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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 | |
| ATC code | N05 |
| PubChem | |
| DrugBank | |
| ChemSpider | |
| Chemical data | |
| Formula | C19H21N3O |
| Mol. mass | 307.395 g/mol |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | 70% (oral) 92% bound in plasma |
| Metabolism | Hepatic CYP34A |
| Half life | 2 to 2.6 hours |
| Excretion | 56% renal 34% fecal |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status |
Schedule IV(US) Class C / POM (UK) |
| Routes | Oral |
Zolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic that potentiates gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, by binding to gamma-aminobutyric acid (GABAA) receptors at the same location as benzodiazepines.1 It works quickly (usually within 15 minutes) and has a short half-life (2–3 hours). Some trade names of zolpidem are: Ambien, Ambien CR, Ivedal, Nytamel, Stilnoct, Stilnox, Zoldem, Zolnod and Zolpihexal.2345
Its hypnotic effects are similar to those of the benzodiazepine class of drugs, but it is molecularly distinct from the classical benzodiazepine molecule and is classified as an imidazopyridine. Flumazenil, a benzodiazepine receptor antagonist, which is used for benzodiazepine overdose, can also reverse zolpidem's sedative/hypnotic and memory impairing effects.67
As an anticonvulsant and muscle relaxant, the beneficial effects start to emerge at 10 and 20 times the dose required for sedation, respectively.8 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 4382938 in the United States on zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis. On April 23, 2007 the U.S. FDA approved 13 generic versions of zolpidem tartrate. Zolpidem is available from several generic manufacturers in the UK, as a 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.910111213
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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 trial published in 1991,14 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),15 and in an open-label trial lasting 179 days published in 1993.16
The United States Air Force uses zolpidem as a substitute for temazepam, under trade name Ambien, as "no-go pills" to help pilots sleep after a mission; the main drug used for the purpose is temazepam (Normison/Restoril). (Cf. the "go-pills" dextroamphetamine, served under the name Dexedrine, or its recent modafinil (Provigil) replacement, act as a stimulant for the same pilots, the effects of which are reversed by the aforementioned "no-go pills")17
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 amphetamines (including methamphetamine), cocaine, and MDMA (ecstasy).18
Recently, the drug has been reported anecdotally to have positive effects for patients in persistent vegetative state.9 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.1920
A clinical trial on a single patient performed at the Toulouse University Hospital using PET shows that zolpidem repeatably improves brain function and mobility of a patient immobilized by akinetic mutism caused by hypoxia.21
Zolpidem binds with high affinity to the α1 containing GABAA receptors, about 10-fold lower affinity for those containing the α2, α3-GABAA receptor subunits, and with no appreciable affinity for α5 subunit containing receptors.22
Like the vast majority of benzodiazepine-like molecules, zolpidem has no affinity for α4 and α6 subunit-containing receptors.23 Zolpidem positively modulates GABAA receptors, probably by increasing the GABAa receptor complexes apparent affinity for GABA, without affecting desensitization or peak current.24 Zolpidem increases slow wave sleep and caused no effect on stage 2 sleep in laboratory tests.25
A meta-analysis of the randomised controlled clinical trials that compared benzodiazepines against Z drugs has shown that there are few consistent differences between zolpidem and benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia, and daytime alertness.26
Zolpidem has recently been very strongly related to certain instances of patients in a minimally conscious coma state being brought to a fully conscious state. While it was initially given to these supposed permanent coma patients to put them to sleep, it actually brought them to a fully conscious state in which they were capable of communicating and interacting for the first time in years. CT scans have shown that the use of the drug actually does dramatically increase the activity in the frontal lobe of the brain in some patients in a minimally conscious state. Large-scale studies are currently being done to see whether it has the same universal effect on all or most patients in a minimally conscious state.27 It may be that zolpidem's ability to stimulate the brain, particularly in the semi-comatose, may be related to one of its side-effects, which sometimes causes sleepwalking and other activity while asleep, that appears to observers to be fully conscious activity.
