| Indication |
For use as a sedative perioperatively. |
| Pharmacodynamics |
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. |
| Mechanism of action |
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. |
| Absorption |
Rapidly absorbed after oral administration (absolute
bioavailability of the midazolam syrup in pediatric patients is about
36%, and intramuscular is greater than 90%). |
| Volume of distribution |
- 1.24 to 2.02 L/kg [pediatric patients (6 months to <16 years) receiving 0.15 mg/kg IV midazolam,]
|
| Protein binding |
97% |
| Metabolism |
Midazolam is primarily metabolized in the liver and gut by human
cytochrome P450 IIIA4 (CYP3A4) to its pharmacologic active metabolite,
(alpha)-hydroxymidazolam, and 4-hydroxymidazolam. |
| Route of elimination |
Midazolam is primarily metabolized in the liver and gut by human
cytochrome P450 IIIA4 (CYP3A4) to its pharmacologic active metabolite,
α-hydroxymidazolam, followed by glucuronidation of the α–hydroxyl
metabolite which is present in unconjugated and conjugated forms in
human plasma. The α- hydroxymidazolam glucuronide is then excreted in
urine. No significant amount of parent drug or metabolites is
extractable from urine before beta-glucuronidase and sulfatase
deconjugation, indicating that the urinary metabolites are excreted
mainly as conjugates. |
| Half life |
2.2-6.8 hours |
| Clearance |
- 9.3 to 11 mL/min/kg [pediatric patients (6 months to <16 years old)]
|
| Toxicity |
LD50=825 mg/kg (Orally in rats). Signs of overdose
include sedation, somnolence, confusion, impaired coordination,
diminished reflexes, coma, and deleterious effects on vital signs. |
