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14-September-2008 18:02:40 - Proton pump inhibitor Proton pump inhibitors or PPIs are a group of drugs whose main action is pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available today. The group followed and has largely superseded another group of pharmaceuticals with similar effects, but different mode-of-action, called H2-receptor antagonists. These drugs are among the most widely-selling drugs in the world as a result of their outstanding efficacy and safety.1 Structurally, the vast majority of these drugs are benzimidazole derivatives; however, promising new research indicates that imidazopyridine derivatives may be a more effective means of treatment.citation needed Contents 1 Clinical use 2 Mechanism of action 3 Pharmacokinetics 4 Examples of proton pump inhibitors 5 Adverse effects 6 References Clinical use These drugs are utilized in the treatment of many conditions such as: Dyspepsia Peptic ulcer disease PUD Gastroesophageal reflux disease GORD/GERD Laryngopharyngeal Reflux Disease Barrett's esophagus prevention of stress gastritis Gastrinomas and other conditions that cause hypersecretion of acid Zollinger-Ellison syndrome Despite their widespread use for these conditions, proton pump inhibitors' effectiveness has not been demonstrated in every case. For example, proton pump inhibitors do not change the length of Barrett's esophagus.2 Mechanism of action Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system the H+/K+ ATPase, or more commonly just gastric proton pump of the gastric parietal cell. The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion. Targeting the terminal-step in acid production, as well as the irreversible nature of the inhibition, result in a class of drugs that are significantly more effective than H2 antagonists and reduce gastric acid secretion by up to 99%. The lack of the acid in the stomach will aid in the healing of duodenal ulcers, and reduces the pain from indigestion and heartburn, which can be exacerbated by stomach acid. However, lack of stomach acid may also contribute to hypochlorhydria, a lack of sufficient hydrochloric acid, or HCl. Hydrochloric acid is required for absorption of nutrients, particularly calcium. The proton pump inhibitors are given in an inactive form. The inactive form is neutrally charged lipophilic and readily crosses cell membranes into intracellular compartments like the parietal cell canaliculus that have acidic environments. In an acid environment, the inactive drug is protonated and rearranges into its active form. As described above, the active form will covalently and irreversibly bind to the gastric proton pump, deactivating it. Pharmacokinetics Generally, the absorption of proton pump inhibitors is unaffected by co-administration with food. The rate of omeprazole absorption, however, is decreased by concomitant food intake. Additionally, the absorption of lansoprazole and esomeprazole is decreased and delayed by food. These pharmacokinetic effects, however, reportedly have no significant impact on efficacy.34 The elimination half-life of proton pump inhibitors ranges from 0.5-2 hours, however the effect of a single dose on acid secretion usually persists up to 2-3 days. This is because of accumulation of the drug in parietal cell canaliculi and the irreversible nature of proton pump inhibition. Examples of proton pump inhibitors The proton pump inhibitor Omeprazole. The proton pump inhibitor Omeprazole. Clinically used proton pump inhibitors: Omeprazole brand names: Losec, Prilosec, Zegerid, ocid Lansoprazole brand names: Prevacid, Zoton, Inhibitol Esomeprazole brand names: Nexium Pantoprazole brand names: Protonix, Somac, Pantoloc, Pantozol, Zurcal, Pan Rabeprazole brand names: Rabecid, Aciphex, Pariet, Rabeloc All five proton pump inhibitors have intravenous formulations. Adverse effects Proton pump inhibitors are generally well tolerated, and the incidence of short-term adverse effects is relatively uncommon. The range and occurrence of adverse effects are similar for all of the proton pump inhibitors, though they have been reported more frequently with omeprazole. This may be due to its longer availability and hence clinical experience. Common adverse effects include: headache, nausea, diarrhea, abdominal pain, fatigue, dizziness.5 Infrequent adverse effects include: rash, itch, flatulence, constipation. Decreased cyanocobalamin vitamin B12 absorption may occur with long-term use.5 Rarely PPI cause 'idiosyncratic' reactions such as erythema multiforme, pancreatitis, Stevens Johnson syndrome and acute interstitial nephritis. 