Mechanism Of Action
Lopressor is a beta1-selective (cardioselective) adrenergic
receptor blocker. This preferential effect is not absolute, however, and at
higher plasma concentrations, Lopressor also inhibits beta2- adrenoreceptors,
chiefly located in the bronchial and vascular musculature.
Clinical pharmacology studies have demonstrated the
beta-blocking activity of metoprolol, 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 mechanism of the antihypertensive effects of
beta-blocking agents has not been fully 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,
Lopressor 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.
The precise mechanism of action of Lopressor in patients
with suspected or definite myocardial infarction is not known.
Relative beta1 selectivity is demonstrated by the following:
(1) In healthy subjects, Lopressor 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, Lopressor reduces FEV1 and
FVC significantly less than a nonselective beta blocker, propranolol, at
equivalent beta1-receptor blocking doses.
Lopressor has no intrinsic sympathomimetic activity, and
membrane-stabilizing activity is detectable only at doses much greater than
required for beta blockade. Animal and human experiments indicate that Lopressor
slows the sinus rate and decreases AV nodal conduction.
When the drug was infused over a 10-minute period, in normal
volunteers, maximum beta blockade was achieved at approximately 20 minutes.
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.
In several studies of patients with acute myocardial
infarction, intravenous followed by oral administration of Lopressor caused a
reduction in heart rate, systolic blood pressure and cardiac output. Stroke
volume, diastolic blood pressure and pulmonary artery end diastolic pressure
The estimated oral bioavailability of immediate release
metoprolol is about 50% because of pre-systemic metabolism which is saturable
leading to non-proportionate increase in the exposure with increased dose.
Metoprolol is extensively distributed with a reported volume
of distribution of 3.2 to 5.6 L/kg. About 10% of metoprolol in plasma is bound
to serum albumin. Metoprolol is known to cross the placenta and is found in
breast milk. Metoprolol is also known to cross the blood brain barrier following
oral administration and CSF concentrations close to that observed in plasma
have been reported. Metoprolol is not a significant P-glycoprotein substrate.
Lopressor is primarily metabolized by CYP2D6. Metoprolol is
a racemic mixture of Rand S- enantiomers, and when administered orally, it
exhibits stereo selective metabolism that is dependent on oxidation phenotype.
CYP2D6 is absent (poor metabolizers) in about 8% of Caucasians and about 2% of
most other populations. Poor CYP2D6 metabolizers exhibit several-fold higher
plasma concentrations of Lopressor than extensive metabolizers with normal
CYP2D6 activity thereby decreasing LopressorÃ¢â¬™s cardioselectivity.
Elimination of Lopressor is mainly by biotransformation in
the liver. The mean elimination half-life of metoprolol is 3 to 4 hours; in
poor CYP2D6 metabolizers the half-life may be 7 to 9 hours. Approximately 95%
of the dose can be recovered in urine. In most subjects (extensive
metabolizers), less than 10% of an intravenous dose are excreted as unchanged
drug in the urine. In poor metabolizers, up to 30% or 40% of oral or
intravenous doses, respectively, may be excreted unchanged; the rest is excreted
by the kidneys as metabolites that appear to have no beta blocking activity.
The renal clearance of the stereo-isomers does not exhibit stereo-selectivity
in renal excretion.
Geriatric patients: The geriatric population may show
slightly higher plasma concentrations of metoprolol as a combined result of a
decreased metabolism of the drug in elderly population and a decreased hepatic
blood flow. However, this increase is not clinically significant or
Renal impairment: The systemic availability and
half-life of Lopressor 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.
Hepatic Impairment: Since the drug is primarily
eliminated by hepatic metabolism, hepatic impairment may impact the
pharmacokinetics of metoprolol. The elimination half-life of metoprolol is
considerably prolonged, depending on severity (up to 7.2 h).
In controlled clinical studies, Lopressor has been shown to
be an effective antihypertensive agent when used alone or as concomitant therapy
with thiazide-type diuretics, at oral dosages of 100-450 mg daily. In
controlled, comparative, clinical studies, Lopressor has been shown to be as
effective an antihypertensive agent as propranolol, methyldopa, and
thiazide-type diuretics, to be equally effective in supine and standing
In controlled clinical trials, Lopressor, administered
orally 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 oral dosage used in these studies ranged from 100-400 mg daily. A
controlled, comparative, clinical trial showed that Lopressor was
indistinguishable from propranolol in the treatment of angina pectoris.
In a large (1,395 patients randomized), double-blind,
placebo-controlled clinical study, Lopressor 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
Lopressor or placebo, given in a coronary care or comparable unit. Oral
maintenance therapy with Lopressor or placebo was then continued for 3 months.
After this double-blind period, all patients were given Lopressor 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 Lopressor- and placebo-treatment
groups. Among patients treated with Lopressor, 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 Lopressor and were independent of the interval
between onset of symptoms and initiation of therapy.
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.