Basic Information
ID DDInter1565 and DDInter1707
Interaction Concomitant use of angiotensin converting enzyme (ACE) inhibitors and potassium-sparing diuretics may increase the risk of hyperkalemia. Inhibition of ACE results in decreased aldosterone secretion, which can lead to increases in serum potassium that may be additive with that induced by potassium-sparing diuretics. ACE inhibitors may also cause deterioration of renal function in patients with chronic heart failure, and the risk is increased if they are sodium-depleted or dehydrated after excessive diuresis.
Management Caution is advised if ACE inhibitors are used with potassium-sparing diuretics, particularly in patients with renal impairment, diabetes, old age, worsening heart failure, and/or a risk for dehydration. Serum potassium and renal function should be checked regularly, and potassium supplementation should generally be avoided unless it is closely monitored. Patients should be given dietary counseling and advised to seek medical attention if they experience signs and symptoms of hyperkalemia such as weakness, listlessness, confusion, tingling of the extremities, and irregular heartbeat.
References [1] Jarman PR, Mather HM "Diabetes may be independent risk factor for hyperkalaemia." BMJ 327 (2003): 812 [2] Bennett WM "Drug interactions and consequences of sodium restriction." Am J Clin Nutr 65 (1997): S678-81 [3] Schepkens H "Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone." Am J Med 111 (2001): 587 [4] Warren SE, O'Connor DT "Hyperkalemia resulting from captopril administration." JAMA 244 (1980): 2551-2 [5] Walmsley RN, White GH, Cain M, McCarthy PJ, Booth J "Hyperkalemia in the elderly." Clin Chem 30 (1984): 1409-12 [6] Radley AS, Fitzpatrick RW "An evaluation of the potential interaction between enalapril and amiloride." J Clin Pharm Ther 12 (1987): 319-23 [7] Johnston RT, de Bono DP, Nyman CR "Preventable sudden death in patients receiving angiotensin converting enzyme inhibitors and loop/potassium sparing diuretic combinations." Int J Cardiol 34 (1992): 213-5 [8] Ponce SP, Jennings AE, Madias NE, Harrington JT "Drug-induced hyperkalemia." Medicine (Baltimore) 64 (1985): 357-70 [9] Martin J, Mourton S, Nicholls G "Severe hyperkalaemia with prescription of potassium-retaining agents in an elderly patient." N Z Med J 116 (2003): U542 [10] "Spironolactone + ace inhibitor or sartan: risk of hyperkalaemia." Prescrire Int 13 (2004): 58 [11] Perazella MA, Mahnensmith RL "Hyperkalemia in the elderly: drugs exacerbate impaired potassium homeostasis." J Gen Intern Med 12 (1997): 646-56 [12] Schuna AA, Schmidt GR, Pitterle ME "Serum potassium concentrations after initiation of captopril therapy." Clin Pharm 5 (1986): 920-3 [13] Large DM, Carr PH, Laing I, Davies M "Hyperkalaemia in diabetes mellitus--potential hazards of coexisting hyporeninaemic hypoaldosteronism." Postgrad Med J 60 (1984): 370-3 [14] Burnakis TG, Mioduch HJ "Combined therapy with captopril and potassium supplementation: a potential for hyperkalemia." Arch Intern Med 144 (1984): 2371-2 [15] Jarman PR, Kehely AM, Mather HM "Hyperkalaemia in diabetes: prevalence and associations." Postgrad Med J 71 (1995): 551-2 [16] Lakhani M "Complete heart block induced by hyperkalaemia associated with treatment with a combination of captopril and spironolactone." Br Med J (Clin Res Ed) 293 (1986): 271 [17] Svensson M, Gustafsson F, Galatius S, Hildebrandt PR, Atar D "Hyperkalaemia and impaired renal function in patients taking spironolactone for congestive heart failure: retrospective study." BMJ 327 (2003): 1141-2 [18] McNay JL, Oran E "Possible predisposition of diabetic patients to hyperkalemia following administration of potassium-retaining diuretic, amiloride (MK 870)." Metabolism 19 (1970): 58-70 [19] Cruz CS, Cruz AA, Marcilio de Souza CA "Hyperkalaemia in congestive heart failure patients using ACE inhibitors and spironolactone." Nephrol Dial Transplant 18 (2003): 1814-7 [20] Berry C, McMurray J "Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone." Am J Med 111 (2001): 587 [21] Obialo CI, Ofili EO, Mirza T "Hyperkalemia in congestive heart failure patients aged 63 to 85 years with subclinical renal disease." Am J Cardiol 90 (2002): 663-5 [22] McMurray JJ, O'Meara E "Treatment of heart failure with spironolactone--trial and tribulations." N Engl J Med 351 (2004): 526-8 [23] Schepkens H, Vanholder R, Billiouw JM, Lameire N "Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: an analysis of 