Lisinopril and Metolazone: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 2, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Metolazone
No brand names on recordLisinopril
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
Metolazone is a water pill (diuretic) that helps your body get rid of extra salt and fluid. Lisinopril is a blood pressure medicine that also relaxes your blood vessels. When you take both, they lower your blood pressure through different paths at the same time. That can add up, and sometimes your pressure drops more than expected, especially with the first few doses of lisinopril.
You might feel dizzy, lightheaded, or faint, particularly when standing up quickly. The good news is this effect is usually temporary, and your care team can manage it easily by adjusting doses and watching how you respond. If you feel dizzy, sit or lie down and let your pharmacist or doctor know.
Effect: Additive blood-pressure lowering; risk of first-dose and postural hypotension when an ACE inhibitor (lisinopril) is added to diuretic therapy (metolazone).
Mechanism: Metolazone-induced volume/sodium depletion heightens dependence on the renin-angiotensin system; lisinopril then blunts compensatory vasoconstriction, producing vasodilation on a relatively hypovolemic background. This is a pharmacodynamic interaction (not CYP-mediated); neither agent's activation is relevant here.
- Onset: rapid (often first dose)
- Evidence: theoretical, more often seen with loop diuretics
- Management: consider reducing/holding the diuretic or liberalizing salt beforehand, or using a low lisinopril starting dose; monitor BP, orthostatics, and renal function/electrolytes.
What happens
Reduction of blood pressure
Interaction Deep Dive
When an ACE inhibitor is started in patients already receiving diuretics, blood pressure may fall to an excessive degree3. The addition of ACE inhibitors to diuretic regimens has been associated with severe postural hypotension. This has been seen more frequently with loop diuretics; however, first dose hypotension occurs commonly in individuals who are sodium depleted or hypovolemic as a result of diuretics or restricted sodium intake. Typically, this hypotensive reaction is transient6271. The likelihood of hypotensive effects can be reduced prior to initiating ACE inhibitor therapy by lowering or stopping the diuretic or by raising salt intake. When such steps cannot be taken, lower the initial ACE inhibitor dose3.
Why it happens (mechanism)
Vasodilation and relative intravascular volume depletion
How to manage this interaction
This combination is used often and can be managed well. Keep taking both medicines as prescribed unless your prescriber tells you otherwise.
- Your care team may reduce or briefly hold the diuretic (metolazone), or start lisinopril at a lower dose, to soften the initial blood-pressure drop.
- They may monitor you more closely, checking blood pressure (including sitting-to-standing) and kidney function around the time of starting or changing doses.
- Rise slowly from sitting or lying down for the first days.
Tell your pharmacist or doctor if you feel dizzy, faint, or unusually weak. The dose can be individualized by your team to fit you.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
2 reports — tap to read
a) In a randomized crossover trial (N=19) evaluating the combined use of hydrochlorothiazide and enalapril in elderly patients (aged 62 to 84 years), the pharmacokinetic profile of enalapril remained largely unchanged by hydrochlorothiazide, although there was a significant rise in AUC (0 to 24 hours) and a significant decrease in the renal clearance of enalaprilat 4.
b) A slight decline in peak serum concentrations of perindoprilat, along with a lower proportion of the perindopril dose eliminated as perindoprilat in the urine, has been documented when perindopril and hydrochlorothiazide are given together 5.
Common questions
Can I take Lisinopril and Metolazone together?
Combining metolazone with lisinopril can lower blood pressure more than either alone, especially with the first doses, which may cause dizziness. Your care team can manage this by adjusting doses and monitoring you, so report any lightheadedness. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Lisinopril and Metolazone interaction?
It is rated moderate. Can be significant — usually manageable with monitoring.
How quickly could this interaction happen?
The documented onset is "rapid". Effects can appear quickly, often within about 24 hours of combining the drugs.
How is the Lisinopril and Metolazone interaction managed?
This combination is used often and can be managed well. Keep taking both medicines as prescribed unless your prescriber tells you otherwise. Your care team may reduce or briefly hold the diuretic (metolazone), or start lisinopril at a lower dose, to soften the initial blood-pressure drop. They may monitor you more closely, checking blood pressure (including sitting-to-standing) and kidney function… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Lisinopril or Metolazone need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there anything you'd monitor while I'm on both?
References (7)
- Vlasses PH, Ferguson RK, & Chatterjee K: Captopril: clinical pharmacology and benefit-to-risk ratio in hypertension and congestive heart failure. Pharmacotherapy 1982; 2:1-17. PubMed
- Gluck Z, Beretta-Piccoli C, & Reubi FC: Long-term effects of captopril on renal function in hypertensive patients. Eur J Clin Pharmacol 1984; 26:315-323. PubMed
- Product Information: QBRELIS(TM) oral solution, lisinopril oral solution. Silvergate Pharmaceuticals (per manufacturer), Greenwood Village, CO, 2016. DailyMed
- Weisser K, Schloos J, Jakob S, et al: The influence of hydrochlorothiazide on the pharmacokinetics of enalapril in elderly patients. Eur J Clin Pharmacol 1992; 43:173-177. PubMed
- Todd PA & Fitton A: Perindopril: a review of its pharmacological properties and therapeutic use in cardiovascular disorders. Drugs 1991; 42:90-114.
- Atkinson AB, Brown JJ, Morton JJ, et al: Captopril in a hyponatremic hypertensive; need for caution initiating therapy (letter). Lancet 1979; 1:557-558.
- Pandhi P, Mondal S, Sharma BK, et al: Low dose captopril alone and in combination with hydrochlorothiazide in treatment of mild to moderate essential hypertension. Int J Clin Pharmacol Ther Toxicol 1986; 24:294-297.
Keep reading about Metolazone
Keep reading about Lisinopril
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