The gastric acid secretion is involved in the digestion process, absorption of nutrients, and the prevention of infectious agents from transiting to the intestines. In the corpus of the stomach localized parietal cells are responsible for the production and release of HCl, which process is physiologically regulated by paracrine and neural pathways (Martinsen et al., 2019; Engevik et al., 2020).

The ultimate effector of the gastric acid secretion pathway is the proton pump, a membrane-bound enzyme called H+/K+-ATPase (H+/K+-adenosine triphosphatase), which is the target of medications used to treat gastric acid-related diseases (Sachs et al., 2006; El et al., 2018; Yao and Smolka, 2019; Strand et al., 2017; Del Re et al., 2021). By irreversible inhibition of the H(+)/K(+)-adenosine triphosphatase in cytoplasmic membranes of parietal cells of the stomach, Proton Pump Inhibitors (PPIs) are able to reduce the secretion of gastric acid (Sachs et al., 2006; El et al., 2018; Yao and Smolka, 2019; Srebro et al., 2022; Robinson and Horn, 2003; Ahmed and Clarke, 2023; Turshudzhyan et al., 2022).

PPIs are the main therapy for gastroesophageal reflux disease (GERD), which is one of the most commonly diagnosed gastrointestinal disorders in the United States with a prevalence of 20% (Cascella and Dulebohn, 2022). GERD is defined as abnormal reflux of gastric contents from the stomach into the esophagus or beyond including the oral cavity (Badillo and Francis, 2014). PPIs also have utility in treating of esophagitis, non-erosive reflux disease, peptic ulcer disease, prevention of nonsteroidal anti-inflammatory drug-induced ulcers, Zollinger-Ellison Syndrome and as a part therapy regimen for Helicobacter pylori infections (Ahmed and Clarke, 2023).

Over the past decade, many studies have evaluated the long-term PPI adverse effects (AEs) (Lehault and Hughes, 2017). Among the effects of long-term PPI intake is vitamin B12 deficiency, which can occur in long-term patients with nutrition disorders and the seniors in whom the risk of deficiency is 2–4 times higher (Novotny et al., 2019). Studies also report reduced calcium levels or even deficiency in patients with elevated stomach pH because calcium is not absorbed into the bloodstream and remains in the gastrointestinal tract for excretion. Without proper calcium levels in the body, osteoclasts and osteoblasts remain inactive, which hinders proper bone turnover (Lehault and Hughes, 2017). Studies have shown that long-term use of PPIs may increase the risk of bone fractures, but this requires further research (Aldulaijan, 2024; Kondapalli et al., 2023). Another reported side effect associated with long-term PPI treatment is an increased risk of infections - like, for example, small intestinal bacterial overgrowth (SIBO), nontyphoidal salmonella and campylobacter infections, Clostridium difficile infections (CDI), and pneumonia (Novotny et al., 2019). Increased risk of serious acute cardiovascular events, including acute myocardial infarction and stroke, has also been correlated with long-term or high-dose PPI treatment (Yibirin et al., 2021). Cardiovascular diseases along with renal failure (i.e., acute interstitial nephritis) and dementia are idiosyncratic side effects that are rare (Helgadottir and Bjornsson, 2019). The effects of short-term and long-term therapy are generally summarized in the table below (Table 1).

Among the six proton pump inhibitors (PPIs) approved by the FDA: omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole and pantoprazole, omeprazole holds a prominent position as one of the top ten most prescribed medications in the United States (Ahmed and Clarke, 2023; Turshudzhyan et al., 2022). In European Union esomeprazole and pantoprazole are the two PPIs which have been authorized by European Medicines Agency (EMA) (Annex, 2020; ROTS and Annex, 2019). Omeprazole, lansoprazole, dexlansoprazole and rabeprazole are authorized for use in the European Union in individual Member States via national procedures (ROTS and Annex, 2019). Furthermore there are PPIs available only in China, India and Korea such as ilaprazole, dexrabeprazole ad s-patoprazole tenatoprazole, AGN201904-Z, azeloprazole adanaprazole are in clinical trials (Ahmed and Clarke, 2023; Novotny et al., 2019).

This narrative review was based on a structured search of relevant literature across leading biomedical databases, primarily PubMed, supplemented by EMBASE, Web of Science, and Cochrane Library, which are widely recognized for their high-quality, peer-reviewed medical content. We considered articles published within the last 20 years, with a particular emphasis on literature from the past 8 years, which constitutes the majority of the references cited. This time frame was selected to ensure the highest possible reliability of our scientific work.

