Mechanism Of Action
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.
The precise mechanism for the beneficial effects of
beta-blockers in heart failure has not been elucidated.
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.
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.
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
The relationship between plasma metoprolol levels and
reduction in exercise heart rate is independent of the pharmaceutical
formulation. Using an Emax model, the maximum effect is a 30% reduction in exercise
heart rate, which is attributed to beta1-blockade. Beta1
-blocking effects in the range of 30- 80% of the maximal effect (approximately
8-23% reduction in exercise heart rate) correspond to metoprolol plasma
concentrations from 30-540 nmol/L. The relative beta1-selectivity of
metoprolol diminishes and blockade of beta2-adrenoceptors increases
at plasma concentration above 300 nmol/L.
Although beta-adrenergic receptor blockade is useful in
the treatment of angina, hypertension, and heart failure 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 other studies, treatment with TOPROL-XL produced an
improvement in left ventricular ejection fraction. TOPROL-XL was also shown to
delay the increase in left ventricular end-systolic and enddiastolic volumes
after 6 months of treatment.
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 bloodbrain barrier
and has been reported in the CSF in a concentration 78% of the simultaneous
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 Senantiomers, and is
primarily metabolized by CYP2D6. When administered orally, it exhibits stereoselective
metabolism that is dependent on oxidation phenotype. 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
Following intravenous administration of metoprolol, the
urinary recovery of unchanged drug is approximately 10%. 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 metoprolol succinate dosage is usually needed in
patients with chronic renal failure.
Metoprolol is metabolized predominantly by CYP2D6, an
enzyme that is absent in about 8% of Caucasians (poor metabolizers) and about
2% of most other populations. CYP2D6 can be inhibited by a number of drugs.
Poor metabolizers and extensive metabolizers who concomitantly use CYP2D6 inhibiting
drugs will have increased (several-fold) metoprolol blood levels, decreasing
metoprolol's cardioselectivity [see DRUG INTERACTIONS].
In comparison to conventional metoprolol, the plasma
metoprolol levels following administration of TOPROL-XL 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
TOPROL-XL 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 TOPROL-XL, 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, β1
-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 TOPROLXL administration.
The pharmacokinetic profile of TOPROL-XL was studied in
120 pediatric hypertensive patients (6-17 years of age) receiving doses ranging
from 12.5 to 200 mg once daily. The pharmacokinetics of metoprolol were similar
to those described previously in adults. Age, gender, race, and ideal body
weight had no significant effects on metoprolol pharmacokinetics. Metoprolol apparent
oral clearance (CL/F) increased linearly with body weight. Metoprolol
pharmacokinetics have not been investigated in patients < 6 years of age.
In five controlled studies in normal healthy subjects,
the same daily doses of TOPROL-XL 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
immediaterelease metoprolol per day. In these studies, TOPROL-XL was
administered once a day and immediaterelease 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, TOPROL-XL
produced significantly higher total beta1 -blockade over 24 hours
than immediate-release metoprolol. For TOPROL-XL, 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 TOPROL-XL once a day,
respectively. In contrast to TOPROL-XL, 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 TOPROL-XL 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. A controlled cross-over study in heart failure patients compared
the plasma concentrations and beta1 -blocking effects of 50 mg
immediate-release metoprolol administered t.i.d., 100 mg and 200 mg TOPROL-XL
once daily. A 50 mg dose of immediate-release metoprolol t.i.d. produced a peak
plasma level of metoprolol similar to the peak level observed with 200 mg of
TOPROL-XL. A 200 mg dose of TOPROL-XL produced a larger effect on suppression
of exercise-induced and Holter-monitored heart rate over 24 hours compared to 50
mg t.i.d. of immediate-release metoprolol.
In a double-blind study, 1092 patients with
mild-to-moderate hypertension were randomized to once daily TOPROL-XL (25, 100,
or 400 mg), PLENDIL® (felodipine extended-release tablets), the combination, or
placebo. After 9 weeks, TOPROL-XL alone decreased sitting blood pressure by 6- 8/4-7
mmHg (placebo-corrected change from baseline) at 24 hours post-dose. The
combination of TOPROL-XL with PLENDIL has greater effects on blood pressure.
