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Midazolam (Versed ®) - Intravenous (IV) Dilution globalrph.com | VERSED (midazolam HCI) - Drug information from MediLexicon medilexicon.com | Hair, Hair treatment, hair recovery, Laser hair removal, most common... drpurnimaskinclinic.com |
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.
[edit] IndicationsIntravenous 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] [edit] AvailabilityDormicum 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. [edit] Side effectsAfter 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] [edit] Tolerance, dependence and withdrawalMidazolam 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] [edit] ContraindicationsBenzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with comorbid psychiatric disorders.[16] Contraindications include hypersensitivity, acute narrow angle glaucoma, shock, hypotension, head injury. Most are relative contraindications. [edit] PregnancyMidazolam 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.[17] [edit] InteractionsMidazolam is metabolized almost completely by cytochrome P450-3A4. Atorvastatin administration along with midazolam results in a reduced elimination rate of midazolam.[18] Grapefruit juice reduces intestinal 3A4 and results in less metabolism and higher plasma concentrations, which could result in overdose. [edit] Mechanism of actionLike 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.[19] [edit] OverdoseSee also: Benzodiazepine overdose Symptoms of midazolam overdose include:
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.[20] [edit] Legal statusIn the Netherlands, midazolam is a List II drug of the Opium Law. Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances.[21] In the United Kingdom midazolam is a Schedule III controlled drug.[22] [edit] Law enforcement and criminal justiceMidazolam 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.[23][24] [edit] See also
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