| 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 today. The group followed and has largely superseded another group of pharmaceuticals with similar effects, but different mode-of-action, called H2-receptor antagonists. These drugs are among the most widely-selling drugs in the world and are generally considered effective.[1] The vast majority of these drugs are benzimidazole derivatives; however, promising new research indicates that imidazopyridine derivatives may be a more effective means of treatment.[2] High dose or long-term use of PPIs carry a possible increased risk of bone fractures.[3]
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Contents
- 1 Indications
- 2 Adverse effects
- 2.1 Short-term
- 2.2 Long-term
- 3 Mechanism of action
- 3.1 Potassium-competitive acid blockers (P-CABs)
- 4 Pharmacokinetics
- 5 Examples
- 6 See also
- 7 References
- 8 External links
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Indications
These drugs are utilized in the treatment of many conditions such as:
- Dyspepsia
- Peptic ulcer disease (PUD)
- Gastroesophageal reflux disease (GERD)
- Laryngopharyngeal reflux
- Barrett's esophagus
- prevention of stress gastritis
- Gastrinomas and other conditions that cause hypersecretion of acid
- Zollinger-Ellison syndrome.
The effectiveness of proton pump inhibitors has not been demonstrated in every case, despite their widespread use for these conditions. For example, proton pump inhibitors do not change the length of Barrett's esophagus.[4] The most objective test to assess success of PPI therapy in patients with GERD is esophageal pH monitoring.
The FDA advises that no more than three 14-day treatment courses should be used in one year.[3]
Adverse effects
Short-term
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 proton pump inhibitors, 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[5]), nausea, diarrhea, abdominal pain, fatigue, and dizziness.[6] Long-term use is associated with hypomagnesemia.[7]
Because the body uses gastric acid to release B12 from food particles, decreased vitamin B12 absorption may occur with long-term use of proton-pump inhibitors and may lead to Vitamin B12 deficiency.[6][8]
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.[9]
It has been observed that gastric acid suppression, using H2-receptor antagonists and proton pump inhibitors, is associated with an increased risk of community-acquired pneumonia. It is suspected that acid suppression results in insufficient elimination of pathogenic organisms. Therefore, it has been suggested that patients at higher risk of pneumonia should be prescribed proton pump inhibitors only at lower doses and only when necessary.[10]
PPIs have been shown to raise risk of Clostridium difficile infection by 1.7X with once daily use and 2.4X with more than once daily use.[11][12] The risk can be minimized by judicious short term prescriptions.[13]
Long-term
Long-term use of proton pump inhibitors has been less studied. 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 years 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.[14][15][16] However, in 2010 data from the same source (the UK General Practice Research Database) was 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 wouldn't be published until a year later - May, 2011 and it wasn't even published online until the following month - 2010 June 19.[17] Furthermore, of the seven studies the FDA did make note of, all but the smallest study found marked increased risks of fractures.[18] 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.[19] Also, the reduction of vitamin B12 may be also increase bone fragility by raising homocysteine). A recent study also suggested that proton pump inhibitors 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.[20]
A 2009 report in Gastroenterology suggests that PPIs may cause dependency by increasing gastric symptoms if they are discontinued.[21] A 2010 report in the American Journal of Gastroenterology reported on healthy volunteers who were given pantoprazole or placebo for 4 weeks and then followed for 6 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.[22] It was hypothesized that such "rebound hyperacidity" is mediated by gastrin hormone secretion which occurred following the discontinuation of PPI's, and that 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.
In December 2010, a published report suggested a nearly four-fold increase in certain heart arrhythmias (focal atrial tachycardia and right ventricular outflow tract, RVOT tachycardia). [23] 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 U.S. Food and Drug Administration (FDA) notified healthcare professionals and the public that prescription proton pump inhibitor drugs may cause low serum magnesium levels (hypomagnesemia) if taken for prolonged periods of time - in most cases, longer than one year.[24]
Omeprazole may increase the elimination of riluzole, a medication often prescribed for people with amyotrophic lateral sclerosis.[25]
Mechanism of action
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 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 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. However, lack of stomach acid is also called hypochlorhydria, the lack of sufficient hydrochloric acid, or HCl. Hydrochloric acid is required for the digestion of proteins and for the absorption of nutrients, particularly of vitamin B12 and of calcium.
