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potassium sparing diuretics

Potassium sparing diuretics

Potassium-sparing diuretics are medicines that increase diuresis (urination) without the loss of potassium. Potassium-sparing diuretics are generally weak diuretics and work by interfering with the sodium-potassium exchange in the distal convoluted tubule of the kidneys or as an antagonist at the aldosterone receptor. Aldosterone promotes the retention of sodium and water, so if potassium-sparing diuretics are used to block this effect, more sodium and water can pass into the collecting ducts of the kidneys, increasing diuresis. Because potassium-sparing diuretics do not promote the secretion of potassium during diuresis they do not cause hypokalemia (low potassium levels). However, there is a risk of hyperkalemia (high potassium levels) if they are used with other agents that also retain potassium, such as ACE inhibitors.

Potassium-sparing diuretics may be used alone or in conjunction with loop or thiazide diuretics.

potassium sparing diuretics

Potassium sparing diuretics list

Amiloride hydrochloride (Midamar)

Amiloride is a potassium-sparing diuretic that does not have much of a diuretic effect when compared to its potassium-sparing activity 1. Amiloride was approved for use in the United States in 1986, but is not widely used.

Amiloride 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 2, thiazolidinediones-induced edema 3, lithium-induced polyuria 4, cystic fibrosis 5, insulin-induced edema 3 and multiple myeloma 6.

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 6.

Amiloride is available in 5 mg tablets in generic forms and under the brand name of Midamor. The typical dose of amiloride is 5 to 20 mg in one or two doses daily. Amiloride causes only a modest diuresis and it is often used in combination with a thiazide diuretic (such as hydrochlorothiazide: Moduretic), which takes advantage of it potassium-sparing characteristics to offset the potassium-wasting characteristics of the thiazides.

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

The major side effects of amiloride include hyperkalemia, headache, dizziness, gastrointestinal upset and rash.

Amiloride 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 FDA pregnancy category B.

Spironolactone (Aldactone)

Spironolactone is particularly helpful in edematous states (fluid retention; excess fluid held in body tissues) caused or exacerbated by hyperaldosteronism (the body produces too much aldosterone, a naturally occurring hormone), which is typical of the edema and ascites caused by cirrhosis. Because of its potassium-sparing actions, spironolactone is also used in combination with thiazide or loop diuretics in an attempt to prevent hypokalemia (low potassium levels). Chronic low dose therapy with spironolactone has also been reported to improve survival in patients with heart failure after myocardial infarction (heart attack).

Spironolactone also is used in combination with other medicines to treat precocious puberty (a condition causing children to enter puberty too soon, resulting in the development of sexual characteristics in girls usually younger than 8 years of age and in boys usually younger than 9 years of age) or myasthenia gravis (a disease in which the nerves do not function properly and patients may experience weakness; numbness; loss of muscle coordination; and problems with vision, speech, and bladder control). Spironolactone also may be used to treat certain female patients with abnormal facial hair. Talk to your doctor about the possible risks of using this medication for your condition.

Spironolactone was approved for use in the United States in 1960 and continues to be widely used. Spironolactone is available in 25, 50, 75 and 100 mg tablets generically and under the brand name of Aldactone. Fixed combinations of spironolactone and hydrochlorothiazide are also available under the brand name Aldactizide. The typical dose of spironolactone is 25 mg one to three times daily initially, with modification of the dose based upon clinical efficacy and tolerance to maintenance doses of 75 to 450 mg daily. The major side effects of spironolactone are due to its antiandrogen-like effects and include hair growth and gynecomastia.

Triamterene (Dyrenium)

Triamterene is used largely in therapy of edema (fluid retention; excess fluid held in body tissues) and can be safely used in patients with cirrhosis. Because of its potassium-sparing actions, triamterene is also used in combination with thiazide or loop diuretics in an attempt to prevent hypokalemia. Triamterene was approved for use in the United States in 1964 and continues to be widely used with more than 20 million prescriptions filled yearly. Triamterene is available in tablets and capsules of 50 and 100 mg in generic forms and under the brand name of Dyrenium. The typical dose of triamterene is 50 to 200 mg daily in one or two divided doses. Triamterene is also available in fixed dose combinations with hydrochlorothiazide (Maxide, Dyazide and generically). The major side effects of triamterene are dizziness, fatigue, headache, dry mouth, hyperkalemia and dehydration.

Potassium sparing diuretics mechanism of action

Amiloride

Amiloride is a pyrazinoylguanidine derivative that works by inhibiting the epithelial sodium channels of renal epithelial cells in the distal nephron (distal convoluted tubule and cortical collecting duct), lung, and colon causing an increase in sodium excretion with little or no effect on potassium excretion, thus accounting for its potassium-sparing characteristics 7. Amiloride is similar in action to triamterene, but differs in chemical structure.

Usually, sodium moves down its electrochemical gradient to enter the tubular cells through the epithelial sodium channels. This gradient results from the basolateral membrane sodium/potassium ATPase. Reabsorption of sodium (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 epithelial sodium channels resulting in a decrease in hyperpolarization of the apical membrane and consequently decreases potassium, hydrogen, calcium, and magnesium secretion. Because amiloride inhibits epithelial sodium channels, it can also lead to mild natriuresis 8. Amiloride also has the potential to cause vasodilation 9. 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 sodium concentration in the distal convoluted tubule and cortical collecting duct. This increase in sodium (Na) concentration couples with increased sodium (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 epithelial sodium channels, which results in increased sodium reabsorption and subsequently increased potassium secretion and excretion. Amiloride is not that effective in cases of hyperaldosteronism when compared to spironolactone and eplerenone.

