Esomeprazole

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Esomeprazole
Esomeprazole2DACS.svg
Systematic (IUPAC) name
(S)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)
methylsulfinyl]-3H-benzoimidazole
Clinical data
Trade names Nexium
AHFS/Drugs.com monograph
MedlinePlus a699054
Licence data US FDA:link
Pregnancy cat. B3 (AU) B (US)
Legal status Prescription Only (S4) (AU) POM (UK) OTC (US)
Routes Oral, IV
Pharmacokinetic data
Bioavailability 50 to 90%
Metabolism Hepatic (CYP2C19, CYP3A4)
Half-life 1–1.5 hours
Excretion 80% Renal
20% Faecal
Identifiers
CAS number 119141-88-7 N
ATC code A02BC05
PubChem CID 9579578
DrugBank DB00736
ChemSpider 7843323 N
UNII N3PA6559FT YesY
KEGG D07917 YesY
ChEBI CHEBI:50275 YesY
ChEMBL CHEMBL1201320 N
Chemical data
Formula C17H19N3O3S 
Mol. mass 345.417 g/mol
 N (what is this?)  (verify)

Esomeprazole /sɵˈmɛprəzl/ is a proton pump inhibitor (brand name Nexium, Essocam, Esomezol) which reduces acid secretion through inhibition of the H+ / K+ ATPase in gastric parietal cells. By inhibiting the functioning of this transporter, the drug prevents formation of gastric acid.

It is used in the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease, and Zollinger-Ellison syndrome.

Esomeprazole is the S-enantiomer of omeprazole (brand name Prilosec/Losec). A generic version of esomeprazole strontium is available in the United States. Generic versions of esomeprazole magnesium are available in several countries of Europe and in emerging markets such as Pakistan, India, Peru, Ecuador, Caribbean Islands, Nigeria, Africa, Sri Lanka, Cambodia, and Myanmar under the brand name Raciper. In Bangladesh, esomeprazole is sold under the brand name Opton by Beximco Pharma, Neptor by Sandoz Bangladesh. In South Africa, it is available generically, as Nexmezol.[1] It is available over-the-counter under the brand name Nexium in the United States.[2]

Medical use[edit]

The primary uses of esomeprazole are gastroesophageal reflux disease, treatment and maintenance of erosive esophagitis, treatment of duodenal ulcers caused by H. pylori, prevention of gastric ulcers in those on chronic NSAID therapy, and treatment of gastrointestinal ulcers associated with Crohn's disease.[3][4]

Gastroesophageal reflux disease[edit]

Gastroesophageal reflux disease (GERD) is a condition in which the digestive acid in the stomach comes in contact with the esophagus. The irritation caused by this disorder is known as heartburn. Long-term contact between gastric acids and the esophagus can cause permanent damage to the esophagus. Esomeprazole reduces the production of digestive acids, thus minimizing their effect on the esophagus.

Duodenal ulcers[edit]

Esomeprazole 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.

Efficacy[edit]

A 2006 meta analysis concluded that compared to other proton pump inhibitors, esomeprazole confers a statistically significant but clinically modest overall benefit in esophageal healing and symptom relief. When broken down by disease severity, the benefit of esomeprazole relative to other proton pump inhibitors was negligible in patients with mild disease (number needed to treat 50), but appeared more substantial in those with severe disease (number needed to treat 8).[5] A second meta analysis also found a relatively modest benefit in broadly selected patient populations.[6]

Adverse effects[edit]

Common side effects include headache, diarrhea, nausea, flatulence, decreased appetite, constipation, dry mouth, and abdominal pain. More severe side effects are severe allergic reactions, chest pain, dark urine, fast heartbeat, fever, paresthesia, persistent sore throat, severe stomach pain, unusual bruising or bleeding, unusual tiredness, and yellowing of the eyes or skin.[7]

Proton pump inhibitors may be associated with a greater risk of hip fractures[8] and Clostridium difficile-associated diarrhea.[9] By suppressing acid-mediated breakdown of proteins, antacid preparations such as esomeprazole lead to an elevated risk of developing food and drug allergies. This happens due to undigested proteins then passing into the gastrointestinal tract where sensitisation occurs. It is unclear whether this risk occurs with only long-term use or with short-term use, as well.[10] 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.[11]

Interactions[edit]

Esomeprazole 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 and warfarin; the concentrations of these drugs may increase if they are used concomitantly with esomeprazole.[12] Conversely, 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.[13][14]

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.[12]

Pharmacokinetics[edit]

Single 20– o 40-mg oral doses generally give rise to peak plasma esomeprazole concentrations of 0.5-1.0 mg/l within 1–4 hours, but after several days of once-daily administration, these levels may increase by about 50%. A 30-minute intravenous infusion of a similar dose usually produces peak plasma levels on the order of 1–3 mg/l. The drug is rapidly cleared from the body, largely by urinary excretion of pharmacologically inactive metabolites such as 5-hydroxymethylesomeprazole and 5-carboxyesomeprazole. Esomeprazole and its metabolites are analytically indistinguishable from omeprazole and the corresponding omeprazole metabolites unless chiral techniques are employed.[15]

Dosage forms[edit]

Esomeprazole strontium delayed-release capsules, 49.3 mg
Some 40-mg Nexium brand esomeprazole magnesium capsules

Esomeprazole is available as delayed-release capsules in the United States or as delayed-release tablets in Australia, the United Kingdom, and Canada (containing esomeprazole magnesium) in strengths of 20 and 40 mg, as delayed-release capsules in the United States (containing esomeprazole strontium) in a 49.3 mg strength (delivering the equivalent of 40 mg of esomeprazole[16]), and as esomeprazole sodium for intravenous injection/infusion. Oral esomeprazole preparations are enteric-coated, due to the rapid degradation of the drug in the acidic conditions of the stomach. This is achieved by formulating capsules using the multiple-unit pellet system.

