Eszopiclone Hypnotic [3336

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Country of origin Originator First introduction Introduced by Trade name CAS registry no Molecular weight

France Aventis US

Sepracor Lunesta 138729-47-2 388.81

Eszopiclone is a non-benzodiazepine hypnotic agent indicated for the treatment of insomnia to induce sleep and for sleep maintenance. It has similar pharmacokinetic and pharmacodynamic parameters as the previously marketed non-benzodiazepine hypnotics zolpidem and zaleplon. However, unlike its predecessors, eszopiclone is not restricted to short-term treatment of insomnia. Clinical studies of up to 6 months of use show that patients do not develop tolerance to its effect. Eszopiclone is the (S)-enantiomer of zopiclone, which has been marketed as the racemic mixture in Europe for almost 20 years. These agents belong to the cyclopyrrolone class of drugs that act as agonists at the type A GABA receptor. Eszopiclone has approximately 50-fold higher binding affinity than its antipode (R)-zopiclone for GABA-A receptor (IC50 = 21 and 1130 nM, respectively). In addition, the two enantiomers exhibit significant differences in their pharmacokinetic parameters and in vivo efficacy. In healthy volunteers, eszopiclone has 2-fold higher Cmax and 2-fold greater elimination half-life than the (R)-enantiomer. In assays for GABA-A mediated effects in monkeys, 0.1-10 mg/kg eszopiclone effectively substituted for the ben-zodiazepine midozalam, showing > 80% midozalam-appropriate response, as compared with only a 45% efficacy for 100mg/kg dose of the (R)-enantiomer. Eszopiclone is rapidly absorbed from the intestinal tract, with peak plasma concentrations occurring one hour after administration. Concomitant consumption of a high-fat meal may reduce the Cmax, but does not alter the area under the curve.

Approximately, 55% of eszopiclone is bound to plasma proteins. Metabolism takes place in the liver through oxidation and demethylation by CYP3A4 and CYP2E1. The primary metabolites are (S)-zopiclone-N-oxide and N-desmethyl-(S)-zopiclone; the latter compound binds to GABA receptor with significantly lower potency than eszopiclone. (S)-zopiclone-N-oxide is inactive. The elimination half-life of eszopiclone is 6h. Approximately 75% of an oral dose is excreted as a combination of unchanged eszopiclone and metabolites in urine. Less than 10% is excreted unchanged. The recommended daily dosage of eszopiclone is 2 mg for sleep induction and 3 mg for sleep maintenance in adults. The recommended dose for elderly patients is 1mg for sleep induction and 2mg for sleep maintenance. Eszopiclone's efficacy in reducing sleep latency and improving sleep maintenance was established in 6 placebo-controlled trials of patients (n — 2100, aged 18-86 years) with chronic and transient insomnia. Elderly patients (n — 523) were studied in 2 of these trials. The efficacy read-outs included objective measurement of wake time after sleep onset (WAS) and subjective measurement of total sleep time. Across all studies, eszopiclone significantly decreased sleep latency and improved measures of sleep maintenance. The two most frequent adverse events associated with eszopiclone treatment are unpleasant taste and headache. Other less frequent side effects include somnolence, dry mouth, and nausea.

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