Does metolazone cause more sodium excretion than furosemide (Lasix)?

From the Guidelines

No, furosemide generally causes more sodium excretion than metolazone. Furosemide is a loop diuretic that acts on the thick ascending limb of the loop of Henle, where it blocks the sodium-potassium-chloride cotransporter (NKCC2), inhibiting the reabsorption of approximately 25% of filtered sodium, as stated in the 2005 ACC/AHA guideline update for the diagnosis and management of chronic heart failure in the adult 1. Metolazone, a thiazide-like diuretic, works on the distal convoluted tubule by blocking the sodium-chloride cotransporter (NCC), which only handles about 5-10% of filtered sodium. This fundamental difference in their sites of action explains why furosemide typically produces more potent natriuresis (sodium excretion) than metolazone when each is used alone at standard doses.

The 2013 ACCF/AHA guideline for the management of heart failure also supports the use of loop diuretics, such as furosemide, as the primary diuretic agents for patients with heart failure, due to their ability to increase sodium excretion and enhance free water clearance 1. In contrast, thiazide diuretics like metolazone are generally less effective in increasing sodium excretion, especially in patients with impaired renal function. However, metolazone can be used in combination with furosemide to enhance its natriuretic effect, as stated in the 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults 1.

Some key points to consider when using these medications include:

• The dose and frequency of diuretic administration may need to be adjusted based on the patient's response and renal function.
• Patients with mild heart failure may respond favorably to low doses of diuretics, while those with more advanced disease may require higher doses or combination therapy.
• The use of diuretics should be guided by the patient's clinical response, including changes in weight, blood pressure, and symptoms of fluid retention.
• The combination of metolazone and furosemide can be an effective strategy for managing resistant edema or heart failure, as it allows for synergistic blockade of sodium reabsorption at different nephron sites.

From the FDA Drug Label

Metolazone acts primarily to inhibit sodium reabsorption at the cortical diluting site and to a lesser extent in the proximal convoluted tubule Sodium and chloride ions are excreted in approximately equivalent amounts. The diuretic potency of metolazone tablets, USP, at maximum therapeutic dosage is approximately equal to thiazide diuretics. Furosemide inhibits primarily the reabsorption of sodium and chloride not only in the proximal and distal tubules but also in the loop of Henle

The FDA drug label does not directly compare the sodium excretion of metolazone and furosemide. No conclusion can be drawn about which drug causes more sodium excretion. 2 3

From the Research

Comparison of Sodium Excretion

• Metolazone and furosemide have been studied in various combinations to evaluate their diuretic effects, including sodium excretion 4, 5, 6, 7.
• A study published in 1980 found that the addition of metolazone to furosemide resulted in a significant increase in sodium excretion, from 131 to 303 mval/d, in patients with severe fluid retention 4.
• Another study in 1985 demonstrated that metolazone increased diuresis, urinary excretion of sodium and chloride, but decreased urinary excretion of calcium, when added to furosemide treatment 5.
• In children with furosemide-resistant edema, the combination of metolazone and furosemide resulted in a significant increase in sodium excretion, from 34 to 155 mEq/d 6.
• A study in 2007 found that combining metolazone and furosemide parenterally resulted in increased urine volume and sodium excretion in rats 7.

Diuretic Effects

• Metolazone has been shown to have a dual diuretic effect on the proximal and distal tubule, with a minimal kaluretic effect 7.
• The combination of metolazone and furosemide offers a useful and effective oral therapy in most children with edema resistant to furosemide 6.
• However, children with chronic renal insufficiency and furosemide-resistant edema did not respond to combination diuretic therapy 6.
• Metolazone can cause hypokalaemia, hypochloraemia, and encephalopathy, particularly when used alone in patients with liver disease 8.