Quazepam

Last updated

Quazepam
Quazepam.svg
Quazepam ball-and-stick model.png
Clinical data
Trade names Doral
AHFS/Drugs.com Monograph
MedlinePlus a684001
Pregnancy
category
  • AU:D
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 29–35%
Metabolism Liver
Elimination half-life 39 hours
Excretion Kidney
Identifiers
  • 7-chloro-5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-3H-1,4-benzodiazepine-2-thione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.048.329 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H11ClF4N2S
Molar mass 386.79 g·mol−1
3D model (JSmol)
  • FC(F)(F)CN1C(=S)C/N=C(\c2cc(Cl)ccc12)c3ccccc3F
  • InChI=1S/C17H11ClF4N2S/c18-10-5-6-14-12(7-10)16(11-3-1-2-4-13(11)19)23-8-15(25)24(14)9-17(20,21)22/h1-7H,8-9H2 Yes check.svgY
  • Key:IKMPWMZBZSAONZ-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Quazepam, sold under the brand name Doral among others, is a relatively long-acting benzodiazepine derivative drug developed by the Schering Corporation in the 1970s. [2] Quazepam is used for the treatment of insomnia, including sleep induction and sleep maintenance. [3] Quazepam induces impairment of motor function and has relatively (and uniquely) selective hypnotic and anticonvulsant properties with considerably less overdose potential than other benzodiazepines (due to its novel receptor-subtype selectivity). [4] [5] Quazepam is an effective hypnotic which induces and maintains sleep without disruption of the sleep architecture. [6]

Contents

It was patented in 1970 and came into medical use in 1985. [7]

Medical uses

Quazepam is used for short-term treatment of insomnia related to sleep induction or sleep maintenance problems and has demonstrated superiority over other benzodiazepines, such as temazepam. It had a lower incidence of side effects than temazepam, including less sedation, amnesia, and motor impairment. [8] [9] [10] [11] Usual dosage is 7.5 to 15 mg orally at bedtime. [12]

Quazepam is effective as a premedication prior to surgery. [13]

Side effects

Quazepam has fewer side effects than other benzodiazepines and less potential to induce tolerance and rebound effects. [14] [15] There is significantly less potential for quazepam to induce respiratory depression or to adversely affect motor coordination than other benzodiazepines. [16] The different side effect profile of quazepam may be due to its more selective binding profile to type 1 benzodiazepine receptors. [17] [18]

In September 2020, the U.S. Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class. [23]

Tolerance and dependence

Tolerance may occur to quazepam, but more slowly than seen with other benzodiazepines such as triazolam. [24] Quazepam causes significantly less drug tolerance and withdrawal symptoms including less rebound insomnia upon discontinuation compared to other benzodiazepines. [25] [26] [27] [28] Quazepam may cause less rebound effects than other type1 benzodiazepine receptor selective nonbenzodiazepine drugs due to its longer half-life. [29] Short-acting hypnotics often cause next-day rebound anxiety. Quazepam, due to its pharmacological profile, does not cause next-day rebound withdrawal effects during treatment. [30]

No firm conclusions can be drawn, however, about whether long-term use of quazepam does not produce tolerance, as few, if any, long-term clinical trials extending beyond 4 weeks of chronic use have been conducted. [31] Quazepam should be withdrawn gradually if used beyond 4 weeks of use to avoid the risk of a severe benzodiazepine withdrawal syndrome developing. Very high dosage administration over prolonged periods of time, up to 52 weeks, of quazepam in animal studies provoked severe withdrawal symptoms upon abrupt discontinuation, including excitability, hyperactivity, convulsions, and the death of two of the monkeys due to withdrawal-related convulsions. More monkeys died however, in the diazepam-treated monkeys. [32] In addition, it has now been documented in the medical literature that one of the major metabolites of quazepam, N-desalkyl-2-oxoquazepam (N-desalkylflurazepam), which is long-acting and prone to accumulation, binds unselectively to benzodiazepine receptors, thus quazepam may not differ all that much pharmacologically from other benzodiazepines. [33]

Special precautions

Benzodiazepines require special precaution if used during pregnancy, in children, alcohol, or drug-dependent individuals, and individuals with comorbid psychiatric disorders. [34]

Quazepam and its active metabolites are excreted into breast milk. [35]

Accumulation of one of the active metabolites of quazepam, N-desalkylflurazepam, may occur in the elderly. A lower dose may be required for the elderly. [36]

Elderly

Quazepam is more tolerable for elderly patients compared to flurazepam due to its reduced next-day impairments. [37] However, another study showed marked next-day impairments after repeated administration due to the accumulation of quazepam and its long-acting metabolites. Thus, the medical literature shows conflicts on quazepam's side effect profile. [38] A further study showed significant balance impairments combined with an unstable posture after administration of quazepam in test subjects. [39] 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, including quazepam, the nonbenzodiazepine 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 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 people with chronic insomnia. [40]

