Omeprazole

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Omeprazole
Omeprazole.svg
Omeprazole 3d structure.png
Systematic (IUPAC) name
6-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl)-1H-benzo[d]imidazole
Clinical data
Trade names Antra, Aspra, Gastroloc, Losectil, Lozeprel, Mopral, Omepral, Omez, Opal, Ozid, Rome 20, Prilosec, Losec, Ulcozol, Segazole, Zegacid, Zegerid
Licence data US FDA:link
Pregnancy cat. B3 (AU) C (US)
Legal status Prescription Only (S4) (AU) POM (UK) OTC (US)
Routes Oral, IV
Pharmacokinetic data
Bioavailability 35–76%[1][2]
Protein binding 95%
Metabolism Hepatic (CYP2C19, CYP3A4)
Half-life 1–1.2 hours
Excretion 80% Renal
20% Faecal
Identifiers
CAS number 73590-58-6 YesY
ATC code A02BC01
PubChem CID 4594
DrugBank DB00338
ChemSpider 4433 YesY
UNII KG60484QX9 YesY
KEGG D00455 YesY
ChEBI CHEBI:7772 YesY
ChEMBL CHEMBL1503 YesY
PDB ligand ID 1C6 (PDBe, RCSB PDB)
Chemical data
Formula C17H19N3O3S 
Mol. mass 345.4 g/mol
 YesY (what is this?)  (verify)

Omeprazole (INN) /ˈmɛprəzl/ (Prilosec and generics such as losepine) is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease, laryngopharyngeal reflux, and Zollinger–Ellison syndrome.

Omeprazole is one of the most widely prescribed drugs internationally and is available over-the-counter in some countries.

Medical uses[edit]

Omeprazole can be used in the treatment of gastroesophageal reflux disease, peptic ulcers, erosive esophagitis, and Zollinger-Ellison syndrome.

Gastroesophageal reflux disease[edit]

Gastroesophageal reflux disease (GERD) is a chronic condition in which acidic stomach content leaks back into the esophagus and irritates it. It may cause heartburn, which is a painful burning feeling in the chest or throat.

Peptic ulcers[edit]

Peptic ulcers are sores that develop in the lining of either the stomach or the duodenum due to damage from stomach acid. The most common cause of a peptic ulcer is infection by Helicobacter pylori. Another major cause of a peptic ulcer is long term usage of nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin or ibuprofen. Treatment of Helicobacter pylori infection can be completed by taking a triple therapy combination of omeprazole, amoxicillin, and clarithromycin for 7–14 days.[3]

Erosive esophagitis[edit]

Erosive esophagitis is due to tissue damage to the lining of the esophagus, because of inflammation or irritation over time. It may be caused by acid reflux from GERD, infection by a virus or fungus, an autoimmune disorder, certain medications,[4] or alcohol abuse.

Zollinger Ellison syndrome[edit]

Zollinger Ellison syndrome is a rare disorder that occurs when a tumor of the pancreas or duodenum releases a hormone that stimulates overproduction of stomach acid. This condition may form multiple peptic ulcers.

Adverse effects[edit]

The most frequent significant adverse effects occuring in at least 1% of patients include:[5]

  • Central nervous system: Headache (7%), dizziness (2%)
  • Respiratory: Upper respiratory infection (2%), cough (1%)
  • Gastrointestinal: Abdominal pain (5%), diarrhea (4%), nausea (4%), vomiting (3%), flatulence (3%), acid regurgitation (2%), constipation (2%)
  • Neuromuscular & skeletal: Back pain (1%), weakness (1%)
  • Dermatologic: Rash (2%)

There are other significant concerns related to adverse effects:

Concern has been expressed regarding vitamin B12[14] and iron malabsorption,[15] but effects seem to be clinically insignificant, especially when supplement therapy is provided.[16]

Since their introduction, proton pump inhibitors (especially omeprazole) have also been associated with several cases of acute interstitial nephritis,[17] an inflammation of the kidneys that often occurs as an adverse drug reaction.

