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Esomeprazole

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Esomeprazole
Clinical data
Trade namesNexium
AHFS/Drugs.comMonograph
MedlinePlusa699054
Pregnancy
category
  • AU: B3
Routes of
administration		Oral, IV
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability50 to 90%
MetabolismHepatic (CYP2C19, CYP3A4)
Elimination half-life1–1.5 hours
Excretion80% Renal
20% Faecal
Identifiers
  • (S)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)
    methylsulfinyl]-3H-benzoimidazole
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.149.048 Edit this at Wikidata
Chemical and physical data
FormulaC17H19N3O3S
Molar mass345.417 g/mol g·mol−1
3D model (JSmol)
  • COc1ccc2nc([nH]c2c1)S(=O)Cc1ncc(C)c(OC)c1C
  • InChI=1S/C17H19N3O3S/c1-10-8-18-15(11(2)16(10)23-4)9-24(21)17-19-13-6-5-12(22-3)7-14(13)20-17/h5-8H,9H2,1-4H3,(H,19,20)/t24-/m1/s1 checkY
  • Key:SUBDBMMJDZJVOS-XMMPIXPASA-N checkY
 ☒NcheckY (what is this?)  (verify)

Esomeprazole (/iːs[invalid input: 'ɵ']ˈmɛprəzoʊl/) is a proton pump inhibitor (brand name Nexium) developed and marketed in Sweden by AstraZeneca which is used in the treatment of dyspepsia, peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD/GERD) and Zollinger-Ellison syndrome. Esomeprazole is the S-enantiomer of omeprazole (brand name Prilosec/Losec) also developed and marketed by AstraZeneca, and AstraZeneca claims improved efficacy of this single enantiomer product over the racemic mixture of omeprazole. Generic version of Esomeprazole is available in many countries made by Ranbaxy Laboratories of India. Ranbaxy's generic version of Esomeprazole is sold in several countries of Europe and in emerging markets like India, Peru,Ecuador, Caribbean Islands, Nigeria, Africa, Srilanka, Cambodia and Myanmar under the brand name Raciper.

Esomeprazole is a proton pump inhibitor which reduces acid secretion through inhibition of ATPase in gastric parietal cells. By inhibiting the functioning of this enzyme, the drug prevents formation of gastric acid.

Medical use

The primary uses of esomeprazole are gastroesophageal reflux disease, treatment of duodenal ulcers caused by H. pylori, preventing of gastric ulcers in those on chronic NSAID therapy, and treatment of gastrointestinal ulcers associated with Crohn's disease.[1]

Gastroesophageal reflux disease

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

Duodenal ulcers

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.

Evidence of efficacy

AstraZeneca claims that esomeprazole provides improved efficacy, in terms of stomach acid control, over the R enantiomer of omeprazole. Many noted health professionals including Dr. Otis Brawley (author of "How We Do Harm: A Doctor Breaks Ranks About Being Sick In America", and currently (as of August 2012) both chief medical officer and executive vice president of the American Cancer Society) have expressed the view that this improvement in efficacy is due to the dose of esomeprazole recommended for therapy rather than any inherent superiority of esomeprazole. And in his 2003 address to the American Medical Association, Thomas Sully, then director of the Center for Medicare & Medicaid Services told his audience "You should be embarrassed if you prescribe Nexium because it increases costs with no medical benefits…. The fact is Nexium is Prilosec …it is the same drug. It is a mirror compound."

An alternative rationale suggested for the use of esomeprazole was the reduction in interindividual variability in efficacy. However the clinical advantage of this hypothesis has not thoroughly been tested in large-scale trials.[2]

Given the large difference in cost between all other proton pump inhibitors and that of omeprazole, many physicians recommend a trial of over-the-counter products before beginning more extensive therapies and testing.

Although the (S)-isomer is more potent in humans, the (R)-isomer is more potent in the testing of rats, while the enantiomers are equipotent in dogs.[3]

Adverse effects

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.[4]

Proton pump inhibitors may be associated with a greater risk of hip fractures[5] and clostridium difficile-associated diarrhea.[6] Antacid preparations such as esomeprazole by suppressing acid mediated break down of proteins, leads 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.[7] 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.[8]

Interactions

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.[9] 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.[10][11]

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.[9]

Pharmacokinetics

Single 20–40 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.[12]

Dosage forms

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 mg and 40 mg; 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

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, 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 which the formulation is of benefit include those requiring nasogastric tube feeding and those with difficulty swallowing (dysphagia)[citation needed].

