What medications raise serum potassium and increase the risk of hyperkalaemia?

Medications That Raise Serum Potassium

Drugs That Impair Renal Potassium Excretion

The most clinically significant medications that raise serum potassium are those that interfere with the renin-angiotensin-aldosterone system (RAAS), which represents the primary mechanism by which drugs cause hyperkalemia in clinical practice. 1

RAAS Inhibitors

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

Aldosterone Antagonists and Potassium-Sparing Diuretics

• Spironolactone and eplerenone cause hyperkalemia in 2-5% of clinical trial patients but 24-36% in real-world practice, with risk increasing progressively when serum creatinine exceeds 1.6 mg/dL 3, 2, 4
• Amiloride causes hyperkalemia commonly (about 10%) when used without a kaliuretic diuretic, with incidence greater in patients with renal impairment, diabetes mellitus, and elderly patients 5
• Triamterene directly blocks potassium excretion in the collecting duct and carries significant hyperkalemia risk, especially when combined with RAAS inhibitors 2, 6

Other Medications Impairing Renal Excretion

• Trimethoprim-sulfamethoxazole blocks epithelial sodium channels in the collecting duct, mimicking amiloride's effect and causing hyperkalemia, particularly when combined with ACE inhibitors or ARBs 3, 2, 1
• Calcineurin inhibitors (cyclosporine, tacrolimus) interfere with aldosterone production and secretion 2, 1
• NSAIDs impair renal potassium excretion by reducing aldosterone secretion and causing sodium retention 3, 2, 1
• Heparin and low molecular weight heparin suppress aldosterone synthesis 2, 4, 1
• Pentamidine blocks aldosterone's kaliuretic effects 1, 7

Drugs That Cause Transcellular Potassium Shift

• Beta-blockers (particularly non-selective agents) impair cellular potassium uptake by blocking beta-2 adrenergic receptors 1, 7
• Succinylcholine causes potassium release from muscle cells 1, 7
• Digitalis overdose inhibits Na-K-ATPase pump, causing potassium shift from intracellular to extracellular space 1, 7
• Hypertonic mannitol causes transcellular potassium redistribution 2, 1

Medications That Increase Potassium Supply

• Potassium supplements (potassium chloride, potassium citrate) directly increase serum potassium, especially when combined with RAAS inhibitors 2, 4
• Salt substitutes contain substantial amounts of potassium (most contain 50-65 mEq per serving) 2, 6
• Stored blood products may contain up to 30 mEq potassium per liter of plasma or up to 65 mEq per liter of whole blood when stored for more than 10 days 2, 6
• Penicillin G potassium in high doses provides significant potassium load 2, 1
• Amino acids (aminocaproic acid, arginine, lysine) can cause hyperkalemia, especially in high doses 2

High-Risk Drug Combinations

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%. 2

• Triple combination of ACE inhibitor + ARB + aldosterone antagonist should be avoided entirely 3, 2
• Amiloride or triamterene combined with ACE inhibitors/ARBs dramatically increases hyperkalemia risk, with rapid life-threatening elevations occurring within 8-18 days 5, 8
• Trimethoprim-sulfamethoxazole with ACE inhibitors or ARBs in patients with reduced kidney function increases hyperkalemia risk 3

Timing of Hyperkalemia Onset

Fifty-two percent of hyperkalemic events occur within the first week after initiation of ARB therapy, with the highest frequency on the first day. 9

• Hyperkalemia occurs earlier in patients with high baseline serum potassium, reduced GFR, diabetes, and those without heart failure 9
• Rapid life-threatening hyperkalemia can develop within 8-18 days when potassium-sparing diuretics are added to ACE inhibitor therapy 8

Critical Monitoring Recommendations

• Check potassium and creatinine within 2-3 days, again at 7 days, then monthly for 3 months after initiating or increasing doses of RAAS inhibitors or aldosterone antagonists 3, 2
• Monitoring should start within a few days or not later than 1 week after ARB initiation, especially in patients with risk factors 9
• Potassium >5.5 mEq/L should trigger discontinuation or dose reduction of the offending agent 2
• Aldosterone antagonists should not be initiated when baseline potassium exceeds 5.0 mEq/L 3, 2

Patient Populations at Highest Risk

• Patients with chronic kidney disease (GFR <45 mL/min) have 2.47-fold increased risk of severe hyperkalemia with RAAS inhibitors 2
• Diabetic patients, particularly those with diabetic nephropathy 5, 8
• Elderly patients (>50 years) on multiple medications 3, 8
• Patients with renal impairment (creatinine >1.6 mg/dL) 3, 2