Metolazone for Diuresis in Heart Failure and Edema
For patients with refractory fluid overload despite optimized loop diuretics, start metolazone at 2.5 mg once daily, administered 30 minutes before the loop diuretic, for a short burst of 2-5 days, with mandatory electrolyte and renal function monitoring within 1-2 days of initiation. 1
Indications for Adding Metolazone
Metolazone should be reserved specifically for patients who demonstrate:
- Inadequate diuresis despite optimized loop diuretic dosing 1
- Persistent NYHA class III-IV symptoms despite standard therapy 1
- Repeated hospitalizations for heart failure 1
- Refractory clinical congestion with persistent edema 1
The combination should only be initiated after maximizing loop diuretic therapy alone, as metolazone is not first-line treatment. 2
Dosing Strategy
Initial Dosing
- Start at 2.5 mg once daily (not 5 mg) when adding to existing loop diuretics 1, 3, 4
- Administer 30 minutes before the loop diuretic to maximize sequential nephron blockade 1
- The FDA label indicates 5-20 mg daily for cardiac edema, but contemporary evidence strongly supports starting at ≤2.5 mg 3, 4
Dose Titration
- Maximum recommended dose: 10 mg daily in heart failure patients 1, 5
- The FDA label allows up to 20 mg daily, but doses above 10 mg significantly increase electrolyte complications without proportional benefit 3, 1
- Most patients respond adequately to 2.5-5 mg daily 4
Duration of Therapy
- Use for short bursts of 2-5 days, then return to maintenance loop diuretic when weight stabilizes 1
- Target weight loss: 0.5-1.0 kg per day 1
- Discontinue metolazone once euvolemia is achieved 1
Mechanism and Rationale
Metolazone creates synergistic diuresis through sequential nephron blockade:
- Loop diuretics act on the loop of Henle 1
- Metolazone blocks sodium reabsorption at the distal convoluted tubule 1
- This combination is superior to simply increasing loop diuretic doses 1
- Metolazone maintains efficacy even when GFR <30 mL/min, unlike other thiazides 1
The greatest diuretic effect occurs within the first 3 days, causing significant electrolyte shifts early in treatment. 1
Critical Monitoring Requirements
Before Initiation
- Baseline serum electrolytes (sodium, potassium, chloride) 1
- Serum creatinine and estimated GFR 1
- Blood pressure 1
- Baseline weight 1
During Treatment
- Recheck electrolytes and renal function within 1-2 days of starting combination therapy 1, 5
- Daily weight monitoring 1
- Daily blood pressure checks 1
- Continue monitoring every 3-7 days initially, then weekly 5
High-Risk Patients Requiring Inpatient Initiation
Electrolyte Complications and Management
Severe electrolyte disturbances occur in approximately 10% of treatment episodes, including hypokalemia, hyponatremia, and hypochloremia with metabolic alkalosis. 1, 4, 6
Hypokalemia Prevention
- Ensure ACE inhibitor or ARB is optimized before adding metolazone 5
- Consider adding or increasing mineralocorticoid receptor antagonist (spironolactone) 1, 5
- Potassium supplementation is frequently unnecessary when ACE inhibitors are prescribed and may be harmful 5
- Monitor for digoxin toxicity if patient is on digitalis, as hypokalemia increases this risk 5
Hyponatremia Management
- Avoid initiation if baseline sodium <125 mEq/L 5
- If sodium drops significantly, reduce metolazone dose or hold temporarily 4
Azotemia Response
- Mild increases in BUN or creatinine are well tolerated and do not require discontinuation 5
- BUN elevation disproportionate to creatinine indicates prerenal azotemia from diuresis—reduce (don't stop) the diuretic dose 5
- If severe worsening of renal function occurs, discontinue metolazone 6
Absolute Contraindications
- Known allergy to metolazone or sulfonamides 5
- Anuria 1
- Severe hyponatremia (sodium <125 mEq/L) 5
- Marked hypovolemia 5
Relative Contraindications and Cautions
- Symptomatic hypotension (SBP <90 mmHg)—use with extreme caution 5
- Baseline potassium ≥5.0 mEq/L 1
- Serum creatinine ≥2.5 mg/dL in men or ≥2.0 mg/dL in women (use only with intensive monitoring) 1
- Avoid as monotherapy if GFR <30 mL/min; only use synergistically with loop diuretics 2, 1, 5
Drug Interactions
Avoid Concurrent Use
- NSAIDs: cause diuretic resistance and worsen renal impairment 5
- COX-2 inhibitors: similar concerns as NSAIDs 2
Use with Caution
- Digoxin: increased toxicity risk with hypokalemia 5
- ACE inhibitors/ARBs: enhanced hypotension, but also protective against hypokalemia 5
- Mineralocorticoid receptor antagonists: risk of hyperkalemia without proper monitoring 5
Special Populations
Renal Insufficiency
- Metolazone remains effective at GFR <30 mL/min when combined with loop diuretics 1, 5
- Requires more intensive monitoring 1
- Never use as monotherapy in severe renal impairment 2, 5
Elderly Patients (≥75 years)
- Start at lowest effective dose (2.5 mg) 5
- Monitor more frequently for orthostatic hypotension and falls 5
Patients with History of Gout
Common Pitfalls to Avoid
- Starting at too high a dose: Always begin at 2.5 mg, not 5 mg 1, 4
- Using as first-line therapy: Only add after optimizing loop diuretics 1, 5
- Inadequate monitoring: Electrolytes must be checked within 1-2 days 1, 5
- Continuing indefinitely: Use short bursts (2-5 days), then reassess 1
- Ignoring mild azotemia: Mild BUN/creatinine elevation is expected and tolerated; reduce dose rather than stopping 5
- Concurrent NSAID use: This combination causes diuretic resistance and renal injury 5
- Using as monotherapy in CKD: Ineffective and potentially harmful when GFR <30 mL/min 2, 5