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Proton-pump inhibitor

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Proton-pump inhibitor
Drug class
General structure of a proton-pump inhibitor
Class identifiers
UseReduction of gastric acid production
ATC codeA02BC
Mechanism of actionEnzyme inhibitor
Biological targetH+/K+ ATPase
Clinical data
Drugs.comDrug Classes
WebMDMedicineNet 
External links
MeSHD054328
Legal status
In Wikidata

Proton pump inhibitors (PPIs) are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. Within the class of medications, there is no clear evidence that one agent works better than another.[1][2]

They are the most potent inhibitors of acid secretion available.[3] This group of drugs followed and largely superseded another group of medications with similar effects, but a different mode of action, called H2-receptor antagonists.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 WHO Model List of Essential Medicines.[4] The cost between different agents varies significantly.[1]

Medical uses

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

associated laryngopharyngeal reflux causing laryngitis[10] and chronic cough[11]

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.[16][17] 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.[18]

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,[12] they do not change the length affected.[19]

Adverse effects

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.[20] 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.[21] 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.[22]

Nutritional

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.[23] With regard to iron and vitamin B12 the data are weak and several confounding factors have been identified.[20][23]

Low levels of magnesium can be found in people on PPI therapy and these can be reversed when they are switched to H2-receptor antagonist drugs.[20][24]

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.[18]

Gastrointestinal

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.[20] Concerns have also been raised about 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.[20] PPIs may predispose an individual to developing small intestinal bacterial overgrowth or small intestinal fungal overgrowth.[25][26]

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[20] or pre-cancer.[27] There is concern that use of PPIs may mask gastric cancers or other serious gastric problems and physicians should be aware of this effect.[20]

PPI use has also been associated with the development of microscopic colitis.[28]

There is also evidence that PPI use alters the composition of the bacterial populations inhabiting the gut.[29] 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.

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.[30][31] PPIs are commonly used in cardiovascular patients for gastric protection when aspirin is given for its antiplatelet actions.[30][32] 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.[33][34]

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.[35]

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.[36][37] A primary research study using pharmacoepidemiological claims data analysis has reported an association between PPI use and the risk of developing dementia in people over the age of 75 (1.4x hazard ratio)[38] but this has not been examined in prospective studies. Inappropriate prescribing of PPIs in the elderly, including those with dementia, has been reported.[39] Weak associations with chronic kidney disease have been found (1.5x hazard ratio), but these low hazard ratios make it doubtful whether such associations are causal relationships.[40]

Mechanism of action

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.[41] 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%.

Decreasing the acid in the stomach can aid the healing of duodenal ulcers and reduce the pain from indigestion and heartburn. Stomach acids are needed however to digest proteins, vitamin B12, calcium, and other nutrients. Too little stomach acid causes the condition hypochlorhydria.

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.

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, however, that these pharmacokinetic effects have no significant impact on efficacy.[42][43]

PPIs have a half-life in human blood plasma of only 60–90 minutes, but because they covalently bind to the pump, the half-life of their inhibition of gastric acid secretion lasts an estimated 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.[44][45]

Examples

Medically used proton pump inhibitors:

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 drugs are benzimidazole derivatives, related to omeprazole, but imidazopyridine derivatives such as tenatoprazole have also been developed.[3] 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.[46]

Cost

In British Columbia, Canada the cost of the PPIs varies significantly from 0.20 CAD to 2.38 CAD per dose while all agents in the class appear more or less equally effective.[1][2]

References

  1. ^ a b c "[99] Comparative effectiveness of proton pump inhibitors | Therapeutics Initiative". 28 June 2016. Retrieved 14 July 2016.
  2. ^ a b Dean, Laura (1 October 2010). "Comparing Proton Pump Inhibitors". PubMed Health. Retrieved 16 July 2016.
  3. ^ a b 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.
  4. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  5. ^ 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.
  6. ^ Wang WH, Huang JQ, Zheng GF, Xia HH, Wong WM, Liu XG, et al. (2007). "Effects of proton-pump inhibitors on functional dyspepsia: a meta-analysis of randomized placebo-controlled trials". Clinical Gastroenterology and Hepatology. 5 (2): 178–85, quiz 140. doi:10.1016/j.cgh.2006.09.012. PMID 17174612.
  7. ^ Sachar H, Vaidya K, Laine L (2014). "Intermittent vs continuous proton pump inhibitor therapy for high-risk bleeding ulcers: a systematic review and meta-analysis". JAMA Internal Medicine. 174 (11): 1755–62. doi:10.1001/jamainternmed.2014.4056. PMC 4415726. PMID 25201154.
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  9. ^ Sigterman KE, van Pinxteren B, Bonis PA, Lau J, Numans ME (2013). "Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease". Cochrane Database of Systematic Reviews. 5: CD002095. doi:10.1002/14651858.CD002095.pub5. PMID 23728637.
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  19. ^ 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.
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  25. ^ Fujimori S (2015). "What are the effects of proton pump inhibitors on the small intestine?". World J. Gastroenterol. 21 (22): 6817–9. doi:10.3748/wjg.v21.i22.6817. PMC 4462721. 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  26. ^ Erdogan A, Rao SS (April 2015). "Small intestinal fungal overgrowth". Curr Gastroenterol Rep. 17 (4): 16. doi:10.1007/s11894-015-0436-2. PMID 25786900. 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.
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  35. ^ 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.
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