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METOPROLOL

Hazardous Substances DataBank Number
6531
Related PubChem Records
Related CIDs

1 Human Health Effects

1.1 Human Toxicity Excerpts (Complete)

/HUMAN EXPOSURE STUDIES/ A fatality involving a 26-year-old male who intentionally ingested approximately 10 g of metoprolol is presented. Autopsy findings revealed foreign material in the gastric content with an acute thrombosis of the left anterior descending coronary artery. Microscopic studies showed evidence of an extremely early infarct. Metoprolol concentrations in the blood, liver, gastric content, and urine are reported by both capillary gas chromatography and ultraviolet spectrophotometric analysis.
Riker CD et al; J Forensic Sci 32 (5): 1447-52 (1987)
/SIGNS AND SYMPTOMS/ Acute beta blocker poisoning is characterized by depression of cardiac conduction and contractility, respiratory depression, coma, seizures, and in some patients, hypoglycemia. Symptoms occur within 1-2 hr of ingestion. /Class II Drugs: Beta-Blockers/
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 525

1.2 Body Burden (Complete)

Metoprolol is distributed into milk in a concentration about 3-4 times that of maternal plasma concentrations, but the actual amount distributed into milk appears to be very small.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1770

1.3 Reported Fatal Dose

Hypotension and nodal rhythm resulted in the survivor of a 50-g overdose. However, cardiac failure and bradycardia occurred in a fatal 7.5 g overdose.
Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 188

2 Emergency Medical Treatment

2.1 Antidote and Emergency Treatment (Complete)

Stabilization: If symptomatic treatment fails, then antidotes should be administered as follows: high doses of glucagon followed by isoproterenol, epinephrine and the new phosphodiesterase inhibitors. Mechanical ventilation should be started at the same time as pharmacologic treatment in cases of severe collapse or prolonged QRS. /Class II Drugs: Beta Blockers/
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 526
Supportive measures: 1. Most overdoses are mild and respond to supportive care. Observe mild overdose cases at least 4 hr for the development of signs of poisoning. 2. Hypotension: Multiple iv boluses of adrenaline may lead to a rise in blood pressure after dopamine, glucagon, sodium bicarbonate, and calcium have not been successful. Amrinone ... is a positive inotropic agent with intrinsic vasodilator activity that may be as effective as glucagon in reversing depressed myocardial function. 3. Electromechanical dissociation: Calcium chloride ... , repeatedly administered, may restore blood pressure and narrowing of the QRS complexes after a propanolol overdose that has not responded to conventional treatment. 4. Beta blockers should be discontinued in patients who are at risk for anaphylaxis, in conditions such as idiopathic anaphylaxis and Hymenoptera venom sensitivity, and in individuals who are to undergo allergy skin tests (inhalant, food, or drug) or receive allergen immunotherapy or contrast medium infusion. 5. Patients receiving beta blockers who experience anaphylaxis are at increased risk for potentiated, "epinephrine-resistant" anaphylaxis. Beta blockers exert their effects by competitive inhibition of catecholamine binding at beta-adrenoceptor sites, such that the dose-response curve for the agonist is shifted to the right. The use of higher than customary doses of a beta agonist may be required for managing bronchospasm in an asthmatic patient undergoing anaphylaxis to achieve therapeutic effects. A lower dose of epinephrine may be appropriate for the management of beta-blocker-associated anaphylaxis, to avoid unopposed alpha-adrenergic effects leading to a paradoxical hypertension and coronary vasoconstriction. 6. Glucagon increases cAMP levels via noncatecholamine mechanisms and can exert potent chronotropic and inotropic effects. This likely explains its use as an antidote in beta-blocker and calcium channel blocker overdoses. /Class II Drugs: Beta Blockers/
