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
Bayer ASA Pharmacology, Pharmacokinetics, Studies, Metabolism - Aspirin
Bayer ASA Pharmacology, Pharmacokinetics, Studies, Metabolism - Aspirin
CLINICAL PHARMACOLOGY
Aspirin is a salicylate
that has demonstrated antiinflammatory, analgesic, antipyretic,
and antirheumatic
activity. Aspirin's mode
of action as an antiinflammatory
and antirheumatic
agent may be due to inhibition
of synthesis and release
of prostaglandins. Aspirin appears to produce analgesia
by virtue of both a peripheral
and CNS effect. Peripherally,
aspirin acts by inhibiting
the synthesis and
release of prostaglandins.
Acting centrally, it would appear to produce analgesia
at a hypothalamic site
in the brain, although the mode
of action is not known.
Aspirin also acts on the hypothalamus to produce antipyresis; heat
dissipation is increased
as a result of vasodilation and increased peripheral
blood flow. Aspirin's
antipyretic activity
may also be related to inhibition
of synthesis and release
of prostaglandins. In a crossover
study, Enteric Coated Aspirin at a dose
of one tablet (15 grains)
three times a day produced an average
fecal blood loss
of 1.54 ml per day. Uncoated
aspirin at a dosage
of three 5-grain tablets given three times a day caused an average
fecal blood loss
of 4.33 ml per
day.
Aspirin is rapidly hydrolyzed primarily in the liver
to salicylic acid, which is conjugated with glycine
(forming salicyluric acid) and glucuronic acid and excreted largely
in the urine. As a result
of the rapid hydrolysis, plasma concentrations of aspirin
are always low and rarely exceed 20 mcg/ml at ordinary therapeutic
doses. The peak salicylate
level for uncoated aspirin occurs in about 2 hours; however with
enteric coated aspirin
tablets this is delayed. A direct correlation
between salicylate
plasma levels and clinical
analgesic effectiveness
has not been definitely established, but effective analgesia is
usually achieved at plasma
levels of 15 to 30 mg per
100 ml. Effective antiinflammatory activity
is usually achieved at salicylate
plasma levels of 20 to 30 mg
per 100 ml.
There is also p.o. correlation
between toxic symptoms and plasma
salicylate concentrations,
but most patients exhibit symptoms of salicylism
at plasma salicylate
levels of 35 mg per 100 ml.
The plasma half-life
for aspirin is approximately
15 minutes; that for salicylate
lengthens as the dose increases:
Doses of 300 to 650 mg have a half-life
of 3.1 to 3.2 hours; with doses of 1 gram, the half-life is increased
to 5 hours and with 2 grams it is increased to about 9 hours. Salicylates
are excreted mainly by the kidney. Studies in man
indicate that salicylate
is excreted in the urine
as free salicylic acid
(10%), salicyluric acid
(75%), salicylic phenolic (10%) and acyl
(5%) glucuronides and gentisic acid
(<1%).
CLINICAL STUDIES
In MI Prophylaxis
Clinical Trials: The indication
is supported by the results of six large randomized, multicenter,
placebo-controlled studies (REF. 1-7) involving 10,816 predominantly
male post-myocardial infarction
(MI) patients and one randomized placebo-controlled study of 1,266
men with unstable angina. Therapy with aspirin
was begun at intervals after the onset of acute
MI varying from less than three days to more than five years and
continuing for periods of from less than one year to four years.
In the unstable angina study,
treatment was started
within one month after the onset of unstable angina and continued
for 12 weeks, and complicating conditions, such
as congestive heart failure,
were not included in the study.
Aspirin therapy in
MI patients was associated
with about a 20% reduction in the risk
of subsequent death and/or
nonfatal reinfarction, a median absolute decrease of 3% from the
12% to 22% event rates in the placebo groups. In
the aspirin-treated unstable angina
patients, the reduction in risk
was about 50%, a reduction
in the event rate of 5%
from the 10% rate in the placebo
group over the 12 weeks
of study.
Daily dosage of aspirin
in the post-myocardial infarction
studies was 300 mg in one
study and 900-1,500 mg in
five studies. A dose of
325 mg was used in the study of unstable angina.
In Transient Ischemic Attacks
Clinical Trials: The indication
is supported by the results of a Canadian study (REF. 8) in which
585 patients with threatened stroke
were followed in a randomized clinical
trial for an average
of 28 months to determine whether aspirin
or sulfinpyrazone, singly or in combination, was superior to placebo
in preventing transient
ischemic attacks, stroke, or death. The study showed that, although
sulfinpyrazone
had no statistically significant
effect, aspirin reduced
the risk of continuing
transient ischemic
attacks, stroke, or death
by 19 percent and reduced
the risk of stroke
or death by 31 percent. Another aspirin
study carried out in the United States with 178 patients showed
a statistically significant
number of "favorable
outcomes," including reduced transient
ischemic attacks, stroke, and death.(REF. 9)
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