Ramelteon

Absorption

Rapid, total absorption is at least 84%.

Description

Unlike most treatments of insomnia that target the GABA (g-aminobutyric acid) receptor complex, ramelteon is an agonist of the melatonin receptor. In particular, it has high selectivity for the MT₁ and MT₂ subtypes, which have been implicated in the maintenance of circadian rhythms, over the MT₃ receptor responsible for other melatonin functions. Its lack of affinity for not only the GABA receptor complex but also neurotransmitter, dopaminerigic, opiate, and benzodiazepine receptors suggests an improved safety profile devoid of the abuse potential of the hypnotic drugs that target these receptors. As such, ramelteon is not a scheduled drug. Primary metabolites include hydroxylation and oxidation to carbonyl species with secondary metabolites resulting from glucuronidation. Since CYP1A2 is the major isozyme involved in the hepatic metabolism of ramelteon, it should not be taken in combination with strong CYP1A2 inhibitors, such as fluvoxamine. Co-administration with either ketoconazole (a CYP3A4 inhibitor) or fluconazole (a potent CYP2C9 inhibitor) resulted in significant increases in AUC and C_max, but the extensive metabolism and highly variable plasma concentrations of ramelteon precluded the need for dose modification. The package insert, however, cautions patients about co-administration with potent CYP3A4 and CYP2C9 inhibitors. Based on the result of the clinical trials, the recommended dose of ramelteon is 8mg taken within 30 min of going to bed. In addition to the precaution of co-administration with CYP inhibitors, it should not be used in patients with severe hepatic impairment. The adverse events, observed in 5% of patients in clinical studies, were somnolence, dizziness, nausea, fatigue, headache, and insomnia.

The Uses of Ramelteon

Melatonin MT1/MT2 receptor agonist. Sedative, hypnotic

What are the applications of Application

Ramelteon is a melatonin MT1/MT2 receptor agonist

Indications

For the treatment of insomnia characterized by difficulty with sleep onset.

Background

Ramelteon is the first in a new class of sleep agents that selectively binds to the melatonin receptors in the suprachiasmatic nucleus (SCN). It is used for insomnia, particularly delayed sleep onset. Ramelteon has not been shown to produce dependence and has shown no potential for abuse.

Pharmacokinetics

Ramelteon is the first selective melatonin agonist. It works by mimicking melatonin (MT), a naturally occuring hormone that is produced during the sleep period and thought to be responsible for the regulation of circadian rhythm underlying the normal sleep-wake cycle. Ramelteon has a high affinity for the MT1 and MT2 receptors. The MT1 and MT2 receptors are located in the brain's suprachiasmatic nuclei (SCN),which is known as the body's "master clock" because it regulates the 24-hour sleep-wake cycle. Ramelteon has an active metabolite that is less potent but circulates in higher concentrations than the parent compound. The metabolite also has weak affinity for the 5HT2b receptor.

Metabolism

Hepatic