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Quazepam
2
Clinical data
Trade namesDoral
AHFS/Drugs.comMonograph
MedlinePlusa684001
Pregnancy
category
  • AU: D
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability29–35%
MetabolismLiver
Elimination half-life39 hours
ExcretionKidney
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 InfoCard100.048.329 Edit this at Wikidata
Chemical and physical data
FormulaC17H11ClF4N2S
Molar mass386.79 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 checkY
  • Key:IKMPWMZBZSAONZ-UHFFFAOYSA-N checkY
 ☒NcheckY (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.[1] Quazepam is used for the treatment of insomnia, including sleep induction and sleep maintenance.[2] 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).[3][4] Quazepam is an effective hypnotic which induces and maintains sleep without disruption of the sleep architecture.[5]

It was patented in 1970 and came into medical use in 1985.[6]

Medical uses

[edit]

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.[7][8][9][10] Usual dosage is 7.5 to 15 mg orally at bedtime.[11]

Quazepam is effective as a premedication prior to surgery.[12]

Side effects

[edit]

Quazepam has fewer side effects than other benzodiazepines and less potential to induce tolerance and rebound effects.[13][14] There is significantly less potential for quazepam to induce respiratory depression or to adversely affect motor coordination than other benzodiazepines.[15] The different side effect profile of quazepam may be due to its more selective binding profile to type 1 benzodiazepine receptors.[16][17]

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.[22]

Tolerance and dependence

[edit]

Tolerance may occur to quazepam, but more slowly than seen with other benzodiazepines such as triazolam.[23] Quazepam causes significantly less drug tolerance and withdrawal symptoms including less rebound insomnia upon discontinuation compared to other benzodiazepines.[24][25][26][27] Quazepam may cause less rebound effects than other type1 benzodiazepine receptor selective nonbenzodiazepine drugs due to its longer half-life.[28] 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.[29]

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.[30] 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.[31] 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.[32]

Special precautions

[edit]

Benzodiazepines require special precaution if used during pregnancy, in children, alcohol, or drug-dependent individuals, and individuals with comorbid psychiatric disorders.[33]

Quazepam and its active metabolites are excreted into breast milk.[34]

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.[35]

Elderly

[edit]

Quazepam is more tolerable for elderly patients compared to flurazepam due to its reduced next-day impairments.[36] 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.[37] A further study showed significant balance impairments combined with an unstable posture after administration of quazepam in test subjects.[38] 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.[39]

Interactions

[edit]

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.[40][41]

Pharmacology

[edit]

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.[42][43][44]

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.[45][46] 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.[47][48][49][50] The longer half-life of quazepam may have the advantage, however, of causing less rebound insomnia than shorter-acting subtype selective nonbenzodiazepines.[8][28] 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.[51]

Pharmacokinetics

[edit]
2-Oxoquazepam, a major active quazepam metabolite
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.[52] 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.[53][54][55][56] The elimination half-life range of quazepam is between 27 and 41 hours.[30]

Mechanism of action

[edit]

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.[57][58][59] Quazepam also has some anticonvulsant properties.[60]

EEG and sleep

[edit]

Quazepam has potent sleep-inducing and sleep-maintaining properties.[61][62] 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.[63][64] 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.[65][66]

Drug misuse

[edit]
See also: Benzodiazepine 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.[67]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Quazepam

View on Grokipedia
from Grokipedia
Quazepam, sold under the brand name Doral among others, is a trifluoroethyl hypnotic agent used for the short-term treatment of characterized by difficulty falling asleep, frequent awakenings during the night, or early morning awakenings. It was approved by the U.S. (FDA) in 1985 as a Schedule IV , reflecting its low potential for abuse relative to higher-scheduled drugs, though it carries risks of dependence and withdrawal with prolonged use. Chemically, quazepam is 7-chloro-5-(o-fluorophenyl)-1,3-dihydro-1-(2,2,2-trifluoroethyl)-2H-1,4-benzodiazepine-2-thione, with the molecular formula C₁₇H₁₁ClF₄N₂S and a molecular weight of 386.8. As a (CNS) depressant, it exerts its therapeutic effects by acting as a positive of the receptor, enhancing the inhibitory actions of the gamma-aminobutyric acid (GABA) to produce and properties. Following oral administration, quazepam is rapidly absorbed, achieving peak plasma concentrations of approximately 20 ng/mL after a 15 mg dose within about 2 hours; it undergoes extensive hepatic to active metabolites, including 2-oxoquazepam and N-desalkyl-2-oxoquazepam, with elimination half-lives ranging from 39 to 73 hours. The recommended initial dosage for adults is 7.5 mg at bedtime, which may be increased to 15 mg if needed; a lower dose of 7.5 mg is recommended for elderly patients or those with hepatic impairment to minimize next-day residual effects. Clinical studies have demonstrated its in improving parameters for up to 28 nights, but long-term use is discouraged due to risks of tolerance, dependence, and rebound upon discontinuation. Common adverse effects include daytime drowsiness (12%), headache (5%), fatigue (2%), dizziness (2%), and dry mouth (2%), while serious risks encompass respiratory depression (especially when combined with opioids or alcohol), , paradoxical reactions, and potential for or misuse. Quazepam is available as 15 mg scored tablets and is generally well-tolerated for short-term , though it has been largely supplanted by non-benzodiazepine hypnotics in contemporary practice due to a more favorable side-effect profile.

