Sedative and Hypnotic Drugs
Sahab Uddin, Rashid Mamunur in Advances in Neuropharmacology, 2020
Orexin-A and orexin-B commonly known as hypocretin-1 and hypocretin-2, respectively, are neuropeptides that have affinity for OX-1 and OX-2 receptors and has pharmacological role on sleep pattern. They play a promoting role in sleep cycle especially wakefulness, metabolism effects, reward, stress, and autonomic function (Roecker et al., 2016). CNS neurons are quiescent during sleep but are active during wakefulness; thus antagonists at orexin receptors enhance the different stages of sleep. This class of drugs is a newly developed class of hypnotic used for the treatment of sleep disorder. Suvorexant, orexin 1 and 2 receptors antagonist was approved by FDA in late 2014 for the treatment of insomnia (Roecker et al., 2016). Its main pharmacological action is to decrease the time to fall asleep and maintain its total duration. The orexin receptor antagonist suvorexant is metabolized by the CYP3A4 enzymes and also it is a substrate of CYP3A4. Its half-life is prolonged by the presence of enzyme inhibitors like ketoconazole, clarithromycin, and verapamil. The drug strength is 10 mg and it is instructed to be taken before sleep. Daytime somnolence and worsening of depression or suicidal ideation are the most common adverse reaction seen with the drug. Its higher dose may disrupt the driving skills of the patients which may lead to road traffic accident. Some newer molecules are undergoing clinical trials (Vermeeren et al., 2015).
Medication effects on sleep
S.R. Pandi-Perumal, Meera Narasimhan, Milton Kramer in Sleep and Psychosomatic Medicine, 2017
Recent studies indicate that the orexin (hypocretin) system that is abnormal in individuals with a diagnosis of narcolepsy is a critical regulator of sleep and wake. Recently, the orexin antagonist, surorexant has been released for the treatment of insomnia associated with daytime arousal.26 Side effects in these clinical trials include sleepiness clinical trials, but only after extensive clinical utilization. Such recent concerns as to the potential effects of insomnia and hypnotics use on falls in the elderly were raised only after decades of the widespread use of generic and easily available medication.27
Clinical drug development for dementia with Lewy bodies: past and present
Published in Expert Opinion on Investigational Drugs, 2019
Garam Lee, Jeffrey Cummings, Boris Decourt, James B. Leverenz, Marwan N. Sabbagh
Modafinil and armodafinil are wake-promoting agents approved for excessive sleepiness associated with narcolepsy and shift work sleep disorder. They have been shown to increase dopamine in the brain by blocking dopamine transporters; however their precise MOA related to sleep/wake regulation is unknown [81]. Interestingly, they are considered to have limited interaction with dopamine receptors, and thus are of interest for excessive daytime somnolence in DLB [81]. An open-label pilot study (NCT01023672) of armodafinil in DLB showed improvements in hypersomnia and wakefulness with reasonable tolerability and no worsening of parkinsonism [81]. Modafinil did not show improvement and exacerbated psychotic symptoms in a small case study [82]. A recent Phase 3 trial of suvorexant showed a benefit in AD patients with insomnia [83]; trials of the dual orexin receptor antagonist class are warranted in DLB [84].
The metabolism of the dual orexin receptor antagonist daridorexant
Published in Xenobiotica, 2023
Alexander Treiber, Stephane Delahaye, Aude Weigel, Päivi Aeänismaa, John Gatfield, Swen Seeland
The work presented herein was performed as part of the preclinical safety assessment of the dual orexin receptor antagonist daridorexant, developed for the treatment of insomnia disorder. The orexin system consists of two G protein-coupled receptors, OX1 and OX2, and two ligand proteins called orexin A and orexin B. Binding of these ligands to OX1 and OX2 controls the awake state during the day, and an overactive orexin system manifests as difficulties in falling and staying asleep. From a drug discovery perspective, the major challenges for a sleep drug are the tailoring of sleep onset and sleep duration in order to minimise the time spent awake in bed, to maintain the sleep effect throughout the entire night and to avoid next-morning residual effects. Physiology-based pharmacokinetic modelling has been used to select daridorexant out of a group of structurally related compounds with proven potency on both target proteins, brain penetration ability and robust effects in animal models of sleep (Treiber et al. 2017; Boss et al. 2020).
Migraine and obesity: what is the real direction of their association?
Published in Expert Review of Neurotherapeutics, 2023
Soodeh Razeghi Jahromi, Fahimeh Martami, Kasra Morad Soltani, Mansoureh Togha
Orexin has been reported to modulate the desire to feed by acting through OXR1 and OXR2 receptors [20]. Central administration of orexin in rats was found to increase food intake [59]. Preclinical and clinical studies also support the role of orexins in pain development [60,61]. In rat pain models, intrathecal administration of OXA showed an anti-hyperalgesic effect [62]. The specificity of the anti-hyperalgesic role of OXA is reflected through its inhibition when pretreated with the orexin receptor antagonist [63]. Moreover, in a human study, an elevated level of OXA was observed in the cerebrospinal fluid of patients with chronic daily headache [64]. Evidence showing an anti-hyperalgesic effect for OXA in animal experiments and increased cerebrospinal fluid levels of OXA among patients with chronic daily headache raises the hypothesis that there may be orexin resistance or receptor dysfunction in chronic headache sufferers.
Related Knowledge Centers
- Insomnia
- Orexin
- Receptor Antagonist
- Sleep Disorder
- Orexin Receptor
- Hypocretin (Orexin) Receptor 1
- Hypocretin (Orexin) Receptor 2
- Daridorexant
- Lemborexant
- Suvorexant