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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/09/18 16:13:02」(JST)
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Not to be confused with Lorazepam.
| Systematic (IUPAC) name | |
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(2Z)-6-(2-Chlorophenyl)-2-[(4-methyl-1-piperazinyl)methylene]-8-nitro-2,4-dihydro-1H-imidazo[1,2-a][1,4]benzodiazepin-1-one
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| Clinical data | |
| Trade names | Dormonoct |
| AHFS/Drugs.com | International Drug Names |
| Pregnancy category |
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| Legal status |
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| Routes of administration |
Oral |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | Hepatic |
| Biological half-life | 6-12 hours |
| Excretion | Renal |
| Identifiers | |
| CAS Registry Number | 61197-73-7 N |
| ATC code | N05CD11 |
| PubChem | CID: 3033860 |
| DrugBank | none N |
| ChemSpider | 2298440 Y |
| UNII | 759N8462G8 Y |
| KEGG | D07326 Y |
| Chemical data | |
| Formula | C23H21ClN6O3 |
| Molecular mass | 464.904 g/mol |
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Loprazolam[1] (triazulenone) marketed under the brand names Dormonoct, Havlane, Sonin, Somnovit, is a drug which is an imidazole benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. It is available in 1 mg and 2 mg tablets. It is licensed and marketed for the short-term treatment of moderately severe insomnia.
Contents
- 1 Indications
- 2 Dose
- 3 Side effects
- 4 Tolerance, dependence and withdrawal
- 5 Contraindications and special caution
- 6 Mechanism of action
- 7 Pharmacokinetics
- 8 See also
- 9 References
- 10 External links
Indications
Insomnia can be described as a difficulty falling asleep, frequent awakening, early awakenings or a combination of each. Loprazolam is a short-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep or have difficulty falling asleep. Hypnotics should only be used on a short-term basis or in those with chronic insomnia on an occasional basis.[2]
Dose
The dose of loprazolam for insomnia is usually 1 mg but can be increased to 2 mg if necessary. In the elderly a lower dose is recommended due to more pronounced effects and a significant impairment of standing up to 11 hours after dosing of 1 mg of loprazolam. The half-life is much more prolonged in the elderly than in younger patients. A half-life of 19.8 hours has been reported in elderly patients.[3] Patients and prescribing physicians should, however, bear in mind that higher doses of loprazolam may impair long-term memory functions.[4]
Side effects
Side effects of loprazolam are generally the same as for other benzodiazepines such as diazepam.[5] The most significant difference in side effects of loprazolam and diazepam is it is less prone to day time sedation as the half-life of loprazolam is considered to be intermediate whereas diazepam has a very long half-life. The side effects of loprazolam are the following:
- drowsiness
- paradoxical increase in aggression
- lightheadedness
- confusion
- muscle weakness
- ataxia (particularly in the elderly)
- amnesia
- headache
- vertigo
- hypotension
- salivation changes
- gastro-intestinal disturbances
- visual disturbances
- dysarthria
- tremor
- changes in libido
- incontinence
- urinary retention
- blood disorders and jaundice
- skin reactions
- dependence and withdrawal reactions
Residual 'hangover' effects after nighttime administration of loprazolam such as sleepiness, impaired psychomotor and cognitive functions may persist into the next day which may increase risks of falls and hip fractures.[6]
Tolerance, dependence and withdrawal
Loprazolam, like all other benzodiazepines, is recommended only for the short-term management of insomnia in the UK, owing to the risk of serious adverse effects such as tolerance, dependence and withdrawal, as well as adverse effects on mood and cognition. Benzodiazepines can become less effective over time, and patients can develop increasing physical and psychological adverse effects, e.g., agorophobia, gastrointestinal complaints, and peripheral nerve abnormalities such as burning and tingling sensations.[7][8]
Loprazolam has a low risk of physical dependence and withdrawal if it is used for less than 4 weeks or very occasionally. However, one placebo-controlled study comparing 3 weeks of treatment for insomnia with either loprazolam or triazolam showed rebound anxiety and insomnia occurring 3 days after discontinuing loprazolam therapy, whereas with triazolam the rebound anxiety and insomnia was seen the next day. The differences between the two are likely due to the differing elimination half-lives of the two drugs.[9][10] These results would suggest that loprazolam and possibly other benzodiazepines should be prescribed for 1–2 weeks rather than 2–4 weeks to reduce the risk of physical dependence, withdrawal, and rebound phenomenon.
