Table 9.

Targeted pharmacotherapy to treat obstructive sleep apnea syndrome (OSAS)

Class	Pharmacotherapeutic agents	Reference	Mechanism of action
Anatomical impairment	Liraglutide	Blackman et al. (2016)721	Reduce body weight, leading to a decrease in upper airway fat (due to obesity) and thus reduce narrowing and/or the propensity for closure during sleep, which may decrease Pcrit in susceptible individuals
	Spironolactone and furosemide	Blackman et al. (2018)722	Reduce fluid retention, thereby reducing nighttime fluid transfer from the limbs to the neck
	Nasal decongestants (Mometasone alone)	Acar et al. (2013)723	Reducing nasal resistance can induce pharyngeal dilatation by decreasing the negative suction pressure downstream in the velo- and oropharynx
	Fluticasone	Kiely et al. (2004)724
	Nasal steroid dexamethasone with the decongestant tramazoline	Koutsourelakis et al. (2013)725
Low arousal threshold	Triazolam	Berry et al. (1995)726	Raising the arousal threshold might have the potential to buy time for the upper airway muscle recruitment and the stabilization of airway patency; zolpidem, diphenhydramine, and lorazepam all increased arousal threshold; lorazepam and zolpidem increased genioglossus activity before arousal in response to hypercapnia
	Lorazepam Zolpidem Diphenhydramine Eszopiclone	Carberry et al. (2017)654 Carter et al. (2016)727 Eckert et al. (2011)653 Rosenberg et al. (2006)728 Carberry et al. (2017)654 Park et al. (2008)729
	Sodium oxybate	George et al. (2011)730	Sodium oxybate reduces the severity of sleep apnea by increasing deep sleep time and increasing the arousal threshold
	Trazodone	Eckert et al. (2014)731 Smales et al. (2015)732	Trazodone can increase the arousal threshold in response to hypercapnia and allow tolerance to higher CO2 levels without arousal, thus stabilizing sleep
High loop gain	Carbonic anhydrase inhibitor: Zonisamide and Acetazolamide	Eskandari et al. (2014)733 Eskandari et al. (2018)658 Edwards et al. (2013)734 Edwards et al. (2012)655 Schmickl et al. (2020)735 Schmickl et al. (2021)656 Tojima et al. (1988)736	Agents targeting loop gain reduce the PCO2 reserve by producing transient metabolic acidosis and relative hyperventilation, thus widening the difference between eupneic paCO2 and the apneic threshold, effectively reducing loop gain by reducing plant gain, stabilizing ventilator drive leading to respiratory tract opening and decreasing obstructive events
	Oxygen therapy	Sands et al. (2018)737 Wellman et al. (2008)738 Pokorski et al. (2000)739 Joosten et al. (2021)740 Wang et al. (2018)741	Oxygen therapy can reduce the circulation gain by quieting the chemosensory output of an overly sensitive chemoreflex system, which converts the perceived change in gas tension into a smaller change in the ventilatory drive.
	Carbon dioxide Rebreathing	Dempsey et al. (2004)742 Messineo et al. (2018)743 Xie et al. (2013)744	CO2 is added during hyperpnea to prevent transient hypocapnia to stabilize periodic respiratory abnormalities. In patients with high loop gain, CO2 rebreathing seems to be a promising treatment
Poor muscle responsiveness	Noradrenergic mechanisms: Desipramine, Protriptyline, Atomoxetine, and Antimuscarinic oxybutynin	Taranto-Montemurro et al. (2016)662 Taranto-Montemurro et al. (2016)745 Hanzel et al. (1991)746 Smith et al. (1983)747 Bart Sangal et al. (2008)748	By identifying the receptor targets that stimulate the upper airway muscles, we can manipulate the airway muscle tone to prevent upper airway muscle relaxation, restore pharyngeal muscle activity, and then restore upper airway patency through reflexive recruitment; desipramine could increase genioglossus activity and reduce upper airway collapse during sleep in humans
	Serotonergic mechanisms: Ondansetron, Buspirone, Mirtazapine, Paroxetine, Fluoxetine, and l-Tryptophan	Veasey et al. (2001)749 Mendelson et al. (1991)750 Carley et al. (2007)751 Berry et al. (1999)752 Hanzel et al. (1991)746 Schmidt et al. (1983)753	Serotonergic drive is attenuated centrally from wakefulness to NREM sleep and reaches a minimum during REM sleep, resulting in a relative reduction in ventilatory drive. Central administration of serotonin mediates respiratory excitation through 5-HT2a/c receptors on upper airway motoneurons and 5-HT1a receptors on respiratory neurons. Serotonin has different effects on central and peripheral respiration, but 5-HT3 antagonists and 5-HT1a agonists consistently improve respiration
	K+ channel blockers: 4-aminopyridine, Tetraethylammonium, and Doxapram	Grace et al. (2013)754 Suratt et al. (1986)755	Blocking potassium channels promotes membrane depolarization and cellular excitability, which leads to increased genioglossus activity during REM and NREM sleep; cannabinoids improve respiratory stability by attenuating the feedback of the vagus nerve to the medulla to help stabilize breathing and activate pharyngeal muscles
	Cannabinoids	Guo et al. (2004)756 Prasad et al. (2013)757
	Nicotine	Gothe et al. (1985)758
Other pharmacotherapeutic agents involved in OSAS
Forskolin		Aoki et al. (1985)759	During wakefulness and non-REM sleep, forskolin increases cAMP at the hypoglossal motor nucleus, which in turn increases the activity of the pharyngeal muscle
Xanthines		Lagercrantz et al. (1985)760	Increase ventilation by antagonizing adenosine in the central nervous system and increasing diaphragm contractility