In patients with decreased creatinine clearance on ACE Inhibitor or ARB, which drug significantly increases the risk of hyperkalemia?

The correct answer is that trimethoprim-sulfamethoxazole (TMP-SMX) significantly increases the risk of hyperkalemia in patients with decreased creatinine clearance who are on ACE inhibitors or angiotensin receptor blockers (ARBs).

This is primarily due to the pharmacological properties of TMP-SMX. Trimethoprim, a component of this antibiotic, can inhibit renal tubular secretion of potassium. This action can lead to higher serum potassium levels, particularly in patients whose kidney function is already compromised, as in the case of those with decreased creatinine clearance. When combined with an ACE inhibitor or ARB, which also compromises potassium excretion in individuals due to their mechanism of inhibiting the renin-angiotensin-aldosterone system, the risk for hyperkalemia increases substantially.

In contrast, furosemide and hydrochlorothiazide are diuretics that generally promote potassium excretion and might mitigate potassium retention. While spironolactone is a potassium-sparing diuretic that can indeed result in hyperkalemia, it wouldn't be selected in the context of those receiving ACE inhibitors or ARBs who are already at risk. TMP-SMX stands out because it does not have a diuretic effect