Zopiclone

Zopiclone is a hypnotic agent belonging to the cyclopyrrolone class of psychotherapeutic agents.

It rapidly initiates and sustains sleep without reduction of total REM sleep and with preservation of slow wave sleep. Negligible residual effects are seen the following morning. Its pharmacological properties include hypnotic, sedative, anxiolytic, anticonvulsant and muscle-relaxant actions. These are related to its high affinity and specific agonist action at central receptors belonging to the ‘GABA’ macromolecular receptor complex modulating the opening of the chloride ion channel. However, it has been shown that zopiclone and other cyclopyrrolones act on a different site to those of benzodiazepines including different conformational changes in the receptor complex.

Absorption

Zopiclone is absorbed rapidly. Peak concentrations are reached within 1.5–2 hours and they are approximately 30 ng/ml and 60 ng/ml after administration of 3.75 mg and 7.5 mg respectively. Absorption is not modified by gender, food or repetition of doses.

Distribution

The product is rapidly distributed from the vascular compartment. Plasma protein binding is weak (approximately 45%) and non-saturable. There is very little risk of drug interactions due to protein binding. The volume of distribution is 91.8–104.6 L.

At doses between 3.75–15 mg, plasma clearance does not depend on dose. The elimination half-life is approximately 5 hours. After repeated administration, there is no accumulation, and inter-individual variations appear to be very small.

Metabolism

Zopiclone is exensively metabolised in humans to two major metabolites, N-oxide zopiclone (pharmacologically active in animals) and N-desmethyl zopiclone (pharmacologically inactive in animals). An in-vitro study indicates that cytochrome P450 (CYP) 3A4 is the major isoenzyme involved in the metabolism of zopiclone to both metabolites, and that CYP2C8 is also involved with N-desmethyl zopiclone formation. Their apparent half-lives (evaluated from the urinary data) are approximately 4.5 hours and 1.5 hours respectively. No significant accumulation is seen on repeated dosing (15 mg) for 14 days. In animals, no enzyme induction has been observed even at high doses.

Excretion

The low renal clearance value of unchanged zopiclone (mean 8.4 ml/min) compared with the plasma clearance (232 ml/min) indicates that zopiclone clearance is mainly metabolic. The product is eliminated by the urinary route (approximately 80%) in the form of free metabolites (n-oxide and n-desmethyl derivatives) and in the faeces (approximately 16%).

Special patient groups

In elderly patients, notwithstanding a slight decrease in hepatic metabolism and lengthening of elimination half-life to approximately 7 hours, various studies have shown no plasma accumulation of drug substance on repeated dosing.

In renal insufficiency, no accumulation of zopiclone or of its metabolites has been detected after prolonged administration. Zopiclone crosses dialysis membranes.

In cirrhotic patients, the plasma clearance of zopiclone is clearly reduced by the slowing of the desmethylation process, dosage will therefore have to be modified in these patients.