Article: Zolpidem

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. weight	307.395 g/mol
Pharmacokinetic data
Bioavailability	92% bound in plasma
Metabolism	Hepatic
Half life	2 to 2.6 hours (normal liver function)
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	B3 (AUS) B (USA)
Legal status	DEA Schedule IV (USA) , Class B / POM (UK)
Routes	Oral

Zolpidem is a prescription drug used for the short-term treatment of insomnia (sleeping pill). It works quickly (usually within 15 minutes) and has a short half-life (2-3 hours), but will last longer in patients with hepatic failure. Some trade names of zolpidem are Ambien®, Stilnox®, Stilnoct®, Hypnogen® or Myslee®.^[1] Its hypnotic effects are similar to those of the benzodiazepines, but it is actually classified as an imidazopyridine, and the anticonvulsant and muscle relaxant effects only appear at 10 and 20 times the dose required for sedation, respectively.^[2] For that reason, it has never been approved for either muscle relaxation or seizure prevention. Such drastically increased doses are likely to induce one or more negative side effects, including hallucinations and/or amnesia.

The patent in the United States on zolpidem is held by the French pharmaceutical corporation Sanofi-Aventis. The patent was due to expire in October 2006, but a six-month extension was granted, pushing the off-patent date to April 2007, so that Sanofi-Aventis can conduct further studies on the effects of zolpidem on children^[3]. 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.

Uses

Zolpidem is approved for the short-term treatment of insomnia, but it has been studied for nightly use up to six months in a single-blind, open-label trial published in 1991^[4], 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)^[5], and in an open-label trial lasting 179 days published in 1993^[6].

The United States Air Force uses zolpidem under trade name Ambien® as "no-go pills" to help the pilots sleep after a mission; another drug used for the same purpose is temazepam (Restoril®).^[7] (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).^[8]

It is also used off-label to treat restless leg syndrome.^[9]

As is the case with many prescription sedative/hypnotic drugs, zolpidem is sometimes used by stimulant users to "come down" after the use of stimulants such as methamphetamine, cocaine, methylenedioxymethamphetamine (MDMA), or pharmaceutical amphetamines.^[10]

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.^[11] 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.^[12] 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.^[13]

Abuse

Abuse of this drug (specifically the Ambien® brand) is becoming more common in young people. Abusers 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. The likelihood of experiencing any of these effects seems to be completely arbitrary regardless of the size of the dose.

Recreational zolpidem use is speculated to lead to tolerance and dependence much more quickly than prescribed use. Recreational use is rising, as demonstrated by the use of street names for the pill, such as: "A-" (which is most likely due to the imprint on the Ambien CR® brand of zolpidem, which consists of a capital A along with a tilde, which looks roughly like A-, as well as for sedative and calming effects, "A+" is a street name for Adderall, named so because of its stimulant effects) and "zombie pills" (because of the waking sleep/sensory deprivation effect some users have reported experiencing).

United States Congressman Patrick J. Kennedy (D-RI) was involved in a car crash in Washington, DC in May 2006, which he stated to police was caused by the effects of Ambien.

Side-effects

Larger doses of the drug can result in a variety of unwanted side effects: hallucinations, delusions, poor motor coordination, euphoria (though many instead report dysphoric reactions) increased appetite, increased sex drive, extremely poor judgment, difficulty maintaining physical balance, and, following use, inability to remember events that took place while under the influence of the drug (anterograde amnesia), especially why the patient took the drug in the first place.

Some users take zolpidem recreationally for these side effects. However, it is not as common as benzodiazepine abuse because of its unique mental imagery (which can distract the user from reality without actually producing genuine hallucinations) and irrational behaviour combined with the amnesia. Accordingly, zolpidem can also become psychologically addictive if taken for extended periods of time, due to dependence on its ability to put one to sleep or to the unique sense of euphoria it can produce. Under the influence of the drug it is common to take more zolpidem than is necessary due to forgetting that one has already taken a pill^{[citation needed]}. Users with a prediliction for abuse are advised to keep additional zolpidem in a safe place that the patient is unlikely to remember or be able to reach while intoxicated to avoid this risk.

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 Ambien to both combat these side effects and to aid in sleep-induction, as they can also act as hypnotics. However, because some antidepressants are known for being mildly sedating (i.e., paroxetine), it may be advisable not to use zolpidem and an antidepressant simultaneously.

Recently, zolpidem has been cited in various medical reports mainly in the United Kingdom as waking persistent vegetative state patients or PVS. More information is available on the BBC world news site under Zolpidem.[14]

See also

• Alpidem