What is the recommended dosage and usage of Metolazone (thiazide-like diuretic) for treating hypertension and edema?

Metolazone Dosing and Usage

For hypertension, start metolazone at 2.5-5 mg once daily; for edema from heart failure or renal disease, start at 5 mg once daily and titrate up to 20 mg daily as needed, with close electrolyte monitoring within 1-2 weeks of initiation. 1

Hypertension Management

Metolazone is not a first-line agent for hypertension and should be reserved for Step 3-4 therapy after ACE inhibitors/ARBs and calcium channel blockers have been tried. 2

Dosing for Hypertension:

• Initial dose: 2.5-5 mg once daily 1
• Lower dose formulation: 0.5-1 mg once daily may be effective for mild-to-moderate hypertension, with 51-58% of patients achieving blood pressure control at 0.5 mg 3
• Time to effect: 3-4 days to 3-6 weeks for blood pressure reduction 1
• Adjust doses at appropriate intervals to achieve maximum therapeutic effect 1

Role in Stepped-Care Approach:

• Use as part of Step 3 combination therapy with ACE inhibitor/ARB plus calcium channel blocker 4
• In Step 4 resistant hypertension, consider increasing thiazide-like diuretic dose if serum potassium >4.5 mmol/L 4

Heart Failure and Edema Management

Metolazone is reserved for refractory heart failure when patients fail to respond adequately to moderate or high-dose loop diuretics alone (Class 1, Level B-NR recommendation). 5

Dosing for Edema:

• Cardiac failure edema: 5-20 mg once daily 1
• Renal disease edema: 5-20 mg once daily 1
• Initial dose: 2.5 mg once daily, maximum 20 mg daily 5
• Duration of action: 12-24 hours 5
• Diuresis typically begins within one hour and persists for 24 hours or longer 1

Sequential Nephron Blockade:

• Combination with loop diuretics produces synergistic effect that overcomes diuretic resistance 5, 6
• This combination is superior to simply increasing loop diuretic doses 4
• Low-dose metolazone (≤5 mg) on top of oral loop diuretics is effective and relatively safe in contemporary outpatients with refractory heart failure 6
• For patients with paroxysmal nocturnal dyspnea, employ larger doses to ensure 24-hour diuresis 1

Critical Monitoring Requirements

Check electrolytes, renal function, and blood pressure within 1-2 weeks after initiation or dose changes, then at 3 months, and subsequently at 6-month intervals. 5

Electrolyte Complications:

• Severe electrolyte disturbances occur with metolazone-loop diuretic combinations, including hyponatremia, disproportionate hypochloremia, metabolic alkalosis, and hypokalemia 7
• Clinically important hypokalemia (<2.5 mM) or hyponatremia (<125 mM) occur in approximately 10% of treatment episodes 6
• The combination significantly increases risk of electrolyte abnormalities requiring close monitoring 5

Renal Function Monitoring:

• Small increases in serum creatinine may occur initially due to volume depletion 8
• Metolazone produces diuretic response despite low glomerular filtration rate 6
• Avoid in severe bilateral renal artery stenosis due to acute renal failure risk 4

Important Clinical Pitfalls

Avoid These Combinations:

• Do not combine with potassium-sparing diuretics during initiation unless hypokalaemia persists despite ACE inhibitor therapy 4
• Avoid NSAIDs during metolazone therapy 4
• Use caution with reduced estimated glomerular filtration rates due to hyperkalaemia risk when adding other agents 4

Dosing Adjustments:

• More careful dosage adjustment needed when given concurrently with other antihypertensive drugs or diuretics 1
• Reduce dose once desired therapeutic effect is obtained 1
• Base decisions to change daily dose on thorough clinical and laboratory evaluations 1

Special Populations:

• Absorption may be reduced in heart failure, requiring dose adjustments 6
• In chronic renal insufficiency with hypertension, maximal response occurs at 10 mg metolazone, though only 25% achieve blood pressure normalization with diuretic monotherapy 9