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Amiloride

Editor: Manouchkathe Cassagnol Updated: 2/28/2024 2:37:18 AM

Indications

Amiloride is a potassium-sparing diuretic with a moderate diuretic effect compared to its potassium-sparing activity. Amiloride is a pyrazinoylguanidine derivative.[1]

FDA-Approved Indications

Amiloride is FDA-approved to be used adjunctively with thiazides (or other kaliuretic agents) for the treatment of chronic heart failure or uncomplicated essential hypertension to help restore normal serum potassium concentrations in those who develop hypokalemia on kaliuretic therapy. Amiloride is also indicated to prevent the development of hypokalemia in patients with a higher risk of hypokalemia (patients on digoxin therapy or patients with significant cardiac arrhythmias).[2][3][4] The American Heart Association/American College of Cardiology (AHA/ACC) guidelines state that amiloride is not the preferred medication for the initial management of hypertension. Amiloride can be combined with thiazide in cases of hypokalemia during thiazide monotherapy.[5]

Off-Label Uses

The American Association for the Study of Liver Diseases endorses amiloride for refractory ascites.[6] As per guidelines by KDIGO (Kidney Disease: Improving Global Outcomes), amiloride can be a helpful add-on therapy for nephrotic syndrome.[7] Amiloride might also be useful in thiazolidinediones-induced edema and lithium-induced polyuria.[8][9] As an epithelial sodium channel blocker, amiloride has been researched in cystic fibrosis due to its ability to inhibit epithelial sodium channels (ENaC), potentially hydrating airway surfaces by reducing sodium absorption. Inhaled amiloride with tobramycin has been investigated to eradicate Burkholderia cepacia complex in patients with cystic fibrosis.[10][11] The case report also describes amiloride for the treatment of severe refractory symptomatic hypokalemia associated with type 1 renal tubular acidosis.[12] Preclinical studies suggest that amiloride can induce apoptosis in multiple myeloma cell lines.[13] Amiloride's inhibition of ENaC and a low-sodium diet contribute to normalizing blood pressure and electrolyte levels in Liddle syndrome.[14] It is necessary to perform randomized controlled trials to validate these findings.

Mechanism of Action

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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 2 domains that span the apical membrane. Those domains are denoted M1 and M2. Intracellularly, there are C and N termini, while extracellularly, there is a large loop that contains 2 or 3 cysteine-rich domains. ENaCs have 3 subunits: α, β, and γ.[15] Mutation in β or γ subunits occurs in Liddle syndrome, where basal ENaCs activity increases. Amiloride is beneficial in Liddle syndrome, as described above.[16]

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. The difference in electric potential enhances potassium secretion through the apical channels, increasing potassium excretion. Amiloride selectively inhibits ENaCs, decreasing hyperpolarization of the apical membrane and consequently decreasing potassium, hydrogen, calcium, and magnesium secretion. Because amiloride inhibits ENaCs, it can also lead to mild natriuresis.[17][18] Amiloride also has the potential to cause vasodilation.[19] Prolonged use of amiloride can reduce the excretion of renal uric acid by causing volume contraction and reabsorption of uric acid from the proximal convoluted tubule.

The loop diuretics and thiazides will increase Na concentration in the distal convoluted tubule and cortical collecting duct. This increase in Na concentration couples with increased Na reabsorption and 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 helps treat insulin-induced edema. In this condition, ENaCs are upregulated, resulting in increased Na reabsorption and potassium secretion and excretion. However, amiloride is not that effective in hyperaldosteronism when compared to spironolactone and eplerenone.[20] Amiloride can induce apoptosis in multiple myeloma cell lines in mice, and therefore, it might be used to treat relapsed multiple myeloma in the future. The combination of amiloride with melphalan, lenalidomide, and dexamethasone showed a synergistic effect.[13]

Pharmacokinetics 

Absorption: Amiloride demonstrates an onset of action of 2 hours upon oral administration, with peak plasma concentrations attained within 3 to 4 hours. The effects of amiloride as a diuretic last for approximately 24 hours.

Distribution: It exhibits extravascular distribution and a high volume of distribution (350 to 380 L) due to its small molecular weight and low plasma protein binding (<40%).[21][22]

Metabolism: Amiloride is excreted unchanged by the kidneys and is not metabolized by the liver. Hence, drug accumulation is not expected in patients with liver dysfunction.

