Gefapixant Mechanism of Action
Gefapixant reduces chronic cough through ATP receptor antagonism (Answer B), specifically by blocking P2X3 receptors on sensory nerve fibers in the airways. 1, 2
Mechanism of Action
Gefapixant is a selective P2X3 receptor antagonist that inhibits ATP-mediated activation of sensory C-fibers in the respiratory tract. 1, 2, 3 This mechanism directly addresses the afferent limb of the cough reflex by preventing adenosine triphosphate (ATP) from activating these purinergic receptors on airway sensory nerves. 2
Why This Matters in COPD-Related Cough
ATP receptors (P2X3) are key mediators of chronic cough hypersensitivity, particularly in conditions like COPD where airway inflammation and irritation lead to increased ATP release. 1, 2
The drug works peripherally at the sensory nerve level, not through central mechanisms like opioid receptors (option D) or NMDA receptors (option A). 2
Potassium channel opening (option C) has been investigated as a potential antitussive mechanism in preclinical studies, but this is not gefapixant's mechanism of action. 4
Clinical Evidence
Gefapixant 45 mg twice daily demonstrated significant efficacy in two phase 3 trials (COUGH-1 and COUGH-2) for refractory and unexplained chronic cough:
- 18.5% reduction in 24-hour cough frequency at 12 weeks in COUGH-1 (p=0.041). 1
- 14.6% reduction in 24-hour cough frequency at 24 weeks in COUGH-2 (p=0.031). 1
- The lower 15 mg twice daily dose did not show significant efficacy compared to placebo. 1
Important Caveats
Taste disturbances are the primary adverse effect, occurring in a dose-dependent manner with dysgeusia being most common (16.2% in COUGH-1 and 21.1% in COUGH-2 at all doses combined). 1 At the effective 45 mg dose, taste disorders are more prevalent but tend to be manageable for most patients. 3
Individual response varies considerably, with some patients showing excellent response while others derive minimal benefit, even in specific populations like interstitial lung disease. 3 However, gefapixant represents the first treatment to show statistically significant efficacy in phase 3 trials for refractory chronic cough. 1