In controlled clinical studies, an immediate-release
dosage form of metoprolol was an effective antihypertensive agent when used
alone or as concomitant therapy with thiazide-type diuretics at dosages of
100-450 mg daily. TOPROL-XL, in dosages of 100 to 400 mg once daily, produces
similar β1 -blockade as conventional metoprolol tablets
administered two to four times daily. In addition, TOPROL-XL administered at a
dose of 50 mg once daily lowered blood pressure 24-hours postdosing in
placebo-controlled studies. In controlled, comparative, clinical studies,
immediate-release metoprolol appeared comparable as an antihypertensive agent
to propranolol, methyldopa, and thiazidetype diuretics, and affected both
supine and standing blood pressure. Because of variable plasma levels attained
with a given dose and lack of a consistent relationship of antihypertensive
activity to drug plasma concentration, selection of proper dosage requires
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.
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. TOPROL-XL, in
dosages of 100 to 400 mg once daily, has been shown to possess beta-blockade
similar to conventional metoprolol tablets administered two to four times
MERIT-HF was a double-blind, placebo-controlled study of
TOPROL-XL conducted in 14 countries including the US. It randomized 3991
patients (1990 to TOPROL-XL) with ejection fraction ≤ 0.40 and NYHA Class
II-IV heart failure attributable to ischemia, hypertension, or cardiomyopathy.
The protocol excluded patients with contraindications to beta-blocker use,
those expected to undergo heart surgery, and those within 28 days of myocardial
infarction or unstable angina. The primary endpoints of the trial were (1)
all-cause mortality plus all-cause hospitalization (time to first event) and
(2) all-cause mortality. Patients were stabilized on optimal concomitant
therapy for heart failure, including diuretics, ACE inhibitors, cardiac
glycosides, and nitrates. At randomization, 41% of patients were NYHA Class II;
55% NYHA Class III; 65% of patients had heart failure attributed to ischemic
heart disease; 44% had a history of hypertension; 25% had diabetes mellitus;
48% had a history of myocardial infarction. Among patients in the trial, 90%
were on diuretics, 89% were on ACE inhibitors, 64% were on digitalis, 27% were
on a lipid-lowering agent, 37% were on an oral anticoagulant, and the mean ejection
fraction was 0.28. The mean duration of follow-up was one year. At the end of
the study, the mean daily dose of TOPROL-XL was 159 mg.
The trial was terminated early for a statistically
significant reduction in all-cause mortality (34%, nominal p= 0.00009). The
risk of all-cause mortality plus all-cause hospitalization was reduced by 19% (p=
0.00012). The trial also showed improvements in heart failure-related mortality
and heart failurerelated hospitalizations, and NYHA functional class.
The table below shows the principal results for the
overall study population. The figure below illustrates principal results for a
wide variety of subgroup comparisons, including US vs. non-US populations (the
latter of which was not pre-specified). The combined endpoints of all-cause
mortality plus all-cause hospitalization and of mortality plus heart failure
hospitalization showed consistent effects in the overall study population and
the subgroups, including women and the US population. However, in the US
subgroup (n=1071) and women (n=898), overall mortality and cardiovascular mortality
appeared less affected. Analyses of female and US patients were carried out
because they each represented about 25% of the overall population. Nonetheless,
subgroup analyses can be difficult to interpret and it is not known whether
these represent true differences or chance effects.
Clinical Endpoints in the MERIT-HF Study
||Number of Patients
||Relative Risk (95% Cl)
||Risk Reduction With TOPROL-XL
|All-cause mortality plus all-caused hospitalization*
|All-cause mortality plus heart failure hospitalization*
|Death due to worsening heart failure
|Hospitalizations due to worsening heart failure†
|*Time to first event
†Comparison of treatment groups examines the number of hospitalizations
(Wilcoxon test); relative risk and risk reduction are not applicable.
1. Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K,
Villar JC et al. Effects of extended-release metoprolol succinate in patients
undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet.