Mechanism Of Action
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
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 FEV 1 and FVC significantly less than a
nonselective beta-blocker, propranolol, at equivalent beta 1-receptor blocking
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.
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.
The relationship between plasma metoprolol levels and
reduction in exercise heart rate is independent of the pharmaceutical
formulation. Beta1-blocking effects in the range of 30 to 80% of the maximal
effect (approximately 8 to 23% reduction in exercise heart rate) correspond to
metoprolol plasma concentrations from 30 to 540 nmol/L. The relative
beta1selectivity of metoprolol diminishes and blockade of beta2-adrenoceptors
increases at plasma concentration above 300 nmol/L.
In five controlled studies in normal healthy subjects,
extended-release metoprolol succinate 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 to 400 mg. In another controlled
study, 50 mg once daily for each product, 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.
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., and 100 mg and 200 mg
extended-release metoprolol succinate once daily. Extended-release metoprolol
succinate 200 mg once daily 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 other studies, treatment with metoprolol succinate
produced an improvement in left ventricular ejection fraction. Metoprolol
succinate was also shown to delay the increase in left ventricular end-systolic
and end-diastolic volumes after 6 months of treatment.
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. Beta 2-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.
The peak plasma levels following once-daily
administration of extended release metoprolol succinate are reduced by 50 to
75% on average compared to a corresponding dose of immediate-release metoprolol
tartrate, both when administered once daily or in divided doses. At steady
state the average bioavailability of metoprolol following administration of
metoprolol succinate, across the dosage range of 50 to 400 mg once daily, was
reduced by 25% relative to the corresponding single or divided doses of
immediate-release metoprolol tartrate. The bioavailability of metoprolol shows
a dose-related, although not directly proportional, increase with dose. The
exposure (Cmax and AUC) of metoprolol succinate extended-release capsule are
similar to that of TOPROL-XL® tablet.
Plasma levels following oral administration of
metoprolol tablet approximate 50% of levels following intravenous
administration, indicating about 50% first-pass metabolism. Peak plasma
concentration of metoprolol is attained at 10 hours following administration of
metoprolol succinate extended-release capsule.
Effect Of Food
Compared to fasted state administration, high-fat,
high-calorie meal (54.3% fat, 15.6% proteins and 30.1% carbohydrates) did not
have a significant effect on the absorption of KAPSPARGO Sprinkle.
KAPSPARGO Sprinkle (metoprolol succinate 200 mg)
administered under fasting conditions to healthy adults by sprinkling the
entire contents on one-tablespoon (15 mL) of applesauce did not significantly
affect Tmax, Cmax, and AUC of metoprolol.
About 12% of the drug is bound to human serum albumin.
Metoprolol crosses the blood-brain barrier and has been reported in the CSF in
a concentration 78% of the simultaneous plasma concentration.
Elimination is mainly by biotransformation in the liver,
and the plasma half-life ranges from approximately 3 to 7 hours.
Metoprolol is a racemic mixture of R-and S-enantiomers,
and is primarily metabolized by CYP2D6. When administered orally, it exhibits
stereoselective metabolism that is dependent on oxidation phenotype.
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 beta-blocking activity. Following intravenous administration
of metoprolol, the urinary recovery of unchanged drug is approximately 10%.
The pharmacokinetic profile of metoprolol succinate was
studied in 120 pediatric hypertensive patients (6 to 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.
Metoprolol is metabolized predominantly by CYP2D6. In
healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration
of quinidine 100 mg, a potent CYP2D6 inhibitor, and immediate-release
metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the
metoprolol elimination half-life. In four patients with cardiovascular disease,
coadministration of propafenone 150 mg t.i.d. with immediate-release metoprolol
50 mg t.i.d. resulted in steady-state concentration of metoprolol 2-to 5-fold
what is seen with metoprolol alone. Extensive metabolizers who concomitantly
use CYP2D6 inhibiting drugs will have increased (several-fold) metoprolol blood
levels, decreasing metoprolol's cardioselectivity [see DRUG INTERACTIONS].
An in vitro dissolution study was conducted to evaluate
the impact of alcohol (5, 10, 20 and 40%), on the extended-release
characteristics of KAPSPARGO Sprinkle. The in vitro study showed that about 89%
of the total metoprolol succinate dose was released at 2 hour at the highest
alcohol level (40%), and about 17% of total drug was released at 2 hour with 5%
alcohol. Alcohol causes a rapid release of metoprolol succinate from KAPSPARGO
Sprinkle that may increase the risk for above events associated with KAPSPARGO
Sprinkle. Consumption of alcohol is not recommended when taking KAPSPARGO
Sprinkle 25 mg, 50 mg, 100 mg and 200 mg.
CYP2D6 is absent in about 8% of Caucasians (poor
metabolizers) and about 2% of most other populations. CYP2D6 can be inhibited by
several drugs. Poor metabolizers of CYP2D6 will have increased (several-fold)
metoprolol blood levels, decreasing metoprolol's cardioselectivity.
In a double-blind study, 1092 patients with
mild-to-moderate hypertension were randomized to once daily metoprolol
succinate (25, 100, or 400 mg), PLENDIL® (felodipine extended-release tablets),
the combination, or placebo. After 9 weeks, metoprolol succinate alone
decreased sitting blood pressure by 6 – 8 mmHg /4 -7 mmHg (placebo-corrected
change from baseline) at 24 hours post-dose. The combination of metoprolol
succinate 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
to 450 mg daily. Metoprolol succinate, 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, metoprolol succinate
administered at a dose of 50 mg once daily lowered 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 a consistent relationship of
antihypertensive activity to drug plasma concentration, selection of proper
dosage requires individual titration.
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. Metoprolol
succinate, 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 daily.
MERIT-HF was a randomized, double-blind study in which
3991 patients with ejection fraction ≤0.40 and NYHA Class II-IV heart
failure attributable to ischemia, hypertension, or cardiomyopathy were
randomized 1:1 to metoprolol or placebo. 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 metoprolol succinate 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 failure-related hospitalizations, and NYHA functional
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. 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 Metoprolol Succinate
|All-cause mortality plus allcaused hospitalization1
(0.73 to 0.90)
(0.53 to 0.81)
|All-cause mortality plus heart failure hospitalization1
(0.60 to 0.80)
(0.45 to 0.78)
|Death due to worsening heart failure
(0.33 to 0.79)
|Hospitalizations due to worsening heart failure2
|1Time to first event
2Comparison of treatment groups examines the number of
hospitalizations (Wilcoxon test); relative risk and risk reduction are not
Results for Subgroups in MERIT-HF