Zolpidem Review

A Review of Zolpidem

Mariah Bezold

Hypnotic agents and sedatives have been around for centuries; zolpidem being just the latest development to emerge as the result of a drug discovery program that aimed to improve upon the existing benzodiazepine compounds, which include psychoactive drugs such as diazepam. While benzodiazepines possess sedative and hypnotic actions which have since marketed these drugs as excellent muscle relaxants and anti-anxiety medications, high dosages and long-term prescriptions of these compounds facilitated decreasing effectiveness, physical dependence, and extreme withdrawal. Therefore, in the early 1990s, a drug discovery program sought to identify a new, non-benzodiazepine compound that would facilitate a rapid, but temporary sedative effect by binding to the same benzodiazepine receptors so that it might produce the similar effects drugs such as diazepam could produce without resulting in the same addictive effects (1). In order to accomplish this, the research program synthesized different ligands that would attach to the benzodiazepine receptors in the same way diazepam and other benzodiazepine compounds could (1). While many imidazopyridine compounds had affinities for the receptor sites, one such derivative, zolpidem, was selected during the in vitrostudies based on its extremely high affinity for the benzodiazepine receptors in the cerebellum and hippocampus regions of the brain (1).

The basic chemical mechanism which facilitates the soporific effect of both benzodiazepine compounds like diazepam and non-benzodiazepine compounds like zolpidem is as a gamma-aminobutyric acid (GABA_A) agonist (2). This involves both types of compounds attacking the same neurotransmitters in the brain and allosterically binding to the GABA_Areceptors (3). Essentially, by stimulating these neurotransmitters, both diazepam and zolpidem inhibit brain function and activity thereby producing the sedative and hypnotic effect in patients. However, further studies which analyzed the mechanism of zolpidem as a non-benzodiazepine sedative discovered acute differences in the binding of the benzodiazepine receptors. While both zolpidem and drugs such as diazepam have similar affinities for the benzodiazepine GABA_Areceptors on these neurotransmitters, the benzodiazepine compounds share an equal affinity for each of the GABA_Areceptors containing either the α₁, α₂, α₃ or α₅ subunits. Zolpidem, however, possesses a unique affinity for only one of these specific receptors: the GABA_Areceptor containing the α₁ subunit (2). It is this extreme selectivity which makes zolpidem the most desirable agent not only as a marketed hypnotic agent, but also as a subject for research concerning the GABA_Areceptors in the brain. 

Zolpidem has been marketed as a prescription medication primarily for the ephemeral treatment of insomnia. It is fast-acting with a half-life of only three hours; zolpidem is therefore extremely successful in initiating sleep (4). While drugs like diazepam were prescribed for both short-term and long-term treatment of insomnia, zolpidem does not possess long-term soporific effects, which greatly reduces the addictive aspects that are prominent and problematic in benzodiazepine compounds like diazepam. As reported in the CNS Drug Reviews, “The Pharmacology and Mechanism of Action of Zolpidem”, several studies repeatedly reported fewer withdrawal symptoms for zolpidem than diazepam even when administered at higher dosages (1). This suggests that even at higher dosages of zolpidem, little tolerance or physical dependence develops. In fact, a study reported by British Journal of Pharmacologyhas proposed a possible link between zolpidem’s unique therapeutic effects and zolpidem’s unique selectivity concerning the GABA_Areceptors. The study found that the sedative effect of zolpidem was found to be mediated by the α₁-GABA_Areceptor up to doses of at least 60 mg/kg based on the failure of zolpidem to reduce motor activity in the α₁subject group (5). These findings have since marketed zolpidem as the safer and more effective short-term hypnotic therapy to replace benzodiazepine compounds such as diazepam. While zolpidem still carries several other adverse effects such as headache, nausea, amnesia, and anxiety, these adverse effects are found in minor, isolated occurrences (6). 

