[2] Common side effects include high blood potassium, vomiting, loss of appetite, rash, and headache.

[1] Amiloride blocks the epithelial sodium channel (ENaC) in the late distal tubule, connecting tubule, and collecting duct of the nephron,[3] which both reduces absorption of sodium ion from the lumen of the nephron and reduces excretion of potassium ion into the lumen.

[6] For example, people that are taking Digitalis (i.e. digoxin) are at higher risk for changes in heart rhythm if their potassium levels get too high.

[6] The 2012 clinical practice guidelines by the American Association for the Study of Liver Diseases (AASLD) states that amiloride can be used to treat ascites in place of spironolactone if it isn't tolerated (e.g. due to the side effect of gynecomastia), though amiloride isn't a preferred drug due to cost and lack of efficacy.

The use of amiloride in people with diabetes requires careful potassium and kidney function monitoring to prevent toxicity.

Amiloride must be discontinued for at least 3 days prior to glucose tolerance testing, due to the risk for fatal hyperkalemia.

[6] People with poor kidney function (e.g. blood urea nitrogen >30 mg/dL, or serum creatinine >1.5 mg/dL) are at high risk for hyperkalemia.

However, when used in combination with the drug acetazolamide during the process of organ formation, amiloride increases the risk for kidney and ureter abnormalities.

[17] Amiloride may have important drug-drug interactions when combined with other medications that also increase potassium levels in the blood, leading to hyperkalemia.

[18] For example, the combination of amiloride with angiotensin-converting enzyme (ACE) inhibitors like lisinopril, or angiotensin II receptor type 1 (AT1) antagonists like losartan, may lead to high levels of potassium in the blood, requiring frequent monitoring.

[18] Amiloride works by directly blocking the epithelial sodium channel (ENaC) with an IC50 around 0.1 μM, indicating potent blockade.

The risk of developing hyperkalemia is increased in patients who are also taking ACE inhibitors, angiotensin II receptor antagonists, other potassium-sparing diuretics, or any potassium-containing supplements.

A fraction of the effects of amiloride is inhibition of cyclic GMP-gated cation channels in the inner medullary collecting duct.

[27] In high pH (alkaline, low hydrogen concentration) environments, the guanidinium group is deprotonated and the compound is rendered neutral, depleting its activity on sodium channels.

Amiloride affects the splicing and regulation of multiple genes involved in cancer, though they do not appear to be directly related to its effects on pH.

Amiloride has been tested in vitro as an adjunct to the anticancer drug imatinib, which appeared to show a synergistic effect.

[19] There is evidence that suggests that the molecular target of amiloride, ENaC, is also implicated in cystic fibrosis due to its effects on mucus in the lungs.

[32] However, longer-acting ENaC inhibitors (i.e. benzamil) have also failed clinical trials, despite an improvement in both the solubility and potency of the drugs.

[19] A third generation amiloride analogue (N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N'-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine methanesulfonate,[33] research name "552-02"), with better pharmacokinetic properties, is being studied.