Which medications can cause hyperkalemia?

Medications That Elevate Potassium

Multiple medication classes can cause hyperkalemia by decreasing renal potassium excretion, with RAAS inhibitors (ACE inhibitors, ARBs, aldosterone antagonists) representing the most common culprits in clinical practice.

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Medications That Decrease Potassium Excretion

RAAS Inhibitors (Most Common)

• ACE inhibitors (lisinopril, enalapril, captopril, ramipril) block aldosterone production and impair renal potassium excretion, causing hyperkalemia in up to 10% of patients 1, 2
• Angiotensin receptor blockers (ARBs) (losartan, valsartan, candesartan, olmesartan) carry equivalent hyperkalemia risk to ACE inhibitors through the same aldosterone suppression mechanism 1, 2
• Direct renin inhibitors (aliskiren) should never be combined with ACE inhibitors or ARBs due to excessive hyperkalemia risk, particularly in patients with chronic kidney disease 1, 2

Aldosterone Antagonists (High Risk)

• Spironolactone and eplerenone cause hyperkalemia in 2–5% of clinical trial patients but up to 24–36% in real-world practice, with risk increasing progressively when serum creatinine exceeds 1.6 mg/dL 3, 1
• The combination of spironolactone with ACE inhibitors or ARBs is particularly dangerous, with reported mean serum potassium of 7.7 mmol/L on admission, requiring hemodialysis in 68% of cases and ICU admission in 48% 1, 4
• Spironolactone doses should not exceed 25 mg daily when combined with RAAS inhibitors, and should be initiated at 12.5 mg in patients with marginal renal function (GFR 30–49 mL/min) 1

Potassium-Sparing Diuretics

• Triamterene and amiloride directly block potassium excretion in the collecting duct and carry significant hyperkalemia risk, especially when combined with RAAS inhibitors 1, 5
• Triamterene may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency, or when given concomitantly with drugs known to induce hyperkalemia such as ACE inhibitors 5

Calcineurin Inhibitors and Antimicrobials

• Cyclosporine and tacrolimus can increase the risk of hyperkalemia, particularly in transplant patients 1
• Trimethoprim-sulfamethoxazole may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency, or when given concomitantly with drugs known to induce hyperkalemia such as ACE inhibitors 6, 7
• The trimethoprim component specifically blocks the epithelial sodium channel in the distal nephron, reducing potassium excretion 1, 6, 7

Other Medications

• NSAIDs and COX-2 inhibitors further impair renal potassium excretion and should be avoided in patients on RAAS inhibitors 1
• Digitalis and mannitol can cause hyperkalemia, especially when used in high doses or in combination with other medications 1
• Penicillin G when used in high doses can increase the risk of hyperkalemia 1
• Heparin and derivatives can cause hyperkalemia through aldosterone suppression 8

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Medications That Increase Potassium Intake/Administration

• Potassium supplements and salt substitutes (e.g., those used in the DASH diet) can increase the risk of hyperkalemia, especially when used in combination with RAAS inhibitors 1
• Stored blood products (may contain up to 30 mEq of potassium per liter of plasma or up to 65 mEq per liter of whole blood when stored for more than 10 days) can cause hyperkalemia 1, 5
• Amino acids (aminocaproic acid, arginine, lysine) can cause hyperkalemia, especially when used in high doses or in combination with other medications 1
• Herbal supplements including alfalfa, dandelion, and hawthorn berry can increase the risk of hyperkalemia 1

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Medications That Cause Transcellular Potassium Shifts

• Beta-blockers can decrease potassium excretion and cause transcellular shifts 8
• Suxamethonium (succinylcholine) causes release of intracellular potassium 8

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High-Risk Clinical Scenarios

Dangerous Medication Combinations

• The triple combination of ACE inhibitor + ARB + aldosterone antagonist should be avoided entirely due to excessive hyperkalemia risk 1
• Combining aliskiren with ACE inhibitors or ARBs is contraindicated due to excessive hyperkalemia risk 1
• The combination of spironolactone with ACE inhibitors or ARBs carries a high risk of severe hyperkalemia requiring hemodialysis 1, 4

Patient Populations at Highest Risk

• Patients with chronic kidney disease (GFR <45 mL/min) are at 2.47-fold increased risk of developing severe hyperkalemia when using RAAS inhibitors or aldosterone antagonists 1
• Elderly patients with complicating conditions (impaired kidney/liver function, possible folate deficiency, concomitant drug use) face increased risk of severe hyperkalemia 6, 7
• Patients with diabetes mellitus have higher baseline hyperkalemia risk with RAAS inhibitors 9
• Low body mass index is an independent risk factor for hyperkalemia associated with ACE inhibitors and ARBs 9

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Prevention and Monitoring Strategies

Monitoring Recommendations

• Check serum potassium within 1 week of initiating or titrating any RAAS inhibitor or aldosterone antagonist, then regularly thereafter 1
• For patients with renal impairment, heart failure, or diabetes, check potassium within 2–3 days and again at 7 days after initiation, then monthly for 3 months 1
• Potassium >5.5 mEq/L should trigger discontinuation or dose reduction of the offending agent unless other reversible causes are identified 1

Dose Limitations

• Avoid exceeding spironolactone 25 mg daily when combined with RAAS inhibitors 1
• Aldosterone antagonists should not be initiated when baseline potassium exceeds 5.0 mEq/L or creatinine exceeds 2.5 mg/dL in men or 2.0 mg/dL in women (GFR <30 mL/min) 1

Adjunctive Strategies

• Consider adding loop or thiazide diuretics concurrently with RAAS inhibitors to promote potassium excretion and reduce hyperkalemia risk 1
• Use the lowest effective dose of medications known to cause hyperkalemia 1
• Educate patients about dietary sources of potassium that should be limited 1

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Common Pitfalls to Avoid

• Never combine potassium supplements with potassium-sparing diuretics without specialist consultation 1
• Avoid NSAIDs entirely in patients on RAAS inhibitors, as they cause acute renal failure and severe hyperkalemia 1
• Do not use aldosterone antagonists in patients with GFR <45 mL/min unless absolutely necessary, due to significantly increased hyperkalemia risk 1
• Failing to check and correct magnesium first is a common reason for treatment failure in managing electrolyte disturbances 1