Influence of methazolamide on the human control of breathing: A comparison to acetazolamide

What is the central question of this study? Acetazolamide and methazolamide both reduce hypoxic pulmonary vasoconstriction equally, but methazolamide does not impair skeletal muscle function. The effect of methazolamide on respiratory control in humans is not yet known. What is the main finding and its importance? Similar to acetazolamide after chronic oral administration, methazolamide causes a metabolic acidosis and shifts the ventilatory CO₂ response curve leftwards without reducing O₂ sensitivity. The change in ventilation over the change in log $$ provides a more accurate measure of hypoxic sensitivity than the change in ventilation over the change in arterial oxyhaemoglobin saturation.

Acetazolamide is used to prevent/treat acute mountain sickness and both central and obstructive sleep apnoea. Methazolamide, like acetazolamide, reduces hypoxic pulmonary vasoconstriction, but has fewer side-effects, including less impairment of skeletal muscle function. Given that the effects of methazolamide on respiratory control in humans are unknown, we compared the effects of oral methazolamide and acetazolamide on ventilatory control and determined the ventilation-log  $$ relationship in humans. In a double-blind, placebo-controlled, randomized cross-over design, we studied the effects of acetazolamide (250 mg three times daily), methazolamide (100 mg twice daily) and placebo in 14 young male subjects who were exposed to 7 min of normoxic hypercapnia and to three levels of eucapnia and hypercapnic hypoxia. With placebo, methazolamide and acetazolamide, the CO₂ sensitivities were 2.39 ± 1.29, 3.27 ± 1.82 and 2.62 ± 1.79 l min^-1  mmHg^-1 (n.s.) and estimated apnoeic thresholds 32 ± 3, 28 ± 3 and 26 ± 3 mmHg, respectively (P < 0.001, placebo versus methazolamide and acetazolamide). The relationship between ventilation ( $$ ) and log  $$ (using arterialized venous $$ in hypoxia) was linear, and neither agent influenced the relationship between hypoxic sensitivity ( $$ ) and arterial [H⁺ ]. Using $$ rather than Δ $$ /Δ arterial oxyhaemoglobin saturation enables a more accurate estimation of oxygenation and ventilatory control in metabolic acidosis/alkalosis when right- or leftward shifts of the oxyhaemoglobin saturation curve occur. Given that acetazolamide and methazolamide have similar effects on ventilatory control, methazolamide might be preferred for indications requiring the use of a carbonic anhydrase inhibitor, avoiding some of the negative side-effects of acetazolamide.