Triazolam

Triazolam

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 category	US: X (Contraindicated)
Legal status	CA: Schedule IV DE: Anlage III (Prescription only) US: Schedule IV ℞ (Prescription only)
Dependence liability	High
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	44% (oral route), 53% (sublingual), 98% (intranasal) []
Metabolism	Hepatic
Biological half-life	1.5–5.5 hours
Excretion	Renal
Identifiers
CAS Number	28911-01-5 Y
ATC code	N05CD05 (WHO)
PubChem	CID: 5556
IUPHAR/BPS	7313
DrugBank	DB00897 Y
ChemSpider	5355 Y
UNII	1HM943223R Y
KEGG	D00387 Y
ChEBI	CHEBI:9674 Y
ChEMBL	CHEMBL646 Y
Chemical data
Formula	C17H12Cl2N4
Molecular mass	343.2 g/mol
SMILES ClC1=CC=CC=C1C2=NCC3=NN=C(C)N3C4=CC=C(Cl)C=C42
InChI InChI=1S/C17H12Cl2N4/c1-10-21-22-16-9-20-17(12-4-2-3-5-14(12)19)13-8-11(18)6-7-15(13)23(10)16/h2-8H,9H2,1H3 Y Key:JOFWLTCLBGQGBO-UHFFFAOYSA-N Y
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Triazolam (original brand name Halcion) is a central nervous system (CNS) depressant in the benzodiazepine class. It possesses pharmacological properties similar to that of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia. In addition to the hypnotic properties triazolam possesses, amnesic, anxiolytic, sedative, anticonvulsant and muscle relaxant properties are also present. Due to its short half-life, triazolam is not effective for patients that suffer from frequent awakenings or early wakening.

Triazolam was initially patented in 1970 and went on sale in the United States in 1982.

Medical uses

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 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.

Triazolam is frequently prescribed as a sleep aid for passengers travellng 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

Adverse drug reactions associated with the use of triazolam include:

• Relatively common (>1% of patients): somnolence, dizziness, feeling of lightness, coordination problems.
• Less common (0.9% to 0.5% of patients): euphoria, tachycardia, tiredness, confusional states/memory impairment, cramps/pain, depression, visual disturbances.
• Rare (<0.5% of patients): constipation, taste alteration, diarrhea, dry mouth, dermatitis/allergy, dreams/nightmares, insomnia, parasthesia, tinnitus, dysesthesia, weakness, congestion.

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. Confusion and amnesia has been reported.

Tolerance, dependence, and withdrawal

Main article: 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. 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. A worsening of insomnia (rebound insomnia) compared to baseline may occur after discontinuation of triazolam even after short-term single-nightly-dose therapy.

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.

Contraindications

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. Triazolam belongs to the Pregnancy Category X of the FDA. This means that 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. There can be daytime withdrawal effects.

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

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

Ketoconazole and Itraconazole have a profound effect on the pharmacokinetics of triazolam, leading to greatly enhanced effects. 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. Caffeine reduces the effectiveness of triazolam. Other important interactions include cimetidine, diltiazem, erythromycin, fluconazole, grapefruit juice, isoniazid, itraconazole, ketoconazole, nefazodone, rifampicin, ritonavir, and troleandomycin. Triazolam should not be administered to patients on Atripla.

Overdose

See also: Benzodiazepine overdose

Symptoms of an overdose include

• Coma
• Hypoventilation (respiratory depression)
• Somnolence (drowsiness)
• Slurred speech
• Seizures have been reported.

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.

Pharmacology

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

History

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

Society and culture

Recreational use

See also: Benzodiazepine drug misuse

Triazolam is a drug that is used non-medically: recreational use wherein the drug is taken to achieve a high or continued long-term dosing against medical advice.

Legal status

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

Brandnames

Marketed in English-speaking countries under the brand names Apo-Triazo, Halcion, Hypam, and Trilam. Other (designer) names include 2'-chloroxanax, chloroxanax, 2'-chloro-alprazolam, triclazolam, and chlorotriazolam.

External links

• PubPK - Triazolam Pharmacokinetics
• Medlineplus.org - Triazolam
• Rx-List.com - Triazolam
• Inchem.org - Triazolam
• MentalHealth.com - Triazolam
• Halcion controversy - Newsweek August 19, 1991 - Sweet Dreams or Nightmare?
• http://www.sussex.ac.uk/sociology/documents/ssm02.pdf