A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Halcion Pharmacology, Pharmacokinetics, Studies, Metabolism - Triazolam
Halcion Pharmacology, Pharmacokinetics, Studies, Metabolism - Triazolam
CLINICAL PHARMACOLOGY
Triazolam is a hypnotic
with a short mean plasma
half-life reported
to be in the range of
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 systemic
bioavailability,
rate of elimination, or
accumulation. Peak plasma
levels are reached within 2 hours following oral
administration. Following recommended doses of Halcion, triazolam
peak plasma levels in
the range of 1 to 6 ng/ml
are seen. The plasma
levels achieved are proportional to the dose
given.
Triazolam and its metabolites, principally as conjugated glucuronides,
which are presumably inactive, are excreted primarily in the urine.
Only small amounts of unmetabolized triazolam appear in the urine.
The two primary metabolites accounted for 79.9% of urinary
excretion. Urinary excretion appeared to be biphasic
in its time course.
Triazolam tablets 0.5 mg, in two separate studies, did not affect
the prothrombin times or plasma
warfarin levels in male
volunteers administered sodium warfarin orally.
Extremely high concentrations of triazolam do not displace bilirubin
bound to human serum
albumin in vitro.
Triazolam 14C was administered orally to pregnant
mice. Drug-related material appeared uniformly distributed in the
fetus with14C
concentrations approximately the same as in the brain
of the mother.
In sleep laboratory
studies, triazolam tablets significantly 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 is decreased,
and the values recorded in the last third of the night approach
baseline levels. 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
(predrug) nights. This effect
is often called "rebound" insomnia.
The type and duration
of hypnotic effects
and the profile of unwanted
effects during administration
of benzodiazepine
drugs may be influenced by the biologic
half-life of administered
drug and any active metabolites
formed. When half-lives are long, the drug
or metabolites may accumulate during periods of nightly administration
and be associated with impairments of cognitive and motor
performance during
waking hours; the possibility of interaction with other psychoactive
drugs or alcohol will
be enhanced. In contrast, if half-lives are short, the drug
and metabolites will be
cleared before the next dose
is ingested, and carry-over
effects related to excessive sedation
or CNS depression
should be minimal or
absent. However, during nightly use for an extended period
pharmacodynamic tolerance
or adaptation to some effects of benzodiazepine
hypnotics may develop. If the drug
has a short half-life
of elimination, it is possible that a relative deficiency of the
drug or its active metabolites
(i.e., in relationship to the receptor
site) may occur at some point
in the interval between
each night's use. This sequence
of events may account for two clinical
findings reported to occur after several weeks of nightly use of
rapidly eliminated benzodiazepine hypnotics: 1) increased wakefulness
during the last third of the night and 2) the appearance
of increased daytime anxiety
after 10 days of continuous treatment.
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