Review Article
Pharmacologically Relevant Drug Interactions of Potassium-Sparing Diuretics
Naina Mohamed Pakkir Maideen*
Corresponding Author: Dr. Naina Mohamed Pakkir Maideen, PhD, Pharmacologist, Dubai Health Authority, PB No: 4545, Dubai, UAE
Received: September 07, 2019; Revised: September 13, 2019; Accepted: June 25, 2020
Citation: Maideen NMP. (2020) Pharmacologically Relevant Drug Interactions of Potassium-Sparing Diuretics. J Pathol Toxicol Res, 1(1): 1-4.
Copyrights: ©2020 Maideen NMP. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Share :

Potassium-sparing diuretics are useful in the treatment of resistant hypertension and salt sensitive forms of hypertension common in black, obese, diabetic and elderly patients and they include Spironolactone, Eplerenone, Amiloride and Triamterene. Potassium-sparing diuretics interact pharmacodynamically with the drugs such as ACE inhibitors, angiotensin receptor blockers, direct renin inhibitor, potassium supplements, trimethoprim and cyclosporine and elevate the risk of hyperkalemia. To predict and prevent the adverse drug interactions, the prescribers and the pharmacists are needed to be aware of the possible drug interactions of Potassium-sparing diuretics.

 

Keywords: Drug interactions, Potassium-sparing diuretics, Spiranolactone, Eplerenone, Amiloride, Triamterene

 

INTRODUCTION

Potassium-sparing diuretics are useful in the treatment of resistant hypertension and salt sensitive forms of hypertension common in black, obese, diabetic and elderly patients [1]. They include Mineralocorticoid Receptor (MR) antagonists (aldosterone antagonists) such as Spironolactone and Eplerenone and Epithelial sodium transport channel blockers like Amiloride and Triamterene [2].

The interference of effects of a drug by the drugs, herbs, supplements or food administered concomitantly, is termed “Drug interactions” [3,4]. Potassium-sparing diuretics have the potential of causing hyperkalemia as the Aldosterone antagonists decrease secretion of potassium by inhibiting the binding of aldosterone to its cytoplasmic receptors while Epithelial sodium transport channel blockers reducing the secretion of potassium by decreasing sodium reabsorption [5]. Hyperkalemia is an electrolyte abnormality and it is associated with cardiac arrhythmias such as ventricular fibrillation and asystole, muscle weakness, paralysis and sudden cardiac death [6].

METHODS

The literature was searched in databases such as Medline/PMC/PubMed, Google Scholar, Science Direct, Cochrane Library, Directory of open access journals (DOAJ) and reference lists to identify related articles using the keywords drug interactions, potassium-sparing diuretics, mineralocorticoid receptor antagonists, aldosterone antagonists, spironolactone, eplerenone, epithelial sodium transport channel blockers, amiloride, triamterene, hyperkalemia inducing drugs and pharmacodynamics interactions.

RESULTS AND DISCUSSION

The use of potassium-sparing diuretics is associated with the risk of hyperkalemia and hence the drugs inducing hyperkalemia could interact pharmacodynamically with Potassium-sparing diuretics. To predict and prevent the adverse drug interactions, the prescribers and the pharmacists are needed to be aware of the possible drug interactions of Potassium-sparing diuretics.

ACE inhibitors (ACEIs)

Angiotensin Converting Enzyme (ACE) inhibitors are recommended as first-line drugs to treat hypertensive patients particularly those having comorbidities such as diabetes, heart failure, ischemic heart disease and chronic kidney disease [7] and they include Captopril, Lisinopril, Perindopril, Enalapril, Ramipril, Trandolapril, Cilazapril and Fosinopril [8].

ACE inhibitors induce hyperkalemia by affecting the secretion of potassium through the inhibition of stimulatory effect of angiotensin II on aldosterone secretion in the adrenal gland [9]. Concomitant use of Potassium-sparing diuretics and ACE inhibitors may lead to severe hyperkalemia particularly in patients with advanced age, type 2 diabetes and reduced renal function [10] and it is recommended to monitor the blood potassium levels when the concomitant use is necessary in the treatment of congestive heart failure [11].

Angiotensin receptor blockers (ARBs)

Angiotensin Receptor Blockers (ARBs) are used as first-line drugs to treat hypertensive patients particularly those having comorbidities such as diabetes, heart failure, ischemic heart disease and chronic kidney disease [7]. The patients who cannot tolerate ACE inhibitors due to persistent dry cough, angioedema and other adverse effects can take ARBs [12] and they include Losartan, Valsartan, Candesartan, Olmesartan, Irbesartan and Telmisartan [13].

