Zolpidem

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Zolpidem


Systematic (IUPAC) name
N,N-dimethyl-2-(6-methyl-2-p-tolylimidazo[1,2-a]pyridin-3-yl)acetamide
Clinical data
Trade names	Ambien
AHFS/Drugs.com	monograph
MedlinePlus	a693025
Pregnancy cat.	B3 (AU) C (US)
Legal status	Schedule IV (US) POM (UK)^[1]
Routes	Oral (tablet), Sublingual, Oromucosal (spray)
Pharmacokinetic data
Bioavailability	70% (oral) 92% bound in plasma
Metabolism	Hepatic – CYP3A4
Half-life	2 to 3 hours
Excretion	56% renal 34% fecal
Identifiers
CAS number	82626-48-0
ATC code	N05CF02
PubChem	CID 5732
DrugBank	DB00425
ChemSpider	5530
UNII	7K383OQI23
KEGG	D08690
ChEBI	CHEBI:10125
ChEMBL	CHEMBL911
Chemical data
Formula	C₁₉H₂₁N₃O
Mol. mass	307.395 g/mol
SMILES [show]
InChI [show]
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Zolpidem (sold under the brand names Ambien, Ambien CR, Stilnox, and Sublinox) is a prescription medication used for the treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class ^[2] that potentiates gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, by binding to GABA_A receptors at the same location as benzodiazepines.^[3] It works quickly (usually within 15 minutes) and has a short half-life (two to three hours).
Zolpidem has not adequately demonstrated effectiveness in maintaining sleep (unless delivered in a controlled-release form); however, it is effective in initiating sleep.^[4] 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.^[5]^[6]
As an anticonvulsant and muscle relaxant, the drug's effects aren't evident until dosages 10 and 20 times those required for sedation, respectively, are reached.^[7] For that reason, zolpidem has never been approved for either muscle relaxation or seizure prevention. Such drastically increased doses are also more inclined to induce one or more of the drug's adverse side effects, including hallucinations and amnesia.
The patent in the United States on zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis.^[8] On April 23, 2007, the U.S. Food and Drug Administration (FDA) approved 13 generic versions of zolpidem tartrate.^[9] Zolpidem is available from several generic manufacturers in the UK, as a generic from Sandoz in South Africa and TEVA in Israel, as well as from other manufacturers such as Ratiopharm (Germany).

Medical uses

Zolpidem tartrate 10 mg tablets

Zolpidem is used for short-term (usually about two to six weeks) treatment of insomnia.^[10] It has been studied for nightly use up to six months in a single-blind 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] Zolpidem has not proven effective in maintaining sleep and is more used for sleep initiation problems.^[4]
Zolpidem is one of the most common GABA-potentiating sleeping medications prescribed in the Netherlands, with a total of 582,660 prescriptions dispensed in 2008.^[14]
The United States Air Force uses zolpidem as one of the hypnotics approved as "no-go pills" to help aviators and special duty personnel sleep in support of mission readiness (the other hypnotics used are temazepam and zaleplon during war time). "Ground tests" are required prior to authorization issued to use the medication in an operational situation.^[15]
There is evidence that zolpidem can rouse patients from a persistent vegetative state.^[16] There has been some evidence of zolpidem being used as a date-rape drug because of its euphoric/hypnotic effect.^{[citation needed]}

Adverse effects

Various zolpidem pills

Side effects may include:

Nausea
Vomiting
Dizziness
Anterograde amnesia
Hallucinations, through all physical senses, of varying intensity^{[citation needed]}
Delusions^{[citation needed]}
Altered thought patterns
Ataxia or poor motor coordination, difficulty maintaining balance^[17]
Euphoria and/or dysphoria
Increased appetite
Increased or decreased libido
Amnesia
Impaired judgment and reasoning
Uninhibited extroversion in social or interpersonal settings
Increased impulsivity
When stopped, rebound insomnia may occur
Headaches
Short-term memory loss

Some users have reported unexplained sleepwalking^[18] while using zolpidem, and a few have reported driving, binge eating, sleep talking, and performing other daily tasks while sleeping. Research by Australia's National Prescribing Service found these events occur mostly after the first dose taken, or within a few days of starting therapy.^[19] Rare reports of sexual parasomnia episodes related to zolpidem intake have also been reported.^[20] Sleepwalkers 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 observers may believe them 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. Those under the influence of this medication may seem fully aware of their environments, though they are still asleep. This can bring about concerns for the safety of the sleepwalkers and others. These side effects may be related to the mechanism that also causes zolpidem to produce its hypnotic properties.^[21] 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 who reported symptoms.^[22] It is possible some users believe they were asleep during these events because they do not remember the events, due to the short-term memory loss and anterograde amnesia side effects.
Residual 'hangover' effects, such as sleepiness and impaired psychomotor and cognitive function, after nighttime administration may persist into the next day, which may impair the ability of users to drive safely and increase risks of falls and hip fractures.^[23]
The Sydney Morning Herald in Australia in 2007 reported 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 as of March 2007, the drug was under review by the Adverse Drug Reactions Advisory Committee.^[24]
In February 2008, the Australian Therapeutic Goods Administration attached a Black Box Warning to zolpidem, stating, that "Zolpidem may be associated with potentially dangerous complex sleep-related behaviours that may include sleep walking, sleep driving, and other bizarre behaviours. Zolpidem is not to be taken with alcohol. Caution is needed with other CNS depressant drugs. Limit use to four weeks maximum under close medical supervision."^[25] This report received widespread media coverage^[26] after the death of Australian student Mairead Costigan, who fell 20 m from the Sydney Harbour Bridge while under the influence of Stilnox.^[27]