Elimination: Around 50% of amiloride is excreted unchanged by the kidneys in urine, while approximately 40% is excreted via feces. In individuals with normal kidney function, amiloride has a serum half-life of 6 to 9 hours.[3]

Administration

Available Dosage Forms and Strengths

Amiloride is available as an oral tablet with a standardized strength of 5 mg. Amiloride is also available in combination with hydrochlorothiazide.[23]

Adult Dosing

Congestive heart failure: 5 to 10 mg by mouth once daily or in divided doses. When managing congestive heart failure and achieving initial diuresis, the potassium loss might diminish, prompting a reassessment of the necessity for amiloride. Dosage adjustments may be required, and the continuation of therapy might be intermittent for maintenance purposes.

Hypertension: 5 mg by mouth once daily. The dosage of amiloride may be increased to 10 mg/d if necessary. As per AHA/ACC guidelines, If hypokalemia is present, primary or secondary aldosteronism should be excluded; after careful evaluation, a potassium-sparing diuretic like amiloride can be considered.[5]

Thiazide-induced hypokalemia: 5 to 10 mg orally once daily or in divided doses.[3]

Specific Patient Populations

Hepatic impairment: The product label does not provide information on dose adjustment in case of hepatic impairment.

Renal impairment: The dosage needs to be adjusted in patients with renal impairment and contraindicated in severe renal impairment. AHA/ACC guidelines recommend avoiding amiloride if GFR <45 mL/min.[5]

Pregnancy considerations: Amiloride is acceptable during pregnancy since it is FDA pregnancy category B.[24] The American College of Obstetricians and Gynecologists recommends the use of labetalol or nifedipine for the treatment of gestational hypertension.[25]

Breastfeeding considerations: No information is available in the case of breastfeeding, so it is recommended to use alternative medicine.[26]

Pediatric patients: According to the FDA label, amiloride has not been established as safe and effective for pediatric patients. It is used off-label for the management of pediatric hypertension.[27] Amiloride is also used off-label in pediatric patients with nephrogenic diabetes insipidus.[28])

Older patients: It should be used cautiously in patients with diabetes and patients 65 and older.[29] As per the American Geriatric Society's 2023 guidelines (Beers criteria), it is advised to refrain from utilizing amiloride in individuals older than 65 with a creatinine clearance of less than 30 mL/min due to the elevated risk of hyperkalemia and hyponatremia.[30]

Adverse Effects

Amiloride is generally well tolerated, with few significant adverse effects other than the risk of hyperkalemia. The most common adverse drug reactions of amiloride include nausea, vomiting, diarrhea, and headache.[3][31] Other adverse drug reactions are listed below.

  • Central nervous system: fatigue and dizziness
  • Musculoskeletal system: muscle cramps and weakness
  • Gastrointestinal system: nausea, vomiting, diarrhea/constipation, abdominal pain, and anorexia
  • Respiratory: dyspnea and cough
  • Genitourinary: impotence
  • Endocrine and metabolic: glucose intolerance, hyperuricemia, hyperchloremic metabolic acidosis, hyperkalemia, and hyponatremia [30]

Drug-Drug Interactions

Simultaneous administration of a non-steroidal anti-inflammatory drug (NSAID) and amiloride can reduce the diuretic and antihypertensive effects of the amiloride. Hence, it is crucial to observe patients when amiloride and NSAIDs are used together to ensure that the desired diuretic effect is achieved. Additionally, monitoring the potassium and renal function is essential since administering amiloride and NSAID may increase serum potassium levels.[23]

It is recommended to avoid concomitant use of drugs that blunt the renin-angiotensin-aldosterone system (angiotensin-converting enzyme inhibitors, beta-blockers, and aliskiren).[32][33]

Amiloride is contraindicated with other potassium-sparing diuretics such as potassium-sparing diuretics (spironolactone or triamterene). Amiloride and cyclosporine both increase serum potassium; coadministration is not recommended.[34]