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 527
In acute metoprolol overdose, the stomach should be emptied immediately by gastric lavage. Supportive and symptomatic treatment should be initiated. For symptomatic bradycardia, iv atropine sulfate may be given; if bradycardia persists, iv isoproterenol hydrochloride may be administered cautiously. A vasopressor (e.g, dopamine, norepinephrine) may be given for severe hypotension; iv glucagon may be useful if hypotension is refractory to vasopressors. A beta-adrenergic agonist (e.g., isoproterenol) and/or a theophylline derivative may be given for bronchospasm. For heart failure, a cardiac glycoside, diuretic, and oxygen should be used; iv glucagon also may be useful.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1769
A 23 year old female was found unconscious and deteriorated rapidly to cardiac asystole. Prolonged resuscitation was required, and she remained in severe cardiogenic shock, despite high doses of positive inotropic agents. Massive beta adrenoceptor blocker specifically, metoprolol overdose was suspected (and subsequently confirmed). IV administration of glucagon was followed by prompt hemodynamic improvement and recovery, illustrating the beneficial role of glucagon in overwhelming beta adrenoceptor blockade.
Tai YT et al; Br J Clin Pract 44 (12): 746-7 (1990)
Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. 2. Treat coma, seizures, hypotension, hyperkalemia, and hypoglycemia if they occur. 3. Treat bradycardia with atropine, ... IV; isoproterenol ... ; or cardiac pacing. 4. Treat bronchospasm with nebulized bronchodilators. 5. Continuously monitor the vital signs and ECG for at least 6 hours after ingestion. /Beta-adrenergic blockers/
Olson, K.R. (ed.) Poisoning & Drug Overdose. 3rd edition. Lange Medical Books/McGraw-Hill, New York, NY. 1999., p. 109
Specific drugs and antidotes. 1. Bradycardia and hypotension resistant to... /normal/ measures should be treated with glucagon, ... . Epinephrine (intravenous) infusion ... and titrating to effect. 2. Wide complex conduction defects caused by membrane-depressant poisoning may respond to sodium bicarbonate, ... , as given for tricyclic antidepressant overdose. 3. Torsades de pointes polymorphous ventricular tachycardia associated with QT prolongation resulting from sotalol poisoning can be treated with isoproterenol infusion, magnesium, or overdrive pacing. Correction of hypokalemia may also be useful. /Beta-adrenergic blockers/
Olson, K.R. (ed.) Poisoning & Drug Overdose. 3rd edition. Lange Medical Books/McGraw-Hill, New York, NY. 1999., p. 109
Decontamination. 1. Prehospital. Administer activated charcoal if available. 2. Hospital. Administer activated charcoal. Consider gastric lavage for large ingestions, especially involving propranolol. Gastric emptying is not necessary for small ingestions if activated charcoal can be given promptly. /Beta-adrenergic blockers/
Olson, K.R. (ed.) Poisoning & Drug Overdose. 3rd edition. Lange Medical Books/McGraw-Hill, New York, NY. 1999., p. 109
/SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/
Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994., p. 139
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/
Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994., p. 139

