Triazolam
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Triazolam
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| Systematic (IUPAC) name | |
| 8-chloro-6-(2-chlorophenyl)-1-methyl-4H- [1,2,4]triazolo[4,3-a][1,4]benzodiazepine |
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| Identifiers | |
| CAS number | |
| ATC code | N05 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C17H12Cl2N4 |
| Mol. mass | 343.2 |
| Pharmacokinetic data | |
| Bioavailability | 44% (oral) 53% (sublingual) |
| Metabolism | Hepatic |
| Half life | 1.5-5.5 hours |
| Excretion | Renal |
| Therapeutic considerations | |
| Pregnancy cat. |
X (US) |
| Legal status |
Schedule IV(US) |
| Routes | Oral |
Triazolam (marketed under brand names Halcion, Novodorm, Songar) is a benzodiazepine derivative drug. It possesses pharmacological properties similar to that of other benzodiazepines, but it is generally only used as a sedative to treat insomnia.[1] Insomnia can best be described as a difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Triazolam is a short acting benzodiazepine and is sometimes used in patients who have difficulty in falling asleep. Short half life hypnotics such as triazolam are not effective in patients who suffer from frequent awakenings or early wakening due to their very short half life. Hypnotics should only be used on a short term basis or in those with chronic insomnia on an occasional basis.[2]
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[edit] History
Triazolam was temporarily withdrawn from the market in several countries because of concerns about serious side effects (mostly psychological) associated with high dosages of the drug. Its use at lower doses has been deemed safe by the American Food and Drug Administration (FDA) and most other countries.[1]
However, Triazolam has remained banned in the UK since 1991, when the Committee on the Safety of Medicines (CSM) concluded that it caused a higher frequency of psychiatric side-effects than other hypnotics.
It has been alleged to cause strange behavior and in some instances violent reactions. However, these allegations are anecdotal in nature. While triazolam as the instigator of violence has been accepted in some trials (particularly criminal offenses of defendants without violent tendencies) the anecdotal evidence has not risen to the level for the FDA to determine it statistically verifiable.
[edit] Pharmacology
The pharmacological effects of triazolam are similar to those of most other benzodiazepines. Triazolam does not generate active metabolites.[1] 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.[3] The half life of triazolam is only 2 hours making it a very short acting benzodiazepine drug.[4] Triazolam has anticonvulsant effects on brain function.[5]
In EEG studies triazolam significantly increases the energy of the beta frequency band and significantly increases the relative EEG power density in the delta frequency band and a decrease in the energy of the theta frequency band. Triazolam causes EEG changes characterised by high-voltage slow waves and desynchronization of hippocampal theta waves and an increase in the energy of the delta frequency band on the spectral analysis of the electroencephalogram. Benzodiazepines induce a light sleep and conversely, suppress deep sleep stages, making benzodiazepines generally poor treatments for insomnia. This is especially true in elderly patients who already have naturally less deep sleep.[6] Triazolam produces a decrease in delta activity. The effect of benzodiazepine drugs on delta however may not be mediated via benzodiazepine receptors. Delta activity is an indicator of depth of sleep within non-REM sleep. Delta activity is thought to reflect sleep quality with lower levels of delta sleep reflecting poorer quality of sleep. Thus triazolam and other benzodiazepines cause a deterioration in sleep quality. Cyproheptadine may be superior to benzodiazepines in the treatment of insomnia as it enhances sleep quality based on EEG studies.[7]
[edit] Dependence and withdrawal
Triazolam has a very high risk of dependency with chronic users often taking exceedingly high daily doses.[8] Regular use of triazolam may cause a hypnotic drug dependence. Withdrawal symptoms typically appear when triazolam dosage is reduced or stopped altogether. Withdrawal symptoms including a worsening of insomnia compared to baseline typically occurs after discontinuation of triazolam even after short term single nightly dose therapy.[9]
Day time withdrawal symptoms are commonly associated with triazolam. This is due to its very short half life. After only 10 nights of triazolam use patients report anxiety, become distressed, weight loss, panics and depression, felt unreal, and develop paranoia. These reactions occurred more commonly with triazolam than lormetazepam which has an intermediate half life. Thus the more short acting a benzodiazepine hypnotic the more severe the day time withdrawal symptoms.[10]
Abrupt withdrawal after long term use from therapeutic doses of triazolam may result in a severe benzodiazepine withdrawal syndrome. Reports in the medical literature report of psychotic states developing after abrupt withdrawal from triazolam. The withdrawal symptoms included auditory hallucinations and visual cognitive disorder. Gradual and careful reduction of the dosage was recommended to prevent severe withdrawal syndromes from developing.[11]
Singer Marc Almond was dependent on Halcion between 1985 and 1994.[12]
[edit] Elderly
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. 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.[13]
[edit] Indications
Triazolam is usually used for short term treatment of acute insomnia including jet lag. It is an ideal benzodiazepine for this use, due to the fact that its fast onset of action and short half-life (approximately 2 hours) allows its user to avoid morning drowsiness. Triazolam is also sometimes used as an adjuvant in medical procedures requiring anesthesia[1] or to reduce anxiety during brief events like MRI scans.
