What medications can cause hyperkalemia?

Medications That Cause Hyperkalemia

The most common drug-related causes of hyperkalemia are ACE inhibitors, ARBs, aldosterone antagonists (spironolactone, eplerenone), and potassium-sparing diuretics, with the highest risk occurring when these agents are combined. 1, 2, 3

Medications That Decrease Potassium Excretion

RAAS Inhibitors (Highest Risk Category)

• ACE inhibitors (lisinopril, enalapril, ramipril) cause hyperkalemia by blocking aldosterone production, thereby reducing renal potassium excretion 1, 3
• ARBs (losartan, valsartan, candesartan) have the same mechanism as ACE inhibitors and carry equivalent hyperkalemia risk 1, 4
• Direct renin inhibitors (aliskiren) also impair the RAAS pathway and increase hyperkalemia risk, particularly when combined with ACE inhibitors or ARBs 5, 1
• Sacubitril/valsartan (neprilysin inhibitor combined with ARB) carries additive hyperkalemia risk 1

Aldosterone Antagonists and Potassium-Sparing Diuretics

• Spironolactone (25-100 mg daily) causes hyperkalemia by blocking aldosterone receptors in the distal nephron; risk increases in a dose-dependent manner 5, 2
• Eplerenone (50-100 mg daily) has the same mechanism as spironolactone but with lower incidence of gynecomastia 5, 1
• Triamterene and amiloride directly block sodium channels in the collecting duct, reducing potassium secretion 1, 4

Critical warning: The combination of RAAS inhibitors with aldosterone antagonists or potassium-sparing diuretics dramatically increases hyperkalemia risk, with reported rates of 11.2% and life-threatening cases requiring hemodialysis 6, 7

Immunosuppressants and Antimicrobials

• Calcineurin inhibitors (cyclosporine, tacrolimus) cause hyperkalemia by impairing renal potassium secretion 1, 4
• Trimethoprim-sulfamethoxazole blocks epithelial sodium channels in the collecting duct, mimicking amiloride's effect 1, 4
• Pentamidine impairs renal potassium excretion through similar mechanisms 4

NSAIDs and Other Agents

• NSAIDs (including COX-2 inhibitors) reduce renin and aldosterone secretion, particularly dangerous when combined with ACE inhibitors or ARBs 3, 4
• Heparin and derivatives suppress aldosterone synthesis 1, 4

Medications That Cause Transcellular Potassium Shift

• Beta-blockers (particularly non-selective agents like propranolol) impair cellular potassium uptake by blocking beta-2 receptors 4
• Succinylcholine causes massive potassium release from muscle cells 4
• Digitalis in toxic doses inhibits Na-K-ATPase pumps 1, 4
• Mannitol can cause hyperkalemia through hyperosmolality-induced transcellular shifts 1, 4

Medications That Increase Potassium Load

• Potassium supplements and potassium-containing salt substitutes directly increase total body potassium 1
• Stored blood products contain high potassium concentrations from hemolysis 8, 1
• Penicillin G in high doses (contains potassium salt formulation) 1, 4
• Amino acids (aminocaproic acid, arginine, lysine) in high doses 1
• Herbal supplements (alfalfa, dandelion, hawthorne berry) 1

High-Risk Clinical Scenarios

The combination of spironolactone with ACE inhibitors or ARBs carries the highest risk, with case series showing mean serum potassium of 7.7 mmol/L on admission, requiring hemodialysis in 68% of cases and ICU admission in 48% 6

Risk Factors for Severe Hyperkalemia:

• Chronic kidney disease (particularly GFR <45 mL/min) increases risk 2.47-fold 5, 7
• Diabetes mellitus (hyporeninemic hypoaldosteronism) 6
• Age >70 years (mean age 74 years in severe cases) 6
• Baseline potassium >4.0 mmol/L increases risk 2.65-fold 7
• Spironolactone dose >25 mg daily increases risk 2.42-fold 6, 7
• Dehydration or worsening heart failure precipitates acute renal dysfunction 6

Monitoring and Prevention Strategies

Monitor serum potassium within 1 week of initiating or titrating any RAAS inhibitor or aldosterone antagonist, then regularly thereafter 2

• Avoid combining ACE inhibitors/ARBs with aldosterone antagonists in patients with GFR <45 mL/min unless absolutely necessary 5
• Never exceed spironolactone 25 mg daily when combined with RAAS inhibitors 6
• Consider adding loop or thiazide diuretics to promote potassium excretion when using RAAS inhibitors 1
• Avoid potassium supplements, salt substitutes, and NSAIDs in patients on RAAS inhibitors 3
• Do not combine aliskiren with ACE inhibitors or ARBs due to excessive hyperkalemia risk 5, 3