3 Animal Toxicity Studies

3.1 Non-Human Toxicity Excerpts (Complete)

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Recent studies suggest that beta adrenergic blocking agents show promise in the management of cardiomyopathies; however, their role in acute myocarditis is unknown. One hundred 3 week old mice were infected with coxsackie virus B3 and were given either metoprolol (n=50) or normal saline solution (n=50) intraperitoneally for 10 days. Twenty mice from each group were observed for mortality for 30 days. Of the remaining 60 mice, 10 from each group were killed on day 3, 6 or 10 and examined for heart viral titers and pathologic changes. Mortality rate in the metoprolol group was 60% compared with 0% in the saline group (p< 0.005). Viral titers on day 10 of infection were 10 (2.6 + or - 0.2) median tissue culture infective dose for the metoprolol group versus 10 (2.1 + or - 0.1) for the saline group (p<0.05). Whereas pathologic changes at days 3, 6 and 10 of infection were similar in both groups, on day 30 of infection, inflammation, necrosis and mineralization scores (mean + or - standard error of the mean) were 1.1 + or - 0.3, 2.1 + or - 0.4, 2.2 + or - 0.5 for the metoprolol group versus 0.3 + or - 0.1, 0.4 + or - 0.3, 0.4 + or - 0.3 for the saline group, respectively (p<0.01). Six noninfected mice received metoprolol intraperitoneally for 10 days; there was no mortality during 30 days of observation. In conclusion, metoprolol administration exerts deleterious effects in acute coxsackie virus B3 murine myocarditis.
Rezkalla S et al; J Am Coll Cardiol 12 (2): 412-4 (1988)
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In chronic toxicity studies, benign lung tumors (small adenomas) occurred more frequently in female Swiss albino mice receiving oral dosages of metoprolol tartrate up to 750 mg/kg daily for 21 months than in untreated control animals, although there was no increase in malignant lung tumors or total (benign plus malignant) lung tumors. In CD-1 mice, however, no differences were observed between treated and control mice of either gender for any tumor. In a 2-yr study in rats, there was no evidence of increased development of spontaneously occurring benign or malignant neoplasms at dosages of metoprolol tartrate up to 800 mg/kg daily. However, in these rats, histologic changes included an increased incidence of mild focal accumulation of foamy macrophages in alveolar spaces and slight increases of biliary hyperplasia.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1768
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ .../Metoprolol tartate was studied/ in rats and rabbits. The rabbits received 64 mg/kg and the rats 500 mg/kg. No adverse fetal effects were noted in either species except for slight growth retardation in the rat. Neonatal mortality was increased among fetuses exposed on days 17-21 gestation. Some increase in embryolethality was noted in the rabbit fetuses exposed to 64 mg/kg.
Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 389
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ...Metoprolol has been shown to increase postimplantation loss and to decrease neonatal survival in rats when given in dosages of 50-500 mg/kg daily.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1768
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction studies in rats using metoprolol tartrate up to 55.5 times the maximum recommended human dosage have not revealed evidence of impaired fertility. /Metoprolol tartrate/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1768
/GENOTOXICITY/ There has been no evidence of mutagenic potential in tests performed to date with metoprolol.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1768

3.2 Non-Human Toxicity Values (Complete)

LD50 Rat oral 3090-4670 mg/kg
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1768
LD50 Mice oral 1158-2460 mg/kg
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1768
LD50 Mouse female iv 118 mg/kg /Metoprolol tartrate/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1096
LD50 Rat male iv ~90 mg/kg /Metoprolol tartrate/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1096

4 Metabolism / Pharmacokinetics

4.1 Metabolism / Metabolites (Complete)

Metoprolol does not inhibit or enhance its own metabolism. Three main metabolites of the drug are formed by oxidative deamination, O-dealkylation with subsequent oxidation, and aliphatic hydroxylation; these metabolites account for 85% of the total urinary excretion of metabolites. The metabolites apparently do not have appreciable pharmacologic activity. The rate of hydroxylation, resulting in alpha-hydroxymetoprolol, is genetically determined and is subject to considerable interindividual variation. Poor hydroxylators of metoprolol have increased areas under the plasma concentration-time curves, prolonged elimination half-lives (about 7.6 hours), higher urinary concentrations of unchanged drug, and negligible urinary concentrations of alpha-hydroxymetoprolol compared with extensive hydroxylators. Beta-adrenergic blockade of exercise-induced tachycardia persists for at least 24 hours after administration of a single 200-mg oral dose of metoprolol tartrate in poor hydroxylators.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1770
Controlled studies have shown that debrisoquine oxidation phenotype is a major determinant of the metabolism, pharmacokinetics and some of the pharmacological actions of metoprolol. The poor metabolizer phenotype is associated with increased plasma drug concentrations, a prolongation of elimination half-life and more intense and sustained beta blockade. Phenotypic differences have also been observed in the pharmacokinetics of the enantiomers of metoprolol. In vivo and in vitro studies have identified some of the metabolic pathways which are subject to the defect, that is alpha-hydroxylation and O-demethylation.
Lennard MS et al; Clin Pharmacokinet 11 (1): 1-17 (1986)
Metropolol is a racemic mixture of R-and S-enantiomers, and is primarily metabolized by CYP2D6.
Medical Economics Co; Physicians Desk Reference 56th ed p. 651 (2002)

