What medications can cause hyperkalemia in patients, particularly those with heart failure, hypertension, or impaired renal function?

Medications That Cause Hyperkalemia

The most clinically significant drugs causing hyperkalemia are RAAS inhibitors (ACE inhibitors, ARBs, mineralocorticoid receptor antagonists), potassium-sparing diuretics, NSAIDs, and trimethoprim—particularly dangerous when combined in patients with heart failure, hypertension, or impaired renal function.

Primary Mechanisms: Drugs That Decrease Renal Potassium Excretion

RAAS Inhibitors (Highest Risk Category)

ACE inhibitors (lisinopril, enalapril, captopril, ramipril) and ARBs (losartan, valsartan, candesartan) cause hyperkalemia by blocking aldosterone production and impairing renal potassium excretion, with up to 10% of patients experiencing at least mild hyperkalemia. 1 Both drug classes carry equivalent hyperkalemia risk through the same mechanism of aldosterone suppression. 1

• 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
• The FDA label for enalapril specifically warns that elevated serum potassium (>5.7 mEq/L) occurs in approximately 1% of hypertensive patients and 3.8% of heart failure patients, with risk factors including renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics or supplements. 3

Mineralocorticoid Receptor Antagonists (MRAs)

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. 1, 2 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. 1, 4
• The triple combination of ACE inhibitor + ARB + aldosterone antagonist should be avoided entirely due to unacceptable hyperkalemia risk. 2, 1
• European guidelines emphasize that if potassium rises above 5.5 mmol/L, the MRA dose should be halved; if potassium exceeds 6.0 mmol/L, MRAs must be stopped immediately. 2

Potassium-Sparing Diuretics

Amiloride and triamterene directly block potassium excretion in the collecting duct and carry significant hyperkalemia risk, especially when combined with RAAS inhibitors. 1 These agents should be avoided in patients with significant chronic kidney disease (GFR <45 mL/min). 1

NSAIDs and COX-2 Inhibitors

NSAIDs further impair renal potassium excretion and should be avoided in patients on RAAS inhibitors, as they can precipitate acute renal failure and severe hyperkalemia, especially in elderly patients. 1, 2 European guidelines specifically warn against NSAIDs not prescribed by a physician (over-the-counter purchases) in heart failure patients on MRAs. 2

Antimicrobials

Trimethoprim-sulfamethoxazole causes hyperkalemia through aldosterone-independent mechanisms, particularly at high doses used for Pneumocystis pneumonia. 2 The FDA label warns that high-dose trimethoprim induces a progressive but reversible increase in serum potassium, especially in patients with underlying potassium metabolism disorders, renal insufficiency, or concurrent use of drugs known to induce hyperkalemia. 5 Close monitoring of serum potassium is warranted in these patients. 5

• Pentamidine also blocks aldosterone effects and can cause hyperkalemia. 6, 7

Calcineurin Inhibitors

Cyclosporine and tacrolimus increase hyperkalemia risk through multiple mechanisms including reduced aldosterone secretion and impaired renal potassium excretion. 2, 7 These immunosuppressants are particularly problematic in transplant patients already at risk due to reduced renal function.

Heparin and Low-Molecular-Weight Heparins

Heparin suppresses aldosterone synthesis and can cause hyperkalemia, particularly with prolonged use. 2, 7 This effect is dose-dependent and more common with unfractionated heparin than low-molecular-weight heparins.

Secondary Mechanisms: Drugs That Cause Transcellular Potassium Shift

Beta-Blockers (Non-Selective)

Non-selective beta-blockers impair cellular potassium uptake by blocking beta-2 receptors, causing extracellular potassium accumulation. 6, 7 This mechanism is particularly relevant during acute potassium loads or in combination with other hyperkalemia-inducing drugs.

Digitalis (in Overdose)

Digitalis overdose inhibits Na-K-ATPase pumps, preventing intracellular potassium shift and causing life-threatening hyperkalemia. 6, 7 This is a medical emergency requiring immediate treatment.

