What is/are Zolpidem?
Zolpidem (brand names Ambien, Ambien CR, Intermezzo, Stilnox, and Sublinox) is a prescription medication used for the treatment of insomnia and some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates GABA, an inhibitory neurotransmitter, by binding to GABAA receptors at the same location as benzodiazepines. It works quickly, usually within 15 minutes, and has a short half-life of two to three hours.
Zolpidem has not adequately demonstrated effectiveness in maintaining sleep, unless delivered in a controlled-release (CR) form. However, it is effective in initiating sleep. 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.
As a muscle relaxant and anticonvulsant, the drug's effects are not evident until dosages 10 and 20 times those required for sedation, respectively, are reached. 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 United States patent for zolpidem was held by the French pharmaceutical corporation Sanofi-Aventis. On April 23, 2007, the U.S. Food and Drug Administration (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 and TEVA in Israel, as well as from other manufacturers such as Ratiopharm (Germany).
On 2012, a study published in the BMJ Open journal revealed that sleeping pills, including zolpidem, are associated with a higher risk of death and cancer diagnosis. Nevertheless, the study only showed a link, and did not prove the deaths were caused by the pills or by other symptoms related to insomnia.
On January 10, 2013, the Food and Drug Administration announced it is requiring the manufacturer of Ambien and Zolpimist to cut the recommended dosage for women in half, after laboratory studies showed that the medicines can leave patients drowsy in the morning and at risk for car accidents.The FDA recommended that manufacturers extend the new dosage cuts to men as well, who process the drug at a faster rate. However, the reasons why men and women catabolize the drugs at different rates is still unknown. In May 2013, the FDA approved label changes specifying new dosage recommendations for Zolpidem products because of concerns regarding next-morning impairment.
Clinicians prescribe zolpidem for short-term (usually about two to six weeks) treatment of insomnia. Zolpidem has not proven effective in maintaining sleep, but addresses sleep-initiation problems. The effect over placebo is of marginal clinical benefit.
Side effects may include:
- Anterograde amnesia
- Hallucinations, through all physical senses, of varying intensity
- Altered thought patterns
- Ataxia or poor motor coordination, difficulty maintaining balance
- Euphoria and/or dysphoria
- Increased appetite
- Increased or decreased libido
- Impaired judgment and reasoning
- Uninhibited extroversion in social or interpersonal settings
- Increased impulsivity
- When stopped, rebound insomnia may occur
Some users have reported unexplained sleepwalking while using zolpidem, as well as sleep driving, binge eating while asleep, 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. Rare reports of sexual parasomnia episodes related to zolpidem intake have also been reported. 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 in contrast to "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. 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. Conversely, it is possible some users believed 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, may persist into the day following nighttime administration. Such effects may impair the ability of users to drive safely and increase risks of falls and hip fractures.
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.
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." This report received widespread media coverage after the death of Australian student Mairead Costigan, who fell 20 m from the Sydney Harbour Bridge while under the influence of Stilnox.
Tolerance, dependence, and withdrawal
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. The 15-mg zolpidem dosage provided no clinical advantage over the 10-mg zolpidem dosage.
Nonpharmacological treatment options (e.g. cognitive behavioral therapy for insomnia), however, were found to have sustained improvements in sleep quality. 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. 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.
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.
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. 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.
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 to rapidly reverse the effects of the zolpidem.
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.
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. Zolpidem binds with high affinity and acts as a full agonist at the α1-containing GABAA receptors, about 10-fold lower affinity for those containing the α2- and α3- GABAA receptor subunits, and with no appreciable affinity for α5 subunit-containing receptors. ω1 type GABAA receptors are the α1-containing GABAA receptors and ω2 GABAA receptors are the α2-, α3-, α4-, α5-, and α6-containing GABAA receptors. ω1 GABAA receptors are found primarily in the brain, whereas ω2 receptors are found primarily in the spine. Thus, zolpidem has a preferential binding for the GABAA-benzodiazepine receptor complex in the brain but a low affinity for the GABAA-benzodiazepine receptor complex in the spine.
Like the vast majority of benzodiazepine-like molecules, zolpidem has no affinity for α4 and α6 subunit-containing receptors. Zolpidem positively modulates GABAA receptors, it is presumed by increasing the GABAA receptor complex's apparent affinity for GABA without affecting desensitization or peak current. Like zaleplon (Sonata), zolpidem may increase slow wave sleep but cause no effect on stage 2 sleep.
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.
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.
This article uses material from the Wikipedia article Zolpidem, which is released under the Creative Commons Attribution-Share-Alike License 3.0.