Effect of acetazolamide on cough induced by low-chloride-ion solutions in normal subjects: Comparison with furosemide

Background: The antitussive activity of inhaled fuorsemide has been attributed to its blocking effect on the Na+-2Cl(-)-K+ cotransporter. It is likely that the antitussive activity of inhaled diuretics is more complex because amiloride, a diuretic that has no effect on the Na+-2Cl(-)-K+ cotransporter, also shows a significant effect against cough induced by low-chloride-ion solutions. Apart from pharmacokinetics of inhaled diuretics, this activity could also depend on the inhibition of carbonic anhydrase. Objectives: We therefore studied the effect of inhaled acetazolamide, a selective inhibitor of carbonic anhydrase activity, on cough induced by the inhalation of different chloride ion solutions in a group of normal subjects. This was compared with the antitussive effect of furosemide. In addition, we attempted to determine whether the effect of acetazolamide is dose-dependent. Methods: Cough challenge consisted of consecutive inhalations of four solutions having decreasing concentrations of chloride ions (150, 75, 37.5 and 0 mmol/L). Nine normal subjects underwent the cough challenge 5 minutes after the inhalation of saline placebo, azetazolamide (500 mg), and furosemide (30 mg) according to a randomized, double-blind study design. A group of six subjects were challenged according to the same procedure and study design, after the inhalation of saline placebo and of two doses of acetazolamide (250 mg and 500 mg). Results: Inhaled acetazolamide significantly reduced cough response to 37.5 and 0 mmol/L chloride solutions compared with placebo (p < 0.015 and p < 0.015, respectively). Furosemide showed a similar protective effect (p < 0.015 and p < 0.025, respectively). Acetazolamide provided a significantly better protective effect than furosemide (p < 0.025 and p < 0.015, respectively). The antitussive activity of the two doses of acetazolamide was not statistically different. Conclusion: These results demonstrate that inhaled acetazolamide, a selective inhibitor of carbonic anhydrase, attenuates cough induced by low-chloride-ion solutions in normal subjects. At the applied doses, its antitussive activity is slightly greater than furosemide. This finding suggests that the inhibition of carbonic anhydrase activity is likely involved in modulating changes caused by absence of a chloride ion in the airway microenvironment of human beings.