PPIs are characterized by relatively short half-life: 0.6–1.9 h. In contrast to the short half-life of PPIs the clinical effect of gastric acid suppression persists longer (Srebro et al., 2022; Turshudzhyan et al., 2022). Extended duration of clinical response after administration of these irreversible PPIs is the result of the time needed to form a new H+/K+-ATPase proton pump (54 h) (El et al., 2018; Turshudzhyan et al., 2022; Lima et al., 2021). Studies show that repeated administration leads to inhibition of more pumps, which enhance the suppression of gastric acid secretion (El et al., 2018; Lima et al., 2021).

Omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole and pantoprazole are metabolized by the liver enzymes, in majority by the isoenzyme CYP2C19, less by CYP3A4 but only two of them: omeprazole and esomeprazole are inhibitors of CYP2C19 which is significant for interactions between PPI and drugs metabolized by CYP2C19 (El et al., 2018). Rabeprazole is metabolized on non-enzymatic pathway (Turshudzhyan et al., 2022; Lima et al., 2021). Because of the impact of genetic and nongenetic factors, the response on treatment with PPIs may vary (Table 2).

PPIs are acid-labile weak bases distributed as inactive agents and need low pH to start the inhibition of the H+,K+-ATPase. To prevent early activation within the stomach, it is necessary to safeguard them from the effects of gastric acid. This can be accomplished, for example, by enteric coating (Srebro et al., 2022; Proton Pump Inhibitors, 2012).

PPIs are benzimidazole derivatives, which optimal activity of PPIs is reached when they are administered in a fasting state. Patients are advised to take their PPIs on an empty stomach to achive maximum absorption of PPIs (Sachs et al., 2006; Strand et al., 2017; Robinson and Horn, 2003; Ahmed and Clarke, 2023). It is important to mention that administration with other anti-secretory agents may also have an impact on the activation and absorption of PPIs (Sachs et al., 2006).

All PPIs as an active sulfenic acid or sulfonamide bind covalently to cysteine residues on the H+/K+ ATPase and start to inhibit acid secretion until new pumps can be synthesized (Sachs et al., 2006; Strand et al., 2017; Ahmed and Clarke, 2023). There are some differences in localization of cysteine molecules: cysteine 813 is exposed on the luminal surface of the pump in a vestibule, cysteines 321, 813 and 822 are in the proton-transport domain of the H⁺K⁺-ATPase, cysteine 892 is localized on the external luminal surface. Cysteines 321 and 813 are in a luminal vestibule of the pump. Such differences in cysteine binding among the PPIs may underlie the differences among them in duration of inhibition of gastric acid secretion (Sachs et al., 2006; Shin and Sachs, 2008).

Wu et al. evaluated the impact of omeprazole and other PPIs (pantoprazole, lansoprazole, esomeprazole, rabeprazole and dexlansoprazole) on the survival of cancer patients treated with programmed death protein-1/ligand-1 (PD-1/L1) inhibitors. Eight studies involving 4,869 patients were included. The results of this meta-analysis showed that omeprazole use was associated with a shorter overall survival. In solid cancer patients receiving PD-1/PD-L1 inhibitors, the use of PPIs was associated with a 43% increased risk of death. Still additional clinical trials and experimental investigations are required to validate the impact and underlying mechanism of PPI on exacerbating the clinical outcome of PD-1/L1 inhibitor (Wu et al., 2022) (Table 5).

The pandemic caused by the SARS-CoV-2 virus was a huge challenge for health protection. During the COVID-19 pandemic, many studies have been conducted on the impact of various factors that may have contributed to the increased risk of illness, severe symptoms of infection, complications and mortality. One of the possible routes of infection with the SARS-CoV-2 virus is the oral route. PPIs are one of the most frequently prescribed drugs, hence the interest of many researchers in the possible impact of the use of these drugs on the course of COVID-19 disease. The effect of PPIs is to increase the pH of the stomach, which promotes the development of the microbiome in the stomach. Based on studies and meta-analyses, it was found that the use of PPIs contributed to the increase in the severity of COVID-19 symptoms and secondary infection. The probable cause is the previously mentioned increase in gastric pH and, as a result, increased virus multiplication, which translated into an increased cytokine storm, leading to more severe symptoms presented by the patient. It was found in this meta-analysis that the use of PPIs did not translate into an increase in mortality due to SARS-CoV-2 virus infection (Shokri et al., 2023). Veettil et al. (2022) showed that the use of PPI has been connected to a higher risk of COVID-19-related mortality as well as other associated side effects, such as severity and longer hospital stays. However, they indicate the need for further research to confirm this theory (Fatima et al., 2022).

