indication

For use as a sedative perioperatively.

pharmacology

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.

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.

biotransformation

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.

absorption

Rapidly absorbed after oral administration (absolute bioavailability of the midazolam syrup in pediatric patients is about 36%, and intramuscular is greater than 90%).

half life

2.2-6.8 hours

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.

drug interactions

Amprenavir: Amprenavir may increase the effect and toxicity of the benzodiazepine, midazolam.

Aprepitant: Aprepitant may increase the effect and toxicity of the benzodiazepine, midazolam.

Atazanavir: Atazanavir may increase the effect and toxicity of the benzodiazepine, midazolam.

Carbamazepine: Carbamazepine may decrease the effect of the benzodiazepine, midazolam.

Cimetidine: Cimetidine may increase the effect of the benzodiazepine, midazolam.

Clarithromycin: The macrolide, clarithromycin, may increase the effect of the benzodiazepine, midazolam.

Clozapine: Increased risk of toxicity

Delavirdine: The antiviral agent, delavirdine, may increase the effect and toxicity of the benzodiazepine, midazolam.

Diltiazem: The calcium channel blocker, diltiazem, may increase the effect and toxicity of the benzodiazepine, midazolam.

Docetaxel: Midazolam may increase the serum levels and toxicity of docetaxel.

Efavirenz: The antiviral agent, efavirenz, may increase the effect and toxicity of the benzodiazepine, midazolam.

Erythromycin: The macrolide, erythromycin, may increase the effect of the benzodiazepine, midazolam.

Ethotoin: Ethotoin may increase the metabolism of midazolam via CYP3A4.

Fluconazole: Fluconazole may increase the effect of the benzodiazepine, midazolam.

Fosamprenavir: Fosamprenavir may increase the effect and toxicity of the benzodiazepine, midazolam.

Fosphenytoin: Fosphenytoin may increase the metabolism of midazolam via CYP3A4.

Indinavir: The protease inhibitor, indinavir, may increase the effect of the benzodiazepine, midazolam.

Itraconazole: Itraconazole may increase the effect of the benzodiazepine, midazolam.

Josamycin: The macrolide, josamycin, may increase the effect of the benzodiazepine, midazolam.

Kava: Kava may increase the effect of the benzodiazepine, midazolam.

Ketoconazole: Ketoconazole may increase the effect of the benzodiazepine, midazolam.

Mephenytoin: Mephenytoin may increase the metabolism of midazolam via CYP3A4.

Nelfinavir: The protease inhibitor, nelfinavir, may increase the effect of the benzodiazepine, midazolam.

Omeprazole: Omeprazole may increase the effect of the benzodiazepine, midazolam.

Phenytoin: Phenytoin may increase the metabolism of midazolam via CYP3A4.

Quinupristin: This combination presents an increased risk of toxicity

Rifampin: Rifampin may increase the metabolism of midazolam. Monitor for changes in the therapeutic and adverse effects of midazolam if rifampin is initiated, discontinued or dose changed.

Ritonavir: The protease inhibitor, ritonavir, may increase the effect of the benzodiazepine, midazolam.

Saquinavir: The protease inhibitor, saquinavir, may increase the effect of the benzodiazepine, midazolam.

St. John's Wort: St. John's Wort may decrease the effect of the benzodiazepine, midazolam.

Telithromycin: Telithromycin may increase the effect and toxicity of the benzodiazepine, midazolam.

Tipranavir: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Midazolam. Concomitant therapy is contraindicated.

Triprolidine: The CNS depressants, Triprolidine and Midazolam, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Verapamil: Verapamil may increase the serum concentration of Midazolam by decreasing its metabolism. Avoid concomitant therapy if possible or consider a dose reduction in the initial dose of Midazolam.

Voriconazole: Voriconazole may increase the serum concentration of midazolam by decreasing its metabolism. Monitor for midazolam toxicity if voriconazole is initiated or dose increased.