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Midazolam

 
Drug Info: Midazolam
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Brand names: Versed®

Chemical formula:



Midazolam injection

What is midazolam injection?

MIDAZOLAM (Versed®) is a benzodiazepine. Benzodiazepines belong to a group of medicines that slow down the central nervous system. Midazolam is a sedative hypnotic that causes relaxation and sleep. In anesthesia it provides loss of awareness and memory for short diagnostic tests and surgical procedures; produces sleep at the beginning of surgery; or supplements other types of general anesthetics. Midazolam does not reduce pain or cause loss of consciousness. Federal law prohibits the transfer of midazolam to any person other than the patient for whom it was prescribed. Generic midazolam injections are available.

What should I tell my health care provider before I take this medicine?

They need to know if you have any of these conditions:
• an alcohol or drug abuse problem
• bipolar disorder, depression, psychosis, or other mental health condition
• glaucoma
• heart, kidney, or liver disease
• history of a stroke
• lung disease, such as chronic obstructive pulmonary disease (COPD), sleep apnea, asthma, or other breathing difficulties
• myasthenia gravis
• Parkinson's disease
• seizures or a history of seizures
• shortness of breath
• snoring
• suicidal thoughts
• an unusual or allergic reaction to midazolam, other benzodiazepines, benzyl alcohol, foods, dyes, or preservatives
• pregnant or trying to get pregnant
• breast-feeding

How should I use this medicine?

Midazolam is for injection into a muscle or slow injection into a vein. It is given by a health-care professional in a hospital or clinic setting.

What if I miss a dose?

This does not apply.

What drug(s) may interact with midazolam?

• alcohol
• bosentan
• caffeine
• cimetidine
• disulfiram
• female hormones, including contraceptive or birth control pills
• flumazenil
• herbal or dietary supplements such as kava kava, melatonin, dehydroepiandrosterone, DHEA, St. John's Wort or valerian
• imatinib, STI-571
• isoniazid
• levodopa
• medicines for anxiety or sleeping problems, such as alprazolam, diazepam, lorazepam or triazolam
• medicines for depression, mental problems or psychiatric disturbances
• medicines for HIV infection or AIDS
• medicines for fungal infections (fluconazole, itraconazole, ketoconazole, voriconazole)
• mifepristone, RU-486
• pioglitazone
• prescription pain medicines
• probenecid
• ranitidine
• rifampin, rifapentine, or rifabutin
• some antibiotics (clarithromycin, erythromycin, troleandomycin)
• some medicines for colds, hay fever or other allergies
• some medicines for high blood pressure or heart problems (amiodarone, diltiazem, nicardipine, verapamil)
• some medicines for seizures (carbamazepine, phenobarbital, phenytoin, primidone)
• theophylline
• zafirlukast
• zileuton

Tell your prescriber or health care professional about all other medicines you are taking, including non-prescription medicines, nutritional supplements, or herbal products. Also tell your prescriber or health care professional if you are a frequent user of drinks with caffeine or alcohol, if you smoke, or if you use illegal drugs. These may affect the way your medicine works. Check with your health care professional before stopping or starting any of your medicines.

What should I watch for while taking midazolam?

Your condition will be closely monitored while you receive midazolam.

The effects of midazolam can last for several hours after use. It can affect your ability to drive or do anything that needs mental alertness. Do not attempt to drive yourself home if you have received midazolam for minor outpatient surgery. You may feel dizzy and lightheaded. To reduce the risk of dizzy or fainting spells, do not sit up or stand up quickly, especially if you are an older patient. Alcohol can make you more drowsy or dizzy, avoid alcoholic drinks for at least 24 hours after you receive midazolam.

What side effects may I notice from receiving midazolam?

Side effects that you should report to your prescriber or health care professional as soon as possible:
• difficulty breathing, wheezing
• disorientation, or hallucinations during recovery
• dizziness or lightheadedness
• fast or irregular heartbeat (palpitations)
• numbness or tingling in the hands or feet
• pain, redness, or swelling at the injection site
• seizures (convulsions)
• skin rash or itching
Call your prescriber or health care professional as soon as you can if you get any of these side effects.

Side effects that usually do not require medical attention (report to your prescriber or health care professional if they continue or are bothersome):
• coughing, hiccups
• difficulty sleeping, nightmares
• drowsiness
• headache
• involuntary eye and muscle movements
• loss of memory of events just before, during, and after use
• nausea, vomiting
• speech difficulty

Where can I keep my medicine?

Keep out of the reach of children.

Do not use if solution is discolored or particulate matter is present. Follow manufacturers advice on storage of diluted solutions. Throw away any unused injection solution.