The proton pump inhibitors are given in an inactive form. The inactive form is neutrally charged (lipophilic) and readily crosses cell membranes into intracellular compartments (like the parietal cell canaliculus) that have 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 (P-CABs)
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).[26] The development of soraprazan, however, has been discontinued in 2007.[27]
Pharmacokinetics
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 that these pharmacokinetic effects, however, have no significant impact on efficacy.[28][29]
The elimination half-life of proton pump inhibitors ranges from 0.5–2 hours, however the effect of a single dose on acid secretion usually persists up to 2–3 days. This is because of accumulation of the drug in parietal cell canaliculi and the irreversible nature of proton pump inhibition.
Examples
Clinically used proton pump inhibitors:
- Omeprazole (brand names: Gasec, Losec, Prilosec, Zegerid, ocid, Lomac, Omepral, Omez,)
- 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)
- Rabeprazole (brand names: AcipHex, Pariet, Erraz, Zechin, Rabecid, Nzole-D, Rabeloc, Razo. Dorafem: combination with domperidone[citation needed]).
See also
- Discovery and development of proton pump inhibitors
- Sucralfate
- Aluminium hydroxide
References
- ^ "Follow The Pill: Understanding the U.S. Commercial Pharmaceutical Supply Chain". The Kaiser Family Foundation. March 2005.
- ^ Sachs G, Shin JM, Howden CW (2006). "Review Article: The clinical pharmacology of proton pump inhibitors". Ailment. Pharmacol. Ther. 23 (2): 2–8. doi:10.1111/j.1365-2036.2006.02943.x.
- ^ a b "Possible Increased Risk of Bone Fractures With Certain Antacid Drugs". U S Food and Drug Administration. 25 May 2010. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm213240.htm. Retrieved 26 May 2010.
- ^ Cooper BT, Chapman W, Neumann CS, Gearty JC (2006). "Continuous treatment of Barrett's esophagus patients with proton pump inhibitors up to 13 years: observations on regression and cancer incidence". Aliment. Pharmacol. Ther. 23 (6): 727–33. doi:10.1111/j.1365-2036.2006.02825.x. PMID 16556174.
- ^ http://www.natap.org/2009/HIV/070409_02.htm
- ^ a b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
- ^ http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm245275.htm
- ^ Melinda Beck (January 18, 2011). "Sluggish? Confused? Vitamin B12 May Be Low". Wall Street Journal. http://online.wsj.com/article/SB10001424052748703396604576087890340653656.html?mod=googlenews_wsj.
- ^ Simpson, I. J. (2006). "Proton pump inhibitors and acute interstitial nephritis: Report and analysis of 15 cases". Nephrology 11: 381–385. doi:10.1111/j.1440-1797.2006.00651.x
- ^ Laheij RJF, Sturkenboom MCJM, Hassing R-J, Dieleman J, Stricker BHC, Jansen JBMJ. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA 2004;292(16): 1955-60. PMID 15507580
- ^ "Arch Intern Med -- Abstract: Iatrogenic Gastric Acid Suppression and the Risk of Nosocomial Clostridium difficile Infection, May 10, 2010, Howell et al. 170 (9): 784". http://archinte.ama-assn.org/cgi/content/abstract/170/9/784.
- ^ Deshpande A, Pant C, Pasupuleti V et al. (2011). "Association between Proton Pump Inhibitor therapy and Clostridium difficile infection in a Meta-Analysis". Clin. Gastroenterol. Hepatol. 10 (3): 225–33. doi:10.1016/j.cgh.2011.09.030. PMID 22019794. http://www.sciencedirect.com/science/article/pii/S1542356511010780.
