Zolpidem

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Zolpidem
Systematic (IUPAC) name
N,N,6-trimethyl-2-(4-methylphenyl)- imidazo(1,2-a)pyridine-3-acetamide
Identifiers
CAS number	82626-48-0
ATC code	N05CF02
PubChem	5732
DrugBank	APRD00095
Chemical data
Formula	C19H21N3O
Mol. mass	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.	B3 (AUS) B (USA)
Legal status	DEA Schedule IV (USA) , Class C / POM (UK)
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, and 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 German-French pharmaceutical corporation Sanofi-Aventis. The patent 4382938 was due to expire on October 21, 2006 but, as listed on the FDA Electronic Orange book site, was granted a six-month extension.^[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^{[7][8][9][10][11]}.

Contents 1 Uses 2 Mechanism of action 3 Recreational use and abuse 4 Side-effects 5 See also 6 References 7 Notes 8 External links

[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,^[12] 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),^[13] and in an open-label trial lasting 179 days published in 1993.^[14]

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).^[15] (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).^[16]

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.^[17]

Recently, the drug has been suggested to have positive effects for sufferers of persistent vegetative state^[7]. Results from phase IIa trials are expected in June 2007. The trials are being conducted by Regen Therapeutics of the UK, who have a patent pending on this new use for Zolpidem.

[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-GABA_A receptor subunits, and found that it had no affinity for the α₅ subunit.^[1] 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.^[2] In other words, it has the highest affinity for ω₁ binding sites on α-₁GABA_A receptor subunits, and it is this that mediates its sedative and weak anticonvulsant properties.^[3]

[edit] Recreational use and abuse

When zolpidem abuse occurs, people may take it orally, crush and snort it, or cook it for an intravenous injection. Zolpidem 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. Zolpidem 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.) However, in some people who are already in an anxious state, or suffer from neurosis it is not hard, if a struggle at all, to fight the side effect of sedation, experiencing the side-effect of euphoria more than the sedation itself. Some recreational users report decreased anxiety, and even mild to moderate euphoria, as well as perceptual changes, visual distortions, and sometimes hallucinations. Auditory distortions 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 is 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 (or in countries, such as the UK, where prescriptions are free or heavily subsidised). It is not yet known whether there is a link between the cost and availability of zolpidem and the level at which it is abused. 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 the user 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 above-mentioned 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 HCl), it may be inadvisable to use zolpidem and an antidepressant simultaneously. Some zolpidem users (especially those suffering from chronic insomnia), however, commonly use these drug combination due to the relative ease with which the user gains no benefit from one or the others of these drugs, while both together can assist sufferers of insomnia in getting to sleep.

Some users have reported unexplained sleepwalking while using Ambien, and a few have reported driving, binge eating, sleep talking, and performing other daily tasks while sleeping. The sleepwalker can sometimes perform these tasks as normally as they might if they were awake. They can sometimes carry on complex conversations and respond appropriately to questions or statements so much so that the observer may believe the sleepwalker to be awake. This is similar to, but unlike typical sleep talking, which can usually be identified easily and is characterised by incoherent speech that often has no relevance to the situation or that is so disorganised as to be completely unintelligible. These statements bare a strong resemblence to that of word salad, one of many symptoms commonly seen in individuals suffering from schizophrenia. A person under the influence of this medication may seem fully aware of their environment even though they are still asleep. This can bring about concerns for the safety of the sleep walker and others.

Driving while under the drug's influence is generally considered several orders of magnitude more dangerous than the average drunk driver, due to the diminished motor controls and delusions that may affect the user. It is unclear if the drug is responsible for the behavior, but a class-action lawsuit was filed against Sanofi-Aventis in March 2006 on behalf of those who reported symptoms.[4]. More recently, the Sydney Morning Herald in Australia reported on 4 March 2007 that a man who fell 30 metres to his death from a high-rise unit balcony may have been sleepwalking under the influence of Stilnox. The coverage prompted over 40 readers to contact the newspaper with their own accounts of Stilnox related automatism and the drug is now under review by the Adverse Drug Reactions Advisory Committee^[18]. On 6 April 2007 Australia's Therapeutic Goods Administration ordered the manufacturer to upgrade its warning about mixing the pills with alcohol[5]. There are many unsubstantiated reports on the internet of people who have had issues with this medication. [6]

On March 14, 2007, the US Food and Drug Administration ordered stronger warnings on 13 prescription sleep-hypnotic drugs including zolpidem and eszopiclone. The dangers of allergic reactions and driving while asleep, while serious, are not thought to be sufficient to withdraw the drugs from the market.^[19]

[edit] See also

• Alpidem

[edit] References

[edit] Notes

1. ^  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
2. ^  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
3. ^  Pidd, Helen. "Reborn." Guardian Unlimited. 2006 Sep 12. Fulltext
4. ^  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
5. ^  Angelettie M.S.W., Lisa. "Ambien Abuse" Fulltext

[edit] External links

• Erowid Zolpidem (Ambien) Vault
• Ambien® CIV (zolpidem tartrate) at the NIH DailyMed website