Proton-pump inhibitor

Proton-pump inhibitors (PPIs) are members of a class of medications whose main action is a profound and prolonged reduction of stomach acid production. Within the class of medications, there is no clear evidence that one agent works better than another.[1][2]

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
In Wikidata

They are the most potent inhibitors of acid secretion available.[3] This group of medications followed and largely superseded another group of medications with similar effects, but a different mode of action, the H2-receptor antagonists.

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] Omeprazole is the specific listed example.[4]

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.[16][17][18] In the United States, the Food and Drug Administration (FDA) has advised that no more than three 14-day treatment courses should be used in one year.[19][20]

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.[21]

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.[22] 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.[23]

After four weeks, if symptoms have resolved, the PPI may be stopped in those who were using them for heartburn, gastroesophageal reflux disease, or inflammation of the esophagus if these last two were not severe.[22] Stopping is not recommended in those with Barrett esophagus or a bleeding stomach ulcer.[22] Stopping may be carried out by first decreasing the amount of medication taken or having the person take the medication only when symptoms are present.[24]

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.

Common adverse effects include headache, nausea, diarrhea, abdominal pain, fatigue, and dizziness.[25] 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.[26]

Long-term use of PPIs requires assessment of the balance of the benefits and risks of the therapy.[27][28][29] 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".[28] 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.[29] Benefits outweigh risks when PPIs are used appropriately, but when used inappropriately, modest risks become important.[28] 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.[29]

A three-year trial of pantoprazole, completed in 2019, did not find any significant adverse events.[30]

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.[31] With regard to iron and vitamin B12, the data are weak and several confounding factors have been identified.[27][31]

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 medications.[27][32][20]

High dose 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.[19]

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.[27] 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.[27] PPIs may predispose an individual to developing small intestinal bacterial overgrowth or fungal overgrowth.[33][34]

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.[27] There is concern that use of PPIs may mask gastric cancers or other serious gastric problems.[27]

PPI use has also been associated with the development of microscopic colitis.[35]

There is also evidence that PPI use alters the composition of the bacterial populations inhabiting the gut.[36] 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. These infections can include Helicobacter pylori due to this species not favouring an acid environment, leading an increased risk of ulcers and Gastric cancer risk in genetically susceptible patients.[37]

PPI use in subjects who have received attempted H. pylori eradication may also be associated with an increased risk of gastric cancer.[38] The validity and robustness of this finding, with the lack of causality, have led to this association being questioned.[39] 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.[40]

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.[41][42] PPIs are commonly used in people with cardiovascular disease for gastric protection when aspirin is given for its antiplatelet actions.[41][43] 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.[44][45][18]

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.[46]

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.[47][48] Other very weak associations of PPI use have been found, such as with chronic kidney disease[49][50][51][18][52][53] and dementia.[54][28][55] As these results were derived from observational studies, it remains uncertain whether such associations are causal relationships.[28][29][56]

Mechanism of action
The activation of PPIs

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.[57] 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 medications that are significantly more effective than H2 antagonists and reduce gastric acid secretion by up to 99%.[3]

Decreasing the acid in the stomach can aid the healing of duodenal ulcers and reduce the pain from indigestion and heartburn. However, stomach acids are needed to digest proteins, vitamin B12, calcium, and other nutrients, and 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.[58] 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.[59][60]

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.[61][62]

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 medications 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.[67]

Society and culture

Cost

In British Columbia, Canada the cost of the PPIs varies significantly from CA$0.13 to CA$2.38 per dose[68] while all agents in the class appear more or less equally effective.[1][2]

Regulatory approval

A comparative table of FDA-approved indications for PPIs is shown below.

Comparative indications[69]
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

Research

COVID-19

According to one study proton-pump inhibitors may affect the severity of symptoms of COVID-19.[70]

References
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