[edit] Dosage
Dosages for triazolam are significantly lower than other benzodiazepines, and should be individualized depending on the needs of the patient. For insomnia, 0.125mg to 0.25mg are given at bedtime. Up to 0.5mg may be needed for resistant individuals. Dosages exceeding 0.5mg are generally considered to be unsafe.
[edit] Side effects
Triazolam causes transient anterograde amnesia (failure to remember new things, especially during the time the medication is in the user's system) at dosages higher than 1-3mg.[14] 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.[15]
Fuzzy, clouded thoughts, as well as incomprehension of the passage of time, may occur in lower doses as well as higher ones. In some cases, violent and unpredictable mood swings can occur.
[edit] Interactions
Triazolam will have interactions similar to those seen with other benzodiazepine and other categories of anxiolytic/hypnotic.
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 erythrommycin may cause serious psychotic symptoms especially in those with other physical complications.[16]
As with most prescription medications, caution is advised when combining other drugs with Triazolam.
[edit] Contraindications
[edit] Pregnancy
Triazolam belongs to the Pregnancy Category X of the FDA [1]. This means that it is known to have the potential to cause birth defects.
[edit] Overdose
Symptoms of an overdose[1] include
- Somnolence (drowsiness)
- Impaired motor function
- Slurred speech
- Coma
- Hypoventilation (respiratory depression)
[edit] Legal status
Internationally, triazolam is a Schedule IV drug under the Convention on Psychotropic Substances.[17]
[edit] See also
[edit] External links
- Medlineplus.org - Triazolam
- Rx-List.com - Triazolam
- Inchem.org - Triazolam
- MentalHealth.com - Triazolam
- Halcion controversy - Newsweek August 19, 1991 - Sweet Dreams or Nightmare?
[edit] Footnotes
- ^ a b c d e Wishart, David (2006). Triazolam. DrugBank. Retrieved on 2006-03-23.
- ^ Rickels K. (1986). "The clinical use of hypnotics: indications for use and the need for a variety of hypnotics.". Acta Psychiatrica Scandinavica Suppl. 332: 132-41. PMID 2883820.
- ^ Oelschläger H. (1989-07-04). "Chemical and pharmacologic aspects of benzodiazepines". Schweiz Rundsch Med Prax. 78 (27-28): 766-72. PMID 2570451.
- ^ Professor heather Ashton (April 2007). BENZODIAZEPINE EQUIVALENCY TABLE. Retrieved on Sept 23, 2007.
- ^ Chweh AY; Swinyard EA, Wolf HH, Kupferberg HJ (25). "Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines". Life Sci 36 (8): 737-44. doi:. PMID 2983169.
- ^ Noguchi H; Kitazumi K, Mori M, Shiba T. (Mar 2004). "Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats." (pdf). J Pharmacol Sci. 94 (3): 246-51. doi:. PMID 15037809.
- ^ Tokunaga S; Takeda Y, Shinomiya K, Hirase M, Kamei C. (Feb 2007). "Effects of some H1-antagonists on the sleep-wake cycle in sleep-disturbed rats." (pdf). J Pharmacol Sci. 103 (2): 201-6. doi:. PMID 17287588.
- ^ Veje JO; Andersen K, Gjesing S, Kielgast H. (1989-08-21). "Prescription of tranquilizers and hypnotics in the municipality of Holbaek". Ugeskr Laeger. 151 (34): 2134-6. PMID 2773144.
- ^ 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:. PMID 430730.
- ^ Adam K; Oswald I (May 1989). "Can a rapidly-eliminated hypnotic cause daytime anxiety?". Pharmacopsychiatry 22 (3): 115-9. PMID 2748714.
- ^ Terao T; Tani Y. (1988-09-01). "Two cases of psychotic state following normal-dose benzodiazepine withdrawal". J UOEH. 10 (3): 337-40. PMID 2902678.
- ^ Tainted Life autobiography of Marc Almond
- ^ Bain KT (Jun 2006). "Management of chronic insomnia in elderly persons". Am J Geriatr Pharmacother 4 (2): 168-92. doi:. PMID 16860264.
- ^ Anterograde amnesia in triazolam overdose despite flumazenil treatment: a case report.. Hum Exp Toxicol. 1992 Jul;11(4):289-90.. Retrieved on 2006-06-25.
- ^ Vermeeren A. (2004). "Residual effects of hypnotics: epidemiology and clinical implications.". CNS Drugs. 18 (5): 297-328. PMID 15089115.
- ^ Tokinaga N; Kondo T, Kaneko S, Otani K, Mihara K, Morita S. (Dec 1996). "Hallucinations after a therapeutic dose of benzodiazepine hypnotics with co-administration of erythromycin." 50 (6): 337-9. PMID 9014234.
- ^ List of psychotropic substances under international control. Green list. International Narcotics Control Board (YEAR). Retrieved on 2006-03-23.
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