ARBs can also induce hyperkalemia by affecting the secretion of potassium through the inhibition of stimulatory effect of angiotensin II on aldosterone secretion in the adrenal gland [14]. Co-administration of potassium-sparing diuretics and ARBs may also lead to severe hyperkalemia particularly in patients with advanced age, type 2 diabetes and reduced renal function [10] and it is recommended to monitor the blood potassium levels if they are used concomitantly to treat congestive heart failure [11].

Direct renin inhibitor (DRI)

Aliskiren is a Direct Renin Inhibitor (DRI) and it helps to manage hypertension in diabetic patients, as an add-on therapy [15]. Serum potassium levels may increase when potassium-sparing diuretics and DRI are used concurrently and it is advised to monitor the blood potassium if their concomitant use is necessary [16].

Potassium supplements

The risk of development of hyperkalemia is higher among the patients using potassium supplements and the co-administration of potassium‐sparing diuretics further increase the risk of hyperkalemia. If concomitant use of these drugs is necessary, close monitoring of serum potassium concentrations [17].

Trimethoprim

Trimethoprim is a synthetic antibacterial drug and it is approved to treat uncomplicated urinary tract infection, respiratory tract infection and other infections [18]. The serum potassium levels could be elevated by the administration of Trimethoprim, which inhibits potassium excretion through the blockade of epithelial sodium channels in the distal nephron [19]. Higher risk of hyperkalemia was demonstrated in elderly patients receiving a potassium-sparing diuretic and trimethoprim concomitantly and it is recommended to monitor blood potassium levels if both these drugs are used together [20].

Cyclosporine

Cyclosporine is a calcineurin inhibitor and it is used as an immunosuppressant agent blocking calcineurin’s phosphatase activity and decreases the production of inflammatory cytokines by T-lymphocytes [21]. Cyclosporine decreases the excretion of potassium and increase the risk of hyperkalemia through decreased activity of the renin-angiotensin-aldosterone system, impaired tubular responsiveness to aldosterone and altered function of several transporters [22]. The concomitant use of a Potassium-sparing diuretic and Cyclosporine may induce additive hyperkalemia which warrants close monitoring of blood potassium levels [23].

Digoxin

Digoxin is a cardiotonic drug, which is obtained from digitalis, and it helps to manage cardiac conditions such as congestive heart failure (CHF), atrial flutter or atrial fibrillation [24,25]. The renal tubular secretion of Digoxin could be reduced by the administration of Potassium‐sparing diuretics, which may result in increased Digoxin concentrations [26].

Eplerenone and CYP3A4 inhibitors

Eplerenone is an aldosterone antagonist and it has been identified as a substrate for Cytochrome P450 3A4 (CYP3A4) enzyme [27]. Hence, the concomitant use of potent CYP3A4 inhibitor such as Ketoconazole in patients receiving Eplerenone caused a fivefold increase in exposure of Eplerenone and while less potent CYP3A4 inhibitors like erythromycin, saquinavir, verapamil and fluconazole increasing twofold exposure of Eplerenone, which may result in eplerenone-induced hyperkalemia or hypotension [28].

CONCLUSION

The drugs having the potential of inducing hyperkalemia such as ACE inhibitors, Angiotensin Receptor Blockers, Direct Renin Inhibitor, Potassium supplements, Trimethoprim and Cyclosporine could interact pharmacodynamically with Potassium-sparing diuretics and further elevate the risk of hyperkalemia. To predict and prevent the adverse drug interactions, the prescribers and the pharmacists are needed to be aware of the possible drug interactions of potassium-sparing diuretics.

CONFLICTS OF INTEREST

Nil

FUNDING

Nil

Roush GC, Ernst ME, Kostis JB, Yeasmin S, Sica DA (2016) Dose doubling, relative potency and dose equivalence of potassium-sparing diuretics affecting blood pressure and serum potassium: Systematic review and meta-analyses. J Hypertens 34: 11-19.

2.     Epstein M, Calhoun DA (2011) Aldosterone blockers (mineralocorticoid receptor antagonism) and potassium‐sparing diuretics. J Clin Hypertens 13: 644-648.

3.     Maideen NM, Balasubramaniam R (2018) Pharmacologically relevant drug interactions of sulfonylurea anti-diabetics with common herbs. J Herbmed Pharmacol 7.

