Do amiloride and hydrochlorothiazide (HCTZ) act on renal tubular segments proximal or distal to the macula densa?

From the Guidelines

Amiloride and hydrochlorothiazide both act on renal tubular segments distal to the macula densa. Specifically:

• Amiloride acts on the collecting duct, as it impairs urinary dilution in this segment 1
• Hydrochlorothiazide acts on the distal convoluted tubule, as it enhances proximal water reabsorption due to volume depletion and impairs urinary dilution in the DCT 1 This location of action is important because it affects how these medications work:

1. Amiloride blocks sodium channels in the distal nephron, reducing sodium reabsorption and potassium excretion.
2. Hydrochlorothiazide inhibits the sodium-chloride symporter in the distal convoluted tubule, also reducing sodium reabsorption. By acting distal to the macula densa, these medications do not directly affect the tubuloglomerular feedback mechanism. This allows them to exert their diuretic effects without significantly altering glomerular filtration rate, making them useful for treating hypertension and edema. Understanding the site of action helps explain why these medications are often used in combination: amiloride can help counteract the potassium loss caused by hydrochlorothiazide, while both contribute to increased sodium excretion and diuresis. The most recent and highest quality study 1 supports the use of these medications in the treatment of polyuria, and their mechanism of action is well-established. In contrast, older studies such as 1 provide less specific information on the mechanism of action of these medications, and are therefore less relevant to this question.

From the FDA Drug Label

Hydrochlorothiazide blocks the reabsorption of sodium and chloride ions, and it thereby increases the quantity of sodium traversing the distal tubule and the volume of water excreted. Amiloride HCl exerts its potassium sparing effect through the inhibition of sodium reabsorption at the distal convoluted tubule, cortical collecting tubule and collecting duct;

Main Action Site:

• Hydrochlorothiazide acts on the distal tubule.
• Amiloride acts on the distal convoluted tubule, cortical collecting tubule, and collecting duct. Both drugs act on renal tubular segments distal to the macula densa 2 3.

From the Research

Action of Amiloride and Hydrochlorothiazide on Renal Tubular Segments

• Amiloride acts on the distal tubule of the nephron, where it selectively blocks sodium transport, thereby inhibiting sodium-potassium exchange 4, 5.
• The primary site of action of amiloride is in postmacula densa segments of the distal nephron 5.
• Hydrochlorothiazide (HCTZ) is a thiazide diuretic that acts on the distal convoluted tubule, which is also distal to the macula densa 6, 7, 8.
• The combination of amiloride and HCTZ has additive effects on reducing urinary calcium excretion and increasing serum phosphate concentration 7, 8.

Mechanism of Action

• Amiloride's mechanism of action is independent of aldosterone 4.
• HCTZ inhibits NaCl transport in the distal convoluted tubule, leading to increased sodium and water excretion 6, 7, 8.
• The combination of amiloride and HCTZ prevents hypokalemia and alkalosis, which can be caused by HCTZ alone 7, 8.

Clinical Implications

• Amiloride and HCTZ can be used in combination to treat conditions such as edematous states, hypertension, and renal hypophosphatemic rickets 4, 7, 8.
• The combination of amiloride and HCTZ can help prevent complications such as hypokalemia and alkalosis, which can occur with HCTZ alone 7, 8.