General structure of a proton-pump inhibitor
|Use||Reduction of gastric acid production|
|Biological target||Hydrogen potassium ATPase|
Proton-pump inhibitors (PPIs) 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. This group of drugs followed and largely superseded another group of medications with similar effects, but a different mode of action, called H2-receptor antagonists.
PPIs are among the most widely sold drugs in the world, and the first one, omeprazole, is on the World Health Organization's List of Essential Medicines.
These drugs are used in the treatment of many conditions, such as:
- Peptic ulcer disease including after endoscopic treatment for bleeding
- As part of Helicobacter pylori eradication therapy
- Gastroesophageal reflux disease (GERD or GORD) including symptomatic endoscopy-negative reflux disease and
- Barrett's esophagus
- Eosinophilic esophagitis
- Stress gastritis and ulcer prevention in critical care
- Gastrinomas and other conditions that cause hypersecretion of acid including Zollinger–Ellison syndrome (often 2–3x the regular dose is required)
Specialty professional organizations recommend that people take the lowest effective PPI dose to achieve the desired therapeutic result when used to treat gastroesophageal reflux disease long-term. In the United States, the Food and Drug Administration has advised that no more than three 14-day treatment courses should be used in one year.
Despite their extensive use, the quality of the evidence supporting their use in some of these conditions is variable. The effectiveness of PPIs has not been demonstrated for every case. For example, although they reduce the incidence of esophageal adenocarcinoma in Barrett's oesophagus, they do not change the length affected.
In general, proton pump inhibitors are well tolerated, and the incidence of short-term adverse effects is relatively low. Long-term use of PPIs has been less studied than short-term use, and the lack of data makes it difficult to make definitive statements. The range and occurrence of adverse effects are similar for all of the PPIs, though they have been reported more frequently with omeprazole. This may be due to its longer availability and, hence, clinical experience.
Common adverse effects include headache, nausea, diarrhea, abdominal pain, fatigue, and dizziness. Infrequent adverse effects include rash, itch, flatulence, constipation, anxiety, and depression. Also infrequently, PPI use may be associated with occurrence of myopathies, including the serious reaction rhabdomyolysis.
Gastric acid is important for breakdown of food and release of micronutrients, and some studies have shown possibilities for interference with absorption of iron, calcium, magnesium, and vitamin B12. With regard to iron and vitamin B12 the data are weak and several confounding factors have been identified.
High dose and/or long-term use of PPIs carries a possible increased risk of bone fractures which was not found with short-term, low dose use; the FDA included a warning regarding this on PPI drug labels in 2010.
Some studies have shown a correlation between use of PPIs and Clostridium difficile infections. While the data are contradictory and controversial, the FDA had sufficient concern to include a warning about this adverse effect on the label of PPI drugs. Concerns have also been raised about small intestinal bacterial overgrowth and spontaneous bacterial peritonitis in older people taking PPIs and in people with irritable bowel syndrome taking PPIs; both types of infections arise in these populations due to underlying conditions and it is not clear if this is a class effect of PPIs.
Long-term use of PPIs is associated with the development of benign polyps from fundic glands (which is distinct from fundic gland polyposis); these polyps do not cause cancer and resolve when PPIs are discontinued. There is no association between PPI use and cancer or pre-cancer. There is concern that use of PPIs may mask gastric cancers or other serious gastric problems and physicians should be aware of this effect.
There is also evidence that PPI use alters the composition of the bacterial populations inhabiting the gut. Although the mechanisms by which PPIs cause these changes are yet to be determined they may have a role in the increased risk of bacterial infections with PPI use.
Associations of PPI use and cardiovascular events have also been widely studied but clear conclusions have not been made as these relative risks are confounded by other factors. PPIs are commonly used in cardiovascular patients for gastric protection when aspirin is given for its antiplatelet actions. An interaction between PPIs and the metabolism of the platelet inhibitor clopidogrel is known and this drug is also often used in patients with cardiac disease.
One suggested mechanism for cardiovascular effects is because PPIs bind and inhibit dimethylargininase, the enzyme that degrades asymmetric dimethylarginine (ADMA), resulting in higher ADMA levels and a decrease in bioavailable nitric oxide.
Mechanism of action
Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase, or, more commonly, the gastric proton pump) of the gastric parietal cells. The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion.
Targeting the terminal step in acid production, as well as the irreversible nature of the inhibition, results in a class of drugs that are significantly more effective than H2 antagonists and reduce gastric acid secretion by up to 99%. ("Irreversibility" refers to the effect on a single copy of the proton pump; the effect on the overall human digestive system is reversible, as the proton pump protein is rendered non-functional and can be replaced with new copies.)
Decreasing the acid in the stomach will aid in the healing of duodenal ulcers, and reduces the pain from indigestion and heartburn, which can be exacerbated by stomach acid. Low amounts of stomach acid, also called hypochlorhydria, is the lack of sufficient hydrochloric acid, HCl, which is required for the digestion of proteins and the absorption of nutrients, in particular vitamin B12 and calcium.
The PPIs are given in an inactive form, which is neutrally charged (lipophilic) and readily crosses cell membranes into intracellular compartments (like the parietal cell canaliculus) with acidic environments. In an acid environment, the inactive drug is protonated and rearranges into its active form. As described above, the active form will covalently and irreversibly bind to the gastric proton pump, deactivating it.
The rate of omeprazole absorption is decreased by concomitant food intake. In addition, the absorption of lansoprazole and esomeprazole is decreased and delayed by food. It has been reported, however, that these pharmacokinetic effects have no significant impact on efficacy.
PPIs have a rather short half-life in human plasma (60–90 min), but because they covalently bind to the pump, their half-life of inhibition of gastric acid secretion is substantially longer. The half-life at the site of action is estimated to be approximately 24 hours. Dissociation of the inhibitory complex is probably due to the effect of the endogenous antioxidant glutathione which leads to the release of omeprazole sulfide and reactivation of the enzyme.
Clinically used proton pump inhibitors:
- Omeprazole (OTC; brand names: Gasec, Losec, Prilosec, Zegerid, ocid, Lomac, Omepral, Zolppi, Omez, Omepep, UlcerGard, GastroGard, Altosec)
- Lansoprazole (brand names: Prevacid, Zoton, Monolitum, Inhibitol, Levant, Lupizole)
- Dexlansoprazole (brand name: Kapidex, Dexilant)
- Esomeprazole (brand names: Nexium, Esotrex, esso)
- Pantoprazole (brand names: Protonix, Somac, Forppi, Pantoloc, Pantozol, Pantomed, Zurcal, Zentro, Pan, Controloc, Tecta)
- Rabeprazole (brand names: AcipHex, Pariet, Erraz, Zechin, Rabecid, Nzole-D, Rabeloc, Razo, Superia. Dorafem: combination with domperidone).
- Ilaprazole (not FDA approved as of October 2013[update]; brand names: Noltec, Yili'an, Ilapro, Lupilla, Adiza)
PPIs were developed in the 1980s with omeprazole being launched in 1988. Most of these drugs are benzimidazole derivatives, related to omeprazole, but imidazopyridine derivatives such as tenatoprazole have also been developed. Potassium-competitive inhibitors such as revaprazan reversibly block the potassium-binding site of the proton pump, acting more quickly, but are not available in most countries.
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It also seems to be the pathophysiological link between the use of proton pump inhibitors and increased cardiovascular event rate because these drugs bind and inhibit DDAH, the enzyme that degrades ADMA, which results in higher ADMA levels and a decrease in bioavailable NO.
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