Amiloride
Regulatory sources consulted
Approved indications
- Adjunctive treatment with a thiazide or other kaliuretic diuretic in congestive heart failure or hypertension to restore or prevent hypokalemia, especially when maintaining potassium is clinically important, such as in digitalized patients or those with arrhythmias.
Contraindications
Absolute
- Serum potassium above 5.5 mEq/L.
- Concomitant use of other potassium-sparing diuretics.
- Potassium supplements or potassium-containing salt substitutes, except for severe or refractory hypokalemia under close monitoring.
- Anuria, acute or chronic renal insufficiency, and diabetic nephropathy.
- Hypersensitivity to amiloride.
Clinical warnings
- Boxed warning · Potentially fatal hyperkalemia may occur, especially with renal impairment, diabetes, and older age. Monitor potassium at initiation, after dose changes, and during illnesses affecting renal function. — https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e0cc2d44-436a-47e8-a890-589882fff4c4
- Major warning · With BUN above 30 mg/dL, serum creatinine above 1.5 mg/dL, or diabetes, do not use without frequent, careful monitoring of electrolytes, creatinine, and BUN. — DailyMed setid e0cc2d44-436a-47e8-a890-589882fff4c4
- Major warning · Hyperkalemia may occur in patients with diabetes even without recognised diabetic nephropathy. Avoid amiloride if possible; if used, monitor electrolytes and renal function frequently. — https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e0cc2d44-436a-47e8-a890-589882fff4c4
- Major warning · In severely ill patients at risk of metabolic or respiratory acidosis, initiate antikaliuretic therapy only with caution and monitor acid-base balance frequently because acidosis may rapidly increase serum potassium. — https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e0cc2d44-436a-47e8-a890-589882fff4c4
- Major warning · In pre-existing severe liver disease, hepatic encephalopathy with tremor, confusion or coma and increased jaundice have been reported with diuretics, including amiloride; monitor closely. — https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e0cc2d44-436a-47e8-a890-589882fff4c4
Drug interactions
- HighACE inhibitors, ARBs, cyclosporine, or tacrolimus
Mechanism: Additive potassium retention increases the risk of hyperkalemia.
Recommendation: Avoid when possible; if combined, closely monitor potassium and renal function.
DailyMed setid e0cc2d44-436a-47e8-a890-589882fff4c4
- HighLithium
Mechanism: Diuretics reduce lithium clearance and increase toxicity.
Recommendation: Generally avoid; if combined, monitor lithium concentrations.
DailyMed setid e0cc2d44-436a-47e8-a890-589882fff4c4
- ModerateNonsteroidal anti-inflammatory drugs
Mechanism: They may reduce diuretic and antihypertensive effects; indomethacin may increase potassium and renal risk.
Recommendation: Monitor response, potassium, and renal function.
DailyMed setid e0cc2d44-436a-47e8-a890-589882fff4c4
Adverse events
Common (≥1%)
Headache · Nausea or anorexia · Diarrhea · Vomiting · Weakness · Fatigue · Abdominal pain · Muscle cramps
Rare but serious
Hyperkalemia with arrhythmia · Jaundice · Gastrointestinal bleeding · Encephalopathy
Pregnancy and lactation
Use during pregnancy only if clearly needed. During breastfeeding, animal data show transfer into milk; decide whether to discontinue nursing or the drug according to its clinical importance.
Recent literature (PubMed)
Nephrogenic diabetes insipidus (NDI) is characterized by the inability to concentrate urine that results in polyuria and polydipsia, despite having normal or elevated plasma concentrations of arginine vasopressin (AVP). In this study, we review the clinical aspects and diagnosis of NDI, the various etiologies, current treatment options and potential future developments. NDI has different clinical manifestations and approaches according to the etiology. Hereditary forms of NDI are mainly caused by mutations in the genes that encode key proteins in the AVP signaling pathway, while acquired causes are normally associated with specific drug exposure, especially lithium, and hydroelectrolytic disorders. Clinical manifestations of the disease vary according to the degree of dehydration and hyperosmolality, being worse when renal water losses cannot be properly compensated by fluid intake. Regarding the diagnosis of NDI, it is important to consider the symptoms of the patient and the diagnostic tests, including the water deprivation test and the baseline plasma copeptin measurement, a stable surrogate biomarker of AVP release. Without proper treatment, patients may developcomplications leading to high morbidity and mortality, such as severe dehydration and hypernatremia. In that sense, the treatment of NDI consists in decreasing the urine output, while allowing appropriate fluid balance, normonatremia, and ensuring an acceptable quality of life. Therefore, therapeutic options include nonpharmacological interventions, including sufficient water intake and a low-sodium diet, and pharmacological treatment. The main medications used for NDI are thiazide diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), and amiloride, used isolated or in combination.
