Drugs-Forum  
Home Wiki Studies Forum Groups Blog Video Images News Chat
Go Back   Drugs Forum > Wiki Articles > Drug Articles
Mark Forums Read
Register Tags

Notices

Drug Articles Articles about drugs

Zolpidem

Zolpidem (Ambien, Ambien CR, Sublinox and Stilnox) is a short acting sedative-hypnotic prescribed to treat insomnia. Zolpidem is in the class of imidazopyridines which have similar effects to benzodiazadine drugs because they potentiate gamma-amino butyric acid (GABA) and thus share some pharmacological properties. Zolpidem causes sedation and can cause anterograde amnesia (forgetting the period during the effects) but has very minimal anti-anxiety, muscle-relaxing and anti-convulsant properties.

Contents




[top]Introduction to Zolpidem

Zolpidem’s main therapeutic use is the treatment of insomnia and it is typically prescribed as a short-acting hypnotic alternative to benzodiazepines. Zolpidem is in the class of imidazopyridines which potentiate gamma-amino butyric acid (GABA). Zolpidem works quickly (usually within 15 minutes) to bind to GABAA receptors at the same location as benzodiazepines but more selectively.[1] However due to its short half-life, immediate release forms of Zolpidem can fail to be adequate to maintain sleep for a full night.


[top]Using Zolpidem

[top]Ways of Administration

Zolpidem can be administered several ways but is standardly prescribed in oral formulation, either a regular instant release or an extended release formulation (Eg. Ambien and Ambien CR). Other formulations include sublingual tablets (Edluar and Intermezzo) which are taken by placing them under the tongue and letting them melt and an oral spray (Zopimis) which is applied into the mouth and over the tongue. Zolpidem is to be taken as needed and not more than once per night. Food taken with Zolpidem may inhibit the speed and effectiveness of the drug.

[top]Dose

The recommended initial therapeutic dose of immediate release zolpidem is 5 mg for women and 5 or 10 mg for men, taken immediately before bedtime, ensuring there is at least 7-8 hours before you need to wake up. Zolpiden has not been shown to be safe or effective for use in children.
Threshold mg
Light mg
Medium mg
Strong mg

[top]Effects of Zolpidem

Zolpidem causes sleepiness and in patients with insomnia it both shortens the time it takes to fall asleep and extends the duration of sleep. Zolpidem has been shown as effective as benzodiazepines in both shortening the time to sleep onset and prolonging total sleep time in patients with insomnia. Unlike benzodiazepines, zolpidem's hypnotic/sedative effects do not appear to have negative effects on the stages of sleep in normal human subjects and it does not appear to disrupt stages 3 or 4 of deep sleep.[2] A meta-analysis of randomized and controlled clinical studies that compared Z-drugs including zolpidem to benzodiazepines found no consistent differences in time to sleep onset, sleep duration, number of awakenings, sleep quality, rebound insomnia, tolerance, daytime alertness or adverse events. [3]

After discontinuation the beneficial effects of zolpidem on sleep have been reported to persist for up to 1 week.[4] Improvement in sleep time during 6 months of continuous treatment with zolpidem has been seen without subsequent discontinuation causing withdrawal or rebound difficulties.[5]

Zolpidem has hypnotic and sedative effects because it is an agonist on GABAA receptors, resembling benzodiazepines in effect (but not mechanism) in this way. But zolpidem has been shown to have only weak anticonvulsant effects in experimental animals, whereas its hypnotic/sedative effects seem to mask anti-anxiety effects in various animal models of anxiety.[6] Chronic administration of zolpidem to rodents does not seem to produce tolerance to its sedative effects nor signs of withdrawal upon discontinuation.[7] Chronic zolpidem administration to baboons, however, has been reported to produce both tolerance and physical dependence.[8] And there have been case reports of tolerance to zolpidem's hypnotic effects developing in patients taking high doses of zolpidem for up to several years.[9]

[top]Zolpidem combinations

[top]Recreational drug combinations with Zolpidem

No Recreational drug combinations with Zolpidem have been added to this wiki yet.

[top]Dangerous interactions with Zolpidem

As a sedative-hypnotic drug, zolpidem is a central nervous system (CNS) depressant, so taking it with other CNS depressants (e.g. benzodiazepines, opioids, tricyclic antidepressants, alcohol) can cause additive effects and increase the risk of CNS depression.

[top]Medication interactions with Zolpidem

Both mipramine and chiorpromazine have been reported to increase the impairment of alertness zolpidem causes, chlorpromazine has also been observed to add to the impairment of psychomotor performance under zolpidem. Ketoconazole combined with zolpidem may increase its effects and their duration.
Rifampin taken with zolpidem may decrease zolpidem’s effects.

