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Midazolam
Systematic (IUPAC) name
8-chloro- 6-(2-fluorophenyl)- 1-methyl- 4H-imidazo[1,5-a] [1,4]benzodiazepine
Identifiers
CAS number 59467-70-8
ATC code N05CD08
PubChem 4192
DrugBank APRD00680
ChemSpider 4047
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.

D (USA)
C (Aus)

Legal status

Schedule IV(US)

Routes Oral, I.M., I.V., parenteral

Midazolam, pronounced mɪˈdæzəlæm (and marketed under brand names in English speaking countries, Dormicum, Hypnovel, Midacum and Versed)[1] is an ultra short-acting benzodiazepine derivative. It has potent anxiolytic, amnestic[2], hypnotic, anticonvulsant, skeletal muscle relaxant, and sedative properties.[3] Midazolam is water-soluble and fat-soluble in physiologic pH. Freely soluble in alcohol and acetone. It is considered an ultra short-acting benzodiazepine, with an elimination half-life of about 2 hours. It is used in some countries for the short term treatment of insomnia and in many countries as a premedication before surgery.[4] 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.

Contents

Indications

Intravenous midazolam is indicated for procedural sedation (often in combination with an opioid, such as fentanyl), for pre-op sedation, for the induction of general anesthesia, and for sedation of ventilated patients in critical care units.

Oral midazolam is indicated for the short term treatment of moderately severe insomnia in patients who did not adequately react to other hypnotics, and who have persistent trouble in falling asleep. Because of midazolam's extremely short duration, midazolam is not used for patients who have trouble staying asleep through the night; moderate to long acting benzodiazepines like temazepam, nitrazepam, flunitrazepam and lormetazepam are used for those purposes. Like other benzodiazepines, midazolam 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.[5]

Midazolam is also 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.[6] 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.[7]

Availability

Dormicum brand midazolam is marketed by Roche as white, oval 7.5 mg tablets in boxes of 2 or 3 blisterstrips of 10 tablets, and as blue, oval 15 mg tablets in boxes of 2 blisterstrips of 10 tablets. The tablets are imprinted with "Roche" on one side and the dose of the tablet on the other side. Dormicum is also available as 1ml, 3ml and 10ml ampoules at a concentration of 5 mg/ml. Another manufacturer, Novell Pharmaceutical Laboratories, makes it available as Miloz in 3 ml and 5 ml ampoules.

Side effects

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.[8] Confusion and amnesia has rarely been reported with midazolam.[9]

Tolerance, dependence and withdrawal

Midazolam can cause a rapid development of drug tolerance, benzodiazepine dependence and upon discontinuation a benzodiazepine withdrawal syndrome can occur, including rebound insomnia. Gradual reduction of midazolam after regular use can minimise withdrawal and rebound effects. Tolerance and the resultant withdrawal syndrome may be due to alterations in gene expression which results in long term changes in the function of the GABAergic neuronal system.[10][11][12] A study in rats found that midazolam is cross tolerant with barbiturates and is able to effectively substitute for barbiturates and suppress barbiturate withdrawal signs.[13] Patients who are chronic users of benzodiazepine medication who are given midazolam experience reduced therapeutic effects of midazolam, due to tolerance to benzodiazepines.[14]

Contraindications

Hypersensitivity, acute narrow angle glaucoma, shock, hypotension, head injury, and drug or alcohol use. Most are relative contraindications.

Pregnancy

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.[15]

Interactions

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.

Mechanism of action

Like other benzodiazepines, midazolam acts on the benzodiazepine binding site of GABAA receptors. When bound it enhances the binding of GABA to the GABAA receptor which results in inhibitory effects on the central nervous system.[16]

Overdose

Symptoms of midazolam overdose include:

  • Somnolence (difficulty staying awake)
  • Mental confusion
  • Hypotension
  • Impaired motor functions
    • Impaired reflexes
    • Impaired coordination
    • Impaired balance
    • Dizziness
  • Coma
  • Death

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.[17]

Legal status

In the Netherlands, midazolam is a List II drug of the Opium Law. Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances.[18] In the United Kingdom midazolam is a Schedule III controlled drug.[19]

Law enforcement and criminal justice

Midazolam is offered to death row inmates before execution in the United States, according to the 1992 film The Execution Protocol. 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.The doctor also reported to HBO that Versed(R) (midazolam)is about 5 times as potent as Valium(R)(diazepam/Roche)which makes it beneficial for the inmate and staff.

