Proton-pump inhibitor

From Wikipedia, the free encyclopedia
  (Redirected from Proton pump inhibitors)
Jump to: navigation, search
It has been suggested that Discovery and development of proton pump inhibitors be merged into this article. (Discuss) Proposed since February 2012.
Proton-pump inhibitor
Drug class

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 The group followed and has largely superseded another group of pharmaceuticals with similar effects, but a different mode of action, called H2-receptor antagonists.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] High dose or long-term use of PPIs carries a possible increased risk of bone fractures.[3]

Contents

Discovery and development of proton pump inhibitors [edit]

See Discovery and development of proton pump inhibitors

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.[5][6] 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.[3]

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]

PPIs (as well as other antacid preparations), by suppressing acid-mediated breakdown of proteins, lead to an elevated risk of developing food allergies. These undigested proteins then pass into the gastrointestinal tract, potentially leading to sensitization to a range of foods or drugs. It is unclear whether this risk occurs with only long-term use or with short-term use as well.[8]

Short-term [edit]

In general, proton pump inhibitors are well tolerated, and the incidence of short-term adverse effects is relatively uncommon. 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 (in 5.5% of users in clinical trials[9]), nausea, diarrhea, abdominal pain, fatigue, and dizziness.[10] Long-term use is associated with hypomagnesemia.[11]

Because the body uses gastric acid to release it from food particles, decreased vitamin B12 absorption may occur with long-term use of PPIs, and may lead to vitamin B12 deficiency.[10][12]

Infrequent adverse effects include rash, itch, flatulence, constipation, anxiety, and depression. In rare cases, PPI use may cause ‘idiosyncratic’ reactions, such as erythema multiforme, pancreatitis, Stevens–Johnson syndrome, and acute interstitial nephritis.[13] It was reported on case of hyperprolactinaemia as an adverse effect of PPI.[14]

Gastric acid suppression, using H2-receptor antagonists and PPIs, is associated with an increased risk of community-acquired pneumonia.[15] Acid suppression may result in insufficient elimination of pathogenic organisms. Therefore, patients at higher risk of pneumonia are suggested to be prescribed proton pump inhibitors only at lower doses and only when necessary.[16]

On 8 February 2012, the US-FDA issued a safety announcement on PPIs, based on the review report from the Adverse Event Reporting System. This review report suggested an increased risk of Clostridium difficile-associated diarrhea with PPI use.[17] The safety announcement reported that PPIs have been shown to raise risk of Clostridium difficile infection by 1.7 times with once-daily use and 2.4 times with more-than-once-daily use.[18][19] The risk can be minimized by judicious short-term prescriptions.[20]

PPI's have been linked with increased skin aging.[21]

Long-term [edit]

In the specific but common case of the use of PPIs as long-term treatment for managing GERD, medical societies recommend that patients use the minimal effective dosage to achieve the goals of the therapy.[5][6][22]

Long-term use of PPIs has been less studied than short-term use. A 2006 study of 135,000 people 50 or older found that those taking high doses of PPIs for longer than one year were 2.6 times more likely to break a hip. Those taking smaller doses for 1 to 4 yr were 1.2 to 1.6 times more likely to break a hip, and the risk of a fracture increased with the length of time taking PPIs.[23][24][25] In 2010, though, data from the same source (the UK General Practice Research Database) were analysed a second time, and reported a different trend: risk of fracture more than doubled immediately after initiation of medication, but dropped to slightly less than double baseline with prolonged use. This information was not taken into account in the 25 May 2010 FDA labeling change because it would not be published until a year later - May, 2011, and it was not even published online until the following month.[26] Furthermore, of the seven studies the FDA did make note of, all but the smallest study found marked increased risks of fractures.[27] Theories as to the cause of the increase are the possibility that the reduction of stomach acid reduces the amount of calcium dissolved in the stomach or that PPIs may interfere with the breakdown and rebuilding of bone by interfering with the acid production of osteoclasts.[28] The reduction of vitamin B12 may also increase bone fragility by raising homocysteine). A recent study also suggested PPIs significantly decreased the effect of clopidogrel on platelets, as tested by VASP phosphorylation. The clinical impact of these results must be assessed by further investigations, but a PPI treatment should not be added to the antiplatelet dual therapy without formal indication.[29]

PPIs may cause dependency by increasing gastric symptoms if they are discontinued.[30] In healthy volunteers who were given pantoprazole or placebo for four weeks and then followed for six additional weeks, one week after treatment was stopped, 44% of the pantoprazole recipients reported symptoms of dyspepsia, compared to 9% of the placebo recipients. By the third week, this difference between the two groups had disappeared.[31] Such "rebound hyperacidity" is thought to be mediated by gastrin hormone secretion which occurred following the discontinuation of PPIs, and patients should expect symptoms of hyperacidity to worsen for a week or two after stopping these drugs.

