Hydrochlorothiazide/Lisinopril Drug Interactions: What to Avoid and What to Tell Your Doctor

Hydrochlorothiazide/Lisinopril interacts with over 160 other medications in ways that can range from reducing its effectiveness to causing potentially dangerous complications. Because it contains two active drugs — each with their own interaction profiles — it's especially important to share a complete medication list with your prescriber and pharmacist before starting or changing any medications.

Medications to Avoid Completely (Do Not Combine)

These combinations are either contraindicated or strongly discouraged:

• Sacubitril/Valsartan (Entresto): Do not use lisinopril within 36 hours of Entresto. Combining these can cause dangerous angioedema (severe throat swelling). This timing restriction applies in both directions.
• Aliskiren (Tekturna) in diabetic patients: This combination creates dual blockade of the renin-angiotensin system, increasing the risk of hypotension, hyperkalemia, and kidney damage. Not recommended in any patient with diabetes.
• MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid): Combination with HCTZ can cause additive hypotensive effects that can be severe. Generally contraindicated.
• ARBs (losartan, valsartan, irbesartan, etc.): Taking an ACE inhibitor AND an ARB together is dual RAAS blockade. Increases risk of hypotension, hyperkalemia, and kidney impairment significantly. Avoid this combination.

Serious Interactions (Require Close Monitoring)

• NSAIDs (ibuprofen, naproxen, aspirin, diclofenac, celecoxib): NSAIDs can significantly reduce the blood pressure-lowering effect of both lisinopril and HCTZ by inhibiting prostaglandins that help the kidneys function. NSAIDs also increase the risk of kidney damage when combined with ACE inhibitors, especially in elderly or volume-depleted patients. Use with extreme caution — discuss all pain medications with your prescriber.
• Lithium: ACE inhibitors reduce the kidneys' ability to excrete lithium, causing lithium levels to rise dangerously. If you take lithium, your doctor should monitor lithium levels closely and may need to reduce your lithium dose.
• Potassium supplements and potassium-sparing diuretics: Lisinopril already raises potassium levels. Adding potassium supplements or potassium-sparing diuretics like spironolactone, triamterene, or amiloride can push potassium levels dangerously high (hyperkalemia). Only use these if your doctor specifically prescribes them and monitors your levels.
• mTOR inhibitors (sirolimus, everolimus, temsirolimus): Used for organ transplant patients. Combining with ACE inhibitors significantly increases the risk of angioedema. Monitor closely.

Moderate Interactions (Use with Caution)

• Diabetes medications (insulin, oral hypoglycemics): HCTZ can raise blood glucose, potentially affecting glycemic control and requiring adjustment of diabetes medication doses. Monitor glucose more closely when starting HCTZ.
• Digoxin (Lanoxin): HCTZ can lower potassium, which increases the heart's sensitivity to digoxin toxicity. Monitor potassium and digoxin levels carefully.
• Cholestyramine and colestipol (bile acid sequestrants): These cholesterol medications bind to HCTZ in the gut and reduce its absorption by up to 85%. Take Hydrochlorothiazide/Lisinopril at least 1 hour before or 4 hours after these medications.
• Corticosteroids (prednisone, methylprednisolone): Can worsen electrolyte depletion, particularly potassium loss, when combined with HCTZ.
• Trimethoprim (Bactrim, Septra): This common antibiotic reduces urinary potassium excretion; combining with lisinopril can cause hyperkalemia.

Food and Supplement Interactions

• Salt substitutes containing potassium chloride: Many salt substitutes (like Nu-Salt or NoSalt) use potassium chloride instead of sodium chloride. These can raise potassium to dangerous levels in patients on lisinopril. Avoid unless your doctor specifically says it's safe.
• Alcohol: Can worsen the blood pressure-lowering effect and increase the risk of orthostatic hypotension (dizziness when standing). Limit alcohol use while on this medication.
• High-sodium diet: Excess sodium blunts the effectiveness of both components. A reduced-sodium diet significantly enhances the blood pressure-lowering effect of this medication.

Over-the-Counter Medications to Watch

Many OTC products can interfere with Hydrochlorothiazide/Lisinopril. Always read labels and tell your pharmacist you take this medication:

• NSAIDs (ibuprofen/Advil, naproxen/Aleve) — reduce efficacy and increase kidney risk
• Decongestants (pseudoephedrine, phenylephrine in cold medicines) — can raise blood pressure
• Diet pills or weight loss supplements containing stimulants — can raise blood pressure

For more information on side effects, see: Hydrochlorothiazide/Lisinopril Side Effects: What to Expect and When to Call Your Doctor. If you need help finding your prescription, medfinder calls pharmacies near you to locate it.