Contraindications

Amiloride can cause fatal hyperkalemia in susceptible patients. Amiloride is contraindicated if serum potassium levels are (>5.5 mEq/L).[35] Amiloride is contraindicated in acute or chronic renal insufficiency (serum creatinine >1.5 mg/dL or [BUN] >30 mg/dL), anuria, with concomitant use of other potassium-sparing diuretics (spironolactone or triamterene). Amiloride is contraindicated in documented hypersensitivity to amiloride or excipients.[36][37][38]

Box Warning

Amiloride has an FDA-box warning for hyperkalemia, either alone or even when combined with hydrochlorothiazide. Hyperkalemia might be fatal, especially in people with diabetes mellitus, older patients, and patients with renal impairment. Hyperkalemia tends to occur in patients who do not receive a concomitant kaliuretic diuretic. When amiloride is used concomitantly with thiazides, the risk of hyperkalemia drops below 2%. Amiloride should be used cautiously, and serum potassium levels should be carefully monitored in patients, especially during initiation, diuretic dosage adjustments, and any illness that could affect renal function.[39]

Monitoring

Amiloride requires monitoring for hyperkalemia and impaired renal function.[24] Therefore, periodic monitoring of serum potassium, BUN, and creatinine concentrations is essential. The parameters that also require monitoring are blood pressure, daily weight, serum bicarbonate, serum magnesium concentrations, and signs or 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, which lowers 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 a shortening of the action potential, which leads to a delay in the conduction in the atrioventricular node and His-Purkinje system. On ECG, it manifests as a peaked "tented" T wave. The QRS complex will widen as the condition worsens, resulting in the so-called ''sine wave''. Therefore, hyperkalemia can lead to increased cardiac excitability or decreased 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.[40] Hyperkalemia can also cause an absence of the P wave on ECG.[41][42] Moreover, patients with hyperkalemia may present with fatigue, dizziness, and weakness.[42]

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% calcium gluconate IV over 5 minutes. Because the effect is temporary, another dose might be necessary after 15 minutes. Treating hyperkalemia includes administering rapid-acting insulin, glucose, potassium-binding resins, salbutamol, and sodium bicarbonate.[41] Normal saline should be administered for volume replacement; hypotensive refractory to volume replacement may require dopamine and norepinephrine.[43]

Enhancing Healthcare Team Outcomes

Healthcare professionals prescribing amiloride should know its indications, dosage, contraindications, and adverse effects. Monitoring serum potassium and renal function is integral to managing heart failure and hypertension when receiving amiloride. In addition, managing 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 initiates amiloride therapy, they should collaborate with other healthcare team members to enhance care coordination and communication. A cardiologist should be consulted for the use of amiloride in settings of resistant hypertension and heart failure. Coordinating with the pathologist for necessary laboratory investigations pertinent to amiloride monitoring (eg, potassium and serum creatinine) is prudent. The pharmacist should also perform a medication reconciliation check for drug interactions and verify dosing. A case-control study explored hyperkalemia prevention strategies in patients with heart failure. It was demonstrated that pharmacist-based multidimensional interventions, as part of an interprofessional healthcare team, are linked to reduced odds of hyperkalemia.[44] Nursing staff should also have involvement, including patient counseling, monitoring medication adherence, and being aware and alert to signs of adverse events and toxicity. It is necessary to have a collaborative interprofessional team that includes clinicians, specialty-trained nurses, specialists, and pharmacists to optimize treatment outcomes related to amiloride and minimize adverse drug reactions.

References


[1]

Vesell ES, Beyer KH Jr. Studies on pyrazinoylguanidine: a novel antihypertensive, hypoglycemic and lipolytic drug intended for adjunctive use in hypertensive patients with type 2 diabetes mellitus. Toxicology. 2000 Apr 3:144(1-3):5-11     [PubMed PMID: 10781866]

Level 3 (low-level) evidence

[2]

Vidt DG. Mechanism of action, pharmacokinetics, adverse effects, and therapeutic uses of amiloride hydrochloride, a new potassium-sparing diuretic. Pharmacotherapy. 1981 Nov-Dec:1(3):179-87     [PubMed PMID: 6927605]


[3]

Sun Q, Sever P. Amiloride: A review. Journal of the renin-angiotensin-aldosterone system : JRAAS. 2020 Oct-Dec:21(4):1470320320975893. doi: 10.1177/1470320320975893. Epub     [PubMed PMID: 33234024]


