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Continuing Education Activity

Amiloride is a medication used in the management and treatment of hypertension and heart failure. It is in the diuretic class of drugs. This activity outlines the indications, action, and contraindications for amiloride as a valuable agent in the treatment of hypertension and heart failure. This activity will highlight the mechanism of action, adverse event profile, and other key factors such as pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions pertinent for members of the interprofessional team in the management of patients with hypertension and heart failure and related conditions.


  • Identify the mechanism of action of amiloride.
  • Describe the adverse effects of amiloride.
  • Outline the appropriate monitoring potential toxicity of amiloride.
  • Summarize interprofessional team strategies for enhancing care coordination and communication to advance knowledge about amiloride and improve patient outcomes.


Amiloride is a potassium-sparing diuretic that does not have much of a diuretic effect when compared to its potassium-sparing activity. It is a pyrazinoylguanidine derivative.

It is FDA indicated to be used adjunctively with thiazides (or other kaliuretic agents) for the treatment of chronic heart failure or uncomplicated essential hypertension to:

  1. Help restore normal serum potassium concentrations in those who develop hypokalemia on kaliuretic therapy
  2. Prevent hypokalemia in patients who would develop significant complications in the incident of hypokalemia 

Amiloride might also be useful as an off-label indication in Liddle syndrome[1] thiazolidinediones-induced edema, lithium-induced polyuria, cystic fibrosis, insulin-induced edema, and multiple myeloma.[1][2][3][4][5]

Mechanism of Action

Amiloride works by inhibiting the epithelial sodium channels (ENaC) in the distal nephron (distal convoluted tubule and cortical collecting duct), lung, and colon. These ENaCs are composed of two domains that span the apical membrane. Those domains are M1 and M2. Intracellularly there C and N termini, while extracellularly, there is a large loop that contains 2 or 3 cysteine-rich domains. ENaCs consist of three subunits; alpha, beta, and gamma [6]. Mutation in beta or gamma subunits occurs in Liddle syndrome in which basal ENaCs activity increases. Amiloride is beneficial in Liddle syndrome.[7]

Usually, sodium moves down its electrochemical gradient to enter the tubular cells through the ENaCs. This gradient results from the basolateral membrane Na/K ATPase. Reabsorption of Na is associated with depolarization of the apical membrane, which creates a lumen-negative transepithelial potential difference. This potential difference enhances potassium secretion through the apical potassium channels and, subsequently, potassium excretion. Amiloride selectively inhibits ENaCs resulting in a decrease in hyperpolarization of the apical membrane and consequently decreases potassium, hydrogen, calcium, and magnesium secretion. Because amiloride inhibits ENaCs, it can also lead to mild natriuresis.[8][9] Amiloride also has the potential to cause vasodilation.[10] Decreased renal uric acid excretion might present when using amiloride for an extended period, and this is secondary to volume contraction and increased uric acid reabsorption in the proximal convoluted tubule.

Both the loop diuretics and thiazides will lead to increased Na concentration in the distal convoluted tubule and cortical collecting duct. This increase in Na concentration couples with increased Na reabsorption as well as increased potassium secretion and excretion. Therefore, co-administration of amiloride with thiazide or loop diuretics decreases their kaliuretic effect and augments their antihypertensive and diuretic effect. 

Amiloride might be useful in treating insulin-induced edema. In this condition, there is upregulation of ENaCs, which results in increased Na reabsorption and subsequently increased potassium secretion and excretion. Amiloride is not that effective in cases of hyperaldosteronism when compared to spironolactone and eplerenone.

Amiloride has the potential to induce apoptosis in multiple myeloma cell lines in mice, and therefore it might be used in the future for the treatment of relapsed multiple myeloma. Also, amiloride had a synergistic effect when combined with melphalan, lenalidomide, and dexamethasone.[5]


Dosing in adults for amiloride's FDA indications:

  • Congestive heart failure: 5 to 10 mg by mouth once daily or in 2 divided doses
  • Hypertension: 5 to 10 mg once orally each day or in 2 divided doses
  • Thiazide-induced hypokalemia: 5 to 10 mg by mouth once daily or in 2 divided doses

Amiloride gets excreted unchanged while triamterene undergoes extensive metabolism in the liver. Oral amiloride dosing should optimally be with food to avoid gastrointestinal upset.

