A patient on a high-ceiling loop diuretic develops metabolic alkalosis. Which mechanism specifically accounts for furosemide-induced metabolic alkalosis?
- A Furosemide inhibits carbonic anhydrase in proximal tubules, reducing H+ secretion and allowing HCO3- to accumulate in plasma
- B Volume contraction elevates angiotensin II and aldosterone, increasing distal H+ and K+ secretion; chloride depletion increases HCO3- reabsorption; and direct collecting duct flow stimulation increases electrogenic H+ secretion — generating and maintaining alkalosis ✓
- C Furosemide blocks NKCC2 in the thick ascending limb, reducing paracellular K+ and Mg2+ reabsorption, which raises plasma HCO3-
- D Furosemide induces aldosterone suppression through volume expansion that eventually overcorrects to hypovolemia, releasing HCO3- from suppressed distal secretion
Explanation
Furosemide-induced metabolic alkalosis is multifactorial. (1) Volume contraction (contraction alkalosis): the diuretic-induced loss of isotonic NaCl-rich urine reduces ECF volume without proportional loss of HCO3-, concentrating plasma bicarbonate. (2) Secondary hyperaldosteronism: reduced perfusion pressure activates the RAAS; elevated aldosterone stimulates ENaC-mediated Na+ reabsorption in the collecting duct, generating a lumen-negative electrochemical gradient that drives H+ secretion by intercalated cells (via H+-ATPase) and K+ secretion — generating new HCO3- and depleting K+. (3) Chloride depletion: Cl- is required for HCO3- secretion by the pendrin transporter (Cl-/HCO3- exchanger) in type B intercalated cells; chloride deficiency impairs this excretory pathway, maintaining alkalosis (chloride-sensitive, chloride-responsive metabolic alkalosis). (4) Hypokalaemia shifts H+ intracellularly, generating a paradoxical aciduria that further sustains alkalosis.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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