Amiloride has been proposed as an alternative to spironolactone for treating resistant hypertension. However, no randomized clinical trials have compared the efficacy of spironolactone and amiloride in patients with resistant hypertension. To determine whether amiloride is noninferior to spironolactone in reducing home-measured systolic blood pressure (SBP) in patients with resistant hypertension. Prospective, open-label, blinded end-point randomized clinical trial conducted at 14 sites in South Korea. From November 16, 2020, to February 29, 2024, 118 patients with home SBP of 130 mm Hg or greater after a 4-week run-in period with a fixed-dose triple medication combination (angiotensin receptor blocker, calcium channel blocker, and thiazide) were enrolled. Patients were randomized in a 1:1 ratio to receive 12.5 mg/d of spironolactone (n = 60) or 5 mg/d of amiloride (n = 58). If home SBP remained 130 mm Hg or greater and serum potassium was less than 5.0 mmol/L after 4 weeks, dosages were increased to 25 mg/d and 10 mg/d, respectively. The primary end point was the between-group difference in home SBP change at week 12, with a noninferiority margin of -4.4 mm Hg for the lower bound of the confidence interval. Secondary end points included achievement rates of home- and office-measured SBP of less than 130 mm Hg. The median age of the study population was 55 years, with 70% male. There were no differences between groups in demographic characteristics other than use of α-blockers (8.6% in the amiloride group and 0% in the spironolactone group). The mean baseline home SBPs were 141.5 (SD, 7.9) mm Hg and 142.3 (SD, 8.5) mm Hg in the amiloride and spironolactone groups, respectively. At week 12, mean home SBP measurements were changed from baseline by -13.6 (SD, 8.6) mm Hg and -14.7 (SD, 11.0) mm Hg in the amiloride and spironolactone groups, respectively (between-group difference in change, -0.68 mm Hg; 90% CI, -3.50 to 2.14 mm Hg), with amiloride demonstrating noninferi
Resistant hypertension is a condition where blood pressure levels remain elevated above target despite changes in lifestyle and concurrent use of at least three antihypertensive agents, including a long-acting calcium channel blocker (CCB), a blocker of the renin-angiotensin system (ACE inhibitor or angiotensin receptor blocker) and a diuretic. To be diagnosed as resistant hypertension, maintaining adherence to therapy is required along with confirmation of blood pressure levels above target by out-of-office blood pressure measurements and exclusion of secondary causes of hypertension. The key management points of this condition include lifestyle changes such as reduced sodium and alcohol intake, regular physical activity, weight loss and discontinuation of substances that can interfere with blood pressure control. It is also recommended that current treatment be rationalised, including single pill combination treatment where antihypertensive drugs should be provided at the maximum tolerated dose. It is further recommended that current drugs be replaced with a more appropriate and less difficult treatment regimen based on the patient's age, ethnicity, comorbidities and risk of drug-drug interactions. The fourth line of treatment for patients with resistant hypertension should include mineralocorticoid receptor antagonists such as spironolactone, as demonstrated in the PATHWAY-2 trial and meta-analyses. Alternatives to spironolactone include amiloride, doxazosin, eplerenone, clonidine and beta-blockers, as well as any other antihypertensive drugs not already in use. New approaches under research are selective non-steroidal mineralocorticoid receptor antagonists such as finerenone, esaxerenone and ocedurenone, selective aldosterone synthase inhibitors such as baxdrostat, and dual endothelin antagonist aprocitentan. Amiloride is a potassium-sparing diuretic used in the therapy of edema often in combination with thiazide diuretics. Amiloride has been linked to rare case