The FDA is revising both the prescription and the over-the-counter (OTC) labels for PPIs to include the possible increased risk of fractures. This new information is based upon FDA review of several long-term studies that reported an increased risk of fractures of the hip, wrist, and spine with PPI use. Some studies found a greater risk for these fractures from higher doses of PPI or use for one year or more. Most studies evaluated individuals aged 50 or older and the increased risk of fractures was primarily in this group.

However, 12 week PPI therapy had no impact on calcium, vitamin D, or bone metabolism in healthy young males.[32]

Long term PPI therapy also interferes with zinc absorption and zinc body stores. None of the PPI users however were found to be classically zinc-deficient.[33]

A December 2010 report suggested a nearly four-fold increase in certain heart arrhythmias (focal atrial tachycardia and right ventricular outflow tract, RVOT tachycardia) in PPI users.[34] The potential mechanism was hypothesized to be related to changes in pH, potassium, and calcium level in selected cardiac cells. Though this has not been confirmed by additional study yet, it is suggested that patients with these focal arrhythmias who are taking PPIs should bring this to the attention of their physician.

In March 2011, the US Food and Drug Administration notified healthcare professionals and the public that PPI drugs may cause low serum magnesium levels (hypomagnesemia) if taken for prolonged periods of time - in most cases, longer than one year.[35] Most patients on long-term PPIs will not develop symptomatic hypomagnesemia unless accompanied by precipitating factors such as gastroenteritis, diuretics, and chronic comorbidities.[36]

Another potential adverse event of PPI administration is chronic interstitial nephritis leading to chronic kidney disease and end-stage renal disease.[citation needed]

Omeprazole may increase the elimination of riluzole, a medication often prescribed for people with amyotrophic lateral sclerosis.[37]

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.[4] 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 enzyme; the effect on the overall human digestive system is reversible, as the enzymes are naturally destroyed and 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, particularly of vitamin B12 and of 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).[38] The development of soraprazan, however, has been discontinued in 2007.[39]

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. These pharmacokinetic effects, however, reportedly have no significant impact on efficacy.[40][41]

The elimination half-life of PPIs ranges from 0.5 to 2.0 hr, but the effect of a single dose on acid secretion usually persists up to three days. This is because of accumulation of the drug in parietal cell canaliculi and the irreversible nature of proton pump inhibition.

Examples [edit]

Clinically used proton pump inhibitors:

  • Omeprazole (brand names: Gasec, Losec, Prilosec, Zegerid, ocid, Lomac, Omepral, Omez,Omepep)
  • 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, Zurcal, Zentro, Pan, Controloc, Tecta)
  • Rabeprazole (brand names: AcipHex, Pariet, Erraz, Zechin, Rabecid, Nzole-D, Rabeloc, Razo. Dorafem: combination with domperidone[citation needed]).
  • Ilaprazole (brand names: Noltec, Yili'an, Ilapro, Lupilla, Adiza)

