Metoprolol Information
Metoprolol ()
Metoprolol () Description
Metoprolol () Tartrate Injection, USP, is a selective beta-adrenoreceptor blocking agent, available as 5 mL vials for intravenous administration. Each vial contains a sterile solution of Metoprolol () tartrate, 5 mg, and sodium chloride, 45 mg, and water for injection. Metoprolol () tartrate is (±)-1-(Isopropylamino)-3-[-(2-methoxyethyl)phenoxy]-2-propanol L-(+)-tartrate (2:1) salt, and its structural formula is:
Metoprolol () tartrate is a white, practically odorless, crystalline powder. It is very soluble in water; freely soluble in methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone; and insoluble in ether.
Metoprolol () Clinical Pharmacology
Metoprolol () is a beta-adrenergic receptor blocking agent. and animal studies have shown that it has a preferential effect on beta adrenoreceptors, chiefly located in cardiac muscle. This preferential effect is not absolute, however, and at higher doses, Metoprolol () also inhibits beta adrenoreceptors, chiefly located in the bronchial and vascular musculature.
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.
Relative beta selectivity has been confirmed by the following: (1) In normal subjects, Metoprolol () is unable to reverse the beta-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective (beta plus beta) beta-blockers, which completely reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, Metoprolol () reduces FEV and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent beta-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. Metoprolol () crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration. Animal and human experiments indicate that Metoprolol () slows the sinus rate and decreases AV nodal conduction.
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 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, and to be equally effective in supine and standing positions.
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. However, in patients with heart failure, beta-adrenergic blockade may increase oxygen requirements by increasing left ventricular fiber length and end-diastolic pressure.
Although beta-adrenergic receptor blockade is useful in the treatment of angina and hypertension, 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-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 controlled clinical trials, Metoprolol () , administered 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 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.
In a large (1,395 patients randomized), double-blind, placebo-controlled clinical study, Metoprolol () was shown to reduce 3-month mortality by 36% in patients with suspected or definite myocardial infarction.
Patients were randomized and treated as soon as possible after their arrival in the hospital, once their clinical condition had stabilized and their hemodynamic status had been carefully evaluated. Subjects were ineligible if they had hypotension, bradycardia, peripheral signs of shock, and/or more than minimal basal rales as signs of congestive heart failure. Initial treatment consisted of intravenous followed by oral administration of Metoprolol () or placebo, given in a coronary care or comparable unit. Oral maintenance therapy with Metoprolol () or placebo was then continued for 3 months. After this double-blind period, all patients were given Metoprolol () and followed up to 1 year.
The median delay from the onset of symptoms to the initiation of therapy was 8 hours in both the Metoprolol () - and placebo-treatment groups. Among patients treated with Metoprolol () , there were comparable reductions in 3-month mortality for those treated early (≤ 8 hours) and those in whom treatment was started later. Significant reductions in the incidence of ventricular fibrillation and in chest pain following initial intravenous therapy were also observed with metopropol and were independent of the interval between onset of symptoms and initiation of therapy.
The precise mechanism of action of Metoprolol () in patients with suspected or definite myocardial infarction is not known.
In this study, patients treated with Metoprolol () received the drug both very early (intravenously) and during a subsequent 3-month period, while placebo patients received no beta-blocker treatment for this period. The study thus was able to show a benefit from the overall Metoprolol () regimen but cannot separate the benefit of very early intravenous treatment from the benefit of later beta-blocker therapy. Nonetheless, because the overall regimen showed a clear beneficial effect on survival without evidence of an early adverse effect on survival, one acceptable dosage regimen is the precise regimen used in the trial. Because the specific benefit of very early treatment remains to be defined however, it is also reasonable to administer the drug orally to patients at a later time as is recommended for certain other beta-blockers.
Metoprolol () Contraindications
Metoprolol () tartrate is contraindicated in sinus bradycardia, heart block greater than first degree, cardiogenic shock, and overt cardiac failure (see ).
Hypersensitivity to Metoprolol () tartrate and related derivatives, or to any of the excipients; hypersensitivity to other beta-blockers (cross sensitivity between beta-blockers can occur).
