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
Toprol Xl Pharmacology, Pharmacokinetics, Studies, Metabolism - Metoprolol Succinate
Toprol Xl Pharmacology, Pharmacokinetics, Studies, Metabolism - Metoprolol Succinate
CLINICAL PHARMACOLOGY
Metoprolol is a beta1-selective (cardioselective) adrenergic
receptor blocking agent.
This preferential effect
is not absolute, however, and at higher plasma
concentrations, metoprolol also inhibits beta2-adrenoreceptors,
chiefly located in the bronchial
and vascular musculature.
Metoprolol has no intrinsic
sympathomimetic
activity, and membrane-stabilizing activity is detectable only at
plasma concentrations
much greater than required for beta-blockade. Animal and human
experiments indicate that metoprolol slows the sinus
rate and decreases AV nodal
conduction.
Clinical pharmacology studies have confirmed the beta-blocking
activity of metoprolol in man, as shown by (1) reduction
in heart rate
and cardiac output at rest
and upon exercise, (2) reduction
of systolic blood
pressure upon exercise, (3) inhibition
of isoproterenol-induced tachycardia, and (4) reduction
of reflex orthostatic
tachycardia.
The relative beta1-selectivity of metoprolol has been
confirmed by the following: (1) In
normal subjects, metoprolol
is unable to reverse the beta2-mediated vasodilating
effects of epinephrine. This contrasts with the effect
of nonselective beta-blockers, which completely reverse the vasodilating
effects of epinephrine. (2) In
asthmatic patients, metoprolol reduces FEV1 and FVC
significantly less than a nonselective beta-blocker, propranolol,
at equivalent beta1-
receptor blocking doses.
In five controlled studies in normal
healthy subjects, the same daily doses of extended release
metoprolol succinate
and immediate release
metoprolol were compared in terms of the extent and duration
of beta1-blockade produced. Both formulations were given
in a dose range
equivalent to 100-400
mg of immediate release
metoprolol per day. In
these studies, extended release metoprolol succinate
was administered once a day and immediate release metoprolol was
administered once to four times a day. A sixth controlled study
compared the beta1-blocking effects of a 50 mg
daily dose of the two formulations. In
each study, beta1-blockade was expressed as the percent
change from baseline, in exercise
heart rate
following standardized submaximal exercise
tolerance tests at
steady state. Toprol- XL administered once a day, and immediate
release metoprolol administered
once to four times a day, provided comparable total beta1-
blockade over 24 hours
(area under the beta1-blockade versus time
curve) in the dose range
100-400 mg. At a dosage
of 50 mg once daily, extended
release metoprolol succinate
produced significantly higher total beta1-blockade over
24 hours than immediate
release metoprolol.
For extended release
metoprolol succinate, the percent
reduction in exercise
heart rate
was relatively stable throughout the entire
dosage interval
and the level of beta1-blockade increased with increasing
doses from 50 to 300 mg daily.
The effects at peak/trough (i.e., at 24 hours post
dosing) were; 14/9, 16/10, 24/14, 27/22 and 27/20% reduction
in exercise heart
rate for doses of 50, 100,
200, 300 and 400 mg extended
release metoprolol succinate
once a day, respectively. In contrast
to extended release
metoprolol succinate, immediate
release metoprolol given at a dose
of 50-100 mg once a day,
produced a significantly larger peak effect
on exercise tachycardia,
but the effect was not
evident at 24 hours. To match
the peak to trough ratio
obtained with extended release metoprolol succinate
over the dosing range
of 200 to 400 mg, a t.i.d. to q.i.d. divided dosing regimen
was required for immediate
release metoprolol.
The relationship between plasma
metoprolol levels and reduction
in exercise heart rate
is independent of the pharmaceutical
formulation. Using the Emax model, the maximal beta1-blocking
effect has been estimated
to produce a 28.3% reduction
in exercise heart
rate. Beta1-blocking effects in the range
of 30-80% of the maximal effect
(corresponding to approximately 8-23% reduction
in exercise heart
rate) are expected to occur at metoprolol plasma
concentrations ranging from 30-540 nmol/L. The concentration-effect
curve begins reaching a plateau
between 200-300 nmol/L, and higher plasma levels produce little
additional beta1-blocking effect. The relative beta1-selectivity
of metoprolol diminishes and blockade of beta2- adrenoceptors
increases at higher plasma
concentrations.