[top]Potentiators of Zolpidem

Ketoconazole, a potent CYP3A4 inhibitor, has been shown to increase zolpidem’s Cmax (maximum blood concentration) by 30% and total AUC (overall blood levels) by 70%, to extend zolpidem’s elimination half-life by 30%, and to increase the pharmacodynamic effects of zolpidem.

[top]Different Uses for Zolpidem

[top]Recreational use of Zolpidem

Zolpidem has the potential for misuse as a drug used to get high rather than medication for treating insomnia. Such misuse becomes more likely with longer term use whether the use is with or without a prescription. But because the sedative effects of zolpidem are far less subject to chronic tolerance effects than are those of benzodiazepines, and because it has very minimal anti-anxiety properties, long term zolpidem use at normal therapeutic levels is thought to present a much lower risk of developing into problematic recreational use than is long term use of benzodiazepines.[1] Recreational misuse tends to occur when physiological drug tolerance leads to inhalation, injection or the drugs is taken for reasons other than medically approved for usually in amounts greater than 5-10 mg.

[top]Using Zolpidem for come down or sleep with stimulant (ab)use

Users of stimulants have long been involved in the misuse of sedative/hypnotics such as Zolpidem as a way to come down or sleep after using methamphetamine or coke.

[top]Using Zolpidem for its hallucinogenic effects

Zolpidem has been reported to have a unique ability to elicit vivid visuals and body highs in some users when they resist the drugs hypnotic effects.


[top]Pharmacology of Zolpidem

[top]General

Zolpidem is a gamma-aminobutyric acid (GABA) A agonist. It interacts with a GABA-BZ receptor complex but in contrast to the benzodiazepines, which are non-selective and bind to and activate all subtypes of BZ receptor, zolpidem in vitro preferentially binds to the BZ1 receptor with a high affinity ratio of the α5 subunits. Zolpidem’s preferential binding on the BZ1 receptor might be the reason zolpidem has been found to have very minimal myorelaxant (muscle-relaxing) and anticonvulsant effects in animals, and might explain data from clinical studies showing therapeutic level doses of zolpidem do not disrupt stages 3 and 4 of deep sleep in humans.[10]

Zolpidem taken orally in immediate release formulation is rapidly absorbed from the gastrointestinal tract; 5mg and 10 mg doses have Tmax of 1.6 hours (the average time to reach maximum blood concentrations). Zolpidem has a short elimination half-life (T½) in healthy subjects with a mean of 2.6 hours and 2.5 hours for 5mg and 10 mg tablets respectively.

In a single-dose crossover study in 45 healthy subjects administered 5 and 10 mg zolpidem tartrate tablets, the mean peak concentrations (Cmax) were 59 (range: 29 to 113) and 121 (range: 58 to 272) ng/mL, respectively.

Zolpidem undergoes hepatic oxidation by the CYP system to inactive products that are eliminated primarily by renal excretion and in the dose range of 5 to 20 mg demonstrates linear kinetics.

Zolpidem has been shown not to accumulate in young adults following nightly dosing with 20 mg zolpidem tartrate tablets for 2 weeks.

[top]Targets, Enzymes, and Transporters

[top]Targets

Target
Action

[top]Enzymes

Enzyme
Action

[top]Transporters

Transporter
Action


[top]Chemistry of Zolpidem


Property
[center]Values
Systematic (IUPAC) name:N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide
Synonyms:N,N,6-trimethyl-2-p-tolylimidazo[1,2-a]pyridine-3-acetamide, SL-80.0750; zolpidem tartrate, SL-80.0750-23N, Ambien, Intermezzo, Ivadal, Myslee, Niotal, Stilnoct, Stilnox, Tovalt (L-(+)-hemitartrate)
Molecular Formula:C19H21N3O; (C19H21N3O)2.C4H6O6 (L-(+)-hemitartrate)
Molar mass: 307.40 g/mol; 764.88 g/mol (L-(+)-hemitartrate)
CAS Registry Number:82626-48-0, 99294-97-4 (L-(+)-hemitartrate)
Melting Point:196°C
Boiling Point:no data
Flash Point:no data
Solubility:L-(+)-hemitartrate : 23 mg/mL (water, 20°C); sparingly soluble in alcohol, propylene glycol
Additionnal data:pKa 6.2, log P (octanol/water) 2.43
Notes:L-(+)-hemitartrate aspect : white to off white crystalline powder
[11]

[top]Reagent test results of Zolpidem



[top]The Dangers of Zolpidem

[top]General Warnings

[top]Side Effects and Interactions

[top]Potential Side Effects

The most common side effects of zolpidem include nightmares, agitation, headache, gastrointestinal upset, dizziness, and daytime drowsiness.[12] Zolpidem has been reported to cause abnormal thinking and behavior changes including decreased inhibition, aggression, extroversion, agitation, bizarre behavious and depersonalization. Hallucinations both visual and auditory have been reported in controlled studies of zolpidem at therapeutic doses (in less than 1% of adults with insomnia but 7% of children treated with zolpidem at bedtime reported hallucinations compared to 0% of those taking placebo).

