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Omeprazole
Systematic (IUPAC) name
(RS)-6-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl)-1H-benzo[d]imidazole
Identifiers
CAS number 73590-58-6
ATC code A02BC01
PubChem 4594
DrugBank APRD00446
ChemSpider 4433
Chemical data
Formula C17H19N3O3S 
Mol. mass 345.4 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 35–76%[1][2]
Metabolism Hepatic (CYP2C19, CYP3A4)
Half life 1 - 1.2 hours
Excretion 80% Renal
20% Faecal
Therapeutic considerations
Pregnancy cat. B3(AU) C(US)
Legal status Prescription Only (S4) (AU) POM (UK) OTC (US)
Routes Oral, IV
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Omeprazole (INN) (pronounced /oʊˈmɛprəzoʊl/) is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD/GERD) and Zollinger-Ellison syndrome. It was first marketed in the US in 1989 by AstraZeneca under the brand names Losec and Prilosec, and is now also available from generic manufacturers under various brand names. AstraZeneca markets omeprazole as Losec, Antra, Gastroloc, Mopral, Omepral, and Prilosec. Omeprazole is marketed as Zegerid by Santarus, Prilosec OTC by Procter & Gamble and Zegerid OTC by Schering-Plough.[3][4] In India it is available as OMEZ (FGP). Omeprazole is one of the most widely prescribed drugs internationally and is available over the counter in some countries. Prilosec contains the active ingredient omeprazole and Prilosec OTC contains the active ingredient omeprazole magnesium.

Contents

Pharmacology

Omeprazole is a racemate. It contains a tricoordinated sulfur atom in a pyramidal structure and therefore can exist in equal amounts of both the S and R enantiomers. In the acidic conditions of the stomach, both are converted to achiral products, which reacts with a cysteine group in H+/K+ ATPase, thereby inhibiting the ability of the parietal cells to produce gastric acid.

Omeprazol rearrangement in the body

Facing the loss of patent protection and competition from generic drug manufacturers, AstraZeneca developed and heavily marketed esomeprazole (Nexium) as a replacement in 2001. Esomeprazole is the S-enantiomer in the pure form.

According to AstraZeneca[5], omeprazole undergoes a chiral shift in vivo which converts the inactive R-enantiomer to the active S-enantiomer doubling the concentration of the active form. This chiral shift is accomplished by the CYP2C19 isozyme of cytochrome P450, which is not found equally in all human populations. Those who do not metabolize the drug effectively are called "poor metabolizers." The approximate proportion of the poor metabolizer phenotype in different populations is as follows:

  • Caucasians 10%
  • Asian 20%
  • South Pacific Islands 70%

In theory, by using pure esomeprazole the effect on the proton pump will be equal in all patients, eliminating the "poor metabolizer effect".[citation needed]

Name change

In 1990, at the request of the U.S. Food and Drug Administration (FDA), the brand name Losec was changed to Prilosec to avoid confusion with the diuretic Lasix (furosemide).[6] Unfortunately, the new name has led to confusion between omeprazole (Prilosec) and fluoxetine (Prozac), an antidepressant.[6] we ea

Clinical use

Use in Helicobacter pylori eradication

Omeprazole is combined with the antibiotics clarithromycin and amoxicillin (or metronidazole in penicillin-hypersensitive patients) in the 7-14 day eradication triple therapy for Helicobacter pylori. Infection by H. pylori is the causative factor in the majority of peptic and duodenal ulcers. [7]

Dosage forms

Package of Losec (Omeprazole) 20 mg, purchased in Hong Kong
Omeprazole 20 mg, From U.K.
Omeprazole 10 mg, From U.K.

Omeprazole is available as tablets and capsules (containing omeprazole or omeprazole magnesium) in strengths of 10 mg, 20 mg, 40 mg, and in some markets 80 mg; and as a powder (omeprazole sodium) for intravenous injection. Most oral omeprazole preparations are enteric-coated, due to the rapid degradation of the drug in the acidic conditions of the stomach. This is most commonly achieved by formulating enteric-coated granules within capsules, enteric-coated tablets, and the multiple-unit pellet system (MUPS).

It is also available for use in injectable form (I.V.) in Europe, but not in the U.S. The injection pack is a combination pack consisting of a vial and a separate ampule of reconstituting solution. Each 10 ml clear glass vial contains a white to off-white lyophilised powder consisting of omeprazole sodium 42.6 mg equivalent to 40 mg of omeprazole.

