Proton pump inhibitors (PPIs) are a class of medications widely used to treat conditions like gastroesophageal reflux disease (GERD), peptic ulcers, and erosive esophagitis. They work by irreversibly blocking the proton pumps in the stomach lining, which are responsible for producing stomach acid. While highly effective, this profound reduction in stomach acid can significantly alter the way other medications are absorbed and metabolized, leading to potentially dangerous drug interactions.
Mechanisms of Interaction
Understanding the two primary ways PPIs interact with other drugs is key to preventing adverse effects:
Altered Absorption Due to Increased Gastric pH
PPIs drastically increase the gastric pH (making the stomach less acidic). For drugs that require an acidic environment to dissolve and be absorbed into the bloodstream, this can significantly reduce their effectiveness. This is a common and predictable interaction for several classes of medication.
Inhibition of Liver Enzymes
The metabolism of most PPIs is primarily handled by the cytochrome P450 (CYP) isoenzymes, particularly CYP2C19 and CYP3A4. Certain PPIs, notably omeprazole and esomeprazole, can inhibit CYP2C19, interfering with the metabolism of other drugs that rely on the same pathway. This can either decrease the effectiveness of a drug that needs this enzyme for activation or increase the concentration and toxicity of another drug that is broken down by it.
Drugs That Should Not Be Taken with PPIs
Blood Thinners and Antiplatelets
One of the most critical interactions involves antiplatelet medications used to prevent blood clots. Omeprazole and esomeprazole inhibit CYP2C19, reducing the conversion of the antiplatelet drug clopidogrel to its active form, which can decrease its antiplatelet activity. This could potentially increase the risk of heart attacks and strokes in at-risk patients. Due to this risk, the FDA has recommended against the concurrent use of omeprazole and clopidogrel.
Another blood thinner, warfarin, can also be affected. Concomitant use with PPIs, including omeprazole and esomeprazole, has been reported to increase a patient's International Normalized Ratio (INR) and prothrombin time, which elevates the risk of abnormal bleeding.
Antiretroviral Drugs
Several HIV medications, particularly protease inhibitors, require an acidic environment for proper absorption. Taking them with a PPI can lead to reduced plasma concentrations, potentially causing the antiretroviral therapy to fail and promoting drug resistance. The following should be avoided or used with caution:
- Rilpivirine, Atazanavir, Nelfinavir: Concurrent use is generally not recommended or is contraindicated.
- Saquinavir: Co-administration may increase saquinavir levels and risk of toxicity.
Antifungals
Antifungal medications like ketoconazole and itraconazole depend on stomach acid for optimal absorption. When gastric pH is increased by PPIs, their absorption is significantly reduced, which can lead to treatment failure.
Certain Cancer Medications
Several oral cancer drugs, including some tyrosine kinase inhibitors (TKIs), need an acidic environment for proper absorption. Combining these with a PPI can reduce their effectiveness. Additionally, PPIs can increase the serum levels of high-dose methotrexate and its metabolites, increasing the risk of methotrexate toxicities.
- TKIs: Dasatinib, erlotinib, gefitinib, and pazopanib require an acidic pH for absorption.
- Methotrexate: High-dose methotrexate should be used cautiously with PPIs, as it can lead to increased toxicity.
Immunosuppressants and Other Medications
Other important interactions include:
- Mycophenolate Mofetil: Its absorption can be decreased by PPIs, leading to reduced immunosuppressant effect.
- Tacrolimus: PPIs can increase tacrolimus blood levels, requiring closer monitoring.
- Digoxin: Taking PPIs can increase digoxin serum concentrations, potentially increasing toxicity.
- Oral Iron Supplements: Iron absorption is dependent on stomach acid, so PPI use can impair the absorption of oral iron salts.
- Diazepam: Omeprazole can increase diazepam concentration, potentially causing excessive drowsiness.
Comparison of PPI Interactions
It's important to note that not all PPIs have the same interaction profile, particularly concerning CYP2C19 inhibition. Some newer PPIs and alternative formulations have a reduced risk of interactions with drugs like clopidogrel.
| Feature | Omeprazole (Prilosec) | Esomeprazole (Nexium) | Pantoprazole (Protonix) | Dexlansoprazole (Dexilant) |
|---|---|---|---|---|
| CYP2C19 Inhibition | Strong inhibitor | Strong inhibitor | Minimal/less likely | Lower potential |
| Interaction with Clopidogrel | Significant. Reduces effectiveness. | Significant. Reduces effectiveness. | Less likely to have significant interaction. | Less likely to have significant interaction. |
| Interaction with Warfarin | Increases INR/bleeding risk. | Increases INR/bleeding risk. | Lower risk of interaction. | Increases INR/bleeding risk. |
| HIV Drug Interactions | Avoid with rilpivirine, atazanavir, nelfinavir. | Avoid with rilpivirine, atazanavir, nelfinavir. | Avoid with rilpivirine, atazanavir, nelfinavir. | Avoid with rilpivirine, atazanavir, nelfinavir. |
| Antifungal Interactions | Decreased absorption of ketoconazole/itraconazole. | Decreased absorption of ketoconazole/itraconazole. | Decreased absorption of ketoconazole/itraconazole. | Decreased absorption of ketoconazole/itraconazole. |
| Methotrexate Interactions | Increased toxicity risk (high dose). | Increased toxicity risk (high dose). | Increased toxicity risk (high dose). | Increased toxicity risk (high dose). |
What to Do Before Starting a PPI
Before beginning a PPI, it is essential to have a thorough discussion with a healthcare provider and pharmacist, providing a complete list of all medications, including over-the-counter drugs, vitamins, and herbal supplements like St. John's Wort. This allows for a comprehensive risk assessment and proper management strategy.
Conclusion
While proton pump inhibitors are powerful tools for managing acid-related conditions, their potential for significant drug interactions cannot be ignored. The primary mechanisms involve altering gastric acidity and inhibiting liver enzymes, which can compromise the effectiveness or increase the toxicity of other medications. Individuals taking blood thinners like clopidogrel and warfarin, HIV antiretrovirals, certain antifungals, and specific cancer drugs should be particularly cautious. Healthcare providers can mitigate these risks by considering alternative therapies, adjusting medication timing, or choosing PPIs with lower interaction potential. Always consult your healthcare team before starting, stopping, or changing any medication to ensure your treatment is safe and effective.
Further information on specific drug interactions can be found from the FDA Drug Safety Communication on Omeprazole and Clopidogrel.
