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| __NOTOC__
| | #REDIRECT [[Metoprolol succinate#Pharmacology]] |
| {{Metoprolol}}
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| {{CMG}}
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| ====Mechanism of Action====
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| '''Hypertension''': The mechanism of the antihypertensive effects of [[beta-blocking agent]]s has not been elucidated. However, several possible mechanisms have been proposed: (1) competitive [[antagonism]] of [[catecholamine]]s 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.
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| '''Heart Failure''': The precise mechanism for the beneficial effects of [[beta-blocker]]s in [[heart failure]] has not been elucidated.
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| ====Pharmacodynamics====
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| 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]].
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| 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. | |
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| The relative [[beta1]]-selectivity of metoprolol has been confirmed by the following: (1) In normal subjects, metoprolol is unable to reverse the [[beta2]]-mediated [[vasodilation|vasodilating]] effects of [[epinephrine]]. This contrasts with the effect of nonselective [[beta-blocker]]s, which completely reverse the [[vasodilation|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.
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| 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.
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| 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 [[bronchodilation|bronchodilator]] activity in patients subject to [[bronchospasm]] and may also interfere with exogenous [[bronchodilation|bronchodilators]] in such patients.
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| 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 end-diastolic volumes after 6 months of treatment.
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| ====Pharmacokinetics====
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| '''Adults''': 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.
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| 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, and is primarily metabolized by [[CYP2D6]]. When administered orally, it exhibits stereoselective metabolism that is dependent on oxidation phenotype.
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| 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 beta-blocking activity.
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| 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]].
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| 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 [[Toprol XL drug interactions|Drug Interactions]]]''.
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| 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, [[beta1|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 TOPROL-XL administration.
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| '''Pediatrics''': 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.<ref name="dailymed.nlm.nih.gov">{{Cite web | last = | first = | title = TOPROL XL (METOPROLOL SUCCINATE) TABLET, EXTENDED RELEASE [BRYANT RANCH PREPACK] | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=01038198-b4f0-41f3-9a9c-5c84e5a0d3b9 | publisher = | date = | accessdate = }}</ref>
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| ==References==
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| {{Reflist}}
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| {{FDA}}
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| [[Category:Beta blockers]]
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| [[Category:Cardiovascular Drugs]]
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| [[Category:Drugs]]
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