See also [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 "Possible Increased Risk of Bone Fractures With Certain Antacid Drugs". U S Food and Drug Administration. 25 May 2010. Retrieved 26 May 2010. 
  4. ^ 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. 
  5. ^ a b "Five Things Physicians and Patients Should Question". American Gastroenterological Association. 
  6. ^ a b Kahrilas, Peter J.; Shaheen, Nicholas J.; Vaezi, Michael F.; Hiltz, SW; Black, E; Modlin, IM; Johnson, SP; Allen, J et al. (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. 
  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. ^ 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. 
  9. ^ McColl, Kenneth E.L.; Gillen, Derek (2009). "Evidence That Proton-Pump Inhibitor Therapy Induces the Symptoms it is Used to Treat". Gastroenterology 137 (1): 20–2. doi:10.1053/j.gastro.2009.05.015. PMID 19482105. 
  10. ^ a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3[page needed]
  11. ^ http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm245275.htm[full citation needed]
  12. ^ Beck, Melinda (January 18, 2011). "Sluggish? Confused? Vitamin B12 May Be Low". Wall Street Journal. 
  13. ^ Simpson, IAN J; Marshall, Mark R; Pilmore, Helen; Manley, Paul; Williams, Laurie; Thein, HLA; Voss, David (2006). "Proton pump inhibitors and acute interstitial nephritis: Report and analysis of 15 cases". Nephrology 11 (5): 381–5. doi:10.1111/j.1440-1797.2006.00651.x. PMID 17014549. 
  14. ^ Jabbar, A; Khan, R; Farrukh, SN (2010). "Hyperprolactinaemia induced by proton pump inhibitor". JPMA 60 (8): 689–90. PMID 20726208. 
  15. ^ Eom, C.-S.; Jeon, C. Y.; Lim, J.-W.; Cho, E.-G.; Park, S. M.; Lee, K.-S. (2010). "Use of acid-suppressive drugs and risk of pneumonia: A systematic review and meta-analysis". Canadian Medical Association Journal 183 (3): 310–9. doi:10.1503/cmaj.092129. PMC 3042441. PMID 21173070. 
  16. ^ Laheij, Robert J. F.; Sturkenboom, Miriam C. J. M.; Hassing, Robert-Jan; Dieleman, Jeanne; Stricker, Bruno H. C.; Jansen, Jan B. M. J. (2004). "Risk of Community-Acquired Pneumonia and Use of Gastric Acid-Suppressive Drugs". JAMA 292 (16): 1955–60. doi:10.1001/jama.292.16.1955. PMID 15507580. 
  17. ^ "http://www.medical-reference.net/2012/02/breaking-news-fda-issues-warning-on.html" FDA Issued Warning on Several Proton Pump Inhibitors
  18. ^ Howell, Michael D.; Novack, Victor; Grgurich, Philip; Soulliard, Diane; Novack, Lena; Pencina, Michael; Talmor, Daniel (2010). "Iatrogenic Gastric Acid Suppression and the Risk of Nosocomial Clostridium difficile Infection". Archives of Internal Medicine 170 (9): 784–90. doi:10.1001/archinternmed.2010.89. PMID 20458086. 
  19. ^ Deshpande, Abhishek; Pant, Chaitanya; Pasupuleti, Vinay; Rolston, David D.K.; Jain, Anil; Deshpande, Narayan; Thota, Priyaleela; Sferra, Thomas J. et al. (2012). "Association Between Proton Pump Inhibitor Therapy and Clostridium difficile Infection in a Meta-Analysis". Clinical Gastroenterology and Hepatology 10 (3): 225–33. doi:10.1016/j.cgh.2011.09.030. PMID 22019794. 
  20. ^ "Gut Reactions". Medical Observer. 
  21. ^ Namazi, Mohammad Reza; Jowkar, Farideh (2010). "Can Proton Pump Inhibitors Accentuate Skin Aging?". Archives of Medical Research 41 (2): 147–8. doi:10.1016/j.arcmed.2010.02.006. PMID 20470945. 
  22. ^ "Treating heartburn and GERD: Use Nexium, Prilosec, and related drugs carefully". American Gastroenterological Association. April 2012. 
  23. ^ Yang, Yu-Xiao; Lewis, James D.; Epstein, Solomon; Metz, David C. (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. 
  24. ^ "Antacids could lead to broken bones, study suggests". Canwest News Service. August 12, 2008. Retrieved October 26, 2009. 
