TRIAZOLAM

Details

Stereochemistry	ACHIRAL
Molecular Formula	C17H12Cl2N4
Molecular Weight	343.21
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=NN=C2CN=C(C3=C(Cl)C=CC=C3)C4=C(C=CC(Cl)=C4)N12

InChI

InChIKey=JOFWLTCLBGQGBO-UHFFFAOYSA-N

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

HIDE SMILES / InChI

Description
Sources: http://www.drugbank.ca/drugs/DB00897
Curator's Comment: Description was created based on several sources, including http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/017892s038lbl.pdf

Triazolam is a short-acting benzodiazepine used as a hypnotic agent in the treatment of insomnia. Some countries temporarily withdrew triazolam from the market because of concerns about adverse reactions, mostly psychological, associated with higher dose ranges. Its use at lower doses with appropriate care and labeling has been reaffirmed by the FDA and most other countries. Triazolam has a shorter half-life than chlordiazepoxide, flurazepam, and prazepam and does not generate active metabolites. Benzodiazepines bind nonspecifically to bezodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABAA) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell. Triazolam is used for the short-term treatment of insomnia. Triazolam`s original brand name is Halcion. Triazolam is withdrawn in the United Kingdom due to risk of psychiatric adverse drug reactions. This drug continues to be available in the U.S. Internationally, triazolam is a Schedule IV drug under the Convention on Psychotropic Substances.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
GABA-A receptor; anion channel 202 Target ID: CHEMBL2093872 Sources: http://www.genome.jp/dbget-bin/www_bget?D00387 \| http://www.drugbank.ca/drugs/DB00897 \| http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/017892s038lbl.pdf	Agonist 2678	0.8 nM [Ki]
GABA-A receptor; alpha-2/beta-3/gamma-2 12 Target ID: CHEMBL2094130 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10633039	Agonist 2678	0.59 nM [Ki]
GABA-A receptor; alpha-1/beta-3/gamma-2 16 Target ID: CHEMBL2094121 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10633039	Agonist 2678	0.8 nM [Ki]
GABA-A receptor; alpha-3/beta-3/gamma-2 11 Target ID: CHEMBL2094120 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10633039	Agonist 2678	1.43 nM [Ki]
GABA-A receptor; alpha-5/beta-3/gamma-2 14 Target ID: CHEMBL2094122 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10633039	Agonist 2678	1.54 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Insomnia 108 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/017892s038lbl.pdf	Primary		Approved 8429	Halcion Approved Use Halcion is indicated for the short-term treatment of insomnia (generally 7–10 days). Use for more than 2–3 weeks requires complete reevaluation of the patient Launch Date 1982

C_max

Value	Dose	Co-administered	Analyte	Population
3.75 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8275618/	0.25 mg single, oral dose: 0.25 mg route of administration: Oral experiment type: SINGLE co-administered:		TRIAZOLAM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
4.39 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8275618/	0.25 mg single, oral dose: 0.25 mg route of administration: Oral experiment type: SINGLE co-administered:		TRIAZOLAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
13.05 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8275618/	0.25 mg single, oral dose: 0.25 mg route of administration: Oral experiment type: SINGLE co-administered:		TRIAZOLAM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
13.78 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8275618/	0.25 mg single, oral dose: 0.25 mg route of administration: Oral experiment type: SINGLE co-administered:		TRIAZOLAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
4.07 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8275618/	0.25 mg single, oral dose: 0.25 mg route of administration: Oral experiment type: SINGLE co-administered:		TRIAZOLAM plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
2.27 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/8275618/	0.25 mg single, oral dose: 0.25 mg route of administration: Oral experiment type: SINGLE co-administered:		TRIAZOLAM plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
3 mg single, oral Highest studied dose Dose: 3 mg Route: oral Route: single Dose: 3 mg Sources: https://pubmed.ncbi.nlm.nih.gov/19327	unhealthy, 21 - 60 years n = 2 Health Status: unhealthy Condition: insomnia Age Group: 21 - 60 years Sex: M Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/19327	Disc. AE: Ataxia, Drowsiness... AEs leading to discontinuation/dose reduction: Ataxia (1 patient) Drowsiness (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/19327
0.25 mg 1 times / day steady, oral Recommended Dose: 0.25 mg, 1 times / day Route: oral Route: steady Dose: 0.25 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/017892s050lbl.pdf	unhealthy n = 1003 Health Status: unhealthy Condition: insomnia Population Size: 1003 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/017892s050lbl.pdf	Disc. AE: Coordination abnormal, Drowsiness... AEs leading to discontinuation/dose reduction: Coordination abnormal Drowsiness Groggy Somnolence Depression Restlessness Dizziness Lightheadedness Headache Nausea Visual disturbance Nervousness Abdominal distress Bladder disorders NEC Aching in limb Backache Blepharitis Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/017892s050lbl.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OAT1 599	CYP3A 191 P-gp 1537