Its selectivity of GABA_Areceptors and its efficacy as a rapid but brief sedative separate zolpidem as a much safer and more reliable hypnotic drug when compared to diazepam and other benzodiazepine compounds like it. In an age where addiction is unpredictable and unrelenting, drug discovery research programs, such as the one which produced zolpidem, should always consider the unexpected effects of chemical mechanisms which repeatedly target biological receptors. Zolpidem is an excellent example, not only of a product of drug discovery and development, but also of continuing drug discovery and development, since zolpidem remains an important experimental tool for neuropharmacological research (1). Until more selective compounds are discovered and synthesized, zolpidem will remain an important drug for both the prescription treatment of insomnia and for the research and development of improved medicines to replace it for the treatment of insomnia.

 References

1.     Sanger, D., & Depoortere H. (1998). The Pharmacology and Mechanism of Action of Zolpidem. CNS Drug Reviews 4(4), 323-340. doi: 10.1111/j.1527-3458.1998.tb00074.x

2.     Elliot, E., & White, J. (2001). The acute effects of zolpidem compared to diazepam and lorazepam using radiotelemetry. Neuropharmacology, 40(5), 717-721. https://doi.org/10.1016/S0028-3908(00)00196-9

3.     Wright, Brittany T. (http://orcid.org/0000-0002-1501-6596), "Repeated Zolpidem Treatment Effects on Sedative Tolerance, Withdrawal, mRNA Levels, and Protein Expression" (2016). Theses and Dissertations(ETD). Paper 406. http://dx.doi.org/10.21007/ etd.cghs.2016.0408.

4.     Zolpidem. (2018). Retrieved from http://pubchem.ncbi.nlm.nih.gov/compound/zolpidem

5.     Crestani, F., Martin, J., Mohler, H., & Rudolph, U. (2000). Mechanism of action of the hypnotic zolpidem vivo. British Journal Of Pharmacology, 131(7), 1251-1254. https://doi.org/10.1038/sj.bjp.0703717.

6.     Krasowski, M., & Brown, J. (2018). Zolpidem (Ambien): An Introduction for Professionals – Concordia University, St. Paul Online. Retrieved from https://online.csp.edu/blog/forensic-scholars-today/introduction-to-ambien

Bibliography

1.     Crestani, F., Martin, J., Mohler, H., & Rudolph, U. (2000). Mechanism of action of the hypnotic zolpidem vivo. British Journal Of Pharmacology, 131(7), 1251-1254. https://doi.org/10.1038/sj.bjp.0703717.

This article published in the British Journal of Pharmacologysummarizes the methods and findings of a study aimed at exploring the selectivity of zolpidem’s mechanism of action. The study focused on examining zolpidem’s affinity for the α₁-GABA_Areceptor as opposed to the other GABA_Areceptors. The study also examined the effects associated with zolpidem’s selectivity to this specific receptor in order to provide evidence for a causal relationship between the specific α₁-GABA_Areceptor and zolpidem’s soporific effects. This article provides data which does support this hypothesis and provides a possible source for the unique selectivity of zolpidem. The results of this study were included in the review as evidence for the mechanism of action of zolpidem and the possible relationship between zolpidem’s unique mechanism and zolpidem’s unique sedative effects.

2.     Elliot, E., & White, J. (2001). The acute effects of zolpidem compared to diazepam and lorazepam using radiotelemetry. Neuropharmacology, 40(5), 717-721. https://doi.org/10.1016/S0028-3908(00)00196-9

This article published in the journal Neuropharmacologysummarizes the methods and results for a study which compared the acute effects of three different sedatives: zolpidem, diazepam, and lorazepam. The study used a radiotelemetric method to compare three separate actions of these compounds. The study focused on measuring the compounds’ effectiveness as muscle relaxants, hypothermic depressants, and locomotor depressants. The subject of the experimental study were rats which were divided into three treatment groups which each received a single dose of each compound. The study found that while zolpidem had similar effects in comparison to the diazepam and lorazepam, the relative magnitude of the effects differed, most notably with zolpidem producing less hypothermia and muscle relaxation than the other two compounds. The data collected from this study provides substantial discussion on the effectiveness of zolpidem as a safer option with fewer possible adverse effects when compared to diazepam and lorazepam.

