What is metolazone?

Metolazone: A Thiazide-like Diuretic

Metolazone is a quinazoline diuretic with properties similar to thiazide diuretics, primarily used for fluid overload management, particularly in patients with heart failure who are resistant to loop diuretics alone. 1

Pharmacology and Mechanism of Action

• Metolazone works by inhibiting sodium reabsorption primarily at the cortical diluting site and to a lesser extent in the proximal convoluted tubule 1
• Unlike thiazide diuretics, metolazone can produce diuresis in patients with glomerular filtration rates below 20 mL/min 1
• Sodium and chloride ions are excreted in approximately equivalent amounts, with increased sodium delivery to distal tubules resulting in increased potassium excretion 1
• Maximum blood levels occur approximately 8 hours after dosing, with most of the drug excreted unconverted in urine 1

Clinical Use

Dosing

• Initial dose: 2.5 mg once daily 2, 3
• Maximum daily dose: 20 mg 2, 3
• Duration of action: 12-24 hours 2
• Usual maintenance dose range: 2.5-10 mg once daily 2, 3

Primary Indications

1. Resistant edema in heart failure: Used when patients don't respond to moderate or high-dose loop diuretics alone 2
2. Sequential nephron blockade: Most commonly used in combination with loop diuretics for enhanced diuresis in refractory heart failure 2, 3
3. Advanced heart failure: Often used when patients require escalation of diuretic therapy to maintain volume status 2

Combination Therapy

• The combination of metolazone with loop diuretics (like furosemide) produces a potent diuretic effect through sequential nephron blockade 3, 4
• A common approach for resistant edema is adding 2.5 mg of metolazone for 2-3 days to the loop diuretic regimen 3
• This combination has shown effectiveness in patients where edema was refractory to maximum recommended doses of other diuretics 1

Monitoring and Safety Considerations

Electrolyte Monitoring

• Close monitoring of electrolytes is essential, particularly:
  • Serum potassium (risk of hypokalemia)
  • Serum sodium (risk of hyponatremia)
  • Renal function 3, 5
• Initial monitoring within 5-7 days after starting therapy, then every 3-6 months once stable 3

Common Adverse Effects

• Electrolyte disturbances: hypokalemia, hyponatremia, hypochloremia 4, 5
• Metabolic alkalosis 5
• Hyperuricemia and glucose intolerance 3
• Worsening renal function, especially with combination therapy 3, 5

Special Considerations

• Daily weight measurements are essential to assess response to therapy 2, 3
• Metolazone may be less effective in heart failure patients due to reduced absorption 4
• Metolazone has been shown to be as effective as chlorothiazide when used as add-on therapy to loop diuretics in acute decompensated heart failure 6
• Lower doses (0.5-1.0 mg) may be effective for hypertension management with fewer electrolyte disturbances 7

Cautions

• The combination of metolazone and loop diuretics should be used with caution due to potential severe electrolyte derangements 5
• Patients with liver disease may experience a high incidence of hypokalemia (80%), hypochloremia (35%), and encephalopathy (35%) when metolazone is used alone 8
• Consider potassium-sparing diuretics (amiloride, spironolactone) to prevent hypokalemia when using metolazone in susceptible patients 8