Tolerance, dependence, and withdrawal

Ambien tablets

A review medical publication found long-term use of zolpidem is associated with drug tolerance, drug dependence, rebound insomnia and CNS-related adverse effects. It was recommended that zolpidem be used for short periods of time using the lowest effective dose. Zolpidem 10 mg is effective in treating insomnia when used intermittently no fewer than three and no more than five pills per week for a period of 12 weeks.^[28] The 15-mg zolpidem dosage provided no clinical advantage over the 10-mg zolpidem dosage.^[29]
Nonpharmacological treatment options (e.g. cognitive behavioral therapy for insomnia), however, were found to have sustained improvements in sleep quality.^[30] Animal studies of the tolerance-inducing properties have shown that in rodents, zolpidem has less tolerance-producing potential than benzodiazepines, but in primates the tolerance-producing potential of zolpidem was the same as that of benzodiazepines.^[31] Tolerance to the effects of zolpidem can develop in some people in just a few weeks. Abrupt withdrawal may cause delirium, seizures, or other severe effects, especially if used for prolonged periods and at high dosages.^[32]^[33]^[34]
When drug tolerance and physical dependence to zolpidem has developed, treatment usually entails a gradual dose reduction over a period of months to minimise withdrawal symptoms, which can resemble those seen during benzodiazepine withdrawal. Failing that, an alternative method may be necessary for some patients, such as a switch to a benzodiazepine equivalent dose of a 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 rapid detoxification program can be used to detoxify from a zolpidem drug dependence or addiction.^[35]
Alcohol has cross tolerance with GABA_A 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. It should be avoided in those with a history of alcoholism, drug misuse, physical dependency, or psychological dependency on sedative-hypnotic drugs. Zolpidem has rarely been associated with drug-seeking behavior, the risk of which is amplified in patients with a history of drug or alcohol abuse.

Overdose

An overdose of zolpidem may cause excessive sedation, pin-point pupils, or depressed respiratory function, which may progress to coma, and possibly death. Combined with alcohol, opiates, or other CNS depressants, it 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 on the benzodiazepine receptor, so rapidly reverses the effects of zolpidem.^[36]

Detection in body fluids

Zolpidem may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest, or to assist in a medicolegal death investigation. Blood or plasma zolpidem concentrations are usually in a range of 30–300 μg/l in persons receiving the drug therapeutically, 100–700 μg/l in those arrested for impaired driving, and 1000–7000 μg/l in victims of acute overdosage. Analytical techniques, in general, involve gas or liquid chromatography.^[37]^[38]^[39]

Special precautions

Driving

Use of zolpidem may impair driving skills with a resultant increased risk of road traffic accidents. This adverse effect is not unique to zolpidem but also occurs with other hypnotic drugs. Caution should be exercised by motor vehicle drivers.^[40]

Elderly

The elderly are more sensitive to the effects of hypnotics including zolpidem. Zolpidem causes an increased risk of falls and may induce adverse cognitive effects.^[41]
An extensive review of the medical literature regarding the management of insomnia and the elderly found there is considerable evidence of the effectiveness and durability of nondrug treatments for insomnia in adults of all ages, and these interventions are underused. 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. Newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, were found to 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. More research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.^[42]

Gastroesophageal reflux disease

Patients suffering from gastroesophageal reflux disease had reflux events measured to be significantly longer when taking zolpidem than on placebo. (The same trend was found for reflux events in patients without GERD). This is assumed to be due to suppression of arousal during the reflux event, which would normally result in a swallowing reflex to clear gastric acid from the esophagus. Patients with GERD who take zolpidem thus experience significantly higher esophageal exposure to gastric acid, which increases the likelihood of developing esophageal cancer.^[43]

Pregnancy

Zolpidem has been assigned to pregnancy category C by the FDA. Animal studies have revealed evidence of incomplete ossification and increased postimplantation fetal loss at doses greater than seven times the maximum recommended human dose or higher; however, teratogenicity was not observed at any dose level. There are no controlled data in human pregnancy. In one case report, zolpidem was found in cord blood at delivery. Zolpidem is only recommended for use during pregnancy when benefits outweigh risks. ^[44]