Multiple unit pellet system

Omeprazole tablets manufactured by AstraZeneca (notably Losec/Prilosec) are formulated as a "multiple unit pellet system" (MUPS). Essentially, the tablet consists of extremely small enteric-coated granules (pellets) of the omeprazole formulation inside an outer shell. When the tablet is immersed in an aqueous solution, as happens when the tablet reaches the stomach, water enters the tablet by osmosis. The contents swell from water absorption causing the shell to burst, releasing the enteric-coated granules. For most patients, the multiple-unit pellet system is of no advantage over conventional enteric-coated preparations. Patients for which the formulation is of benefit include those requiring nasogastric tube feeding and those with difficulty swallowing (dysphagia).[citation needed]

The granules are manufactured in a fluid air bed system. Sugar spheres in suspension are sequentially sprayed with aqueous suspensions of omeprazole, a protective layer, an enteric coating and an outer layer to reduce granule aggregation. The granules are mixed with other excipients and compressed into tablets. Finally, the tablets are film-coated to improve the stability and appearance of the preparation.

Immediate release formulation

In June 2004 the FDA approved an immediate release preparation of omeprazole and sodium bicarbonate that does not require an enteric coating. This preparation employs sodium bicarbonate as a buffer to protect omeprazole from gastric acid degradation. This allows for the production of chewable tablets. This combination preparation is marketed in the United States by Santarus under the brand name Zegerid. Zegerid is marketed as capsules, chewable tablets, and powder for oral suspension. Zegerid is most useful for those patients who suffer from nocturnal acid breakthrough (NAB) or those patients who desire immediate relief. In India it is marketed by Dr. Reddy's Laboratories as powder formulation with the brand name OMEZ-INSTA. It is reported to have additional benefits with patients suffering from alcoholic gastritis and life-style associated gastritis.[citation needed]

Side effects

Some of the most frequent side effects of omeprazole (experienced by over 1% of those taking the drug) are headache, diarrhea, abdominal pain, nausea, dizziness, trouble awakening and sleep deprivation, although in clinical trials the incidence of these effects with omeprazole was mostly comparable to that found with placebo.[8]

Proton pump inhibitors may be associated with a greater risk of hip fractures,[9][10][11] and clostridium difficile-associated diarrhea.[12] Patients are frequently administered the drugs in intensive care as a protective measure against ulcers, but this use is also associated with a 30% increase in occurrence of pneumonia.[13]

Other side effects may include bone rebuild interference and B12 vitamin reduction.[14]

Interactions

Omeprazole is a competitive inhibitor of the enzymes CYP2C19 and CYP2C9, and may therefore interact with drugs that depend on them for metabolism, such as diazepam, escitalopram, and warfarin; the concentrations of these drugs may increase if they are used concomitantly with omeprazole.[15] Clopidogrel (Plavix) is an inactive prodrug that partially depends on CYP2C19 for conversion to its active form; inhibition of CYP2C19 blocks the activation of clopidogrel, thus reducing its effects and potentially increasing the risk of stroke or heart attack in people taking clopidogrel to prevent these events.[16][17] Omeprazole is also a competitive inhibitor of p-glycoprotein, as are other PPIs.[18]

Drugs that depend on stomach pH for absorption may interact with omeprazole; drugs that depend on an acidic environment (such as ketoconazole or atazanavir) will be poorly absorbed, whereas drugs that are broken down in acidic environments (such as erythromycin) will be absorbed to a greater extent than normal.[15]

St. John's wort (Hypericum perforatum) and Gingko biloba significantly reduce plasma concentrations of omeprazole through induction of CYP3A4 and CYP2C19.[19]

Absorption and distribution

The absorption of omeprazole takes place in the small intestine and is usually completed within 3–6 hours. The systemic bioavailability of omeprazole after repeated dose is about 60%. Omeprazole bioavailability is significantly impaired by the presence of food and, therefore, patients should be advised to take omeprazole before eating. The capsule should be taken immediately before a meal. The MUPS tablet may be taken with or without food. The powder for oral suspension should be taken on an empty stomach at least 1 hour before a meal. [20] Plasma protein binding is about 95%.

