Loprazolam

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Loprazolam
Loprazolam structure.svg
Loprazolam molecule ball.png
Clinical data
Trade names Dormonoct, Havlane, Sonin, Somnovit, others
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • D
Routes of
administration 		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Hepatic
Elimination half-life 6–12 hours
Excretion Renal
Identifiers
  • (2Z)-6-(2-Chlorophenyl)-2-[(4-methyl-1-piperazinyl)methylene]-8-nitro-2,4-dihydro-1H-imidazo[1,2-a][1,4]benzodiazepin-1-one
CAS Number
PubChem CID
DrugBank
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UNII
KEGG
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ECHA InfoCard 100.293.781 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C23H21ClN6O3
Molar mass 464.91 g·mol−1
3D model (JSmol)
  • [O-][N+](=O)c1cc4c(cc1)N/2C(=O)C(\N=C\2C/N=C4/c3ccccc3Cl)=C\N5CCN(C)CC5
  • InChI=1S/C23H21ClN6O3/c1-27-8-10-28(11-9-27)14-19-23(31)29-20-7-6-15(30(32)33)12-17(20)22(25-13-21(29)26-19)16-4-2-3-5-18(16)24/h2-7,12,14H,8-11,13H2,1H3/b19-14- Yes check.svgY
  • Key:UTEFBSAVJNEPTR-RGEXLXHISA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)
French Loprazolam pills sold as Havlane LOPRA.jpg
French Loprazolam pills sold as Havlane

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.

Contents

It was patented in 1975 and came into medical use in 1983. [2]

Medical uses

Insomnia can be described as a difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Loprazolam is a short-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or have difficulty falling asleep. Hypnotics should only be used on a short-term basis or in those with chronic insomnia on an occasional basis. [3]

Dose

The dose of loprazolam for insomnia is usually 1 mg but can be increased to 2 mg if necessary. In the elderly a lower dose is recommended due to more pronounced effects and a significant impairment of standing up to 11 hours after dosing of 1 mg of loprazolam. The half-life is much more prolonged in the elderly than in younger patients. A half-life of 19.8 hours has been reported in elderly patients. [4] Patients and prescribing physicians should, however, bear in mind that higher doses of loprazolam may impair long-term memory functions. [5]

Side effects

Side effects of loprazolam are generally the same as for other benzodiazepines such as diazepam. [6] The most significant difference in side effects of loprazolam and diazepam is it is less prone to day time sedation as the half-life of loprazolam is considered to be intermediate whereas diazepam has a very long half-life. The side effects of loprazolam are the following:

Residual 'hangover' effects after nighttime administration of loprazolam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day which may increase risks of falls and hip fractures. [7]

Tolerance, dependence and withdrawal

Loprazolam, like all other benzodiazepines, is recommended only for the short-term management of insomnia in the UK, owing to the risk of serious adverse effects such as tolerance, dependence and withdrawal, as well as adverse effects on mood and cognition. Benzodiazepines can become less effective over time, and patients can develop increasing physical and psychological adverse effects, e.g., agoraphobia, gastrointestinal complaints, and peripheral nerve abnormalities such as burning and tingling sensations. [8] [9]

Loprazolam has a low risk of physical dependence and withdrawal if it is used for less than 4 weeks or very occasionally. However, one placebo-controlled study comparing 3 weeks of treatment for insomnia with either loprazolam or triazolam showed rebound anxiety and insomnia occurring 3 days after discontinuing loprazolam therapy, whereas with triazolam the rebound anxiety and insomnia was seen the next day. The differences between the two are likely due to the differing elimination half-lives of the two drugs. [10] [11] These results would suggest that loprazolam and possibly other benzodiazepines should be prescribed for 1–2 weeks rather than 2–4 weeks to reduce the risk of physical dependence, withdrawal, and rebound phenomenon.

Withdrawal symptoms

Slow reduction of the dosage over a period of months at a rate that the individual can tolerate greatly minimizes the severity of the withdrawal symptoms. Individuals who are benzodiazepine dependent often cross to an equivalent dose of diazepam to taper gradually, as diazepam has a longer half-life and small dose reductions can be achieved more easily. [12] [13]

Major complications can occur after abrupt or rapid withdrawal, especially from high doses, producing symptoms such as:

It has been estimated that between 30% and 50% of long-term users of benzodiazepines will experience withdrawal symptoms. [14] However, up to 90% of patients withdrawing from benzodiazepines experienced withdrawal symptoms in one study, but the rate of taper was very fast at 25% of dose per week. [15] Withdrawal symptoms tend to last between 3 weeks to 3 months, although 10–15% of people may experience a protracted benzodiazepine withdrawal syndrome with symptoms persisting and gradually declining over a period of many months and occasionally several years. [16]

Contraindications and special caution

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders. [17] Loprazolam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments. [18]

