Review Question - QID 217631

This patient with heart failure presents after a prolonged period of accidental medication overuse with hyponatremia, hypokalemia, metabolic alkalosis, and hypocalcemia. The most likely medication to have caused these electrolyte abnormalities is furosemide, a loop diuretic.

Loop diuretics are commonly used in the treatment of heart failure. Loop diuretics inhibit the Na-K-2Cl cotransporter (NKCC) at the thick ascending limb of the loop of Henle. Since this transporter is responsible for the reabsorption of sodium and potassium along with chloride, patients present with hyponatremia and hypokalemia. Normally, the NKCC cotransporter results in transport of potassium from the lumen into the cell; however, this potassium then leaks back into the lumen via ROMK channels, resulting in an electrochemical gradient. This gradient promotes the paracellular reabsorption of calcium. Since loop diuretics inhibit this process, hypocalcemia (hypercalciuria) is also seen. Increased sodium delivery to more distal segments of the nephron, along with the volume contraction secondary to diuresis, results in activation of the renin-angiotensin-aldosterone system, which augments urinary potassium excretion and causes a metabolic alkalosis.

Bartoli et al. outline the uses and abuses of diuretics. They illustrate the mechanism underlying the metabolic alkalosis generated by these diuretics.

Incorrect Answers:
Answer 2: Hydrochlorothiazide is a thiazide diuretic that is a commonly-used first-line treatment for primary hypertension. Thiazides inhibit the Na-Cl cotransporter at the distal convoluted tubule. This reduces sodium reabsorption and promotes diuresis. Thiazides also cause a hypokalemic metabolic alkalosis via volume contraction. However, thiazides cause hypercalcemia rather than hypocalcemia because of compensatory proximal tubule reabsorption of both sodium and calcium.

Answer 3: Metformin is a medication used to decrease hepatic gluconeogenesis and increase insulin sensitivity in the treatment of diabetes mellitus. It has a well-known but rare side effect of lactic acidosis, which would present as a high anion gap metabolic acidosis rather than an alkalosis. It does not cause hyponatremia, hypokalemia, or hypocalcemia.

Answer 4: Metoprolol is a beta-adrenergic antagonist that is commonly used in the treatment of heart failure due to its beneficial effects on cardiac remodeling. Side effects include bradycardia and fatigue; metoprolol would not cause the electrolyte imbalances seen in this patient.

Answer 5: Spironolactone is an aldosterone antagonist and potassium-sparing diuretic that is used in the chronic management of heart failure due to its mortality benefits. It causes hyperkalemia because it inhibits aldosterone action at the epithelial sodium channels of the collecting tubule.

Bullet Summary:
Overuse of loop diuretics can cause hyponatremia, hypokalemia, hypocalcemia, and metabolic alkalosis.