Pharmacotherapy of oral proton pump inhibitors (PPIs)

Overview

Proton pump inhibitors (PPIs) effectively block gastric acid secretion by irreversibly binding to and inhibiting the hydrogen-potassium ATPase pump that resides on the luminal surface of the parietal cell membrane.

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Dosage and indications

For patients admitted with suspected upper gastrointestinal (GI) bleeding, discontinuing contributory medications where possible is recommended, weighing the risks and benefits. PPIs should not be used prior to an endoscopic diagnosis in acute upper GI bleeding cases.

In peptic ulcer disease, if the patient is taking non-steroidal anti-inflammatory drugs (NSAIDs), discontinuing NSAIDs is advised where feasible, and initiating double-dose PPI or histamine-2 receptor antagonist (H2RA) therapy for 8 weeks. H. pylori eradication therapy should be offered to those who test positive for H. pylori. For patients not taking NSAIDs, a double-dose PPI or H2RA for 4 to 8 weeks is recommended, alongside H. pylori eradication therapy if necessary.

Table (1). Doses of proton pump inhibitors
PPI	Full dose	Low dose (on-demand dose)	Double dose
Esomeprazole (Nexium)	20 mg once a day	Not available	40 mg once a day
Lansoprazole (Zoton, Lanzor)	30 mg once a day	15 mg once a day	30 mg twice a day
Omeprazole (Losec)	20 mg once a day	10 mg once a day	40 mg once a day
Pantoprazole (Controloc)	40 mg once a day	20 mg once a day	40 mg twice a day
Rabeprazole (Pariet, Bepra)	20 mg once a day	10 mg once a day	20 mg twice a day

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For gastro-esophageal reflux disease (GERD), a full-dose PPI for 4 to 8 weeks is suggested for mild cases. If symptoms recur, a PPI at the lowest dose necessary to control symptoms, or an 'as required' dosing approach, is recommended. H2RA therapy may be considered if PPIs are inadequate. For moderate to severe GERD, esomeprazole (Nexium) 40 mg daily for 4 to 8 weeks should be followed by long-term 20 mg daily maintenance.

In Barrett’s oesophagus, a full-dose PPI is recommended for symptomatic control. However, in asymptomatic patients, routine PPI use lacks sufficient evidence.

For dyspepsia, stopping contributory medications and offering an empirical full-dose PPI for 4 weeks is recommended. If symptoms recur, recommencing the PPI at the lowest dose necessary to control symptoms, or considering 'as required' dosing, is advisable. H2RA therapy may be used if PPIs are inadequate. In functional dyspepsia, a 'test and treat' approach for H. pylori is recommended. If H. pylori has been excluded and symptoms persist, a low-dose PPI or H2RA for 4 weeks is suggested. Long-term, frequent dose, continuous antacid therapy should be avoided as it only offers short-term symptom relief.

For gastro-protection in patients on NSAIDs, co-prescribing a full-dose PPI is essential for those with dyspepsia or risk factors for GI complications. This includes a history of gastrointestinal bleeding, peptic ulcer, age over 65, maximum recommended NSAID dose, concomitant use of drugs increasing GI risk (e.g., anticoagulants, aspirin, corticosteroids, antidepressants like SSRIs, venlafaxine, duloxetine), significant comorbidities (e.g., diabetes, renal/hepatic impairment, cardiovascular disease, advanced cancer), or anticipated prolonged NSAID use in conditions such as rheumatoid arthritis, osteoarthritis, or chronic back pain in patients over 45 years old.

• Corticosteroids may cause GI ulceration and dyspepsia, and can increase the risk of gastrointestinal bleeding or perforation, particularly in hospitalized patients.
• Co-prescribing a full-dose PPI is advisable if the patient develops dyspepsia or has one or more risk factors for GI bleeding, such as a history of gastrointestinal bleeding, age over 65, or concomitant use of medications that increase GI risk.

For stress ulcer prophylaxis in the Intensive Care Unit (ICU), early enteric feeding is the goal. The evidence supporting stress ulcer prophylaxis in critically ill patients is weak and observational, with studies indicating potential harm, mainly ventilator-associated pneumonia. Therefore, acid-suppression therapy is recommended only for patients not being enterally-fed, based on individual risk factors. Full-dose PPI or H2RA may be considered, factoring in respiratory failure, coagulopathy, sepsis, severe hypotension, renal failure, recent gastrointestinal ulcer or bleed, hepatic failure, major trauma, burns, organ transplantation, Glasgow Coma Scale (GCS) score below 11, surgery, concomitant use of medications increasing GI risk, and ICU stays of at least 6 days. For patients on enteral feed, acid-suppression should only continue if they were already on such medication or if there is a concern about GI bleeding. Prophylaxis should be reviewed once high-risk factors resolve or the patient is transferred from the ICU.

