Proton-pump inhibitor

From Wikipedia, the free encyclopedia
  (Redirected from Proton pump inhibitors)
Jump to: navigation, search
Proton-pump inhibitor
Drug class
Proton pump inhibitors structure.svg
General structure of a proton-pump inhibitor
Use Reduction of gastric acid production
Biological target Hydrogen potassium ATPase
ATC code A02BC
External links
MeSH D054328
AHFS/Drugs.com Drug Classes
WebMD medicinenet 

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. The group followed and has largely superseded another group of medications with similar effects, but a different mode of action, called H2-receptor antagonists. These drugs are among the most widely sold drugs in the world, and are generally considered effective.[1] The vast majority of these drugs are benzimidazole derivatives, but promising new research indicates the imidazopyridine derivatives may be a more effective means of treatment.[2]

Medical uses[edit]

These drugs are used in the treatment of many conditions, such as:

Specialty professional organizations recommend that people take the lowest effective dose possible to achieve the desired therapeutic result when using proton pump inhibitors to treat gastroesophageal reflux disease long-term.[4][5] In the United States, the Food and Drug Administration advises that no more than three 14-day treatment courses should be used in one year.[6]

The effectiveness of PPIs has not been demonstrated in every case, despite their widespread use for these conditions. For example, they do not change the length of Barrett's esophagus.[7] The most objective test to assess success of PPI therapy in patients with GERD is esophageal pH monitoring.

Adverse effects[edit]

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.[8] 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.[9]

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.[10]

Gastrointestinal[edit]

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.[8] Reduction in calcium absorption has been especially concerning, which led the FDA to include a warning on PPI drug labels in 2010.[8] Interference with magnesium absorption is accepted as a class effect and people who have low levels of magnesium as a result of PPI therapy are switched to H2-receptor antagonist drugs.[8] High dose or long-term use of PPIs carries a possible increased risk of bone fractures.[6]

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.[8] 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.[8]

Long-term use of PPIs is strongly 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[8] or pre-cancer.[11] There is concern that use of PPIs may mask gastric cancers or other serious gastric problems and physicians should be aware of this effect.[8]

Other[edit]

Per a meta-analysis, the overall risk of pneumonia is about 25% higher among PPI users.[12]

PPIs are linked with an increased cardiovascular event rate.[13] This 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.[13]

Mechanism of action[edit]

The activation of PPIs
Micrograph of the gastric antrum showing G cell hyperplasia, a histomorphologic change seen with PPI use (H&E stain)

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.[3] 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.)

The lack of 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. The lack 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.

Potassium-competitive acid blockers[edit]

Potassium-competitive inhibitors are experimental drugs that reversibly block the potassium-binding site of the proton pump. Soraprazan and revaprazan block H+ secretion much more quickly than classical PPIs (within a half-hour).[14] The development of soraprazan, however, was discontinued in 2007.[15]

Pharmacokinetics[edit]

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.[16][17]

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.[18][19]

Examples[edit]

Clinically used proton pump inhibitors:

  • Omeprazole (OTC; brand names: Gasec, Losec, Prilosec, Zegerid, ocid, Lomac, Omepral, 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, 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[citation needed]).
  • Ilaprazole (not FDA approved as of October 2013; brand names: Noltec, Yili'an, Ilapro, Lupilla, Adiza)

History[edit]

References[edit]

