Metoprolol tartrate is a beta-adrenergic receptor blocking agent. In vitro and in vivo animal
studies have shown that it has a preferential effect on beta1 adrenoreceptors, chiefly located in cardiac muscle. This
preferential effect is not absolute, however, and at higher doses, metoprolol
also inhibits beta2 adrenoreceptors, chiefly located in
the bronchial and vascular musculature.
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.
Relative beta1 selectivity 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 (beta1 plus beta2)
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.
Metoprolol has no intrinsic sympathomimetic activity, and
membrane-stabilizing activity is detectable only at doses much greater than
required for beta-blockade. Metoprolol crosses the blood-brain barrier and has
been reported in the CSF in a concentration 78% of the simultaneous plasma
concentration. Animal and human experiments indicate that metoprolol slows the
sinus rate and decreases AV nodal conduction.
In controlled clinical
studies, metoprolol tartrate has been shown to be an effective antihypertensive
agent when used alone or as concomitant therapy with thiazide-type diuretics, at
dosages of 100 to 450 mg daily. In controlled, comparative, clinical studies,
metoprolol has been shown to be as effective an antihypertensive agent as
propranolol, methyldopa, and thiazide-type diuretics, and to be equally
effective in supine and standing positions.
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.
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.
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.
In controlled clinical trials, metoprolol tartrate,
administered two or four times daily, 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. A
controlled, comparative, clinical trial showed that metoprolol was
indistinguishable from propranolol in the treatment of angina
pectoris.
In a large (1,395 patients randomized), double-blind,
placebo-controlled clinical study, metoprolol was shown to reduce 3-month
mortality by 36% in patients with suspected or definite myocardial
infarction.
Patients were randomized and treated as soon as possible
after their arrival in the hospital, once their clinical condition had
stabilized and their hemodynamic status had been carefully evaluated. Subjects
were ineligible if they had hypotension, bradycardia, peripheral signs of shock,
and/or more than minimal basal rales as signs of congestive heart failure.
Initial treatment consisted of intravenous followed by oral administration of
metoprolol tartrate or placebo, given in a coronary care or comparable unit.
Oral maintenance therapy with metoprolol or placebo was then continued for 3
months. After this double-blind period, all patients were given metoprolol and
followed up to 1 year.
The median delay from the onset of symptoms to the
initiation of therapy was 8 hours in both the metoprolol and placebo treatment
groups. Among patients treated with metoprolol, there were comparable reductions
in 3-month mortality for those treated early (≤ 8 hours) and those in whom
treatment was started later. Significant reductions in the incidence of
ventricular fibrillation and in chest pain following initial intravenous therapy
were also observed with metoprolol and were independent of the interval, between
onset of symptoms and initiation of therapy.
The precise mechanism of
action of metoprolol in patients with suspected or definite myocardial
infarction is not known.
In this study, patients treated with metoprolol
received the drug both very early (intravenously) and during a subsequent
3-month period, while placebo patients received no beta-blocker treatment for
this period. The study thus was able to show a benefit from the overall
metoprolol regimen but cannot separate the benefit of very early intravenous
treatment from the benefit of later beta-blocker therapy. Nonetheless, because
the overall regimen showed a clear beneficial effect on survival without
evidence of an early adverse effect on survival, one acceptable dosage regimen
is the precise regimen used in the trial. Because the specific benefit of very
early treatment remains to be defined however, it is also reasonable to
administer the drug orally to patients at a later time as is recommended for
certain other beta-blockers.
Pharmacokinetics
In man, absorption of
metoprolol is rapid and complete. Plasma levels following oral administration,
however, approximate 50% of levels following intravenous administration,
indicating about 50% first-pass metabolism.
Plasma levels achieved are
highly variable after oral administration. Only a small fraction of the drug
(about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of
R- and S-enantiomers. 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. The systemic availability and half-life
of 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.
Metoprolol is extensively metabolized by the cytochrome P450
enzyme system in the liver. The oxidative metabolism of metoprolol is under
genetic control with a major contribution of the polymorphic cytochrome P450
isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of
the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and less
than 1% Asian are poor metabolizers.
Poor CYP2D6 metabolizers exhibit
several-fold higher plasma concentrations of metoprolol than extensive
metabolizers with normal CYP2D6 activity. The elimination half-life of
metoprolol is about 7.5 hours in poor metabolizers and 2.8 hours in extensive
metabolizers. However, the CYP2D6 dependent metabolism of metoprolol seems to
have little or no effect on safety or tolerability of the drug. None of the
metabolites of metoprolol contribute significantly to its beta-blocking
effect.
Significant beta-blocking effect (as measured by reduction of
exercise heart rate) occurs within 1 hour after oral administration, and its
duration is dose-related. For example, a 50% reduction of the maximum registered
effect after single oral doses of 20, 50, and 100 mg occurred at 3.3, 5, and 6.4
hours, respectively, in normal subjects. After repeated oral dosages of 100 mg
twice daily, a significant reduction in exercise systolic blood pressure was
evident at 12 hours.
Following intravenous administration of metoprolol,
the urinary recovery of unchanged drug is approximately 10%. When the drug was
infused over a 10-minute period, in normal volunteers, maximum beta-blockade was
achieved at approximately 20 minutes. Doses of 5 mg and 15 mg yielded a maximal
reduction in exercise-induced heart rate of approximately 10% and 15%,
respectively. The effect on exercise heart rate decreased linearly with time at
the same rate for both doses, and disappeared at approximately 5 hours and 8
hours for the 5 mg and 15 mg doses, respectively.
Equivalent maximal
beta-blocking effect is achieved with oral and intravenous doses in the ratio of
approximately 2.5:1.
There is a linear relationship between the log of
plasma levels and reduction of exercise heart rate. However, antihypertensive
activity does not appear to be related to plasma levels. Because of variable
plasma levels attained with a given dose and lack of a consistent relationship
of antihypertensive activity to dose, selection of proper dosage requires
individual titration.
In several studies of patients with acute
myocardial infarction, intravenous followed by oral administration of metoprolol
caused a reduction in heart rate, systolic blood pressure, and cardiac output.
Stroke volume, diastolic blood pressure, and pulmonary artery end diastolic
pressure remained unchanged.
In patients with angina pectoris, plasma
concentration measured at 1 hour is linearly related to the oral dose within the
range of 50 to 400 mg. Exercise heart rate and systolic blood pressure are
reduced in relation to the logarithm of the oral dose of metoprolol. The
increase in exercise capacity and the reduction in left ventricular ischemia are
also significantly related to the logarithm of the oral dose.
In elderly
subjects with clinically normal renal and hepatic function, there are no
significant differences in metoprolol pharmacokinetics compared to young
subjects.
