An Expert Report on Amiloride (DB00594)

I. Introduction and Overview

A. Executive Summary

Amiloride is a small molecule drug classified as a potassium-sparing diuretic, belonging to the pyrazine-carbonyl-guanidine chemical class.[1] It is identified by DrugBank Accession Number DB00594 and CAS Number 2609-46-3.[1] Developed in 1967 and first approved by the U.S. Food and Drug Administration (FDA) in 1981, amiloride is recognized on the World Health Organization's List of Essential Medicines, underscoring its global importance.[5]

The primary therapeutic indications for amiloride are the management of hypertension and edematous states, such as those associated with congestive heart failure and hepatic cirrhosis with ascites.[9] However, its clinical utility in these prevalent conditions is nuanced. Amiloride possesses only weak intrinsic natriuretic and antihypertensive properties and is therefore rarely employed as a monotherapy.[4] Its principal role in mainstream cardiovascular medicine is as an adjunctive agent, co-administered or co-formulated with more potent kaliuretic diuretics, such as thiazides (e.g., hydrochlorothiazide) or loop diuretics (e.g., furosemide). In this capacity, its primary function is to counteract the significant adverse effect of these diuretics: the excessive urinary loss of potassium (hypokalemia).[5]

The pharmacological basis for this potassium-sparing effect is the direct, reversible blockade of the epithelial sodium channel (ENaC) located on the apical membrane of principal cells in the late distal convoluted tubule and collecting duct of the nephron.[1] This mechanism is distinct from that of other potassium-sparing diuretics like spironolactone, as it is independent of aldosterone levels.[3] By inhibiting sodium reabsorption at this site, amiloride reduces the electrical driving force for potassium secretion into the tubular lumen, thereby conserving body potassium stores.