In July 2020, a large study found that PPI users were more likely to report a positive test for SARS-CoV-2.6 In contrast, Lee et al. (2021) found that current PPI use was associated with an increased risk of serious COVID-19 outcomes, but not with a risk of infection. Similarly, Zhou et al. (2021) reported an association with serious outcomes, including the need for intensive care unit (ICU) admission, intubation or death (Israelsen et al., 2021).

Meta-analysis by Yan et al. showed that there is no association between use of PPI and higher risk of infection with COVID-19. In this publication the analysis of two original studies showed that PPI use was associated with increased risk of secondary infection by Clostridium difficile, Campylobacter, Salmonella and also with a higher risk of nosocomial pneumonia in patients in intensive care units (Yan et al., 2022). Also Veettil et al. (2022) found that previous use of PPIs may put patients at risk for problems such as an increased risk of C. diff., which could have a significant impact on the course of treatment.

The associations observed between PPI use and adverse COVID-19 outcomes should be interpreted with caution. Further randomized controlled trials or well-adjusted prospective cohorts are warranted to better delineate these relationships.

Over the past few decades, the utilization of proton pump inhibitors has significantly risen, giving rise to concerns regarding their toxicity and reported adverse effects associated with them. Still, future studies are needed to fully explain the toxicity of long-term-use of PPI.

It has been shown that omeprazole, especially for long-term use, may induce DNA damage by inducing oxidative stress, apoptosis and necrosis. All of the available PPIs can induce chromosomal damage (Paz et al., 2020).

Many studies have indicated that hypoacidity and hypergastrinemia can elevate the chances of developing gastric cancer (Fossmark et al., 2015). Proton pump inhibitors (PPIs) can potentially exhibit tumor-promoting effects through elevation of plasma gastrin levels (Bridoux et al., 2022). A recent report in a Swedish population has highlighted that individuals who use PPI medications are more prone to developing gastric adenocarcinoma (Brusselaers et al., 2017). During pregnancy, esomeprazol can cause harm to the liver, leading to a decrease in the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes (Thomas et al., 2016). Chronic use of omeprazole has been associated with detrimental impacts on the liver and kidneys, such as hepatotoxicity and nephrotoxicity (Paz et al., 2020). Patients with liver disease may face a heightened susceptibility to hepatotoxicity, potentially resulting in the development of carcinogenic effects induced by hypergastrinemia, affecting liver cells (Fossmark et al., 2015). It also has been shown that chronic utilization of PPIs in individuals suffering from chronic kidney disease heightens the risk of mortality and progression of the kidney disease (Giusti et al., 2021).

Currently available meta-analyses indicate an association between PPI use and, among others, an increased incidence of gastric atrophy and gastric cancer, and between PPI use and an increased risk of chronic kidney disease and end-stage renal disease. However, further research is needed to confirm these correlations (Gao H. et al., 2022; Vengrus et al., 2021; Li et al., 2017).

IPP as mentioned earlier in this article are frequently prescribed drugs. It is worth leaning into their effectiveness. In the case of GERD, with the use of PPIs overall, there was a reduction in complaints in about 70% of patients (Liakakos et al., 2010). However, efficacy in GERD strongly depends on the age group to which we refer, because, for example, clinical trials reveal that PPI therapy is not an effective treatment for common infant GERD-associated symptoms (Higginbotham, 2010). In the case of eosinophilic esophagitis (EoE), high-dose PPI treatment was effective in half of the EoE patientsin cohort study of 236 adult with EoE (Frandsen et al., 2021). The importance of PPIs is also emphasized in preventing complications from NSAID use. Namely, PPIs have been shown to reduce NSAID-induced indigestion (Leontiadis et al., 2007). It is emphasized that currently the best way to reduce iatrogenic ulcer bleeding from gastric and duodenal ulcer is the administration of anti-ulcer drugs, including proton pump inhibitors (PPIs) (Kim et al., 2019). As the article shows PPIs find effective use in many diseases and conditions. In Tables 6, 7, we discuss the clinical problems resulting from the use of PPIs and clinical indications for PPI: their corresponding benefits and potential risks (Tables 6, 7).

