Triazolam

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Triazolam
Triazolam structure.svg
Triazolam ball-and-stick.png
Systematic (IUPAC) name
8-chloro-6-(2-chlorophenyl)-1-methyl-4H-
[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
Clinical data
Trade names Halcion
AHFS/Drugs.com monograph
MedlinePlus a684004
Pregnancy cat.
Legal status
Routes Oral
Pharmacokinetic data
Bioavailability 44% (oral), 53% (sublingual)
Metabolism Hepatic
Half-life 1.5–5.5 hours
Excretion Renal
Identifiers
CAS number 28911-01-5 YesY
ATC code N05CD05
PubChem CID 5556
DrugBank DB00897
ChemSpider 5355 YesY
UNII 1HM943223R YesY
KEGG D00387 YesY
ChEBI CHEBI:9674 YesY
ChEMBL CHEMBL646 YesY
Chemical data
Formula C17H12Cl2N4 
Mol. mass 343.2 g/mol
 YesY (what is this?)  (verify)


Triazolam[1] (marketed in English-speaking countries under the brand names Apo-Triazo, Halcion, Hypam, and Trilam. Other names include 2'-chloroxanax, Chloroxanax, 2'-chloro-alprazolam, Triclazolam, and Chlorotriazolam) is a benzodiazepine drug.[2] It possesses pharmacological properties similar to that of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia.[3] In addition to the hypnotic properties triazolam possesses, amnesic, anxiolytic, sedative, anticonvulsant and muscle relaxant properties are also present.[4] Due to its short half-life, triazolam is not effective for patients that suffer from frequent awakenings or early wakening.[5]

History[edit]

Its use at low doses has been deemed acceptable by the American Food and Drug Administration (FDA) and several other countries.[3]

Indications[edit]

Triazolam is usually used for short-term treatment of acute insomnia including jet lag. It is an ideal benzodiazepine for this use because its fast onset of action and short half-life. It puts one to sleep for not more than 1.5 hours (approximately 1–2 hours), allowing its user to avoid morning drowsiness. Triazolam is also sometimes used as an adjuvant in medical procedures requiring anesthesia[3] or to reduce anxiety during brief events like MRI scans. Triazolam is ineffective in maintaining sleep however, due to its short half-life with quazepam showing superiority.[6]

Triazolam is frequently prescribed as a sleep aid for passengers travelling on short to medium duration flights. If this use is contemplated, it is especially important to avoid the consumption of alcoholic beverages, and to do a ground based "trial" 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).

Side effects[edit]

Adverse drug reactions associated with the use of triazolam include:

Triazolam, although a short-acting benzodiazepine, may still 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, 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.[8] Confusion and amnesia has been reported.[9]

Tolerance, dependence, and withdrawal[edit]

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. It recommended that benzodiazepine hypnotics are used at their lowest possible dose and for a short period of time. Non-pharmacological treatment options however, were found to have sustained improvements in sleep quality.[10] Aworsening of insomnia (rebound insomnia) compared to baseline may occur after discontinuation of triazolam even after short term single nightly dose therapy.[11]

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.[12]

Contraindications and special cautions[edit]

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcoholics, or other drug-dependent individuals and individuals with comorbid psychiatric disorders.[13] Triazolam belongs to the Pregnancy Category X of the FDA.[14] This means that it is known to have the potential to cause birth defects.

Elderly[edit]

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.[15] There can be daytime withdrawal effects.[16]

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 triazolam, 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 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.[16] One study found no evidence of sustained hypnotic efficacy throughout the 9 weeks of treatment for triazolam.[16]

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.[17]

Pharmacology[edit]

The pharmacological effects of triazolam are similar to those of most other benzodiazepines. Triazolam does not generate active metabolites.[3] 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.[18] The half-life of triazolam is only 2 hours making it a very short acting benzodiazepine drug.[19] Triazolam has anticonvulsant effects on brain function.[20]

Interactions[edit]

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 renal failure. 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, erythromycin, fluconazole, grapefruit juice, isoniazid, itraconazole, ketoconazole, nefazodone, rifampicin, ritonavir, and troleandomycin.[24][25]

Overdose[edit]

Symptoms of an overdose[3] include

Death can occur from triazolam overdose but is more likely to occur in combination with other depressant drugs such as opiates, alcohol, or tricyclic antidepressants.[28]

Drug misuse[edit]

Triazolam is a drug with the potential for misuse: recreational use wherein the drug is taken to achieve a "high" or continued long-term dosing against medical advice.[29]

Legal status[edit]

Triazolam is a Schedule IV drug under the Convention on Psychotropic Substances[30] and the US Controlled Substances Act.