[4]

Sethy VH, Patel DG, Doshi JC, Mehta JM, Sheth UK. The potassium-sparing effect of amiloride hydrochloride (MK-870) on the kaliuretic effect of ethacrynic acid. The Journal of clinical pharmacology and the journal of new drugs. 1968 Sep-Oct:8(5):309-14     [PubMed PMID: 5244660]


[5]

Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr, Williamson JD, Wright JT Jr. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension (Dallas, Tex. : 1979). 2018 Jun:71(6):e13-e115. doi: 10.1161/HYP.0000000000000065. Epub 2017 Nov 13     [PubMed PMID: 29133356]

Level 1 (high-level) evidence

[6]

Biggins SW, Angeli P, Garcia-Tsao G, Ginès P, Ling SC, Nadim MK, Wong F, Kim WR. Diagnosis, Evaluation, and Management of Ascites, Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome: 2021 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology (Baltimore, Md.). 2021 Aug:74(2):1014-1048. doi: 10.1002/hep.31884. Epub     [PubMed PMID: 33942342]


[7]

Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney international. 2021 Oct:100(4S):S1-S276. doi: 10.1016/j.kint.2021.05.021. Epub     [PubMed PMID: 34556256]

Level 1 (high-level) evidence

[8]

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:8(2):225-32. doi: 10.2215/CJN.06330612. Epub 2012 Nov 26     [PubMed PMID: 23184569]

Level 1 (high-level) evidence

[9]

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:59(3):391-392. doi: 10.4103/psychiatry.IndianJPsychiatry_168_17. Epub     [PubMed PMID: 29085107]


[10]

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:148(4 Pt 1):1002-7     [PubMed PMID: 8214916]

Level 1 (high-level) evidence

[11]

Akkerman-Nijland AM, Rottier BL, Holstein J, Winter RLJ, Touw DJ, Akkerman OW, Koppelman GH. Eradication of Burkholderia cepacia complex in cystic fibrosis patients with inhalation of amiloride and tobramycin combined with oral cotrimoxazole. ERJ open research. 2023 May:9(3):. pii: 00055-2023. doi: 10.1183/23120541.00055-2023. Epub 2023 Jun 26     [PubMed PMID: 37377654]


[12]

Oguejiofor P, Chow R, Yim K, Jaar BG. Successful Management of Refractory Type 1 Renal Tubular Acidosis with Amiloride. Case reports in nephrology. 2017:2017():8596169. doi: 10.1155/2017/8596169. Epub 2017 Jan 3     [PubMed PMID: 28127482]

Level 3 (low-level) evidence

[13]

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 1:23(21):6602-6615. doi: 10.1158/1078-0432.CCR-17-0678. Epub 2017 Aug 8     [PubMed PMID: 28790111]


[14]

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 11:19(3):. doi: 10.3390/ijms19030812. Epub 2018 Mar 11     [PubMed PMID: 29534496]

Level 3 (low-level) evidence

[15]

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 15:280(28):26206-15     [PubMed PMID: 15908426]

Level 3 (low-level) evidence

[16]

Aziz DA, Memon F, Rahman A, Ali M. Liddle's Syndrome. Journal of Ayub Medical College, Abbottabad : JAMC. 2016 Oct-Dec:28(4):809-811     [PubMed PMID: 28586600]


[17]

Kleyman TR, Cragoe EJ Jr. The mechanism of action of amiloride. Seminars in nephrology. 1988 Sep:8(3):242-8     [PubMed PMID: 2849182]

Level 3 (low-level) evidence

[18]

Shah SU, Anjum S, Littler WA. Use of diuretics in cardiovascular diseases: (1) heart failure. Postgraduate medical journal. 2004 Apr:80(942):201-5     [PubMed PMID: 15082840]


[19]

Epstein M, Calhoun DA. Aldosterone blockers (mineralocorticoid receptor antagonism) and potassium-sparing diuretics. Journal of clinical hypertension (Greenwich, Conn.). 2011 Sep:13(9):644-8. doi: 10.1111/j.1751-7176.2011.00511.x. Epub 2011 Aug 9     [PubMed PMID: 21896143]


[20]