Adverse Effects

Amiloride has a FDA boxed warning for hyperkalemia, either alone or even when combined with hydrochlorothiazide.[11] Hyperkalemia might be fatal, especially in people with diabetes mellitus, elderly patients, and patients with renal impairment. Hyperkalemia tends to occur in patients not receiving a concomitant kaliuretic diuretic. When amiloride is used concomitantly with thiazides, the risk of hyperkalemia drops to 1 to 2%. 

Other adverse effects include[12]:

  • Central nervous system: headache, fatigue, and dizziness
  • Musculoskeletal system: muscle cramps and weakness
  • Gastrointestinal system: nausea, vomiting, diarrhea/constipation, abdominal pain, and anorexia
  • Endocrine and metabolic: glucose intolerance, hyperuricemia as a side effect of all potassium-sparing diuretics including amiloride, and hyperchloremic metabolic acidosis, hyponatremia, and gynecomastia. 
  • Respiratory: dyspnea and cough
  • Genitourinary: impotence 


Amiloride can cause fatal hyperkalemia in susceptible patients. It is contraindicated to use amiloride in the following conditions: Chronic renal insufficiency, concomitant use of drugs that blunt the renin-angiotensin-aldosterone system (angiotensin-converting enzyme inhibitors, beta-blockers, NSAIDs, and aliskiren), concomitant use of other potassium-sparing diuretics, anuria, diabetic nephropathy, and hypersensitivity to amiloride. The clinician should discontinue oral vitamin K administration in patients receiving potassium-sparing diuretics. Amiloride is acceptable during pregnancy since it is FDA pregnancy category B.


Amiloride requires monitoring for hyperkalemia and impaired renal function. Therefore, periodic monitoring of serum potassium concentrations and serum BUN and creatinine concentrations is crucial. The following also require monitoring: serum bicarbonate, blood pressure, serum magnesium concentrations, daily weight, and signs or symptoms of hyperkalemia.


The most toxic effect of amiloride is hyperkalemia. A rapid increase in the extracellular potassium leads to an increase in cardiac conduction velocity secondary to lowering the threshold for rapid phase Na-dependent depolarization. Furthermore, after the initial increase in cardiac conduction velocity, there will be a prolongation of phase-4 diastolic depolarization and shortening of the action potential, which leads to delay in the conduction in the atrioventricular node and His-Purkinje system. On ECG, it manifests as peaked "tented" T wave. As the condition worsens, the QRS complex will widen, resulting in the so-called ''sine-wave''. Therefore hyperkalemia can lead to increased cardiac excitability or decrease in cardiac excitability. Increased cardiac excitation can lead to ventricular tachycardia and ventricular fibrillation, while a decrease in cardiac depression leads to various degrees of heart block and asystole.[13] Hyperkalemia can also cause an absence of the P wave on ECG.[14][15] Moreover, patients with hyperkalemia may present with fatigue, dizziness, and weakness.[15]

The initial step in managing amiloride toxicity is to stop all drugs that increase potassium concentrations (including amiloride). The next step is to treat hyperkalemia with 10 mL of 10% of calcium gluconate IV over 5 minutes. Because the effect is temporary, another dose might be necessary after 15 minutes. Additionally, treating hyperkalemia also includes administering rapid-acting insulin, glucose, potassium-binding resins, salbutamol, and sodium bicarbonate.[14] Normal saline may be administered for volume replacement, and if the patient is hypotensive, dopamine and norepinephrine might be appropriate.

Enhancing Healthcare Team Outcomes

Healthcare workers who prescribe amiloride should be aware of its indications, dosage, contraindication, and adverse effects. Periodic monitoring of serum potassium and renal function is an integral part of the management of heart failure and hypertension when the patient is receiving amiloride. Management of hypertension usually involves prescribing angiotensin-converting enzyme (ACE) inhibitors. Nevertheless, concomitant use of amiloride and ACE inhibitors carries a significant risk of developing symptomatic hyperkalemia.

