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Obstructive sleep apnea (OSA) is a common and serious breathing disorder. Several pathophysiological factors predispose individuals to OSA. These factors are quantifiable, and modifiable pharmacologically. Four key pharmacotherapeutic targets are identified and mapped to the major determinants of OSA pathophysiology. PubMed and Clinicaltrials.gov were searched through April 2023. Target #1: Pharyngeal Motor Effectors. Increasing pharyngeal muscle activity and responsivity with noradrenergic-antimuscarinic combination is central to recent breakthrough OSA pharmacotherapy. Assumptions, knowledge gaps, future directions, and other targets are identified. #2: Upper Airway Sensory Afferents. There is translational potential of sensitizing and amplifying reflex pharyngeal dilator muscle responses to negative airway pressure via intranasal delivery of new potassium channel blockers. Rationales, advantages, findings, and potential strategies to enhance effectiveness are identified. #3: Chemosensory Afferents and Ventilatory Control. Strategies to manipulate ventilatory control system sensitivity by carbonic anhydrase inhibitors are supported in theory and initial studies. Intranasal delivery of agents to stimulate central respiratory activity are also introduced. #4: Sleep-Wake Mechanisms. Arousability is the fourth therapeutic target rationalized. Evolving automated tools to measure key pathophysiological factors predisposing to OSA will accelerate pharmacotherapy. Although not currently ready for general clinical settings, the identified targets are of future promise.

Targets for obstructive sleep apnea pharmacotherapy: principles, approaches, and emerging strategies