Withdrawal symptoms
Slow reduction of the dosage over a period of months at a rate that the individual can tolerate greatly minimizes the severity of the withdrawal symptoms. Individuals who are benzodiazepine dependent often cross to an equivalent dose of diazepam to taper gradually, as diazepam has a longer half-life and small dose reductions can be achieved more easily.[11][12]
- anxiety and panic attacks
- sweating
- nightmares
- insomnia
- headache
- tremor
- nausea and vomiting
- feelings of unreality
- abnormal sensation of movement
- hypersensitivity to stimuli
- hyperventilation
- flushing
- sweating
- palpitations
- dimensional distortions of rooms and television pictures
- paranoid thoughts and feelings of persecution
- depersonalization
- fears of going mad
- heightened perception of taste, smell, sound, and light; photophobia
- agoraphobia
- clinical depression
- poor memory and concentration
- aggression
- excitability
- Somatic Symptoms
- numbness
- altered sensations of the skin
- pain
- stiffness
- weakness in the neck, head, jaw, and limbs
- muscle fasciculation, ranging from twitches to jerks, affecting the legs or shoulders
- ataxia
- paraesthesia
- influenza-like symptoms
- blurred double vision
- menorrhagia
- loss of or dramatic gain in appetite
- thirst with polyuria
- urinary incontinence
- dysphagia
- abdominal pain
- diarrhoea
- constipation
Major complications can occur after abrupt or rapid withdrawal, especially from high doses, producing symptoms such as:
- psychosis
- confusion
- visual and auditory hallucinations
- delusions
- epileptic seizures (which may be fatal)
- suicidal thoughts or actions
- abnormal, often severe, drug seeking behavior
It has been estimated that between 30% and 50% of long-term users of benzodiazepines will experience withdrawal symptoms.[13] However, up to 90% of patients withdrawing from benzodiazepines experienced withdrawal symptoms in one study, but the rate of taper was very fast at 25% of dose per week.[14] Withdrawal symptoms tend to last between 3 weeks to 3 months, although 10 - 15% of people may experience a protracted benzodiazepine withdrawal syndrome with symptoms persisting and gradually declining over a period of many months and occasionally several years.[15]
Contraindications and special caution
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.[16] Loprazolam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs 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.[17]
Mechanism of action
Loprazolam is a benzodiazepine, which acts via positively modulating the GABAA receptor complex via a binding to the benzodiazepine receptor which is situated on alpha subunit containing GABAA receptors. This action enhances the effect of the neurotransmitter GABA on the GABAA receptor complex by increasing the opening frequency of the chloride ion channel. This action allows more chloride ions to enter the neuron which in turn produces such effects as; muscle relaxation, anxiolytic, hypnotic, amnesic and anticonvulsant action. These properties can be used for therapeutic benefit in clinical practice. These properties are also sometimes used for recreational purposes in the form of drug abuse of benzodiazepines where high doses are used to achieve intoxication and or sedation.[18][19]
Pharmacokinetics
After oral administration of loprazolam on an empty stomach, it takes 2 hours for serum concentration levels to peak, significantly longer than other benzodiazepine hypnotics. This delay brings into question the benefit of loprazolam for the treatment of insomnia when compared to other hypnotics (particularly when the major complaint is difficulty falling asleep instead of difficulty maintaining sleep for the entire night), although some studies show that loprazolam may induce sleep within half an hour, indicating rapid penetration into the brain. The peak plasma delay of loprazolam, therefore, may not be relevant to loprazolam's efficacy as a hypnotic. If taken after a meal it can take even longer for loprazolam plasma levels to peak and peak levels may be lower than normal. Loprazolam significantly alters electrical activity in the brain as measured by EEG, with these changes becoming more pronounced as the dose increases. Roughly half of each dose is metabolized in humans to produce an active metabolite with similar potency to loprazolam, the other half is excreted unchanged. The half-life of the active metabolite is about the same as the parent compound loprazolam.[20]
See also
- Benzodiazepine
- List of benzodiazepines
- Benzodiazepine dependence
- Benzodiazepine withdrawal syndrome
- Long-term effects of benzodiazepines
References
- ^ US Patent 4044142
- ^ 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.
- ^ Swift CG, Swift MR, Ankier SI, Pidgen A, Robinson J. (1985). "Single dose pharmacokinetics and pharmacodynamics of oral loprazolam in the elderly". British journal of clinical pharmacology. Retrieved 2007-03-21.
- ^ Bareggi SR, Ferini-Strambi L, Pirola R, Franceschi M, Smirne S. (1991). "Effects of loprazolam on cognitive functions". Psychopharmacology (Berl). Retrieved 2007-03-21.
- ^ British National Formulary Benzodiazepines Information
- ^ 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.
- ^ Committee on Safety of Medicines (1988). "BENZODIAZEPINES, DEPENDENCE AND WITHDRAWAL SYMPTOMS". Medicines Control Agency UK Government. Retrieved 2007-03-21.
- ^ Professor C Heather Ashton (1987). "Benzodiazepine Withdrawal: Outcome in 50 Patients". benzo. Retrieved 2007-03-21.
- ^ Morgan K, Oswald I (1982). "Anxiety caused by a short-life hypnotic". British medical journal (Clinical research ed.). Retrieved 2007-03-21.
- ^ Morgan K, Adam K, Oswald I (1984). "Effect of loprazolam and of triazolam on psychological functions". Psychopharmacology. Retrieved 2007-03-21.
- ^ McConnell JG (2007). "The Clinicopharmacotherapeutics of Benzodiazepine and Z drug dose Tapering Using Diazepam". BCNC. Retrieved 2007-06-09.
