Quazepam, sold under brand name Doral among others, is a relatively long-acting

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), sometimes 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, ...

derivative drug developed by the Schering Corporation in the 1970s. Quazepam is used for the treatment of

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy ...

including sleep induction and sleep maintenance. Quazepam induces impairment of motor function and has relatively (and uniquely) selective

hypnotic Hypnotic (from Greek ''Hypnos'', sleep), or soporific drugs, commonly known as sleeping pills, are a class of (and umbrella term for) psychoactive drugs whose primary function is to induce sleep (or surgical anesthesiaWhen used in anesthesia ...

and

anticonvulsant Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of ...

properties with considerably less overdose potential than other benzodiazepines (due to its novel receptor-subtype selectively). Quazepam is an effective hypnotic which induces and maintains sleep without disruption of the sleep architecture. It was patented in 1970 and came into medical use in 1985.

Medical uses

Quazepam is used for short-term treatment of

related to sleep induction or sleep maintenance problems and has demonstrated superiority over other benzodiazepines such as

temazepam Temazepam (sold under the brand names 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 hypn ...

. It had a fewer incidence of side effects than temazepam, including less sedation,

amnesia Amnesia is a deficit in memory caused by brain damage or disease,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be caused temporarily by the use ...

, and less motor-impairment. Usual dosage is 7.5 to 15 mg orally at bedtime. Quazepam is effective as a

premedication Premedication is using medication before some other therapy (usually surgery or chemotherapy) to prepare for that forthcoming therapy. Typical examples include premedicating with a sedative or analgesic before surgery; using prophylactic (prevent ...

prior to surgery.

Side effects

Quazepam has fewer side effects than other benzodiazepines and less potential to induce tolerance and rebound effects. There is significantly less potential for quazepam to induce

respiratory depression Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide ( hypercapn ...

or to adversely affect motor coordination than other

benzodiazepines Benzodiazepines (BZD, BDZ, BZs), sometimes 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, ...

. The different side effect profile of quazepam may be due to its more selective binding profile to type 1 benzodiazepine receptors. *

Ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of t ...

*Daytime

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

Hypokinesia Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a sy ...

Cognitive Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought ...

and performance impairments In September 2020, the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) required the

boxed warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that it ...

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.

Tolerance and dependence

Tolerance may occur to quazepam but more slowly than seen with other benzodiazepines such as

triazolam 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 ...

. Quazepam causes significantly less

drug tolerance Drug tolerance or drug insensitivity is a pharmacological concept describing subjects' reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug's effects; however, this may accelerate tolerance, furthe ...

and less withdrawal symptoms including less

rebound insomnia The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of re ...

upon discontinuation compared to other benzodiazepines. Quazepam may cause less rebound effects than other type1 benzodiazepine receptor selective

nonbenzodiazepine Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep proble ...

drugs due to its longer half-life. 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. No firm conclusions can be drawn, however, 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. Quazepam should be withdrawn gradually if used beyond 4 weeks of use to avoid the risk of a severe

benzodiazepine withdrawal syndrome Benzodiazepine withdrawal syndrome often abbreviated to benzo withdrawal or BZD withdrawal is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines, either medically or recreationally develops a phys ...

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 Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inappr ...

convulsions A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is sometimes used as a ...

and the death of two of the monkeys due to withdrawal-related convulsions. More monkeys died however, in the diazepam-treated monkeys. 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.

Special precautions

Benzodiazepines require special precaution if used in the during pregnancy, in children, alcohol or drug-dependent individuals and individuals with

comorbid In medicine, comorbidity - from Latin morbus ("sickness"), co ("together"), -ity (as if - several sicknesses together) - is the presence of one or more additional conditions often co-occurring (that is, concomitant or concurrent) with a primary ...

psychiatric disorders A mental disorder, also referred to as a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitti ...

. Quazepam and its

active metabolites An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

are excreted into

breast milk Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by mammary glands located in the breast of a human female. Breast milk is the primary source of nutrition for newborns, containing fat, protein, carbohydrates (lac ...

. Accumulation of one of the

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

s of quazepam, ''N''-desalkylflurazepam, may occur in the elderly. A lower dose may be required in the elderly.

