Midazolam

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[[Image:{{{image|Midazolam.png}}}|{{{width|220}}}px|Midazolam chemical structure]]
Midazolam

8-chloro-6-(2-fluorophenyl)-1-methyl-
4H-Imidazo(1,5-a)(1,4)benzodiazepine
IUPAC name
CAS number
59467-70-8 		}}}
PubChem
4192 		DrugBank
APRD00680
Chemical formula {{Carbon
Molecular weight {{{molecular_weight}}}
Bioavailability {{{bioavailability}}}
Metabolism {{{metabolism}}}
Elimination half-life {{{elimination_half-life}}}
Excretion {{{excretion}}}
Pregnancy category {{{pregnancy_category}}}
Legal status {{{legal_status}}}
Routes of administration {{{routes_of_administration}}}

18H{{#if:{{{1|}}}|{{{1}}}}}13Cl{{#if:{{{1|}}}|{{{1}}}|}}F{{#if:{{{1|}}}|{{{1}}}|}}N{{#if:{{{1|}}}|{{{1}}}|}}3 | molecular_weight = 325.78 | bioavailability = Oral ~36%
I.M. 90%+ | metabolism = Hepatic | elimination_half-life = 1.8-6.4 hours | excretion = Renal | pregnancy_category = C (USA)
C (Aus) | legal_status = Schedule IV(US) | routes_of_administration = Oral, I.M., I.V., parenteral }}

Midazolam, (marketed under brand names Versed®, Hypnovel® and Dormicum®) 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.

Midazolam was first synthesized in 1976 by Fryer and Walser.

This drug is considered quite addictive [1], as should be expected given its potent anxiolytic properties and rapid onset of action.

Contents

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Pharmacology

Unlike other benzodiazepines such as diazepam and lorazepam, midazolam is water soluble because the imidazole ring is open at pH under 4. However, when it is injected and the pH is 7.4, the imidazole ring closes and it becomes much more lipid soluble, facilitating its rapid uptake into nerve tissue. This, and the fact that it has a pKa of 6.15 and is therefore predominantly unionised (>90%) at physiological pH, accounts for its rapid onset of action and its high protein binding in the blood (up to 97%).

Metabolism is by the hepatic Cytochrome p450 enzyme 3A3/3A4. It is hydroxylated to the active metabolite 1-hydroxy-midazolam and then glucuronidated before being renally excreted.

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Indications

Midazolam is frequently used (usually in combination with other agents, such as morphine) by anesthesiologists for sedating patients prior to surgery or other invasive medical procedures, such as endoscopy.

Due to its high potency and fast onset of effects, it is rarely prescribed outside of hospitals. An exception is buccal midazolam, used for the rapid treatment of prolonged seizures. This is an off-label use usage of midazolam, although it has become increasingly common. When using it for this purpose, the drug is squirted slowly between the gums and the inside of the cheek, where it is absorbed directly into the blood stream.

  • Intramuscular or intravenous:
  • Intravenous:
    • For sedation, anxiolysis, and amnesia prior to endoscopic procedures. Often used in combination with other CNS depressants.
    • For general anesthesia, often in combination with other anesthetic agents.
  • Continuous I.V. infusion:
    • For sedation of intubated patients in an intensive care setting.
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Dosage

The dosing of midazolam is highly variable depending on other patient factors and other concurrently administered drugs.

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Side effects

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Interactions

Midazolam ia 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.

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Contraindications

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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®).

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Legal Status

Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances[2].

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External links

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References

  • Status Epilepticus: Clinical Analysis of a Treatment Protocol Based on Midazolam and Phenytoin, Brevoord, J. D. et al., Journal of Child Neurology 2005;20(6):476-48
  • Successful treatment of 75 patients in status epilepticus with intravenous midazolam., Galvin GM, Jelinek GA., Emerg Med 1992;4:11-12.
  • Contribution of midazolam and its 1-hydroxy metabolite to preoperative sedation in children: a pharmacokinetic-pharmacodynamic analysis, Johnson, TN, et al, Br J Anaesth 2002:89(3)428-437.
  • 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.

Template:Benzodiazepines Template:Anticonvulsantsde:Midazolam fi:Midatsolaami pl:Midazolam pt:Midazolam sv:Midazolam

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