Mechanism of action

Loprazolam is a benzodiazepine, which acts via positively modulating the GABAA receptor complex via a binding to the benzodiazepine receptor which is situated on alpha subunit containing GABAA receptors. This action enhances the effect of the neurotransmitter GABA on the GABAA receptor complex by increasing the opening frequency of the chloride ion channel. This action allows more chloride ions to enter the neuron which in turn produces such effects as; muscle relaxation, anxiolytic, hypnotic, amnesic and anticonvulsant action. These properties can be used for therapeutic benefit in clinical practice. These properties are also sometimes used for recreational purposes in the form of drug abuse of benzodiazepines where high doses are used to achieve intoxication and or sedation. [19] [20]

Pharmacokinetics

After oral administration of loprazolam, it takes about 3 hours and a half for serum concentration levels of loprazolam plus its active metabolite piperazine N-Oxide to peak (source https://www.medicines.org.uk/emc/product/4192/smpc, significantly longer than other benzodiazepine hypnotics. This delay brings into question the benefit of loprazolam for the treatment of insomnia when compared to other hypnotics (particularly when the major complaint is difficulty falling asleep instead of difficulty maintaining sleep for the entire night), although some studies show that loprazolam may induce sleep within half an hour, indicating rapid penetration into the brain. The peak plasma delay of loprazolam, therefore, may not be relevant to loprazolam's efficacy as a hypnotic. If taken after a meal it can take even longer for loprazolam plasma levels to peak and peak levels may be lower than normal. Loprazolam significantly alters electrical activity in the brain as measured by EEG, with these changes becoming more pronounced as the dose increases. Roughly half of each dose is metabolized in humans to produce an active metabolite, (a piperazine with lesser potency), [21] the other half is excreted unchanged. The half-life of the active metabolite is about the same as the parent compound loprazolam. [22]

See also

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, 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.

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

Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, and restless legs syndrome. It may also be used to cause memory loss during certain medical procedures. It can be taken orally, as a suppository inserted into the rectum, intramuscularly, intravenously or used as a nasal spray. When injected intravenously, effects begin in one to five minutes and last up to an hour. Orally, effects begin after 15 to 60 minutes.

<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">Lorazepam</span> Benzodiazepine medication

Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication. It is used to treat anxiety, trouble sleeping, severe agitation, active seizures including status epilepticus, alcohol withdrawal, and chemotherapy-induced nausea and vomiting. It is also used during surgery to interfere with memory formation and to sedate those who are being mechanically ventilated. It is also used, along with other treatments, for acute coronary syndrome due to cocaine use. It can be given by mouth or as an injection into a muscle or vein. When given by injection, onset of effects is between one and thirty minutes and effects last for up to a day.

<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 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.

<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">Eszopiclone</span> Hypnotic medication

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.

<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 drugs that are benzodiazepine-like in uses, such as for treating insomnia and anxiety.

<span class="mw-page-title-main">Quazepam</span> Benzodiazipine

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.

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

Nordazepam is a 1,4-benzodiazepine derivative. Like other benzodiazepine derivatives, it has amnesic, anticonvulsant, anxiolytic, muscle relaxant, and sedative properties. However, it is used primarily in the treatment of anxiety disorders. It is an active metabolite of diazepam, chlordiazepoxide, clorazepate, prazepam, pinazepam, and medazepam.

<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">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">Chlordiazepoxide</span> Benzodiazepine class sedative and hypnotic medication

Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol and other drugs.

<span class="mw-page-title-main">Benzodiazepine withdrawal syndrome</span> Signs and symptoms due to benzodiazepines discontinuation in physically dependent persons

Benzodiazepine withdrawal syndrome is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines as prescribed develops a physical dependence on them and then reduces the dose or stops taking them without a safe taper schedule.

<span class="mw-page-title-main">Benzodiazepine dependence</span> Medical condition

Benzodiazepine dependence defines a situation in which one has developed one or more of either tolerance, withdrawal symptoms, drug seeking behaviors, such as continued use despite harmful effects, and maladaptive pattern of substance use, according to the DSM-IV. In the case of benzodiazepine dependence, however, the continued use seems to be associated with the avoidance of unpleasant withdrawal reaction rather than from the pleasurable effects of the drug. Benzodiazepine dependence develops with long-term use, even at low therapeutic doses, without the described dependence behavior.

<span class="mw-page-title-main">Effects of long-term benzodiazepine use</span>

The effects of long-term benzodiazepine use include drug dependence as well as the possibility of adverse effects on cognitive function, physical health, and mental health. Long-term use is sometimes described as use not shorter than three months. Benzodiazepines are generally effective when used therapeutically in the short term, but even then the risk of dependency can be significantly high. There are significant physical, mental and social risks associated with the long-term use of benzodiazepines. Although anxiety can temporarily increase as a withdrawal symptom, there is evidence that a reduction or withdrawal from benzodiazepines can lead in the long run to a reduction of anxiety symptoms. Due to these increasing physical and mental symptoms from long-term use of benzodiazepines, slow withdrawal is recommended for long-term users. Not everyone, however, experiences problems with long-term use.

<span class="mw-page-title-main">Benzodiazepine use disorder</span> Medical condition

Benzodiazepine use disorder (BUD), also called misuse or abuse, is the use of benzodiazepines without a prescription and/or for recreational purposes, which poses risks of dependence, withdrawal and other long-term effects. Benzodiazepines are one of the more common prescription drugs used recreationally. When used recreationally benzodiazepines are usually administered orally but sometimes they are taken intranasally or intravenously. Recreational use produces effects similar to alcohol intoxication.