The drug is also used by trained Paramedics to assist in controlling psychotic or mentally disturbed patients.[20][21]

See also

Notes

  1. "Benzodiazepine Names". non-benzodiazepines.org.uk. http://www.non-benzodiazepines.org.uk/benzodiazepine-names.html. Retrieved on 2008-12-29. 
  2. http://www.mayoclinic.com/health/drug-information/DR600929
  3. Mandrioli R, Mercolini L, Raggi MA (October 2008). "Benzodiazepine metabolism: an analytical perspective". Curr. Drug Metab. 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614. http://www.benthamdirect.org/pages/content.php?CDM/2008/00000009/00000008/0009F.SGM. 
  4. Kanto JH (1985). "Midazolam: the first water-soluble benzodiazepine. Pharmacology, pharmacokinetics and efficacy in insomnia and anesthesia". Pharmacotherapy 5 (3): 138–55. PMID 3161005. 
  5. Tokunaga S; Takeda Y, Shinomiya K, Hirase M, Kamei C. (February 2007). "Effects of some H1-antagonists on the sleep-wake cycle in sleep-disturbed rats" (pdf). J Pharmacol Sci. 103 (2): 201–6. doi:10.1254/jphs.FP0061173. PMID 17287588. http://www.jstage.jst.go.jp/article/jphs/103/2/201/_pdf. 
  6. Isojärvi, JI; Tokola RA. (December 1998). "Benzodiazepines in the treatment of epilepsy in people with intellectual disability". J Intellect Disabil Res. 42 (1): 80–92. PMID 10030438. 
  7. Garratt JC; Gent JP, Feely M, Haigh JR. (January 5, 1988). "Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential?". Eur J Pharmacol. 145 (1): 75–80. doi:10.1016/0014-2999(88)90351-2. PMID 2894998. 
  8. 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. 
  9. Lieberherr S, Scollo-Lavizzari G, Battegay R (June 1991). "[Confusional states following administration of short-acting benzodiazepines (midazolam/triazolam)]" (in German). Schweiz. Rundsch. Med. Prax. 80 (24): 673–5. PMID 2068441. 
  10. Fukuda K, Shoda T, Mima H, Uga H (August 2002). "Midazolam induces expression of c-Fos and EGR-1 by a non-GABAergic mechanism". Anesth. Analg. 95 (2): 373–8, table of contents. doi:10.1097/00000539-200208000-00024. PMID 12145054. http://www.anesthesia-analgesia.org/cgi/pmidlookup?view=long&pmid=12145054. 
  11. Kales A, Soldatos CR, Bixler EO, Goff PJ, Vela-Bueno A (1983). "Midazolam: dose-response studies of effectiveness and rebound insomnia". Pharmacology 26 (3): 138–49. doi:10.1159/000137795. PMID 6132414. 
  12. Cho HH, O'Connell JP, Cooney MF, Inchiosa MA (2007). "Minimizing tolerance and withdrawal to prolonged pediatric sedation: case report and review of the literature". J Intensive Care Med 22 (3): 173–9. doi:10.1177/0885066607299556. PMID 17569173. http://jic.sagepub.com/cgi/pmidlookup?view=long&pmid=17569173. 
  13. Yutrzenka GJ, Patrick GA, Rosenberger W (July 1989). "Substitution of temazepam and midazolam in pentobarbital-dependent rats". Physiol. Behav. 46 (1): 55–60. doi:10.1016/0031-9384(89)90321-1. PMID 2573097. http://linkinghub.elsevier.com/retrieve/pii/0031-9384(89)90321-1. 
  14. Potokar J, Coupland N, Wilson S, Rich A, Nutt D (September 1999). "Assessment of GABA(A)benzodiazepine receptor (GBzR) sensitivity in patients on benzodiazepines". Psychopharmacology (Berl.) 146 (2): 180–4. doi:10.1007/s002130051104. PMID 10525753. http://link.springer.de/link/service/journals/00213/bibs/9146002/91460180.htm. 
  15. McElhatton PR. (Nov-Dec 1994). "The effects of benzodiazepine use during pregnancy and lactation". Reprod Toxicol. 8 (6): 461–75. doi:10.1016/0890-6238(94)90029-9. PMID 7881198. 
  16. Skerritt JH; Johnston GA. (May 6, 1983). "Enhancement of GABA binding by benzodiazepines and related anxiolytics". Eur J Pharmacol. 89 (3-4): 193–8. doi:10.1016/0014-2999(83)90494-6. PMID 6135616. 
  17. Lai, SH; Yao YJ, Lo DS. (October 2006). "A survey of buprenorphine related deaths in Singapore". Forensic Sci Int. 162(1-3): 80–6. doi:10.1016/j.forsciint.2006.03.037. PMID 16879940. 
  18. List of psychotropic substances under international control
  19. Blackpool NHS Primary Care Trust (2007). "Medicines Management Update" (PDF). United Kingdom: National Health Service. http://www.blackpool.nhs.uk/images/uploads/CD-update-GP-v2-may08.pdf. 
  20. Demetria Kalodimos. "I-Team: Injection Used To Subdue Prisoners:Medical Expert Says Practice Is Troubling". WSMV Nashville. http://www.wsmv.com/news/16844880/detail.html. 
  21. Jacob Goldstein. "Taking Sedatives to the Streets". The Wall Street Journal Health Blog. http://blogs.wsj.com/health/2008/07/17/taking-sedatives-to-the-streets/. 

References

External links


Wiktionary

Up to date as of January 15, 2010

Definition from Wiktionary, a free dictionary

English

Noun

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Wikipedia has an article on:

Wikipedia

Singular
midazolam

Plural
uncountable

midazolam (uncountable)

  1. (medicine) A benzodiazepine drug that has anxiolytic, amnestic, hypnotic and anticonvulsant activity







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