- ^ Hanrahan, C (Sept 04 2009). "Gut Reactions". Medical Observer: 23–25.
- ^ Yang, YX; Lewis JD, Epstein S, Metz DC (Dec 27 2006). "Long-term proton pump inhibitor therapy and risk of hip fracture". Journal of the American Medical Association 296 (24): 2947–53. doi:10.1001/jama.296.24.2947. PMID 17190895.
- ^ "Antacids could lead to broken bones, study suggests". Canwest News Service. August 12, 2008. http://www.canada.com/topics/bodyandhealth/story.html?id=518c33ea-1b11-4fcd-bbba-98a1102370bb. Retrieved October 26, 2009.
- ^ Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S, Leslie WD (August 12, 2008). "Use of proton pump inhibitors and risk of osteoporosis-related fractures". CMAJ 179 (4): 319–26. doi:10.1503/cmaj.071330. PMC 2492962. PMID 18695179. http://www.cmaj.ca/cgi/content/full/179/4/319.
- ^ de Vries F et al. et al. (2010). "Proton pump inhibitors, fracture risk and selection bias: three studies, same database, two answers". Osteoporos Int. 22 (5): 1641–1642. doi:10.1007/s00198-010-1323-1. PMC 3073046. PMID 20563562. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3073046.
- ^ http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm#TableofEpidemiologicalstudiesevaluatingfractureriskwithprotonpumpinhibitors Table of epidemiological studies evaluating fracture risk with proton pump inhibitors
- ^ Seppa, Nathan (January 7 2007). "Bad to the Bone: Acid stoppers appear to have a downside". Science News 171 (1): 3. doi:10.1002/scin.2007.5591710102.
- ^ Gilard, M; Bertrand Arnaud, PHARMD, Jean-Christophe Cornily, MD, Grégoire Le Gal, MD, Karine Lacut, MD, Geneviève Le Calvez, PHARMD, Jacques Mansourati, MD, Dominique Mottier, MD, Jean-François Abgrall, MD, Jacques Boschat, MD (Jan 22 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.
- ^ "Acid-Reducing Medicines May Lead to Dependency" July 1, 2009
- ^ Niklasson A et al. Dyspeptic symptom development after discontinuation of a proton pump inhibitor: A double-blind placebo-controlled trial. Am J Gastroenterol 2010 Jul; 105:1531
- ^ Marcus, GM, Smith LM et al. (2010). "Proton Pump Inhibitors are Associated with Focal Arrhythmias". The Journal of Innovations in Cardiac Rhythm Management 1 (4): 85–89. http://www.innovationscrm.com/showarticle.aspx?id=79. Retrieved 6 June 2011.
- ^ http://www.drugs.com/fda/proton-pump-inhibitor-ppis-safety-communication-low-magnesium-levels-can-associated-long-term-12913.html
- ^ http://products.sanofi-aventis.us/rilutek/rilutek.html
- ^ Schubert-Zsilavecz, M, Wurglics, M: Neue Arzneimittel 2005. Soraprazan (in German).
- ^ Nycomed Annual Report 2007
- ^ AstraZeneca Pty Ltd. Nexium (Australian approved prescribing information). North Ryde: AstraZeneca; 2005.
- ^ Wyeth Australia Pty Ltd. Zoton (Australian approved prescribing information). Baulkham Hills: Wyeth; 2004.
External links
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Drugs for acid related disorders: Drugs for peptic ulcer and GERD/GORD (A02B)
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| Proton-pump inhibitors ("-prazole") |
- Dexlansoprazole
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- See also: Helicobacter pylori eradication protocols
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anat(t, g, p)/phys/devp/enzy
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noco/cong/tumr, sysi/epon
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proc, drug(A2A/2B/3/4/5/6/7/14/16), blte
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