References

  1. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  2. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 539. ISBN   9783527607495.
  3. ↑ Rickels K (1986). "The clinical use of hypnotics: indications for use and the need for a variety of hypnotics". Acta Psychiatrica Scandinavica. Supplementum. 332 (S332): 132–141. doi:10.1111/j.1600-0447.1986.tb08990.x. PMID   2883820. S2CID   46560074.
  4. ↑ Swift CG, Swift MR, Ankier SI, Pidgen A, Robinson J (August 1985). "Single dose pharmacokinetics and pharmacodynamics of oral loprazolam in the elderly". British Journal of Clinical Pharmacology. 20 (2): 119–128. doi:10.1111/j.1365-2125.1985.tb05041.x. PMC   1400680 . PMID   2864049.
  5. ↑ Bareggi SR, Ferini-Strambi L, Pirola R, Franceschi M, Smirne S (1991). "Effects of loprazolam on cognitive functions". Psychopharmacology. 104 (3): 337–342. doi:10.1007/bf02246033. PMID   1681558. S2CID   20804897.
  6. ↑ British National Formulary Benzodiazepines Information
  7. ↑ Vermeeren A (2004). "Residual effects of hypnotics: epidemiology and clinical implications". CNS Drugs. 18 (5): 297–328. doi:10.2165/00023210-200418050-00003. PMID   15089115. S2CID   25592318.
  8. ↑ Committee on Safety of Medicines (1988). "Benzodiazepines, Dependence and Withdrawal Symptoms". Medicines Control Agency UK Government. Retrieved 2007-03-21.
  9. ↑ Ashton CH (1987). "Benzodiazepine Withdrawal: Outcome in 50 Patients". British Journal of Addiction. benzo. 82 (6): 665–671. doi:10.1111/j.1360-0443.1987.tb01529.x. PMID   2886145 . Retrieved 2007-03-21.
  10. ↑ Morgan K, Oswald I (March 1982). "Anxiety caused by a short-life hypnotic". British Medical Journal. 284 (6320): 942. doi:10.1136/bmj.284.6320.942. PMC   1496517 . PMID   6121606.
  11. ↑ Morgan K, Adam K, Oswald I (1984). "Effect of loprazolam and of triazolam on psychological functions". Psychopharmacology. 82 (4): 386–388. doi:10.1007/BF00427691. PMID   6145178. S2CID   26198409.
  12. ↑ McConnell JG (2007). "The Clinicopharmacotherapeutics of Benzodiazepine and Z drug dose Tapering Using Diazepam". BCNC. Archived from the original on 2015-03-07. Retrieved 2007-06-09.
  13. ↑ (Roche Products (UK) Ltd 1990) Benzodiazepines and Your Patients: A Management Programme
  14. ↑ Ashton CH (1985). "Benzodiazepine Dependence and Withdrawal: An Update". benzo org uk. Retrieved 2007-03-21.
  15. ↑ Schweizer E, Rickels K, Case WG, Greenblatt DJ (October 1990). "Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper". Archives of General Psychiatry. Arch Gen Psychiatry. 47 (10): 908–915. doi:10.1001/archpsyc.1990.01810220024003. PMID   2222130.
  16. ↑ Ashton CH (2002). "BENZODIAZEPINES: How They Work and How to Withdraw". benzo org uk. Retrieved 2007-03-21.
  17. ↑ Authier N, Balayssac D, Sautereau M, Zangarelli A, Courty P, Somogyi AA, et al. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Annales Pharmaceutiques Françaises. 67 (6): 408–413. doi:10.1016/j.pharma.2009.07.001. PMID   19900604.
  18. ↑ Mets MA, Volkerts ER, Olivier B, Verster JC (August 2010). "Effect of hypnotic drugs on body balance and standing steadiness". Sleep Medicine Reviews. 14 (4): 259–267. doi:10.1016/j.smrv.2009.10.008. PMID   20171127.
  19. ↑ Bateson AN (2002). "Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal". Current Pharmaceutical Design. ingentaconnect. 8 (1): 5–21. doi:10.2174/1381612023396681. PMID   11812247.
  20. ↑ Ashton CH (2002). "BENZODIAZEPINE ABUSE". Harwood Academic. Retrieved 2007-03-22.
  21. ↑ Clark BG, Jue SG, Dawson GW, Ward A (June 1986). "Loprazolam. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in insomnia". Drugs. 31 (6): 500–516. doi:10.2165/00003495-198631060-00003. PMID   2874007.
  22. ↑ Mamelak M, Bunting P, Galin H, Price V, Csima A, Young T, et al. (April 1988). "Serum and quantitative electroencephalographic pharmacokinetics of loprazolam in the elderly". Journal of Clinical Pharmacology. 28 (4): 376–383. doi:10.1002/j.1552-4604.1988.tb03162.x. PMID   3392236. S2CID   681684.
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