Chemistry:Triazolam

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Short description: Triazolobenzodiazepine class medication
Triazolam
Triazolam.svg
Triazolam ball-and-stick model.png
Clinical data
Trade namesHalcion
AHFS/Drugs.comMonograph
MedlinePlusa684004
License data
Pregnancy
category
  • AU: C[1]
  • US: X (Contraindicated)[1]
Routes of
administration		Oral (by mouth)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability44% (oral route), 53% (sublingual)
MetabolismLiver
Onset of action15–30 minutes[2]
Elimination half-life1.5–5.5 hours
ExcretionKidney
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC17H12Cl2N4
Molar mass343.21 g·mol−1
3D model (JSmol)
  (verify)

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.[3] It possesses pharmacological properties similar to those of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia.[4] In addition to the hypnotic properties, triazolam's amnesic, anxiolytic, sedative, anticonvulsant, and muscle relaxant properties are pronounced as well.[5]

Triazolam was initially patented in 1970 and went on sale in the United States in 1982.[6] In 2017, it was the 289th most commonly prescribed medication in the United States, with more than one million prescriptions.[7]

Medical uses

Triazolam is usually used for short-term treatment of acute insomnia and circadian rhythm sleep disorders, including jet lag. It is an ideal benzodiazepine for this use because of its fast onset of action and short half-life. It puts a person to sleep for about 1.5 hours, allowing its user to avoid morning drowsiness. Triazolam is also sometimes used as an adjuvant in medical procedures requiring anesthesia[4] or to reduce anxiety during brief events, such as MRI scans and nonsurgical dental procedures. Triazolam is ineffective in maintaining sleep, however, due to its short half-life, with quazepam showing superiority.[8]

Triazolam is frequently prescribed as a sleep aid for passengers travelling on short- to medium-duration flights. If this use is contemplated, the user avoiding the consumption of alcoholic beverages is especially important, as is trying a ground-based "rehearsal" of the medication to ensure that the side effects and potency of this medication are understood by the user prior to using it in a relatively more public environment (as disinhibition can be a common side effect, with potentially severe consequences). [citation needed] Triazolam causes anterograde amnesia, which is why so many dentists administer it to patients undergoing even minor dental procedures. This practice is known as sedation dentistry.[9]

Side effects

Adverse drug reactions associated with the use of triazolam include:

Triazolam, although a short-acting benzodiazepine, may cause residual impairment into the next day, especially the next morning. A meta-analysis demonstrated that residual "hangover" effects after nighttime administration of triazolam such as sleepiness, psychomotor impairment, and diminished 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.[11] Confusion and amnesia have been reported.[12]

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.[13]

Tolerance, dependence, and withdrawal

Main page: Medicine:Benzodiazepine withdrawal syndrome

A review of the literature found that long-term use of benzodiazepines, including triazolam, is associated with drug tolerance, drug dependence, rebound insomnia, and CNS-related adverse effects. Benzodiazepine hypnotics should be used at their lowest possible dose and for a short period of time. Nonpharmacological treatment options were found to yield sustained improvements in sleep quality.[14] A worsening of insomnia (rebound insomnia) compared to baseline may occur after discontinuation of triazolam, even following short-term, single-dose therapy.[15]

Other withdrawal symptoms can range from mild unpleasant feelings to a major withdrawal syndrome, including stomach cramps, vomiting, muscle cramps, sweating, tremor, and in rare cases, convulsions.[10]

Contraindications

Benzodiazepines require special precautions if used in the elderly, during pregnancy, in children, in alcoholics, or in other drug-dependent individuals and individuals with comorbid psychiatric disorders.[16] Triazolam belongs to the Pregnancy Category X of the FDA.[17][1] It is known to have the potential to cause birth defects.

Elderly

Triazolam, similar to other benzodiazepines and nonbenzodiazepines, 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] Daytime withdrawal effects can occur.[19]

An extensive review of the medical literature regarding the management of insomnia and the elderly found considerable evidence of the effectiveness and durability of nondrug treatments for insomnia in adults of all ages and that these interventions are underused. Compared with the benzodiazepines including triazolam, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. 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, daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls.[19] One study found no evidence of sustained hypnotic efficacy throughout the 9 weeks of treatment for triazolam.[19]

In addition, the effectiveness and safety of long-term use of these agents remain to be determined. More research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.[20]