Medical Uses and Dosage

Indications

Quazepam is indicated for the treatment of in adults, particularly when characterized by difficulty falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. It received FDA approval in 1985 specifically for this short-term application. Clinical trials have established quazepam as an effective agent that reduces sleep latency, increases total duration, and improves overall sleep maintenance. For instance, in an open-label study of psychiatric patients with , a 15 mg dose led to significant improvements in sleep quality after the first night, with 85% of participants rating their sleep as fair to excellent after one week of use. Importantly, these benefits occur without substantial disruption to normal sleep architecture, including minimal changes to EEG-measured stages 2, 3-4, and REM sleep. Due to its potential for tolerance and dependence, quazepam is recommended solely for short-term lasting 7-10 days and is not approved for chronic management. Limited evidence from clinical studies supports its off-label application as a preoperative night , where doses of 30-45 mg improved presurgical sleep quality compared to , potentially offering a profile with fewer severe side effects such as rebound or daytime anxiety relative to alternatives like .

Dosage and Administration

Quazepam is administered orally in the form of 15 mg scored tablets, which may be split along the score line to provide a 7.5 mg dose. The recommended initial dose for adults with is 7.5 mg taken once daily at bedtime, which may be increased to 15 mg if clinically necessary and tolerated. The lowest effective dose should always be used to minimize the risk of adverse effects. For elderly or debilitated patients, a lower initial dose of 7.5 mg is advised due to increased sensitivity to benzodiazepines, often associated with age-related decreases in hepatic, renal, or cardiac function. In patients with hepatic impairment, dose reduction is recommended because of the potential for prolonged and accumulation; caution is also warranted in those with renal impairment, with similar downward adjustments considered based on individual response. Prolonged continuous use beyond 7 to 10 days is generally not recommended, as is typically transient; if longer treatment is required, the dose should be tapered gradually to avoid withdrawal symptoms. In the event of overdose, treatment is primarily supportive, including monitoring , ensuring airway patency, and providing intravenous fluids as needed. The antagonist may be used as an adjunct to reverse if severe respiratory depression or occurs, though it should be administered cautiously due to the risk of precipitating seizures or acute withdrawal. or activated charcoal may be considered if was recent, but is of limited value given quazepam's high protein binding.

Adverse Effects and Precautions

Common Side Effects

The most frequently reported adverse reactions to quazepam in clinical trials are daytime drowsiness (12%), headache (5%), and fatigue (2%), with dizziness and dry mouth each occurring at an incidence of 2%; these rates are notably higher than those observed with placebo (3% for drowsiness, 2% for headache, and 0-1% for the others). Less common effects include dyspepsia (1%), while quazepam generally exhibits a lower incidence of amnesia and ataxia compared to other benzodiazepines like triazolam or temazepam, attributed to its preferential affinity for BZ1 receptor subtypes. In short-term use, these side effects are typically mild and transient, often resolving as the body adjusts to the medication. Management of common side effects primarily involves dose reduction from the initial 15 mg to 7.5 mg at , particularly if persists, or temporary discontinuation if symptoms are severe; this approach minimizes residual effects given quazepam's long . In 2020, the FDA updated the for all benzodiazepines, including quazepam, to highlight risks of , , and overdose, though quazepam's BZ1 selectivity may confer a relatively lower potential for these issues compared to non-selective agents in the class. Overall, quazepam demonstrates a favorable profile with reduced next-day relative to short-acting benzodiazepines, supporting its use for short-term treatment.

