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Clinical data | |||
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Trade names | Sonata, Starnoc, Andante, others | ||
AHFS/Drugs.com | Monograph | ||
MedlinePlus | a601251 | ||
Routes of administration | By mouth | ||
Drug class | Pyrazolopyrimidine | ||
ATC code | |||
Legal status | |||
Legal status | |||
Pharmacokinetic data | |||
Bioavailability | 30% (oral) [3] | ||
Metabolism | Liver aldehyde oxidase (91%), CYP3A4 (9%) [4] | ||
Elimination half-life | 1 hr [3] | ||
Excretion | Kidney | ||
Identifiers | |||
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CAS Number | |||
PubChem CID | |||
IUPHAR/BPS | |||
DrugBank | |||
ChemSpider | |||
UNII | |||
KEGG | |||
ChEBI | |||
ChEMBL | |||
CompTox Dashboard (EPA) | |||
ECHA InfoCard | 100.126.674 | ||
Chemical and physical data | |||
Formula | C17H15N5O | ||
Molar mass | 305.341 g·mol−1 | ||
3D model (JSmol) | |||
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Zaleplon, sold under the brand name Sonata among others, is a sedative and hypnotic which is used to treat insomnia. It is a nonbenzodiazepine or Z-drug of the pyrazolopyrimidine class. [5] It was developed by King Pharmaceuticals and approved for medical use in the United States in 1999. [6]
Zaleplon is slightly effective in treating insomnia, [7] primarily characterized by difficulty falling asleep. Zaleplon significantly reduces the time required to fall asleep by improving sleep latency and may therefore facilitate sleep induction rather than sleep maintenance. [8] [9] [10] Due to its ultrashort elimination half-life, zaleplon may not be effective in reducing premature awakenings; however, it may be administered to alleviate middle-of-the-night awakenings. [8] However, zaleplon has not been empirically shown to increase total sleep time. [10] [8]
Zaleplon does not significantly affect driving performance the morning following bedtime administration or 4 hours after middle-of-the-night administration. [11] It may have advantages over benzodiazepines with fewer adverse effects. [12]
Zaleplon is not recommended for chronic use in the elderly. [13] The elderly are more sensitive to the adverse effects of zaleplon such as cognitive side effects. Zaleplon may increase the risk of injury among the elderly. It should not be used while in pregnancy or lactation, and in patients with a history of alcohol or drug abuse, psychotic illness or depression, clinicians should devote more attention. [14]
In addition, some contend the efficacy and safety of long-term use of these agents remains to be enumerated, but nothing concrete suggests long-term use poses any direct harm to a person. [15]
The adverse effects of zaleplon are similar to the adverse effects of benzodiazepines, although with less next-day sedation, [16] and in two studies zaleplon use was found not to cause an increase in traffic accidents, as compared to other hypnotics currently on the market. [17] [18]
Sleeping pills, including zaleplon, have been associated with an increased risk of death. [19]
Some evidence suggests zaleplon is not as chemically reinforcing and exhibits far fewer rebound effects when compared with other nonbenzodiazepines, or Z-drugs. [20]
The CYP3A4 liver enzyme is a minor metabolic pathway for zaleplon, normally metabolizing about 9% of the drug. [4] CYP3A4 inducers such as rifampicin, phenytoin, carbamazepine, and phenobarbital can reduce the effectiveness of zaleplon, and therefore the FDA suggests that other hypnotic drugs be considered in patients taking a CYP3A4 inducer. [4]
Additional sedation has been observed when zaleplon is combined with thioridazine, but it is not clear whether this was due to merely an additive effect of taking two sedative drugs at once or a true drug-drug interaction. [21] Diphenhydramine, a weak inhibitor of aldehyde oxidase, has not been found to affect the pharmacokinetics of zaleplon. [21]
Zaleplon is a high-selectivity, [22] high-affinity ligand of positive modulator sites of GABAA receptors, which enhances GABAergic inhibition of neurotransmission in the central nervous system. The ultrashort half-life gives zaleplon a unique advantage over other hypnotics because of its lack of next-day residual effects on driving and other performance-related skills. [23] [24] Unlike nonselective benzodiazepine drugs and zopiclone, which distort the sleep pattern, zaleplon appears to induce sleep without disrupting the normal sleep architecture. [25]