Matthesen SK, Larsen T, Vase H, Lauridsen TG, Jensen JM, Pedersen EB. Effect of amiloride and spironolactone on renal tubular function and central blood pressure in patients with arterial hypertension during baseline conditions and after furosemide: a double-blinded, randomized, placebo-controlled crossover trial. Clinical and experimental hypertension (New York, N.Y. : 1993). 2013:35(5):313-24. doi: 10.3109/10641963.2012.721843. Epub 2012 Sep 11     [PubMed PMID: 22966789]

Level 1 (high-level) evidence

[21]

Smith AJ, Smith RN. Kinetics and bioavailability of two formulations of amiloride in man. British journal of pharmacology. 1973 Aug:48(4):646-9     [PubMed PMID: 4788208]


[22]

Uribe B, González O, Blanco ME, Albóniga OE, Alonso ML, Alonso RM. Analysis of the Heterogeneous Distribution of Amiloride and Propranolol in Dried Blood Spot by UHPLC-FLD and MALDI-IMS. Molecules (Basel, Switzerland). 2019 Nov 26:24(23):. doi: 10.3390/molecules24234320. Epub 2019 Nov 26     [PubMed PMID: 31779239]


[23]

Brown MJ, Williams B, Morant SV, Webb DJ, Caulfield MJ, Cruickshank JK, Ford I, McInnes G, Sever P, Salsbury J, Mackenzie IS, Padmanabhan S, MacDonald TM, British Hypertension Society's Prevention and Treatment of Hypertension with Algorithm-based Therapy (PATHWAY) Studies Group. Effect of amiloride, or amiloride plus hydrochlorothiazide, versus hydrochlorothiazide on glucose tolerance and blood pressure (PATHWAY-3): a parallel-group, double-blind randomised phase 4 trial. The lancet. Diabetes & endocrinology. 2016 Feb:4(2):136-47. doi: 10.1016/S2213-8587(15)00377-0. Epub 2015 Oct 18     [PubMed PMID: 26489809]

Level 1 (high-level) evidence

[24]

Krysiak R, Samborek M, Stojko R. Primary aldosteronism in pregnancy. Acta clinica Belgica. 2012 Mar-Apr:67(2):130-4     [PubMed PMID: 22712170]

Level 3 (low-level) evidence

[25]

American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 203: Chronic Hypertension in Pregnancy. Obstetrics and gynecology. 2019 Jan:133(1):e26-e50. doi: 10.1097/AOG.0000000000003020. Epub     [PubMed PMID: 30575676]


[26]

. Amiloride. Drugs and Lactation Database (LactMed®). 2006:():     [PubMed PMID: 30000009]


[27]

Lande MB, Flynn JT. Treatment of hypertension in children and adolescents. Pediatric nephrology (Berlin, Germany). 2009 Oct:24(10):1939-49     [PubMed PMID: 17690916]

Level 3 (low-level) evidence

[28]

Vaz de Castro PAS, Bitencourt L, de Oliveira Campos JL, Fischer BL, Soares de Brito SBC, Soares BS, Drummond JB, Simões E Silva AC. Nephrogenic diabetes insipidus: a comprehensive overview. Journal of pediatric endocrinology & metabolism : JPEM. 2022 Apr 26:35(4):421-434. doi: 10.1515/jpem-2021-0566. Epub 2022 Feb 11     [PubMed PMID: 35146976]

Level 3 (low-level) evidence

[29]

By the 2019 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults. Journal of the American Geriatrics Society. 2019 Apr:67(4):674-694. doi: 10.1111/jgs.15767. Epub 2019 Jan 29     [PubMed PMID: 30693946]


[30]

By the 2023 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. Journal of the American Geriatrics Society. 2023 Jul:71(7):2052-2081. doi: 10.1111/jgs.18372. Epub 2023 May 4     [PubMed PMID: 37139824]


[31]

Arai AE, Greenberg BH. Medical management of congestive heart failure. The Western journal of medicine. 1990 Oct:153(4):406-14     [PubMed PMID: 2244376]


[32]

Villa-Zapata L, Carhart BS, Horn JR, Hansten PD, Subbian V, Gephart S, Tan M, Romero A, Malone DC. Serum potassium changes due to concomitant ACEI/ARB and spironolactone therapy: A systematic review and meta-analysis. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2021 Dec 9:78(24):2245-2255. doi: 10.1093/ajhp/zxab215. Epub     [PubMed PMID: 34013341]