4.     Maideen NM (2019) Tobacco smoking and its drug interactions with co-medications involving CYP and UGT enzymes and nicotine. World J Pharmacol 8: 14-25.

5.     Perazella MA (2000) Drug-induced hyperkalemia: Old culprits and new offenders. Am J Med 109: 307-314.

6.     Chang AR, Sang Y, Leddy J, Yahya T, Kirchner HL, et al. (2016) Antihypertensive medications and the prevalence of hyperkalemia in a large health system. Hypertension 67: 1181-1188.

7.     James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, et al. (2014) 2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 311: 507-520.

8.     Brown NJ, Vaughan DE (1998) Angiotensin-converting enzyme inhibitors. Circulation 97: 1411-1420.

9.     Raebel MA (2012) Hyperkalemia associated with use of angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers. Cardiovasc Ther 30: e156-166.

10.  Wrenger E, Müller R, Moesenthin M, Welte T, Frölich JC, et al. (2003) Interaction of spironolactone with ACE inhibitors or angiotensin receptor blockers: Analysis of 44 cases. BMJ 327: 147-149.

11.  Palmer BF (2004) Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 351: 585-592.

12.  Telmisartan Randomised Assessment Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators (2008) Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: A randomised controlled trial. Lancet 372: 1174-1183.

13.  Ostroff JL, Wolff ML (2016) An overview of generic angiotensin receptor blockers. US Pharm 41: 44-50.

14.  Raebel MA (2012) Hyperkalemia associated with use of angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers. Cardiovasc ther 30: e156-166.

15.  Riccioni G (2013) The role of direct renin inhibitors in the treatment of the hypertensive diabetic patient. Ther Adv Endocrinol Metab 4: 139-145.

16.  Tabassum N (2011) Aliskiren: A new renin inhibitor as anti-hypertensive. J Appl Pharm Sci 1: 30-33.

17.  Uijtendaal EV, Zwart-van Rijkom JE, van Solinge WW, Egberts TC (2011) Frequency of laboratory measurement and hyperkalaemia in hospitalised patients using serum potassium concentration increasing drugs. Eur J Clin Pharmacol 67: 933-940.

18.  Mohamed N, Maideen P (2018) Thiazolidinediones and their drug interactions involving CYP enzymes. Am J Physiol Biochem Pharmacol 8: 47-54.

19.  Chan WY, Clark AB, Wilson AM, Loke YK, TIPAC Investigators (2017) The effect of co‐trimoxazole on serum potassium concentration: Safety evaluation of a randomized controlled trial. Br J Clin Pharmacol 83: 1808-1814.

20.  Antoniou T, Gomes T, Mamdani MM, Yao Z, Hellings C, et al. (2011) Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: Nested case-control study. BMJ 343: d5228.

21.  Pakkir Maideen NM, Manavalan G, Balasubramanian K (2018) Drug interactions of meglitinide anti-diabetics involving CYP enzymes and OATP1B1 transporter. Ther Adv Endocrinol Metab 9: 259-268.

22.  Lee CH, Kim GH (2007) Electrolyte and acid-base disturbances induced by calcineurin inhibitors. Electrolyte Blood Press 5: 126-130.

23.  Bertocchio JP, Barbe C, Lavaud S, Toupance O, Nazeyrollas P, et al. (2016) Safety of eplerenone for kidney-transplant recipients with impaired renal function and receiving cyclosporine A. PLoS One 11: e0153635.

24.  Maideen NMP (2019) Pharmacologically relevant drug interactions of α-glucosidase inhibitors. J Diabetes Metab Disord Control 6: 28-30.

25.  Maideen NMP (2019) Pharmacologically relevant drug interactions of glucagon-like peptide-1 receptor agonists. J Anal Pharm Res 8: 51-53.

26.  Wang MT, Su CY, Chan AL, Lian PW, Leu HB, et al. (2010) Risk of digoxin intoxication in heart failure patients exposed to digoxin-diuretic interactions: A population‐based study. Br J Clin Pharmacol 70: 258-267.

27.  Barnes BJ, Howard PA (2005) Eplerenone: A selective aldosterone receptor antagonist for patients with heart failure. Ann Pharmacother 39: 68-76.

28.  Craft J (2004) Eplerenone (Inspra), a new aldosterone antagonist for the treatment of systemic hypertension and heart failure. In: Baylor University Medical Center Proceedings, Taylor & Francis 17: 217-220.