Proton-pump inhibitor

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Proton-pump inhibitor
A02BC
Mechanism of actionEnzyme inhibitor
Biological targetH+/K+ ATPase
Clinical data
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MeSHD054328
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In Wikidata

Proton-pump inhibitors (PPIs) are a class of

H+/K+ ATPase proton pump.[1]

They are the most potent inhibitors of acid secretion available.

antacids.[3]

PPIs are among the most widely sold medications in the world. The class of proton-pump inhibitor medications is on the World Health Organization's List of Essential Medicines.[4][5] Omeprazole is the specific listed example.[4][5]

Medical uses

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

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.[17][18][19] In the United States, the Food and Drug Administration (FDA) has advised that over-the-counter PPIs, such as Prilosec OTC, should be used no more than three 14-day treatment courses over one year.[20][21]

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,[13] they do not change the length affected.[22] In addition, research in the UK has suggested that PPIs are not effective at treating persistent throat symptoms.[23][24]

Indications for stopping PPIs

PPIs are often used longer than necessary. In about half of people who are hospitalized or seen at a primary care clinic there is no documented reason for their long-term use of PPIs.[25] Some researchers believe that, given the little evidence of long-term effectiveness, the cost of the medication and the potential for harm means that clinicians should consider stopping PPIs in many people.[26]

Adverse effects

In general, proton pump inhibitors are well tolerated, and the incidence of short-term adverse effects is relatively low. 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.[citation needed
]

Common adverse effects include

fatigue, and dizziness.[27] 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.[28]

Long-term use of PPIs requires assessment of the balance of the

benefits and risks of the therapy.[29][30][31][32] As of March 2017 various adverse outcomes have been associated with long-term PPI use in several primary reports, but reviews assess the overall quality of evidence in these studies as "low" or "very low".[31] They describe inadequate evidence to establish causal relationships between PPI therapy and many of the proposed associations, due to study design and small estimates of effect size.[32] As of March 2017 Benefits outweighed risks when PPIs are used appropriately, but when used inappropriately, modest risks become important.[31][33] They recommend that PPIs should be used at the lowest effective dose in people with a proven indication, but discourage dose escalation and continued chronic therapy in people unresponsive to initial empiric therapy.[32]

Nutritional

Gastric acid is important for breakdown of food and release of

confounding factors have been identified.[30][34][citation needed
]

H2-receptor antagonist medications.[30][35][21]

Bone fractures

High dose or long-term use of PPIs carries an 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.[20]

In infants, acid suppression therapy is frequently prescribed to treat symptomatic gastroesophageal reflux in otherwise healthy infants (that is: without gastroesophageal reflux disease). A study from 2019 showed that PPI use alone and together with histamine H2-receptor antagonists was associated with an increased bone fracture hazard, which was amplified by days of use and earlier initiation of therapy.[36] The reason is not clear, increased bone break down by osteoclasts has been suggested.[37]

Gastrointestinal

Some studies have shown a correlation between use of PPIs and Clostridioides difficile infection. 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 medications.[30] Concerns have also been raised about spontaneous bacterial peritonitis (SBP) 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.[30] PPIs may predispose an individual to developing small intestinal bacterial overgrowth or fungal overgrowth.[38][39]

In cirrhotic patients, large volume of ascites and reduced esophageal motility by varices can provoke GERD.[40][41][42] Acidic irritation, in return, may induce the rupture of varices.[43] Therefore, PPIs are often routinely prescribed for cirrhotic patients to treat GERD and prevent variceal bleeding. However, it has been recently shown that long term use of PPIs in patients with cirrhosis increases the risk of SBP and is associated with the development of clinical decompensation and liver-related death during long-term follow-up.[44]

There is evidence that PPI use alters the composition of the bacterial populations inhabiting the gut, the gut microbiota.[45] 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.[46] These infections can include Helicobacter pylori due to this species not favouring an acid environment, leading to an increased risk of ulcers and gastric cancer risk in genetically susceptible patients.[46]

PPI use in people who have received attempted H. pylori eradication may also be associated with an increased risk of gastric cancer.[47] The validity and robustness of this finding, with the lack of causality, have led to this association being questioned.[48] It is recommended that long-term PPIs should be used judiciously after considering individual's risk–benefit profile, particularly among those with history of H. pylori infection, and that further, well-designed, prospective studies are needed.[49]

