How does metolazone work (mechanism of action)?
Metolazone is a thiazide-like diuretic. It lowers blood pressure and increases urine output by blocking sodium reabsorption in the kidney, which increases sodium and water excretion.
At the cellular level, metolazone inhibits the sodium-chloride (NaCl) cotransporter in the distal convoluted tubule (part of the nephron). When the transporter is blocked, less sodium is reabsorbed back into the bloodstream, so more sodium stays in the tubular fluid and pulls water with it, leading to diuresis. This same process can also increase urinary loss of potassium and other electrolytes, which is why electrolyte disturbances are a known risk with diuretic therapy.
Where in the kidney does metolazone act, and why does that matter?
Metolazone acts in the distal convoluted tubule, later in the nephron than loop diuretics. Because of this downstream site of action, it can still be effective when kidney function is reduced and when upstream transport (in the loop of Henle) is impaired.
Clinically, this “distal” mechanism is one reason metolazone is sometimes used with other diuretics in resistant fluid overload: blocking NaCl reabsorption downstream can increase total diuretic effect by targeting a different nephron segment.
What happens downstream after metolazone blocks NaCl reabsorption?
By reducing sodium reabsorption in the distal convoluted tubule, metolazone increases urine volume. The increased flow and sodium delivery to later segments of the nephron can promote potassium secretion, which can lead to hypokalemia. It can also contribute to other electrolyte and metabolic effects, such as changes in sodium, chloride, and acid-base balance, which are consistent with the way thiazide-like diuretics alter distal tubular transport.
How does metolazone’s mechanism differ from thiazides and loop diuretics?
Metolazone is “thiazide-like,” so its core mechanism is similar to classic thiazide diuretics: inhibition of the NaCl cotransporter in the distal convoluted tubule.
Loop diuretics work earlier (in the thick ascending limb) by blocking a different transporter (the Na-K-2Cl cotransporter). Because they act in different nephron segments, they can have additive effects when used together.