Overview ã…¡ 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.
DOSAGE AND INDICATIONS
| 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 |
- Patients admitted with suspected upper GI bleeding, discontinue contributory medications where possible on a risk versus benefit basis. PPIs should not be used prior to endoscopic diagnosis in patients presenting with acute upper gastrointestinal bleeding.
- Peptic ulcer (gastric or duodenal), if taking Non-steroidal anti-inflammatory drugs (NSAIDs), stop NSAIDs where possible and offer double-dose PPI or histamine-2 receptor antagonist (H2RA) therapy for 8 weeks. Offer H. pylori eradication therapy to people who have tested positive for H. pylori and who have peptic ulcer disease. If not taking NSAIDs, offer double-dose PPI or H2RA for 4 to 8 weeks. Offer H. pylori eradication therapy to people who have tested positive for H. pylori and who have peptic ulcer disease.
- Gastro-esophageal reflux disease (GERD) ã…¡ For mild GERD, offer full-dose PPI for 4 to 8 weeks. If symptoms recur after initial treatment, offer PPI at the lowest dose necessary to control symptoms and consider an 'as required' dosing approach. Offer H2RA therapy if there is an inadequate response to PPIs. For moderate-severe GERD, use esomeprazole (Nexium) 40 mg once daily for 4 to 8 weeks, then continue long-term 20 mg once daily.
- Barrett’s oesophagus, use of full-dose PPI is recommended for symptom control. In asymptomatic patients with Barrett's oesophagus there is insufficient evidence to recommend routine PPI use.
- Dyspepsia, discontinue contributory medications where possible. Offer empirical full-dose PPI for 4 weeks. If symptoms recur after the initial PPI course then recommence the PPI at the lowest dose necessary to control symptoms and consider 'as required' dosing. H2RA therapy if there is an inadequate response to a PPI. Functional dyspepsia, offer H. pylori 'test and treat'. If H. pylori has been excluded and symptoms persist offer either a low-dose PPI or H2RA for 4 weeks. If symptoms persist offer a PPI or H2RA at the lowest dose necessary to control symptoms and consider 'as required' dosing. Avoid long-term, frequent dose, continuous antacid therapy (it only relieves symptoms in the short term rather than preventing them).
- Use of PPIs for gastro-protection if patient on NSAIDs, co-prescribe a PPI at full-dose in patients commencing NSAIDs who develop dyspepsia or have one or more risk factors, or who have history of gastrointestinal bleeding, peptic ulcer or gastroduodenal perforation, aged 65 years or older, using maximum recommended NSAID dose, concomitant use of drugs known to increase the risk of gastrointestinal bleeding / dyspepsia (e.g., anticoagulants, aspirin, corticosteroids, antidepressants (selective serotonin reuptake inhibitors, venlafaxine or duloxetine), significant co-morbidity (e.g., diabetes, renal/hepatic impairment, cardiovascular disease, advanced cancer or hypertension) and anticipated prolonged NSAIDs use, including patients with rheumatoid arthritis or osteoarthritis or chronic back pain if over 45 years old.
- Corticosteroids may cause GI ulceration, dyspepsia and may be associated with an increased risk of gastrointestinal bleeding or perforation in hospitalized patients. Consider co-prescribing PPI at full-dose whilst the patient is taking corticosteroids if the patient develops dyspepsia or there are one or more risk factors for GI bleeding including: (1) History of gastrointestinal bleeding, peptic ulcer or gastroduodenal perforation. (2) Aged 65 years or over. (3) Concomitant use of drugs known to increase the risk of gastrointestinal bleeding/dyspepsia (e.g., anticoagulants, aspirin, NSAIDs, antidepressants (selective serotonin reuptake inhibitors, venlafaxine or duloxetine). (4) Significant co-morbidity (e.g. advanced cancer).
- Stress ulcer prophylaxis on the Intensive Care Unit (ICU). Aim to commence early enteric feeding. The evidence for stress ulcer prophylaxis in critically ill patients is extremely weak and mostly observational with several studies suggesting harm – predominantly ventilator associated pneumonia. There is also limited evidence for the drug choice in these cases. On this basis, local practice is to only give acid-suppression therapy in patients who are not being enterally-fed on a case by case basis. A full dose PPI or H2RA may be used. Consider risk factors such as respiratory failure, coagulopathy, sepsis, severe hypotension, renal failure, history of gastrointestinal ulcer or bleed within 1 year of admission, hepatic failure, major trauma, burns, organ transplantation, GCS < 11, surgery, concomitant use of medications that are known to increase the risk of gastrointestinal bleeding/dyspepsia (e.g., anticoagulants, aspirin, NSAIDs, corticosteroids, antidepressants [selective serotonin reuptake inhibitors, venlafaxine or duloxetine]) and ICU stay of at least 6 days.
In patients who are receiving enteral feed only use acid-suppression in patients taking pre-existing acid-suppressing medications or where there is concern about GI bleeding. If prophylaxis commenced, review on-going need once high risk factors are resolved or transferred from ICU. - Oesophagitis, for mild/moderate cases, offer a full dose PPI for 4 to 8 weeks, then if clinical improvement has occurred then reduce the PPI dose to the lowest necessary to control symptoms and consider an 'as required' dosing approach. If there has been no clinical improvement then escalate PPI therapy to a double dose regimen or consider switching to an alternative PPI or H2RA. For severe cases, please note specific PPI dosing for severe oesophagitis (from Table 2). Offer full dose PPI for 8 weeks for healing and then if healing has been achieved then continue the full dose as long-term maintenance therapy taking into account patient preferences and tolerability. If healing is not achieved then consider escalating therapy to a double dose of the initial PPI or switching to an alternative PPI at full or double dose.
| 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 |
CLINICAL NOTES
Interaction with clopidogrel (Plavix). Concomitant use of clopidogrel with omeprazole or esomeprazole is not recommended by FDA. 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. Nottingham University Hospitals recommend using lansoprazole or H2 receptor antagonist (ranitidine) with clopidogrel. 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. Get our note, "Hypomagnesemia associated with PPI therapy".
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. Get our note, "Management of community-acquired pneumonia".
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.
REFERENCES
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
Wolfe M, 'Proton Pump Inhibitors: Overview of Use and Adverse Effects in the Treatment of Acid Related Disorders' (Uptodate.com, 2020); https://www.uptodate.com/contents/proton-pump-inhibitors-overview-of-use-and-adverse-effects-in-the-treatment-of-acid-related-disorders