There have been reports of mild rebound insomnia on the first night after discontinuation of zolpidem at therapeutic doses (5–10mg).[13] It appears to be rare and to take unusual circumstances for tolerance or physical dependence to happen.[14] At therapeutic doses (5–10mg), zolpidem infrequently produces residual daytime sedation or amnesia, and the incidence of other adverse effects (e.g., gastrointestinal complaints or dizziness) also is low. As with the benzodiazepines, large overdoses of zolpidem typically do not produce severe respiratory depression unless other agents (e.g., ethanol) also are ingested [15] Hypnotic doses increase the hypoxia and hypercarbia of patients with obstructive sleep apnea.

[top]Potential Drug Interactions

Central nervous system (CNS) depressants including benzodiazepines, opiate/oid drugs, alcohol, other z-drugs, and tricyclic antidepressants can cause additive effects and increase the risk of CNS depression when taken with zolpidem because it a sedative-hypnotic drug so also a CNS depressant.
It has been established that alcohol taken with zolpidem has an additive effect increasing the adverse effect on psychomotor performance.

[top]Medication interactions with Zolpidem

Both imipramine and chlorpromazine have been reported to have an additive effect when combined with zolpidem which increases the impairment of alertness; chlorpromazine has also been observed to add to the impairment of both alertness and psychomotor performance under zolpidem. Ketoconazole combined with zolpidem may increase its effects and their duration.
Rifampin taken with zolpidem may decrease zolpidem’s effects.
Sertraline (Zoloft) in combination with zolpidem increases exposure to zolpidem
Fluoxetine (Prozac) in combination with zolpidem increases zolpidem half-life but it hasn’t been shown this causes an additive effect in psychomotor performance

[top]Potential Food Interactions

[top]Physical Health Risks

[top]Next-day Psychomotor Impairment and Impaired Driving

Double-blind controlled studies have found that zolpidem impairs performance in tests of psychomotor skills (e.g. critical tracking, body sway, divided attention) and highway driving the following morning. This effect is significantly increased when zolpidem is taken in the middle of the night as opposed to a full 8 hours before getting up.[16]

[top]Withdrawal Seizures

Zolpidem withdrawal does involve some risk of seizure, especially if zolpidem is abruptly stopped or doses increased beyond normal therapeutic amounts.[17][18]

[top]Mental Health Risks

[top]Development of Psychiatric Problems, Worsening of depression or suicidal thinking and action

Use of zolpidem at therapeutic doses can cause the worsening of depression and suicidal thinking and actions (including successful suicide attempts).[19] Treatment of insomnia with zolpidem can also seem to cause the development of new psychiatric problems because insomnia can be the symptom of otherwise unrecognized mental health problems. While the risk of these adverse effects are low the consequences can be very serious and therefore it is very important that any increased or new depression, suicidal thinking or other mental health problem while taking zolpidem be treated seriously and discussed with one's doctor.

[top]Memory impairment

Zolpidem has been shown to cause antereograde amnesia in controlled studies and via case reports. This amnesia for the time during the drug’s effects appears to be much more likely at doses higher than 10mg.

[top]Hallucinations and Psychosis

There have been case reports of hallucinations (and some delusions) occurring at normal therapeutic doses of zolpidem as low as 2.5mg.[20] Zolpidem-induced episodes of hallucination typically start shortly after taking zolpidem and last less than half an hour, but episodes of several hours have been been reported and an association with use of antidepressant serotonin reuptake-inhibition medications (SSRIs) suggested.[21] Hallucinations triggered by zolpidem seem to resolve once the medication is stopped and they do not appear to be cases of psychotic illness being triggered or caused.

