Amiloride is used as potassium-sparing diuretic and also in Liddle syndrome. In Liddle syndrome, its mechanism differs from the primary action in normal physiology because:

• A In Liddle syndrome, amiloride inhibits aldosterone synthesis rather than blocking its receptor
• B In Liddle syndrome, amiloride inhibits the H+/K+ ATPase rather than the sodium channel to correct alkalosis
• C In Liddle syndrome, ENaC channels are constitutively active independent of aldosterone; amiloride blocks ENaC directly, reducing Na+ reabsorption regardless of aldosterone status ✓
• D In Liddle syndrome, amiloride acts on beta-subunit of ENaC while in normal physiology it acts on alpha-subunit

Explanation

In normal physiology, amiloride blocks epithelial sodium channels (ENaC) in the cortical collecting duct, reducing Na+ reabsorption (and indirectly reducing K+ and H+ secretion). ENaC activity is normally regulated by aldosterone. In Liddle syndrome, gain-of-function mutations in the beta or gamma subunit of ENaC remove a PY motif that normally tags ENaC for Nedd4-mediated ubiquitination and endocytosis, leading to constitutive, aldosterone-independent channel activity. Spironolactone (aldosterone antagonist) is ineffective; amiloride (direct ENaC blocker) treats both conditions.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.