From the Guidelines
Metolazone works primarily by inhibiting sodium and chloride reabsorption in the distal convoluted tubule of the nephron, making it a thiazide-like diuretic. According to the most recent guidelines, specifically the 2022 AHA/ACC/HFSA guideline for the management of heart failure 1, metolazone acts in the distal convoluting tubule, whereas loop diuretics act at the loop of Henle.
Mechanism of Action
The mechanism of action of metolazone involves blocking the sodium-chloride symporter (NCC), preventing sodium reabsorption and increasing sodium and water excretion, which reduces blood volume and lowers blood pressure. This is crucial in managing conditions like heart failure and hypertension.
Clinical Use
Metolazone is particularly effective in patients with reduced kidney function where other diuretics may be less effective. It can be used in combination with loop diuretics for resistant edema due to their synergistic effect at different sites in the nephron, a strategy called sequential nephron blockade. The typical dosing of metolazone ranges from 2.5-10 mg once daily for hypertension or edema.
Important Considerations
Metolazone can cause electrolyte disturbances, particularly hypokalemia, hyponatremia, and hypercalcemia, so electrolyte monitoring is essential during therapy. The treatment goal of diuretic use, including metolazone, is to eliminate clinical evidence of fluid retention, using the lowest dose possible to maintain euvolemia, as stated in the 2022 guideline 1.
Guideline Recommendations
The 2022 AHA/ACC/HFSA guideline recommends that diuretics, including metolazone, should be prescribed to patients who have evidence of congestion or fluid retention, and maintenance diuretics should be considered to avoid recurrent symptoms 1. It's also emphasized that diuretics should not be used in isolation but always combined with other guideline-directed medical therapy (GDMT) for heart failure that reduces hospitalizations and prolongs survival.
From the FDA Drug Label
Metolazone is a quinazoline diuretic, with properties generally similar to the thiazide diuretics. The actions of metolazone result from interference with the renal tubular mechanism of electrolyte reabsorption. 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 mechanism of action of Metolazone is through inhibition of sodium reabsorption at the cortical diluting site and to a lesser extent in the proximal convoluted tubule, resulting in increased excretion of sodium and chloride ions [ 2 ].
- The increased delivery of sodium to the distal tubular exchange site results in increased potassium excretion.
- Metolazone does not inhibit carbonic anhydrase.
From the Research
Mechanism of Action of Metolazone
The mechanism of action of Metolazone, a thiazide-like diuretic, involves the inhibition of NaCl reabsorption in the distal tubule of the kidney 3. This is achieved through binding to a high-affinity site in the renal cortex, which has characteristics of the thiazide-sensitive ion transporter 3, 4. The binding of Metolazone to this site inhibits the reabsorption of sodium and chloride ions, leading to an increase in salt and water excretion 5.
Key Features of Metolazone's Mechanism of Action
- Metolazone binds to a high-affinity site in the renal cortex with a Kd of 4.27 nM 3
- The binding site is localized to the distal tubule of the kidney 3, 4
- Metolazone inhibits the reabsorption of sodium and chloride ions, leading to an increase in salt and water excretion 5
- The mechanism of action of Metolazone is similar to that of thiazide diuretics, which also inhibit NaCl reabsorption in the distal tubule 5
Effects of Metolazone on Ion Transport
- Metolazone increases the excretion of sodium and chloride ions 5
- Metolazone stimulates the secretion of potassium ions, possibly due to the increase in distal tubule fluid flow rate 5
- Metolazone may also stimulate the absorption of calcium ions, possibly via a decrease in distal convoluted tubule cell sodium activity and an increase in basolateral sodium/calcium exchange 5