4.2 Absorption, Distribution and Excretion (Complete)

Plasma levels following oral administration of conventional metoprolol tablets, however, approximate 50% of levels following intravenous adminsitration, indicating about 50% first-pass metabolism... Elimination is mainly by biotransformation in the liver.
Medical Economics Co; Physicians Desk Reference 56th ed p. 651 (2002)
Metoprolol tartrate is rapidly and almost completely absorbed from the GI tract; absorption of a single oral dose of 20-100 mg is complete in 2.5-3 hours. After an oral dose, about 50% of the drug administered as conventional tablets appears to undergo first-pass metabolism in the liver. Bioavailability of orally administered metoprolol tartrate increases with increased doses, indicating a possible saturable disposition process of low capacity such as tissue binding in the liver. Steady-state oral bioavailability of extended-release tablets of metoprolol succinate given once daily at dosages equivalent to 50-400 mg of metoprolol tartrate is about 77% of that of conventional tablets at corresponding dosages given once daily or in divided doses. Food does not appear to affect bioavailability of metoprolol succinate extended-release tablets. Following a single oral dose as conventional tablets, metoprolol appears in the plasma within 10 minutes and peak plasma concentrations are reached in about 90 minutes. When metoprolol tartrate conventional tablets are administered with food rather than on an empty stomach, peak plasma concentrations are higher and the extent of absorption of the drug is increased. Following oral administration of metoprolol succinate as extended-release tablets, peak plasma metoprolol concentrations are aobut 25-50% of those attained after administration of metoprolol tartrate conventional tablets given once daily or in divided doses. Time to peak concentration is longer with extended-release tablets, with peak plasma coentrations being reached in about 7 hours following administration of such tablets. Plasma concentrations attained 1 hour after an oral dose are linearly related to metoprolol tartrate doses ranging from 50-400 mg as conventional tablets.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1769
Plasma metoprolol concentrations attained after iv administration of the drug are approximately 2 times those attained following oral administration. Following iv infusion of metoprolol over 10 minutes in healthy individuals, maximum beta-adrenergic blocking activity occurred at 20 minutes. In healthy individuals, a maximum reduction in exercise-induced heart rate of approximately 10 and 15% occurs following iv administration of a single 5 mg and 15 mg metoprolol dose, respectively; the effect on exercise-induced heart rate decreased linearly with time at the same rate for both doses and persisted for approximately 5 and 8 hours for the 5 mg and 15 mg doses, respectively.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1769
Elimination of metoprolol appears to follow first-order kinetics and occurs mainly in the liver; the time required for the process apparently is independent of dose and duration of therapy. In healthy individuals and hypertensive patients, the elimination half-life of both unchanged drug and metabolites is about 3-4 hours. In poor hydroxylators of the drug, the elimination half-life is prolonged to about 7.6 hours. There is more interindividual variation in elimination half-lives in geriatric patients than in young healthy individuals. The half-life of metoprolol does not increase appreciably with impaired renal function.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1770
Metoprolol is widely distributed into body tissues. The concentrations of the drug is greater in the heart, liver, lungs, and saliva than in the plasma. Metoprolol is 11-12% bound to serum proteins, apparently only to albumin. Following therapeutic doses, metoprolol concentrations in erythrocytes are about 20% greater than those in plasma, but the drug is available for elimination from these two sites at the same rate. Metoprolol crosses the placenta, and maternal and fetal blood concentrations are about equal. The drug crosses the blood-brain barrier; the concentration of metoprolol in CSF is about 78% of the simultaneous concentration in plasma. Metoprolol is distributed into milk in a concentration about 3-4 times that of maternal plasma concentrations, but in a small amount.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1770
Metoprolol and its metabolites are excreted in urine mainly via glomerular filtration, although tubular secretion and reabsorption may be involved. About 95% of a single oral dose is excreted in urine within 72 hours. Less than 5% and approximately 10% of a metoprolol dose is excreted unchanged in urine following oral and iv administration of the drug, respectively.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1770
Not removable by hemodialysis; moderate lipid solubility.
US Pharmacopeial Convention; US Pharmacopeia Dispensing Information (USP DI); Drug Information for the Health Care Professional 12th ed, V.I p.637 (1992)

4.3 Biological Half-Life (Complete)

The plasma half-life ranges from approximately 3 to 7 hours.
Medical Economics Co; Physicians Desk Reference 56th ed p. 651 (2002)

