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
Xanax Pharmacology, Pharmacokinetics, Studies, Metabolism - Alprazolam
Xanax Pharmacology, Pharmacokinetics, Studies, Metabolism - Alprazolam
CLINICAL PHARMACOLOGY
CNS agents of the 1,4 benzodiazepine
class presumably exert their
effects by binding at stereo specific
receptors at several sites within the central nervous system. Their exact
mechanism of action
is unknown. Clinically, all benzodiazepines cause
a dose-related central nervous
system depressant activity
varying from mild impairment
of task performance to
hypnosis.
Following oral administration,
alprazolam is readily absorbed. Peak concentrations in the plasma
occur in 1-2 hours following administration. Plasma levels are proportionate
to the dose given; over the dose
range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/ml were observed.
Using a specific assay methodology, the mean
plasma elimination
half-life of alprazolam
has been found to be about 11.2 hours (range: 6.3-26.9 hours) in healthy
adults.
The predominant metabolites are a-hydroxy-alprazolam
and a benzophenone derived from alprazolam. The biological
activity of a-hydroxy-alprazolam is approximately
one-half that of alprazolam. The benzophenone metabolite
is essentially inactive. Plasma levels of these metabolites are extremely
low, thus precluding precise pharmacokinetic description. However, their
half-lives appear to be of the same order
of magnitude as that of
alprazolam. Alprazolam and its metabolites are excreted primarily in the
urine.
The ability of alprazolam to induce human
hepatic enzyme
systems has not yet been determined. However, this is not a property of
benzodiazepines in general. Further, alprazolam did not affect
the prothrombin or plasma
warfarin levels in male volunteers
administered sodium warfarin
orally.
In vitro, alprazolam is bound
(80%) to human serum
protein.
Changes in the absorption, distribution, metabolism, and excretion
of benzodiazepines have been reported in a variety of disease
states including alcoholism, impaired hepatic
function, and impaired renal
function. Changes have also been demonstrated in geriatric patients. A
mean half-life
of alprazolam of 16.3 hours has been observed in healthy elderly subjects
(range: 9.0-26.9 hours, n = 16) compared to 11.0 hours (range: 6.3-15.8
hours, n = 16) in healthy adult
subjects. In patients with alcoholic
liver disease the half-life
of alprazolam ranged between 5.8 and 65.3 hours (mean: 19.7 hours, n =
17) as compared to between 6.3 and 26.9 hours (mean = 11.4 hours, n =
17) in healthy subjects. In an
obese group
of subjects the half-life of alprazolam ranged between 9.9 and 40.4 hours
(mean = 21.8 hours, n = 12) as compared to between 6.3 and 15.8 hours
(mean = 10.6 hours, n = 12) in healthy subjects.
Because of its similarity to other benzodiazepines, it is assumed that
alprazolam undergoes transplacental
passage and that it is excreted
in human milk.
CLINICAL STUDIES
Anxiety Disorders: Alprazolam tablets were compared to
placebo in double blind
clinical studies (doses up
to 4 mg/day) in patients with a diagnosis
of anxiety or anxiety with associated depressive symptomatology. Alprazolam
was significantly better than placebo
at each of the evaluation periods of these four week studies as judged
by the following psychometric instruments: Physician's Global Impressions,
Hamilton Anxiety Rating Scale, Target Symptoms, Patient's Global Impressions,
and Self-Rating Symptom Scale.
Panic Disorder: Support for the effectiveness
of alprazolam in the treatment
of panic disorder
came from three short-term, placebo-controlled studies (up to 10 weeks)
in patients with diagnoses closely corresponding to DSM-III-R criteria
for panic disorder.
The average dose
of alprazolam was 5-6 mg/day in two of the studies, and the doses of alprazolam
were fixed at 2 and 6 mg/day in the third study. In all three studies,
alprazolam was superior to
placebo on a variable defined
as "the number of patients
with zero panic
attacks" (range, 37-83% met this criterion), as well as on a global
improvement score. In two of the three studies, alprazolam was superior
to placebo on a variable defined
as "change from baseline
on the number of panic
attacks per week" (range, 3.3-5.2), and also on a phobia
rating scale. A subgroup of patients who were improved on alprazolam during
short-term treatment in one of these trials was continued on an open
basis up to 8 months, without
apparent loss of benefit.
ANIMAL PHARMACOLOGY
When rats were treated with alprazolam at 3, 10, and 30 mg/kg/day (15-150
times the maximum recommended
human dose) orally for 2 years,
a tendency for a dose related
increase in the number of cataracts
was observed in females and a tendency for a dose
related increase in corneal vascularization was observed in males. These
lesions did not appear until after 11 months of treatment.
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