6 It has been observed that gastric acid suppression, using H2-receptor antagonists and proton pump inhibitors, is associated with an increased risk of community-acquired pneumonia. It is suspected that acid suppression results in insufficient elimination of pathogenic organisms. It has therefore been suggested that patients at higher risk of pneumonia should only be prescribed proton pump inhibitors at lower doses and only when necessary. 7 PPIs have also been shown to raise risk of Clostridium difficile infection.8 Long-term use of proton pump inhibitors has been less studied. But in a study of 135,000 people 50 or older, those taking high doses of PPIs for longer than one year have been found to be 2.6 times more likely to break a hip. Those taking smaller doses for 1 to 4 years were 1.2 to 1.6 times more likely to break a hip. The risk of a fracture increased with the length of time taking PPIs.9 Theories as to the cause of the increase are the possibility that the reduction of stomach acid reduces the amount of calcium dissolved in the stomach or that PPIs may interfere with the breakdown and rebuilding of bone by interfering with the acid production of osteoclasts.10 References ^ Follow The Pill: Understanding the U.S. Commercial Pharmaceutical Supply Chain, The Kaiser Family Foundation March 2005. Retrieved on 2008-02-29. ^ Cooper BT, Chapman W, Neumann CS, Gearty JC 2006. Continuous treatment of Barrett's oesophagus patients with proton pump inhibitors up to 13 years: observations on regression and cancer incidence. Aliment. Pharmacol. Ther. 23 6: 727-33. doi:10.1111/j.1365-2036.2006.02825.x. PMID 16556174. ^ AstraZeneca Pty Ltd. Nexium Australian approved prescribing information. North Ryde: AstraZeneca; 2005. ^ Wyeth Australia Pty Ltd. Zoton Australian approved prescribing information. Baulkham Hills: Wyeth; 2004. ^ a b Rossi S, or. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3 ^ Simpson IJ et all. NEPHROLOGY 2006;11, 381-385 ^ Laheij RJF, Sturkenboom MCJM, Hassing R-J, Dieleman J, Stricker BHC, Jansen JBMJ. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA 2004;29216: 1955-60. PMID 15507580 ^ Branswell, Helen September 25, 2006. McGill researchers say re-analysis confirms antacids raise risk of C. difficile. CBC News. Retrieved on January 15, 2007. ^ Yang, YX; Lewis JD, Epstein S, Metz DC Dec 27 2006. Long-term proton pump inhibitor therapy and risk of hip fracture. Journal of the American Medical Association 296 24: 2947-53. doi:10.1001/jama.296.24.2947. PMID 17190895. ^ Seppa, Nathan January 7 2007. Bad to the Bone: Acid stoppers appear to have a downside. Science News 171 1: 3. v d e Major drug groups Gastrointestinal tract/metabolism A stomach acid Antacids, H2 antagonists, Proton pump inhibitors Antiemetics Laxatives Antidiarrhoeals/Antipropulsives Anti-obesity drugs Anti-diabetics Vitamins Dietary minerals Blood and blood forming organs B Antithrombotics Anticoagulants, Antiplatelets, Thrombolytics Antihemorrhagics Cardiovascular system C cardiac therapy/antianginals Cardiac glycosides, Antiarrhythmics, Cardiac stimulant Antihypertensives Diuretics Vasodilators Beta blockers renin-angiotensin system ACE inhibitors, Angiotensin II receptor antagonists, Renin inhibitors Antihyperlipidemics Skin D Emollients Cicatrizant Antipruritics Reproductive system G Hormonal contraception Fertility agents SERMs Sex hormones Endocrine system H Corticosteroids Sex hormones Thyroid hormones Antithyroid agent Infections and infestations J, P Antibiotics Antivirals Vaccines Antifungals Antiparasitic Antiprotozoals, Anthelmintics Malignant and immune disease L Anticancer agents Immunostimulators Immunosuppressants Muscles, bones, and joints M Anabolic steroids Anti-inflammatories NSAID Antirheumatics Corticosteroids Muscle relaxants Brain and nervous system N Anesthetics General, Local Analgesics Anticonvulsants Mood stabilizers Psycholeptic Anxiolytics, Antipsychotics, Hypnotics/Sedatives Psychoanaleptic Antidepressants, Stimulants/Psychostimulants Respiratory system R Bronchodilators Decongestants H1 antagonists Other ATC V Antidotes Contrast media Radiopharmaceuticals Dressing v d e Drugs for acid related disorders: Drugs for peptic ulcer and GERD/GORD A02B H2 antagonists Cimetidine, Famotidine, Lafutidine, Niperotidine, Nizatidine, Ranitidine, Roxatidine Prostaglandins/analogues Misoprostol, Enprostil Proton pump inhibitors Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole, Tenatoprazole Other Carbenoxolone, Cetraxate, Gefarnate, Pirenzepine, Sucralfate, Teprenone, Troxipide Retrieved from http://en..org/wiki/Proton_pump_inhibitor Categories: Proton pump inhibitors | GastroenterologyHidden categories: All articles with statements | Articles with statements since June 2008 Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Türkçe العربية Deutsch Español Français Italiano Nederlands 日本語 Polski Português РуÑ?Ñ?кий SlovenÄ?ina Svenska ไทย Türkçe УкраїнÑ?ька This page was last modified on 10 September 2008, at 15:19
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