indication

For the short-term management of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings.

pharmacology

Estazolam, a triazolobenzodiazepine derivative, is an oral hypnotic agent with anticonvulsant, hypnotic, and muscle relaxant properties. It has been shown in some cases to be more potent than diazepam or nitrazepam.

mechanism of action

Benzodiazepines bind nonspecifically to benzodiazepine receptors, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABA_A) receptors, this enhances the effects GABA by increasing GABA affinity for the GABA receptor. Binding of the inhibitory neurotransmitter GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.

toxicity

Symptoms of overdose include confusion, depressed breathing, drowsiness and eventually coma, lack of coordination, and slurred speech.

biotransformation

Extensively metabolized in the liver. In vitro studies with human liver microsomes indicate that the biotransformation of estazolam to the major circulating metabolite 4-hydroxy-estazolam is mediated by cytochrome P450 3A (CYP3A).

absorption

Tablets have been found to be equivalent in absorption to an orally administered solution of estazolam. In healthy subjects who received up to three times the recommended dose, peak estazolam plasma concentrations occurred within two hours after dosing (range 0.5 to 6.0 hours) and were proportional to the administered dose, suggesting linear pharmacokinetics over the dosage range tested.

half life

The range of estimates for the mean elimination half-life of estazolam varies from 10 to 24 hours.

route of elimination

Estazolam is extensively metabolized. The elimination of the parent drug takes place via hepatic metabolism of estazolam to hydroxylated and other metabolites that are eliminated largely in the urine both free and conjugated. Less than 5% of a 2 mg dose of estazolam was excreted unchanged in the urine, with only 4% of the dose appearing in the feces. Radiolabel mass balance studies indicate that the main route of excretion is via the kidneys. After 5 days, 87% of the administered radioactivity was excreted in human urine. Less than 4% of the dose was excreted unchanged.

drug interactions

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

Clozapine: Increased risk of toxicity

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

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

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

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

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

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

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

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

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

Tipranavir: Tipranavir may decrease the metabolism and clearance of Estazolam. Consider alternate therapy or monitor for Estazolam toxic effects if Tipranavir is initiated or dose increased.

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

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