight times that of conventional PPIs. Thus, a product like S.tenatoprazole could have a longer duration of action and better nocturnal effect than conventional PPIs. This has been achieved by substation of the benzimidazole nucleus by an imidazopyridine nucleus. The drug is used in Japan, China, and East Asia but is still under study in western counties .
Some of the new PPIs have achieved significant success in overcoming some of the limitations of conventional PPIs, but we still lack a single PPI that can overcome all of the limitations mentioned above and hence we still lack the ideal PPI, although the present PPIs are potent and safe.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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