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Proton Pump Inhibitors in Veterinary Medicine

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Proton Pump Inhibitors in Veterinary Medicine American Journal of Animal and Veterinary Sciences Review Proton Pump Inhibitors in Veterinary Medicine 1Oguzhan Yavuz and 2Handan Hilal Arslan 1Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Ondokuz Mayis University, Samsun, Turkey 2Department of Internal Medicine, Faculty of Veterinary Medicine, Ondokuz Mayis University, Samsun, Turkey Article history Abstract: Inhibition of gastric acid secretion is necessary to treat many Received: 01-04-2017 gastrointestinal diseases. Proton Pump Inhibitors (PPIs) are very effective Revised: 02-06-2017 drugs, used for gastric acid inhibition and therapy of important erosive and Accepted: 23-06-2017 non-erosive gastrointestinal disorders in animals as well as humans. In this review, general properties of PPIs, their mode of action, pharmacokinetics, Corresponding Author: OguzhanYavuz efficacy, adverse effects, drug interactions and clinical and alternative uses Department of Pharmacology in veterinary medicine were evaluated. and Toxicology, Faculty of Veterinary Medicine, Keywords: Gastrointestinal Disorders, Proton Pump Inhibitors, Veterinary OndokuzMayis University, Medicine Samsun, Turkey Tel: 00903623121919/2830 Fax: 00903624576922 E-mail: [email protected] Introduction All clinically used PPIs contain a pyridyl methylsulfinyl benzimidazole group and differ only type Gastric acid is the secretion of parietal cells of of substituents on the pyridine and benzimidazole rings stomach and it is controlled by paracrine, endocrine and + + (Kosma et al ., 2016). Some important physicochemical neuronal systems. An important enzyme, H /K ATPase, properties of PPIs are shown in Table 1. is the main actor to pump hydrogen ions into the + + stomach lumen (H /K proton pump) (Shin and Sachs, Mode of Action 2008; Hori et al ., 2011; Garcia-Mazcorro et al ., 2012). + + The Proton Pump Inhibitors (PPIs) provide an The gastric H /K ATPase is in the cytoplasmic irreversible inhibition of the gastric pump in parietal tubuler membranes of the parietal cells in the resting cells (Papich, 2009; Kosma et al ., 2016). state. After the activation of the parietal cells by a + + Thanks to this effect, PPIs are widely used for treatment stimulant (acetylcholine, histamine etc.), H /K of many erosive and non-erosive gastrointestinal ATPase appears to be in the microvilli of the disorders, such as peptic ulcers, Gastro-Oesophageal expanded secretory canalicus and an ATP-dependent Reflux Disease (GERD), Barrett’s oesophagus, Zollinger- hydrogen-potassium exchange and gastric acid Ellison syndrome, dyspepsia and Helicobacter pylori secretion occurs (Shin and Sachs, 2008). infection in humans and different animal species (Shin and PPIs are weak bases and potent acid suppressing Sachs, 2004; 2008; Papich, 2009). The pharmacological prodrugs. Due to their weak base features (pKa 1 values acid suppression in these diseases, especially in ulcers are between 3.8 and 4.9), they can accumulate in the and GERD, causes very important benefits, such as acidic environment of the secretory canalicus of the abolition of elective surgery and reduction in non-steroidal parietal cells. In this compartment, PPIs becomes active anti-inflammatory drugs-associated gastropaties after two protonation (pyridine and benzimidazole). (Scarpignato and Pelosini, 2006). Protonated drug split to sulfenic acid and sulfenamide The first registered PPI is omeprazole for humans in + + 1989. Afterwards, lansoprazole, rabeprazole, active forms. Sulfenamide covalent binds to H /K pantoprazole, esomeprazole and tenatoprazole were ATPase and the effect occurs (Shin et al ., 2006; Papich, released to the market. Clinical usage of PPIs 2009; Huttunen et al ., 2011). Conversion of omeprazole dramatically increased year by year in humans and to sulfenamide in the parietal cells and covalent animals (Papich, 2009; Ortiz de Garcia et al ., 2014; interaction of sulfenamide to H+/K+ ATPase are shown Kosma et al ., 2016). in Fig. 1. © 2017 Oguzhan Yavuz and Handan Hilal Arslan. This open access article is distributed under a Creative Commons Attribution (CC-BY) 3.0 license. Oguzhan Yavuz and Handan Hilal Arslan / American Journal of Animal and Veterinary Sciences 2017, 12 (3): 132.138 DOI: 10.3844/ajavsp.2017.132.138 Table 1. Important physical and chemical properties of PPIs PPI Structural formula Molecular formula Molecular weight Melting point (°C) Omeprazole C17 H19 N3O3S 345.42 156.2-157.2 Lansoprazole C16 H14 F3N3O2S 369.36 178-182 Rabeprazole C18 H21 N3O3S 359.44 99-100 Pantoprazole C16 H15 F2N3O4S 383.37 139-140 Esomeprazole C17 H19 N3O3S 345.42 155 Tenatoprazole C16 H18 N4O3S 346.40 178-180 Table 2. Clinical use of PPIs in veterinary medicine Gastrointestinal disorder PPI Animal species Treatment −1 Gastric ulcers Omeprazole Dog 0.5-1 mg/kg/day PO (total 20 mg ) −1 Cat 0.5-1.5 mg kg once or twice a day Horse 4 mg/kg/day PO for treatment (4 weeks) 2 mg/kg/day PO for prevention −1 Swine 40 mg total Pantoprazole Dog/Cat 0.5-1 mg/kg/day IV Acute gastritis Omeprazole Dog/Cat 0.7-2 mg/kg/day PO Pantoprazole Dog/Cat 1 mg/kg/day IV Helicobacter pylori Omeprazole Dog 0.66 mg/kg/day (combination with amoxicillin or tetracycline, metronidazole and bismuth subsalicylate) for 2-3 weeks −1 Abomasal ulcers Omeprazole Ruminants 2 mg kg IV −1 Milk-fed calves 4 mg kg PO Pharmacokinetics excretion half-life is about 50 min in humans and 30 min in dogs. (Kaya, 2007; Wallacei and Sharkey, After the oral administration, PPIs are rapidly and 2011; Kosugi et al ., 2015). highly absorbed in the small bowel. Approximately PPIs are rapidly and broadly metabolized by 70% of omeprazole is absorbed from the hepatic cytochromes (CYPs). Especially, CYP2C19 gastrointestinal system. An acidic pH in the parietal cells is required for activation of PPIs and food and CYP3A4 have important roles in the stimulates acid production. Therefore, PPIs should be biotransformation of PPIs. Several metabolites were administered about 30 min before meals and feeding. determined for each PPI, for example at least six PPIs are highly protein bound drugs. Omeprazole metabolites of omeprazole were identified. The main extremely (95%) binds to plasma proteins, α 1-acid excretion route is urine; however they are also glycoprotein and albumin. It reaches plasma peak eliminated by excretion in the bile (Kaya, 2007; concentration within 30-120 min in humans. Volume Wallacei and Sharkey, 2011; Zullo et al ., 2012; −1 of distribution values 0.3 L kg in humans and Kosma et al ., 2016). 133 Oguzhan Yavuz and Handan Hilal Arslan / American Journal of Animal and Veterinary Sciences 2017, 12 (3): 132.138 DOI: 10.3844/ajavsp.2017.132.138 Fig. 1. Conversion of omeprazole to sulfenamide in the parietal cells and covalent interaction of sulfenamide in the proton pump (Huttunen et al ., 2011) + + Efficacy secretion and H , K -ATPase activity returned with a + + half-life of only 15-20 h in rats and about 17 h in dogs. The H /K ATPase is the last stage of the gastric acid These values are about three times faster than the half- secretion. Therefore, PPIs are accepted as more effective life of the α-subunit of the pump (54 h in rats). The than receptor antagonists in suppressing gastric acid newly synthesis of the proton pump is generally greater secretion (Shin and Sachs, 2008; Papich, 2009). It was at night than day and PPIs are less effective during the reported that PPIs are 10-30 times potent acid night. Also, inhibition of the H +/K +-ATPase can be suppressing drugs than cimetidine. Therefore, PPIs are recovered either by new synthesis of the enzyme or evaluated as a superior alternative to H 2 receptor reduction of the disulfide bond between the PPI and the antagonists and other anti-secretory drugs for treatment protein (Shin et al ., 2006; Hori et al ., 2011). and prevention of ulcers caused by NSAIDs, some other There are some approaches to increase the plasma types of ulcers, esophagitis and H. pylori . Many studies half-life of the PPIs and improve the acid inhibition. One showed that there are no differences in efficacy among of them is replacement of the benzimidazole with PPIs (Kaya, 2007; Papich, 2009). However, some imidazopyridine for slowing metabolism and prolonging researchers reported that esomeprazole and tenatoprazole the half-life of PPIs. Tenatoprazole is a good example are more effective with a longer period for the acid for this path. It has an important advantage in suppression (Liu et al ., 2007; Shin and Sachs, 2008). suppressing of the pump during the night, however its The efficacy of PPIs depends on their covalent slow activation is a disadvantage for daytime acid binding to the pump and therefore their effect is longer suppression. Although this disadvantage, it has been than their plasma residence time above minimum reported that the anti-secretory and anti-ulcer effects of effective level, which is about 10-120 min. tenatoprazoleare 2-4 times more potent than omeprazole An important point for the activation of PPIs is that (Liu et al ., 2007; Shin and Sachs, 2008). the parietal cells of stomach have to secret the gastric Adverse Effects and Drug Interactions acid at the time of the administration. Therefore, PPIs cannot inhibit all gastric acid pumps with oral dosing, PPIs are relatively safe drugs and very few adverse because all pumps are not active during the 90-min half- effects were reported. Nausea, abdominal pain, life of many PPIs (except tenatoprazole, its half-life is 9 constipation, flatulence and diarrhea are common side h). Because of short half-life of PPIs only 70% of the effects in humans (1.5-3% of patients for omeprazole), but pump enzymes can be inhibited. Especially, due to all most of these effects are not observed in animals (Kaya, pumps are not activated by breakfast or other meals and 2007; Papich, 2009; Wallacei and Sharkey, 2011). the cumulative effect of PPIs, reaching steady state Säfholm et al .
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