Long-term use of PPIs is associated with the development of benign

gastric cancers or other serious gastric problems.[30]

PPI use has also been associated with the development of microscopic colitis.[50]

Cardiovascular

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.[51][52] PPIs are commonly used in people with cardiovascular disease for gastric protection when aspirin is given for its antiplatelet actions.[51][53] An interaction between PPIs and the metabolism of the platelet inhibitor clopidogrel is known and this drug is also often used in people with cardiac disease.[54][55][19] There are associations with an increased risk of stroke, but this appears to be more likely to occur in people who already have an elevated risk.[56]

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.[57]

Cancer

A 2022 umbrella review of 21 meta-analyses shows an association between proton-pump inhibitor use and an increased risk of four types of cancer.[58]

Other

Associations have been shown between PPI use and an increased risk of pneumonia, particularly in the 30 days after starting therapy, where it was found to be 50% higher in community use.[59][60] Other very weak associations of PPI use have been found, such as with chronic kidney disease,[61][62][63][19][64][65] dementia[66][31][67] and Hepatocellular carcinoma (HCC).[68]

As of 2016, results were derived from observational studies, it remained uncertain whether such associations were causal relationships.[31][32][69]

Mechanism of action

The activation of PPIs

parietal cells.[70] 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.[citation needed] Because the H,K-ATPase is the final step of acid secretion, an inhibitor of this enzyme is more effective than receptor antagonists in suppressing gastric acid secretion.[71] All of these drugs inhibit the gastric H,K-ATPase by covalent binding, so the duration of their effect is longer than expected from their levels in the blood.[72]

Targeting the terminal step in acid production, as well as the

H2 antagonists and reduce gastric acid secretion by up to 99%.[2]

Decreasing the acid in the stomach can aid the healing of

hypochlorhydria.[citation needed
]

The PPIs are given in an inactive form, which is neutrally charged (

covalently
and irreversibly bind to the gastric proton pump, deactivating it.

In H. pylori eradication, PPIs help by increasing the stomach pH, causing the bacterium to shift out of its coccoid form which is resistant to both acids and antibiotics. PPIs also show some weaker additional effects in eradication.[73]

Pharmacokinetics

The rate of omeprazole absorption is decreased by concomitant food intake.

pharmacokinetic effects have no significant impact on efficacy.[75][76]

In healthy humans, the half-life of PPIs is about 1 hour (9 hours for

endogenous antioxidant glutathione which leads to the release of omeprazole sulfide and reactivation of the enzyme.[78][79]

Examples

Medically used proton pump inhibitors:[citation needed]

There is no clear evidence that one proton pump inhibitor works better than another.[1][84]

History

See also: Discovery and development of proton pump inhibitors

PPIs were developed in the 1980s, with omeprazole being launched in 1988. Most of these medications are benzimidazole derivatives, related to omeprazole, but imidazopyridine derivatives such as tenatoprazole have also been developed.[2] 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.[85]

Society and culture

Economics

In British Columbia, Canada the cost of the PPIs varies significantly from CA$0.13 to CA$2.38 per dose[86] while all agents in the class appear more or less equally effective.[1][84]

Regulatory approval

A comparative table of

FDA
-approved indications for PPIs is shown below.

Comparative indications[87]
Indication Omeprazole Esomeprazole Lansoprazole Dexlansoprazole Pantoprazole Rabeprazole
Gastroesophageal reflux disease
Erosive esophagitis-healing Yes Yes Yes Yes Yes Yes
Erosive esophagitis-maintenance Yes Yes Yes Yes Yes Yes
Nonerosive reflux disease Yes Yes Yes Yes No Yes
Peptic ulcer disease
Duodenal ulcer-healing Yes No Yes No No Yes
Duodenal ulcer-maintenance No No Yes No No No
Gastric ulcer-healing Yes No Yes No No No
NSAID induced ulcer-healing No No Yes No No No
NSAID induced ulcer-prophylaxis No Yes Yes No No No
Zollinger-Ellison syndrome
 Yes Yes Yes No Yes Yes
Treatment of Helicobacter pylori
Dual therapy Yes No Yes No No No
Triple therapy Yes Yes Yes No No Yes