PPI use has also been associated with fundic gland polyps,[18] whereas other authors have demonstrated a lack of association [19][20]

Interactions[edit]

Omeprazole is a drug of the proton pump inhibitor (PPI) class. Although the potential for drug interactions is high, clinically important drug interactions are rare.[21][22]

However, the most significant major drug interaction concern is the decreased activation of clopidogrel when taken together with omeprazole.[23] Although still controversial,[24] this may increase the risk of stroke or heart attack in people taking clopidogrel to prevent these events.

The mechanism that this potential interaction occurs is because omeprazole is an inhibitor of the enzymes CYP2C19 and CYP3A4.[25] Clopidogrel is an inactive prodrug that partially depends on CYP2C19 for conversion to its active form. Inhibition of CYP2C19 may block the activation of clopidogrel, which could reduce its effects.[26][27]

Almost all benzodiazepines are metabolised via the CYP3A4 and CYP2D6 pathway, and inhibition of these enzymes will result in a higher AUC (bloodlevels of the drug/compound). Other examples of drugs that are dependent on CYP3A4 for their metabolism are escitalopram, warfarin, oxycodone, tramadol, and oxymorphone. The concentrations of these drugs may increase if they are used concomitantly with omeprazole.[28]

Omeprazole is also a competitive inhibitor of p-glycoprotein, as are other PPIs.[29]

Drugs that depend on an acidic stomach environment (such as ketoconazole or atazanavir) may be poorly absorbed, whereas acid-labile antibiotics (such as erythromycin which is a very strong CYP3A4 inhibitor) may be absorbed to a greater extent than normal due to the more alkaline environment of the stomach.[28]

St. John's wort, an MAO-inhibitor (Hypericum perforatum) and Gingko biloba significantly reduce plasma concentrations of omeprazole through induction of CYP3A4 and CYP2C19.[30]

Pregnancy and breast-feeding[edit]

Epidemiological data do not show an increased risk of major birth defects after maternal use of omeprazole during pregnancy.[31]

No clinical trials have deeply evaluated the potential consequences of the use of omeprazole in breastfeeding. However, the pharmacokietics of omeprazole molecule strongly suggest the safety of omeprazole use during breastfeeding:

  • Omeprazole has a high plasma protein binding rate (95%),[32] indicating that little amount of drug is transferred to the milk duct during breast milk formation.
  • Omeprazole needs to be administrated in an enteric-coated formulation due to its rapid degradation in the acidic conditions of the stomach. This suggests that free molecules of omeprazole uptaken by the rapidly degraded in the acidic conditions of the stomach, that most of the molecules ingested by the infant are degraded before being absorbed.

The safety of omeprazole use in breastfeeding deduced from pharmacokinetic characteristics of the omeprazole molecule agree with a case report in which the presence of omeprazole in breast milk was analysed over 4 hours after omeprazole uptake.[33] The study revealed that the peak omeprazole concentration in breast milk (that occurred 3h after omeprazole ingestion) was 7% of peak serum concentration, which corresponds to less than 1% of the usual adult dose (200 to 400 ug of omeprazole/Kg of body weight) for a 5 kg infant consuming 200 ml of breast milk per day.

Mechanism of action[edit]

Omeprazole is a selective and irreversible proton pump inhibitor. It suppresses stomach acid secretion by specific inhibition of the H +/K + ATPase system found at the secretory surface of gastric parietal cells. Because this enzyme system is regarded as the acid (proton, or H+) pump within the gastric mucosa, omeprazole will inhibit the final step of acid production.

Omeprazole will also inhibit both basal and stimulated acid secretion irrespective of the stimulus.[34]

Pharmacodynamics[edit]

The inhibitory effect of omeprazole occurs within 1 hour after oral administration. The maximum effect occurs within 2 hours. The duration of inhibition lasts 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.[35]

Pharmacokinetics[edit]

The absorption of omeprazole takes place in the small intestine and is usually completed within 3–6 hr. The systemic bioavailability of omeprazole after repeated dose is about 60%.