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
OAT1 603	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/21561794/	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15258104/	no
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/16158798/	yes
CYP3A 191	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/017892s055lbl.pdf Page: 7.0	yes	yes (co-administration study) Comment: contraindicated with strong CYP3A inhibitors such as ketoconazole, itraconazole, nefazodone, ritonavir, indinavir, nelfinavir, saquinavir, and lopinavir; from 2019 label: grapefruit juice increased maximum plasma concentration of triazolam by 25% and increased AUC by 48% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/017892s055lbl.pdf Page: 7.0

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:9674	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:9674
ZINC	ZINC000000002212	http://zinc15.docking.org/substances/ZINC000000002212
eMolecules	595231	https://www.emolecules.com/cgi-bin/more?vid=595231

PubMed

Title	Date	PubMed
Triazolam substrate inhibition: evidence of competition for heme-bound reactive oxygen within the CYP3A4 active site.	2001	11764967
Pharmacokinetic aspects of treating infections in the intensive care unit: focus on drug interactions.	2001	11735605
Treatment regimen and hypnotic self-administration.	2001 Apr	11374329
Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram.	2001 Aug	11532381
Pregabalin enhances nonrapid eye movement sleep.	2001 Dec	11714899
Behavioral pharmacological similarities between methylphenidate and cocaine in cocaine abusers.	2001 Feb	11519636
Covalent alteration of the CYP3A4 active site: evidence for multiple substrate binding domains.	2001 Jul 1	11414684
Benzodiazepines as a social problem: the case of halcion.	2001 Jul-Aug	11592471
A double-blind, randomized and placebo-controlled study on the polysomnographic withdrawal effects of zopiclone, zolpidem and triazolam in healthy subjects.	2001 Jun	11697572
CYP3A inductive potential of the rifamycins, rifabutin and rifampin, in the rabbit.	2001 May	11745918
Circadian phase shifting: Relationships between photic and nonphotic phase-response curves.	2001 May	11399309
Functional pharmacology of GABA(A) receptors containing the chicken brain gamma 4 subunit.	2001 May 4	11348623
Triazolam impairs inhibitory control of behavior in humans.	2001 Nov	11764012
Retrograde facilitation of memory by triazolam: effects on automatic processes.	2001 Nov	11713622
Isobolographic analysis of chlordiazepoxide and triazolam combinations in squirrel monkeys discriminating triazolam.	2001 Nov	11702092
The hypnotic actions of the fatty acid amide, oleamide.	2001 Nov	11682271
Effects of triazolam on brain activity during episodic memory encoding: a PET study.	2001 Nov	11682258
Effect of methylprednisolone on CYP3A4-mediated drug metabolism in vivo.	2001 Sep	11699609
Oral mucosal drug delivery: clinical pharmacokinetics and therapeutic applications.	2002	12126458
Sensitive method for the detection of 22 benzodiazepines by gas chromatography-ion trap tandem mass spectrometry.	2002 Apr 19	12058908
Alcohol and triazolam: differential effects on memory, psychomotor performance and subjective ratings of effects.	2002 Dec	12478216
A role for cryptochromes in sleep regulation.	2002 Dec 20	12495442
[Identification of estazolam, alprazolam and triazolam in human urine by LC/MSn].	2002 Feb	12579961
[Pharmacological profile and clinical effect of zolpidem (Myslee tablets), a hypnotic agent].	2002 Feb	11862759
Binding and neuropharmacological profile of zaleplon, a novel nonbenzodiazepine sedative/hypnotic.	2002 Jan 2	11755161
Safety of zaleplon in the treatment of insomnia.	2002 May	11978165
Feeding melatonin enhances the phase shifting response to triazolam in both young and old golden hamsters.	2002 May	11959680
Effects of endogenous steroids on CYP3A4-mediated drug metabolism by human liver microsomes.	2002 May	11950784
Acute and chronic effects of the neuroactive steroid pregnanolone on schedule-controlled responding in rhesus monkeys.	2002 Nov	12409993
Development and use of a computer program to detect potentially inappropriate prescribing in older adults residing in Canadian long-term care facilities.	2002 Oct 14	12379159
Melatonin microinjection into the medial preoptic area increases sleep in the rat.	2002 Sep 13	12175899
Pharmacokinetic interactions with rifampicin : clinical relevance.	2003	12882588
[Cytochrome P450 3A4 and Benzodiazepines].	2003	12875231
Study of nocturnal sleep and the carryover effects of triazolam and brotizolam using neurophysiological and subjective methods.	2003	12759560
Clinically important drug interactions with zopiclone, zolpidem and zaleplon.	2003	12751920
Lopinavir/ritonavir: a review of its use in the management of HIV infection.	2003	12662125
Clinical pharmacokinetic profile of modafinil.	2003	12537513
Discriminative-stimulus effects of triazolam in light and moderate drinkers.	2003 Apr	12711926
A study into the rate of incorporation of eight benzodiazepines into rat hair.	2003 Apr 23	12742689
[Diagnostics and treatment of sleep disorders in elderly people].	2003 Apr-Jun	12889368
Long-, intermediate- and short-acting benzodiazepine effects on human sleep EEG spectra.	2003 Feb	12519461
Semi-micro column HPLC of triazolam in rat plasma and brain microdialysate and its application to drug interaction study with itraconazole.	2003 Jan 15	12485722
Effects of short-acting hypnotics on sleep latency in rats placed on grid suspended over water.	2003 Jan 24	12559374
In vitro metabolism of midazolam, triazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes p450: role of cyp3a4 and cyp3a5.	2003 Jul	12814972
Comparative abuse liability and pharmacological effects of meprobamate, triazolam, and butabarbital.	2003 Jun	12826989
Comparison of hangover effects among triazolam, flunitrazepam and quazepam in healthy subjects: a preliminary report.	2003 Jun	12753571
Apparent mechanism-based inhibition of human CYP3A in-vitro by lopinavir.	2003 Mar	12724045
Anxiolysis in general dental practice.	2003 Mar	12705021
Triazolam-amphetamine interaction: dissociation of effects on memory versus arousal.	2003 Mar	12680736
Cocaine-like subjective effects of nicotine are not blocked by the D1 selective antagonist ecopipam (SCH 39166).	2003 Mar	12658071

