Description: Metoprolol Tartrate Injection is a selective beta 1-adrenoreceptor blocking agent, available in 5 mL single dose vials for intravenous administration. Each vial contains a sterile solution of Metoprolol Tartrate 5 mg, Sodium Chloride 45 mg, and Water for Injection Metoprolol Tartrate is (±)-1-(Isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol L-(+)-tartrate (2:1) salt .

Pharmacological effects: Metoprolol is a beta1-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.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, 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 of action of metoprolol in patients with suspected or definite myocardial infarction is not known.Relative beta1 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 (beta1 plus beta2) 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 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: 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 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 severalfold 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.

Indications: Metoprolol Tartrate Injection is indicated in the treatment of hemodynamically stable patients with definite or suspected acute myocardial infarction to reduce cardiovascular mortality when used in conjunction with oral metoprolol maintenance therapy.

Precautions: While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents or monoamine oxidase (MAO) inhibitors. Observe patients treated with metoprolol plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension. In addition, possibly significant hypertension may theoretically occur up to 14 days following discontinuation of the concomitant administration with an irreversible MAO inhibitor. Both digitalis glycosides and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Monitor heart rate and PR interval. Concomitant administration of a beta-adrenergic antagonist with a calcium channel blocker may produce an additive reduction in myocardial contractility because of negative chronotropic and inotropic effects. Some inhalation anesthetics may enhance the cardiodepressant effect of beta blockers. Potent inhibitors of the CYP2D6 enzyme may increase the plasma concentration of metoprolol which would mimic the pharmacokinetics of CYP2D6 poor metabolizer. Increase in plasma concentrations of metoprolol would decrease the cardioselectivity of metoprolol.Hydralazine: Concomitant administration of hydralazine may inhibit presystemic metabolism of metoprolol leading to increased concentrations of metoprolol.Concomitant administration with beta-blockers may enhance the vasoconstrictive action of ergot alkaloids.In general, administration of a beta-blocker should be withheld before dipyridamole testing, with careful monitoring of heart rate following the dipyridamole injection. Carcinogenesis, Mutagenesis, Impairment of FertilityUpon confirming the diagnosis of pregnancy, women should immediately inform the doctor.There are no adequate and well-controlled studies in pregnant women. The amount of data on the use of metoprolol in pregnant women is limited. The risk to the fetus/mother is unknown.

Adverse reaction: These adverse reactions were reported for treatment with oral metoprolol. Most adverse effects have been mild and transient.Tiredness and dizziness, Depression has been reported . Mental confusion and short-term memory loss have been reported. Headache, nightmares, and insomnia have also been reported.Shortness of breath and bradycardia, cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations; congestive heart failure; peripheral edema; and hypotension have been reported. Gangrene in patients with pre-existing severe peripheral circulatory disorders has also been reported very rarely. Respiratory: Wheezing (bronchospasm) and dyspnea has also been reported.Diarrhea, Nausea, dry mouth, gastric pain, constipation, flatulence, and heartburn have been reported . Vomiting was a common occurrence.