Succinylcholine

Succinylcholine causes massive potassium release from muscle cells, particularly dangerous in patients with burns, trauma, or neuromuscular disease. 6, 7

Hypertonic Mannitol

Hypertonic solutions create osmotic gradients that draw water from cells, concentrating extracellular potassium. 6, 7

Potassium Supply: Exogenous Sources

Potassium Supplements and Salt Substitutes

Potassium supplements and "low-salt" substitutes with high potassium content are contraindicated in patients on RAAS inhibitors or potassium-sparing diuretics. 2, 1 European guidelines specifically warn patients to avoid these products. 2

Stored Blood Products

Massive transfusion of stored blood releases potassium from hemolyzed red blood cells, causing acute hyperkalemia. 1, 7

Herbal Supplements

Alfalfa, dandelion, and hawthorn berry supplements contain significant potassium and can contribute to hyperkalemia. 1

Amino Acids

Intravenous amino acids (aminocaproic acid, arginine, lysine) can cause hyperkalemia, especially at high doses or with concurrent medications affecting potassium. 1, 7

High-Risk Clinical Scenarios Requiring Vigilant Monitoring

Patients with Chronic Kidney Disease

Patients with CKD (eGFR <60 mL/min) have dramatically increased hyperkalemia risk when combining RAAS inhibitors with any of the above medications. 2, 1 The risk increases exponentially as GFR declines, with patients having eGFR <30 mL/min at highest risk. 2

Heart Failure Patients

Up to one-third of NYHA Class II-IV heart failure patients starting an MRA develop hyperkalemia (>5.0 mEq/L) over 2 years. 2 Real-world incidence can be as high as 50% in unselected populations receiving RAAS inhibitors without proper monitoring. 2

Diabetic Patients

Diabetes mellitus is an independent risk factor for hyperkalemia, particularly when combined with diabetic nephropathy and RAAS inhibitor therapy. 2, 3 The combination of diabetes, CKD, and RAAS inhibitors creates a "perfect storm" for severe hyperkalemia.

Elderly Patients

Advanced age increases hyperkalemia risk due to reduced GFR, polypharmacy, and altered potassium homeostasis. 2, 5 The FDA label for trimethoprim-sulfamethoxazole specifically warns of increased severe adverse reactions in elderly patients, particularly hyperkalemia. 5

Critical Monitoring and Prevention Strategies

Check potassium and creatinine within 2-3 days and again at 7 days after initiating or titrating RAAS inhibitors, aldosterone antagonists, or other high-risk medications, then monthly for 3 months, and every 3-6 months thereafter. 1 European guidelines recommend even more frequent monitoring (1 and 4 weeks, then 8 and 12 weeks, then 6,9, and 12 months, then 4-monthly) when using MRAs. 2

• If potassium rises to 5.5-6.0 mEq/L, halve the dose of the offending agent and monitor closely. 2, 1
• If potassium exceeds 6.0 mEq/L, stop the medication immediately and seek specialist advice. 2, 1
• Use the lowest effective dose of medications known to cause hyperkalemia. 1
• Consider concurrent use of loop or thiazide diuretics with RAAS inhibitors to reduce hyperkalemia risk. 1
• Educate patients about dietary potassium sources and the dangers of salt substitutes. 2, 1

Common Pitfalls to Avoid

The most dangerous error is combining multiple potassium-retaining drugs without adequate monitoring—particularly the combination of RAAS inhibitors with MRAs, potassium supplements, or NSAIDs in patients with any degree of renal impairment. 2, 1

• Never assume mild renal impairment alone explains hyperkalemia—systematically evaluate all medications. 6, 8
• Recognize that causes of hyperkalemia are additive; patients often have multiple contributing factors simultaneously. 6, 8
• Don't discontinue life-saving RAAS inhibitors permanently for hyperkalemia—instead, use newer potassium binders (patiromer, sodium zirconium cyclosilicate) to maintain these medications. 2, 1, 9
• Quality improvement programs are needed to improve monitoring rates, as potassium levels are frequently under-monitored in patients on RAAS inhibitors. 2