Patents

Sample Use Guides

In Vivo Use Guide

The recommended dose for most adults is 0.25 mg before retiring. A dose of 0.125 mg may be found to be sufficient for some patients (e.g., low body weight). A dose of 0.5 mg should be used only for exceptional patients who do not respond adequately to a trial of a lower dose since the risk of several adverse reactions increases with the size of the dose administered. A dose of 0.5 mg should not be exceeded.

Route of Administration: Oral

In Vitro Use Guide

Triazolam inhibited [3H]flunitrazepam binding with an IC50 value of 0.85 nM and a Ki value of 0.50 nM in mice.

Name

Type

Language

TRIAZOLAM

Official Name

English

TRIAZOLAM [HSDB]

Common Name

English

N05CD05

Code

English

TRIAZOLAM [JAN]

Common Name

English

U-33,030

Code

English

TRIAZOLAM [MART.]

Common Name

English

TRIAZOLAM [VANDF]

Common Name

English

4H-(1,2,4)TRIAZOLO(4,3-A)(1,4)BENZODIAZEPINE, 8-CHLORO-6-(2-CHLOROPHENYL)-1-METHYL-

Systematic Name

English

Triazolam [WHO-DD]

Common Name

English

TRIAZOLAM [MI]

Common Name

English

U-33030

Code

English

triazolam [INN]

Common Name

English

TRIAZOLAM [USAN]

Common Name

English

TRIAZOLAM [ORANGE BOOK]

Common Name

English

TRIAZOLAM [USP MONOGRAPH]

Common Name

English

8-CHLORO-6-(O-CHLOROPHENYL)-1-METHYL-4H-S-TRIAZOLO(4,3-A)(1,4)BENZODIAZEPINE

Common Name

English

TRIAZOLAM CIV [USP-RS]

Common Name

English

HALCION

Brand Name

English

TRIAZOLAM CIV

Common Name

English

Classification Tree Code System Code

WHO-VATC

QN05CD05