Midazolam

Midazolam is the most commonly used parenteral sedative in anaesthetic practice. The structure of midazolam is altered by local changes in pH (tautomerism), and the two different forms confer either water or lipid solubility to the drug . At pH<4 the benzodiazepine nucleus opens because of an ionisable amine group in the molecule's structure, and this increases water solubility. At plasma pH the amine group is incorporated back into the unionised ring form of the molecule, which is highly lipid soluble and diffuses rapidly into the brain. A concentrated preparation (5mgml ?1 ) is available for i.m. injection and absorption is rapid compared with diazepam.

White Crystaline Solid

Dormicum,Roche,Switz.,1982

Anti-Depressant

In many countries this product is controlled. An import permit may be required. Anesthetic; anticonvulsant; sedative; hypnotic

ChEBI: Midazolam is an imidazobenzodiazepine that is 4H-imidazo[1,5-a][1,4]benzodiazepine which is substituted by a methyl, 2-fluorophenyl and chloro groups at positions 1, 6 and 8, respectively. It has a role as a GABAA receptor agonist, an anticonvulsant, an anxiolytic drug, an apoptosis inducer, an antineoplastic agent, a muscle relaxant, a sedative, a general anaesthetic and a central nervous system depressant. It is an organochlorine compound, an imidazobenzodiazepine and a member of monofluorobenzenes.

Acetic anhydride (7 ml) was added to a solution of 6.16 g of crude 2- aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepine in 200 ml of methylene chloride. The solution was added to 200 ml of saturated aqueous sodium bicarbonate and the mixture was stirred for 20 minutes. The organic layer was separated, washed with sodium bicarbonate, dried over sodium sulfate and evaporated to leave resinous 2- acetylaminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-lH -l,4- benzodiazepine. This material was heated with 40 g of polyphosphoric acid at 150°C for 10 minutes. The cooled reaction mixture was dissolved in water, made alkaline with ammonia and ice and extracted with methylene chloride. The extracts were dried and evaporated and the residue was chromatographed over 120 g of silica gel using 20% methanol in methylene chloride. The clean fractions were combined and evaporated to yield resinous 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-1- methyl-4H-imidazo[1,5-a][1,4] - benzodiazepine.
A mixture of this material with 500 ml of toluene and 30 g of manganese dioxide was heated to reflux for 1? hours. The manganese dioxide was separated by filtration over Celite. The filtrate was evaporated and the residue was crystallized from ether to yield 8-chloro-6-(2-fluorophenyl)-1-methyl-4Himidazo[1,5-a][1,4]benzodiazepine, melting point 152°C to 154°C. The analytical sample was recrystallized from methylene chloride/hexane.
A warm solution of 6.5 g (0.02 mol) of 8-chloro-6-(2-fluorophenyl)-1-methyl- 4H-imidazo[1,5-a] [1,4]-benzodiazepine in 30 ml of ethanol was combined with a warm solution of 2.6 g (0.022 mol) of maleic acid in 20 ml of ethanol. The mixture was diluted with 150 ml of ether and heated on the steam bath for 3 minutes. After cooling, the crystals were collected, washed with ether and dried in vacuo to yield 8-chloro-6-(2-fluorophenyl)-1-methyl-4Himidazo[1.5-a] [1,4]-benzodiazepine maleate, melting point 148°C to 151°C.

Versed (Roche).

Anesthetic

Midazolam is a benzodiazepine, sold as Dormicum, Hypnovel^?, and Versed as a sedative and treatment for insomnia and seizures. This Snap-N-Spike^? Reference Solution is suitable for many GC/MS or LC/MS applications from clinical toxicology and urine drug testing to pain prescription monitoring or forensic analysis.

Midazolam undergoes hepatic oxidative metabolism and has an elimination half-life of 2–4h. The major metabolite is 1-hydroxymidazolam, which is biologically active. Midazolam has been used as a sole hypnotic for TI VA and produces superior procedural amnesia compared with propofol, but CSHT increases significantly when used by continuous infusion, and this delays recovery. Clinical studies demonstrate the inferiority of midazolam in terms of time to onset of desired sedation score, slower recovery, less clear-headedness, and significantly longer period of postoperative amnesia compared with propofol.

Benzodiazepine:
Sedation with amnesia in conjunction with local anaesthesia, premedication, induction
Status epilepticus (unlicensed)

Potentially hazardous interactions with other drugs
Antibacterials: concentration increased by erythromycin, clarithromycin and telithromycin (profound sedation); metabolism possibly accelerated by rifampicin.
Antidepressants: concentration of oral midazolam possibly reduced by St John’s wort.
Antifungals: concentration increased by itraconazole, fluconazole, ketoconazole, posaconazole and voriconazole (prolonged sedative effect).
Antipsychotics: increased sedative effects; increased risk of hypotension, bradycardia and respiratory depression when parenteral benzodiazepines are given with IM olanzapine.
Antivirals: concentration increased by atazanavir, boceprevir, efavirenz, indinavir, fosamprenavir, ritonavir, saquinavir and telaprevir increase risk of prolonged sedation; avoid with oral midazolam.
Ciclosporin: in vitro studies suggested that ciclosporin could inhibit the metabolism of midazolam. However, blood ciclosporin concentrations in patients given ciclosporin to prevent graft rejection were considered too low to result in an interaction.
Cobicistat: avoid with oral midazolam.
Cytotoxics: concentration increased by crizotinib and nilotinib; concentration reduced by enzalutamide.
Sodium oxybate: enhanced effects of sodium oxybate - avoid.

Metabolised in the liver via the cytochrome P450 isoenzyme CYP3A4. The major metabolite, alpha hydroxymidazolam has some activity; its half-life is less than 1 hour. Midazolam metabolites are excreted in the urine, mainly as glucuronide conjugates.