Amiloride


Article Author:
Ali Almajid


Article Editor:
Manouchkathe Cassagnol


Editors In Chief:
Jon Parham
Jon Sivoravong


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
5/10/2019 11:37:06 PM

Indications

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,[2] lithium-induced polyuria,[3] cystic fibrosis,[4] and insulin-induced edema,[2] multiple myeloma.[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 has been found to be 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 subsequently decrease in 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 a long 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 used to tread 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]

Administration

Dosing in adults for amiloride's FDA indications:

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

Amiloride gets excreted unchanged while triamterene undergoes extensive metabolism in the liver. Amiloride is given orally with food to avoid gastrointestinal upset.

Adverse Effects

Amiloride has a boxed warning for hyperkalemia either alone or even when combined with hydrochlorothiazide.[11] Hyperkalemia might be fatal especially in people with diabetes, elderly patients, and patients with renal impairment. Hyperkalemia tends to occur in patients not receiving 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 

Contraindications

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. Oral vitamin K administration should be discontinued in patients receiving potassium-sparing diuretics. Amiloride is acceptable during pregnancy since it is pregnancy category B.

Monitoring

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

Toxicity

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 absence P wave on ECG.[14][15] Moreover, patients with hyperkalemia may complain of fatigue, dizziness, and weakness.[15]

The initial step in managing amiloride toxicity is to stop all the drugs that increase potassium level (including amiloride). The next step is to treat the 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

Health-care 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 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 V]


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Amiloride - Questions

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An 18-year-old male patient presents to the hospital complaining of headache for three weeks duration. The headache is not associated with autonomic features, and it is not unilateral. Along with the headache, the patient states that he has a weakness and myalgia that started five months ago. The patient says that his father had the same thing at the age of 20. His vitals are as follows, a blood pressure of 180/110 mmHg and a heart rate of 80 bpm, normal temperature, and normal respiratory rate. Initial workup reveals a potassium level of 2.5 mEq/L, very low serum aldosterone, and low serum renin levels. After thorough investigations, the patient was treated with amiloride, and he became much better on amiloride. Why the provider prescribed amiloride?



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A 70-year-old female patient known to have hypertension, diabetes mellitus type 2, and chronic kidney disease presents to the internal medicine clinic for regular follow-up. Her GFR is below 40 mL/min. Her provider prescribed her amiloride in order to prevent hypokalemaia and its complications. Why is prescribing amiloride a bad idea?



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A 63-year-old male patient known to have hypertension presents to the cardiology clinic for follow-up. The patient was treated with thiazide and amiloride was added to his current medications. Why did the cardiologist add amiloride?



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A 50-year-old woman with congestive heart failure and hypertension presents complaining of frequent urination of large volumes. She also states that she is thirsty most of the time throughout the day. History taking reveals that she did not pass stool since the last week. Physical examination is unremarkable except for muscle weakness. Her ECG and vitals were normal. Her potassium was found to be 2.5 mEq/L, and her blood glucose was 400 mg/dl. Her current medications include hydrochlorothiazide, lisinopril, and carvedilol. Which of the following diuretics does not require blood glucose monitoring that will alleviate muscle weakness and constipation if added to her current medications?



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A 45-year-old male patient known to have diabetes mellitus type 2 and hypertension presents to the internal medicine clinic for regular follow-up. His current medications include verapamil and metformin. The provider would like to add another a drug that does not cause hyperglycemia, which one of the following drugs would be an appropriate choice in this case?



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A 68-year-old man comes to the clinic for regular follow up. He is being treated for his congestive heart failure and diabetes mellitus with furosemide, potassium, metformin, and carvedilol. Amiloride is added. Which of the following should be done with all these medications?



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A 55-year-old man was recently diagnosed with hypertension. He was started on hydrochlorothiazide and amiloride. The coadministration of thiazide with amiloride is done because amiloride does which of the following?



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A 60-year-old male comes to your clinic for a follow-up visit. He has a past medical history of heart failure. He was admitted to the hospital 2 weeks ago for acute decompensated heart failure. He says he feels better now and he no longer has shortness of breath. On examination, BP: 123/60, HR: 83, RR: 19, O2: 97%. He has trace lower limb edema that has greatly improved since his last visit. His medications include metoprolol, hydrochlorothiazide, and aspirin. His most recent lab tests show K: 3.3, Na: 140, Cl: 100, HCO3: 23. The clinician decided to start a medication that will work to improve this patient's elevated potassium levels. This medication is also used to treat lithium-induced syndrome of inappropriate ADH secretion (SIADH). What is the mechanism of action of this medication?



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A 23-year-old male patient presents to the hospital because he is experiencing swelling in his ankles and sometimes around the eye early in the morning. He is known to have diabetes mellitus type 1 diagnosed 10 years ago. The patient is on insulin treatment. All investigations are normal including a kidney biopsy. The clinician prescribes a medication that blocks the epithelial sodium channels in the principal cells of the collecting tubules. Which of the following is a potential side effect of this medication?



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Amiloride - References

References

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]
Aziz DA,Memon F,Rahman A,Ali M, Liddle's Syndrome. Journal of Ayub Medical College, Abbottabad : JAMC. 2016 Oct-Dec;     [PubMed]
Kleyman TR,Cragoe EJ Jr, The mechanism of action of amiloride. Seminars in nephrology. 1988 Sep;     [PubMed]
Shah SU,Anjum S,Littler WA, Use of diuretics in cardiovascular diseases: (1) heart failure. Postgraduate medical journal. 2004 Apr;     [PubMed]
Epstein M,Calhoun DA, Aldosterone blockers (mineralocorticoid receptor antagonism) and potassium-sparing diuretics. Journal of clinical hypertension (Greenwich, Conn.). 2011 Sep;     [PubMed]
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]
Wan HH,Lye MD, Moduretic-induced metabolic acidosis and hyperkalaemia. Postgraduate medical journal. 1980 May;     [PubMed]
Arai AE,Greenberg BH, Medical management of congestive heart failure. The Western journal of medicine. 1990 Oct;     [PubMed]
Montford JR,Linas S, How Dangerous Is Hyperkalemia? Journal of the American Society of Nephrology : JASN. 2017 Nov;     [PubMed]
Kokot F,Hyla-Klekot L, Drug-induced abnormalities of potassium metabolism. Polskie Archiwum Medycyny Wewnetrznej. 2008 Jul-Aug;     [PubMed]
Belkouch A,Belyamani L, An unusual manifestation of hyperkalemia. The Pan African medical journal. 2014;     [PubMed]
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]
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]
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]
    [PubMed]

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