Sick-sinus syndrome.
Severe peripheral arterial circulatory disorders.
Metoprolol () Warnings
Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and beta-blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. In hypertensive and angina patients who have congestive heart failure controlled by digitalis and diuretics, Metoprolol () tartrate should be administered cautiously.
Continued depression of the myocardium with beta-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or given a diuretic. The response should be observed closely. If cardiac failure continues, despite adequate digitalization and diuretic therapy, Metoprolol () tartrate should be withdrawn.
The necessity or desirability of withdrawing beta-blocking therapy, including Metoprolol () tartrate, prior to major surgery is controversial; the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. Metoprolol () tartrate, like other beta-blockers, is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Difficulty in restarting and maintaining the heart beat has also been reported with beta-blockers.
Metoprolol () tartrate should be used with caution in diabetic patients if a beta-blocking agent is required. Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.
If Metoprolol () tartrate is used in the setting of pheochromocytoma, it should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle.
Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-blockade, which might precipitate a thyroid storm.
Sympathetic stimulation is a vital component supporting circulatory function, and beta-blockade carries the potential hazard of depressing myocardial contractility and precipitating or exacerbating minimal cardiac failure.
During treatment with Metoprolol () tartrate, the hemodynamic status of the patient should be carefully monitored. If heart failure occurs or persists despite appropriate treatment, Metoprolol () tartrate should be discontinued.
Metoprolol () tartrate produces a decrease in sinus heart rate in most patients; this decrease is greatest among patients with high initial heart rates and least among patients with low initial heart rates. Acute myocardial infarction (particularly inferior infarction) may in itself produce significant lowering of the sinus rate. If the sinus rate decreases to
Metoprolol () tartrate slows AV conduction and may produce significant first- (P-R interval ≥ 0.26 sec), second-, or third-degree heart block. Acute myocardial infarction also produces heart block.
If heart block occurs, Metoprolol () tartrate should be discontinued and atropine (0.25 to 0.5 mg) should be administered intravenously. If treatment with atropine is not successful, cautious administration of isoproterenol or installation of a cardiac pacemaker should be considered.
If hypotension (systolic blood pressure ≤ 90 mmHg) occurs, Metoprolol () tartrate should be discontinued, and the hemodynamic status of the patient and the extent of myocardial damage carefully assessed. Invasive monitoring of central venous, pulmonary capillary wedge, and arterial pressures may be required. Appropriate therapy with fluids, positive inotropic agents, balloon counterpulsation, or other treatment modalities should be instituted. If hypotension is associated with sinus bradycardia or AV block, treatment should be directed at reversing these (see above).
Metoprolol () Precautions
Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients treated with Metoprolol () tartrate plus a catecholamine depletor should therefore be closely observed for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
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.
Long-term studies in animals have been conducted to evaluate carcinogenic potential. In a 2-year study in rats at three oral dosage levels of up to 800 mg/kg per day, there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg per day, benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, or in the overall incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor.
All mutagenicity tests performed (a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) were negative.
No evidence of impaired fertility due to Metoprolol () tartrate was observed in a study performed in rats at doses up to 55.5 times the maximum daily human dose of 450 mg.
Clinical trials of Metoprolol () tartrate in hypertension did not include sufficient numbers of elderly patients to determine whether patients over 65 years of age differ from younger subjects in their response to Metoprolol () tartrate. Other reported clinical experience in elderly hypertensive patients has not identified any difference in response from younger patients.
In worldwide clinical trials of Metoprolol () tartrate in myocardial infarction, where approximately 478 patients were over 65 years of age (0 over 75 years of age), no age-related differences in safety and effectiveness were found. Other reported clinical experience in myocardial infarction has not identified differences in response between the elderly and younger patients. However, greater sensitivity of some elderly individuals taking Metoprolol () tartrate cannot be categorically ruled out. Therefore, in general, it is recommended that dosing proceed with caution in this population.
Metoprolol () Adverse Reactions
Most adverse effects have been mild and transient.
