Esomeprazole
Encyclopedia
Esomeprazole is a proton pump inhibitor
(brand name Nexium) developed and marketed 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
(marketed as Losec/Prilosec), and AstraZeneca claims improved efficacy
of this single enantiomer product over the racemic
mixture of omeprazole. However, this greater efficacy has been disputed, with some claiming it offers no benefit from its older form.
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.
, 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
.
. Long term contact between the acid and esophagus can cause permanent damage to the esophagus. Esomeprazole (Nexium) reduces the production of digestives acids, thus minimizing their effect on the esophagus.
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
.
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.
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.
Proton pump inhibitors may be associated with a greater risk of hip fractures and clostridium difficile
-associated diarrhea. 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
.
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. 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.
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.
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Esomeprazole is available as delayed-release capsules in the United States or as delayed release tablets in Australia 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 acid
ic conditions of the stomach
. This is achieved by formulating capsules using the multiple-unit pellet system.
. 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
).
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 excipient
s and compressed into tablets. Finally, the tablets are film-coated to improve the stability and appearance of the preparation.
'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), and that the company was trying to "evergreen" its patent by patenting the pure esomeprazole and aggressively marketing to doctors that it is more effective than the mixture, claiming that omeprazole has no beneficial effects on the patient. However, 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.
Dr. 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 accused AstraZeneca's scientists of deceptively doctoring their comparative studies such that the difference to Omeprazole would look larger, providing a marketing advantage. For more information, see AstraZeneca's article.
Thomas A. Scully
, head of the Federal Centers for Medicare and Medicaid services also criticized AstraZeneca for their aggressive marketing of Nexium. At a conference of the American Medical Association
he went so far as to suggest that Astra was using the new drug to overcharge consumers and insurance companies. "You should be embarrassed if you prescribe Nexium," he claimed, "because you're screwing your patients and you're screwing the taxpayers."
An AstraZeneca sponsored study showed that 40 mg of esomeprazole provided more effective acid control than 40 mg of omeprazole, however this has not been borne out in large scale trials in humans and may be a result of the dosage formulation of Nexium.
Proton pump inhibitor
Proton-pump inhibitors are a group of drugs whose main action is a 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...
(brand name Nexium) developed and marketed by AstraZeneca
AstraZeneca
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...
which is used in the treatment of dyspepsia
Dyspepsia
Dyspepsia , also known as upset stomach or indigestion, refers to a condition of impaired digestion. It is a medical condition characterized by chronic or recurrent pain in the upper abdomen, upper abdominal fullness and feeling full earlier than expected when eating...
, peptic ulcer disease
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
(PUD), gastroesophageal reflux disease
Gastroesophageal reflux disease
Gastroesophageal reflux disease , gastro-oesophageal reflux disease , gastric reflux disease, or acid reflux disease is chronic symptoms or mucosal damage caused by stomach acid coming up from the stomach into the esophagus...
(GORD/GERD) and Zollinger-Ellison syndrome
Zollinger-Ellison syndrome
Zollinger–Ellison syndrome is a triad of gastric acid hypersecretion, severe peptic ulceration, and non-beta cell islet tumor of pancreas . In this syndrome increased levels of the hormone gastrin are produced, causing the stomach to produce excess hydrochloric acid. Often the cause is a tumor of...
. Esomeprazole is the S-enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
of omeprazole
Omeprazole
Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...
(marketed as Losec/Prilosec), and AstraZeneca claims improved efficacy
Efficacy
Efficacy is the capacity to produce an effect. It has different specific meanings in different fields. In medicine, it is the ability of an intervention or drug to reproduce a desired effect in expert hands and under ideal circumstances.- Healthcare :...
of this single enantiomer product over the racemic
Racemic
In chemistry, a racemic mixture, or racemate , is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule. The first known racemic mixture was "racemic acid", which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid.- Nomenclature :A...
mixture of omeprazole. However, this greater efficacy has been disputed, with some claiming it offers no benefit from its older form.
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 diseaseGastroesophageal reflux disease
Gastroesophageal reflux disease , gastro-oesophageal reflux disease , gastric reflux disease, or acid reflux disease is chronic symptoms or mucosal damage caused by stomach acid coming up from the stomach into the esophagus...
, 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
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
.
Gastroesophageal reflux disease
Gastroesophageal Reflux Disease (GERD) is a condition in which the digestive acid in the stomach comes in contact with the oesophagus (food pipe). The irritation caused by this disorder is known as heartburnHeartburn
Heartburn, also known as pyrosis or acid indigestion is a burning sensation in the chest, just behind the breastbone or in the epigastrium...
. Long term contact between the acid and esophagus can cause permanent damage to the esophagus. Esomeprazole (Nexium) reduces the production of digestives acids, thus minimizing their effect on the esophagus.
Duodenal ulcers
Esomeprazole is combined with the antibiotics clarithromycinClarithromycin
Clarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia , skin and skin structure infections...
and amoxicillin
Amoxicillin
Amoxicillin , formerly amoxycillin , and abbreviated amox, is a moderate-spectrum, bacteriolytic, β-lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms. It is usually the drug of choice within the class because it is better absorbed, following oral...
(or metronidazole
Metronidazole
Metronidazole is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal....
in penicillin-hypersensitive patients) in the 7-14 day eradication triple therapy for Helicobacter pylori
Helicobacter pylori
Helicobacter pylori , previously named Campylobacter pyloridis, is a Gram-negative, microaerophilic bacterium found in the stomach. It was identified in 1982 by Barry Marshall and Robin Warren, who found that it was present in patients with chronic gastritis and gastric ulcers, conditions that were...