Interactions

The absorption rate is likely to be significantly reduced if quazepam is taken in a fasted state, reducing the hypnotic effect of quazepam. If 3 or more hours have passed since eating food, then some food should be eaten before taking quazepam. [41] [42]

Pharmacology

Quazepam is a trifluoroalkyl type of benzodiazepine. Quazepam is unique amongst benzodiazepines in that it selectively targets the GABAA α1 subunit receptors, which are responsible for inducing sleep. Its mechanism of action is very similar to zolpidem and zaleplon in its pharmacology and can successfully substitute for zolpidem and zaleplon in animal studies. [43] [44] [45]

Quazepam is selective for type I benzodiazepine receptors containing the α1 subunit, similar to other drugs such as zaleplon and zolpidem. As a result, quazepam has little or no muscle-relaxant properties. Most other benzodiazepines are unselective and bind to type1 GABAA receptors and type2 GABAA receptors. Type1 GABAA receptors include the α1 subunit containing GABAA receptors, which are responsible for the hypnotic properties of the drug. Type 2 receptors include the α2, α3 and α5 subunits, which are responsible for anxiolytic action, amnesia, and muscle relaxant properties. [46] [47] Thus, quazepam may have less side effects than other benzodiazepines, but, it has a very long half-life of 25 hours, which reduces its benefits as a hypnotic due to likely next day sedation. It also has two active metabolites with half-lives of 28 and 79 hours. Quazepam may also cause less drug tolerance than other benzodiazepines such as temazepam and triazolam, perhaps due to its subtype selectivity. [48] [49] [50] [51] The longer half-life of quazepam may have the advantage, however, of causing less rebound insomnia than shorter-acting subtype selective nonbenzodiazepines. [9] [29] However, one of the major metabolites of quazepam, the N-desmethyl-2-oxoquazepam (aka N-desalkylflurazepam), binds unselectively to both type1 and type2 GABAA receptors. The N-desmethyl-2-oxoquazepam metabolite also has a very long half-life and likely contributes to the pharmacological effects of quazepam. [52]

Pharmacokinetics

2-Oxoquazepam, a major active quazepam metabolite. 2-Oxoquazepam.svg
2-Oxoquazepam, a major active quazepam metabolite.

Quazepam has an absorption half-life of 0.4 hours with a peak in plasma levels after 1.75 hours. It is eliminated both renally and through feces. [53] The active metabolites of quazepam are 2-oxoquazepam and N-desalkyl-2-oxoquazepam. The N-desalkyl-2-oxoquazepam metabolite has only limited pharmacological activity compared to the parent compound quazepam and the active metabolite 2-oxoquazepam. [ citation needed ] Quazepam and its major active metabolite 2-oxoquazepam both show high selectivity for the type1 GABAA receptors. [54] [55] [56] [57] The elimination half-life range of quazepam is between 27 and 41 hours. [31]

Mechanism of action

Quazepam modulates specific GABAA receptors via the benzodiazepine site on the GABAA receptor. This modulation enhances the actions of GABA, causing an increase in the opening frequency of the chloride ion channel, which results in an increased influx of chloride ions into the GABAA receptors. Quazepam, unique amongst benzodiazepine drugs, selectively targets type 1 benzodiazepine receptors, which results in reduced sleep latency and promotion of sleep. [58] [59] [60] Quazepam also has some anticonvulsant properties. [61]

EEG and sleep

Quazepam has potent sleep-inducing and sleep-maintaining properties. [62] [63] Studies in both animals and humans have demonstrated that EEG changes induced by quazepam resemble normal sleep patterns, whereas other benzodiazepines disrupt normal sleep. Quazepam promotes slow-wave sleep. [64] [65] This positive effect of quazepam on sleep architecture may be due to its high selectivity for type 1 benzodiazepine receptors, as demonstrated in animal and human studies. This makes quazepam unique in the benzodiazepine family of drugs. [66] [67]

Drug misuse

Quazepam is a drug with the potential for misuse. Two types of drug misuse can occur: either recreational misuse, where the drug is taken to achieve a high, or when the drug is continued long term against medical advice. [68]

Related Research Articles

<span class="mw-page-title-main">Benzodiazepine</span> Class of depressant drugs

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, which followed with the development of diazepam (Valium) three years later, 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.

<span class="mw-page-title-main">Hypnotic</span> Drug whose use induces sleep

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).

<span class="mw-page-title-main">Temazepam</span> Insomnia medication

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.

