Zaleplon
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Zaleplon
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| Systematic (IUPAC) name | |
| N-[3-(7-cyano-1,5,9-triazabicyclo[4.3.0]nona- 2,4,6,8-tetraen-2-yl)phenyl]-N-ethyl-acetamide |
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| Identifiers | |
| CAS number | |
| ATC code | N05 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C17H15N5O |
| Mol. mass | 305.34 |
| Pharmacokinetic data | |
| Bioavailability | 30% (oral) |
| Metabolism | Hepatic |
| Half life | 1 hour |
| Excretion | Renal |
| Therapeutic considerations | |
| Pregnancy cat. |
C(US) |
| Legal status | |
| Routes | Oral |
Zaleplon (marketed under the brand names Sonata and Starnoc) is a sedative/hypnotic, mainly used for insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class.
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[edit] Chemistry
Pure zaleplon in its solid state is a white to off-white powder that has very low solubility in water as well as low solubility in alcohol and propylene glycol. It has a partition coefficient in octanol/water that is constant (log PC = 1.23) when the pH range is between 1 and 7.
[edit] Pharmacology
Taken orally, zaleplon reaches full concentration in approximately one hour. It is extensively metabolised, into 5-oxo-zaleplon and 5-oxo-desethylzaleplon (the latter via desethylzaleplon), with less than 1% of it excreted intact in urine.
Zaleplon interacts with the GABA receptor complex and shares some of the pharmacological properties of the benzodiazepines. Although not a benzodiazepine, zaleplon can cause similar effects: anterograde amnesia (forgetting the period during the effects) as the most common.
Zaleplon is primarily metabolised by aldehyde oxidase, and its half-life can be affected by substances which inhibit or induce aldehyde oxidase.
A meta-analysis of randomised controlled clinical trials which compared benzodiazepines against Zaleplon or other Z Drugs such as zolpidem and zopiclone, has found that there are few clear and consistent differences between Zaleplon and the benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, quality of sleep, adverse events, tolerance, rebound insomnia and daytime alertness.[1]
Zaleplon has a pharmacological profile similar to benzodiazepines, that is characterized by an increase in SWDS with rapid onset of hypnotic action. Zaleplon is a full agonist for the benzodiazepine α1 receptor located on the GABAA receptor ionophore complex in the brain, with lower affinity for the α2 and α3 subtypes. It selectively enhances the action of GABA similar to but more selectively than benzodiazepines. Zaleplon, although not benzodiazepine-like in chemical structure induces sedative-hypnotic, anticonvulsant and anticonflict effects via by its binding to the central nervous system (CNS) type benzodiazepine receptors. The elimination half life of zaleplon is 1 hour irrespective of dose. Absorption is rapid. Zaleplon can be classed as an ultra short acting sedative hypnotic drug for the treatment of insomnia characterised by difficulty in falling asleep. Zaleplon increases EEG power density in the delta frequency band and a decrease in the energy of the theta frequency band. In tests on rabbits zaelplon shows drowsy pattern of spontaneous EEG characterized by high-voltage slow waves and desynchronization of hippocampal theta waves and an increase in the energy of the delta frequency band on the spectral analysis of the electroencephalogram.[2]
[edit] Elderly
An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines, the nonbenzodiazepine (including zaleplon) sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, 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. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.[3]
[edit] Side-effects
Zaleplon may cause hallucinations, abnormal behavior, severe confusion, day-time drowsiness, dizziness or lightheadedness, unsteadiness and/or falls, double vision or other vision problems, agitation, headache, nausea, vomiting, diarrhea or abdominal pain, depression, muscle weakness, tremor, vivid or abnormal dreams and memory difficulties or amnesia.
Zaleplon is habit-forming, meaning addiction may occur. Stopping this medication suddenly after prolonged or frequent use may cause withdrawal effects such as mood changes, anxiety, and restlessness.
[edit] Carcinogenicity
A recent extensive analysis of FDA data and clinical trials has demonstrated that nonbenzodiazepine Z-drugs cause cancer in humans. The data shows that trial subjects receiving hypnotic drugs had an increased the risk of developing cancer and malignancies. There have been 15 epidemiologic studies which have shown that hypnotic drugs cause increased mortality, mainly due to increased cancer deaths. The cancers included cancer of the brain, lung, bowel, breast, and bladder, and the neoplasms. Initially FDA reviewers did not want to approve the drugs due to concerns of cancer but ultimately changed their mind and approved the drugs despite the concerns. FDA data has shown that zolpidem, zaleplon and eszopiclone are clastogenic and cause cancer in rodents. Benzodiazepine agonists are associated with an increased risk of ovarian cancer in humans. Zopiclone was reportedly refused a product license by the FDA due to indications that zopiclone caused cancer. Development of a malignant neoplasm has been associated with zolpidem usage but the rate of incidence of neoplasm in zolpidem users is as yet unknown. The rates, in clinical trials for the nonbenzodiazepine Z drugs, of malignancies and neoplasms are significantly higher in hypnotic groups than in placebo groups. Also the analysis of clinical trials and FDA data showed that eszopiclone, zaleplon, and zolpidem appeared to have an adverse effect on the immune system causing an increased rate of infections and colds in hypnotic users. Suppression of immune function might be the cause of the increased rate of cancer in nonbenzodiazepine hypnotic users. Indiplon has also shown an increased rate of cancers in clinical trials. The review author concluded saying; "the likelihood of cancer causation is sufficiently strong now that physicians and patients should be warned that hypnotics possibly place patients at higher risk for cancer".[4]
[edit] Recreational use
Zaleplon (Sonata) has a relatively high potential to be abused. Often this use involves a different delivery method (insufflation) to induce effects faster.
The side effects of zaleplon are greatly increased when taken improperly, especially anterograde amnesia - the inability to remember the time during which one was under the influence of the drug. Because of this, a person may lose track of how much zaleplon they ingested, and take more than they originally intended. Zaleplon is a nonbenzodiazepine drug, and research on other drugs in this class has indicated that their potential for abuse was far lower than that of benzodiazepine drugs, but that they still carried a risk higher than first believed. The study specifically mentions persons with prior substance abuse problems as individuals with a high risk for addiction to nonbenzodiazepine type drugs. [5]
[edit] References
- ^ Dündar, Y; Dodd S, Strobl J, Boland A, Dickson R, Walley T. (Jul 2004). "Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis.". Hum Psychopharmacol. 19 (5): 305–22. doi:. PMID 15252823.
- ^ Noguchi H; Kitazumi K, Mori M, Shiba T. (Mar 2004). "Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats." (pdf). J Pharmacol Sci. 94 (3): 246–51. doi:. PMID 15037809.
- ^ Bain KT (Jun 2006). "Management of chronic insomnia in elderly persons". Am J Geriatr Pharmacother 4 (2): 168–92. doi:. PMID 16860264.
- ^ Kripke, Daniel F (2008). "Evidence That New Hypnotics Cause Cancer" (PDF). Department of Psychiatry, UCSD. University of California. “the likelihood of cancer causation is sufficiently strong now that physicians and patients should be warned that hypnotics possibly place patients at higher risk for cancer.”
- ^ Abuse and dependence potential for the non-benzodi...[Addiction. 2003] - PubMed Result
