Proton-pump inhibitor

Template:Short description Template:Use dmy dates Template:Cs1 config Template:Infobox drug class Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H⁺/K⁺ ATPase proton pump.<ref name=TI(99)2016/> The body eventually synthesizes new proton pumps to replace the irreversibly inhibited ones, a process driven by normal cellular turnover, which gradually restores acid production.<ref>Template:Cite journal</ref>

Proton-pump inhibitors have largely superseded the H₂-receptor antagonists, a group of medications with similar effects but a different mode of action, and heavy use of antacids.<ref>Template:Cite journal</ref> A potassium-competitive acid blocker (PCAB) revaprazan was marketed in Korea as an alternative to a PPI. A newer PCAB vonoprazan with a faster and longer lasting action than revaprazan, and PPIs has been marketed in Japan (2013), Russia (2021), and the US (2023).<ref>Template:Cite journal</ref><ref>Template:Cite web</ref><ref>Template:Cite press release</ref>

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.<ref name="WHO21st">Template:Cite book</ref><ref name="WHO22nd">Template:Cite book</ref> Omeprazole is the specific listed example.<ref name="WHO21st" /><ref name="WHO22nd" />

Medical uses

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

• Dyspepsia<ref name="Overview">Template:Cite journal</ref><ref name="pmid17174612">Template:Cite journal</ref>
• Peptic ulcer disease including after endoscopic treatment for bleeding<ref name="pmid25201154">Template:Cite journal</ref>
• As part of Helicobacter pylori eradication therapy<ref name="pmid24338763">Template:Cite journal</ref>
• Gastroesophageal reflux disease (GERD or GORD) including symptomatic endoscopy-negative reflux disease<ref name="pmid23728637">Template:Cite journal</ref> and associated laryngopharyngeal reflux causing laryngitis<ref name="pmid17037995">Template:Cite journal</ref> and chronic cough<ref name="pmid16330475">Template:Cite journal</ref>
• Barrett's esophagus<ref name="pmid24221456">Template:Cite journal</ref>
• Eosinophilic esophagitis<ref name="pmid26247167">Template:Cite journal</ref>
• Stress gastritis and ulcer prevention in critical care<ref name="pmid23318494">Template:Cite journal</ref>
• Gastrinomas
• Zollinger–Ellison syndrome (often 2–3× the regular dose is required)<ref name="pmid24319020">Template:Cite journal</ref>

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.<ref name="AGAfive">Template:Cite web</ref><ref name="refluxstate">Template:Cite journal</ref><ref name="doi/10.1136/bmj.l1580" /> 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.<ref name="fda" /><ref name="FDA magnesium" />

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,<ref name="pmid24221456" /> they do not change the length affected.<ref name="pmid16556174">Template:Cite journal</ref> In addition, research in the UK has suggested that PPIs are not effective at treating persistent throat symptoms.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

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.<ref name=Far2017>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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.Template:Citation needed

Common adverse effects include headache, nausea, diarrhea, abdominal pain, fatigue, and dizziness.<ref name="Rossi">Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. Template:ISBNTemplate:Page needed</ref> 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.<ref>Template:Cite journal</ref>

Long-term use of PPIs requires assessment of the balance of the benefits and risks of the therapy.<ref>Template:Cite journal</ref><ref name=Corleto2014>Template:Cite journal</ref><ref name="pmid28257716">Template:Cite journal</ref><ref name="pmid28528705">Template:Cite journal</ref> 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".<ref name="pmid28257716"/> 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.<ref name="pmid28528705"/>

As of March 2017, benefits outweighed risks when PPIs are used appropriately, but when used inappropriately, modest risks become important.<ref name="pmid28257716"/><ref>Template:Cite journal</ref> 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.<ref name="pmid28528705"/>

With regard to iron and vitamin B₁₂, the data is weak and several confounding factors have been identified.<ref name="Corleto2014" /> 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.<ref name=Corleto2014 /><ref name="pmid25394217">Template:Cite journal</ref><ref name="FDA magnesium">Template:Cite web</ref>

Bone

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.<ref name="fda">Template:Cite web</ref>

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.<ref name="ped">Template:Cite journal</ref> The reason is not clear; increased bone break down by osteoclasts has been suggested.<ref>Template:Cite journal</ref>

A recent 2024 study published in the Journal of Clinical Endocrinology & Metabolism found that chronic use of PPIs in men is linked to lower trabecular bone quality.<ref>Template:Cite web</ref> Specifically, PPI use was associated with reduced lumbar spine trabecular bone score (TBS), as well as lower bone mineral density (BMD) T-scores in the lumbar spine, total hip, and femoral neck.<ref>Template:Cite journal

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.<ref name="pmid20882439">Template:Cite journal</ref> These findings suggest that long-term PPI use may negatively affect bone health in men.