Tiredness and dizziness have occurred in about 10 of 100 patients. Depression has been reported in about 5 of 100 patients. Mental confusion and short-term memory loss have been reported. Headache, nightmares, and insomnia have also been reported.
Shortness of breath and bradycardia have occurred in approximately 3 of 100 patients. Cold extremities; arterial insufficiency, usually of the Raynaud type; palpitations; congestive heart failure; peripheral edema; and hypotension have been reported in about 1 of 100 patients. Gangrene in patients with preexisting severe peripheral circulatory disorders has also been reported very rarely (see , , and ).
Wheezing (bronchospasm) and dyspnea have been reported in about 1 of 100 patients (see ). Rhinitis has also been reported.
Diarrhea has occurred in about 5 of 100 patients. Nausea, dry mouth, gastric pain, constipation, flatulence, and heartburn have been reported in about 1 of 100 patients. Vomiting was a common occurrence. Postmarketing experience reveals very rare reports of hepatitis, jaundice and non-specific hepatic dysfunction. Isolated cases of transaminase, alkaline phosphatase, and lactic dehydrogenase elevations have also been reported.
Pruritus or rash have occurred in about 5 of 100 patients. Very rarely, photosensitivity and worsening of psoriasis has been reported.
Peyronie’s disease has been reported in fewer than 1 of 100,000 patients. Musculoskeletal pain, blurred vision, and tinnitus have also been reported.
There have been rare reports of reversible alopecia, agranulocytosis, and dry eyes. Discontinuation of the drug should be considered if any such reaction is not otherwise explicable. There have been very rare reports of weight gain, arthritis, and retroperitoneal fibrosis (relationship to Metoprolol () tartrate has not been definitely established).
The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with Metoprolol () tartrate.
Tiredness has been reported in about 1 of 100 patients. Vertigo, sleep disturbances, hallucinations, headache, dizziness, visual disturbances, confusion, and reduced libido have also been reported, but a drug relationship is not clear.
In the randomized comparison of Metoprolol () tartrate and placebo described in the section, the following adverse reactions were reported:
Hypotension (systolic BP
Bradycardia (heart rate
Second- or third-degree heart block 4.7% 4.7%
First-degree heart block (P-R ≥ 0.26 sec) 5.3% 1.9%
Dyspnea of pulmonary origin has been reported in fewer than 1 of 100 patients.
Nausea and abdominal pain have been reported in fewer than 1 of 100 patients.
Rash and worsened psoriasis have been reported, but a drug relationship is not clear.
Unstable diabetes and claudication have been reported, but a drug relationship is not clear.
A variety of adverse reactions not listed above have been reported with other beta-adrenergic blocking agents and should be considered potential adverse reactions to Metoprolol () tartrate.
Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics.
Intensification of AV block (see ).
Agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura.
Fever combined with aching and sore throat, laryngospasm, and respiratory distress.
Metoprolol () Overdosage
Several cases of overdosage have been reported, some leading to death.
Oral LD’s (mg/kg): mice, 1158 to 2460; rats, 3090 to 4670.
There is no specific antidote.
In general, patients with acute or recent myocardial infarction may be more hemodynamically unstable than other patients and should be treated accordingly (see , ).
On the basis of the pharmacologic actions of Metoprolol () tartrate, the following general measures should be employed:
Atropine should be administered. If there is no response to vagal blockade, isoproterenol should be administered cautiously.
A vasopressor should be administered, e.g., norepinephrine or dopamine.
A beta-stimulating agent and/or a theophylline derivative should be administered.
A digitalis glycoside and diuretic should be administered. In shock resulting from inadequate cardiac contractility, administration of dobutamine, isoproterenol, or glucagon may be considered.
Metoprolol () How Supplied
Metoprolol () Tartrate Injection, USP is available as 5 mL vials, each containing 5 mg of Metoprolol () tartrate:
Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Do not freeze. Protect from light.
Retain in carton until time of use.
Vial stoppers do not contain natural rubber latex.
Metoprolol ()
Metoprolol ()
