Metolazone

Approved Indications:

A. Edema:

• Edema associated with congestive heart failure
• Edema due to renal disorders, including:
• Chronic renal failure
• Nephrotic syndrome
• Acute glomerulonephritis

B. Hypertension:

• Used alone or in combination with other antihypertensive agents for mild to moderate essential hypertension.

Off-Label / Clinically Accepted Uses:

• Refractory edema in combination with loop diuretics (e.g., furosemide) in patients with advanced heart failure or renal insufficiency.
• Diuretic-resistant states: Synergistic use in diuretic stacking protocols.
• Pulmonary edema (adjunctive therapy).

Route: Oral
Formulations Available: Tablets (e.g., 2.5 mg, 5 mg, 10 mg)

Adults:

• Edema (CHF, renal disease):
• Initial: 2.5–5 mg once daily
• Maintenance: 2.5–10 mg once daily
• Max: 20 mg/day (higher doses increase risk of electrolyte imbalance)
• Hypertension:
• Initial: 2.5–5 mg once daily
• May be titrated at intervals of 2–3 weeks
• Maintenance: 2.5–10 mg/day
• With Loop Diuretics:
• Often 2.5–5 mg metolazone given 30–60 minutes before loop diuretic for synergy

Pediatrics:

• Limited safety and efficacy data; not routinely recommended
• Occasionally used off-label in severe pediatric edema at specialist discretion

Elderly:

• Use lower starting doses due to increased risk of volume depletion and electrolyte imbalance

Renal Impairment:

• Moderate impairment (CrCl 10–50 mL/min): May still be effective
• Severe impairment (CrCl <10 mL/min): Use cautiously; efficacy may decrease, but some effect remains due to distal tubular action

Hepatic Impairment:

• Use with caution; risk of electrolyte imbalance and hepatic encephalopathy in cirrhosis

Metolazone is a quinazoline-derived thiazide-like diuretic that acts primarily on the distal convoluted tubule in the nephron. It inhibits the Na⁺/Cl⁻ symporter, leading to decreased reabsorption of sodium and chloride, thereby promoting natriuresis and diuresis. Unlike traditional thiazides, it retains activity at lower glomerular filtration rates (GFR). The reduction in plasma volume and peripheral vascular resistance leads to its antihypertensive effect. Additionally, it indirectly increases potassium and magnesium excretion while promoting calcium retention.

• Absorption: Well absorbed orally (~65%)
• Onset of Action: 1 hour
• Peak Effect: 6–8 hours
• Duration of Action: 12–24 hours
• Bioavailability: Variable (~65%)
• Distribution: Crosses placenta; not significantly bound to plasma proteins
• Metabolism: Minimally metabolized; majority remains unchanged
• Half-life: ~14 hours (can be prolonged in renal impairment)
• Excretion: Primarily via kidneys (unchanged); requires dose adjustment in renal impairment

• Pregnancy: Category B. No evidence of fetal harm in animal studies. Use only if clearly needed. May cause fetal or neonatal electrolyte disturbances if used long-term.
• Lactation: Unknown if excreted in human milk; use caution. Potential diuresis in the nursing infant and reduction in milk production.

• Primary Class: Thiazide-like Diuretic
• Subclass: Quinazoline derivative
• Key Distinction: Active even at lower GFR, unlike typical thiazide diuretics

• Hypersensitivity to metolazone or other sulfonamide-derived drugs
• Anuria (complete renal shutdown)
• Hepatic coma or precoma
• Electrolyte depletion (especially severe hyponatremia or hypokalemia)
• Concomitant lithium use without close monitoring (risk of toxicity)

• Electrolyte Imbalance: Monitor for hypokalemia, hyponatremia, hypomagnesemia, hypercalcemia
• Volume Depletion: Risk of hypotension and prerenal azotemia
• Gout: May increase serum uric acid levels
• Diabetes Mellitus: Can elevate blood glucose levels
• Renal Function: Use with caution in advanced kidney disease; monitor creatinine and electrolytes
• Hepatic Disease: May precipitate hepatic encephalopathy
• Sulfa Allergy: Use with caution in sulfonamide-sensitive patients

Common:

• Metabolic/Electrolyte:
• Hypokalemia, hyponatremia, hypomagnesemia
• Hyperuricemia, hyperglycemia
• GI: Nausea, vomiting, anorexia
• CNS: Dizziness, headache, weakness

Serious/Rare:

• Cardiovascular: Orthostatic hypotension, arrhythmias (secondary to electrolyte imbalance)
• Renal: Azotemia, acute kidney injury (especially with volume depletion)
• Hematologic: Leukopenia, thrombocytopenia (rare)
• Dermatologic: Rash, photosensitivity
• Other: Pancreatitis, cholestatic jaundice (rare)

Onset/Severity: Most adverse effects are dose-dependent and related to electrolyte or fluid shifts. Onset typically occurs within days to weeks of therapy initiation.

• Loop Diuretics: Additive diuretic effect; monitor for severe electrolyte loss
• ACE Inhibitors/ARBs: Increased risk of hypotension and renal impairment
• NSAIDs: May blunt antihypertensive and diuretic effect; risk of nephrotoxicity
• Lithium: Increased serum lithium levels and toxicity risk
• Corticosteroids: Enhanced potassium loss
• Antidiabetic Agents: May reduce efficacy (hyperglycemic effects)
• Digitalis (Digoxin): Increased risk of arrhythmias due to hypokalemia

Enzyme Involvement: Not significantly metabolized via CYP450 pathways; limited drug interaction via hepatic enzymes

• Heart Failure Guidelines (AHA/ESC): Continue to endorse metolazone as a synergistic option for diuretic resistance in advanced CHF
• KDIGO Renal Guidelines: Caution advised in CKD patients; monitor for electrolyte and volume status
• New Safety Monitoring Alerts: Emphasis on close monitoring when combined with loop diuretics due to potential for severe hypokalemia and volume depletion

• Temperature: Store at 20°C to 25°C (68°F to 77°F)
• Humidity/Light: Protect from excessive moisture and light
• Handling: Store in tightly closed container
• Reconstitution/Refrigeration: Not applicable (tablet form only)