Zolpidem

🧬 Receptor activity

Mechanism of action

Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic substance with a chemical structure that is not related to the structure benzodiazepines, barbiturates, pyrrolopyrazines, pyrazolopyrimidines or other drugs exerting hypnotic effects. It interacts with a _GABA-BZ_ receptor complex and shares various pharmacological properties with the _benzodiazepine_ class of drugs. Subunit binding of the _GABAA_ receptor chloride channel macromolecular complex is thought to lead to the sedative, anticonvulsant, anxiolytic, and myorelaxant drug effects of zolpidem. The main regulatory site of the GABAA receptor complex can be found on its _alpha (α) subunit_ and is called the _benzodiazepine_ (BZ) or _omega (ω)_ receptor. At least three different subtypes of the (ω) receptor have been identified to this date. In contrast to benzodiazepine drugs, which are found to modulate all benzodiazepine receptor subtypes in a non-selective fashion, zolpidem binds the (BZ1) receptor specifically with a potent affinity for the alpha 1/alpha 5 subunits (in vitro). More recent studies suggest that zolpidem binds primarily to the alpha 1, 2, and 3 subunits of the GABA receptor,,, and not the alpha 5 subunit. The (_BZ1_) receptor is found primarily on the Lamina IV of the brain sensorimotor cortical regions, substantia nigra (pars reticulata), cerebellum molecular layer, olfactory bulb, ventral thalamic complex, pons, inferior colliculus, and globus pallidus. Specific and selective binding of zolpidem on the (BZ1) receptor is not considered absolute, however, this binding could potentially explain the relative lack of myorelaxant and anticonvulsant activity in animal studies in addition to the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem at hypnotic doses.

Pharmacodynamics

**Effects on the central nervous system (CNS)** This drug has CNS depressant effects, which may include somnolence, decreased alertness, sedation, drowsiness, dizziness, and other changes in psychomotor function. Due to the above effects, the FDA has recommended an initial dose of zolpidem (immediate-acting) is a single dose of 5 mg for women and a single dose of 5 or 10 mg for men, immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening. Refer to product labeling for detailed information,. **Effects on memory** Controlled studies in adults using objective measures of memory demonstrated no significant evidence of next-day memory impairment after the administration of zolpidem. On the contrary, in a clinical study involving the administration of zolpidem doses of 10 and 20 mg, a marked reduction in a next-morning recall of information relayed to subjects during peak drug effect (90 minutes after dosing) was observed. These subjects experienced a condition known as _anterograde amnesia_. Subjective evidence from adverse event data has suggested that anterograde amnesia may occur after zolpidem administration, mainly at doses above 10 mg. **Effects on psychomotor function** This drug may cause decreased psychomotor performance. Additive psychomotor effects may occur with other drugs that cause depression of psychomotor function, including alcohol. Patients taking zolpidem should be cautioned against participating in hazardous activities or occupations requiring complete mental alertness or motor coordination, including operating machinery or driving a motor vehicle after ingesting the drug. Potential impairment of the performance of the above types of activities may also occur the day after zolpidem ingestion, especially at higher doses and ingestion of the extended-release form,. **Effects on insomnia and sleep stages** Evidence suggests that this drug is associated with minimal rebound insomnia. During clinical trials with patients using zolpidem on an ‘as-needed’ basis, zolpidem use resulted in global improvements in sleep. Zolpidem has been demonstrated to decrease sleep latency (the time it takes to fall asleep) for up to 35 days in controlled clinical studies. In studies measuring the percentage of sleep time spent in each sleep stage, zolpidem has primarily been shown to preserve sleep stages. Sleep time spent in stages 3 and 4 (deep sleep) was measured as similar to placebo with only minor and inconsistent changes in REM (paradoxical) sleep at the recommended dose. **Next-day residual effects** In 2013, the FDA issued a statement warning that patients who take zolpidem extended-release (Ambien CR)―either 6.25 mg or 12.5 mg―should not drive or participate in other activities requiring full mental alertness the day after taking the drug, due to the fact that zolpidem concentrations can remain increased the next day, and impair the ability to perform these activities,. Patients may decrease their risk of next-morning impairment by taking the lowest dose of their insomnia medicine that treats their symptoms, according to the FDA. Specific dosing recommendations for both men and women are included in this statement. This information is also available on product labeling,. **Rebound effects** There was no polysomnographic (objective) evidence of rebound insomnia at normal doses, in studies evaluating sleep on the nights following discontinuation of zolpidem tartrate. Subjective evidence of impaired sleep in the elderly on the first post-treatment night was observed at doses higher than the recommended 5mg dose for elderly patients.

Pharmacokinetics

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