Multiple-unit pellet system[edit]

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

Production and manufacture[edit]

The granules are manufactured in a fluid bed system with small sugar spheres as the starting material. The sugar spheres are sequentially spray-coated with a suspension containing esomeprazole, a protective layer to prevent degradation of the drug in manufacturing, an enteric coating, and an outer layer to reduce granule aggregation. The granules are mixed with other inactive excipients and compressed into tablets. Finally, the tablets are film-coated to improve the stability and appearance of the preparation.

Global distribution[edit]

In late 2010, AstraZeneca announced a co-promotion agreement with Daiichi Sankyo to distribute Nexium in Japan.[17] In September 2011, Nexium was approved for sale and was launched by Daiichi Sankyo in Japan.[18] Nexium is also sold online with a prescription via Nexium direct.

Economics[edit]

Between the launch of esomeprazole in 2001 and 2005, the drug has netted AstraZeneca about $14.4 billion.[19]

Controversy[edit]

There has been some controversy about AstraZeneca's behaviour in creating, patenting, and marketing of the drug. Esomeprazole's successful predecessor, omeprazole, is a mixture of two mirror-imaged molecules (esomeprazole which is the S-enantiomer, and R-omeprazole); critics said the company was trying to "evergreen" its omeprazole patent by patenting the pure esomeprazole and aggressively marketing to doctors that it is more effective than the mixture,[20]

Thomas A. Scully, head of the Centers for Medicare and Medicaid Services, also criticized AstraZeneca for their aggressive marketing of Nexium. At a conference of the American Medical Association, he said that Astra was using the new drug to overcharge consumers and insurance companies. "You should be embarrassed if you prescribe Nexium",[21] he said, "because you're screwing your patients and you're screwing the taxpayers."[22]

References[edit]

  1. ^ "Sandoz launches Nexmezol, treatment for digestive disorders, in South Africa". 
  2. ^ "Nonprescription Nexium Heartburn Medicine Launches". ABC News. May 27, 2014. 
  3. ^ "Esomeprazole Magnesium". The American Society of Health-System Pharmacists. Retrieved 3 April 2011. 
  4. ^ Li J, Zhao J, Hamer-Maansson JE, Andersson T, Fulmer R, Illueca M, Lundborg P (March 2006). "Pharmacokinetic properties of esomeprazole in adolescent patients aged 12 to 17 years with symptoms of gastroesophageal reflux disease: A randomized, open-label study". Clinical Therapeutics 28 (3): 419–427. doi:10.1016/j.clinthera.2006.03.010. PMID 16750456. 
  5. ^ Gralnek IM, Dulai GS, Fennerty MB, Spiegel BM (December 2006). "Esomeprazole versus other proton pump inhibitors in erosive esophagitis: a meta-analysis of randomized clinical trials". Clin. Gastroenterol. Hepatol. 4 (12): 1452–8. doi:10.1016/j.cgh.2006.09.013. PMID 17162239. 
  6. ^ Edwards SJ, Lind T, Lundell L (September 2006). "Systematic review: proton pump inhibitors (PPIs) for the healing of reflux oesophagitis - a comparison of esomeprazole with other PPIs". Aliment. Pharmacol. Ther. 24 (5): 743–50. doi:10.1111/j.1365-2036.2006.03074.x. PMID 16918878. 
  7. ^ "Nexium side effects". Drug information online. Drugs.com. Retrieved 2009-06-23. 
  8. ^ 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. 
  9. ^ "Proton pump inhibitors and Clostridium difficile". Bandolier. 2003. Retrieved 2007-07-13. 
  10. ^ Pali-Schöll I, Jensen-Jarolim E (April 2011). "Anti-acid medication as a risk factor for food allergy". Allergy 66 (4): 469–77. doi:10.1111/j.1398-9995.2010.02511.x. PMID 21121928. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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. PMC 2659824. PMID 19332744. 
  14. ^ 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. 
  15. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 388-389.
  16. ^ http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=61a5a84e-0194-4f11-91f8-83d7ac404932
  17. ^ Press Release: AstraZeneca announces co-promotion agreement with Daiichi Sankyo for NEXIUM in Japan [1]
  18. ^ Press Release: Daiichi Sankyo and AstraZeneca Launch NEXIUM(R) 10mg and 20mg Capsules in Japan [2]
  19. ^ Financial impact information: 2005, $4.6 billion; 2004, $3.9 billion; 2003, $3.3 billion; 2002, $2 billion; 2001, launch and $580 million.
  20. ^ Gladwell, Malcolm (2004-10-25). "High Prices: How to think about prescription drugs". The New Yorker. Retrieved 2006-06-23. 
  21. ^ Harris, G (2003-08-20). "Heartburn Drug Battle Likely". The New York Times. Retrieved 2012-10-25. 
  22. ^ "Esomeprazole (Nexium) - What is Esomeprazole?". News-Medical.Net. Retrieved 2012-10-25. 

External links[edit]