How do thiazide and loop diuretics reduce sodium and potassium levels?

From the Guidelines

Thiazide and loop diuretics reduce sodium and potassium through different mechanisms in the kidneys, with loop diuretics being more effective in increasing sodium excretion, as stated in the 2022 AHA/ACC/HFSA guideline for the management of heart failure 1.

Mechanism of Action

Loop diuretics like furosemide (Lasix), bumetanide (Bumex), and torsemide (Demadex) work in the thick ascending limb of the loop of Henle by inhibiting the sodium-potassium-chloride cotransporter (NKCC2), preventing sodium reabsorption and causing increased sodium and water excretion in urine.

• This process creates an electrical gradient that drives potassium secretion, resulting in potassium loss.
• Thiazide diuretics such as hydrochlorothiazide (HCTZ), chlorthalidone, and indapamide act in the distal convoluted tubule by blocking the sodium-chloride cotransporter (NCC), increasing sodium excretion but to a lesser extent than loop diuretics.

Clinical Implications

Both classes of diuretics cause potassium wasting because the increased sodium delivery to the distal tubule enhances potassium secretion through the sodium-potassium exchange mechanism, which can lead to hypokalemia.

• According to the 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults, loop diuretics increase sodium excretion up to 20% to 25% of the filtered load of sodium, whereas thiazide diuretics increase the fractional excretion of sodium to only 5% to 10% of the filtered load 1.
• The 2022 AHA/ACC/HFSA guideline recommends loop diuretics as the preferred diuretic agents for use in most patients with heart failure, while thiazide diuretics may be considered in patients with hypertension and heart failure and mild fluid retention 1.

Monitoring and Management

Monitoring of electrolytes is essential when using these medications, particularly in the first few weeks of therapy and after dose adjustments, as stated in the example answer.

• Potassium supplementation or potassium-sparing diuretics may be necessary in some patients to prevent hypokalemia.
• The treatment goal of diuretic use is to eliminate clinical evidence of fluid retention, using the lowest dose possible to maintain euvolemia, as recommended in the 2022 AHA/ACC/HFSA guideline 1.

From the FDA Drug Label

e. hyponatremia, hypochloremic alkalosis, and hypokalemia and hypomagnesemia. Hypokalemia may develop, especially with brisk diuresis when severe cirrhosis is present, during concomitant use of corticosteroid or adrenocorticotropic hormone (ACTH) or after prolonged therapy.

The FDA drug label does not answer the question.

From the Research

Mechanism of Action

• Thiazide diuretics inhibit an enzyme in the basolateral cell membrane in the distal tubule, leading to impaired absorption and enhanced excretion of Na+ and Cl- ions 2.
• Loop diuretics inhibit a carrier mechanism that enhances the inward transport of Na+, K+, and Cl- ions, as well as water, in the thick ascending limb of Henle's loop, resulting in increased urinary excretion of these ions and water 2.
• The loss of Na+ ions is countered by the exchange of Na+ against K+, leading to a loss of K+ ions 2.

Effects on Sodium and Potassium

• Thiazide diuretics increase the excretion of Na+ ions, which can lead to a decrease in plasma volume and cardiac output 2, 3.
• Loop diuretics also increase the excretion of Na+ ions, as well as K+ ions, leading to a loss of potassium 2, 3.
• The combination of loop diuretics with thiazide-type diuretics can produce diuretic synergy, increasing the excretion of Na+ ions and potentially leading to hypokalemia 4, 5.

Clinical Implications

• Thiazide diuretics are effective in reducing blood pressure and are commonly used in the treatment of hypertension 6.
• Loop diuretics are less effective in lowering blood pressure but are useful in treating edematous patients with congestive heart failure, cirrhosis with ascites, and nephritic edema 3.
• The combination of loop diuretics with thiazide-type diuretics may be beneficial in patients with decompensated heart failure, but requires careful monitoring due to the risk of hypokalemia and other adverse effects 4, 5.