Zolpidem
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Zolpidem
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| Systematic (IUPAC) name | |
| N,N,6-trimethyl-2-(4-methylphenyl)- imidazo(1,2-a)pyridine-3-acetamide |
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| Identifiers | |
| CAS number | 82626-48-0 |
| ATC code | N05CF02 |
| PubChem | 5732 |
| DrugBank | APRD00095 |
| Chemical data | |
| Formula | C19H21N3O |
| Mol. weight | 307.395 g/mol |
| Pharmacokinetic data | |
| Bioavailability | 92% bound in plasma |
| Metabolism | Hepatic |
| Half life | 2 to 2.6 hours |
| Excretion | Renal |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status |
DEA Schedule IV (USA) , |
| Routes | Oral |
Zolpidem is a prescription short-acting nonbenzodiazepine hypnotic that potentiates gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, by binding to benzodiazepine type 1 (BZ1) receptors. Zolpidem is used for the short-term treatment of insomnia. It works quickly (usually within 15 minutes) and has a short half-life (2-3 hours). Some trade names of zolpidem are Ambien®,[1] Stilnox®,[2] Stilnoct®, Hypnogen®, Zolfresh®, or Myslee®.[3] Its hypnotic effects are similar to those of the benzodiazepine class of drugs, but it is actually classified as an imidazopyridine. Flumazenil, which is used for benzodiazepine overdose, can also reverse zolpidem's sedative/hypnotic effects. As an anticonvulsant and muscle relaxant, the beneficial effects start to emerge at 10 and 20 times the dose required for sedation, respectively.[4] For that reason, it has never been approved for either muscle relaxation or seizure prevention. Such drastically increased doses are more inclined to induce one or more negative side effects, including hallucinations and/or amnesia. (See below.)
The patent in the United States on zolpidem is held by the French pharmaceutical corporation Sanofi-Aventis. The patent 4382938, as listed on the FDA Electronic Orange Book site is due to expire in October 21, 2006. As of September 16, 2006, no six-month extension is listed in the Orange Book as having been granted.[5][6] Zolpidem is available from several generic manufacturers in the UK, as generic from Sandoz in South Africa, as well as from other manufacturers such as Ratiopharm.
Recently, zolpidem has been cited in various medical reports mainly in the United Kingdom as waking persistent vegetative state (PVS) patients, and dramatically improving the conditions of people with brain injuries. This use of zolpidem has been reported originally in the South African Medical Journal [7] and in the BBC[8] and The Guardian.[9][10]
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[edit] Uses
Zolpidem is approved for the short-term (usually two to six weeks) treatment of insomnia, and it has been studied for nightly use up to six months in a single-blind, open-label trial published in 1991,[11] an open-label study lasting 180 days published in 1992 (with continued efficacy in patients who had kept taking it as of 180 days after the end of the trial),[12] and in an open-label trial lasting 179 days published in 1993.[13]
The United States Air Force uses zolpidem, under trade name Ambien®, as "no-go pills" to help pilots sleep after a mission; another drug used for the same purpose is temazepam (Restoril®).[14] (Cf. the "go-pills" amphetamine served under the name Dexedrine® act as a stimulant for the same pilots, ostensibly to reverse the effects of the "no-go pills," or its recent modafinil (Provigil®) replacement).[15]
Zolpidem is also used off-label to treat restless leg syndrome and, as is the case with many prescription sedative/hypnotic drugs, it is sometimes used by stimulant users to "come down" after the use of stimulants such as methamphetamine, cocaine, MDMA (ecstasy), or amphetamine.[16]
Recently, the drug has been suggested to have positive effects for sufferers of persistent vegetative state.
[edit] Mechanism of action
In 1990, Pritchett and Seeburg noted that zolpidem binds with high affinity to the α1, with medium affinity to the α2, α3-GABAA receptor subunits, and found that it had no affinity for the α5 subunit. Two years later, zolpidem was noted to have a high affinity for ω1; benzodiazepine receptors, a low affinity for ω2 and a very low affintity for ω3, respectively by Ruano et al in 1992. In other words, it has the highest affinity for ω1 binding sites on α-1GABAA receptor subunits, and it is this that mediates its sedative and weak anticonvulsant properties.
