Flurazepam

Flurazepam
Names
Trade namesDalmane, Dalmadorm, Fluzepam, others
Other namesFlurazepam hydrochloride
IUPAC name
  • 7-Chloro-1-[2-(diethylamino)ethyl]-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one
Clinical data
Drug classBenzodiazepine[1]
Main usesTrouble sleeping[2]
Side effectsDizziness, poor coordination, falls[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • X (Contraindicated)
Routes of
use		By mouth
Onset of actionWithin 45 min[1]
Duration of actionUp to 8 hrs[1]
Typical dose15 to 30 mg[2]
External links
AHFS/Drugs.comMonograph
MedlinePlusa682051
Legal
Legal status
Pharmacokinetics
Bioavailability83%
MetabolismLiver
MetabolitesN-desalkylflurazepam (active metabolite)
Elimination half-life2.3 hours
N-desalkylflurazepam: 47–100 hours
ExcretionKidney
Chemical and physical data
FormulaC21H23ClFN3O
Molar mass387.88 g·mol−1
3D model (JSmol)
Melting point79.5 °C (175.1 °F)
SMILES
  • FC1=CC=CC=C1C2=NCC(N(CCN(CC)CC)C3=C2C=C(C=C3)Cl)=O
InChI
  • InChI=1S/C21H23ClFN3O/c1-3-25(4-2)11-12-26-19-10-9-15(22)13-17(19)21(24-14-20(26)27)16-7-5-6-8-18(16)23/h5-10,13H,3-4,11-12,14H2,1-2H3 checkY
  • Key:SAADBVWGJQAEFS-UHFFFAOYSA-N checkY

Flurazepam, sold under the brand names Dalmane among others, is a medication used to treat trouble sleeping.[2] It may be useful for up to 4 weeks.[1] It is taken by mouth.[2] Effects begin within 45 minutes and last for up to 8 hours.[1]

Common side effects include dizziness, poor coordination, and falls.[1] Other side effects may include addiction, suicide, and agitation.[1] Use with opioids is generally not recommended.[1] Use during pregnancy may harm the baby.[1] It is a benzodiazepine.[1]

Flurazepam was patented and came into medical use in 1968.[3] In the United Kingdom 30 tablets costs the NHS less than £10 as of 2021.[2] This amount in the United States is about 16 USD.[4]

Medical uses

Flurazepam is officially indicated for mild to moderate insomnia and as such it is used for short-term treatment of patients with mild to moderate insomnia such as difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Flurazepam is a long-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep, though benzodiazepines with intermediate half-lives such as loprazolam, lormetazepam, and temazepam are also indicated for patients with difficulty maintaining sleep.

Dosage

It is taken at a dose of 15 to 30 mg before bed.[2]

Side effects

The most common adverse effects are dizziness, drowsiness, light-headedness, and ataxia. Flurazepam has abuse potential and should never be used with alcoholic beverages or any other substance that can cause drowsiness. Addictive and possibly fatal results may occur. Flurazepam users should only take this drug strictly as prescribed, and should only be taken directly before the user plans on sleeping a full night. Next day drowsiness is common and may increase during the initial phase of treatment as accumulation occurs until steady-state plasma levels are attained.

A 2009 meta-analysis found a 44% higher rate of mild infections, such as pharyngitis or sinusitis, in people taking hypnotic drugs compared to those taking a placebo.[5]

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.[6]

Tolerance and dependence

Main article: Benzodiazepine withdrawal syndrome

A review paper found that long-term use of flurazepam is associated with drug tolerance, drug dependence, rebound insomnia and central nervous system (CNS) related adverse effects. Flurazepam is best used for a short time period and at the lowest possible dose to avoid complications associated with long-term use. Non-pharmacological treatment options however, were found to have sustained improvements in sleep quality.[7] Flurazepam and other benzodiazepines such as fosazepam, and nitrazepam lost some of their effect after seven days administration in psychogeriatric patients.[8] Flurazepam shares cross tolerance with barbiturates and barbiturates can easily be substituted by flurazepam in those who are habituated to barbiturate sedative hypnotics.[9]

After discontinuation of flurazepam a rebound effect or benzodiazepine withdrawal syndrome may occur about four days after discontinuation of medication.[10]

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.[11]

Flurazepam, 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.[12] 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 flurazepam, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy in elderly persons. Tolerability in elderly patients, however, is improved marginally in that benzodiazepines have moderately higher risks of falls, memory problems, and disinhibition ("paradoxical agitation") when compared to non-benzodiazepine sedatives. 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. Chronic use of sedative-hypnotic drugs for the management of insomnia does not have an evidence base and has been discouraged due to concerns including 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 sedative hypnotics has been determined to be no better than placebo after 3 months of therapy and worse than placebo after 6 months of therapy.[13][14]

Pharmacology

Flurazepam is a "classical" benzodiazepine; some other classical benzodiazepines include diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, bromazepam, and clorazepate.[15] Flurazepam generates an active metabolite, N-desalkylflurazepam, with a very long elimination half-life.[16] Flurazepam could be therefore unsuitable as a sleeping medication for some individuals due to next-day sedation; however, this same effect may also provide next-day anxiety relief. Residual 'hangover' effects after nighttime administration of flurazepam, such as sleepiness, impaired psychomotor and cognitive functions, may persist into the next day, which may impair the ability of users to drive safely and increase risks of falls and hip fractures.[17]

Flurazepam is lipophilic, is metabolized hepatically via oxidative pathways. The main pharmacological effect of flurazepam is to increase the effect of GABA at the GABAA receptor via binding to the benzodiazepine site on the GABAA receptor causing an increase influx of chloride ions into the GABAA neuron.[18][19]

