Midazolam

Midazolam

Clinical data
Pregnancy category	C (USA) C (Aus)
Routes of administration	Oral, I.M., I.V., parenteral
ATC code	N05CD08 (WHO)
Legal status
Legal status	Schedule IV(US)
Pharmacokinetic data
Bioavailability	Oral ~36% I.M. 90%+
Metabolism	Hepatic
Elimination half-life	1.8-6.4 hours
Excretion	Renal
Identifiers
IUPAC name 8-chloro-6-(2-fluorophenyl)-1-methyl -4H-Imidazo(1,5-a)(1,4)benzodiazepine
CAS Number	59467-70-8
PubChem CID	4192
DrugBank	APRD00680
CompTox Dashboard (EPA)	DTXSID5023320
ECHA InfoCard	100.056.140
Chemical and physical data
Formula	C18H13ClFN3
Molar mass	325.78

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.

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 unionised 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.

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:
  • Preoperative sedation, anxiolysis, amnesia,
  • Treatment of epileptic seizures.
• 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.

Dosage

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

• Preoperative anxiolysis: 0.5-2.5 mg.

• Endoscopy: 3-5 mg (rarely 10mg) IV, often with 50mg pethidine or fentanyl.

• Status epilepticus: 10mg intranasally or as buccal.

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®).

Legal Status

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

External links

• Rx-List - Midazolam (Versed)
• Inchem - Midazolam

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.