Tolerance and Dependence

Tolerance to quazepam develops more slowly compared to short-acting benzodiazepines, owing to its average elimination of 39 hours for the parent compound and its 2-oxoquazepam, with the primary N-desalkyl-2-oxoquazepam having an even longer of 73 hours. This prolonged pharmacokinetic profile results in sustained plasma levels that delay the onset of tolerance, particularly during initial and intermediate-term use. Clinical studies indicate that while quazepam remains effective for over extended periods, tolerance may emerge more noticeably in maintenance after several weeks of continuous administration. Limited long-term trials beyond four weeks reveal conflicting evidence on the severity of this tolerance, with some demonstrating partial loss of efficacy in reducing wake time after onset, while others report sustained benefits due to carryover effects from s. The risk of with quazepam increases with prolonged use, typically after several weeks at therapeutic doses, as with other benzodiazepines, potentially necessitating higher doses to achieve initial effects. However, is considered lower due to quazepam's minimal euphoric effects, which stem from its primary action rather than or reinforcing properties that drive abuse in shorter-acting agents. This reduced potential for psychological reliance makes quazepam less prone to misuse in patients without a history of , though monitoring is still essential for all users. Withdrawal symptoms upon discontinuation of quazepam are generally milder than those associated with other benzodiazepines, attributed to the lingering effects of its long-acting active metabolites that help mitigate abrupt cessation. Common manifestations include rebound , anxiety, and tremors, but studies report no significant rebound even after 15 days of withdrawal following intermediate-term use, with carryover efficacy persisting for 2-3 nights post-discontinuation. Abrupt termination after chronic use can still precipitate more severe reactions, such as seizures, underscoring the need for caution. To prevent tolerance and dependence, quazepam is recommended for strict short-term use, generally limited to 7-10 days, with reevaluation if persists. For patients requiring therapy beyond two weeks, gradual dose tapering is advised to minimize withdrawal risks, starting with the lowest effective dose of 7.5-15 mg and reducing incrementally over several weeks.

Special Populations

In elderly patients, quazepam use requires caution due to increased sensitivity to benzodiazepines, which may manifest as enhanced , , and a higher risk of falls from drowsiness or impaired coordination. These individuals often have diminished hepatic, renal, or cardiac function, amplifying adverse effects. Dosage should start at the lower end, typically 7.5 mg, with close monitoring. Data on next-day impairment are conflicting; while accumulation of quazepam's long-acting metabolites (with half-lives up to 73 hours) can lead to residual cognitive and psychomotor deficits, a small clinical study (n=30) found 7.5 mg and 15 mg doses generally well-tolerated in older adults, though broader caution is advised due to limited evidence. Quazepam is classified under FDA Pregnancy Category C (legacy system), indicating no adequate well-controlled studies in women but potential risks to the based on animal data and class effects. Late- exposure can cause neonatal , including respiratory depression, , and (known as floppy infant syndrome), as well as withdrawal symptoms such as , , tremors, and feeding difficulties. Use is generally avoided unless the potential benefits clearly outweigh these risks, with neonates requiring monitoring for signs of or withdrawal; a registry is available for reporting outcomes. During lactation, quazepam and its active metabolites are excreted into , potentially causing , poor feeding, and inadequate in exposed infants. Infants should be monitored closely for these effects if maternal use is unavoidable, though quazepam is not recommended in individuals due to these risks. Patients with hepatic impairment may experience prolonged elimination of quazepam and its metabolites due to reduced , necessitating dose reductions and careful monitoring to prevent excessive accumulation and enhanced . In renal impairment, caution is advised as the primary (N-desalkyl-2-oxoquazepam) is renally excreted, potentially leading to buildup and prolonged effects, though specific adjustments are not well-defined beyond general dose caution. Quazepam is not approved for use in children, with and not established in pediatric populations under 18 years. Limited data suggest heightened risks of and withdrawal compared to adults, consistent with class concerns in youth.

