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Midazolam
From Wikipedia, the free encyclopedia
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Midazolam
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| Systematic (IUPAC) name | |
| 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine | |
| Identifiers | |
| CAS number | |
| ATC code | N05 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C18H13ClFN3 |
| Mol. mass | 325.78 |
| Pharmacokinetic data | |
| Bioavailability | Oral ~36% I.M. 90%+ |
| Metabolism | Hepatic |
| Half life | 1.8-6.4 hours |
| Excretion | Renal |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status |
Schedule IV(US) |
| Routes | Oral, I.M., I.V., parenteral |
Midazolam (marketed under brand names Versed®, Hypnovel®, Dormicum® and Dormonid®, pronounced mɪˈdæzəlæm) is a drug which is a benzodiazepine derivative. It has powerful anxiolytic, amnestic, hypnotic, anticonvulsant, skeletal muscle relaxant and sedative properties. It is considered a fast-acting benzodiazepine, with a short elimination half-life. It is therefore a very useful drug to use for short minor procedures such as dental extraction.
Midazolam was first synthesized in 1976 by Fryer and Walser.
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Like other benzodiazepines, midazolam acts on benzodiazepine receptors which enhance the binding of GABA to the GABAA receptor which results in inhibitory effects on the central nervous system.[1]
Midazolam is indicated for the acute management of aggressive or delirious patients and also is sometimes used for the acute management of seizures such as status epilepticus. Long term use for the management of epilepsy is not recommended however, due to the significant risk of tolerance which renders midazolam and other benzodiazepines ineffective and as well the significant side effect of sedation.[2] In mice given chronic midazolam a slowly evolving tolerance developed to the anticonvulsant properties of midazolam over 15 days, although some anticonvulsant effects were still apparent after 15 days of continued administration.[3]
Midazolam is occasionally used as a hypnotic, especially in hospitals. Like other benzodiazepines, it produces a decrease in delta activity, though the effect of benzodiazepines on delta may not be mediated via benzodiazepine receptors. Delta activity is an indicator of depth of sleep within non-REM sleep; it is thought to reflect sleep quality, with lower levels of delta sleep reflecting poorer sleep. Thus midazolam and other benzodiazepines cause a deterioration in sleep quality. Cyproheptadine may be superior to nitrazepam in the treatment of insomnia as it enhances sleep quality based on EEG studies.[4]
Midazolam is metabolized almost completely by cytochrome P450-3A4. Grapefruit juice reduces intestinal 3A4 and results in less metabolism and higher plasma concentrations, which could result in overdose.
Hypersensitivity, acute narrow angle glaucoma, shock, hypotension, head injury, and drug or alcohol use. Most are relative contraindications.
Residual 'hangover' effects after nighttime administration of midazolam 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.[5]
Midazolam (as with other central nervous system depressants, if taken regularly in pregnancy, may result in reduced IQ, developmental problems, physical malformations--however this data is inconclusive. Midazolam when taken during the third trimester of pregnancy may cause severe risk to the neonate, including benzodiazepine withdrawal syndrome with possible symptoms including hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Symptoms of hypotonia and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.[6]
Symptoms of midazolam overdose include:
- Somnolence (difficulty staying awake)
- Mental confusion
- Hypotension
- Impaired motor functions
- Impaired reflexes
- Impaired coordination
- Impaired balance
- Dizziness
- Coma
In animal models, the oral LD50 of midazolam is 825 mg/kg.
Midazolam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of midazolam (or any other benzodiazepine) is flumazenil (Anexate®). The risk of midazolam overdose is increased significantly if midazolam is abused in conjunction with opiates as was highlighted in a review of deaths of users of the opiate buprenorphine in Singapore.[7]
Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances.[8]
Midazolam is offered to death row inmates before execution in the United States, according to the film The Missouri Protocol (1990). A Missouri prison doctor interviewed in the film said virtually no prisoners turned down the drug when it was offered a few hours prior to execution.
Prolonged after-effects of midazolam dosing after dental surgery inspired Duran Duran vocalist Simon Le Bon to entitle the group's 1997 album Medazzaland, likely in reference to psychotropic effects he experienced.
Used by Alexander Mahone in the show Prison Break, under the alias "Varatril."
- ^ Skerritt JH; Johnston GA. (6). "Enhancement of GABA binding by benzodiazepines and related anxiolytics.". Eur J Pharmacol. 89 (3-4): 193-8. PMID 6135616.
- ^ Isojärvi, JI; Tokola RA. (Dec 1998). "Benzodiazepines in the treatment of epilepsy in people with intellectual disability.". J Intellect Disabil Res. 42 (1): 80-92. PMID 10030438.
- ^ Garratt JC; Gent JP, Feely M, Haigh JR. (5). "Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential?". Eur J Pharmacol. 145 (1): 75-80. PMID 2894998.
- ^ 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. PMID 17287588.
- ^ Vermeeren A. (2004). "Residual effects of hypnotics: epidemiology and clinical implications.". CNS Drugs. 18 (5): 297-328. PMID 15089115.
- ^ McElhatton PR. (Nov-Dec 1994). "The effects of benzodiazepine use during pregnancy and lactation.". Reprod Toxicol. 8 (6): 461-75. PMID 7881198.
- ^ Lai, SH; Yao YJ, Lo DS. (Oct 2006). "A survey of buprenorphine related deaths in Singapore.". Forensic Sci Int. 162(1-3): 80-6. PMID 16879940.
- ^ List of psychotropic substances under international control
- EMEA Summary of Product Characteristics: Hypnovel and associated names.
- Clinical Use of Midazolam by John Shou.
- Brevoord J, Joosten K, Arts W, van Rooij R, de Hoog M (2005). "Status epilepticus: clinical analysis of a treatment protocol based on midazolam and phenytoin.". J Child Neurol 20 (6): 476-81. PMID 15996395.
- Wolfe T, Macfarlane T (2006). "Intranasal midazolam therapy for pediatric status epilepticus.". Am J Emerg Med 24 (3): 343-6. PMID 16635708.
- Johnson T, Rostami-Hodjegan A, Goddard J, Tanner M, Tucker G (2002). "Contribution of midazolam and its 1-hydroxy metabolite to preoperative sedation in children: a pharmacokinetic-pharmacodynamic analysis.". Br J Anaesth 89 (3): 428-37. PMID 12402721.
- Prediction of the disposition of midazolam in surgical patients by a physiologically based pharmacokinetic model, Bjorkman, S et al, J Pharm Sci 2001:90(9)1226-1241.
- Merritt P, Hirshman E, Hsu J, Berrigan M (2005). "Metamemory without the memory: are people aware of midazolam-induced amnesia?". Psychopharmacology (Berl) 177 (3): 336-43. PMID 15290003.