One direction for further research may be the association between long-term PPI use and the development of dementia. Further well-designed cohort studies with control for confounding factors are needed to clearly determine the effect of PPIs on the risk of dementia, as there is currently insufficient evidence (Li M. et al., 2019; Ahn et al., 2023). In addition, a systematic review found that in 20 of 21 meta-analyses, the use of proton pump inhibitors (PPIs) was consistently associated with an increased risk of gastric cancer, with reported relative risks ranging from 1.3 to 2.9. However, the available studies were of limited statistical power, highlighting the need for further studies that take into account factors such as Helicobacter pylori infection, PPI dosage, and duration of therapy to better understand the mechanisms underlying the increased risk of gastric cancer (Brusselaers et al., 2025; Abrahami et al., 2022). Potassium-competitive acid blockers (P-CABs), such as vonoprazan, may be a safe and effective alternative to PPIs, but further study is needed, especially considering the long-term use of these drugs in the context of adverse effects (St. Onge and Phillips, 2023). Effective educational and intervention strategies should be developed to reduce PPI overuse and monitor their long-term impact on patient health (Dharmarajan, 2021).

Knowledge of drug interactions is essential for proper treatment and to avoid possible adverse drug reactions. Drugs should be selected with great care when used by the patient, as the intensification of effects resulting from the interaction of certain groups of drugs may be life-threatening. Sometimes a drug can be replaced with another drug from the same class to avoid adverse interactions, as this review confirms. Some of the interactions are highly complicated, and many other processes are still unknown, which is why continuous research on interactions between drugs, especially frequently used ones such as PPIs, is very important for the health and life of patients.

Long-term use of PPIs must be tailored to the clinical context and in accordance with the indications that are approved by the US Food and Drug Administration (FDA) for the treatment of various gastrointestinal conditions associated with hyperacidity. Considering the comorbidities, different drug combinations can be considered, taking into account the potential for interactions. In elderly patients or those taking multiple medications, unnecessary continued use of PPIs may contribute to the risk of polypharmacy. In elderly patients or those taking multiple medications, it is recommended to choose a PPI with a lower potential for drug interactions, such as pantoprazole or rabeprazole. Similarly, patients with chronic kidney disease, osteoporosis or vitamin B12 deficiency may be susceptible to the adverse effects of long-term PPI use, therefore the need for medication should be reassessed, with the aim of discontinuing the medication or using the lowest effective dose, as some conditions, such as Barrett’s esophagus or eosinophilic esophagitis, justify continuous PPI therapy due to their protective benefits. In patients with mild or remitting symptoms (e.g., GERD or functional dyspepsia), discontinuation may be considered with appropriate monitoring. In addition, when PPIs are used for gastroprotection (e.g., during dual antiplatelet therapy), the choice of the appropriate PPI (such as pantoprazole to avoid CYP2C19 inhibition) is crucial. Patients taking warfarin for atrial fibrillation and concomitant Duodenal Ulcer should be wary of omeprazole and lansoprazole, which interact with this drug. Pantoprazole or dexlansoprazole would be a safer option. If ivabradine is necessary, omeprazole or lansoprazole can be used. Additionally, in patients taking citalopram for depression, pantoprazole would be a good choice if a PPI is necessary.

Clinical decision-making should also take into account the risk of infections such as Clostridioides difficile, especially in elderly or hospitalized patients. Ultimately, a risk-benefit assessment for the individual patient should guide both continuation and discontinuation of PPIs. Another aspect that requires reassessment of the appropriateness of PPI use is emerging anemia, as the causes to be eliminated include the use of PPIs, which due to adverse effects can lead to reduced vitamin B12 availability. The indications should be monitored, as in patients without a clear indication for therapy, PPIs should be discontinued. An example of short-term use (up to 8 weeks) are GERD symptoms, after which the efficacy of treatment and further management should be assessed.

Direct comparative studies of different PPIs are needed to establish relative efficacy and safety profiles, and studying genetic factors influencing PPI metabolism can lead to personalized therapy, optimizing efficacy while minimizing adverse effects. Potassium-competitive acid blockers (P-CABs), such as vonoprazan, have shown promise as effective alternatives to PPIs, offering rapid and sustained acid inhibition. Further studies are needed to assess their long-term safety and potential role in clinical practice.

In summary, although PPIs are effective, their use should be individualized, regularly assessed, and based on emerging evidence to ensure optimal patient outcomes. Knowledge of drug interactions is essential for proper treatment and to avoid possible adverse drug reactions. Drugs should be selected with great care when used by the patient, because the intensity of the effects resulting from the interaction of some drug groups can be life-threatening. Sometimes a drug can be replaced by another drug from the same class to avoid adverse interactions, as confirmed by this review. Some interactions are highly complex, and many other processes are still unknown, so continued research on drug interactions, especially frequently used ones such as PPIs, is very important for the health and life of patients.