Zolpidem effects

A class of sedative/hypnotic type drug that exert their effects through the benzodiazepine binding site on GABAa receptors. The class consists both of molecules that contain the benzodiazepine moiety, for example diazepam, lorazepam and flunitrazepam, and the newer, non-benzodiazepine compounds such as zolpidem, zopiclone, indiplon and zaleplon. BzRAs are primarily used for the treatment of anxiety, insomnia and to elicit varying levels of sedation. The wide selection of compounds currently available affords the prescribing clinician extensive options in terms of relative efficacies and durations of action. 

Limited results from clinical laboratory evaluations suggested that the GABAj l agonists zaleplon (Rush et al. 1999b) and Zolpidem (Rush et al. 1999a) produce effects that are consistent with abuse potential comparable to that of the benzodiazepine triazolam. The reported incidence of dependence on Zolpidem in the medical literature is low, compared with that for benzodiazepines, and is characterized by use of high doses, often in individuals with a history of substance abuse (Hajak et al. 2003 Vartzopoulos et al. 2000). 

Ator NA Relation between discriminative and reinforcing effects of midazolam, pentobarbital, chlordiazepoxide, Zolpidem, and imidazenil in baboons. Psychopharmacology (Berl) 163 477 87, 2002... 

Sanna E, Busonero F, Talani G, et al Comparison of the effects of zaleplom, zolpidem, and triazolam at various GABA, receptor subtypes. Eur J Pharmacol 431 103— 110, 2002... 

Voderholzer U, Riemann D, Hornyak M, et al A double-blind, randomized and placebo-controlled study on the polysomnographic withdrawal effects of zopiclone, zolpidem and triazolam in healthy subjects. Eur Arch Psychiatry Clin Neurosci 251 117-123, 2001... 

Walker BM, Ettenberg A The effects of alprazolam on conditioned place preferences produced by intravenous heroin. Pharmacol Biochem Behav 75 75 80, 2003 Weens EM, Griffiths RR Zolpidem self-injection with concurrent physical dependence under conditions of long-term continuous availability in baboons. Behav Pharmacol 9 285—297, 1998... 

Zolpidem (Ambien ) Zolpidem CR (AmbienCR ) 2-2.6 6-8 Perhaps longer 5-10 6.25-12.5 Oxidation Short-moderate duration, no effects on sleep architecture... 

Declerck A. C., Ruwe F., O Hanlon J. F., Wauquier A. (1992). Effects of Zolpidem and fhmitrazepam on nocturnal sleep of women subjectively complaining of insomnia. Psychopharmacology 106, 497-501. 

Lund R., Riither E., Wober W Hippius, H. (1988). Effects of Zolpidem (10 and 20 mg), lormetazepam, triazolam and placebo on night sleep and residual effects during the day. In Sauvanet J. P., Langer S. Z., Morselli P. L (eds.), Imidazopyridines in Sleep Disorders. New York, NY Raven Press, pp. 193-203. 

Zolpidem, chemically unrelated to benzodiazepines or barbiturates, acts selectively at the y-aminobutyric acidA (GABAA)-receptor and has minimal anxiolytic and no muscle relaxant or anticonvulsant effects. It is comparable in effectiveness to benzodiazepine hypnotics, and it has little effect on sleep stages. Its duration is approximately 6 to 8 hours, and it is metabolized to inactive metabolites. Common side effects are drowsiness, amnesia, dizziness, headache, and GI complaints. Rebound effects when discontinued and tolerance with prolonged use are minimal, but theoretical concerns about abuse exist. It appears to have minimal effects on next-day psychomotor performance. The usual dose is 10 mg (5 mg in the elderly or those with liver impairment), which can be increased up to 20 mg nightly. Cases of psychotic reactions and sleep-eating have been reported. 

Herzog C, Gahndi C, Bhattacharya P, Walsh TJ. 2000. Effects of intraseptal zolpidem and chlordiazepoxide on spatial working memory and high-afhnity choline uptake in the hippocampus. Neurobiology of Learning and Memory 73 168-179. 

One principal difference between the medications is half-life, that is, the time required to metabolize 50% of the compound present in the body. Zolpidem has a half-life of 1.4-4.5 honrs, zaleplon has a half-life of 0.9-1.1 hours, and eszopiclone has a half-life of abont 6 honrs. The key is the markedly shorter half-lives that are displayed by many other sedative-hypnotics, as shown in Eigure 9.1. Only eszopiclone has been shown effective for the long-term (np to 6 months) treatment of chronic insomnia. 

