What are the uses and considerations for epithelial sodium-channel (ENaC) inhibitors, such as amiloride and triamterene, in managing conditions like hypertension and edema?

Epithelial Sodium-Channel (ENaC) Inhibitors: Clinical Uses and Considerations

Primary Indications

ENaC inhibitors (amiloride and triamterene) are FDA-approved as adjunctive therapy with thiazide or loop diuretics in hypertension and heart failure to prevent or correct hypokalemia, particularly in digitalized patients or those with significant cardiac arrhythmias. 1, 2

Key FDA-Approved Uses:

• Adjunctive treatment with kaliuretic diuretics in congestive heart failure or hypertension to restore normal serum potassium levels 1, 2
• Prevention of hypokalemia in high-risk patients (digitalized patients, those with cardiac arrhythmias) 1
• Treatment of edema associated with heart failure, cirrhosis, nephrotic syndrome, and steroid-induced or idiopathic edema 2
• Promotion of diuresis in patients resistant or partially responsive to thiazides due to secondary hyperaldosteronism 2

Dosing and Administration

Amiloride:

• Initial dose: 0.4-0.625 mg/kg/day in children; 5 mg/day in adults 3, 1
• Maximum dose: 20 mg/day 3, 1
• Frequency: Once daily (advantage over triamterene due to longer duration of action) 3, 4

Triamterene:

• Initial dose: 1-2 mg/kg/day in children 3
• Maximum dose: 3-4 mg/kg/day up to 300 mg/day 3
• Frequency: Twice daily 3

Special Clinical Applications

Nephrotic Syndrome and Proteinuric Conditions:

Amiloride is particularly effective in nephrotic syndrome because proteases in nephrotic urine directly activate ENaC independent of aldosterone, making it superior to spironolactone in this setting. 3, 5

• Mechanism: Urinary serine proteases (including plasmin) proteolytically cleave and activate the γENaC subunit, causing sodium retention independent of mineralocorticoid receptor activation 3, 5
• Clinical efficacy: Amiloride resolves resistant edema and low-renin hypertension in nephrotic patients with high efficacy 6, 5
• Preference over spironolactone: Since ENaC activation is mineralocorticoid receptor-independent in nephrotic syndrome, amiloride (direct ENaC blocker) is preferable to spironolactone 3

Resistant Hypertension:

Spironolactone should be considered first-line for resistant hypertension, but amiloride is equally effective and may be substituted if spironolactone is not tolerated. 3, 7

• Amiloride has been shown to be as effective as spironolactone in resistant hypertension 7
• Consider as fourth-line therapy after maximally tolerated triple combination (RAS blocker, CCB, thiazide diuretic) 3

Glomerular Disease Management:

In nephrotic syndrome with severe edema, use furosemide as first-line, but add amiloride (not spironolactone) as potassium-sparing agent for synergistic effect. 3

• Amiloride provides improvement in edema/hypertension and counters hypokalemia from loop or thiazide diuretics 3
• Particularly useful for metabolic alkalosis associated with diuresis 3

Critical Safety Considerations

Hyperkalemia Risk:

ENaC inhibitors carry approximately 10% risk of hyperkalemia when used alone and significantly higher risk when combined with ACE inhibitors, ARBs, or in renal insufficiency. 3, 1

• Contraindications: Serum potassium ≥5.0 mEq/L, serum creatinine ≥2.5 mg/dL (men) or ≥2.0 mg/dL (women) 3
• Dangerous combination: Adding amiloride to patients already on ACE inhibitors AND spironolactone can cause life-threatening hyperkalemia and acute kidney injury 6
• Monitoring required: Frequent serum potassium and creatinine monitoring, especially when combined with RAS blockade 3

Renal Function Monitoring:

• Expected effect: Decreased eGFR may occur with amiloride initiation (due to reduced hyperfiltration) 6
• Close monitoring: Required in patients with baseline renal impairment 3
• Sick day rules: Hold ENaC inhibitors during volume depletion (vomiting, diarrhea, excessive sweating) 3

Clinical Pitfalls and How to Avoid Them

Common Mistakes:

1. Using ENaC inhibitors as monotherapy: These have weak diuretic and antihypertensive effects alone; should rarely be used without thiazide or loop diuretics 1, 8

2. Combining with multiple RAAS blockers: The combination of amiloride + ACE inhibitor + spironolactone creates extreme hyperkalemia risk 6

3. Inadequate electrolyte monitoring: All patients on ENaC inhibitors require electrolyte monitoring shortly after initiation and periodically thereafter 3

4. Using spironolactone instead of amiloride in nephrotic syndrome: Spironolactone is less effective because ENaC activation is aldosterone-independent in this condition 3, 5

Optimal Use Strategy:

• Start low: Begin with lowest effective dose (amiloride 5 mg daily) 1
• Monitor early: Check potassium and creatinine within 1 week of initiation 3
• Titrate cautiously: Only increase dose if hyperkalemia does not develop 1
• Educate patients: Teach sick day rules to hold medication during acute illness 3

Pediatric Considerations

In children with nephrotic syndrome and edema, amiloride is preferred over spironolactone as the potassium-sparing diuretic when combined with furosemide. 3

• Dosing: 0.4-0.625 mg/kg/day, maximum 20 mg/day 3
• Monitor for hyperkalemia, especially if combined with ACE inhibitors 3
• Useful for countering hypokalemia and metabolic alkalosis from loop diuretics 3

Evidence Quality Note

The blood pressure lowering efficacy of ENaC blockers as monotherapy remains poorly established, with no high-quality trials demonstrating significant BP reduction at low doses 8. However, their role as adjunctive therapy for potassium conservation and in specific conditions like nephrotic syndrome is well-supported by mechanistic studies and clinical experience 3, 6, 5.