PHARMACOLOGIC TARGETS

Benzodiazepine Receptor Antagonists

This class includes eszopiclone Zaleplon, eszopiclone, and zolpidem.5-10 While they aren’t chemically benzodiazepines but they do interact with benzodiazepine receptors which results in an agonist effect on GABA. They decrease the duration of sleep (the duration it takes for the person to go to sleep after shutting off their light) and are deemed safe for the short-term treatment of insomnia with the onset of sleep.

Eszopiclone and controlled-release zolpidem are approved for the treatment of sleep insomnia.5,8 Zolpidem is available in different dosage forms. In addition, it is available as a sublingual tablet (Intermezzo) and is approved for midnight awakening.11 Benzodiazepine receptor agonists can cause dizziness and drowsiness; they can cause an increase in the impact with other central nerve system (CNS) depressants. Furthermore, various sleep-related disorders have been observed. Patients taking the eszopiclone drug may suffer from dizziness (altered tasting). Rifampin may trigger metabolic changes in benzodiazepine agonists. Buy Zopiclon Online can interact in conjunction with CYP3A4 inhibitors as well as inducers. Cimetidine could inhibit zaleplon’s metabolism, and the potent CYP3A4 inhibitors can reduce the metabolism of Zolpidem.

Benzodiazepines

The benzodiazepine class of drugs connects to benzodiazepine receptors in the post-synaptic GABA neuron at various sites within the CNS and enhances GABA’s inhibitory effect.12 Estazolam, flurazepam, triazolam, temazepam, and Quazepam are hypnotic medications and are typically used to induce and sustain sleep.13-17 Benzodiazepines can reduce the time it takes to sleep, but they differ in the time of onset and the way they work. Physical dependence and tolerance are rapidly developing, so these drugs are not recommended for long-term usage. Sleep-related disorders that are complex have been observed. Beer’s criteria, a guideline developed by the American Geriatrics Society to reduce complications caused by drugs in patients with dementia and their families, don’t recommend benzodiazepines.18 Triazolam is used for sleep-related problems, while temazepam and estazolam treat early morning awakenings. The long-acting drugs (flurazepam and Quazepam) are intended for those with problems with maintaining sleep. Benzodiazepines must be used cautiously in patients suffering from hypercapnia (commonly caused by chronic obstructive pulmonary disorder) and avoided in those with sleep apnea. Anterograde amnesia was reported in patients treated with triazolam. The agents that act long-term can hinder the performance of everyday activities, like driving. They can also cause a fatal overdose when combined with alcohol and opioids.19 There are safer alternatives available.

Histamine Receptor Antagonists

Histamine is a neurotransmitter stimulant that enhances sleep by activating H1 receptors within the cerebral cortex.20 Antihistamines of the first generation, like diphenhydramine, are extremely sedating due to their actions in the H1 receptor. The OTC drugs diphenhydramine and Doxylamine are frequently used to treat insomnia since they are readily available to sufferers. Prescription drugs (e.g., low-dose doxepin) have been identified as suitable for insomnia treatment due to their antihistamine properties.

OTC sleep aids like diphenhydramine and Doxylamine aren’t suggested for treating chronic insomnia.3 Antihistamines may cause CNS depression that can result in the feeling of sedation and also anticholinergic effects. The tolerance to diphenhydramine may develop when the drug is consumed continuously.21 Diphenhydramine can cause a significant “hangover” effect, as confirmed through positron emission tomography.22 The ability to function the next day is a significant problem for elderly patients who self-medicate using these drugs. Patients are often unaware that diphenhydramine is an ingredient of multiple combination products in PM formulations (e.g., acetaminophen/diphenhydramine). Drug interactions can result in an anticholinergic effect or sedation when combined with different CNS depressants. Doxylamine is not recommended for patients who are younger than 12 years old. 