Metabolism and excretion

Omeprazole is completely metabolized by the cytochrome P450 system, mainly in the liver. Identified metabolites are the sulfone, the sulfide and hydroxy-omeprazole, which exert no significant effect on the acid secretion. About 80% 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.

References

  1. ^ http://www1.astrazeneca-us.com/pi/Prilosec.pdf
  2. ^ http://www.medscape.com/viewarticle/508018
  3. ^ Santarus Receives FDA Approval for Immediate-Release Omeprazole Tablet with Dual Buffers
  4. ^ FDA Approves Zegerid OTC for Over-the-Counter Treatment of Frequent Heartburn
  5. ^ http://www1.astrazeneca-us.com/pi/Nexium.pdf
  6. ^ a b Farley D. Making It Easier to Read Prescriptions. FDA Consumer magazine. July-August 1995. URL: http://www.fda.gov/fdac/features/695_prescrip.html. Accessed on: June 11, 2006.
  7. ^ http://www.medicinenet.com/script/main/art.asp?articlekey=43451
  8. ^ "Prilosec Side Effects & Drug Interactions". RxList.com. 2007. http://www.rxlist.com/cgi/generic/omepra_ad.htm. Retrieved 2007-06-16. 
  9. ^ Yang YX, Lewis JD, Epstein S, Metz DC (2006). "Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture". JAMA 296 (24): 2947–53. doi:10.1001/jama.296.24.2947. PMID 17190895. 
  10. ^ "Antacids could lead to broken bones, study suggests". Canwest News Service. August 12, 2008. http://www.canada.com/topics/bodyandhealth/story.html?id=518c33ea-1b11-4fcd-bbba-98a1102370bb. Retrieved October 26, 2009. 
  11. ^ Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S, Leslie WD (August 12, 2008). "Use of proton pump inhibitors and risk of osteoporosis-related fractures". CMAJ 179 (4): 319–26. doi:10.1503/cmaj.071330. PMID 18695179. PMC 2492962. http://www.cmaj.ca/cgi/content/full/179/4/319. 
  12. ^ "Proton pump inhibitors and Clostridium difficile". Bandolier. 2003. http://www.medicine.ox.ac.uk/bandolier/booth/Pharmacy/PPIcdiff.html. Retrieved 2007-07-13. 
  13. ^ Shoshana J. Herzig, MD; Michael D. Howell, MD, MPH; Long H. Ngo, PhD; Edward R. Marcantonio, MD, SM (2009). "Acid-Suppressive Medication Use and the Risk for Hospital-Acquired Pneumonia=JAMA". JAMA the Journal of the American Medical Association 301 (20): 2120–2128. doi:10.1001/jama.2009.722. PMID 19470989. http://jama.ama-assn.org/cgi/content/abstract/301/20/2120?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=shoshana+herzig&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT. 
  14. ^ http://www.mahalo.com/omeprazole#Side_effects
  15. ^ a b Stedman CA, Barclay ML (August 2000). "Review article: comparison of the pharmacokinetics, acid suppression and efficacy of proton pump inhibitors". Aliment Pharmacol Ther 14 (8): 963–78. doi:10.1046/j.1365-2036.2000.00788.x. PMID 10930890. 
  16. ^ Lau WC, Gurbel PA (March 2009). "The drug-drug interaction between proton pump inhibitors and clopidogrel". CMAJ 180 (7): 699–700. doi:10.1503/cmaj.090251. PMID 19332744. 
  17. ^ Norgard NB, Mathews KD, Wall GC (July 2009). "Drug-drug interaction between clopidogrel and the proton pump inhibitors". Ann Pharmacother 43 (7): 1266–74. doi:10.1345/aph.1M051. PMID 19470853. 
  18. ^ Pauli-Magnus C, Rekersbrink S, Klotz U, Fromm MF (December 2001). "Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein". Naunyn Schmiedebergs Arch Pharmacol 364 (6): 551–7. doi:10.1007/s00210-001-0489-7. PMID 11770010. 
  19. ^ Izzo AA, Ernst E (2009). "Interactions between herbal medicines and prescribed drugs: an updated systematic review". Drugs 69 (13): 1777–98. doi:10.2165/11317010-000000000-00000. PMID 19719333. 
  20. ^ omeprazole essential drug information MIMS USA. URL http://www.mims.com/page.aspx?menuid=mng&name=omeprazole+ Accessed 20 Dec 2009

External links








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