Acetazolamide is used in altitude sickness prophylaxis. Beyond its inhibition of carbonic anhydrase in the kidney producing metabolic acidosis, what is the mechanism by which the induced metabolic acidosis helps acclimatization?

• A Metabolic acidosis increases 2,3-BPG in RBCs, shifting the oxyhemoglobin dissociation curve left, enhancing oxygen loading at altitude
• B The lower blood pH from metabolic acidosis stimulates peripheral chemoreceptors in the carotid body to increase the ventilatory drive, counteracting the blunted hypoxic ventilatory response at altitude and producing hyperventilation that raises arterial PO2 ✓
• C Metabolic acidosis reduces CSF bicarbonate, directly blunting central chemoreceptor sensitivity and allowing carbon dioxide to accumulate
• D The bicarbonate diuresis reduces plasma volume, decreasing the hematocrit and improving high-altitude pulmonary blood flow

Explanation

At altitude, the hypoxic environment stimulates peripheral chemoreceptors, causing hyperventilation that lowers PaCO2, producing respiratory alkalosis. This alkalosis paradoxically reduces central chemoreceptor (medullary) stimulation, blunting the drive to breathe further. Acetazolamide inhibits renal carbonic anhydrase, causing bicarbonate wasting in urine and producing metabolic acidosis. This metabolic acidosis stimulates peripheral chemoreceptors (carotid bodies) and partially compensates for the respiratory alkalosis, maintaining a heightened respiratory drive — producing deeper, more regular breathing that increases PAO2 and thus arterial oxygen saturation at altitude. This is the primary mechanism of benefit, not the oxyhemoglobin curve shift (option A would worsen oxygen delivery) or CSF changes (option C is inaccurate in direction).

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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