4.4 Mechanism of Action (Complete)

Beta-adenoreceptor blocking property the amount of beta1 and beta2 effect depends on the cardioselectivity of the drug. Decreased automaticity. Reduced conduction velocity and increased refractoriness in accessory bundles (Wolff- Parkinson-White syndrome). /Class II- beta-Blocking Agents/
Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988., p. 172
At low doses, metoprolol is a selective inhibitor of beta 1-adrenergic receptors. Like propranolol, metoprolol inhibits response to adrenergic stimuli by competitively blocking b1-adrenergic receptors within the myocardium. Unlike propranolol, however, metoprolol blocks b2-adrenergic receptors within bronchial and vascular smooth muscle only in high doses.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1769
The precise mechanism of metoprolol's hypotensive action has not been determined. It has been postulated that beta-adrenergic blocking agents reduce blood pressure by blocking peripheral (especially cardiac) adrenergic receptors (decreasing cardiac output), by decreasing sympathetic outflow from the CNS, and/or by suppressing renin release.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1769
In the management of angina pectoris, the mechanism of action of metoprolol is thought to be blockage of catecholamine-induced increases in heart rate, velocity and extent of myocardial contraction, and blood pressure, which results in a net decrease in myocardial oxygen consumption.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1769
The exact mechanism of action of metoprolol in patients with suspected or definite myocardial infarction has not been determined. In patients with myocardial infarction, metoprolol reduces heart rate, systolic blood pressure, and cardiac output, but stroke volume, diastolic blood pressure, and pulmonary artery end diastolic pressure remain unchanged; the drug also appears to decrease the occurrence of ventricular fibrillation in these patients.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1769
In patients with normal or high concentrations of circulatiing renin, low doses of metoprolol are associated with a fall in plasma renin concentrations, possibly due, at least partly, to acute peripheral beta-1-adrenergic blockade. Metoprolol also substantially reduces furosemide-induced renin release. Metoprolol and propranolol produce similar decrease in plasma renin activity in patients with high plasma renin activity. The importance of these effects in decreasing blood pressure in hypertensive patients requires further investigation.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1769
A small increase in serum potassium has been observed during metoprolol therapy and may be related to beta-2-adrenergic blockade and reduced plasma renin activity and plasma aldosterone concentration.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1769

5 Pharmacology

5.1 Therapeutic Uses (Complete)

Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Antihypertensive Agents; Sympatholytics
National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)
Metoprolol /is/ used in the treatment of mitral value prolapse syndrome. /NOT included in US product labeling/
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 551
Metoprolol ... /is/ used for thyrotoxicosis. /NOT included in US product labeling/
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 551
/Metoprolol has been used/ to control the physical manifestations of anxiety such as tachycardia and tremor. It is not particularly useful for chronic anxiety or panic attacks but is most useful for reducing anxiety and improving performance in specific stressful situations. /NOT included in US product labeling/
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 551
... Metoprolol ... may be used to treat tremors. /NOT included in US product labeling/
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 551
... Metoprolol /is/ useful for prophylaxis of migrane. /NOT included in US product labeling/
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 551
... /Metoprolol may be used/ in the management of symptoms of tachycardia due to excessive beta-receptor stimulation in pheochromocytoma. However, it should be used only after primary treatment with an alpha-adrenergic blocking agent (since use without concomitant alpha-blockade could lead to serious blood pressure elevation). /NOT included in US product labeling/
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 551
Metoprolol ... /is/ indicated in clinically stable patients recovering from an initial definite or suspected acute myocardial infarction in order to reduce cardiovascular mortality and to decrease the risk of reinfarction. /Included in US product labeling/
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 551
Metoprolol /is/ ... indicated in the management of angina, palpitations, and syncope associated with hypertrophic subaortic stenosis. /NOT included in US product labeling/
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 550
... Metoprolol /is/ indicated in the treatment of hypertension when used alone or in combination with other antihypertensive medication. ... Intravenous metoprolol ... /is/ not indicated in the treatment of hypertensive emergencies. /Included in US product labeling/
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 550
... Metoprolol ... /is/ used for their antiarrhythmic effects, especially in supraventricular arrhythmias and ventricular tachycardias. /NOT included in US product labeling/
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 550
Metoprolol ... /is/ indicated in the treatment of classic angina pectoris, also referred to as "effort-associated angina". /Included in US product labeling/
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 550