25 cases." Am J Med 110 (2001): 438-41 [24] Schoolwerth AC, Sica DA, Ballermann BJ, Wilcox CS, Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association "Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association." Circulation 104 (2001): 1985-91 [25] Marcy TR, Ripley TL "Aldosterone antagonists in the treatment of heart failure." Am J Health Syst Pharm 63 (2006): 49-58 [26] Bozkurt B, Agoston I, Knowlton AA "Complications of inappropriate use of spironolactone in heart failure: when an old medicine spirals out of new guidelines." J Am Coll Cardiol 41 (2003): 211-4 [27] Chiu TF, Bullard MJ, Chen JC, Liaw SJ, Ng CJ "Rapid life-threatening hyperkalemia after addition of amiloride HCI/hydrochlorothiazide to angiotensin-converting enzyme inhibitor therapy." Ann Emerg Med 30 (1997): 612-5 [28] Speirs CJ, Dollery CT, Inman WH, et al "Postmarketing surveillance of enalapril II: investigation of the potential role of enalapril in deaths with renal failure." Br Med J 297 (1988): 830-2 [29] Juurlink DN, Mamdani MM, Lee DS, et al. "Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study." N Engl J Med 351 (2004): 543-51 [30] "Product Information. K-Dur (potassium chloride)." Schering Laboratories, Kenilworth, NJ. [31] Tamirisa KP, Aaronson KD, Koelling TM "Spironolactone-induced renal insufficiency and hyperkalemia in patients with heart failure." Am Heart J 148 (2004): 971-8 [32] Hu Y, Carpenter JP, Cheung AT "Life-threatening hyperkalemia: a complication of spironolactone for heart failure in a patient with renal insufficiency." Anesth Analg 95 (2002): 39-41 [33] Lawson DH, O'Connor PC, Jick H "Drug attributed alterations in potassium handling in congestive cardiac failure." Eur J Clin Pharmacol 23 (1982): 21-5 [34] Perazella MA "Drug-induced hyperkalemia: old culprits and new offenders." Am J Med 109 (2000): 307-14 [35] Masoudi FA, Gross CP, Wang Y, et al. "Adoption of spironolactone therapy for older patients with heart failure and left ventricular systolic dysfunction in the United States, 1998-2001." Circulation 112 (2005): 39-47 [36] Murphy BF, Whitworth JA, Kincaid-Smith P "Renal insufficiency with combinations of angiotensin converting enzyme inhibitors and diuretics." Br Med J 288 (1984): 844-5 [37] Atlas SA, Case DB, Sealey JE, Laragh JH, McKinstry DN "Interruption of the renin-angiotensin system in hypertensive patients by captopril induces sustained reduction in aldosterone secretion, potassium retention and natriuresis." Hypertension 1 (1979): 279-80 [38] Berry C, McMurray JJ "Serious adverse events experienced by patients with chronic heart failure taking spironolactone." Heart 85 (2001): E8 [39] Wrenger E, Muller R, Moesenthin M, Welte T, Frolich JC, Neumann KH "Interaction of spironolactone with ACE inhibitors or angiotensin receptor blockers: analysis of 44 cases." BMJ 327 (2003): 147-9 [40] Reardon LC, Macpherson DS "Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors. How much should we worry?" Arch Intern Med 158 (1998): 26-32 [41] Juurlink DN, Mamdani M, Kopp A, Laupacis A, Redelmeier DA "Drug-drug interactions among elderly patients hospitalized for drug toxicity." JAMA 289 (2003): 1652-8 [42] Ray K, Dorman S, Watson R "Severe hyperkalaemia due to the concomitant use of salt substitutes and ACE inhibitors in hypertension: a potentially life threatening interaction." J Hum Hypertens 13 (1999): 717-20 [43] "Product Information. Vasotec (enalapril)." Merck & Co, Inc, West Point, PA. [44] Good CB, McDermott L "Diet and serum potassium in patients on ACE inhibitors." JAMA 274 (1995): 538
Alternative for Ramipril C09B

C10B
Bempedoic acid

C09A
Alternative for Spironolactone -
Potential Metabolism Interactions
Substrate-Substrate Interaction：If more than one drug is metabolized by the same CYP, it is possible that its metabolism is inhibited because of the competition between the drugs. That means, it can be useful to lower the dosage of the drugs in the drug-cocktail because they remain longer in the organism than in monotherapy.
Inhibitor-Inhibitor Interaction：Combining two or more inhibitors of one CYP, should be compensated by lowering the dosage of these drugs because the metabolism is reduced and the drugs remain longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.
Inhibitor-Substrate Interaction：Combining drugs that have inhibitory effect and are substrates of one particular CYP, should be compensated by lowering the dosage. They rest longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.