How do loop diuretics cause metabolic alkalosis?

Mechanism of Loop Diuretic-Induced Metabolic Alkalosis

Loop diuretics cause metabolic alkalosis primarily through increased sodium delivery to the distal tubule, leading to enhanced sodium reabsorption and potassium secretion, which stimulates hydrogen ion secretion and bicarbonate reabsorption in the collecting duct. 1

Primary Mechanisms

• Loop diuretics (furosemide, bumetanide, torsemide) act by inhibiting the Na⁺-K⁺-2Cl⁻ cotransporter in the thick ascending limb of the loop of Henle, reducing sodium reabsorption and increasing sodium delivery to distal nephron segments 1, 2

• This increased distal sodium delivery leads to several key processes:

  • Enhanced sodium reabsorption via the epithelial sodium channel (ENaC) in the distal tubule and collecting duct 1
  • Increased potassium secretion to maintain electrical neutrality, resulting in hypokalemia 1
  • Stimulation of hydrogen ion secretion in the distal tubule, promoting bicarbonate reabsorption and contributing to metabolic alkalosis 1, 3

• The resulting hypokalemia further exacerbates metabolic alkalosis through:

  • Increased intracellular shift of hydrogen ions to compensate for potassium loss 1
  • Enhanced renal ammoniagenesis and bicarbonate reabsorption 3

Contributing Factors

• Volume contraction from diuresis activates the renin-angiotensin-aldosterone system (RAAS), which:

  • Increases aldosterone secretion, further stimulating sodium reabsorption and potassium secretion 1
  • Promotes hydrogen ion secretion in the distal tubule, contributing to metabolic alkalosis 1, 3

• Chloride depletion (hypochloremia) plays a critical role:

  • Reduced chloride availability limits the kidney's ability to excrete bicarbonate 1
  • Creates a "chloride-depletion metabolic alkalosis" that is resistant to correction without chloride repletion 4

• Hypokalemia from loop diuretic use enhances distal tubular hypertrophy and hyperplasia, leading to:

  • Increased sodium chloride reabsorption through the sodium chloride cotransporter 1
  • Further potentiation of metabolic alkalosis 1

Clinical Implications

• The metabolic alkalosis induced by loop diuretics can:

  • Worsen respiratory drive in patients with chronic respiratory acidosis 5
  • Contribute to diuretic resistance through reduced intraluminal chloride availability 1, 4
  • Exacerbate hypokalemia, creating a vicious cycle 1

• Hypochloremic metabolic alkalosis is a common finding in patients on chronic loop diuretic therapy, especially in heart failure 1

• Metabolic alkalosis can be corrected by:

  • Potassium and chloride supplementation 1
  • Addition of potassium-sparing diuretics like spironolactone, which can counteract the kaliuresis and alkalosis 3
  • In severe cases, acetazolamide may be used to promote bicarbonate excretion 5

Pitfalls and Caveats

• Avoid excessive loop diuretic dosing, which can worsen metabolic alkalosis and lead to diuretic resistance 4

• Monitor serum electrolytes regularly in patients on chronic loop diuretic therapy to detect and correct hypokalemia and hypochloremia early 1

• Be cautious when combining loop diuretics with thiazides, as this can potentiate metabolic alkalosis through sequential nephron blockade 3

• Recognize that hypercalcemia can mimic the effects of loop diuretics on the thick ascending limb, potentially worsening metabolic alkalosis if loop diuretics are added 6