Contraindications and Interactions

Contraindications

Quazepam is contraindicated in patients with known to quazepam or other benzodiazepines, including rare instances of involving the , , or , which may progress to with symptoms such as dyspnea, throat closing, , or ; such patients should not be rechallenged with the drug. It is also absolutely contraindicated in individuals with established or suspected or pulmonary insufficiency, as these conditions can exacerbate respiratory risks. Relative contraindications include a history of , due to the potential for misuse, , and dependence with benzodiazepines like quazepam. Caution is advised in patients with , where use may be allowable only in limited circumstances owing to possible exacerbation of . Concurrent use with opioids or alcohol is relatively contraindicated, as it heightens the risk of profound sedation and respiratory depression, though not an absolute bar in all cases. Additionally, acute narrow-angle glaucoma represents a relative , given evidence linking benzodiazepines to increased risk of angle closure in predisposed patients, potentially through effects on pupillary muscles. Regarding allergies, quazepam exhibits with other benzodiazepines in hypersensitive individuals, necessitating avoidance in those with prior reactions. The tablets contain inactive ingredients such as , which may trigger reactions in patients with or related allergies, along with potential sensitizers like FD&C Yellow No. 6. Prior to initiating quazepam, baseline assessment for depression or is essential, as benzodiazepines can worsen these conditions and increase the risk of . Recent FDA warnings highlight complex sleep behaviors, such as sleep-driving, as a in at-risk patients, with immediate discontinuation recommended if such events occur to prevent serious injury.

Drug Interactions

Quazepam undergoes hepatic metabolism primarily via the enzyme, leading to pharmacokinetic interactions with inhibitors and inducers of this pathway. Strong CYP3A4 inhibitors, such as , decrease quazepam metabolism, resulting in increased plasma levels and potential for enhanced or . Conversely, CYP3A4 inducers like rifampin accelerate quazepam clearance, reducing its plasma concentrations and thereby diminishing therapeutic efficacy for treatment. Pharmacodynamic interactions with quazepam primarily involve additive (CNS) depression when co-administered with other . Alcohol potentiates quazepam's effects, increasing risks of drowsiness, impaired psychomotor performance, and next-day impairment. Concomitant use with opioids heightens the potential for profound , respiratory depression, , and , necessitating careful monitoring and limited dosing if co-prescribed. Similarly, other CNS depressants, including certain and hypnotics, amplify these effects, often requiring avoidance or dose reduction. Food intake significantly influences quazepam absorption, with studies showing reduced under conditions compared to postprandial administration. If more than 3 hours have elapsed since the last meal, absorption may be decreased; thus, consuming a light meal is recommended prior to dosing in states to optimize . Specific interactions warrant caution with sedating antihistamines (e.g., diphenhydramine) and antidepressants (e.g., those with sedative properties like amitriptyline), which can exacerbate CNS depression and increase risks of excessive drowsiness or falls. Monitoring is advised when quazepam is used with oral contraceptives, as they may alter metabolism variably, potentially affecting quazepam levels. Clinically, these interactions often necessitate dose adjustments, such as lowering quazepam to 7.5 mg or avoiding concurrent use altogether to mitigate risks. involving quazepam heightens overdose potential, particularly , underscoring the need for comprehensive patient medication reviews. Certain combinations, like quazepam with strong inhibitors in high-risk patients, may be contraindicated to prevent severe adverse outcomes.

Pharmacology

Chemical Structure and Properties

Quazepam is a trifluoroethyl derivative of the benzodiazepine class, characterized by the molecular formula C17_{17}H11_{11}ClF4_{4}N2_{2}S. It features a 1,4-benzodiazepine-2-thione core substituted at the 7-position with chlorine, at the 5-position with a 2-fluorophenyl group, and at the N1-position with a 2,2,2-trifluoroethyl moiety, giving it the systematic name 7-chloro-5-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-thione. Developed by Schering Corporation in the 1970s, quazepam has a molecular weight of 386.8 g/mol. As a long-acting benzodiazepine, it exhibits selectivity for the α1 subunit of GABAA receptors, contributing to its hypnotic profile. Physicochemically, quazepam is a white crystalline powder that is soluble in but insoluble in , reflecting its high with a log P value of 4.03. This facilitates rapid penetration into the . The compound demonstrates stability under normal storage conditions.

Mechanism of Action

Quazepam functions as a positive of γ-aminobutyric acid type A (GABAA) receptors, binding to the recognition site located at the interface between the α and γ subunits. This interaction enhances the binding affinity of the endogenous GABA to its site on the receptor, thereby increasing the frequency of opening and promoting chloride influx into neurons. The resulting hyperpolarization inhibits neuronal excitability, amplifying GABA-mediated inhibitory primarily in brain regions involved in sleep regulation, such as the and . The compound demonstrates high selectivity for GABAA receptors containing the α1 subunit, which are predominantly associated with and effects, while exhibiting lower affinity for α2- and α3-containing subtypes linked to and actions. This profile leads to with minimal interference in motor function or anxiety reduction at therapeutic doses. Quazepam's active metabolites, particularly 2-oxoquazepam, further extend its pharmacological effects by exhibiting similar binding characteristics at the site on GABAA receptors, thereby sustaining inhibitory over time. This metabolite-driven prolongation distinguishes quazepam from shorter-acting benzodiazepines within its class.