Doxepin with a low dose (Silenor) is licensed to treat sleep-maintenance insomnia. Doxepin (Sinequan) is an antidepressant drug prescribed off-label to treat insomnia in 150 mg-300 mg, taken before bedtime. In a dose lower (3-6 mg), this H1 antagonist can induce hypnosis without significant anticholinergic side effects. Doxepin is not recommended to be taken within 3 hours after a meal. The simultaneous use of cimetidine (inhibitor of CYP2C19, CYP2D6, CYP1A2) is to be avoided.23

Melatonin Receptor Agonists

Two melatonin receptor antagonists can be found: ramelteon as well as Tasimelteon. Ramelteon is recommended for the treatment of insomnia with onset sleep. Ramelteon is an agonist at the Melatonin MT1 as well as MT2 receptors. Melatonin receptor agonists have an effect that is primary in reducing sleep latency. Ramelteon isn’t restricted to use for short periods and does not come with a prescribed drug. Studies comparing it to other treatments are not available. Ramelteon is not a drug that could cause misuse. However, its overall effects on hypnosis are limited.24 The absence of a withdrawal or rebound insomnia was reported. Ramelteon should be taken cautiously when combined with CYP1A2 inhibitors like ciprofloxacin or CYP3A4 inhibitors like fluconazole. Rifampin can be a potent stimulator of the metabolism of ramelteon. Ramelteon-related adverse reactions include complex sleep behavior, higher prolactin, and a lower testosterone level.25

Tasimelteon (Hetlioz) Tasimelteon (Hetlioz) is prescribed to treat sleep-wake disorders (non-24). Non-24 is a chronic circadian rhythm disorder that affects blind people and alters sleep time. Since the light doesn’t reach through the eye, our bodies can’t adjust to the 24-hour dark-light cycle. The dose is 20 mg, given once an hour before bedtime at the same interval each evening. Potent CYP3A4 inhibitors (fluvoxamine) and inducers (rifampin) must be avoided.26

Alternative Sleep Medications

For patients with comorbidities like seizures, depression, and psychotic disorder, insomnia could be treated using antidepressants or antipsychotics.3 Some examples of alternative treatments for sleep disorders are alprazolam, Clonidine, amitriptyline mirtazapine, trazodone, and quetiapine. There is no evidence to support the use of these drugs for insomnia unrelated to comorbidity. Quetiapine is one of the frequently prescribed antipsychotics used to treat sleep disorders. It is interesting to note that trazodone is one of the most commonly utilized sedatives, but it has the slightest evidence.27 For mirtazapine to be used as a sedative-hypnotic dosage, it should be administered at 7.5 mg to 15 mg before the time of bed, which gives the highest affinity to anticholinergic effects. Read more: Buying Zopiclon Online

Orexin Receptor Antagonists

Orexins (formerly called hypocretins) are neuropeptides in the body that activate orexin receptors 1 and 2 located in the hypothalamic lateral region within the brain.29 Orexin receptor stimulation is mostly excitatory and produces a range of neurotransmitters responsible for maintaining wakefulness, arousal, and appetite. Currently, three orexin receptor antagonists–suvorexant, lemborexant, and daridorexant–are FDA approved for the treatment of insomnia (TABLE 2).30-32 Several orexin receptor antagonists are being investigated for insomnia in Alzheimer’s disease, appetite suppression in obesity, and several mental health conditions, including depression, drug dependence, panic disorder, and posttraumatic stress disorder.

Traditional Herbal Remedies

Certain supplements in the diet are promoted to aid sleep. Examples include melatonin valerian root German chamomile, kava L-tryptophan (L-tryptophan), little leaf linden (Tilia) and vervain (verbena), and Melissa (lemon balm), as well as skullcap (Scutellaria). These aren’t regulated as such, and the purity of the ingredients and the clinical effects will vary. There needs to be more research supporting the use of herbal remedies. Even though they are considered safe, research on interactions between prescription drugs has yet to be found to be lacking.3 Melatonin, the most commonly used treatment for insomnia, is offered in various dosage forms and is a good choice when used in a short-term manner; however, it is not recommended for continuous insomnia. To ensure optimal performance, melatonin is dosed from three to five mg and is best taken at least a couple of hours before the time you go to bed. Melatonin’s long-term safety isn’t known.