[edit] Recreational use and abuse
When Ambien abuse occurs, people may take it orally, crush and snort it, or cook it for an intravenous injection. Ambien abuse can occur when used longer than recommended (no longer than a few weeks), at high doses (more than the usual 10mg), and in people who have been dependent on other drugs or alcohol in the past. Ambien effects can increase and intensify if mixed with other substances like alcohol.
Recreational use of this drug (specifically the Ambien® brand) is becoming more common in young people. Recreational users claim that "fighting" the effects of the drug by forcing themselves to stay awake will sometimes cause vivid visuals and a body high (see side-effects below.) Some recreational users report decreased anxiety, and even mild to moderate euphoria, as well as moderate perceptual changes and slight visual distortions, but lacking hallucinogenic entities. The likelihood of experiencing any of these effects seems to be completely arbitrary regardless of the size of the dose. Audiotory disortions have been reported in some users. The drug can make them believe that the room they are in is fully crowded, while in reality it is empty.
To counteract recreational use of zolpidem in the United States, Sanofi-Aventis coats their pills with a flexible plastic-like coating, which sticks to unpulverized "bumps" or "chunks" and can be difficult to remove, thus hindering the process of insufflation; although this a relatively minor obstacle to a serious drug abuser.
[edit] Side-effects
Side effects at any dose may include:
- Anterograde amnesia
- Hallucinations, through all physical senses, of varying intensity
- Delusions
- Ataxia or poor motor coordination, difficulty maintaining balance
- Euphoria and/or dysphoria
- Increased appetite
- Increased libido
- Impaired judgment and reasoning
- Uninhibited extroversion in social or interpersonal settings
- Increased impulsivity
- When stopped rebound insomnia may occur
Some users take zolpidem recreationally for these side effects. However, it may be less common than benzodiazepine abuse. In the United States, recreational use may be less common than in countries where the drug is available as a less expensive generic. Zolpidem can become addictive if taken for extended periods of time, due to dependence on its ability to put one to sleep or to the euphoria it can sometimes produce. Like most addictive drugs, a tolerance in the zolpidem user develops and increases all the more quickly the longer she or he has been regularly taking it. Under the influence of the drug it is common to take more zolpidem than is necessary due to either forgetting that one has already taken a pill (elderly users are particularly at risk here), or knowingly taking more than the prescribed dosage. Users with a predilection for abuse are advised to keep additional zolpidem in a safe place that is unlikely to be remembered or accessed while intoxicated to avoid this risk. A trustworthy friend or relative is the best defense if such people are available; otherwise, a box or cupboard locked with a combination padlock is a good defense against this tendency, as the abovementioned side-effects can easily prevent a user from operating such a lock while under the drug's influence.
The recent release of Ambien CR® (zolpidem tartrate extended release) in the United States renewed interest in the drug among recreational drug users.
Before a user becomes fully acclimated to these effects (or if the user does not become acclimated), these symptoms can be severe enough to be deemed as drug-induced psychosis. Incidentally, antipsychotics like ziprasidone (Geodon®) or quetiapine (Seroquel®) may be prescribed alongside zolpidem to both combat these side effects and to aid in sleep-induction, as both of them contain mild hypnotic properties. However, because some antidepressants are known for being mildly sedating (i.e., paroxetine), it may be inadvisable to use zolpidem and an antidepressant simultaneously.
[edit] See also
[edit] References
- ^ Ambien.com (2004). AMBIEN® Prescribing Information. Information About a Short-term Treatment for Insomnia - Ambien.com Home Page for Health-care Professionals. Sanofi-Synthelabo Inc. New York, NY 10016. Retrieved on 2005-06-27.