When a clinician (MD, DO, NP, PA) initiates amiloride therapy, they do not do so in a vacuum, but rather as part of an interprofessional healthcare team. It is prudent to work with a pharmacist, and to coordinate with the lab for necessary blood values pertinent to amiloride monitoring (e.g., potassium). The pharmacist will also perform medication reconciliation and check for drug interactions and verify dosing. Nursing should also have involvement, including patient counseling, monitoring medication adherence, and being aware and alert to signs of adverse events and toxicity. When using amiloride for its indicated purpose, it is necessary to have a collaborative interprofessional team that includes physicians, specialty-trained nursing, and pharmacists working together to monitor therapy and achieve optimal patient outcomes. [Level 5]

Article Details

Article Author

Ali Almajid

Article Editor:

Manouchkathe Cassagnol


11/4/2020 1:42:34 AM

PubMed Link:




Tetti M,Monticone S,Burrello J,Matarazzo P,Veglio F,Pasini B,Jeunemaitre X,Mulatero P, Liddle Syndrome: Review of the Literature and Description of a New Case. International journal of molecular sciences. 2018 Mar 11     [PubMed PMID: 29534496]


Viswanathan V,Mohan V,Subramani P,Parthasarathy N,Subramaniyam G,Manoharan D,Sundaramoorthy C,Gnudi L,Karalliedde J,Viberti G, Effect of spironolactone and amiloride on thiazolidinedione-induced fluid retention in South Indian patients with type 2 diabetes. Clinical journal of the American Society of Nephrology : CJASN. 2013 Feb     [PubMed PMID: 23184569]


Pattanayak RD,Rajhans P,Shakya P,Gautam N,Khandelwal SK, Lithium-induced polyuria and amiloride: Key issues and considerations. Indian journal of psychiatry. 2017 Jul-Sep     [PubMed PMID: 29085107]


Tomkiewicz RP,App EM,Zayas JG,Ramirez O,Church N,Boucher RC,Knowles MR,King M, Amiloride inhalation therapy in cystic fibrosis. Influence on ion content, hydration, and rheology of sputum. The American review of respiratory disease. 1993 Oct     [PubMed PMID: 8214916]


Rojas EA,Corchete LA,San-Segundo L,Martínez-Blanch JF,Codoñer FM,Paíno T,Puig N,García-Sanz R,Mateos MV,Ocio EM,Misiewicz-Krzeminska I,Gutiérrez NC, Amiloride, An Old Diuretic Drug, Is a Potential Therapeutic Agent for Multiple Myeloma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2017 Nov 1;     [PubMed PMID: 28790111]


Kashlan OB,Sheng S,Kleyman TR, On the interaction between amiloride and its putative alpha-subunit epithelial Na channel binding site. The Journal of biological chemistry. 2005 Jul 15;     [PubMed PMID: 15908426]


Aziz DA,Memon F,Rahman A,Ali M, Liddle's Syndrome. Journal of Ayub Medical College, Abbottabad : JAMC. 2016 Oct-Dec;     [PubMed PMID: 28586600]


Kleyman TR,Cragoe EJ Jr, The mechanism of action of amiloride. Seminars in nephrology. 1988 Sep;     [PubMed PMID: 2849182]


Shah SU,Anjum S,Littler WA, Use of diuretics in cardiovascular diseases: (1) heart failure. Postgraduate medical journal. 2004 Apr;     [PubMed PMID: 15082840]


Epstein M,Calhoun DA, Aldosterone blockers (mineralocorticoid receptor antagonism) and potassium-sparing diuretics. Journal of clinical hypertension (Greenwich, Conn.). 2011 Sep;     [PubMed PMID: 21896143]


Wan HH,Lye MD, Moduretic-induced metabolic acidosis and hyperkalaemia. Postgraduate medical journal. 1980 May;     [PubMed PMID: 7443596]


Arai AE,Greenberg BH, Medical management of congestive heart failure. The Western journal of medicine. 1990 Oct;     [PubMed PMID: 2244376]


Montford JR,Linas S, How Dangerous Is Hyperkalemia? Journal of the American Society of Nephrology : JASN. 2017 Nov;     [PubMed PMID: 28778861]


Kokot F,Hyla-Klekot L, Drug-induced abnormalities of potassium metabolism. Polskie Archiwum Medycyny Wewnetrznej. 2008 Jul-Aug;     [PubMed PMID: 18714739]


Belkouch A,Belyamani L, An unusual manifestation of hyperkalemia. The Pan African medical journal. 2014;     [PubMed PMID: 25852794]