Pharmacokinetics

Absorption and Distribution

Quazepam is rapidly and well absorbed from the following , with an absorption half-life of approximately 30 minutes in young adults. The absolute has not been determined. Peak plasma concentrations of quazepam are typically achieved within 1 to 2 hours post-dose, averaging about 20 ng/mL after a 15 mg dose. intake, particularly light meals or those with dietary fat, increases both the rate and extent of absorption, potentially enhancing . There is no significant first-pass , contributing to its predictable absorption profile. In the elderly, absorption is somewhat slower, with an absorption half-life of about 0.8 hours compared to 0.4 hours in younger adults. effects onset within 30 minutes due to rapid gastrointestinal uptake. With daily dosing, steady-state plasma concentrations of quazepam and its 2-oxoquazepam are generally reached within 2 to 3 days, though full equilibration for all metabolites may take up to 7 to 13 days. Quazepam exhibits extensive distribution throughout the body, with a estimated at 5 to 8 L/kg, reflecting substantial tissue uptake. It is highly bound to plasma proteins, exceeding 95% for both the parent drug and its major metabolites. The drug's high facilitates rapid penetration into the , supporting its hypnotic action.

Metabolism and Elimination

Quazepam undergoes extensive hepatic metabolism primarily mediated by the enzyme , with minor contributions from and CYP2C19. The parent compound is first converted to the 2-oxoquazepam via oxidative desulfuration. This intermediate is then further metabolized along two primary pathways: N-dealkylation to form N-desalkyl-2-oxoquazepam (another ) and to produce 3-hydroxy-2-oxoquazepam, which is also pharmacologically active. Both major metabolites, 2-oxoquazepam and N-desalkyl-2-oxoquazepam, exhibit activity similar to quazepam, contributing to its prolonged therapeutic effects. Elimination of quazepam occurs mainly through renal and fecal routes following . After oral administration of radiolabeled quazepam, approximately 31% of the dose is recovered in and 23% in over five days, with only trace amounts of unchanged drug excreted in ; the remainder consists of conjugated metabolites. The mean plasma clearance is approximately 0.9 L/h/kg (ranging from 0.6 to 1.2 L/h/kg), reflecting efficient hepatic processing. In patients with hepatic impairment, is slowed, leading to accumulation of the parent drug and active metabolites, which may prolong and intensify effects. The elimination of quazepam and its 2-oxoquazepam is approximately 39 hours (range 27–41 hours), while N-desalkyl-2-oxoquazepam has a longer of about 73 hours (range 50–76 hours). The of 3-hydroxy-2-oxoquazepam is shorter but not well-characterized in plasma, as it is rapidly conjugated and excreted. In elderly individuals, clearance is reduced, resulting in up to a twofold prolongation of the N-desalkyl-2-oxoquazepam (to approximately 146 hours), necessitating dose adjustments to avoid excessive .

Effects on Sleep and EEG

Impact on Sleep Architecture

Quazepam promotes by significantly increasing total time and efficiency while reducing wake time after onset, as demonstrated in controlled polysomnographic studies of chronic insomniacs. In a double-blind, -controlled involving nightly administration of 15 mg or 30 mg quazepam over multiple nights, total time increased by approximately 33 to 42 minutes compared to baseline (from 378 minutes), with efficiency improving from 84% to 91-93%. These effects contribute to better maintenance, particularly effective for middle-of-night awakenings, owing to quazepam's long elimination of about 39 hours and active metabolites that provide sustained coverage without marked next-day impairment. Regarding sleep stages, quazepam exerts minimal disruptive effects, with no significant suppression of (stages 3 and 4) and only modest reductions in sleep percentage (approximately 5-6% decrease at therapeutic doses). Stage 2 sleep increases by 8-9%, but overall architecture is preserved more effectively than with non-selective benzodiazepines, which often substantially suppress deep sleep and to a greater degree. In the same intermediate-term evaluation, these stage changes remained stable without progressive deterioration over 12-16 nights of use. Clinically, quazepam's impact supports short-term treatment of , with polysomnographic data from a 28-night study confirming sustained increases in total time and reductions in latency without evidence of rebound upon discontinuation. Post-treatment, efficiency and reduced wake after onset persisted for several nights, attributed to the accumulation of its long-acting N-desalkyl-2-oxoquazepam. However, while benefits are evident in trials up to four weeks, long-term use beyond this period may lead to subtle shifts in stage distributions, though specific chronic effects require further investigation. In older adults, low doses (7.5-15 mg) similarly enhance total time and latency reduction without notable architecture disruption over seven nights.

