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'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.

Contents

Mechanism of action

Indications

Interactions

Contraindications

Side Effects

Overdose

Legal status

Popular Culture

See Also

External links

Notes

References

Mechanism of action

Like other benzodiazepines, midazolam acts on benzodiazepine receptors which enhance the binding of GABA to the GABA_A receptor which results in inhibitory effects on the central nervous system.^[1]

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.^[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]

Interactions

Midazolam is metabolized almost completely by cytochrome P450-3A4. Vmax in microsomes is reported as 850 pmol/min/mg microsomal protein. Km is reported as 3.7 uMol. Metabolism in the gut wall is reported as nearly equal to metabolism in liver by CYP3A4. Therefore, midazolam will interact with other 3A4 substrates and inhibitors. Grapefruit juice reduces intestinal 3A4 and results in less gut wall 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. Some may be 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.^[4]

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.^[5]

Legal status

Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances.^[6]

Popular Culture

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.
Consumed by FBI Special Agent Alexander Mahone on fictional television series Prison Break, played by William Fichtner. Is shown taking the pills on various occasions during his hunt of escaped convicts. Absence of these medications result in expressions of agitation.

See Also

★ Automatism (toxicology)

External links

★ Rx-List - Midazolam (Versed)

★ Inchem - Midazolam

Notes

1. Enhancement of GABA binding by benzodiazepines and related anxiolytics., Skerritt JH, , , Eur J Pharmacol., 1983
2. Benzodiazepines in the treatment of epilepsy in people with intellectual disability., , JI, Isojärvi, J Intellect Disabil Res., 1998
3. Can benzodiazepines be classified by characterising their anticonvulsant tolerance-inducing potential?, Garratt JC, , , Eur J Pharmacol., 1988
4. Residual effects of hypnotics: epidemiology and clinical implications., Vermeeren A., , , CNS Drugs., 2004
5. A survey of buprenorphine related deaths in Singapore., , SH, Lai, Forensic Sci Int., 2006
6. List of psychotropic substances under international control

References

★ EMEA Summary of Product Characteristics: Hypnovel and associated names.

★ Clinical Use of Midazolam by John Shou.

★ Status epilepticus: clinical analysis of a treatment protocol based on midazolam and phenytoin., Brevoord J, Joosten K, Arts W, van Rooij R, de Hoog M, , , J Child Neurol, 2005

★ Intranasal midazolam therapy for pediatric status epilepticus., Wolfe T, Macfarlane T, , , Am J Emerg Med, 2006

★ Contribution of midazolam and its 1-hydroxy metabolite to preoperative sedation in children: a pharmacokinetic-pharmacodynamic analysis., Johnson T, Rostami-Hodjegan A, Goddard J, Tanner M, Tucker G, , , Br J Anaesth, 2002

★ ''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.

★ Metamemory without the memory: are people aware of midazolam-induced amnesia?, Merritt P, Hirshman E, Hsu J, Berrigan M, , , Psychopharmacology (Berl), 2005