Spironolactone

Spironolactone is a competitive inhibitor of the aldosterone receptor in the late distal tubule and collecting duct of the kidneys, which causes a decrease in sodium reabsorption and potassium excretion in the distal tubule. As a result, causes the kidneys to eliminate unneeded water and sodium from the body into the urine but reduces the loss of potassium from the body, thus maintains body potassium levels 10. Spironolactone .

Triamterene

Triamterene is an inhibitor of renal epithelial sodium channels in the late distal tubule and collecting ducts of the kidney. As a result, triamterene promotes a mild sodium diuresis, but maintains body potassium levels 11.

Potassium sparing diuretics side effects

Amiloride side effects

The major side effects of amiloride include hyperkalemia, headache, dizziness, gastrointestinal upset and rash. Amiloride has a boxed warning for hyperkalemia, either alone or even when combined with hydrochlorothiazide 12. 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%.

Amiloride other side effects include 13:

  • 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

The most toxic effect of amiloride is hyperkalemia. The initial step in managing amiloride toxicity is to stop all drugs that increase potassium levels (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.

Spironolactone side effects

The major side effects of spironolactone are due to its antiandrogen-like effects and include hair growth and gynecomastia.

Spironolactone may cause these side effects. Tell your doctor if any of these symptoms are severe or do not go away:

  • vomiting
  • diarrhea
  • stomach pain or cramps
  • enlarged or painful breasts in men or women
  • irregular menstrual periods
  • vaginal bleeding in post-menopausal (‘after the change of life’, the end of monthly menstrual periods) women
  • difficulty maintaining or achieving an erection
  • deepening of voice
  • increased hair growth on parts of the body
  • drowsiness
  • tiredness
  • restlessness

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately:

  • muscle weakness, pain, or cramps
  • pain, burning, numbness, or tingling in the hands or feet
  • inability to move arms or legs
  • changes in heartbeat
  • confusion
  • nausea
  • extreme tiredness
  • dry mouth, thirst, dizziness, unsteadiness, headache, or other signs of dehydration
  • unusual bleeding or bruising
  • lack of energy
  • loss of appetite
  • pain in the upper right part of the stomach
  • yellowing of the skin or eyes
  • flu-like symptoms
  • rash
  • hives
  • itching
  • difficulty breathing or swallowing
  • vomiting blood
  • blood in stools
  • decreased urination
  • fainting

Triamterene side effects

The major side effects of triamterene are dizziness, fatigue, headache, dry mouth, hyperkalemia and dehydration.

Triamterene may cause these side effects. Tell your doctor if any of these symptoms are severe or do not go away:

  • vomiting
  • dizziness
  • headache

Some side effects can be serious. If you experience any of the following symptoms, call your doctor immediately:

  • muscle weakness or cramps
  • slow or irregular heartbeat
  • diarrhea
  • rash
  • difficulty breathing or swallowing
  • upset stomach
  • extreme tiredness
  • unusual bleeding or bruising
  • lack of energy
  • loss of appetite
  • pain in the upper right part of the stomach
  • yellowing of the skin or eyes
  • flu-like symptoms
  • sore throat
  • severe dry mouth
  • unusual bruising or bleeding
References
  1. Almajid AN, Cassagnol M. Amiloride. [Updated 2019 Oct 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK542303
  2. 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. Int J Mol Sci. 2018 Mar 11;19(3).
  3. 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. Clin J Am Soc Nephrol. 2013 Feb;8(2):225-32.
  4. Pattanayak RD, Rajhans P, Shakya P, Gautam N, Khandelwal SK. Lithium-induced polyuria and amiloride: Key issues and considerations. Indian J Psychiatry. 2017 Jul-Sep;59(3):391-392.
  5. 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. Am. Rev. Respir. Dis. 1993 Oct;148(4 Pt 1):1002-7.
  6. 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. Clin. Cancer Res. 2017 Nov 01;23(21):6602-6615.
  7. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Amiloride. [Updated 2017 Oct 5]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547934
  8. Shah SU, Anjum S, Littler WA. Use of diuretics in cardiovascular diseases: (1) heart failure. Postgrad Med J. 2004 Apr;80(942):201-5.
  9. Epstein M, Calhoun DA. Aldosterone blockers (mineralocorticoid receptor antagonism) and potassium-sparing diuretics. J Clin Hypertens (Greenwich). 2011 Sep;13(9):644-8.
  10. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Spironolactone. [Updated 2017 Oct 21]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547921
  11. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Triamterene. [Updated 2015 Jun 18]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547859
  12. Wan HH, Lye MD. Moduretic-induced metabolic acidosis and hyperkalaemia. Postgrad Med J. 1980 May;56(655):348-50.
  13. Arai AE, Greenberg BH. Medical management of congestive heart failure. West. J. Med. 1990 Oct;153(4):406-14.
  14. Kokot F, Hyla-Klekot L. Drug-induced abnormalities of potassium metabolism. Pol. Arch. Med. Wewn. 2008 Jul-Aug;118(7-8):431-4.
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