Pharmacology - Estazolam (ProSum)

[Jatelka]

Estazolam is 8-chloro-6-phenyl-4H-s-triazolo[4,3-a ] [1,4]benzodiazepine. It is a white powder which is practically insoluble in water and freely soluble in alcohol. The formula is C16H11ClN4. The molecular mass is 294.7



Pharmacokinetics

It is well absorbed orally with peak levels occurring within two hours after dosing (range 0.5 to 6.0 hours)

Independent of concentration, estazolam is 93% protein bound.

Estazolam is extensively metabolized. Two metabolites (1-oxo-estazolam & 4-hydroxy-estazolam) can be detected in urine, up to 18 hrs.
Activity of estazolam is primarily from the parent drug. Elimination takes place via hepatic metabolism to hydroxylated metabolites that are excreted in urine. Greater than 70% of a single dose of estazolam is recovered in the urine. Less than 5% is excreted unchanged, with about 4% excreted in faeces.

4-hydroxy-estazolam is the major metabolite, with concentrations approaching 12% of those of the parent eight hours after administration. Urinary 4-hydroxy-estazolam and 1-oxo-estazolam account for 11.9% and 4.4% of the dose respectively. Metabolism of estazolam is mediated by CY3PA .While 4-hydroxy-estazolam and, 1-oxo-estazolam have some activity, their low potencies and low concentrations are not thought to contribute to the effects of estazolam.

The mean elimination half-life of estazolam varies from 10 to 24 hours. Tthe main route of excretion is via the kidneys. After 5 days, 87% of the administered dose is excreted. Eleven metabolites have been identified in urine, including: 1 -oxo-estazolam, 4†-hydroxy-estazolam, 4-hydroxy-estazolam, and benzophenone. The predominant metabolite in urine (17% of the administered dose) has not been identified, but is likely to be a metabolite of 4-hydroxy-estazolam.

Indications

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

Usual therapeutic dose is 1mg

Adverse Effects

Common: The usual benzo stuff really. Somnolence, poor coordination, dizziness, motor slowing, anterograde amnesia, and rebound anxiety
Infrequent: Allergy, chills, fever, myalgia, flushing, palpitations, constipation, dry mouth, thirst, muscle spasm, hallucinations, agitation, emotional lability

Rare: Anaphylaxis, oedema, cardiac arythmia, syncope, changes in appetite, changes in libido, mouth ulceration, thyroid nodules, rashes, low blood counts, photosensitivity, deranged liver function tests, neuritis, and nystagmus
.
Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during estazolam treatment and withdrawal (unknown clinical significance)

As with all benzodiazepines physical dependence can occur with short term therapy (as little as 14 days). It should not be discontinued suddenly.

Interactions

Compounds that are potent CYP3A inhibitors (such as ketoconazole, itraconazole, nefazodone, fluvoxamine, and erythromycin) would be expected to increase plasma concentrations of estazolam, and CYP3A inducers (such as carbamazepine, phenytoin, rifampin and barbiturates) would be expected to decrease concentrations. Action of estazolam may be potentiated by anticonvulsants, anttihistamines alcohol, barbiturates, monoamine oxidase inhibitors, narcotics, phenothiazines, psychotropic medications, and other drugs that produce CNS depression. Smokers have an increased clearance of benzodiazepines as compared to nonsmokers

Contraindications

The usual benzodiazepine things: Severe respiratory or liver disease, pregnancy and lactation. Also concommitant administration of antifungal agents (itraconozole and ketonoazole).

(Mostly pulled from rxlist)