In oesophagitis, for mild to moderate cases, a full-dose PPI for 4 to 8 weeks is recommended. If there is clinical improvement, reducing the dose to the lowest necessary to control symptoms or considering 'as required' dosing is suggested. If no improvement occurs, escalating to a double-dose PPI regimen or switching to an alternative PPI or H2RA is advised. For severe oesophagitis, a full-dose PPI for 8 weeks is recommended for healing, with long-term maintenance therapy at the lowest effective dose, considering patient preferences and tolerability. If healing is not achieved, therapy escalation to a double-dose of the initial PPI or switching to an alternative PPI at full or double dose is advisable.

Table (2). Proton pump inhibitors dosing for severe oesophagitis
PPI	Full dose	Low dose (on-demand dose)	Double dose
Esomeprazole	40 mg once a day	40 mg once a day	40 mg once a day
Lansoprazole	30 mg once a day	15 mg once a day	30 mg twice a day
Omeprazole	40 mg once a day	20 mg once a day	40 mg once a day
Pantoprazole	40 mg once a day	20 mg once a day	40 mg twice a day
Rabeprazole	20 mg once a day	10 mg once a day	20 mg twice a day

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Clinical notes

Interaction with clopidogrel (Plavix)

Concomitant use of clopidogrel with omeprazole or esomeprazole is not recommended by FDA.

1. On 17 November 2009, the US Food and Drug Administration (FDA) issued an alert to health care professionals and the public about the potential interaction between clopidogrel and omeprazole. In this alert, FDA stated that the use of omeprazole or esomeprazole (Nexium) with clopidogrel should be avoided while rabeprazole or pantoprazole may be lower risk alternatives to omeprazole.
2. Nottingham University Hospitals recommend using lansoprazole or H2 receptor antagonist (ranitidine) with clopidogrel.
3. According to UpToDate website: the only large-scale randomized trial comparing omeprazole to placebo in clopidogrel users showed NO significant difference in cardiovascular events when omeprazole and clopidogrel were combined, although there was a significant reduction in gastrointestinal events!

My Opinion: because the half-lives of clopidogrel and omeprazole are short, separating their administration could decrease or eliminate the risk of competitive inhibition. Omeprazole could be given in the morning before breakfast and the clopidogrel could be given at night or clopidogrel could be given at lunchtime and omeprazole before dinner. Although FDA does not believe this strategy will reduce this interaction!

Hypomagnesemia

Severe hypomagnesemia has been reported infrequently in patients treated with PPIs although the exact incidence is unknown. In some cases, hypomagnesemia occurred after 3 months of PPI therapy, but most occurred after 1 year of treatment. In most case reports, hypomagnesemia improved after magnesium replacement and discontinuation of the PPI. Consider optimizing magnesium levels before starting treatment and periodically during prolonged treatment, especially in those taking digoxin or other drugs that can cause hypomagnesemia (e.g., diuretics). PPIs must only be commenced and continued with a clear indication and their ongoing use regularly reviewed.

Community Acquired Pneumonia

PPIs may be associated with an increased risk of community-acquired pneumonia, particularly within the first 30 days of PPI use. PPIs must only be commenced and continued with a clear indication and their ongoing use regularly reviewed.

Clostridium difficile infection (CDI)

It is recommended to stop PPIs and H2RA in patients with or at high risk of CDI. Given the extent of PPI prescribing, the number of potentially avoidable CDI cases could be significant. The challenge presented by CDI, the evidence of an association with PPI use, and current concerns about overuse of PPIs, provide good reasons to critically review PPI and H2RA prescribing.

Osteoporosis

There may be a modest increase in the risk of hip, wrist or spinal fracture with PPIs especially if used in high doses and for prolonged durations (> 1 year). The increased risk was observed mainly in elderly patients, but confounding factors may have contributed.

Kidney injury

PPI use may rarely cause acute interstitial nephritis (AIN). Ongoing PPI use should be reviewed if an acute kidney injury (AKI) develops following the recent prescription of a PPI or if AIN develops following acute or chronic use. Current evidence does not recommend withholding PPI in all cases of AKI regardless of cause. Long-term PPI use may be associated with a higher risk of CKD findings and may be confounded by other factors such as NSAID use and hence there is a need for further investigation. PPIs must be commenced and continued only with a clear indication and their ongoing use regularly reviewed.

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References

1. Scarpignato C and others, 'Effective And Safe Proton Pump Inhibitor Therapy In Acid-Related Diseases – A Position Paper Addressing Benefits and Potential Harms of Acid Suppression' (BMC medicine 2016). https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0718-z.
2. Wolfe M, 'Proton Pump Inhibitors: Overview of Use and Adverse Effects in the Treatment of Acid Related Disorders' (uptodate 2020). https://www.uptodate.com/contents/proton-pump-inhibitors-overview-of-use-and-adverse-effects-in-the-treatment-of-acid-related-disorders.

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