Flurazepam is contraindicated in pregnancy. It is recommended to withdraw flurazepam during breast feeding, as flurazepam is excreted in breast milk.[20]

It produces a metabolite with a long half-life, which may stay in the bloodstream for days.[16]

History

It was developed by Roche Pharmaceuticals was one of the first benzo hypnotics (sleeping pills) to be marketed.[21]

Society and culture

Drug misuse

See also: Benzodiazepine drug misuse

Flurazepam is a drug with 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.[22]

Flurazepam is a Schedule IV drug under the Convention on Psychotropic Substances.[23]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 "Flurazepam Monograph for Professionals". Drugs.com. Archived from the original on 6 May 2021. Retrieved 14 December 2021.
  2. 1 2 3 4 5 6 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 508. ISBN 978-0857114105.
  3. ↑ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 538. ISBN 9783527607495. Archived from the original on 2021-11-01. Retrieved 2021-10-22.
  4. ↑ "Flurazepam Prices, Coupons & Savings Tips - GoodRx". GoodRx. Archived from the original on 12 October 2016. Retrieved 14 December 2021.
  5. ↑ Joya, FL; Kripke, DF; Loving, RT; Dawson, A; Kline, LE (2009). "Meta-Analyses of Hypnotics and Infections: Eszopiclone, Ramelteon, Zaleplon, and Zolpidem". Journal of Clinical Sleep Medicine. 5 (4): 377–383. doi:10.5664/jcsm.27552. PMC 2725260. PMID 19968019.
  6. ↑ "FDA expands Boxed Warning to improve safe use of benzodiazepine drug". U.S. Food and Drug Administration (FDA). 23 September 2020. Archived from the original on 24 September 2020. Retrieved 23 September 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  7. ↑ Kirkwood CK (1999). "Management of insomnia". J Am Pharm Assoc (Wash). 39 (5): 688–96, quiz 713–4. doi:10.1016/s1086-5802(15)30354-5. PMID 10533351.
  8. ↑ Viukari M; Linnoila M; Aalto U (January 1978). "Efficacy and side effects of flurazepam, fosazepam, and nitrazepam as sleeping aids in psychogeriatric patients". Acta Psychiatrica Scandinavica. 57 (1): 27–35. doi:10.1111/j.1600-0447.1978.tb06871.x. PMID 24980. S2CID 23137060.
  9. ↑ Rooke KC. (1976). "The use of flurazepam (dalmane) as a substitute for barbiturates and methaqualone/diphenhydramine (mandrax) in general practice". J Int Med Res. 4 (5): 355–9. doi:10.1177/030006057600400510. PMID 18375. S2CID 23780461.
  10. ↑ Hindmarch I. (November 1977). "A repeated dose comparison of three benzodiazepine derivative (nitrazepam, flurazepam and flunitrazepam) on subjective appraisals of sleep and measures of psychomotor performance the morning following night-time medication". Acta Psychiatrica Scandinavica. 56 (5): 373–81. doi:10.1111/j.1600-0447.1977.tb06678.x. PMID 22990. S2CID 38591190.
  11. ↑ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM.; Eschalier, A. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Ann Pharm Fr. 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604.
  12. ↑ Mets, MA.; Volkerts, ER.; Olivier, B.; Verster, JC. (Feb 2010). "Effect of hypnotic drugs on body balance and standing steadiness". Sleep Med Rev. 14 (4): 259–67. doi:10.1016/j.smrv.2009.10.008. PMID 20171127.
  13. ↑ NEJM, 1983, 1994, et seq.
  14. ↑ Bain KT (June 2006). "Management of chronic insomnia in elderly persons". Am J Geriatr Pharmacother. 4 (2): 168–92. doi:10.1016/j.amjopharm.2006.06.006. PMID 16860264.
  15. ↑ Braestrup C; Squires RF (1 April 1978). "Pharmacological characterization of benzodiazepine receptors in the brain". Eur J Pharmacol. 48 (3): 263–70. doi:10.1016/0014-2999(78)90085-7. PMID 639854.
  16. 1 2 "FLURAZEPAM HCl CAPSULES, USP". dailymed.nlm.nih.gov. Archived from the original on 2019-06-17. Retrieved 2021-10-22.
  17. ↑ 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.
  18. ↑ Oelschläger H. (July 4, 1989). "[Chemical and pharmacologic aspects of benzodiazepines]". Schweiz Rundsch Med Prax. 78 (27–28): 766–72. PMID 2570451.
  19. ↑ Lehoullier PF, Ticku MK (March 1987). "Benzodiazepine and beta-carboline modulation of GABA-stimulated 36Cl-influx in cultured spinal cord neurons". Eur. J. Pharmacol. 135 (2): 235–8. doi:10.1016/0014-2999(87)90617-0. PMID 3034628.
  20. ↑ Olive G; Dreux C. (January 1977). "Pharmacologic bases of use of benzodiazepines in peréinatal medicine". Arch Fr Pediatr. 34 (1): 74–89. PMID 851373.
  21. ↑ Shorter, Edward (2005). "B". A Historical Dictionary of Psychiatry. Oxford University Press. ISBN 978-0-19-029201-0. Archived from the original on 2021-08-28. Retrieved 2021-10-22.
  22. ↑ Griffiths RR, Johnson MW (2005). "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". J Clin Psychiatry. 66 Suppl 9: 31–41. PMID 16336040.
  23. ↑ "green-lists". incb.org. Archived from the original on 2015-12-08. Retrieved 2015-12-03.
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