- ^ STILNOX (zolpidem tartrate) PRODUCT INFORMATION Sanofi-Synthelabo Australia Pty Limited. 15 April 2004
- ^ sanofi-aventis : Drugs and Products - CNS - Stilnox®/Ambien®/Myslee® (2006-11-07). Retrieved on 2006-11-22.
- ^ Depoortere H., Zivkovic B., Lloyd K.G., Sanger D.J., Perrault G., Langer S.Z., Bartholini G. (1986). Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects. Journal of Pharmacology and Experimental Therapeutics 237:649-58. PMID 2871178
- ^ Kang, Peter. "Ambien Patent Extension Seen Positive For Pfizer, Neurocrine", Forbes.com, 2006-04-10. Retrieved on 2006-11-22.
- ^ Patent and Exclusivity Search Results. Food and Drug Administration.
- ^ S. Afr. Med. J. (January 2000). Extraordinary arousal from semi-comatose state on zolpidem. A case report.. National Center for Biotechnology Information (NCBI). Retrieved on 2006-11-22.
- ^ "Pill 'reverses' vegetative state", BBC, 2006-05-23. Retrieved on 2006-11-20.
- ^ Pidd, Helen. "Reborn", the Guardian, 2006-09-12. Retrieved on 2006-11-20.
- ^ "Judge rejects right-to-die plea by family", The Guardian, 2006-11-20. Retrieved on 2006-11-20.
- ^ Schlich D., L'Heritier C., Coquelin J.P., Attali P., Kryrein H.J. (1991) Long-term treatment of insomnia with zolpidem: a multicentre general practitioner study of 107 patients. J. Int. Med. Res. 19:271-9. PMID 1670039
- ^ Maarek L., Cramer P., Attali P., Coquelin J.P., Morselli P.L. (1992). The safety and efficacy of zolpidem in insomniac patients: a long-term open study in general practice. J. Int. Med. Res. 20:162-70. PMID 1521672
- ^ Kummer J., Guendel L., Linden J., Eich F.X., Attali P., Coquelin J.P., Kyrein H.J. (1993). Long-term polysomnographic study of the efficacy and safety of zolpidem in elderly psychiatric in-patients with insomnia. J. Int. Med. Res. 21:171-84. PMID 8112475
- ^ Caldwell J.A., Caldwell J.L. (2005). Fatigue in military aviation: an overview of US military-approved pharmacological countermeasures. Aviation, Space, and Environmental Medicine 76:C39-51. PMID 16018329
- ^ see Caldwell et al., 1993.
- ^ Evidente, Virgilio Gerald H., Caviness, John N., and Adler, Charles H. (2003). Case Studies in Movement Disorders. Seminars in Neurology 23:277-284. Thieme Medical Publishers. 26 Jan 2004. Medscape Fulltext Thieme Fulltext PMID 14722823
[edit] Notes
- ↑ Pritchett DB, Seeburg PH. "Gamma-aminobutyric acidA receptor alpha 5-subunit creates novel type II benzodiazepine receptor pharmacology." Journal of Neurochemistry. 1990 May;54(5):1802-4. PMID 2157817
- ↑ Ruano D, Vizuete M, Cano J, Machado A, Vitorica J. "Heterogeneity in the allosteric interaction between the gamma-aminobutyric acid (GABA) binding site and three different benzodiazepine binding sites of the GABAA/benzodiazepine receptor complex in the rat nervous system." Journal of Neurochemistry. 1992 Feb;58(2):485-93. PMID 1309562
- ↑ Pidd, Helen. "Reborn." Guardian Unlimited. 2006 Sep 12. Fulltext
- ↑ Crestani F, Martin JR, Mohler H, Rudolph U. "Mechanism of action of the hypnotic zolpidem in vivo." British Journal of Pharmacology. 2000 Dec;131(7):1251-4. PMID 11090095 Fulltext
- ↑ Angelettie M.S.W., Lisa. "Ambien Abuse" Fulltext
[edit] External links
- Erowid Zolpidem (Ambien) Vault
- Ambien® CIV (zolpidem tartrate) at the NIH DailyMed website