. Infection by H. pylori is the causative factor in the majority of peptic and duodenal ulcers
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
.
Evidence of efficacy
AstraZeneca claims that esomeprazole provides improved efficacy, in terms of stomach acid control, over the R enantiomer of omeprazole. Many health professionals 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.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.
Given the large difference in cost between all other proton pump inhibitors and that of omeprazole
Omeprazole
Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...
, 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.
Adverse effects
Common side effects include headache, diarrhea, nausea, gas, 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.Proton pump inhibitors may be associated with a greater risk of hip fractures and clostridium difficile
Clostridium difficile
Clostridium difficile , also known as "CDF/cdf", or "C...
-associated diarrhea. 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
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
.
Interactions
Esomeprazole is a competitive inhibitorEnzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of the enzymes CYP2C19
CYP2C19
Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
and CYP2C9
CYP2C9
Cytochrome P450 2C9 is a protein that in humans is encoded by the CYP2C9 gene.- Function :CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes...
, and may therefore interact
Drug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...
with drugs that depend on them for metabolism
Drug metabolism
Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...
, such as diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
and warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
; the concentrations of these drugs may increase if they are used concomitantly with esomeprazole. Conversely, Clopidogrel
Clopidogrel
Clopidogrel is an oral, thienopyridine class antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It is marketed by Bristol-Myers Squibb and Sanofi-Aventis under the trade name Plavix. The drug works by irreversibly...
(Plavix) is an inactive prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
that partially depends on CYP2C19 for conversion to its active form; inhibition of CYP2C19 blocks the activation of clopidogrel, thus reducing its effects.
Drugs that depend on stomach pH for absorption may interact with omeprazole; drugs that depend on an acidic environment (such as ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
or atazanavir
Atazanavir
Atazanavir, marketed under the trade name Reyataz by Bristol Myers, is an antiretroviral drug of the protease inhibitor class...
) will be poorly absorbed, whereas drugs that are broken down in acidic environments (such as erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
) will be absorbed to a greater extent than normal.
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.Dosage forms
Enteric coating
An enteric coating is a barrier applied to oral medication that controls the location in the digestive system, where it is absorbed. Enteric refers to the small intestine, therefore enteric coatings prevent release of medication before it reaches the small intestine.Most enteric coatings work by...
, due to the rapid degradation of the drug in the acid
Acid
An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...
ic conditions of the stomach
Stomach
The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
. 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 osmosisOsmosis
Osmosis is the movement of solvent molecules through a selectively permeable membrane into a region of higher solute concentration, aiming to equalize the solute concentrations on the two sides...
. 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
Dysphagia
Dysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....
).
Society and culture
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 suspensionSuspension (chemistry)
In chemistry, a suspension is a heterogeneous fluid containing solid particles that are sufficiently large for sedimentation. Usually they must be larger than 1 micrometer. The internal phase is dispersed throughout the external phase through mechanical agitation, with the use of certain...
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 excipient
Excipient
An excipient is generally a pharmacologically inactive substance used as a carrier for the active ingredients of a medication. In many cases, an "active" substance may not be easily administered and absorbed by the human body; in such cases the substance in question may be dissolved into or...
s 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.Controversy
There has been some controversy about AstraZenecaAstraZeneca
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...
's behaviour in creating, patenting and marketing of the drug. Esomeprazole's successful predecessor omeprazole
Omeprazole
Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...
is a mixture of two mirror-imaged molecules
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....
(esomeprazole which is the S-enantiomer, and R-omeprazole), and that the company was trying to "evergreen" its patent by patenting the pure esomeprazole and aggressively marketing to doctors that it is more effective than the mixture, claiming that omeprazole has no beneficial effects on the patient. However, 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.
Dr. Marcia Angell
Marcia Angell
Marcia Angell, M.D. is an American physician, author, and the first woman to serve as editor-in-chief of the New England Journal of Medicine...
, former Editor-in-Chief of the New England Journal of Medicine
New England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...
, spoke at Harvard Medical School
Harvard Medical School
Harvard Medical School is the graduate medical school of Harvard University. It is located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts....
to a German magazine on August 16, 2007 and accused AstraZeneca's scientists of deceptively doctoring their comparative studies such that the difference to Omeprazole would look larger, providing a marketing advantage. For more information, see AstraZeneca's article.
Thomas A. Scully
Thomas A. Scully
Thomas A. Scully was the Administrator of the Centers for Medicare and Medicaid Services from 2001-2003 under President George W. Bush. Scully currently is Senior Counsel at Alston & Bird LLP, a law and lobbying firm, where he focuses on health care regulatory and legislative matters, as well as...
, head of the Federal Centers for Medicare and Medicaid services also criticized AstraZeneca for their aggressive marketing of Nexium. At a conference of the American Medical Association
American Medical Association
The American Medical Association , founded in 1847 and incorporated in 1897, is the largest association of medical doctors and medical students in the United States.-Scope and operations:...
he went so far as to suggest that Astra was using the new drug to overcharge consumers and insurance companies. "You should be embarrassed if you prescribe Nexium," he claimed, "because you're screwing your patients and you're screwing the taxpayers."
An AstraZeneca sponsored study showed that 40 mg of esomeprazole provided more effective acid control than 40 mg of omeprazole, however this has not been borne out in large scale trials in humans and may be a result of the dosage formulation of Nexium.