- ^ (Roche Products (UK) Ltd 1990) Benzodiazepines and Your Patients: A Management Programme
- ^ Ashton CH (1985). "BENZODIAZEPINE DEPENDENCE AND WITHDRAWAL: AN UPDATE". benzo org uk. Retrieved 2007-03-21.
- ^ Schweizer E, Rickels K, Case WG, Greenblatt DJ. (1990). "Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper". Arch Gen Psychiatry. Retrieved 2007-03-21.
- ^ Ashton CH (2002). "BENZODIAZEPINES: How They Work and How to Withdraw". benzo org uk. Retrieved 2007-03-21.
- ^ 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.
- ^ Mets, MA.; Volkerts, ER.; Olivier, B.; Verster, JC. (Feb 2010). "Effect of hypnotic drugs on body balance and standing steadiness". Sleep Med Rev 14 (4): 259–67. doi:10.1016/j.smrv.2009.10.008. PMID 20171127.
- ^ Bateson AN (2002). "Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal". ingentaconnect. Retrieved 2007-03-21.
- ^ Professor C Heather Ashton (2002). "BENZODIAZEPINE ABUSE". Harwood Academic. Retrieved 2007-03-22.
- ^ Mamelak M, Bunting P, Galin H, Price V, Csima A, Young T, Klein D, Pelchat JR. (1988). "Serum and quantitative electroencephalographic pharmacokinetics of loprazolam in the elderly". Journal of clinical pharmacology. Retrieved 2007-03-21.
External links
- Inchem.org - Loprazolam
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English Journal
- Detection of Benzodiazepines and z-Drugs in Hair Using an UHPLC-MS/MS Validated Method: Application to Workplace Drug Testing.
- Ramírez Fernández Mdel M1, Wille SM, di Fazio V, Kummer N, Hill V, Samyn N.
- Therapeutic drug monitoring.Ther Drug Monit.2015 Oct;37(5):600-8. doi: 10.1097/FTD.0000000000000188.
- BACKGROUND: A sensitive and reproducible Ultra High Performance Liquid Chromatography-Tandem Mass Spectrometry method has been developed for the simultaneous quantification of the 29 commonly prescribed benzodiazepines and z-drugs in hair. The method was validated according to international guidelin
- PMID 25627407
- The evaluation of the applicability of a high pH mobile phase in ultrahigh performance liquid chromatography tandem mass spectrometry analysis of benzodiazepines and benzodiazepine-like hypnotics in urine and blood.
- Verplaetse R1, Cuypers E, Tytgat J.
- Journal of chromatography. A.J Chromatogr A.2012 Aug 3;1249:147-54. doi: 10.1016/j.chroma.2012.06.023. Epub 2012 Jun 15.
- A sensitive liquid chromatography tandem mass spectrometry method was developed and validated for simultaneous detection of benzodiazepines, benzodiazepine-like hypnotics and some metabolites (7-aminoflunitrazepam, alprazolam, bromazepam, brotizolam, chlordiazepoxide, chlornordiazepam, clobazam, clo
- PMID 22749457
- Muscle relaxants for pain management in rheumatoid arthritis.
- Richards BL1, Whittle SL, Buchbinder R.
- The Cochrane database of systematic reviews.Cochrane Database Syst Rev.2012 Jan 18;1:CD008922. doi: 10.1002/14651858.CD008922.pub2.
- BACKGROUND: Pain management is a high priority for patients with rheumatoid arthritis (RA). Muscle relaxants include drugs that reduce muscle spasm (for example benzodiazepines such as diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan) and non-benzodiazepines such as metaxalone (Skelaxin) or
- PMID 22258993
Japanese Journal
- Comparison of five benzodiazepine-receptor agonists on buprenorphine-induced μ-opioid receptor regulation
- POISNEL Geraldine,DHILLY Martine,BOISSELIER Reynald Le,BARRE Louisa,DEBRUYNE Daniele
- Journal of pharmacological sciences 110(1), 36-46, 2009-05-20
- … In this study, we compared the effects of five short-, medium-, or long-acting benzodiazepine-receptor agonists (BZDs) [alprazolam (APZ), clonazepam (CLZ), flunitrazepam (FLZ), loprazolam (LPZ), zolpidem (ZLP)], at two distinct doses, 0.2 and 2 mg/kg, on the cell surface regulation of μ-opioid receptor induced by 0.15 mg/kg buprenorphine (BPN) in specific regions of the rat brain. …
- NAID 10025736509
Related Links
- Assessment | Biopsychology | Comparative | Cognitive | Developmental | Language | Individual... ... Loprazolam (Triazulenone) marketed under the brand names Dormonoct, Havlane, Sonin, Somnovit, is a drug which is an imidazole benzodiazepine ...
- Insomnia, or poor sleep , is fairly common but does not usually last for long. If you have problems sleeping, it may mean that you have difficulty getting... ... Loprazolam will help you to sleep. You should take it just before you go to ...
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