Medications That Increase the Risk of Hyperkalemia
Common medications used in patients with CKD and heart failure
Several medications are frequently used in patients with comorbidities associated with poor kidney or heart function. Many of these drugs—like nonsteroidal anti-inflammatory drugs (NSAIDs), digoxin, and K+-sparing diuretics—have been shown to be associated with elevated serum K+.1

Reproduced with permission from Weiner ID, Linas SL, Wingo CS. Disorders of Potassium Metabolism. In: Johnson R, Fluege J, Feehally J, eds. Comprehensive Clinical Nephrology. 4th ed. Philadelphia, PA: Saunders Elsevier; 2010:118-129.
Key principles in the development of hyperkalemia2

Reproduced with permission from Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med. 2004;351(6):585-592.
Clinical data mine: Explore evidence of RAASi use and its association with hyperkalemia
Of the commonly used medications known to cause hyperkalemia and play a prominent role in the management of CKD and heart failure,8 the effects and implications of RAASi use on serum potassium levels has been the most systematically documented. It has been well documented that the use of RAASi (renin-angiotensin-aldosterone system inhibitors) compounds the risk for hyperkalemia, especially in patients with renal insufficiency.1
(Click on any study below to expand and view clinical evidence.)
Weir et al: Data review of association between the incidence of hyperkalemia and RAASi use in CKD and heart failure patients
RALES Study: Hyperkalemia rates increased with spironolactone use among heart failure patients
EPHESUS Study: Increased risk of hyperkalemia associated with eplerenone use in heart failure patients
RALES/EMPHASIS rates vs real-world rates: Real-world hyperkalemia rates shown to be higher with RAASi use in heart failure patients
RENAAL Study: Increased risk of adverse kidney outcomes with losartan use among type 2 diabetes mellitus patients
Inhibition of the RAAS results in elevated serum potassium levels
In patients on RAASi therapy, serum/extracellular K+ is further elevated because these medications, especially MRAs, have a critical impact on the levels or activity of aldosterone. RAASi can interfere with the stimulatory effect of angiotensin II on aldosterone secretion in the adrenal gland, while MRAs block the interaction of aldosterone with its receptor.1,3,4 This prevents K+ resorption back into the distal tubule for urinary excretion, thus further perturbing the extracellular/intracellular K+ balance.1,4,5
Most current treatment guidelines support the practice of RAASi dose adjustments or discontinuation based on serum potassium levels. (See recommended RAASi modifications) While this may reduce the immediate risk of hyperkalemia or lower potassium levels, it may put patients with CKD and heart failure at greater risk for progression or exacerbation of their underlying disease.6-10
Clinical considerations of other common medications and hyperkalemia
Overall, the incidence of hyperkalemia as a result of non-selective NSAID use is fairly infrequent. Nevertheless, it remains a concern in patients with very low kidney function because NSAIDs may further alter function through their effects on renal prostaglandins. Particularly, concomitant use with ACEs and ARBs may worsen functional renal insufficiency. Standard precautions are advised to avoid renal toxicity in these high-risk patients.5
The use of COX-2 inhibitors has also been associated with hyperkalemia because it hinders potassium secretion at the distal tube by inhibiting prostacyclin synthesis. In fact, results suggest that these medications pose a greater threat for increased serum potassium than non-selective NSAIDs.11
Heparin is a medication that impacts the RAAS through multiple mechanisms, including by decreasing the principal stimulus for aldosterone synthesis. This has resulted in hyperkalemia being noted in 7% to 8% of patients treated with at least 5000 U of heparin twice a day.12