A meta-analysis of randomized, controlled clinical trials which compared benzodiazepines against zaleplon or other Z-drugs such as zolpidem, zopiclone, and eszopiclone has found 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. [26]
Zaleplon should be understood as an ultrashort-acting sedative-hypnotic drug for the treatment of insomnia. Zaleplon increases EEG power density in the δ-frequency band and a decrease in the energy of the θ-frequency band [27] [28]
Zaleplon is primarily metabolised by aldehyde oxidase into 5-oxozaleplon, and its half-life may be affected by substances which inhibit or induce aldehyde oxidase. According to urine analysis, about 9% of zaleplon is metabolized by CYP3A4 to form desethylzaleplon, which is quickly metabolized by aldehyde oxidase to 5-oxodesethylzaleplon. [4] [3] All of these metabolites are inactive. [3] When taken orally, zaleplon reaches maximum concentration in about 45 minutes. [3]
Zaleplon is classified as a pyrazolopyrimidine. [29] Pure zaleplon in its solid state is a white to off-white powder with very low solubility in water, as well as low solubility in ethanol and propylene glycol. [4] It has a constant octanol-water partition coefficient of log P = 1.23 in the pH range between 1 and 7. [4]
The synthesis starts with the condensation of 3-acetylacetanilide [32] [33] (1) with N,N-dimethylformamide dimethyl acetal (DMFDMA) [34] to give the eneamide (2). The anilide nitrogen is then alkylated by means of sodium hydride and ethyl iodide to give 3. The first step in the condensation with 3-amino-4-cyanopyrazole can be visualized as involving an addition-elimination reaction sequence on the eneamide function to give a transient intermediate such as 5. Cyclization then leads to formation of the fused pyrimidine ring to afford zaleplon (6).
Zaleplon has the potential to be a drug of recreational use, and has been found to have an addictive potential similar to benzodiazepine and benzodiazepine-like hypnotics. [35]
Some individuals use a different delivery method than prescribed, such as insufflation, to induce effects faster. [36]
Anterograde amnesia can occur and can cause one to lose track of the amount of zaleplon already ingested, prompting the ingesting of more than originally planned. [37] [38]
The Federal Aviation Administration allows zaleplon with a 12-hour wait period and no more than twice a week, which makes it the sleep medication with the shortest allowed waiting period after use. [39] The substances with the 2nd shortest period, which is of 24 hours, are zolpidem and ramelteon. [39]
The United States Air Force uses zaleplon as one of the hypnotics approved as a "no-go pill" to help aviators and special-duty personnel sleep in support of mission readiness (with a four-hour restriction on subsequent flight operation). "Ground tests" are required prior to authorization being issued to use the medication in an operational situation. [40] The other hypnotics used as "no-go pills" are temazepam and zolpidem, which both have longer mandatory recovery periods. [40]
Benzodiazepines, colloquially called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, insomnia, and seizures. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955 and was made available in 1960 by Hoffmann–La Roche, who soon followed with diazepam (Valium) in 1963. By 1977, benzodiazepines were the most prescribed medications globally; the introduction of selective serotonin reuptake inhibitors (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide.
Flunitrazepam, also known as Rohypnol among other names, is a benzodiazepine used to treat severe insomnia and assist with anesthesia. As with other hypnotics, flunitrazepam has been advised to be prescribed only for short-term use or by those with chronic insomnia on an occasional basis.
Hypnotic, or soporific drugs, commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to induce sleep and to treat insomnia (sleeplessness).
Temazepam, sold under the brand name Restoril among others, is a medication of the benzodiazepine class which is generally used to treat severe or debilitating insomnia. It is taken by mouth. Temazepam is rapidly absorbed, and significant hypnotic effects begin in less than 30 minutes and can last for up to eight hours. Prescriptions for hypnotics such as temazepam have seen a dramatic decrease since 2010, while anxiolytics such as alprazolam, clonazepam, and lorazepam have increased or remained stable. Temazepam and similar hypnotics, such as triazolam (Halcion) are generally reserved for severe and debilitating insomnia. They have largely been replaced by z-drugs and atypical antidepressants as first line treatment for insomnia.