Last updated: 7/1/2002

Important Disclaimer: The drug information provided here is for educational purposes only. It is intended to supplement, not substitute for, the diagnosis, treatment and advice of a medical professional. This drug information does not cover all possible uses, precautions, side effects and interactions. It should not be construed to indicate that this or any drug is safe for you. Consult your medical professional for guidance before using any prescription or over the counter drugs.

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Medical Dictionary: mi·daz·o·lam
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Home > Library > Health > Medical Dictionary
(mĭ-dăz'ə-lăm')
n.

A colorless crystalline derivative of diazepam with sedative and anxiolytic properties, usually used in its hydrochloride form as an intravenous anesthetic.

WordNet: midazolam
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Home > Library > Literature & Language > WordNet
Note: click on a word meaning below to see its connections and related words.

The noun has one meaning:

Meaning #1: an injectable form of benzodiazepine (trade name Versed) useful for sedation and for reducing pain during uncomfortable medical procedures
  Synonym: Versed

Wikipedia: Midazolam
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Home > Library > Miscellaneous > Wikipedia
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
 Yes check.svgY(what is this?)  (verify)

Midazolam (pronounced /mɪˈdæzəlæm/, and marketed in English-speaking countries under brand names 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 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

After nighttime administration of midazolam, residual 'hangover' effects—such as sleepiness and impaired psychomotor and cognitive functions—may persist into the next day. This may impair the ability of users to drive safely and may increase the risk of falls and hip fractures.[8] Confusion and amnesia are reported with midazolam.[9]

In susceptible individuals, Midazolam has been known to cause a paradoxical reaction, a well-documented complication with benzodiazapines. When this occurs, the individual may experience anxiety, involuntary movements, aggressive or violent behavior, uncontrollable crying or verbalization, and other similar effects. This seems to be related to the altered state of consciousness or disinhibition produced by the drug.

Case studies have suggested that this type of negative reaction may be more likely in individuals with a history of psychiatric disorder or substance abuse, though it has also been shown to occur in patients with no such history. This reaction may be linked to use of midazolam in higher doses, among children, or among the elderly. Case studies involving identical twins have demonstrated a possible genetic susceptibility. Paradoxical behavior is often not recalled by the patient due to the amnesia-producing properties of the drug. In extreme situations, flumazenil can be administered to inhibit or reverse the effects of midazolam. Anti-psychotic medications such as haloperidol have also been used for this purpose.[10]

Tolerance, dependence and withdrawal

Midazolam can cause a rapid development of drug tolerance and benzodiazepine dependence. 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.[11][12][13] 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.[14] Chronic users of benzodiazepine medication who are given midazolam experience reduced therapeutic effects of midazolam, due to tolerance to benzodiazepines.[15]

Contraindications

Contraindications include 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.[16]

Interactions

Midazolam is metabolized almost completely by cytochrome P450-3A4. Atorvastatin administration along with midazolam results in a reduced elimination rate of midazolam.[17] 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.[18]

Overdose

See also: Benzodiazepine 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 opioid buprenorphine in Singapore.[19]

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.[20] In the United Kingdom midazolam is a Schedule III controlled drug.[21]

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 (midazolam) is about five times as potent as Valium (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.[22][23]

See also

Notes

  1. ^ "Benzodiazepine Names". non-benzodiazepines.org.uk. http://www.non-benzodiazepines.org.uk/benzodiazepine-names.html. Retrieved 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. ^ Carissa E. Mancuso, Maria G. Tanzi, Michael Gabay (2004). "[Paradoxical Reactions to Benzodiazepines: Midazolam [language=English]". Pharmacotherapy. http://www.medscape.com/viewarticle/489358_6. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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. 
  14. ^ 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. 
  15. ^ 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. 
  16. ^ 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. 
  17. ^ Mc Donnell, CG; Harte; O'driscoll; O'loughlin; Van Pelt; Shorten (2003). "The effects of concurrent atorvastatin therapy on the pharmacokinetics of intravenous midazolam.". Anaesthesia 58 (9): 899–904. PMID 12911366. 
  18. ^ 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. 
  19. ^ Lai, SH; Yao YJ, Lo DS. (October 2006). "A survey of buprenorphine related deaths in Singapore". Forensic Sci Int. 162(1-3) (1-3): 80–6. doi:10.1016/j.forsciint.2006.03.037. PMID 16879940. 
  20. ^ List of psychotropic substances under international control
  21. ^ 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. 
  22. ^ 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. 
  23. ^ 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/. 

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Drug Info. Gold Standard. Copyright © 2008 by Gold Standard. All rights reserved.  Read more
Medical Dictionary. The American Heritage® Stedman's Medical Dictionary Copyright © 2002, 2001, 1995 by Houghton Mifflin Company.  Read more
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