Metolazone

Mechanism

Pharmacological Group

High potency thiazide-like diuretic, derived from quinazoline.

Mechanism of Action

Selectively inhibits sodium chloride reabsorption by reversible blocking of the NCC cotransporter in the Distal Convoluted Tubule. It has two molecular characteristics that differentiate it from other thiazides: it exerts an additional inhibitory effect on sodium reabsorption in the proximal tubule and it has an extremely high binding affinity to the NCC, which allows it to remain active and block the cotransporter even in the presence of markedly depressed glomerular filtration rates.

Pharmacokinetics

Key Pharmacokinetics

• Bioavailability: 40-60% (highly variable depending on the formulation). Micronized formulations (such as Mykrox) have much higher bioavailability and are not interchangeable milligram for milligram with conventional ones (Zaroxolyn).
• Protein binding: ~95%, bound to albumin and erythrocytes.
• Excretion: 80-90% is excreted unchanged through the urinary route through filtration and tubular secretion.
• Half-life: 14 to 20 hours.

Indicators and dose

Clinical Indications

• Severe refractory congestive heart failure: Used almost exclusively for sequential nephron synergy in combination with loop diuretics to break diuretic resistance.
• Nephrotic syndrome and advanced CKD: Useful for controlling volume overload when other non-thiazide diuretics have failed.

Dosage and Settings

• Sequential Blockade (in combination with loop): 2.5 mg to 5 mg orally once daily, typically administered 30 minutes before the furosemide dose. In some refractory cases, it is prescribed 2 or 3 times a week instead of daily.
• Renal adjustment: It is the only thiazide-like diuretic that retains excellent diuretic efficacy in Advanced Renal Failure (CrCl < 30 mL/min), which makes it the choice in CKD grade IV or V refractory to loop monotherapy.

Security

Risk of Mass Electrolyte Depletion

The combination of metolazone with loop diuretics (such as furosemide) produces massive, synergistic and disproportionate diuretic blockade. A massive urinary loss of water, sodium and potassium can occur in a few hours. This combination should only be initiated in controlled hospital environments or under strict daily monitoring. Serum potassium rates should be measured every 24-48 hours initially, as the risk of profound hypokalemia and associated arrhythmias is extremely high.

Contraindications

Established anuria; hepatic coma; Refractory severe hyponatremia and hypokalemia.

Adverse Effects (ADR)

• Very common: Severe hypokalemia, hyponatremia, prerenal azotemia (due to rapid contraction of plasma volume), painful cramps.
• Common: Marked hyperuricemia, rebound hyperglycemia, symptomatic orthostatic hypotension.

Interactions

Deep potentiation of digoxin toxicity. Antagonism with NSAIDs. Extreme synergy with other diuretics.

Pregnancy and Breastfeeding

Category B. Crosses the placental barrier; It is associated with the risk of neonatal thrombocytopenia. Not recommended.