[top]Sleep-driving, sleep-eating, sleep-sex and Other Complex Behaviors

Like other sedative hypnotic drugs, zolpidem can cause behaviours such as sleep-driving and other complex behaviours like preparing and eating food, making phone calls, or having sex when not fully awake.[22] These events appear to be more likely to happen when treatment with zolpidem is initiated, with a dose increased, or with a switch made to extended release formulations. Though they do not seem to be dose-dependent but they may be associated with higher blood levels caused by drug interactions or other factors extending the elimination half life of zolpidem.[23] [24][25]
Zolpidem may also induce bizarre and compulsive behaviours during sleep which the patient then does not remember when they wake up. Reported cases include zolpidem related self-harm during sleep as serious as self-inflicted gunshot to the head.[26][27]

[top]Overdose

Zolpidem overdose alone, or in combination with CNS-depressant agents causes impairment of consciousness ranging from from sleepiness to coma, and it can endanger both respiration and cardiovascular health. These effects are potentially serious enough to be fatal, though as with benzodiazapines fatal outcomes from overdose almost always involves additional depressant drugs in combination. [28]

[top]Reported Deaths



[top]Producing Zolpidem



[top]Forms of Zolpidem



[top]Legal Status of Zolpidem

[top]United Nations

Zolpidem is a controlled substance 21 CFR 1308.14

[top]USA

Zolpidem is Schedule IV in the U.S. This means it is illegal to sell without a license and illegal to possess without a valid license or prescription

[top]EU

Zolpidem is available only with a prescription and is a Class C drug under the Misuse of Drugs Act.

[top]Other Countries



[top]History of Zolpidem



[top]Insights for Zolpidem



[top]More Zolpidem Sections and Information


Zolpidem image Gallery
: Post and view pictures of Zolpidem.
Addiction Calculator: Do this small test to calculate your dependency.


[top]The Latest Zolpidem Threads


  Article / Page Starter Last Post Comments Views
omgbethany
29-09-2016 07:04
by ladywolf2012 Go to last post
1 104
Ready2quit
28-09-2016 18:46
by Sushi Go to last post
3 119
AZ8990
25-09-2016 18:04
by Hardstepa Go to last post
5 20,351
TramsUckdol
25-09-2016 04:28
by TramsUckdol Go to last post
4 163
CABS205
25-09-2016 00:41
by bloodskall Go to last post
217 134,128
puffyjones
23-09-2016 07:55
by puffyjones Go to last post
0 183
Catharsys
23-09-2016 07:53
by Catharsys Go to last post
2 154
Whatdidido
22-09-2016 21:25
by skippy1234 Go to last post
3 1,228
ecodesmoker
21-09-2016 05:40
by ecodesmoker Go to last post
10 397
SarcasticCaptain
21-09-2016 03:55
by hunterhoffman Go to last post
1 128