Omeprazole, as well as other proton pump inhibitors, are only effective on active H+/K+ 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 on an empty stomach about 30–60 minutes before a meal to allow the drug to reach peak levels once food is ingested.[36][37] Additionally, most sources recommend that after taking omeprazole at least 30 minutes should be allowed to elapse before eating[38][39] (at least 60 minutes for immediate-release omeprazole plus sodium bicarbonate products, such as Zegerid),[40] though some sources say that with delayed-release forms of omeprazole it is not necessary to wait before eating after taking the medication.[41] Plasma protein binding is about 95%.

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 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.

Measurement in body fluids[edit]

Omeprazole may be quantified in plasma or serum to monitor therapy or to confirm a diagnosis of poisoning in hospitalized patients. Plasma omeprazole concentrations are usually in a range of 0.2–1.2 mg/l in persons receiving the drug therapeutically via the oral route and 1–6 mg/l in victims of acute overdosage. Enantiomeric chromatographic methods are available to distinguish esomeprazole from racemic omeprazole.[42][43]

Chemistry[edit]

(S)- and (R)-enantiomers of omeprazole, a racemate (1:1 mixture of both enantiomers)

Omeprazole contains a tricoordinated sulfinyl sulfur in a pyramidal structure and therefore can exist as either the (S)- or (R)-enantiomers. Omeprazole is a racemate, an equal mixture of the two. In the acidic conditions of the canaliculi of parietal cells, both enantiomers are converted to achiral products (sulfenic acid and sulfenamide configurations) which react 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

AstraZeneca has also developed esomeprazole (Nexium) which is a eutomer, purely the (S)-enantiomer, rather than a racemate like omeprazole.

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.[44] 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 proportion of the poor metabolizer phenotype varies widely between populations, from 2.0–2.5% in African-Americans and white Americans to >20% in Asians; several pharmacogenomics studies have suggested that PPI treatment should be tailored according to CYP2C19 metabolism status.[45]

History[edit]

Omeprazole was first marketed in the United States in 1989 by Astra AB, now AstraZeneca, under the brand names Losec and Prilosec. An over-the-counter brand, Prilosec OTC, is available in the US for treatment of heartburn. It is now also available from generic manufacturers under various brand names.

In 1990, at the request of the U.S. Food and Drug Administration, the brand name Losec was changed to Prilosec to avoid confusion with the diuretic Lasix (furosemide).[46] The new name has led to confusion between omeprazole (Prilosec) and fluoxetine (Prozac), an antidepressant.[46]

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 and as Segazole by Star Laboratories in Pakistan.[47][48] In the Philippines, Ajanta Pharma markets omeprazole under the brand name Zegacid. Dr. Reddy's Laboratories markets it as Omez in India, Russia, Romania, and South Africa. In Bangladesh, Healthcare Pharmaceuticals Ltd. marketed omeprazole under the brand name Opal, Eskayef Bangladesh Limited marketed it under the brand name Losectil, Acme Laboratories Limited marketed it under the brand name PPI, and Apex Pharma also markets it under the brand name Aspra. It is also available under the brand name Rome 20 marketed by Rephco Pharmaceuticals Ltd. In Argentina, it is made by Laboratorios Bagó S.A. and available there and in Ecuador as Ulcozol.[49] In Indonesia, Darya-Varia Laboratories marketed omeprazole as Ozid. In Brazil, omeprazole is produced by Multilab under the name Lozeprel. In Spain, it is produced by Cantabria Pharma S.L. under the name emeprotón. In Bangladesh, In 1999, antiulcerants were the leading class of therapeutic drugs, with $15.6 billion in global sales. Of that, Prilosec accounted for $5.91 billion, making it the best-selling drug on the market.[50]

Although Prilosec's U.S. patent expired in April 2001, AstraZeneca was able to delay the introduction of generic versions through lawsuits and peripheral patent claims. It introduced Nexium as a patented replacement drug.[51]

Dosage forms[edit]

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

Omeprazole is available as tablets and capsules (containing omeprazole or omeprazole magnesium) in strengths of 10, 20, 40, 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).[52] An immediate release formulation was approved by the FDA in the United States,[53] which does not require enteric coating.

It is also available for use in injectable form (IV) 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.


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External links[edit]