  25. ^ Targownik, L. E.; Lix, L. M.; Metge, C. J.; Prior, H. J.; Leung, S.; Leslie, W. D. (2008). "Use of proton pump inhibitors and risk of osteoporosis-related fractures". Canadian Medical Association Journal 179 (4): 319–26. doi:10.1503/cmaj.071330. PMC 2492962. PMID 18695179. 
  26. ^ Vries, F.; Staa, T.-P.; Leufkens, H. G. M. (2010). "Proton pump inhibitors, fracture risk and selection bias: Three studies, same database, two answers". Osteoporosis International 22 (5): 1641–2. doi:10.1007/s00198-010-1323-1. PMC 3073046. PMID 20563562. 
  27. ^ http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm#TableofEpidemiologicalstudiesevaluatingfractureriskwithprotonpumpinhibitors Table of epidemiological studies evaluating fracture risk with proton pump inhibitors
  28. ^ Seppa, Nathan (2009). "Bad to the bone: Acid stoppers appear to have a downside". Science News 171: 3. doi:10.1002/scin.2007.5591710102. 
  29. ^ Gilard, Martine; Arnaud, Bertrand; Cornily, Jean-Christophe; Le Gal, Grégoire; Lacut, Karine; Le Calvez, Geneviève; Mansourati, Jacques; Mottier, Dominique et al. (2008). "Influence of Omeprazole on the Antiplatelet Action of Clopidogrel Associated with Aspirin". Journal of the American College of Cardiology 51 (3): 256–60. doi:10.1016/j.jacc.2007.06.064. PMID 18206732. 
  30. ^ "Acid-Reducing Medicines May Lead to Dependency" July 1, 2009
  31. ^ Niklasson, Anna; Lindström, Lina; Simrén, Magnus; Lindberg, Greger; Björnsson, Einar (2010). "Dyspeptic Symptom Development After Discontinuation of a Proton Pump Inhibitor: A Double-Blind Placebo-Controlled Trial". The American Journal of Gastroenterology 105 (7): 1531–7. doi:10.1038/ajg.2010.81. PMID 20332770. 
  32. ^ Sharara, Ala I.; El-Halabi, Mustapha M.; Ghaith, Ola A.; Habib, Robert H.; Mansour, Nabil M.; Malli, Ahmad; El Hajj-Fuleihan, Ghada (2012). "Proton Pump inhibitors have no measurable effect on calcium and bone metabolism in healthy young males: A prospective matched controlled Study". Metabolism. doi:10.1016/j.metabol.2012.09.011. PMID 23102518. 
  33. ^ Farrell (2011). "Proton Pump Inhibitors Interfere with Zinc Absorption and Zinc Body Stores". Gastroenterology Research. doi:10.4021/gr379w. 
  34. ^ Marcus, GM (2010). "Proton Pump Inhibitors are Associated with Focal Arrhythmias". The Journal of Innovations in Cardiac Rhythm Management 1 (4): 85–89. 
  35. ^ http://www.drugs.com/fda/proton-pump-inhibitor-ppis-safety-communication-low-magnesium-levels-can-associated-long-term-12913.html[full citation needed]
  36. ^ Cundy, Tim; MacKay, Jonathan (2011). "Proton pump inhibitors and severe hypomagnesaemia". Current Opinion in Gastroenterology 27 (2): 180–5. doi:10.1097/MOG.0b013e32833ff5d6. PMID 20856115. 
  37. ^ http://products.sanofi-aventis.us/rilutek/rilutek.html[full citation needed]
  38. ^ Schubert-Zsilavecz, M, Wurglics, M: Neue Arzneimittel 2005. Soraprazan (in German).[page needed]
  39. ^ Nycomed Annual Report 2007
  40. ^ AstraZeneca Pty Ltd. Nexium (Australian approved prescribing information). North Ryde: AstraZeneca; 2005.
  41. ^ Wyeth Australia Pty Ltd. Zoton (Australian approved prescribing information). Baulkham Hills: Wyeth; 2004.

External links [edit]

Wikimedia Commons has media related to: Proton pump inhibitors
Gastrointestinal tract/metabolism (A)
Blood and blood forming organs (B)
Cardiovascular system (C)
Skin (D)
Genitourinary system (G)
Endocrine system (H)
Infections and infestations (J, P, QI)
Malignant disease (L01-L02)
Immune disease (L03-L04)
Muscles, bones, and joints (M)
Brain and nervous system (N)
Respiratory system (R)
Sensory organs (S)
Other ATC (V)
H2 antagonists ("-tidine")
Prostaglandins (E)/analogues ("-prost-")
Proton-pump inhibitors ("-prazole")
Other

Retrieved from "http://en.wikipedia.org/w/index.php?title=Proton-pump_inhibitor&oldid=556018129"