Amiloride Blocks the Epithelial Sodium Channel (ENaC) to Treat Lithium-Induced Nephrogenic Diabetes Insipidus
Amiloride treats lithium-induced nephrogenic diabetes insipidus by blocking the epithelial sodium channel (ENaC) in the apical membrane of principal cells in the collecting duct, thereby preventing lithium entry into these cells and attenuating the downstream aquaporin-2 downregulation that causes polyuria. 1
Mechanism of Action: Sodium Channel Blockade
Amiloride antagonizes ENaC, the epithelial sodium channel located in the distal collecting duct of the kidney, functioning as an indirect aldosterone antagonist by blocking sodium reabsorption at this site. 2
ENaC serves as the primary entry pathway for lithium into principal cells of the collecting duct, and blocking this channel with amiloride reduces transcellular lithium transport and intracellular lithium accumulation. 1, 3
By preventing lithium entry through ENaC, amiloride blocks the cascade of lithium toxicity: lithium accumulation → glycogen synthase kinase-3β inhibition → aquaporin-2 (AQP2) downregulation → impaired water reabsorption → polyuria. 1, 3
Clinical Evidence Supporting Amiloride Use
In experimental models, amiloride prevented lithium-induced downregulation of AQP2 expression, reduced the principal-to-intercalated cell ratio changes, and attenuated polyuria when administered simultaneously with lithium. 1
Clinical trials demonstrate that amiloride 10-20 mg daily increases renal concentrating ability and reduces polyuria in patients with lithium-induced nephrogenic diabetes insipidus, without affecting serum lithium or potassium levels. 4
Amiloride is recommended as add-on therapy in patients with hypokalaemia induced by thiazide diuretics, which are often used as first-line treatment for nephrogenic diabetes insipidus. 2
Advantages Over Alternative Treatments
Unlike thiazide diuretics, amiloride does not cause hypokalemia or reduce lithium excretion, thereby avoiding the risk of lithium toxicity that can occur when thiazides increase lithium reabsorption. 4
Amiloride may counter hypokalemia and metabolic alkalosis caused by loop or thiazide diuretics when used in combination therapy for resistant edema or polyuria. 2
The potassium-sparing effect of amiloride makes it particularly useful in patients already experiencing electrolyte disturbances from other diuretics. 2
Treatment Context and Combination Therapy
For symptomatic patients with nephrogenic diabetes insipidus (including lithium-induced), combination therapy with thiazide diuretics plus prostaglandin synthesis inhibitors (NSAIDs) is recommended as first-line treatment, with amiloride added specifically to address thiazide-induced hypokalaemia. 2
Nonsteroidal anti-inflammatory drugs like indomethacin can dramatically reduce urine volume within hours by inhibiting prostaglandin synthesis, and may be more effective than thiazides or amiloride alone in acute severe cases. 5, 6
In emergency situations with severe hypernatremia (sodium >170 mmol/L), indomethacin 150 mg can immediately reduce urinary output to one-half, though renal function must be monitored closely. 6
Common Pitfalls to Avoid
Do not use amiloride as monotherapy for lithium-induced nephrogenic diabetes insipidus—it is most effective when combined with thiazides and dietary sodium restriction to potentiate diuretic efficacy. 2
Monitor for hyperkalemia when using amiloride, especially in patients with chronic kidney disease, diabetes, or those taking ACE inhibitors or ARBs, as the potassium-sparing effect can lead to dangerous elevations. 2
Recognize that amiloride addresses the mechanism of lithium toxicity but does not reverse established chronic kidney disease from years of lithium exposure—early intervention is critical. 3