EEG Changes

Quazepam, a long-acting with preferential affinity for α1-containing GABA_A receptors, produces characteristic alterations in electroencephalographic (EEG) patterns that contribute to its profile while minimizing certain disruptive effects on activity. During , quazepam elevates activity (typically 13-30 Hz), manifesting as mild cortical activation without eliciting anxiety or excessive . This increase in beta power is observed in preclinical models, where higher doses enhance fast rhythms in the 10-14 Hz range, distinguishing quazepam's effects from those seen with other s. The α1 selectivity of quazepam supports these effects by targeting -promoting pathways with reduced influence on thresholds compared to non-selective agents, thereby preserving overall sleep architecture to a greater degree. In sleep EEG recordings, quazepam sustains spindle activity (sigma band, 12-16 Hz), a hallmark of stage 2 non-REM , without significantly elevating power (4-8 Hz). These EEG modifications underscore quazepam's specificity in promoting consolidated through targeted modulation of thalamocortical oscillations, with minimal intrusion from (8-12 Hz) during light sleep transitions.

History and Non-Medical Use

Development and Approval

Quazepam was synthesized in the 1970s by Schering Corporation as part of efforts to develop selective hypnotic benzodiazepines with enhanced specificity for and maintenance, incorporating a trifluoroethyl substitution at the position to improve its pharmacological profile over earlier benzodiazepines. This structural modification aimed to minimize and effects while preserving properties, positioning quazepam as a targeted agent for treatment. The compound was patented in 1974 (US Patent 3,845,039, filed 1972), reflecting early recognition of its potential in the class. Subsequent clinical trials in the and , including double-blind, -controlled studies, demonstrated quazepam's efficacy in reducing sleep latency, total wake time, and nocturnal awakenings in patients with , with a favorable profile characterized by low incidence of daytime and minimal rebound upon discontinuation. For instance, doses of 15 mg and 30 mg showed significant improvements in sleep efficiency over 7-14 nights compared to , supporting its role as an effective short-term . Quazepam received FDA approval on December 27, 1985, under the brand name Doral, for the short-term treatment of involving difficulties in onset or . Initial indications emphasized its use for up to 7-10 days to avoid dependence risks inherent to benzodiazepines. After a period of discontinuation, quazepam was reintroduced to the market in 2016 under the brand name Doral by Questcor Pharmaceuticals. Post-approval, generic versions became available starting October 13, 2005, broadening access while maintaining the original formulation. In September 2020, the FDA updated the for all benzodiazepines, including quazepam, to highlight risks of abuse, , , withdrawal, and serious respiratory depression when combined with opioids or alcohol.

Drug Misuse

Quazepam exhibits a low potential for relative to other benzodiazepines, such as , owing to its long elimination and lack of significant euphoric effects, which diminish its recreational appeal. Instead, non-medical use typically involves to enhance sleep or alleviate anxiety, often through escalating prescribed doses or obtaining the drug without a prescription. Patterns of misuse for quazepam are uncommon compared to shorter-acting benzodiazepines like , with no widely recognized street names identified in surveillance reports. It occasionally appears in polydrug contexts, particularly when combined with opioids to potentiate sedative effects, contributing to heightened risks in such scenarios. Risks associated with non-medical use include the development of during prolonged misuse, leading to withdrawal symptoms upon cessation, though overdose at therapeutic doses is less lethal due to the absence of significant respiratory depression when used alone. However, combining quazepam with other depressants substantially elevates the danger of fatal overdose. Epidemiologically, quazepam diversion rates remain low, reflecting its limited prevalence in non-medical contexts, with overall benzodiazepine misuse affecting about 1.3% of the U.S. population aged 12 and older as of 2023, though specific data for quazepam are scarce due to its niche use. Classified as a Schedule IV by the DEA since its approval in 1985, quazepam's regulatory status underscores its relatively low abuse liability. To mitigate misuse, interventions emphasize prescription monitoring, patient screening for substance use history, and education on the importance of short-term use to prevent dependence, mirroring risks observed even in legitimate medical applications.

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