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.<ref name=Corleto2014 /> 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.<ref name=Corleto2014 /> PPIs may predispose an individual to developing small intestinal bacterial overgrowth or fungal overgrowth.<ref name="SIBO">Template:Cite journal</ref><ref name="SIFO">Template:Cite journal</ref>

In cirrhotic patients, large volume of ascites and reduced esophageal motility by varices can provoke GERD.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Acidic irritation, in return, may induce the rupture of varices.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

There is evidence that PPI use alters the composition of the bacterial populations inhabiting the gut, the gut microbiota.<ref>Template:Cite journal</ref> 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.<ref name=":1" /> 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.<ref name=":1">Template:Cite journal</ref>

PPI use in people who have received attempted H. pylori eradication may also be associated with an increased risk of gastric cancer.<ref name="pmid29089382">Template:Cite journal</ref> The validity and robustness of this finding, with the lack of causality, have led to this association being questioned.<ref name="PMID31294357">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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.<ref name="Corleto2014" /> There is concern that use of PPIs may mask gastric cancers or other serious gastric problems.<ref name="Corleto2014" />

PPI use has also been associated with the development of microscopic colitis.<ref name="pmid22704658">Template:Cite journal</ref>

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.<ref name="pmid23425521">Template:Cite journal</ref><ref name="pmid25587094">Template:Cite journal</ref> PPIs are commonly used in people with cardiovascular disease for gastric protection when aspirin is given for its antiplatelet actions.<ref name="pmid23425521" /><ref name="pmid21047145">Template:Cite journal</ref> 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.<ref name="pmid22851683">Template:Cite journal</ref><ref name="pmid26196021">Template:Cite journal</ref><ref name="doi/10.1136/bmj.l1580">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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.<ref name="pmid24780466">Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

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.<ref name="pmid26042842">Template:Cite journal</ref><ref name=pmid21173070>Template:Cite journal</ref> Other very weak associations of PPI use have been found, such as with chronic kidney disease,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="doi/10.1136/bmj.l1580" /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> dementia<ref>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</ref><ref name="pmid28257716"/><ref name="pmid28130652">Template:Cite journal</ref> and Hepatocellular carcinoma (HCC).<ref>Template:Cite journal</ref>

As of 2016, results were derived from observational studies, it remained uncertain whether such associations were causal relationships.<ref name="pmid28257716"/><ref name="pmid28528705"/><ref name="pmid27006255">Template:Cite journal</ref>

Mechanism of action

File:Proton pump inhibitors mechanism.svg

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.<ref>Template:Cite book</ref> 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.Template: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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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%.<ref name="pmid16700898">Template:Cite journal</ref>

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.Template:Citation needed

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.

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.<ref name="pmid31558859">Template:Cite journal</ref>

Pharmacokinetics

The rate of omeprazole absorption is decreased by concomitant food intake.<ref>Template:Cite journal</ref> 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.<ref>AstraZeneca Pty Ltd. Nexium (Australian approved prescribing information). North Ryde: AstraZeneca; 2005.</ref><ref>Wyeth Australia Pty Ltd. Zoton (Australian approved prescribing information). Baulkham Hills: Wyeth; 2004.</ref>

In healthy humans, the half-life of PPIs is about 1 hour (9 hours for tenatoprazole), but the duration of acid inhibition is 48 hours because of irreversible binding to the H,K-ATPase.<ref name=":0">Template:Cite journal</ref> All the PPIs except tenatoprazole are rapidly metabolized in the liver by CYP enzymes (mostly by CYP2C19 and 3A4).<ref name=":0" /> 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.<ref name="Shin 2009">Template:Cite journal</ref><ref name="Carlsson 2002">Template:Cite journal</ref>

Examples

Medically used proton pump inhibitors:Template:Citation needed

• Dexlansoprazole<ref name= ld/>
• Esomeprazole (OTC and Rx-only in the US and Australia)<ref name= oe/>
• Ilaprazole (not FDA-approved Template:As of)
• Lansoprazole (OTC and Rx-only in the US)<ref name= ld>"Lansoprazole, Dexlansoprazole". Clinical and Research Information on Drug-induced Liver Injury. National Institutes of Health (NIH). Retrieved May 8, 2018.</ref>
• Omeprazole (over-the-counter drug)<ref name= oe>"Omeprazole and Esomeprazole". Clinical and Research Information on Drug-induced Liver Injury. National Institutes of Health (NIH). Retrieved May 8, 2018.</ref>
• Pantoprazole<ref>"Pantoprazole". Clinical and Research Information on Drug-induced Liver Injury. National Institutes of Health (NIH). Retrieved May 8, 2018.</ref>
• Rabeprazole<ref>"Rabeprazole". Clinical and Research Information on Drug-induced Liver Injury. National Institutes of Health (NIH). Retrieved May 8, 2018.</ref>

There is no clear evidence that one proton pump inhibitor works better than another.<ref name="TI(99)2016" /><ref name="De2010">Template:Cite book</ref>

History

Template:See also 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.<ref name="pmid16700898" /> 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.<ref name="pmid20880169">Template:Cite journal</ref>

Society and culture

Economics

In British Columbia, Canada the cost of the PPIs varies significantly from Template:CAD to Template:CAD per dose<ref>Template:Cite web</ref> while all agents in the class appear more or less equally effective.<ref name=TI(99)2016>Template:Cite web</ref><ref name=De2010/>

Regulatory approval

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

Comparative indications<ref name="Strand et al 2017">Template:Cite journal</ref>

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

External links

• Template:Cite web