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Omeprazole
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==Pharmacology== Omeprazole irreversibly blocks the enzyme system on parietal cells that is needed for the secretion of gastric acid. It is a specific H{{sup|+}}/K{{sup|+}}ATPase inhibitor. This is the enzyme needed for the final step in the secretion of gastric acid.<ref name=":0">{{cite journal | vauthors = Howden CW | title = Clinical pharmacology of omeprazole | journal = Clinical Pharmacokinetics | volume = 20 | issue = 1 | pages = 38β49 | date = January 1991 | pmid = 2029801 | doi = 10.2165/00003088-199120010-00003 | s2cid = 25855436 }}</ref> ===Pharmacokinetics=== The absorption of omeprazole takes place in the small intestine and is usually completed within 3 to 6 hours. The systemic [[bioavailability]] of omeprazole after repeated doses is about 60%.<ref>{{cite journal | vauthors = Cederberg C, Andersson T, SkΓ₯nberg I | title = Omeprazole: pharmacokinetics and metabolism in man | journal = Scandinavian Journal of Gastroenterology. Supplement | volume = 166 | issue = sup166 | pages = 33β40 | date = 1 January 1989 | pmid = 2690330 | doi = 10.3109/00365528909091241 }}</ref> Omeprazole has a volume of distribution of 0.4 L/kg. It has high plasma protein binding of 95%.<ref name="Omeprazole"/> <!-- Metabolism --> Omeprazole is completely metabolized by the [[cytochrome P450]] system, mainly in the liver, by [[CYP2C19]] and [[CYP3A4]] [[Isozyme|isoenzymes]].<ref name=Dav2015 /> Identified metabolites are the [[sulfone]], the [[sulfide]], and hydroxy-omeprazole. About 77% of an orally given dose is excreted as metabolites in the urine, and the remainder is found in the feces, primarily originating from bile secretion.<ref name=":1" /> Omeprazole has a half life of 0.5 to 1 hour.<ref name=":1">{{cite web |title=Omeprazole |url=https://www.drugbank.ca/drugs/DB00338 |website=www.drugbank.ca |access-date=29 January 2019 |archive-date=30 January 2019 |archive-url=https://web.archive.org/web/20190130053122/https://www.drugbank.ca/drugs/DB00338 |url-status=live }}</ref> ==== Bioactivation ==== As with all structually-similar benzimidazole [[proton pump inhibitor]]s, omeprazole is a [[prodrug]]. A basic molecule, it accumulates in the acidic [[canaliculus (parietal cell)|canaliculi]] of [[parietal cells]] in a protonated form where the S=O group becomes S-OH, which in turn is interconvertible with an achiral, reactive [[sulfonamide]] form. The sulfonamide form is able to attach onto the [[cysteine]] residue on the H<sup>+</sup>/K<sup>+</sup>-ATPase, thereby irreversibly inhibiting it.<ref name=Huttunen>{{cite journal | vauthors = Huttunen KM, Raunio H, Rautio J | title = Prodrugs--from serendipity to rational design | journal = Pharmacological Reviews | volume = 63 | issue = 3 | pages = 750β771 | date = September 2011 | pmid = 21737530 | doi = 10.1124/pr.110.003459 }}</ref> : [[File:Omeprazole Mechanism V1.svg|class=skin-invert-image|500px|Omeprazol rearrangement in the body]] This process is not affected by chirality, by AstraZeneca's own admission.<ref name="www1.astrazeneca-us.com">{{cite web | url = http://www1.astrazeneca-us.com/pi/Nexium.pdf | title = Nexium Prescribing Information | archive-url = https://web.archive.org/web/20091008000830/http://www1.astrazeneca-us.com/pi/Nexium.pdf | archive-date=8 October 2009 | publisher = AstraZeneca Pharmaceuticals }}</ref> ==== Chirality ==== The two different chiralities of omeprazole are both metabolized into inactive products by [[cytochrome P450]] enzymes, but each chirality are differently inactivated by specific isozymes. Compared to the (''R'')-enantiomer, the (''S'')-enantiomer is relatively more resistant to metabolism, especially metabolism by [[CYP2C19]]<ref>{{cite journal | vauthors = Roche VF | title = The chemically elegant proton pump inhibitors | journal = American Journal of Pharmaceutical Education | volume = 70 | issue = 5 | pages = 101 | date = October 2006 | pmid = 17149430 | doi = 10.5688/aj7005101 | pmc = 1637016 }}</ref> (if it's processed by CYP2C19 at all).