<span class="mw-page-title-main">Zolpidem</span> Hypnotic medication

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 after 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.

<span class="mw-page-title-main">Triazolam</span> Triazolobenzodiazepine class medication

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.

<span class="mw-page-title-main">Zopiclone</span> Hypnotic medication

Zopiclone, sold under the brand name Imovane among others, is a nonbenzodiazepine, specifically a cyclopyrrolone, 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 inducing sedation but not with the anti-anxiety properties of the benzodiazepines.

<span class="mw-page-title-main">Nitrazepam</span> Benzodiazepine sedative

Nitrazepam, sold under the brand name Mogadon among others, is a hypnotic drug of the benzodiazepine class used for short-term relief from severe, disabling anxiety and insomnia. It also has sedative (calming) properties, as well as amnestic, anticonvulsant, and skeletal muscle relaxant effects.

<span class="mw-page-title-main">Flurazepam</span> Hypnotic medication

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.

<span class="mw-page-title-main">Zaleplon</span> Medication used to treat insomnia

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. It was developed by King Pharmaceuticals and approved for medical use in the United States in 1999.

<span class="mw-page-title-main">Nonbenzodiazepine</span> Class of psychoactive drugs

Nonbenzodiazepines, sometimes referred to colloquially as Z-drugs, are a class of psychoactive, depressant, sedative, hypnotic, anxiolytic drugs that are benzodiazepine-like in uses, such as for treating insomnia and anxiety.

<span class="mw-page-title-main">Estazolam</span> Triazolobenzodiazepine tranquilizer drug

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.

<span class="mw-page-title-main">Clorazepate</span> Benzodiazepine medication

Clorazepate, sold under the brand name Tranxene among others, is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. Clorazepate is an unusually long-lasting benzodiazepine and serves as a prodrug for the equally long-lasting desmethyldiazepam, which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.

<span class="mw-page-title-main">Alpidem</span> Anxiolytic medication

Alpidem, sold under the brand name Ananxyl, is a nonbenzodiazepine anxiolytic medication which was briefly used to treat anxiety disorders but is no longer marketed. It was previously marketed in France, but was discontinued due to liver toxicity. Alpidem is taken by mouth.

<span class="mw-page-title-main">Loprazolam</span> Benzodiazepine

Loprazolam (triazulenone) marketed under many brand names is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It is licensed and marketed for the short-term treatment of moderately-severe insomnia.

<span class="mw-page-title-main">Lormetazepam</span> Benzodiazepine medication

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.

<span class="mw-page-title-main">Brotizolam</span> Benzodiazepine

Brotizolam is a sedative-hypnotic thienotriazolodiazepine drug which is a benzodiazepine analog. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties, and is considered to be similar in effect to other short-acting hypnotic benzodiazepines such as triazolam or midazolam. It is used in the short-term treatment of severe insomnia. Brotizolam is a highly potent and short-acting hypnotic, with a typical dose ranging from 0.125 to 0.25 milligrams, which is rapidly eliminated with an average half-life of 4.4 hours.

<span class="mw-page-title-main">Bretazenil</span> Chemical compound

Bretazenil (Ro16-6028) is an imidazopyrrolobenzodiazepine anxiolytic drug which is derived from the benzodiazepine family, and was invented in 1988. It is most closely related in structure to the GABA antagonist flumazenil, although its effects are somewhat different. It is classified as a high-potency benzodiazepine due to its high affinity binding to benzodiazepine binding sites where it acts as a partial agonist. Its profile as a partial agonist and preclinical trial data suggests that it may have a reduced adverse effect profile. In particular bretazenil has been proposed to cause a less strong development of tolerance and withdrawal syndrome. Bretazenil differs from traditional 1,4-benzodiazepines by being a partial agonist and because it binds to α1, α2, α3, α4, α5 and α6 subunit containing GABAA receptor benzodiazepine receptor complexes. 1,4-benzodiazepines bind only to α1, α2, α3 and α5GABAA benzodiazepine receptor complexes.

<span class="mw-page-title-main">QH-II-66</span> Benzodiazepine sedative drug

QH-II-66 (QH-ii-066) is a sedative drug which is a benzodiazepine derivative. It produces some of the same effects as other benzodiazepines, but is much more selective than most other drugs of this class and so produces somewhat less sedation and ataxia than other related drugs such as diazepam and triazolam, although it still retains anticonvulsant effects.

<span class="mw-page-title-main">SL651498</span> Chemical compound

SL651498 is an anxiolytic and anticonvulsant drug used in scientific research, with a chemical structure most closely related to β-carboline derivatives such as abecarnil and gedocarnil. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic.

<span class="mw-page-title-main">CL-218,872</span> Chemical compound

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.

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