A patient with chronic heart failure is on furosemide. Over time, she develops 'diuretic resistance.' Thiazide addition (e.g., metolazone) is recommended. Which pharmacological principle underlies this combination?
- A Metolazone inhibits the same NKCC2 transporter in the thick ascending limb as furosemide, doubling its effect
- B Metolazone increases furosemide bioavailability by inhibiting intestinal P-glycoprotein
- C Sequential nephron blockade: furosemide blocks NKCC2 in the thick ascending limb, and metolazone blocks NCC in the distal convoluted tubule, preventing compensatory Na+ reabsorption that develops in response to loop diuretic monotherapy ✓
- D Metolazone blocks the collecting duct aquaporin-2 channels, enhancing free water excretion
Correct answer: C. Sequential nephron blockade: furosemide blocks NKCC2 in the thick ascending limb, and metolazone blocks NCC in the distal convoluted tubule, preventing compensatory Na+ reabsorption that develops in response to loop diuretic monotherapy
Explanation
In furosemide-treated patients, compensatory sodium reabsorption in the distal convoluted tubule (DCT) via NCC (the sodium-chloride cotransporter) blunts the overall diuretic response—a form of 'braking phenomenon' or diuretic resistance. Metolazone (a thiazide-like diuretic) specifically inhibits NCC in the DCT, preventing this compensatory reabsorption and producing synergistic diuresis. This 'sequential nephron blockade' approach can mobilise significant oedema. Furosemide targets NKCC2 in the thick ascending limb; metolazone does not act there.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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