Production and manufacture

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.

Economics

Between the launch of esomeprazole in 2001 and 2005, the drug has netted AstraZeneca about $14.4 billion.[13]

Controversy

Main article: AstraZeneca's marketing of Nexium

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 that 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,[14] claiming that omeprazole has no beneficial effects on the patient. In the acidic environment of the parietal cells, both esomeprazole and omeprazole are converted to the same active drug which stops the gastric acid production.[citation needed]

Marcia Angell, former Editor-in-Chief of the New England Journal of Medicine, spoke at Harvard Medical School to a German magazine on August 16, 2007, and said that AstraZeneca's scientists deceptively doctored their comparative studies such that the difference from omeprazole would look larger, providing a marketing advantage.[15]

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,"[16] he claimed, "because you're screwing your patients and you're screwing the taxpayers."[17]

An AstraZeneca sponsored study showed that 40 mg of esomeprazole provided more effective acid control than 40 mg of omeprazole;[18] this has not been borne out in large scale trials in humans and may be a result of the dosage formulation of Nexium.[2]

References

  1. ^ "Esomeprazole Magnesium". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
  2. ^ a b Somogyi, A; Bochner, F; Foster, D (2004). "Inside the isomers: the tale of chiral switches". Australian Prescriber. 27 (2). National Prescribing Service: 47–9. Retrieved 2009-06-23.
  3. ^ Silverman, Richard B. (2004). "3: Receptors". The organic chemistry of drug design and drug action (2nd ed.). Academic Press. p. 148. ISBN 978-0-12-643732-4. Retrieved 2009-06-23. {{cite book}}: External link in |chapterurl= (help); Unknown parameter |chapterurl= ignored (|chapter-url= suggested) (help)
  4. ^ "Nexium side effects". Drug information online. Drugs.com. Retrieved 2009-06-23.
  5. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ "Proton pump inhibitors and Clostridium difficile". Bandolier. 2003. Retrieved 2007-07-13.
  7. ^ Pali-Schöll I, Jensen-Jarolim E (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. {{cite journal}}: Unknown parameter |month= ignored (help)
  8. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ a b Stedman CA, Barclay ML (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. {{cite journal}}: Unknown parameter |month= ignored (help)
  10. ^ Lau WC, Gurbel PA (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. {{cite journal}}: Unknown parameter |month= ignored (help)
  11. ^ Norgard NB, Mathews KD, Wall GC (2009). "Drug-drug interaction between clopidogrel and the proton pump inhibitors". Ann Pharmacother. 43 (7): 1266–74. doi:10.1345/aph.1M051. PMID 19470853. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 388-389.
  13. ^ Financial impact information: 2005, $4.6 billion; 2004, $3.9 billion; 2003, $3.3 billion; 2002, $2 billion; 2001, launch and $580 million.
  14. ^ Gladwell, Malcolm (2004-10-25). "High Prices: How to think about prescription drugs". The New Yorker. Retrieved 2006-06-23.
  15. ^ von Markus, Grill (2007-08-14). "Vorsicht, Pharma - Wie die Industrie Ärzte manipuliert und Patienten täuscht" (in German). Der Stern. Retrieved 2009-06-23.
  16. ^ Harris, G (2003-08-20). "Heartburn Drug Battle Likely". The New York Times. Retrieved 2012-10-25.
  17. ^ "Esomeprazole (Nexium) - What is Esomeprazole?". News-Medical.Net. Retrieved 2012-10-25.
  18. ^ Röhss K, Hasselgren G, Hedenström H (2002). "Effect of esomeprazole 40 mg vs omeprazole 40 mg on 24-hour intragastric pH in patients with symptoms of gastroesophageal reflux disease". Digestive Diseases and Sciences. 47 (5): 954–8. doi:10.1023/A:1015009300955. PMID 12018920. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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