Drug information of Midazolam

Mechanism of effect

It is thought that the actions of benzodiazepines such as midazolam are mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which is one of the major inhibitory neurotransmitters in the brain. Benzodiazepines increase the activity of GABA, thereby producing a calming effect, relaxing skeletal muscles, and inducing sleep. Benzodiazepines bind to the benzodiazepine site on GABA-A receptors, which potentiates the effects of GABA by increasing the frequency of chloride channel opening.

Pharmacodynamic

Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant. Pharmacodynamic properties of midazolam and its metabolites, which are similar to those of other benzodiazepines, include sedative, anxiolytic, amnesic and hypnotic activities.

 Benzodiazepine pharmacologic effects appear to result from reversible interactions with the (gamma)-amino butyric acid (GABA) benzodiazepine receptor in the CNS, the major inhibitory neurotransmitter in the central nervous system. The action of midazolam is readily reversed by the benzodiazepine receptor antagonist, flumazenil.

Pharmacokinetics

• Bioavailability: 36% (children); 40-50% (PO); >90% (IM)
• Onset: 15-20 min (IM, PO); 3-5 min (IV)
• Duration: 1-6 hr (IM)
• Duration of anterograde amnesia: 1 hr (IM); 20-40 min (IV)
• Peak plasma concentration: 90 ng/mL (IM)
• Peak effect: 0.5 hr (IM)
• Peak sedation: 30-60 min
• Protein bound: 97%
• Vd: 1.0-3.1 L/kg
• Metabolism:Metabolized by liver via CYP3A4
• Metabolites: 1-hydroxymethylmidazolam
• Half-life: 2-6 hr
• Total body clearance: 0.25-0.54 L/hr/kg

Excretion: Urine (90%); feces (2%)

Drug indications

Anxiety , Seizures

Dosage

Adult

Preoperative Sedation/Anxiolysis With Anterograde Amnesia

IM

• 70-80 mcg/kg (dose range ~5 mg) 30-60 minutes before surgery (reduce 50% for chronically ill or geriatric patients) 

IV

• Initial: Usually 0.5-1 mg given over 2 minutes (not to exceed 2.5 mg/dose); wait 2-3 minutes to evaluate sedative effect after each dose adjustment; total dose >5 mg usually not necessary to reach desired sedation; use 30% less midazolam if patient premedicated with narcotics or other CNS depressants
• Debilitated or chronically ill patients: 1.5 mg IV initially; may repeat with 1 mg/dose IV q2-3 min PRN; not to exceed cumulative dose of 3.5 mg; peak effect may be delayed in elderly, so increments should be smaller and rate of injection slower
• Maintenance: 25% of initial effective dose PRN by slow titration; reduce 30% if premedicated with opiate (50% in elderly/chronically ill)

Anesthesia

Induction

• <55 years without premedication: 300-350 mcg/kg IV injection over 20-30 seconds; wait 2-3 minutes to evaluate sedative effect after each dose adjustment; may use increments of 25% of initial dose PRN to complete induction; may use up to 0.6 mg/kg total dose in resistant cases, but such dosing may prolong recovery 
• >55 years without premedication and with no systemic disease, in a patient who is not weak: 300 mcg/kg over 20-30 seconds initially; wait 2-3 minutes to evaluate sedative effect after each dose adjustment
• >55 years without premedication but presence of systemic disease or weak patient: 200-250 mcg/kg over 20-30 seconds usually enough; 0.15 mg/kg enough in some cases; wait 2-3 minutes to evaluate sedative effect after each dose adjustment
• >55 years with premedication: 150-350 mcg/kg IV injection over 20-30 seconds; wait 2-3 minutes to evaluate sedative effect after each dose adjustment; a dose of 250 mcg/kg usually enough to achieve desired effect

Maintenance

• May administer increments of 25% of induction dose PRN when there are signs that anesthetic effects are lightening

Sedation of Intubated/Ventilated Patients

Load: 10-50 mcg/kg (dose range 0.5-4 mg) slow IV injection or infusion over several minutes; repeat q5-15min PRN 

Maintenance: Initial, 20-100 mcg/kg/hr infusion; titrate up or down 25-50% PRN

Pediatric

Sedation

500-750 mcg/kg PO once diluted by juice 20-30 minutes prior to procedure; not to exceed 20 mg 