<ref>{{cite journal | vauthors = Shiohira H, Yasui-Furukori N, Yamada S, Tateishi T, Akamine Y, Uno T | title = Hydroxylation of R(+)- and S(-)-omeprazole after racemic dosing are different among the CYP2C19 genotypes | journal = Pharmaceutical Research | volume = 29 | issue = 8 | pages = 2310β2316 | date = August 2012 | pmid = 22549736 | doi = 10.1007/s11095-012-0757-x }}</ref> As a result, among people with a more active version of CYP2C19 ("extensive metabolizers"), the (''R'') half of a dose of omeprazole is likely to perform more poorly. Conversely, among those with a less active version of CYP2C19 ("poor metabolizers"), more the (''R'') half is expected to survive metabolism and end up useful. The proportion of the poor metabolizer [[phenotype]] varies widely between populations, from 2.0 to 2.5% in African Americans and white Americans to >20% in Asians. Several [[pharmacogenomics]] studies have suggested that PPI treatment should be [[personalized medicine|tailored]] according to CYP2C19 metabolism status.<ref>{{cite journal | vauthors = Furuta T, Shirai N, Sugimoto M, Nakamura A, Hishida A, Ishizaki T | title = Influence of CYP2C19 pharmacogenetic polymorphism on proton pump inhibitor-based therapies | journal = Drug Metabolism and Pharmacokinetics | volume = 20 | issue = 3 | pages = 153β167 | date = June 2005 | pmid = 15988117 | doi = 10.2133/dmpk.20.153 | s2cid = 19090952 }}</ref> [[AstraZeneca]] also [[drug development|developed]] [[esomeprazole]] (Nexium) which is a [[eutomer]], purely the (''S'')-enantiomer, rather than a racemate like omeprazole.<ref name="www1.astrazeneca-us.com"/> ===Mechanism of action=== Omeprazole is a selective and irreversible proton pump inhibitor. It suppresses stomach acid secretion by specific inhibition of the H<sup>+</sup>/K<sup>+</sup>-ATPase system found at the secretory surface of gastric [[parietal cells]]. Because this enzyme system is regarded as the acid (proton, or H<sup>+</sup>) pump within the [[gastric mucosa]], omeprazole inhibits the final step of acid production.<ref name=":0" /> Omeprazole also inhibits both basal and stimulated acid secretion irrespective of the stimulus<ref name=":1" /> as it blocks the last step in acid secretion.<ref name=":1" /> The drug binds [[Non-competitive inhibition|non-competitively]] so it has a dose-dependent effect.<ref name="Omeprazole">{{cite journal | vauthors = Clissold SP, Campoli-Richards DM | title = Omeprazole. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in peptic ulcer disease and Zollinger-Ellison syndrome | journal = Drugs | volume = 32 | issue = 1 | pages = 15β47 | date = July 1986 | pmid = 3527658 | doi = 10.2165/00003495-198632010-00002 }}</ref> The inhibitory effect of omeprazole occurs within 1 hour after oral administration. The maximum effect occurs within 2 hours. The duration of inhibition is up to 72 hours. When omeprazole is stopped, baseline stomach acid secretory activity returns after 3 to 5 days. The inhibitory effect of omeprazole on acid secretion will plateau after 4 days of repeated daily dosing.<ref>{{cite web | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=bced816b-6927-49fb-851f-f83a678dac97#nlm34090-1 | title = Omeprazole package insert | archive-url = https://web.archive.org/web/20140419020303/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=bced816b-6927-49fb-851f-f83a678dac97 | archive-date=19 April 2014 | location = India | publisher = Dr. Reddy's Laboratories Limited | date = June 2013 }}</ref> Omeprazole, as well as other PPIs, are only effective on active H<sup>+</sup>/K<sup>+</sup>-ATPase pumps. These pumps are stimulated in the presence of food to aid in digestion. For this reason, patients should be advised to take omeprazole with a glass of water, before a meal.<ref>{{cite journal | vauthors = Katz PO, Gerson LB, Vela MF | title = Guidelines for the diagnosis and management of gastroesophageal reflux disease | journal = The American Journal of Gastroenterology | volume = 108 | issue = 3 | pages = 308β28; quiz 329 | date = March 2013 | pmid = 23419381 | doi = 10.1038/ajg.2012.444 | s2cid = 8198975 | doi-access = free }}</ref> Additionally, most sources recommend that after taking omeprazole, at least 30 minutes should be allowed to elapse before eating<ref>{{cite web|url=http://medical-dictionary.thefreedictionary.com/omeprazole|title=Omeprazole, in The Free Medical Dictionary|access-date=11 November 2010|archive-date=12 June 2011|archive-url=https://web.archive.org/web/20110612172513/http://medical-dictionary.thefreedictionary.com/omeprazole|url-status=live}}</ref><ref>{{cite web|url=https://www.drugs.com/monograph/omeprazole.html|title=Omeprazole|publisher=Drugs.com|access-date=11 November 2010|url-status=live|archive-url=https://web.archive.org/web/20110219135631/http://www.drugs.com/monograph/omeprazole.html|archive-date=19 February 2011}}</ref> (at least 60 minutes for immediate-release omeprazole plus sodium bicarbonate products, such as Zegerid).<ref name="Zegerid OTC FDA label" />
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