Mechanism of action

Zaleplon and Zolpidem both are agonists at the GABA A ɣ 1 subunit. Due to its selective binding, Zolpidem has very weak anxiolytic, myorelaxant, and anticonvulsant properties but very strong hypnotic properties.^[45] Zolpidem binds with high affinity and acts as a full agonist at the α₁-containing GABA_A receptors, about 10-fold lower affinity for those containing the α₂- and α₃- GABA_A receptor subunits, and with no appreciable affinity for α₅ subunit-containing receptors.^[46]^[47] ω₁ type GABA_A receptors are the α₁-containing GABA_A receptors and ω₂ GABA_A receptors are the α₂-, α₃-, α₄-, α₅-, and α₆-containing GABA_A receptors. ω₁ GABA_A receptors are found primarily in the brain, whereas ω₂ receptors are found primarily in the spine. Thus, zolpidem has a preferential binding for the GABA_A-benzodiazepine receptor complex in the brain but a low affinity for the GABA_A-benzodiazepine receptor complex in the spine.^[48]
Like the vast majority of benzodiazepine-like molecules, zolpidem has no affinity for α₄ and α₆ subunit-containing receptors.^[49] Zolpidem positively modulates GABA_A receptors, it is presumed by increasing the GABA_A receptor complex's apparent affinity for GABA without affecting desensitization or peak current.^[50] Like zaleplon (Sonata), zolpidem may increase slow wave sleep but cause no effect on stage 2 sleep.^[51]
A meta-analysis of the randomised, controlled, clinical trials that compared benzodiazepines against Z-drugs such as zolpidem has shown 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.^[52]

Drug-drug interactions

Notable drug-drug interactions with the pharmacokinetics of zolpidem include chlorpromazine, fluconazole, imipramine, itraconazole, ketoconazole, rifampicin, and ritonavir. Interactions with carbamazepine and phenytoin can be expected based on their metabolic pathways, but have not yet been studied. There does not appear to be any interaction between zolpidem and cimetidine or ranitidine.^[53]^[54]

Abuse

Recreational use

Zolpidem has a potential for either medical misuse when the drug is continued long term without or against medical advice, or recreational use when the drug is taken to achieve a "high".^[55] The transition from medical use of zolpidem to high-dose addiction or drug dependence can occur when used without a doctor's recommendation to continue using it, when physiological drug tolerance leads to higher doses than the usual 5 mg or 10 mg, when consumed through inhalation or injection, or when taken for purposes other than as a sleep aid. Misuse is more prevalent in those who have been dependent on other drugs in the past, but tolerance and drug dependence can still sometimes occur in those without a history of drug dependence. Chronic users of high doses are more likely to develop physical dependence on the drug, which may cause severe withdrawal symptoms, including seizures, if abrupt withdrawal from zolpidem occurs.^[56]
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, methamphetamine, cocaine, and MDMA (ecstasy).^[57]^{[not in citation given]}
One case history reported a woman detoxifying from a high dose of zolpidem experiencing a generalized seizure, with clinical withdrawal and dependence effects reported to be similar to the benzodiazepine withdrawal syndrome.^[58]
Nonmedical use of zolpidem is increasingly common in U.S.A, Canada, and the UK. Recreational users report that resisting the drug's hypnotic effects can in some cases elicit vivid visuals and a body high.^[59] Some users have reported decreased anxiety, mild euphoria, perceptual changes, visual distortions, and hallucinations.^[60]
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.^[61] U.S. Congressman Patrick J. Kennedy says that he was using Zolpidem (Ambien) and Phenergan when caught driving erratically at 3AM.^[62] "I simply do not remember getting out of bed, being pulled over by the police, or being cited for three driving infractions," Kennedy said.
Zolpidem, along with the other benzodiazepine-like Z-drugs, is a Schedule IV controlled substance in the USA, according to the Controlled Substances Act, given its potential for abuse and dependence.

Date-rape drug

According to the U.S. Drug Enforcement Administration, zolpidem (Ambien, Stilnox) is quickly overtaking illegal sedatives as the most common date-rape drug. Perpetrators of sexual assault have used zolpidem on unsuspecting victims.^[63]^[64]
With more than 250,000 prescriptions written in the last year, zolpidem is more accessible to potential sexual abusers than rohypnol, or "roofies," and its side effects when mixed with alcohol can exacerbate the sedative effects.

Research

Zolpidem may provide short-lasting but effective improvement in symptoms of aphasia present in some survivors of stroke. The mechanism for improvement in these cases remains unexplained and is the focus of current research by several groups, to explain how a drug which acts as a hypnotic-sedative in people with normal brain function, can paradoxically increase speech ability in people recovering from severe brain injury. Use of zolpidem for this application remains experimental at this time, and is not officially approved by any pharmaceutical manufacturers of zolpidem or medical regulatory agencies worldwide.^[65]^[66]^[67]^[68]^[69]

news

Sunday, July 8, 2012

Zolpidem or Stilnox effect