Although beta-adrenergic receptor
blockade is useful
in the treatment of angina
and hypertension, there are situations in which sympathetic
stimulation is vital. In
patients with severely damaged hearts, adequate ventricular function
may depend on sympathetic
drive. In the presence of
AV block, beta-blockade may prevent the necessary facilitating effect
of sympathetic activity on conduction. Beta2-adrenergic
blockade results in
passive bronchial
constriction by
interfering with endogenous
adrenergic bronchodilator activity in patients subject
to bronchospasm
and may also interfere with exogenous
bronchodilators in such patients.
Hypertension
The mechanism of
the antihypertensive
effects of beta-blocking agents has not been elucidated. However,
several possible mechanisms have been proposed: (1) competitive
antagonism of catecholamines
at peripheral (especially
cardiac) adrenergic
neuron sites, leading
to decreased cardiac
output; (2) a central
effect leading to reduced
sympathetic outflow
to the periphery; and (3) suppression
of renin activity.
In controlled clinical
studies, an immediate
release dosage
form of metoprolol has
been shown to be an effective antihypertensive
agent when used alone
or as concomitant
therapy with thiazide-type diuretics at dosages of 100-450 mg
daily. Extended release
metoprolol succinate, in dosages of 100 to 400 mg
once daily, has been shown to possess comparable b1-blockade
as conventional metoprolol tablets administered two to four times
daily. In addition, extended release
metoprolol succinate
administered at a dose of 50 mg
once daily has been shown to lower blood
pressure 24-hours post-dosing
in placebo controlled
studies. In controlled, comparative,
clinical studies, immediate
release metoprolol appeared
comparable as an antihypertensive agent to propranolol, methyldopa,
and thiazide-type diuretics, and affected both supine
and standing blood pressure.
Because of variable
plasma levels attained
with a given dose and lack
of consistent relationship of antihypertensive activity to drug
plasma concentration,
selection of proper
dosage requires individual
titration.
Angina Pectoris
By blocking catecholamine-induced
increases in heart rate,
in velocity and extent of myocardial
contraction, and in blood
pressure, metoprolol reduces the oxygen
requirements of the heart
at any given level of effort, thus making it useful in the long-term
management of angina
pectoris. However, in patients with heart
failure, beta-adrenergic blockade
may increase oxygen requirements by increasing left
ventricular fiber
length and end-diastolic
pressure.
In controlled clinical
trials, an immediate
release formulation
of metoprolol has been shown to be an effective antianginal agent,
reducing the number of angina
attacks and increasing exercise
tolerance. The dosage
used in these studies ranged from 100 to 400 mg
daily. Extended release
metoprolol succinate, in dosages of 100 to 400 mg
once daily, has been shown to possess comparable b1-blockade
as conventional metoprolol tablets administered two to four times
daily.
Pharmacokinetics
In man, absorption
of metoprolol is rapid and complete. Plasma levels following oral
administration
of conventional metoprolol tablets, however, approximate 50% of
levels following intravenous
administration, indicating about 50% first-pass metabolism. Metoprolol
crosses the blood- brain
barrier and has been reported in the CSF
in a concentration
78% of the simultaneous plasma concentration.
Plasma levels achieved are highly variable
after oral administration.
Only a small fraction
of the drug (about 12%)
is bound to human
serum albumin. Elimination
is mainly by biotransformation
in the liver, and the plasma half-life ranges from approximately
3 to 7 hours. Less than 5% of an oral dose of metoprolol is recovered
unchanged in the urine; the rest
is excreted by the kidneys as metabolites that appear to have no
clinical significance.
Following intravenous
administration
of metoprolol, the urinary recovery of unchanged drug
is approximately 10%. The systemic
availability and half-life on metoprolol in patients with renal
failure do not differ
to a clinically significant degree
from those in normal
subjects. Consequently, no reduction in dosage
is usually needed in patients with chronic
renal failure.
In comparison to conventional metoprolol, the plasma
metoprolol levels following administration
of extended release
metoprolol succinate
are characterized by lower peaks, longer time
to peak and significantly lower peak to trough variation. The peak
plasma levels following
once daily administration
of extended release
metoprolol succinate
average one-fourth to
one-half the peak plasma
levels obtained following a corresponding
dose of conventional metoprolol,
administered once daily or in divided doses. At
steady state the average
bioavailability of metoprolol following administration
of extended release metoprolol succinate, across the dosage
range of 50 to 400 mg
once daily, was 77% relative to the corresponding
single or divided doses of conventional metoprolol. Nevertheless,
over the 24 hour dosing interval, b1-blockade
is comparable and dose- related. The bioavailability of metoprolol
shows a dose-related, although not directly proportional increase
with dose and is not significantly
affected by food following
extended release metoprolol
succinate administration.
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