Mechanism of Action of Belsomra (Suvorexant)
Belsomra (suvorexant) works by blocking orexin receptors OX1R and OX2R, which suppresses the wake-promoting signals in the brain, thereby facilitating sleep without altering natural sleep architecture. 1
How Suvorexant Targets the Wake-Sleep System
Suvorexant is a dual orexin receptor antagonist that binds to both OX1R and OX2R receptors with high affinity (Ki = 0.55 nM and 0.35 nM, respectively). 1
The orexin neuropeptide signaling system plays a critical role in maintaining wakefulness. When orexin A and orexin B neuropeptides bind to their receptors, they promote arousal and keep you awake. 1
By blocking these receptors, suvorexant prevents the wake-promoting neuropeptides from binding, which suppresses the wake drive and allows the natural sleep process to occur. 1, 2
Key Distinguishing Features from Traditional Sleep Medications
Unlike benzodiazepines and Z-drugs that enhance GABA activity to induce sedation, suvorexant specifically targets the wake system rather than forcing sleep. 3, 2
Suvorexant preserves natural sleep architecture, meaning it prolongs the time spent in each natural sleep state without distorting the normal sleep profile. 3
This mechanism reduces arousals during sleep rather than chemically inducing unconsciousness, which theoretically promotes more restorative sleep. 3
Clinical Implications of This Mechanism
The antagonism of orexin receptors may also explain potential adverse effects such as signs resembling narcolepsy or cataplexy, since genetic mutations in the orexin system in animals result in hereditary narcolepsy, and loss of orexin neurons has been reported in humans with narcolepsy. 1
The most common adverse effect is somnolence (daytime drowsiness), occurring in approximately 7% of patients versus 3% with placebo, which is a direct extension of its wake-suppressing mechanism. 4, 5
CYP3A is the predominant enzyme metabolizing suvorexant, with minor contribution from CYP2C19, which is important for drug interaction considerations. 1, 6
Metabolic Considerations
The major circulating entities are suvorexant itself and a hydroxy-suvorexant metabolite (M9), though this metabolite is not expected to be pharmacologically active due to reduced orexin receptor binding affinity and limited brain penetration. 1, 6
Suvorexant is primarily eliminated through feces (66%) compared to urine (23%), with a mean half-life of approximately 12 hours. 1