What medications can cause an increase in potassium levels, particularly in patients with impaired renal function or those taking multiple medications?

Medications That Cause Hyperkalemia

The most clinically significant medications that increase potassium levels are ACE inhibitors, angiotensin receptor blockers (ARBs), aldosterone antagonists (spironolactone/eplerenone), potassium-sparing diuretics, NSAIDs, and trimethoprim-containing antibiotics, with the highest risk occurring when these agents are combined, particularly in patients with renal impairment or diabetes. 1, 2, 3

Primary Offenders: RAAS Inhibitors

ACE Inhibitors and ARBs

• ACE inhibitors (enalapril, lisinopril, captopril) and ARBs (candesartan, valsartan) cause hyperkalemia by blocking the renin-angiotensin-aldosterone system, reducing aldosterone-mediated potassium excretion in the distal nephron 3, 4
• Risk increases with higher doses: captopril ≥75 mg daily, enalapril or lisinopril ≥10 mg daily 1
• Hyperkalemia occurs in approximately 1% of hypertensive patients but up to 11.8% in patients with diabetes and heart failure 1, 3
• Critical warning: The combination of ACE inhibitor + ARB is NOT recommended due to excessive hyperkalemia risk 1

Aldosterone Antagonists

• Spironolactone and eplerenone directly block aldosterone receptors, causing potassium retention 1, 2
• Should never be initiated if baseline potassium >5.0 mEq/L 1
• Real-world hyperkalemia rates (up to 24%) far exceed clinical trial rates (2%), with half experiencing potassium >6.0 mEq/L 1
• After widespread spironolactone adoption post-RALES trial, hospitalizations for hyperkalemia increased from 2.4 to 11 per thousand patients, with associated mortality rising from 0.3 to 2 per thousand 1

Potassium-Sparing Diuretics

• Amiloride, triamterene, and spironolactone block sodium channels in the collecting duct, preventing potassium secretion 1
• Life-threatening hyperkalemia (9.4-11 mEq/L) can develop within 8-18 days when combined with ACE inhibitors, particularly in diabetic patients over age 50 5
• These agents should be avoided entirely in patients with GFR <60 mL/min and hyperkalemia 6

NSAIDs and COX-2 Inhibitors

• Reduce renal potassium excretion by inhibiting prostaglandin synthesis, which decreases renin release and aldosterone production 1, 4
• Should be avoided in patients taking aldosterone antagonists or ACE inhibitors/ARBs 1
• Can precipitate acute renal failure when combined with ACE inhibitors, further impairing potassium excretion 7

Antibiotics

Trimethoprim-Sulfamethoxazole (TMP-SMX)

• Trimethoprim blocks epithelial sodium channels in the distal nephron, mimicking amiloride's effect 1
• Use with extreme caution in patients taking ACE inhibitors or ARBs, especially with reduced kidney function 1
• Risk of worsening renal function and severe hyperkalemia when combined with RAAS inhibitors 1

Additional Medications

Beta-Blockers

• Impair cellular potassium uptake by blocking β2-adrenergic receptors, causing transcellular potassium shift from intracellular to extracellular space 4
• Effect is dose-dependent and may impair athletic performance 1

Calcineurin Inhibitors

• Cyclosporine and tacrolimus reduce renal potassium excretion through multiple mechanisms including decreased aldosterone responsiveness 4

Heparin and Low-Molecular-Weight Heparins

• Suppress aldosterone synthesis in the adrenal zona glomerulosa 4

Digoxin

• Inhibits Na-K-ATPase pump, causing transcellular potassium shift, though clinical hyperkalemia is uncommon at therapeutic doses 4

Potassium Supplements and Salt Substitutes

• Direct potassium loading can overwhelm renal excretory capacity, especially when combined with medications impairing potassium excretion 1, 6
• "Low-salt" substitutes often contain high potassium content and should be avoided 1, 3

High-Risk Clinical Scenarios

The Triple Threat

The combination of ACE inhibitor/ARB + aldosterone antagonist + potassium-sparing diuretic is absolutely contraindicated due to extreme hyperkalemia risk 1

Renal Impairment

• Risk increases progressively when serum creatinine exceeds 1.6 mg/dL or GFR <60 mL/min 1
• Aldosterone antagonists should not be used if creatinine >2.5 mg/dL or GFR <30 mL/min 1

Diabetes Mellitus

• Diabetic patients have impaired cellular potassium uptake and often have underlying renal disease, amplifying hyperkalemia risk 1, 5, 8

Elderly Patients

• Age >70 years independently predicts severe hyperkalemia (>6.0 mEq/L) in patients on ACE inhibitors 9
• Serum creatinine may not accurately reflect GFR in elderly patients with low muscle mass; calculate creatinine clearance or GFR directly 1

Monitoring Requirements

Initial Monitoring

• Check potassium and renal function at 3 days and 1 week after initiating RAAS inhibitors or aldosterone antagonists 1, 6
• Recheck at 1,2,3,6,9, and 12 months, then every 4 months thereafter 1

Action Thresholds

• Potassium 5.5-6.0 mEq/L: Halve the dose of offending medication and monitor closely 1
• Potassium >6.0 mEq/L: Stop medication immediately and treat hyperkalemia urgently; this is life-threatening 1, 6
• Creatinine >2.5 mg/dL or GFR <30 mL/min: Halve dose or discontinue aldosterone antagonist 1

Critical Clinical Pitfalls

• Dehydration from diarrhea or vomiting can precipitate severe hyperkalemia in patients on aldosterone antagonists; patients should stop the medication and contact their physician immediately 1
• Combination diuretic preparations (e.g., furosemide with amiloride or triamterene) are easily overlooked sources of potassium-sparing agents 1
• Over-the-counter NSAIDs purchased without physician knowledge are a common cause of unexpected hyperkalemia 1
• Loop or thiazide diuretics are actually protective against hyperkalemia and their concurrent use reduces risk 9