3.    Krasowski, M., & Brown, J. (2018). Zolpidem (Ambien): An Introduction for Professionals – Concordia University, St. Paul Online. Retrieved from https://online.csp.edu/blog/forensic-scholars-today/introduction-to-ambien

This article written by Matthew Krasowski and Jerrod Brown at Concordia University for an issue of Forensics Scholars Today, provides a complete summary of zolpidem and its development as a prescription medication for insomnia. The article provides reliable information surrounding the toxicology and misuse of zolpidem as compared with benzodiazepine compounds. Not only does the article provide complete summaries of such topics, the article supplies plenty of references for further reading and research on the zolpidem compound.

4.     Mahapatra, A. K., Sameeraja, N. H., & Murthy, P. N. (2015). Development of Modified-Release Tablets of Zolpidem Tartrate by Biphasic Quick/Slow Delivery System. AAPS PharmSciTech, 16(3), 579–588. http://doi.org/10.1208/s12249-014-0236-2.

This article published in the AAPS PharmSciTech Journalrecords the methods and findings of a development study for modified release tablets of zolpidem. The study was aimed at developing a modified release tablet for zolpidem in order to lengthen the duration of action. The methods of the study involved preparing extended-release tablets of zolpidem tartrate using the biphasic delivery system technology. The mechanism of drug release was analyzed using mathematical models and accelerated stability studies were performed on the formulation. The results of the study were promising for the development and commercialization of an extended-release tablet for zolpidem. The data and discussion supplied by this article provide information on the chemical mechanism of zolpidem as a GABA_Aagonist and how this chemical mechanism differs from benzodiazepines.

5.     Sanger, D., & Depoortere H. (1998). The Pharmacology and Mechanism of Action of Zolpidem. CNS Drug Reviews 4(4), 323-340. https://doi.org/10.1111/j.1527-3458.1998.tb00074.x.

This extensive article published in theCNS Drug Reviewsprovides a complete review of zolpidem, including its discovery, development, commercialization, toxicology, efficacy, and adverse effects. The article supplies much quantitative and qualitative data for analysis. The article also summarizes key differences in the chemical mechanisms between benzodiazepine compounds and non- benzodiazepine compounds like zolpidem. These discussions and data supply substantial background for an abbreviated review of zolpidem.

6.     Wright, Brittany T. (http://orcid.org/0000-0002-1501-6596), "Repeated Zolpidem Treatment Effects on Sedative Tolerance, Withdrawal, mRNA Levels, and Protein Expression" (2016). Theses and Dissertations(ETD). Paper 406. http://dx.doi.org/10.21007/ etd.cghs.2016.0408.

This dissertation written at the University of Tennessee analyzes the effects produced by repeated zolpidem treatment when compared to repeated diazepam treatment. The paper focuses on the effects of sedative tolerance, withdrawal, mRNA levels, and protein expression produced by both compounds. The data provided in this dissertation provides reliable evidence for the safety of zolpidem, specifically when the effects of sedative tolerance and withdrawal are studied. The dissertation found that zolpidem produced fewer evidences of tolerance and withdrawal which the paper attributed to the selectivity of zolpidem with GABA_A receptors when compared to diazepam. The results and data supplied by this dissertation provide further support for the safety of zolpidem as a sedative which produces few addictive effects and withdrawal symptoms. 

7.     Zolpidem. (2018). Retrieved from http://pubchem.ncbi.nlm.nih.gov/compound/zolpidem.

This informational articles published by PubChem provides a complete summary of zolpidem as a chemical compound, including its chemical and physical properties. The page contains reliable information surrounding the compound and provides a technical background for zolpidem as a chemical compound. Particularly, the article summarizes the organic structure of the molecule which aids in understanding the mechanism of action of zolpidem as a GABA_Aagonist.