Zopim Mechanism of Action

Pharmacology: Pharmacodynamics: Subunit modulation of the GABAa receptor chloride channel macromolecular complex is hypothesized to be responsible for sedative, anticonvulsant, anxiolytic, and myorelaxant drug properties. The major modulatory site of the GABA_a receptor complex is located on its alpha subunit and is referred to as the benzodiazepine (BZ) or receptor. At least three subtypes of the receptor have been identified.
While zolpidem is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines. In contrast to the benzodiazepines, which non-selectively bind to and activate all three omega receptor subtypes, zolpidem in vitro binds the receptor preferentially. The receptor is found primarily on the Lamina IV of the sensorimotor cortical regions, substantia nigra (pars reticulata), cerebellum molecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. This selective binding of zolpidem on the receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses.
Pharmacokinetics: The pharmacokinetic profile of Zolpidem Hemitartrate is characterized by rapid absorption from the GI tract and a short elimination half-life (T_½) in healthy subjects. In a single-dose crossover study in 45 healthy subjects administered 5 and 10 mg Zolpidem Hemitartrate tablets, the mean peak concentrations (C_max) were 59 (range: 29 to 113) and 121(range: 58 to 272) ng/ml, respectively, occurring at a mean time (T_max) of 1.6 hours for both. The mean Zolpidem Hemitartrate elimination half-life was 2.6 (range: 1.4 to 4.5) and 2.5 (range: 1.4 to 3.8) hours, for the 5 and 10 mg tablets, respectively. Zolpidem Hemitartrate is converted to inactive metabolites that are eliminated primarily by renal excretion. Zolpidem Hemitartrate demonstrated linear kinetics in the dose range of 5 to 20 mg. Total protein binding was found to be 92.5±0.1% and remained constant, independent of concentration between 40 and 790 ng/ml. Zolpidem did not accumulate in young adults following nightly dosing with 20 mg Zolpidem Hemitartrate tablets for 2 weeks.
A food-effect study in 30 healthy male volunteers compared the pharmacokinetics of Zolpidem Hemitartrate 10 mg when administered while fasting or 20 minutes after a meal. Results demonstrated that with food, mean AUC and C_max were decreased by 15% and 25% respectively, while mean T_max was prolonged by 60% (from 1.4 to 2.2 hr). The half-life remained unchanged. These results suggest that, for faster sleep onset, Zolpidem Hemitartrate should not be administered with or immediately after a meal.
In the elderly, the dose for Zolpidem Hemitartrate should be 5 mg. This recommendation is based on several studies in which the mean C_max, T_½, and AUC were significantly increased when compared to results in young adults. In one study of eight elderly subjects (>70 years), the means for C_max, T_½, and AUC significantly increased by 50% (255 vs 284 ng/ml), 32% (2.2 vs 2.9 hr), and 64% (955 vs 1,562 ng·hr/ml), respectively, ascompared to younger adults (20 to 40 years) following a single 20 mg oral Zolpidem dose. Zolpidem Hemitartrate did not accumulate in elderly subjects following nightly oral dosing of 10 mg for 1 week.