Elderly

Quazepam is more tolerable for elderly patients compared to

flurazepam Flurazepam (marketed under the brand names Dalmane and Dalmadorm) 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 ...

due to its reduced next day impairments. However, another study showed marked next day impairments after repeated administration due to accumulation of quazepam and its long-acting metabolites. Thus the medical literature shows conflicts on quazepam's side effect profile. A further study showed significant balance impairments combined with an unstable posture after administration of quazepam in test subjects. 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

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 In neurology, anterograde amnesia is the inability to create new memories after the event that caused amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. ...

), 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.

Interactions

The absorption rate is likely to be significantly reduced if quazepam is taken in the fasted state reducing the

effect of quazepam. If 3 or more hours have passed since eating food then some food should be eaten before taking quazepam.

Pharmacology

Quazepam is a trifluoroalkyl type of benzodiazepine. Quazepam is unique amongst benzodiazepines in that it selectively targets the GABA_A α₁ subunit receptors which are responsible for inducing sleep. Its mechanism of action is very similar to

zolpidem 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 behavior ...

and

zaleplon Zaleplon, sold under the brand names Sonata among others, is a sedative-hypnotic, used to treat insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. It is manufactured by King Pharmaceuticals and Gedeon Richter Plc. ...

in its pharmacology and can successfully substitute for zolpidem and zaleplon in animal studies. Quazepam is selective for type I benzodiazepine receptors containing the α₁ subunit, similar to other drugs such as

and

. As a result, quazepam has little or no

muscle relaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therape ...

properties. Most other benzodiazepines are unselective and bind to type1 GABA_A receptors and type2 GABA_A receptors. Type1 GABA_A receptors include the α₁ subunit containing GABA_A receptors which are responsible for

properties of the drug. Type 2 receptors include the α₂, α₃ and α₅ subunits which are responsible for

anxiolytic An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

action,

and muscle relaxant properties. 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

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

than other benzodiazepines such as

and

perhaps due to its subtype selectivity. The longer half-life of quazepam may have the advantage however, of causing less

than shorter acting subtype selective

nonbenzodiazepines Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive drugs that are very benzodiazepine-like in nature. They are used in the treatment of sleep proble ...

. However, one of the major metabolites of quazepam, the ''N''-desmethyl-2-oxoquazepam (aka ''N''-desalkylflurazepam), binds unselectively to both type1 and type2 GABA_A receptors. The ''N''-desmethyl-2-oxoquazepam metabolite also has a very long half-life and likely contributes to the pharmacological effects of quazepam.

Pharmacokinetics

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. 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. Quazepam and its major active metabolite 2-oxoquazepam both show high selectivity for the type1 GABA_A receptors. The

elimination half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

range of quazepam is between 27 and 41 hours.

Mechanism of action

Quazepam modulates specific GABA_A receptors via the

benzodiazepine site The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Upon opening, the GABAA receptor on ...

on the GABA_A receptor. This modulation enhances the actions of GABA, causing an increase in opening frequency of the chloride ion channel which results in an increased influx of chloride ions into the GABA_A receptors. Quazepam, unique amongst benzodiazepine drugs selectively targets type1 benzodiazepine receptors which results reduced sleep latency in promotion of sleep. Quazepam also has some

properties.

EEG and sleep

Quazepam has potent sleep inducing and sleep maintaining properties. 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 Slow-wave sleep (SWS), often referred to as deep sleep, consists of stage three of non-rapid eye movement sleep. It usually lasts between 70 and 90 minutes and takes place during the first hours of the night. Initially, SWS consisted of both St ...

. This positive effect of quazepam on sleep architecture may be due to its high selectivity for type1 benzodiazepine receptors as demonstrated in animal and human studies. This makes quazepam unique in the

family of drugs.

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.

References

External links

* {{Portal bar , Medicine Benzodiazepines Sedatives Hypnotics Anticonvulsants Muscle relaxants Chloroarenes Fluoroarenes GABAA receptor positive allosteric modulators Thioamides Trifluoromethyl compounds