From the Guidelines
Furosemide can cause metabolic alkalosis. This loop diuretic works by inhibiting the Na-K-2Cl cotransporter in the thick ascending limb of the loop of Henle, which increases sodium, chloride, and water excretion. The resulting contraction of extracellular fluid volume stimulates the renin-angiotensin-aldosterone system, leading to increased hydrogen ion secretion and bicarbonate reabsorption in the distal tubule. Additionally, the increased delivery of sodium to the distal tubule enhances sodium reabsorption in exchange for potassium and hydrogen ions, further contributing to alkalosis. The hypokalemia that commonly occurs with furosemide use also promotes intracellular shift of hydrogen ions, worsening the alkalosis. According to the guidelines on the management of ascites in cirrhosis 1, high doses of frusemide (another name for furosemide) are associated with severe electrolyte disturbance and metabolic alkalosis, and should be used cautiously. In contrast, acetazolamide is a carbonic anhydrase inhibitor that typically causes metabolic acidosis, while methanol and ethylene glycol ingestion result in severe anion gap metabolic acidosis due to their toxic metabolites formic acid and glycolic/oxalic acids, respectively. Key points to consider when using furosemide include:
- Initial dose of 40 mg/day, increased every 2–3 days up to a dose not exceeding 160 mg/day
- Simultaneous administration with spironolactone increases the natriuretic effect
- High doses should be used cautiously due to the risk of severe electrolyte disturbance and metabolic alkalosis, as noted in the guidelines 1.
From the FDA Drug Label
The principal signs and symptoms of overdose with Furosemide are dehydration, blood volume reduction, hypotension, electrolyte imbalance, hypokalemia and hypochloremic alkalosis, and are extensions of its diuretic action. All patients receiving Furosemide tablets therapy should be observed for these signs or symptoms of fluid or electrolyte imbalance (hyponatremia, hypochloremic alkalosis, hypokalemia, hypomagnesemia or hypocalcemia)
- Furosemide can cause metabolic alkalosis, specifically hypochloremic alkalosis 2 2.
- The other options, Acetazolamide, methanol, and ethylene glycol, are not mentioned in the provided drug labels as causing metabolic alkalosis.
From the Research
Causes of Metabolic Alkalosis
The following substances can cause metabolic alkalosis:
- Furosemide: Studies have shown that furosemide can induce metabolic alkalosis, particularly when used in high doses or for prolonged periods 3, 4.
- Acetazolamide is not typically a cause of metabolic alkalosis, but rather a treatment for it. However, methanol and ethylene glycol are not directly related to the development of metabolic alkalosis in the provided studies.
Mechanism of Furosemide-Induced Metabolic Alkalosis
Furosemide-induced metabolic alkalosis is thought to occur due to the following mechanisms:
- Increased excretion of hydrogen ions and chloride ions in the urine, leading to a net gain of bicarbonate ions in the blood 4
- Activation of renal transport enzymes, such as H-K-ATPase and Na-K-ATPase, which contribute to the development of metabolic alkalosis 3
Treatment of Metabolic Alkalosis
Acetazolamide has been shown to be effective in treating metabolic alkalosis, particularly when used in conjunction with furosemide 5, 6. It works by inhibiting the reabsorption of bicarbonate ions in the kidney, thereby reducing the severity of metabolic alkalosis.