Midazolam

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.

Mechanism of action
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.

Indications
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. 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.

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.

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.

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

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.

Pregnancy
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.

Overdose
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.

Legal status
Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances.

Popular Culture
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 "Veritril."