Metoprolol Tartrate

METOPROLOL TARTRATE- metoprolol tartrate injection, solution
Fosun Pharma USA Inc.

DESCRIPTION

Metoprolol tartrate USP, is a selective beta 1 -adrenoreceptor blocking agent, available in 5-mL vials for intravenous administration. Each vial contains a sterile solution of metoprolol tartrate USP, 5 mg, and sodium chloride USP, 45 mg, and water for injection USP.

Metoprolol tartrate USP is (±)-1-(Isopropylamino)-3-[ p -(2-methoxyethyl)phenoxy]-2-propanol L- (+)-tartrate (2:1) salt, and its structural formula is:

Figure
(click image for full-size original)

Metoprolol tartrate USP is a white, practically odorless, crystalline powder with a molecular weight of 684.82. It is very soluble in water; freely soluble in methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone; and insoluble in ether.

CLINICAL PHARMACOLOGY

Mechanism of Action

Metoprolol is a beta 1 -selective (cardioselective) adrenergic receptor blocker. This preferential effect is not absolute, however, and at higher plasma concentrations, metoprolol also inhibits beta 2 -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.

Hypertension

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.

Angina Pectoris

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.

Myocardial Infarction

The precise mechanism of action of metoprolol in patients with suspected or definite myocardial infarction is not known.

Pharmacodynamics

Relative beta 1 selectivity is demonstrated by the following: (1) in healthy subjects, metoprolol is unable to reverse the beta 2 -mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective (beta 1 plus beta 2 ) 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 doses.

Metoprolol 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 metoprolol 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 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.

Pharmacokinetics

Absorption: 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.

Distribution: 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.

Metabolism: Metoprolol is primarily metabolized by CYP2D6. Metoprolol is a racemic mixture of R- and 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 metoprolol than extensive metabolizers with normal CYP2D6 activity thereby decreasing metoprolol’s cardioselectivity.

Elimination: Elimination of metoprolol 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.

Special populations

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 therapeutically relevant.

Renal impairment: 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.

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).

Clinical Studies

Hypertension

In controlled clinical studies, metoprolol 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 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, to be equally effective in supine and standing positions.

Angina Pectoris

In controlled clinical trials, metoprolol, 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 to 400 mg daily. A controlled, comparative, clinical trial showed that metoprolol was indistinguishable from propranolol in the treatment of angina pectoris.

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