Pharmacology - Triazolam (Halcion)

[Jatelka]

Triazolam is 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-
[1,2,4]triazolo[4,3-a][1,4]benzodiazepine.

It isa white crystalline powder, soluble in alcohol and poorly soluble in water. It has a molecular weight of 343.21 and the chemical formula C17H12Cl2N4.

Pharmacokinetics

Triazolam is well absorbed after an oral dose. Peak plasma levels are reached within 2 hours following oral administration. Plasma levels achieved are proportional to the dose given (typically 1-6ng/ml).

Half-life is 1.5 to 5.5 hours. In normal subjects treated for 7 days with four times the recommended dosage, there was no evidence of altered bioavailability, rate of elimination, or accumulation.

Triazolam and its metabolites, principally as conjugated glucuronides, which are presumably inactive, are excreted primarily in theurine. Only small amounts of unmetabolized triazolam appear in the urine. The two primary metabolites account for 79.9% of excretion, which is biphasic in its time course.

Research

In short-term clinical studies, triazolam decreased sleep latency, increased the duration of sleep, and decreased the number of nocturnal awakenings. After 2 weeks of consecutive nightly administration, the drug's effect on total wake time was decreased, and the values recorded in the last third of the night approach baseline. On the first and/or second night after drug discontinuance (first or second post-drug night), total time asleep, percentage of time spent sleeping, and rapidity of falling asleep frequently were significantly less than on baseline (pre-drug) nights.

In a study of elderly (62-83 years old) versus younger subjects (21-41 years old) who received triazolam at the same dose levels (0.125 mg and 0.25 mg), the elderly experienced both greater sedation and impairment of psychomotor performance. These effects result from higher plasma concentrations of triazolam in the elderly.

Indications

The short-term treatment of insomnia. Usual therapeutic dose is 0.25mg at night, although this should be lower in elderly or debilitated patients (0.125mg)

Adverse Effects

Common: Drowsiness, headache, dizziness, rebound anxiety, reduced coordination, nausea and vomiting.

Uncommon :Euphoria, tachycardia, confusional states/memory impairment, cramps/pain, depression, visual disturbances.

Rare: Constipation, taste alteration, diarrhoea, dry mouth, dermatitis/allergy, dreaming/nightmares, paraesthesia (pins and needles), and tinnitus.

Paradoxical reactions such as stimulation, mania, restlessness, irritability, and excitation, increased muscle tone, sleep disturbances, hallucinations, delusions, aggressiveness and somnambulism have been reported.

When treatment with triazolam is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are advisable. Minor changes in EEG patterns, usually low-voltage fast activity, have been observed and are of no known significance.

Interactions

Triazolam produces additive depressant effects when co-administered with other psychotropic medications, anticonvulsants, antihistamines, ethanol, and other drugs which themselves produce CNS depression.

The initial step in triazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP 3A). Drugs which inhibit this pathway may have a profound effect on the clearance of triazolam.

Isoniazid—Co-administration of isoniazid increases the maximum plasmaconcentration of triazolam by 20%, decreases clearance by 42%, and increases half-life by 31%.

Oral contraceptives—Co-administration of oral contraceptives increases maximum plasma concentration by 6%, decreases clearance by 32%, and increases half-life by 16%.

Grapefruit juice—Co-administration of grapefruit juice increases the maximum plasma concentration of triazolam by 25%, increases the area under the concentration curve by 48%, and increases half-life by 18%.

Possible Interactions: Fluvoxamine, diltiazem, verapamil, sertraline, paroxetine, ergotamine, cyclosporin, amiodarone, nicardipine, and nifedipine.

Ranitidine—Co-administration of ranitidine increases the maximum plasma concentration of triazolam by 30%, increases the area under the concentration curve by 27%, and increases half-life by 3.3%. This is not mediated by Cytochrome P450 inhibition

Carcinogenesis, Mutagenesis, and Impairment of Fertility

No evidence of carcinogenic potential was observed in mice during a 24-month study with triazolam in doses up to 4,000 times the human dose.

Geriatric use:

The elderly are susceptible to the dose-related adverse effects of triazolam. They exhibit higher plasma triazolam concentrations due to reduced clearance of the drug as compared with younger subjects at the same dose.

Overdosage

Because of the potency of triazolam, some manifestations of overdosage may occur at 2 mg, four times the maximum recommended therapeutic dose (0.5 mg).

Manifestations of overdosage with triazolam tablets include somnolence, confusion, impaired coordination, slurred speech, and ultimately, coma. Respiratory depression and apnoea have also been reported, as have seizures.

The oral LD50 in mice is greater than 1,000 mg/kg and in rats is greater than 5,000 mg/kg.