Zolpidem is an imidazopyridine but not a benzodiazepine however, it acts on the same receptors as benzodiazepines. Zolpidem has a short duration of action and is indicated for patients who have difficulty sleeping. It does not have any hangover effects. The dose of Zolpidem should be reduced in patients with hepatic impairment and it should be avoided in cases of severe hepatic impairment. 

Downward dosage adjustment may be necessary when zolpidem is administered with agents having known CNS-depressant effects because of the potentially additive effects. 

Elderly or debilitated patients, hepatic function Impairments mg of the immediate-release tablet or 6.25 mg of the extended-release tablet taken immediately before bedtime. Elderly or debilitated patients may be especially sensitive to the effects of zolpidem. 

CNS-depressant effects Zolpidem, like other sedative/hypnotic drugs, has CNS-depressant effects. Because of the rapid onset of action, only ingest immediately prior to going to bed. Zolpidem had additive effects when combined with alcohol therefore, do not take with alcohol. 

Respiratory depression Although preliminary studies did not reveal respiratory depressant effects at hypnotic doses in healthy individuals, observe caution if zolpidem is prescribed to patients with compromised respiratory function, since sedative/hypnotics have the capacity to depress respiratory drive. 

Rifampin is known to induce the hepatic microsomal enzymes that metabolize various drugs such as acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta blockers, chloramphenicol, clofibrate, oral contraceptives, corticosteroids, cyclosporine, disopyramide, estrogens, hydantoins, mexiletine, quinidine, sulfones, sulfonylureas, theophyllines, tocainide, verapamil, digoxin, enalapril, morphine, nifedipine, ondansetron, progestins, protease inhibitors, buspirone, delavirdine, doxycycline, fluoroquinolones, losartan, macrolides, sulfonylureas, tacrolimus, thyroid hormones, TCAs, zolpidem, zidovudine, and ketoconazole. The therapeutic effects of these drugs may be decreased. 

Zolpidem (1) is an effective hypnotic agent indicated for the short-term treatment of insomnia. Zolpidem interacts with the GABAa receptor, and its pharmacological effect is blocked by the benzodiazepine-receptor antagonist fiumazenil (Sanger and Depoortere, 1998). Zolpidem displaces benzodiazepines more selectively from the cerebellum than the hippocampus or spinal cord, consistent with preferential interaction with the ajGABAA receptor subtype (sometimes referred to as the benzodiazepine coi receptor). Studies... 

In chnical trials, zolpidem shortened sleep latency, improved the quahty of sleep, and accelerated the restoration of normal sleep patterns (Lee, 2004). In insomniac patients it increased the amount of slow wave, restorative sleep as seen in normal sleepers. Zolpidem has high oral bioavailability (70%), a short duration of action (tj /2 = 2 h), and is relatively highly bound to plasma proteins (92%). The recommended dose is generally 10 mg/day as needed. Zolpidem is extensively metabolized, mainly by CYP3A4 but also by CYP1A2 and CYP2C9, and its major metabolites do not appear to have pharmacological activity. It has minimal daytime residual effects, and a low risk for tolerance and abuse. The safety profile showed a low incidence of adverse events, close to that observed with placebo. The medicine is available in over 80 countries. 

Related hypnotics that also act at benzodiazepine receptors are the newer agents zolpidem, a imida-zopyridine, zaleplon a pyrazolopyrimidine and the cyclopyrrolone zopiclone. Zopiclone might have a role for the treatment of benzodiazepine addiction. In patients in whom zopiclone was substituted for a benzodiazepine for 1 month and then itself abmptly terminated, improved sleep was reported during the zopiclone treatment, and withdrawal effects were absent on discontinuation of zopiclone. A series of non-sedating anxiolytic drugs derived from the same structural families as the above mentioned nonbenzodiazepines, have been developed, such as alpi-dem and pagoclone. 

Among ai-, a2- and as-point-mutated mice, only the ai(HlOlR) mutants were resistant to the depression of motor activity by diazepam and zolpidem (Rudolph et al. 1999 Low et al. 2000 Crestani et al. 2000). This effect was specific for ligands of the benzodiazepine site, since pentobarbital or a neurosteroid remained as effective in ai(HlOlR) mice as in wild-type mice in inducing sedation. An ai(HlOlR) mouse line was also generated by McKernan et al. (2000), confirming that sedation is finked to ai GABAa receptors and differs mechanistically from the anxiolytic action of benzodiazepines. 

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