Interactions

Ketoconazole and itraconazole have a profound effect on the pharmacokinetics of triazolam, leading to greatly enhanced effects.[21] Anxiety, tremor, and depression have been documented in a case report following administration of nitrazepam and triazolam. Following administration of erythromycin, repetitive hallucinations and abnormal bodily sensations developed. The patient had, however, acute pneumonia, and kidney failure.[citation needed] Co-administration of benzodiazepine drugs at therapeutic doses with erythromycin may cause serious psychotic symptoms, especially in those with other physical complications.[22] Caffeine reduces the effectiveness of triazolam.[23] Other important interactions include cimetidine, diltiazem, fluconazole, grapefruit juice, isoniazid, itraconazole, nefazodone, rifampicin, ritonavir, and troleandomycin.[24][25] Triazolam should not be administered to patients on Atripla.[why?]

Overdose

Symptoms of an overdose[4] include:

  • Coma
  • Hypoventilation (respiratory depression)
  • Somnolence (drowsiness)
  • Slurred speech
  • Seizures[10]

Death can occur from triazolam overdose, but is more likely to occur in combination with other depressant drugs such as opioids, alcohol, or tricyclic antidepressants.[26]

Pharmacology

The pharmacological effects of triazolam are similar to those of most other benzodiazepines. It does not generate active metabolites.[4] Triazolam is a short-acting benzodiazepine, is lipophilic, and is metabolised hepatically via oxidative pathways. The main pharmacological effects of triazolam are the enhancement of the neurotransmitter GABA at the GABAA receptor.[27] The half-life of triazolam is only 2 hours making it a very short acting benzodiazepine drug.[28] It has anticonvulsant effects on brain function.[29]

History

Its use at low doses has been deemed acceptable by the U.S. Food and Drug Administration (FDA) and several other countries.[4]

Society and culture

Recreational use

Triazolam, like other benzodiazepines, is susceptible to misuse and abuse. Its rapid onset of action and short half life contribute to its abuse potential, but its relative obscurity compared to other fast-acting benzodiazepines (such as alprazolam or lorazepam) prevent its abuse from becoming particularly commonplace. Likewise, because it is not prescribed as often or as readily as alprazolam or lorazepam, there is less triazolam available to be diverted for recreational use.[30]

Legal status

Triazolam is a Schedule IV drug under the Convention on Psychotropic Substances[31] and the U.S. Controlled Substances Act.

Brandnames

The drug is marketed in English-speaking countries under the brand names Apo-Triazo, Halcion, Hypam, and Trilam. Other names include 2'-chloroxanax, chloroxanax, triclazolam, and chlorotriazolam.[citation needed]

