Which medications can cause hyperkalemia?

Medications That Cause Hyperkalemia

The medications most likely to cause hyperkalemia are those that interfere with the renin-angiotensin-aldosterone system (RAAS), potassium-sparing diuretics, and several other drug classes that impair renal potassium excretion or cause transcellular potassium shifts.

Primary Culprits: RAAS Inhibitors

ACE inhibitors (lisinopril, enalapril, etc.) and ARBs (losartan, valsartan, etc.) are the most common drug-related causes of hyperkalemia 1, 2. These medications reduce aldosterone production, thereby decreasing renal potassium excretion 3.

• The FDA labels for both lisinopril and enalapril explicitly warn that concomitant use with potassium-sparing diuretics, potassium supplements, or salt substitutes can increase hyperkalemia risk and require frequent serum potassium monitoring 4, 5.
• Direct renin inhibitors like aliskiren carry similar risks, particularly in patients with chronic kidney disease or those on potassium supplements 6.
• Sacubitril/valsartan (neprilysin inhibitor combined with ARB) also increases hyperkalemia risk 2.

Potassium-Sparing Diuretics and Aldosterone Antagonists

Mineralocorticoid receptor antagonists (spironolactone, eplerenone) are high-risk medications that must be avoided with potassium supplements, other potassium-sparing diuretics, or significant renal dysfunction 6.

• Spironolactone's FDA label specifically warns that concomitant use with potassium supplementation, salt substitutes, ACE inhibitors, ARBs, NSAIDs, or heparin may lead to severe hyperkalemia 7.
• Other potassium-sparing diuretics (amiloride, triamterene) carry the same risk and should be avoided in patients with GFR <45 mL/min 6.
• The combination of spironolactone with ACE inhibitors or ARBs is particularly dangerous, with documented cases of life-threatening hyperkalemia (mean potassium 7.7 mmol/L) requiring hemodialysis in 68% of cases and ICU admission in 48% 8.
• Daily spironolactone doses should not exceed 25 mg when combined with RAAS inhibitors 8.

NSAIDs and Other Renal Function Modulators

NSAIDs reduce renal potassium excretion by decreasing renin release and aldosterone secretion, particularly dangerous in elderly, volume-depleted, or renally compromised patients 4, 3.

• Trimethoprim-sulfamethoxazole blocks epithelial sodium channels in the collecting duct, acting like a potassium-sparing diuretic 2, 3.
• Calcineurin inhibitors (cyclosporine, tacrolimus) impair aldosterone production and tubular potassium secretion 2, 3.
• Heparin and low molecular weight heparin suppress aldosterone synthesis 2, 7.
• Pentamidine blocks distal tubular potassium secretion 3, 9.

Medications Causing Transcellular Potassium Shifts

Beta-blockers (particularly non-selective agents) can cause hyperkalemia by impairing cellular potassium uptake via beta-2 receptor blockade 3, 9.

• Succinylcholine causes massive potassium release from muscle cells 3, 9.
• Digitalis overdose inhibits Na-K-ATPase, causing potassium to shift extracellularly 3, 9.
• Hypertonic mannitol creates an osmotic gradient that pulls potassium out of cells 3, 9.

Potassium-Containing Medications and Supplements

Potassium supplements, salt substitutes (common in DASH diet), stored blood products, and certain herbal supplements (alfalfa, dandelion, hawthorne berry) directly increase potassium load 2.

• Amino acids (aminocaproic acid, arginine, lysine) can cause hyperkalemia, especially at high doses 2.
• High-dose penicillin G contains significant potassium 2.

Critical Clinical Pitfalls

Never attribute hyperkalemia solely to mild-to-moderate renal failure (GFR >30 mL/min)—always search for medication causes and additive factors 9.

• Risk factors that amplify medication-induced hyperkalemia include: chronic kidney disease, diabetes mellitus, advanced age (>70 years), dehydration, worsening heart failure, and polypharmacy with multiple hyperkalemia-inducing drugs 8, 10.
• Patients with initial serum potassium >4.0 mmol/L have 2.65 times higher risk of developing hyperkalemia when starting spironolactone with RAAS inhibitors 10.
• Dual RAAS blockade (combining ACE inhibitors, ARBs, or aliskiren) is associated with increased hyperkalemia risk and should generally be avoided 4.

Prevention Strategy

Use the lowest effective doses of hyperkalemia-inducing medications and consider adding loop or thiazide diuretics when combining RAAS inhibitors with aldosterone antagonists 2.

• Monitor serum potassium within 1-2 weeks of initiating or dose-adjusting any RAAS inhibitor, aldosterone antagonist, or combination therapy 7, 4.
• Educate patients to limit dietary potassium sources and avoid salt substitutes when on these medications 2.