Synthesis[edit]

Manufacturing triazolam involves the reaction of o-aminobenzophenones with α-amino acid derivatives. The reaction of 2-amino-2′,5-dichlorobenzophenone with glycine ethyl ester gives 7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-H-1,4-benzodiazepin-2-one. By interacting this with phosphorus pentasulfide, the carbonyl group is transformed into a thiocarbonyl group, giving 7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-H-1,4-benzodiazepin-2-thione. The resulting cyclic thioamide on interaction with acetylhydrazine, gives the corresponding acetylhydrazone, which upon heating cyclizes into triazolam.

Triazolam synthesis.png

See also[edit]

References[edit]

  1. ^ DE Patent 2012190
  2. ^ "Benzodiazepine Names". non-benzodiazepines.org.uk. Retrieved 2008-12-29. 
  3. ^ a b c d e Wishart, David (2006). "Triazolam". DrugBank. Retrieved 2006-03-23. 
  4. ^ Mandrioli R, Mercolini L, Raggi MA (October 2008). "Benzodiazepine metabolism: an analytical perspective". Curr. Drug Metab. 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614. 
  5. ^ Rickels K. (1986). "The clinical use of hypnotics: indications for use and the need for a variety of hypnotics". Acta Psychiatrica Scandinavica Suppl. 74 (S332): 132–41. doi:10.1111/j.1600-0447.1986.tb08990.x. PMID 2883820. 
  6. ^ Mauri MC, Gianetti S, Pugnetti L, Altamura AC (1993). "Quazepam versus triazolam in patients with sleep disorders: a double-blind study". Int J Clin Pharmacol Res 13 (3): 173–7. PMID 7901174. 
  7. ^ a b http://www.pfizer.com/files/products/uspi_halcion.pdf
  8. ^ 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. 
  9. ^ Lieberherr, S; Scollo-Lavizzari, G; Battegay, R (1991). "Confusional states following administration of short-acting benzodiazepines (midazolam/triazolam)". Schweizerische Rundschau fur Medizin Praxis = Revue suisse de médecine Praxis 80 (24): 673–5. PMID 2068441. 
  10. ^ Kirkwood CK (1999). "Management of insomnia". J Am Pharm Assoc (Wash) 39 (5): 688–96; quiz 713–4. PMID 10533351. 
  11. ^ Kales A; Scharf MB; Kales JD; Soldatos CR. (1979-04-20). "Rebound insomnia. A potential hazard following withdrawal of certain benzodiazepines". JAMA : the Journal of the American Medical Association. 241 (16): 1692–5. doi:10.1001/jama.241.16.1692. PMID 430730. 
  12. ^ "www.accessdata.fda.gov". 
  13. ^ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM.; Eschalier, A. (Nov 2009). "Benzodiazepine dependence: focus on withdrawal syndrome". Ann Pharm Fr 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604. 
  14. ^ http://www.fda.gov/medwatch/SAFETY/2003/03Jun_PI/Halcion_PI.pdf
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  16. ^ a b c Bayer, A.J.; Bayer EM; Pathy MSJ; Stoker MJ. (1986). "A Double-Blind Controlled Study of Chlormethiazole and Triazolam in the Elderly.". Acta Psychiatrica Scandinavica 73 (suppl 329): 104–111. doi:10.1111/j.1600-0447.1986.tb10544.x. PMID 3529832. 
  17. ^ 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. 
  18. ^ Oelschläger H. (1989-07-04). "Chemical and pharmacologic aspects of benzodiazepines". Schweiz Rundsch Med Prax. 78 (27–28): 766–72. PMID 2570451. 
  19. ^ Professor heather Ashton (April 2007). "BENZODIAZEPINE EQUIVALENCY TABLE". Retrieved September 23, 2007. 
  20. ^ Chweh AY; Swinyard EA; Wolf HH; Kupferberg HJ (February 25, 1985). "Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines". Life Sci 36 (8): 737–44. doi:10.1016/0024-3205(85)90193-6. PMID 2983169. 
  21. ^ Varhe A, Olkkola KT, Neuvonen PJ (December 1994). "Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole". Clin. Pharmacol. Ther. 56 (6 Pt 1): 601–7. doi:10.1038/clpt.1994.184. PMID 7995001. 
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  23. ^ Mattila, Me; Mattila, Mj; Nuotto, E (April 1992). "Caffeine moderately antagonizes the effects of triazolam and zopiclone on the psychomotor performance of healthy subjects". Pharmacology & toxicology 70 (4): 286–9. doi:10.1111/j.1600-0773.1992.tb00473.x. ISSN 0901-9928. PMID 1351673. 
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