[top]References

  1. ^ a b Haas, S. L. Da. Schoemaker, R. C. Van Gerven, J. M. A. Hoever, P. Cohen, A. F. Dingemanse, J. (2010) Pharmacokinetics, pharmacodynamics and the pharmacokinetic/ pharmacodynamic relationship of zolpidem in healthy subjects. Journal of Psychopharmacology 24, 1619-1629.
  2. ^ Harry G. Brittain. (2012) Profiles of Drug Substances, Excipients and Related Methodology, Vol. 37 - Ch. 11: Zolpidem Tartrate. Pages 413–438. ISBN: 9780123972200
  3. ^ J.S. Wang, C.L. DeVane, (2003). Pharmacokinetics and drug interactions of the sedative hypnotics, Psychopharmacol. Bull. 37 10–29.
  4. ^ W.M. Herrmann, S.T. Kubicki, S. Boden, et al., (1993) Pilot controlled, double-blind study of the hypnotic effects of zolpidem in patients with chronic ‘‘learned’’ insomnia: psychometric and polysomnographic evaluation, J. Int. Med. Res. 21. 306–322.
  5. ^ J. Kummer, L. Guendel, J. Linden, et al., (1993) Long-term polysomnographic study of the efficacy and safety of zolpidem in elderly psychiatric in-patients with insomnia, J. Int. Med. Res. 21. 171–184
  6. ^ K. J.Holm, K. L. Goa, (2000) Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia, Drugs 59. 865–889.
  7. ^ G. Perrault, E. Morel, D.J. Sanger, B. Zivkovic, (1992) Lack of tolerance and physical dependence upon repeated treatment with the novel hypnotic zolpidem, J. Pharmacol. Exp. Ther. 263. 298–303.
  8. ^ R.R. Griffiths, C.A. Sannerud, N.A. Ator, J.V. Brady, (1992) Zolpidem behavioral pharmacology in baboons: self-injection, discrimination, tolerance and withdrawal J. Pharmacol. Exp. Ther. 260 1199–1208.
  9. ^ Holm KJ, Goa KL. (2000) Zolpidem: An Update of its Pharmacology, Therapeutic Efficacy and Tolerability in the Treatment of Insomnia. Drugs. 59(4):865.
  10. ^ D.B. Pritchett, P.H. Seeburg. (1990) Gamma-aminobutyric acidA receptor alpha 5-subunit creates novel type II benzodiazepine receptor pharmacology. J. Neurochem. 54. 1802–1804.
  11. ^ Merck Index, fifteenth edition (2013)
  12. ^ Mario Giovanni Terzano, Mariano Rossi, Vincenzo Palomba, Arianna Smerieri and Liborio Parrino. (2003)New Drugs for Insomnia: Comparative Tolerability of Zopiclone, Zolpidem and Zaleplon. Drug Safety; 26 (4): 261-282
  13. ^ Anonymous. (1993) Zolpidem for insomnia. Med. Lett. Drugs Ther. 35. 35–36.
  14. ^ R. Cavallaro, M.G. Regazzetti, G. Covelli, E. Smeraldi, (1993) Tolerance and withdrawal with zolpidem, Lancet 342 (1993) 374–375.
  15. ^ R. Garnier, E. Guerault, D. Muzard, et al., (1994) Acute zolpidem poisoning—analysis of 344 cases J. Toxicol. Clin. Toxicol. 32. 391–404.
  16. ^ Leufkens TR, Lund JS, Vermeeren A . (2009)Highway driving performance and cognitive functioning the morning after bedtime and middle-of-the-night use of gaboxadol, zopiclone and zolpidem. J Sleep Res. 18(4):387-96.
  17. ^ Cubała WJ, Landowski J. (2007) Seizure following sudden zolpidem withdrawal. Prog Neuropsychopharmacol Biol Psychiatry. 31:539–540.
  18. ^ Yi-Wei Yeh, Hsin-An Chang, and Chih-Lun Chen (2008) Zolpidem Dependence, Withdrawal Seizure and Comorbidity Following Different Outcomes: Two case Reports and a Review of the Literature. J Med Sci 28(6):263-267
  19. ^ Mortaz Hejri et al. (2013) Zolpidem-induced suicide attempt: a case report. DARU Journal of Pharmaceutical Sciences 21:77.
  20. ^ John S. Markowitz, Timothy D. Brewerton. (1996) Zolpidem Induced Psychosis. Annals of Clinical Psychiatry, Vol. 8, No. 2, 1996
  21. ^ Curtis J. Elko; Jefferey L. Burgess; William 0. Robertson. (1998) Zolpidem-Associated Hallucinations and Serotonin Reuptake Inhibition: A Possible Interaction. Clinical Toxicology, 36(3), 195-203
  22. ^ MING-JUN TSAI, YI-HUNG TSAI, and YAW-BIN HUANG. (2007) Compulsive activity and anterograde amnesia after zolpidem use (2007) Clinical Toxicology 45, 179–181
  23. ^ Dolder CR, Nelson MH. (2008) Hyposedative-induced complex behaviours: incidence, mechanisms and management. CNS Drugs 22:1021–1036.
  24. ^ Tsai JH, Yang P, Chen CC, et al. (2009) Zolpidem-induced amnesia and somnambulism: Rare occurrences? European Neuropsychopharmacology. 2009;19(1):74–76.
  25. ^ Chiang A, Krystal A. (2008) Report of two cases where sleep related eating behavior occurred with the extended-release formulation but not the immediate-release formulation of a sedative-hypnotic agent. Journal of Clinical Sleep Medicine 4(2):155-6
  26. ^ Gibson, C. E. Caplan, J. P. (2011) Zolpidem-Associated Parasomnia with Serious Self-Injury: A Shot in the Dark. Psychosomatics 52:88–91
  27. ^ Tsai MJ, Tsai YH, Huang YB. (2007) Compulsive behavior and anterograde amnesia after zolpidem use. Clin Toxicol (Phila) 45:179–181.
  28. ^ R. Garnier, E. Guerault, D. Muzard, et al. (1994). Acute zolpidem poisoning—analysis of 344 casesJ. Toxicol. Clin. Toxicol. 32. 391–404.


Created by makin, 21-08-2012 at 03:35
Last edited by Calliope, 01-07-2016 at 06:43
Last comment by Calliope on 30-06-2016 at 11:29
6 Comments, 54,697 Views

Share this on:
Page Tools


Posting Rules
You may not create new articles
You may not edit articles
You may not protect articles

You may not post comments
You may not post attachments
You may not edit your comments

BB code is On
Smilies are On
[IMG] code is On
HTML code is Off

Sitelinks: Information:

All times are GMT +1. The time now is 19:55.


Copyright: SIN Foundation 2003 - 2014, All rights reserved