References

  1. ^
    ISSN 2369-8691
    . Retrieved 14 July 2016.
  2. ^
    S2CID 30413194
    .
  3. PMID 28427116
    .
  4. ^
    hdl:10665/325771
    . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  5. ^
    hdl:10665/345533
    . WHO/MHP/HPS/EML/2021.02.
  6. doi:10.1016/j.osfp.2012.10.005
    .
  7. PMID 17174612
    .
  8. PMID 25201154
    .
  9. PMID 24338763
    .
  10. PMID 23728637
    .
  11. PMID 17037995
    .
  12. PMID 16330475
    .
  13. ^
    PMID 24221456
    .
  14. PMID 26247167
    .
  15. S2CID 8138473
    .
  16. PMID 24319020
    .
  17. ^ "Five Things Physicians and Patients Should Question". American Gastroenterological Association. 24 February 2015.
  18. PMID 18789939
    .
  19. ^
    PMID 31147311
    . Taking PPIs is associated with a small excess of cause specific mortality including death due to cardiovascular disease, chronic kidney disease, and upper gastrointestinal cancer. The burden was also observed in patients without an indication for PPI use.
  20. ^ a b "FDA Drug Safety Communication: Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors". U.S. Food and Drug Administration (FDA). 23 March 2011. Retrieved 23 August 2015.
  21. ^ a b "Low magnesium levels can be associated with long-term use of PPIs". U.S. Food and Drug Administration (FDA). 17 November 2009. Retrieved 23 February 2020.
  22. S2CID 6969621
    .
  23. S2CID 245960803
    . Retrieved 6 July 2022.
  24. S2CID 231702049
    .
  25. PMID 28500192
    .
  26. ISSN 0828-282X
    .
  27. ISBN 0-9757919-2-3[page needed
    ]
  28. S2CID 33139851
    .
  29. PMID 31264165
    .
  30. ^
    S2CID 205791135
    .
  31. ^
    PMID 28257716
    . Conclusions:Baseline differences between PPI users and non-users make it challenging to study potential PPI adverse effects retrospectively. Despite a large number of studies, the overall quality of evidence for PPI adverse effects is low to very low. When PPIs are appropriately prescribed, their benefits are likely to outweigh their risks. When PPIs are inappropriately prescribed, modest risks become important because there is no potential benefit. There is currently insufficient evidence to recommend specific strategies for mitigating PPI adverse effects.
  32. ^
    PMID 28528705
    . In turn, this has caused unnecessary concern among patients and prescribers. The benefits of PPI therapy for appropriate indications need to be considered, along with the likelihood of the proposed risks. Patients with a proven indication for a PPI should continue to receive it in the lowest effective dose. PPI dose escalation and continued chronic therapy in those unresponsive to initial empiric therapy is discouraged.
  33. PMID 34856983
    .
  34. ^
    PMID 20882439
    .
  35. PMID 25394217
    .
  36. S2CID 182948146
    .
  37. S2CID 20212012
    .
  38. PMID 26078557
    . Generally, proton-pump inhibitors (PPIs) have great benefit for patients with acid related disease with less frequently occurring side effects. According to a recent report, PPIs provoke dysbiosis of the small intestinal bacterial flora, exacerbating nonsteroidal anti-inflammatory drug-induced small intestinal injury. Several meta-analyses and systematic reviews have reported that patients treated with PPIs, as well as post-gastrectomy patients, have a higher frequency of small intestinal bacterial overgrowth (SIBO) compared to patients who lack the aforementioned conditions. Furthermore, there is insufficient evidence that these conditions induce Clostridium difficile infection. At this time, PPI-induced dysbiosis is considered a type of SIBO.
  39. S2CID 3098136