The transition from medicinal use to recreational use of zolpidem can occur when the drug is used without the doctor's recommendation to continue using it, in high doses (more than the usual 5mg or 10 mg), when consumed other than orally (snorting or injecting), or when taken for purposes other than as a sleep aid. Abuse is more prevalent in those that have been dependent on other drugs in the past. Zolpidem effects can increase and intensify if mixed with other substances like alcohol and cannabis.
In the U.S., recreational use of this drug 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). Thus, some users report decreased anxiety, and even mild euphoria, as well as perceptual changes, visual distortions, and light-based hallucinations.28
With regular use at high dosage, there can be a risk of a severe physical dependence on zolpidem, with cases being reported in the medical literature of epileptic seizures forming part of the withdrawal syndrome. One case involved a woman detoxing off a high dose of zolpidem experiencing a generalized seizure. The clinical withdrawal and dependence effects were reported to be similar to the benzodiazepine withdrawal syndrome in this case report.29
Zolpidem and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other drugs including the benzodiazepines and zopiclone are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range suggesting a high degree of excessive-use potential for benzodiazepines, zolpidem and zopiclone.30
As Ambien's patent expired April 21, 2007, new generic versions were approved, which do not have the "protective cover" present on the Sanofi name-brand Ambien they once previously had to prevent users from crushing, snorting, or injecting the drugs.
Alcohol has cross tolerance with GABAa receptor positive modulators such as the benzodiazepines and the nonbenzodiazepine drugs. For this reason alcoholics or recovering alcoholics may be at increased risk of physical dependency on zolpidem. Also, alcoholics and drug abusers may be at increased risk of abusing and or becoming psychologically dependent on zolpidem. Zolpidem should be avoided in those with a history of Alcoholism, drug misuse, or in those with history of physical dependency or psychological dependency on sedative-hypnotic drugs.
When a physical dependence has developed to zolpidem, treatment usually entails a gradual dose reduction over a period of months in order to minimise withdrawal symptoms which can resemble those seen during the benzodiazepine withdrawal syndrome. Failing that an alternative method which may be necessary for some patients is a switch to a benzodiazepine equivalent dose of a more longer acting benzodiazepine drug such as diazepam or chlordiazepoxide followed by a gradual reduction in dosage of the long acting benzodiazepine. Sometimes for difficult to treat patients an inpatient flumazenil detoxification program can be used to detox from a zolpidem drug dependence or addiction.31
Overdose of zolpidem may present with excessive sedation, pin-point pupils, depressed respiratory function, which may progress to coma and possibly death. Zolpidem combined with alcohol, opiates or other CNS depressants may be even more likely to lead to fatal overdoses. Zolpidem overdosage can be treated with the benzodiazepine receptor antagonist flumazenil, which displaces zolpidem from its binding site the benzodiazepine receptor and therefore rapidly reverses the effects of zolpidem.32
An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines, the nonbenzodiazepine (including zolpidem) sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.33
Side-effects at any dose may include:
Some users take zolpidem recreationally for some of these side-effects, notably sedation, hallucinations and euphoria. However, the abuse of zolpidem may be less common than benzodiazepine abuse. Zolpidem can become addictive if taken for extended periods of time, due to drug tolerance and physical dependence or the euphoria it can sometimes produce. As with 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 for one 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. The recent release of Ambien CR (zolpidem tartrate extended release) in the United States renewed interest in the drug among recreational drug users.
Some users have reported unexplained sleepwalking while using zolpidem, 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 effects make a strong suggestion to schizophasia, 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 sleepwalker and others. These side-effects may be related to the mechanism that also causes zolpidem to bring some semi-comatose people back to consciousness.
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 whether the drug is responsible for the behavior, but a class-action lawsuit was filed against Sanofi-Aventis in March 2006 on behalf of those that reported symptoms.35 Residual 'hangover' effects such as sleepiness, impaired psychomotor and cognitive after nighttime administration may persist into the next day which may impair the ability of users to drive safely, increase risks of falls and hip fractures.36
More recently, the Sydney Morning Herald in Australia reported on 4 March 2007 that a man who fell 30 meters 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.37
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