Can metolazone be used for hypertension and edema?

Can Metolazone Be Used for Hypertension and Edema?

Yes, metolazone is FDA-approved and guideline-recommended for both hypertension and edema, but it should be reserved as second-line therapy for hypertension (starting at 2.5-5 mg daily) and primarily used for refractory edema in heart failure when combined with loop diuretics (starting at 2.5 mg daily). 1

FDA-Approved Indications

Metolazone has two distinct FDA-approved uses 1:

• Edema management: Salt and water retention from congestive heart failure, renal diseases including nephrotic syndrome, and states of diminished renal function 1
• Hypertension: As monotherapy or in combination with other antihypertensive drug classes 1

Use in Hypertension

Dosing and Efficacy

• Start with 2.5-5 mg once daily for mild to moderate essential hypertension 1
• The antihypertensive effect may take 3-4 days to 3-6 weeks to manifest, requiring patient counseling about delayed onset 1
• At low doses (0.5-1.0 mg of rapid-acting formulation), metolazone controls blood pressure in 51-58% of patients with mild to moderate hypertension 2

Position in Treatment Algorithm

• The 2022 AHA/ACC/HFSA guidelines suggest metolazone as an option in patients with hypertension and concomitant mild fluid retention 3
• It is not a first-line agent for uncomplicated hypertension—thiazide diuretics, ACE inhibitors, ARBs, and calcium channel blockers are preferred 4
• Consider metolazone when a patient needs both blood pressure control and enhanced diuresis 3

Use in Edema

Heart Failure with Reduced Ejection Fraction

• Loop diuretics (furosemide) are first-line for edema in heart failure 4, 3
• Add metolazone 2.5 mg daily when patients show diuretic resistance to moderate or high-dose loop diuretics (Class I, Level B-NR recommendation from ACC/AHA/HFSA 2022 guidelines) 3
• The combination of metolazone with loop diuretics produces synergistic effects that overcome resistance 4, 3
• This synergy is so potent that some patients may require reduction in loop diuretic dose to avoid excessive diuresis 5

Dosing for Edema

• Cardiac failure edema: 5-20 mg once daily 1
• Renal disease edema: 5-20 mg once daily 1
• Diuresis typically begins within one hour and persists for 24 hours or longer 1
• For patients with paroxysmal nocturnal dyspnea, use larger doses to ensure 24-hour diuresis 1

Evidence for Combination Therapy

• When metolazone (starting at 2.5 mg daily) is added to furosemide in patients with refractory edema, sodium excretion increases from mean 131 to 303 mEq/day, urine volume increases from 1677 to 2940 mL/day, and mean weight loss is 6.1 kg within 7 days 5
• This combination is effective even in patients with moderately severe renal insufficiency 6

Critical Safety Considerations

Electrolyte Monitoring (Highest Priority)

• The risk of severe electrolyte depletion is markedly enhanced when metolazone is combined with loop diuretics 4
• The ACC warns that adding metolazone to loop diuretics significantly increases the risk of hypokalemia, hyponatremia, hypochloremia, and metabolic alkalosis 3
• Monitor electrolytes closely, especially potassium and magnesium, as depletion predisposes to serious cardiac arrhythmias, particularly with concurrent digitalis therapy 4
• Severe electrolyte disturbances follow a pattern of hyponatremia, disproportionate hypochloremia, alkalosis, and hypokalemia 7

Renal Function Monitoring

• Initial treatment may produce small increases in serum creatinine due to volume depletion-induced decreased GFR 6
• If hypotension and azotemia occur without signs of fluid retention, this likely reflects volume depletion and requires diuretic dose reduction 4
• If hypotension and azotemia occur with signs of fluid retention, this reflects worsening heart failure and is an ominous clinical scenario requiring advanced heart failure management 4

When to Use Caution or Avoid

• Use with extreme caution when combining with loop diuretics due to severe electrolyte disturbances 7
• In liver disease with ascites, metolazone causes hypokalaemia in 80%, hypochloraemia in 35%, and encephalopathy in 35% when used alone—always combine with potassium-sparing agents like amiloride or spironolactone 8
• Avoid NSAIDs (including COX-2 inhibitors) as they block diuretic effects 4

Practical Management Algorithm

For Hypertension:

1. Use metolazone only if patient has concurrent mild fluid retention 3
2. Start at 2.5-5 mg once daily 1
3. Wait 3-6 weeks before assessing full effect 1
4. Target BP <140/90 mmHg (or <130/80 mmHg if tolerated) 4

For Refractory Edema in Heart Failure:

1. Confirm patient is on adequate doses of loop diuretic (e.g., furosemide 80-160 mg daily or higher) 3
2. Add metolazone 2.5 mg once daily 3, 1
3. Monitor daily weights—expect rapid diuresis within 24 hours 1, 5
4. Check electrolytes within 24-48 hours and then frequently 3
5. Consider reducing loop diuretic dose if excessive diuresis occurs 5
6. Once euvolemia achieved, continue maintenance dosing to prevent recurrence 4

Electrolyte Protection Strategy:

• If using metolazone with loop diuretic, ensure patient is on ACE inhibitor or ARB to help prevent potassium depletion 4
• Consider adding aldosterone antagonist (spironolactone 12.5-25 mg daily) if ejection fraction <40%, creatinine <2.5 mg/dL (men) or <2.0 mg/dL (women), and potassium <5.0 mEq/L 4, 3
• Long-term oral potassium supplementation is frequently not needed with ACE inhibitor/ARB and may be deleterious 4