References

  1. ↑ 1.0 1.1 1.2 "Triazolam (Halcion) Use During Pregnancy". 18 September 2020. https://www.drugs.com/pregnancy/triazolam.html. 
  2. ↑ "What Is Triazolam Used For?" (in en). 2022-11-01. https://www.icliniq.com/articles/drug-and-supplements/triazolam. 
  3. ↑ "Benzodiazepine Names". non-benzodiazepines. http://www.non-benzodiazepines.org.uk/benzodiazepine-names.html. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Wishart, David (2006). "Triazolam". DrugBank. http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD00313.txt. 
  5. ↑ "Benzodiazepine metabolism: an analytical perspective". Current Drug Metabolism 9 (8): 827–844. October 2008. doi:10.2174/138920008786049258. PMID 18855614. https://zenodo.org/record/1067769. 
  6. ↑ "B". A Historical Dictionary of Psychiatry. Oxford University Press. 2005. ISBN 9780190292010. https://books.google.com/books?id=juAJCAAAQBAJ&pg=PT66. 
  7. ↑ "Triazolam - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Triazolam. 
  8. ↑ "Quazepam versus triazolam in patients with sleep disorders: a double-blind study". International Journal of Clinical Pharmacology Research 13 (3): 173–177. 1993. PMID 7901174. 
  9. ↑ "Comparison of Triazolam and Zaleplon for Sedation of Dental Patient". September 2005. http://www.dentistrytoday.com/ce-articles/286-comparison-of-triazolam-and-zaleplon-for-sedation-of-dental-patients. 
  10. ↑ 10.0 10.1 10.2 "Halcion- triazolam tablet". 10 December 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a0da0dba-a56d-486b-a45b-e8a7cdfbeac6. 
  11. ↑ "Residual effects of hypnotics: epidemiology and clinical implications". CNS Drugs 18 (5): 297–328. 2004. doi:10.2165/00023210-200418050-00003. PMID 15089115. 
  12. ↑ "[Confusional states following administration of short-acting benzodiazepines (midazolam/triazolam)]". Schweizerische Rundschau für Medizin Praxis 80 (24): 673–675. June 1991. PMID 2068441. 
  13. ↑ "FDA expands Boxed Warning to improve safe use of benzodiazepine drug". 23 September 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requiring-boxed-warning-updated-improve-safe-use-benzodiazepine-drug-class.  This article incorporates text from this source, which is in the public domain.
  14. ↑ "Management of insomnia". Journal of the American Pharmaceutical Association 39 (5): 688–96; quiz 713–4. 1999. doi:10.1016/S1086-5802(15)30354-5. PMID 10533351. 
  15. ↑ "Rebound insomnia. A potential hazard following withdrawal of certain benzodiazepines". JAMA 241 (16): 1692–1695. April 1979. doi:10.1001/jama.241.16.1692. PMID 430730. 
  16. ↑ "Benzodiazepine dependence: focus on withdrawal syndrome". Annales Pharmaceutiques Françaises 67 (6): 408–413. November 2009. doi:10.1016/j.pharma.2009.07.001. PMID 19900604. 
  17. ↑ "Halcion triazolam tablets". http://www.fda.gov/Medwatch/SAFETY/2003/03Jun_PI/Halcion_PI.pdf. 
  18. ↑ "Effect of hypnotic drugs on body balance and standing steadiness". Sleep Medicine Reviews 14 (4): 259–267. August 2010. doi:10.1016/j.smrv.2009.10.008. PMID 20171127. 
  19. ↑ 19.0 19.1 19.2 "A double-blind controlled study of chlormethiazole and triazolam as hypnotics in the elderly". Acta Psychiatrica Scandinavica. Supplementum 329 (suppl 329): 104–111. 1986. doi:10.1111/j.1600-0447.1986.tb10544.x. PMID 3529832. 
  20. ↑ "Management of chronic insomnia in elderly persons". The American Journal of Geriatric Pharmacotherapy 4 (2): 168–192. June 2006. doi:10.1016/j.amjopharm.2006.06.006. PMID 16860264. 
  21. ↑ "Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole". Clinical Pharmacology and Therapeutics 56 (6 Pt 1): 601–607. December 1994. doi:10.1038/clpt.1994.184. PMID 7995001. 
  22. ↑ "Hallucinations after a therapeutic dose of benzodiazepine hypnotics with co-administration of erythromycin". Psychiatry and Clinical Neurosciences 50 (6): 337–339. December 1996. doi:10.1111/j.1440-1819.1996.tb00577.x. PMID 9014234. 
  23. ↑ "Caffeine moderately antagonizes the effects of triazolam and zopiclone on the psychomotor performance of healthy subjects". Pharmacology & Toxicology 70 (4): 286–289. April 1992. doi:10.1111/j.1600-0773.1992.tb00473.x. PMID 1351673. 
  24. ↑ "Pharmacokinetics and drug interactions of the sedative hypnotics". Psychopharmacology Bulletin 37 (1): 10–29. 2003. doi:10.1007/BF01990373. PMID 14561946. http://www.medworksmedia.com/psychopharmbulletin/pdf/12/010-029_PB%20W03_Wang_final.pdf. 
  25. ↑ "Grape fruit juice-drug interactions". Pakistan Journal of Pharmaceutical Sciences 18 (4): 45–57. October 2005. PMID 16380358. 
  26. ↑ "Death attributed to the toxic interaction of triazolam, amitriptyline and other psychotropic drugs". Forensic Science International 86 (1–2): 35–41. April 1997. doi:10.1016/S0379-0738(97)02110-5. PMID 9153780. 
  27. ↑ "[Chemical and pharmacologic aspects of benzodiazepines]". Schweizerische Rundschau für Medizin Praxis 78 (27–28): 766–772. July 1989. PMID 2570451. 
  28. ↑ Professor heather Ashton (April 2007). "Benzodiazepine equivalency table". http://www.bcnc.org.uk/equivalence.html. 
  29. ↑ "Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines". Life Sciences 36 (8): 737–744. February 1985. doi:10.1016/0024-3205(85)90193-6. PMID 2983169. 
  30. ↑ "Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds". The Journal of Clinical Psychiatry 66 (Suppl 9): 31–41. 2005. PMID 16336040. 

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