A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but the majority of them affect the neurotransmitter gamma-aminobutyric acid (GABA). In spite of the fact that each sedative acts in its own way, most produce relaxing effects by increasing GABA activity.
Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and behavioral changes, such as sleep hygiene, have been tried. It decreases the time to sleep onset by about fifteen minutes and at larger doses helps people stay asleep longer. It is taken by mouth and is available in conventional tablets, sublingual tablets, or oral spray.
Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives. It possesses pharmacological properties similar to those of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia. In addition to the hypnotic properties, triazolam's amnesic, anxiolytic, sedative, anticonvulsant, and muscle relaxant properties are pronounced as well.
Zopiclone, sold under the brand name Imovane among others, is a nonbenzodiazepine used to treat difficulty sleeping. Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases the normal transmission of the neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system, via modulating GABAA receptors similarly to the way benzodiazepine drugs do.
Flurazepam is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It produces a metabolite with a long half-life, which may stay in the bloodstream for days. Flurazepam was patented in 1968 and came into medical use the same year. Flurazepam, developed by Roche Pharmaceuticals, was one of the first benzodiazepine hypnotic medications to be marketed.
Eszopiclone, sold under the brand name Lunesta among others, is a medication used in the treatment of insomnia. Evidence supports slight to moderate benefit up to six months. It is taken by mouth.
Nonbenzodiazepines, sometimes referred to colloquially as Z-drugs, are a class of psychoactive drugs that are benzodiazepine-like in uses, such as for treating insomnia and anxiety.
Quazepam, sold under brand name Doral among others, is a relatively long-acting benzodiazepine derivative drug developed by the Schering Corporation in the 1970s. Quazepam is used for the treatment of insomnia including sleep induction and sleep maintenance. Quazepam induces impairment of motor function and has relatively selective hypnotic and anticonvulsant properties with considerably less overdose potential than other benzodiazepines. Quazepam is an effective hypnotic which induces and maintains sleep without disruption of the sleep architecture.
Estazolam, sold under the brand name Prosom among others, is a tranquilizer medication of the triazolobenzodiazepine (TBZD) class, which are benzodiazepines (BZDs) fused with a triazole ring. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. Estazolam is an intermediate-acting oral benzodiazepine. It is used for short-term treatment of insomnia.
Lormetazepam, sold under the brand name Noctamid among others, is a drug which is a short to intermediate acting 3-hydroxy benzodiazepine derivative and temazepam analogue. It possesses hypnotic, anxiolytic, anticonvulsant, sedative, and skeletal muscle relaxant properties.
CL-218,872 is a sedative and hypnotic drug used in scientific research. It has similar effects to sedative-hypnotic benzodiazepine drugs such as triazolam, but is structurally distinct and so is classed as a nonbenzodiazepine hypnotic.
SX-3228 is a sedative and hypnotic drug used in scientific research. It has similar effects to sedative-hypnotic benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine hypnotic.
Suvorexant, sold under the brand name Belsomra, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maintenance in adults. Suvorexant helps with falling asleep faster, sleeping longer, being awake less in the middle of the night, and having better quality of sleep. Its effectiveness is modest, and is similar to that of other orexin antagonists, but is lower than that of benzodiazepines and Z-drugs. Suvorexant is taken by mouth.
Cinazepam is an atypical benzodiazepine derivative. It produces pronounced hypnotic, sedative, and anxiolytic effects with minimal myorelaxant side effects. In addition, unlike many other benzodiazepine and nonbenzodiazepine hypnotics such as diazepam, flunitrazepam, and zopiclone, cinazepam does not violate sleep architecture, and the continuity of slow-wave sleep and REM sleep are proportionally increased. As such, cinazepam produces a sleep state close to physiological, and for that reason, may be advantageous compared to other, related drugs in the treatment of insomnia and other sleep disorders.
Daridorexant, sold under the brand name Quviviq, is an orexin antagonist medication which is used for the treatment of insomnia. Daridorexant is taken by mouth.
Somnifacient, also known as sedatives or sleeping pills, is a class of medications that induces sleep. It is mainly used for treatment of insomnia. Examples of somnifacients include benzodiazepines, barbiturates and antihistamines.
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