Level 1 (high-level) evidence

[33]

Yusuff KB, Okoh CN. Frequency, types and factors associated with potentially harmful drug interactions in ambulatory elderly patients in Nigeria. The International journal of pharmacy practice. 2015 Oct:23(5):353-6. doi: 10.1111/ijpp.12167. Epub 2014 Dec 4     [PubMed PMID: 25474395]

Level 2 (mid-level) evidence

[34]

Lehnhardt A, Kemper MJ. Pathogenesis, diagnosis and management of hyperkalemia. Pediatric nephrology (Berlin, Germany). 2011 Mar:26(3):377-84. doi: 10.1007/s00467-010-1699-3. Epub 2010 Dec 22     [PubMed PMID: 21181208]


[35]

Berkova M, Berka Z, Topinkova E. Arrhythmias and ECG changes in life threatening hyperkalemia in older patients treated by potassium sparing drugs. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia. 2014:158(1):84-91. doi: 10.5507/bp.2012.087. Epub 2012 Oct 31     [PubMed PMID: 23128820]

Level 3 (low-level) evidence

[36]

Spahn H, Reuter K, Mutschler E, Gerok W, Knauf H. Pharmacokinetics of amiloride in renal and hepatic disease. European journal of clinical pharmacology. 1987:33(5):493-8     [PubMed PMID: 3428342]


[37]

Svendsen UG, Ibsen H, Rasmussen S, Leth A, Nielsen MD, Dige-Petersen H, Giese J. Effects of combined therapy with amiloride and hydrochlorothiazide on plasma and total body potassium, blood pressure, and the renin-angiotensin-aldosterone system in hypertensive patients. European journal of clinical pharmacology. 1986:30(2):151-6     [PubMed PMID: 3519243]

Level 1 (high-level) evidence

[38]

Andersen H, Hansen PB, Bistrup C, Nielsen F, Henriksen JE, Jensen BL. Significant natriuretic and antihypertensive action of the epithelial sodium channel blocker amiloride in diabetic patients with and without nephropathy. Journal of hypertension. 2016 Aug:34(8):1621-9. doi: 10.1097/HJH.0000000000000967. Epub     [PubMed PMID: 27214087]


[39]

Wan HH, Lye MD. Moduretic-induced metabolic acidosis and hyperkalaemia. Postgraduate medical journal. 1980 May:56(655):348-50     [PubMed PMID: 7443596]

Level 3 (low-level) evidence

[40]

Montford JR, Linas S. How Dangerous Is Hyperkalemia? Journal of the American Society of Nephrology : JASN. 2017 Nov:28(11):3155-3165. doi: 10.1681/ASN.2016121344. Epub 2017 Aug 4     [PubMed PMID: 28778861]


[41]

Kokot F, Hyla-Klekot L. Drug-induced abnormalities of potassium metabolism. Polskie Archiwum Medycyny Wewnetrznej. 2008 Jul-Aug:118(7-8):431-4     [PubMed PMID: 18714739]


[42]

Belkouch A, Belyamani L. An unusual manifestation of hyperkalemia. The Pan African medical journal. 2014:19():251. doi: 10.11604/pamj.2014.19.251.5007. Epub 2014 Nov 7     [PubMed PMID: 25852794]


[43]

Foulon P, De Backer D. The hemodynamic effects of norepinephrine: far more than an increase in blood pressure! Annals of translational medicine. 2018 Nov:6(Suppl 1):S25. doi: 10.21037/atm.2018.09.27. Epub     [PubMed PMID: 30613600]


[44]

Gallo-Bernal S, Calixto CA, Molano-González N, Moreno MPD, Tamayo MF, Contreras JP, Medina HM, Rodríguez MJ. Impact of a pharmacist-based multidimensional intervention aimed at decreasing the risk of hyperkalemia in heart failure patients: A Latin-American experience. International journal of cardiology. 2021 Apr 15:329():136-143. doi: 10.1016/j.ijcard.2020.12.081. Epub 2021 Jan 4     [PubMed PMID: 33412183]