  1. ^ The Health Strategies Consultancy LLC (March 2005). "Follow The Pill: Understanding the U.S. Commercial Pharmaceutical Supply Chain". The Kaiser Family Foundation. 
  2. ^ Sachs, G.; Shin, J. M.; Howden, C.W. (2006). "Review article: The clinical pharmacology of proton pump inhibitors". Alimentary Pharmacology and Therapeutics 23: 2–8. doi:10.1111/j.1365-2036.2006.02943.x. PMID 16700898. 
  3. ^ a b Zajac, P; Holbrook, A; Super, ME; Vogt, M (March–April 2013). "An overview: Current clinical guidelines for the evaluation, diagnosis, treatment, and management of dyspepsia". Osteopathic Family Physician 5 (2): 79–85. doi:10.1016/j.osfp.2012.10.005. 
  4. ^ "Five Things Physicians and Patients Should Question". American Gastroenterological Association. 
  5. ^ Kahrilas, Peter J.; Shaheen, Nicholas J.; Vaezi, Michael F.; Hiltz, SW; Black, E; Modlin, IM; Johnson, SP; Allen, J; Brill, JV (2008). "American Gastroenterological Association Medical Position Statement on the Management of Gastroesophageal Reflux Disease". Gastroenterology 135 (4): 1383–1391, 1391.e1–5. doi:10.1053/j.gastro.2008.08.045. PMID 18789939. 
  6. ^ a b "Possible Increased Risk of Bone Fractures With Certain Antacid Drugs". U S Food and Drug Administration. 25 May 2010. Retrieved 26 May 2010. 
  7. ^ Cooper, B. T.; Chapman, W.; Neumann, C. S.; Gearty, J. C. (2006). "Continuous treatment of Barrett's oesophagus patients with proton pump inhibitors up to 13 years: Observations on regression and cancer incidence". Alimentary Pharmacology and Therapeutics 23 (6): 727–33. doi:10.1111/j.1365-2036.2006.02825.x. PMID 16556174. 
  8. ^ a b c d e f g h Corleto VD et al. Proton pump inhibitor therapy and potential long-term harm. Curr Opin Endocrinol Diabetes Obes. 2014 Feb;21(1):3-8. doi:10.1097/MED.0000000000000031 PMID 24310148
  9. ^ Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3[page needed]
  10. ^ Clark, DW; Strandell J (June 2006). "Myopathy including polymyositis: a likely class adverse effect of proton pump inhibitors?". European Journal of Clinical Pharmacology 62 (6): 473–479. doi:10.1007/s00228-006-0131-1. PMID 16758264. 
  11. ^ Song, H; Zhu, J; Lu, D (2 December 2014). "Long-term proton pump inhibitor (PPI) use and the development of gastric pre-malignant lesions.". The Cochrane database of systematic reviews 12: CD010623. doi:10.1002/14651858.CD010623.pub2. PMID 25464111. 
  12. ^ Eom, CS; Jeon, CY; Lim, JW; Cho, EG; Park, SM; Lee, KS (22 February 2011). "Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis.". CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 183 (3): 310–9. PMID 21173070. 
  13. ^ a b Schepers E, Speer T, Bode-Böger SM, Fliser D, Kielstein JT (2014). "Dimethylarginines ADMA and SDMA: the real water-soluble small toxins?". Seminars in Nephrology 34 (2): 97–105. doi:10.1016/j.semnephrol.2014.02.003. PMID 24780466. Retrieved 2015-06-11. 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. 
  14. ^ Schubert-Zsilavecz, M, Wurglics, M: Neue Arzneimittel 2005. Soraprazan (in German).[page needed]
  15. ^ Nycomed Annual Report 2007
  16. ^ AstraZeneca Pty Ltd. Nexium (Australian approved prescribing information). North Ryde: AstraZeneca; 2005.
  17. ^ Wyeth Australia Pty Ltd. Zoton (Australian approved prescribing information). Baulkham Hills: Wyeth; 2004.
  18. ^ Shin, Jai Moo; Munson, Keith; Vagin, Olga; Sachs, George (2008). "The gastric HK-ATPase: Structure, function, and inhibition". Pflügers Archiv - European Journal of Physiology 457 (3): 609–22. doi:10.1007/s00424-008-0495-4. PMC 3079481. PMID 18536934. 
  19. ^ Carlsson, E.; Lindberg, P. (2002). "Two of a kind". Chemistry in Britain 38 (5): 42–5. 

External links[edit]