    . Small intestinal fungal overgrowth (SIFO) is characterized by the presence of excessive number of fungal organisms in the small intestine associated with gastrointestinal (GI) symptoms. Candidiasis is known to cause GI symptoms particularly in immunocompromised patients or those receiving steroids or antibiotics. However, only recently, there is emerging literature that an overgrowth of fungus in the small intestine of non-immunocompromised subjects may cause unexplained GI symptoms. Two recent studies showed that 26% (24/94) and 25.3% (38/150) of a series of patients with unexplained GI symptoms had SIFO. The most common symptoms observed in these patients were belching, bloating, indigestion, nausea, diarrhea, and gas. The underlying mechanism(s) that predisposes to SIFO is unclear but small intestinal dysmotility and use of proton pump inhibitors has been implicated. However, further studies are needed; both to confirm these observations and to examine the clinical relevance of fungal overgrowth, both in healthy subjects and in patients with otherwise unexplained GI symptoms.
  40. PMID 20525368
    .
  41. PMID 2734592
    .
  42. PMID 6606991
    .
  43. S2CID 5205186
    .
  44. PMID 31464790
    .
  45. PMID 26719299
    .
  46. ^
    PMID 25743791
    .
  47. PMID 29089382
    .
  48. PMID 31294357
    .
  49. PMID 30886648
    .
  50. PMID 22704658
    .
  51. ^
    PMID 23425521
    .
  52. PMID 25587094
    .
  53. S2CID 21231797
    .
  54. S2CID 23689175
    .
  55. PMID 26196021
    .
  56. S2CID 244803096
    .
  57. PMID 24780466
    . It also seems to be the pathophysiological link between the use of proton pump inhibitors and increased cardiovascular event rate because these medications bind and inhibit DDAH, the enzyme that degrades ADMA, which results in higher ADMA levels and a decrease in bioavailable NO.
  58. S2CID 252970194
    .
  59. PMID 26042842
    .
  60. PMID 21173070
    .
  61. doi:10.1016/j.cegh.2017.12.008
    .
  62. PMID 26752337
    .
  63. PMID 28237709
    .
  64. PMID 27080978
    .
  65. PMID 27080976
    .
  66. ^ Salman Hussain, Ambrish Singh et al. No association between proton pump inhibitors use and risk of dementia: Evidence from a meta-analysis. J Gastroenterol Hepatol. https://doi.org/10.1111/jgh.14789
  67. S2CID 24718665
    . The methodology of these studies allows us to find an association with these events but does not provide us with sufficient evidence to determine causality. In general, the findings of the available studies do not fit with our clinical experience nor is the magnitude of the association sufficient to result in a major change in our practice. Nevertheless, the recent literature has resulted in our careful reevaluation of PPI use across both FDA indications and in general.
  68. S2CID 238746424
    .
  69. S2CID 19207074
    .
  70. PMID 26860309
    .
  71. S2CID 4368190
    .
  72. PMID 12404233
    .
  73. PMID 31558859
    .
  74. S2CID 36206292
    .
  75. ^ AstraZeneca Pty Ltd. Nexium (Australian approved prescribing information). North Ryde: AstraZeneca; 2005.
  76. ^ Wyeth Australia Pty Ltd. Zoton (Australian approved prescribing information). Baulkham Hills: Wyeth; 2004.
  77. ^
    PMID 19006606
    .
  78. PMID 18536934
    .
  79. ^ Carlsson E, Lindberg P (2002). "Two of a kind". Chemistry in Britain. 38 (5): 42–5.
  80. ^ a b "Lansoprazole, Dexlansoprazole". Clinical and Research Information on Drug-induced Liver Injury. National Institutes of Health (NIH). Retrieved May 8, 2018.
  81. ^ a b "Omeprazole and Esomeprazole". Clinical and Research Information on Drug-induced Liver Injury. National Institutes of Health (NIH). Retrieved May 8, 2018.
  82. ^ "Pantoprazole". Clinical and Research Information on Drug-induced Liver Injury. National Institutes of Health (NIH). Retrieved May 8, 2018.
  83. ^ "Rabeprazole". Clinical and Research Information on Drug-induced Liver Injury. National Institutes of Health (NIH). Retrieved May 8, 2018.
  84. ^ a b Dean L (1 October 2010). Comparing Proton Pump Inhibitors. PubMed Clinical Q&A. National Center for Biotechnology Information (US).
  85. S2CID 41932174
    .
  86. ^ "Proton Pump Inhibitors in Primary Care" (PDF). Province of British Columbia. January 2015.
  87. PMID 27840364
    .

External links
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