What is the mechanism of action (MOA) of Metalazone (a thiazide-like diuretic)?

Mechanism of Action of Metolazone

Metolazone is a thiazide-like diuretic that primarily inhibits sodium and chloride reabsorption at the distal convoluted tubule (cortical diluting segment), with a secondary action in the proximal tubule that distinguishes it from standard thiazides. 1

Primary Site of Action

• Metolazone acts primarily at the cortical diluting site (distal convoluted tubule) to inhibit sodium reabsorption, resulting in approximately equivalent excretion of sodium and chloride ions 1
• The drug interferes with the renal tubular mechanism of electrolyte reabsorption through inhibition of the sodium-chloride cotransporter in the distal tubule 2, 3
• This primary action is similar to other thiazide-type diuretics, which inhibit electroneutral sodium and chloride transport by distal convoluted tubule cells 4

Secondary Proximal Tubule Action

• Unlike standard thiazides, metolazone has a clinically significant secondary action in the proximal convoluted tubule 1
• This proximal action is demonstrated by increased excretion of phosphate and magnesium ions and markedly increased fractional excretion of sodium, particularly in patients with severely compromised glomerular filtration 1, 5
• Metolazone does NOT inhibit carbonic anhydrase, distinguishing it from some other thiazide-type agents 1

Downstream Effects on Potassium

• The increased delivery of sodium to the distal tubular exchange site results in increased potassium excretion 1
• This occurs because enhanced sodium reabsorption via the epithelial sodium channel (ENaC) requires increased potassium secretion to maintain electrical neutrality 2

Unique Clinical Advantage

• Metolazone retains efficacy even when glomerular filtration rate falls below 20 mL/min, unlike standard thiazides which lose effectiveness when creatinine clearance drops below 40 mL/min 2, 1, 5
• This preserved efficacy in renal impairment is attributed to its dual site of action (both proximal and distal tubule) 5

Synergistic Effect with Loop Diuretics

• When administered concurrently with furosemide, metolazone produces marked diuresis through sequential nephron blockade, even in patients refractory to maximum doses of either drug alone 1, 2
• The mechanism of this synergistic interaction remains unknown but likely involves blocking sodium reabsorption at multiple nephron segments to overcome adaptive compensatory mechanisms 1, 2

Pharmacokinetics

• Maximum blood levels occur approximately 8 hours after dosing 1
• Most of the drug is excreted unchanged in urine, with only minimal metabolism 1
• Diuresis typically begins within one hour and may persist for 24 hours or more 1