What is the recommended use and dosage of Metolazone (a diuretic) for treating hypertension and edema?

Metolazone: Recommended Use and Dosage

Primary Indications

Metolazone is indicated for edema associated with heart failure and renal disease at 5-20 mg once daily, and for mild-to-moderate hypertension at 2.5-5 mg once daily. 1

Heart Failure with Fluid Retention

• Loop diuretics (furosemide, bumetanide, torsemide) are the preferred first-line diuretic agents for most heart failure patients. 2, 3
• Metolazone should be reserved for patients with diuretic resistance—those who fail to respond adequately to moderate or high-dose loop diuretics alone. 3
• The 2022 AHA/ACC/HFSA guidelines provide a Class 1, Level B-NR recommendation for adding metolazone to loop diuretics in refractory heart failure. 3

Hypertension

• For new hypertension treatment, thiazide-like diuretics such as chlorthalidone (12.5-25 mg once daily) or indapamide (1.5 mg modified-release or 2.5 mg once daily) are preferred over conventional thiazides. 2
• Metolazone at 2.5-5 mg once daily is effective for mild-to-moderate essential hypertension, with blood pressure response typically occurring within 3-4 days to 3-6 weeks. 1, 4
• Studies show 48-58% of patients achieve blood pressure control with low-dose metolazone (0.5-2.5 mg daily). 4, 5

Dosing Protocols

Monotherapy for Edema

• Initial dose: 5-20 mg once daily for cardiac or renal edema. 1
• Diuresis typically begins within one hour and persists for 24 hours or longer. 1
• For patients with paroxysmal nocturnal dyspnea, use a larger dose to ensure 24-hour diuresis. 1

Combination Therapy with Loop Diuretics (Diuretic Resistance)

The American College of Cardiology recommends administering metolazone 30 minutes before the loop diuretic (e.g., bumetanide, furosemide) for optimal synergistic effect through sequential nephron blockade. 6, 7

Burst Therapy Protocol:

• Starting dose: 2.5 mg once daily, given 30 minutes before the loop diuretic. 6, 7, 3
• Duration: Short-term therapy for 2-5 days, then return to usual maintenance loop diuretic dose when weight stabilizes. 6, 7
• Target weight loss: 0.5-1.0 kg per day during combination therapy. 6, 7
• Maximum daily dose: 10-20 mg, though most patients respond to ≤5 mg. 2, 3, 8

Mechanism:

• Metolazone blocks sodium reabsorption at the distal convoluted tubule while loop diuretics act on the loop of Henle, creating powerful synergistic diuresis. 6, 7
• Unlike other thiazides, metolazone maintains efficacy even when GFR falls below 30 mL/min. 7

Hypertension Dosing

• Initial dose: 2.5-5 mg once daily. 1
• Lower doses (0.5-1.0 mg) of rapid-acting formulations are also effective and minimize electrolyte disturbances. 5

Critical Monitoring Requirements

Before Initiating Combination Therapy:

• Check baseline serum electrolytes (sodium, potassium, chloride), creatinine, and blood pressure. 6, 7

During Treatment:

• Monitor daily weight, with target reduction of 0.5-1.0 kg per day. 6, 7
• Recheck electrolytes, renal function, and blood pressure 1-2 days after initiating metolazone-loop diuretic combination. 6, 7
• Continue monitoring throughout treatment course, as severe electrolyte and volume depletion can occur. 2, 9

High-Risk Patients Requiring Hospital Admission:

Consider inpatient initiation of combination therapy for: 6, 7

• Elderly patients
• Severe heart failure (NYHA class III-IV)
• Baseline renal dysfunction
• Presence of hypotension, azotemia, oliguria, or ascites

Major Adverse Effects and Precautions

Electrolyte Disturbances

The combination of metolazone with loop diuretics significantly increases the risk of severe electrolyte abnormalities. 3, 9

• Hypokalemia: Mean potassium decrease of 0.5-0.6 mEq/L even with low doses; clinically important hypokalemia (<2.5 mM) occurs in ~10% of treatment episodes. 4, 8
• Hyponatremia: Particularly with combination therapy; clinically significant hyponatremia (<125 mM) occurs in ~10% of cases. 9, 8
• Hypochloremia and metabolic alkalosis: Common with combination therapy. 9
• Consider adding potassium-sparing diuretics (spironolactone 25-50 mg or amiloride 5 mg) if hypokalemia persists despite ACE inhibitor therapy. 2, 7

Renal Function

• Small increases in serum creatinine are expected initially due to volume depletion and should not prompt immediate discontinuation if the patient remains asymptomatic. 2, 10
• Do not use thiazides as monotherapy if eGFR <30 mL/min, except when prescribed synergistically with loop diuretics. 2, 7

Volume Depletion

• Excessive diuresis can cause hypotension and azotemia. 2
• Persistent volume overload is preferable to aggressive diuresis causing symptomatic hypotension, but mild-to-moderate decreases in blood pressure or renal function are acceptable if the patient remains asymptomatic. 2

Drug Interactions

• NSAIDs (including COX-2 inhibitors) can block diuretic effects and should be avoided. 2

Special Populations

Renal Insufficiency

• Metolazone remains effective even with severe renal impairment (GFR <30 mL/min), unlike conventional thiazides. 7, 10
• More careful monitoring is required due to higher risk of adverse effects. 6
• Long-term use (up to 44 months) has been demonstrated as safe and effective in chronic renal insufficiency. 10

Heart Failure with Preserved Ejection Fraction (HFpEF)

• Diuretics are used to control sodium and water retention and relieve breathlessness and edema, though no treatment has convincingly reduced morbidity and mortality in HFpEF. 2

Common Pitfalls to Avoid

1. Underdosing loop diuretics before adding metolazone: Ensure loop diuretics are optimized to moderate-to-high doses before adding metolazone. 3

2. Prolonged continuous use: Metolazone should be used as short-term burst therapy (2-5 days), not as chronic daily therapy in combination with loop diuretics. 6, 7

3. Inadequate monitoring: Failure to check electrolytes within 1-2 days of initiating combination therapy can lead to life-threatening electrolyte disturbances. 6, 9

4. Premature discontinuation due to mild azotemia: Small increases in creatinine are expected and acceptable if the patient remains asymptomatic and volume overload is resolving. 2

5. Forgetting the 30-minute timing: Administering metolazone 30 minutes before the loop diuretic is essential for optimal sequential nephron blockade. 6, 7