100-150 mcg/kg IM; up to 500 mcg/kg used; not to exceed 10 mg

IV

• <6 months: Initial, 50 mcg/kg IV over 2-3 minutes; titrate with small increments to clinical effect; monitor closely
• 6 months-6 years: Initial, 50-100 mcg/kg IV over 2-3 minutes; repeat q2-3min PRN; may require up to 600 mcg/kg total dose; not to exceed 6 mg total dose
• 6-12 years: Initial, 25-50 mcg/kg IV over 2-3 minutes; repeat q2-3min PRN; may require up to 400 mcg/kg; not to exceed 10 mg total dose

Anesthesia (Non-neonatal)

Loading dose: 50-150 mcg/kg IV over 2-3 minutes PRN to achieve desired effect 

Continuous infusion: 1-2 mcg/kg/min IV infusion

Anesthesia (Neonatal)

IV loading dose should not be used in neonates

Continuous infusion: 0.5 mcg/kg/min IV infusion

Drug contraindications

Hypersensitivity

Side effects

nausea , vomiting , difficulty urinating

Interactions

Atomoxetine , Aprepitant , Erlotinib , Itraconazole , Imatinib , Propofol , Drospirenone , Docetaxel , Libidox , Erythromycin , Olanzapine , Posaconazole , Rifampin , Cimetidine , Fluconazole , Delavirdine , conivaptan , brigatinib , Efavirenz , Valeriana officinalis , Tipranavir , Telaprevir , cobicistat , Mifepristone , boceprevir , Droperidol , Hydrocodone , Idelalisib , Ivacaftor , propoxyphene , Nefazodone , saquinavir , nelfinavir , Amprenavir , Fosamprenavir , Voriconazole , Carbamazepine , Clarithromycin , Buprenorphine , Sodium Oxybate , Nilotinib , Ketoconazole , Clobazam , Clozapine , Yohimbine , Enzalutamide , Diltigel , Rifabutin , Darunavir , ritonavir , Procaine , Telithromycin , Indinavir , lumacaftor and Ivacaftor , Acetaminophen and benzhydrocodone , Tasimelteon , Desloratadine , Dexlansoprazole , Lercanidipine , Lopinavir and Ritonavir , Glycerol Phenylbutyrate , Ethchlorvynol , Roxithromycin , tibolone , Brivaracetam , Netupitant , sirukumab , Ombitasvir, Paritaprevir, and Ritonavir , Florbetapir F18

Alerts

Black Box Warnings

Respiratory depression/arrest has been associated with use, especially when used for sedation in noncritical care settings

Use lower end of dosing range in debilitated patients, including the elderly

Do not administer by rapid IV injection in neonates (hypotension and seizures reported, especially when used concomitantly with fentanyl)

Respiratory depression, airway obstruction, desaturation, hypoxia, and apnea, particularly when used with concomitant CNS depressants (eg, opioids), have been reported

Should be used only in settings (eg, hospital, ambulatory care settings, including physicians' or dentists' offices) that can provide continuous monitoring of respiratory and cardiac function; immediate availability of resuscitative drugs and age- and size-appropriate equipment for ventilation and intubations, as well as personnel trained in their use and skilled in airway management, should be ensured

General anesthetics and sedation drugs in young children and pregnant women

• Brain development
• Prolonged or repeated exposure may result in negative effects on fetal or young children’s brain development
• Caution with use during surgeries or procedures in children younger than 3 yr or in pregnant women during their third trimester
• Assess the risk:benefit ratio in these populations, especially for prolonged procedures (ie, >3 hr) or multiple procedures

Points of recommendation

• Avoid driving and doing other tasks or actions that call for you to be alert for 1 full day after getting midazolam injection and until the effects of midazolam injection have worn off.
• Use care moving around after getting midazolam injection. You may need help with standing and walking until the effects of midazolam injection have worn off.
• Avoid grapefruit and grapefruit juice.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant. If you are pregnant or you get pregnant while taking midazolam injection, call your doctor right away.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.
• Some products have benzyl alcohol. Do not give a product that has benzyl alcohol in it to a newborn or infant. Talk with the doctor to see if this product has benzyl alcohol in it.

Pregnancy level

D

Related drugs

Alprazolam , Oxazepam , Diazepam , Flurazepam , Lorazepam , Clobazam , Clonazepam , Triazolam , Chlordiaze poxide