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
Inderal Pharmacology, Pharmacokinetics, Studies, Metabolism - Propranolol
Inderal Pharmacology, Pharmacokinetics, Studies, Metabolism - Propranolol
CLINICAL PHARMACOLOGY
Propranolol HCl is a nonselective beta-adrenergic receptor
blocking agent possessing no other autonomic
nervous system
activity. It specifically competes with beta-adrenergic receptor
stimulating agents for available receptor sites. When access to
beta-receptor sites is blocked by Propranolol HCl, the chronotropic,
inotropic, and vasodilator
responses to beta-adrenergic stimulation are decreased proportionately.
Propranolol is almost completely absorbed from the gastrointestinal
tract, but a portion is immediately bound
by the liver. Peak effect
occurs in one to one-and-one-half hours. The biologic
half-life is approximately
four hours.
There is no simple correlation
between dose or plasma
level and therapeutic effect, and the dose-sensitivity range
as observed in clinical
practice is wide. The
principal reason for
this is that sympathetic
tone varies widely between
individuals. Since there is no reliable test
to estimate sympathetic tone or to determine whether total beta
blockade has been achieved,
proper dosage requires titration.
The mechanism of
the antihypertensive
effect of Propranolol
HCl has not been established. Among the factors that may be involved
in contributing to the antihypertensive
action are (1) decreased
cardiac output, (2)
inhibition of renin release
by the kidneys, and (3) diminution of tonic
sympathetic nerve
outflow from vasomotor
centers in the brain. Although total peripheral
resistance may increase initially, it readjusts to or below the
pretreatment level
with chronic use. Effects on plasma
volume appear to be minor
and somewhat variable. Propranolol HCl has been shown to cause
a small increase in serum
potassium concentration when used in the treatment
of hypertensive
patients.
In angina pectoris,
propranolol generally reduces the oxygen
requirement of the heart
at any given level of effort
by blocking the catecholamine-induced
increases in the heart
rate, systolic blood
pressure, and the velocity and extent of myocardial
contraction. Propranolol may increase oxygen
requirements by increasing left
ventricular fiber
length, end diastolic
pressure, and systolic ejection period. The net physiologic effect
of beta-adrenergic blockade
is usually advantageous and is manifested during exercise
by delayed onset of pain and increased work
capacity.
Propranolol exerts its antiarrhythmic
effects in concentrations associated with beta-adrenergic blockade,
and this appears to be its principal
antiarrhythmic mechanism of action. In
dosages greater than required for beta
blockade, Propranolol HCl also exerts a quinidine-like or anesthetic-like
membrane action, which
affects the cardiac
action potential. The
significance of the membrane
action in the treatment
of arrhythmias is uncertain.
The mechanism of
the antimigraine effect
of propranolol has not been established. Beta-adrenergic receptors
have been demonstrated in the pial vessels of the brain.
The specific mechanism
of Propranolol HCl's antitremor effects has not been established,
but beta-2 (noncardiac) receptors may be involved. A central effect
is also possible. Clinical studies have demonstrated that Propranolol
HCl is of benefit in
exaggerated physiological
and essential (familial)
tremor.
Beta-receptor blockade
can be useful in conditions in which, because of pathologic
or functional changes,
sympathetic activity
is detrimental to the patient. But there are also situations in
which sympathetic
stimulation is vital. For example, in patients with severely damaged
hearts, adequate ventricular function
is maintained by virtue of sympathetic
drive, which should be preserved. In
the presence of AV block
greater than first degree, beta blockade may prevent the necessary
facilitating effect of
sympathetic activity
on conduction. Beta blockade
results in bronchial
constriction by
interfering with adrenergic
bronchodilator
activity, which should be preserved in patients subject to bronchospasm.
Propranolol is not significantly dialyzable.
The Beta-Blocker Heart Attack Trial (BHAT) was a National Heart,
Lung and Blood Institute-sponsored multicenter, randomized, double-blind,
placebo-controlled trial conducted in 31 U.S. centers (plus one
in Canada) in 3,837 persons without history of severe congestive
heart failure
or presence of recent heart
failure; certain conduction
defects; angina since
infarction, who had survived the acute phase
of myocardial infarction.
Propranolol was administered at either 60 or 80 mg
t.i.d. based on blood
levels achieved during an initial
trial of 40 mg t.i.d. Therapy
with Propranolol HCl, begun 5 to 21 days following infarction, was
shown to reduce overall
mortality up to 39 months, the longest period of follow-up. This
was primarily attributable to a reduction
in cardiovascular mortality. The protective
effect of Propranolol
HCl was consistent regardless of age, sex, or site
of infarction. Compared with placebo, total mortality was reduced
39% at 12 months and 26% over an average
follow-up period
of 25 months. The Norwegian Multicenter Trial in which propranolol
was administered at 40 mg
q.i.d. gave overall results which support
the findings in the BHAT.
Although the clinical
trials used either t.i.d. or q.i.d. dosing, clinical, pharmacologic,
and pharmacokinetic data provide a reasonable basis
for concluding that b.i.d. dosing with propranolol should be adequate
in the treatment of
postinfarction patients.
Clinical: In
the BHAT, patients on Propranolol HCl were prescribed either 180
mg/day (82% of patients) or 240 mg/day (18% of patients). Patients
were instructed to take
the medication 3
times a day at mealtimes. This dosing schedule
would result in an overnight dosing interval
of 12 to 14 hours, which is similar to the dosing interval
for a b.i.d. regimen. In addition, blood
samples were drawn at various times and analyzed for propranolol.
When the patients were grouped into tertiles based on the blood
levels observed and the mortality in the upper and lower tertiles
was compared, there was no evidence
that blood levels affected
mortality.
Pharmacologic: Studies in normal
volunteers have shown that a 90 mg
b.i.d. regimen maintains
beta blockade
at, or above, the minimum for 60 mg
t.i.d. dosing for 24 hours even though differences occurred at two
time intervals. At 10 to
12 hours after the first dose
of the day, t.i.d. dosing gave more beta
blockade than b.i.d.
dosing; at 20 to 24 hours the trend of the relationship was reversed.
These relationships were similar in direction to those observed
for plasma propranolol
levels. (See Pharmacokinetics)
Pharmacokinetics A bioavailability study in normal
volunteers showed that the blood
levels produced by 180 mg/day given b.i.d. are below those provided
by the same daily dosage
given t.i.d. at 10 to 12 hours after the first dose
of the day, but above those of a t.i.d. regimen at 20 to 24 hours.
However, the blood levels
produced by b.i.d. dosing were always equivalent
to or above the minimum
for t.i.d. dosing throughout the 24 hours. In
addition, the mean AUC
on the fourth day for the b.i.d. regimen was about 17% greater than
for the t.i.d. regimen
(1,194 vs.1,024 ng/ml/hr).
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