5.2 Drug Warnings (Complete)

Tiredness or dizziness has occurred in about 10% of patients with hypertension or angina receiving metoprolol tartrate in clinical trials; tiredness has been reported in about 1% of patients with myocardial infarction receiving the drug. In addition, vertigo, sleep disturbances/insomnia, hallucinations, nightmares, headache, dizziness, visual disturbances, and confusion have been reported in patients with myocardial infarction receiving the drug, although a causal relationship is unclear. Somnolence or increased dreaming also has been reported with metoprolol therapy; these effects may be alleviated by avoiding late-evening dosing. rarely, impotence, nervousness, and general weakness have occurred. Depression has been reported in about 5% of patients receiving metoprolol tartrate for hypertension or angina. ... /Metoprolol tartrate/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1766
Diarrhea has occurred in about 5% of patients receiving metoprolol tartrate in clinical trials. Other GI symptoms such as nausea, gastric pain, constipation, flatulence, digestive tract disorders, heartburn, xerostomia, and hiccups also have been reported with oral metoprolol therapy. Nausea and abdominal pain have occurred in less than 1% of patients with myocardial infarction receiving IV or oral metoprolol.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1767
In 10 healthy subjects administration of metoprolol tartrate 50 mg by mouth increased the peripheral platelet count.
Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982., p. 1342
Peyronie's disease, tinnitus, restless legs, a polymyalgia-like syndrome, decreased libido, blurred vision, dry eyes, dry mucous membranes, agranulocytosis, and sweating have occurred rarely in patients receiving metoprolol. Pruritus, dry skin, worsening of psoriasis, and psoriasiform, maculopapular, and urticarial rash have occurred in some patients receiving metoprolol.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1767
The most common adverse cardiovascular effects of metoprolol are shortness of breath and bradycardia ... .
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1766
Since metoprolol is distributed into milk, the drug should be used with caution in nursing women. The extent to which metoprolol distributes into milk has not been clearly established, but the amount of drug a nursing infant would ingest (less than 1 mg/l of milk consumed daily) is believed to be too small to be clinically important; however, if a woman receiving metoprolol breastfeeds, the infant should be monitored for potential systemic effects of the drug.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1768
Metoprolol should be used with caution, if at all, in patients with atrioventricular conduction defects. The drug should be used with extreme caution in patients with substantial cardiomegaly. Metoprolol is contraindicated in hypertensive patients with sinus bradycardia, heart block greater than first degree, cardiogenic shock, overt cardiac failure, or right ventricular failure secondary to pulmonary hypertension. The drug is contraindicated in patients with acute myocardial infarction who have a heart rate less than 45 beats/minute, heart block greater than first degree, systolic blood pressure less than 100 mm Hg, or moderate to severe cardiac failure.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1768
Administration of a beta-adrenergic blocker with a vasodilator, such as hydralazine, in patients with uremia could cause pulmonary hypertension secondary to beta-adrenergic blockade of the pulmonary vasculature and to the increase cardiac output caused by the vasodilator.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1768
Use of myocardial depressant general anesthetics (e.g., diethyl ether) in patients receiving a beta-adrenergic blocker, such as metoprolol, leads to a risk of hypotension and heart failure.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1768
When metoprolol is administered with diuretics or other hypotensive drugs, the hypotensive effect of metoprolol may be increased.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1768

5.3 Interactions (Complete)

The effect of verapamil coadministration on the hepatic first pass clearance of metoprolol was investigated in dogs. Plasma concentration-time course of metoprolol enantiomers and urinary recovery of oxidative metabolites were determined after a single iv (0.51 mg/kg) and an oral (1.37 mg/kg) dose of deuterium labeled pseudoracemic metoprolol, with or without concomitant administration of racemic verapamil (3 mg/kg). Verapamil inhibited both the systemic and oral clearance of metoprolol by about 50-70%. The first pass effect of metoprolol was completely abolished after coadministration of verapamil, reflecting a marked alteration in the degree of hepatic extraction of metoprolol from intermediate to low. The hepatic clearance of metoprolol was slightly (S)-enantioselective (R/S ratio = 0.89 + or - 0.04) in control dogs. Inhibition of hepatic clearance of metoprolol by verapamil was selective towards (S)-metoprolol, such that the enantioselectivity in hepatic clearance toward (S)-metoprolol disappeared following verapamil coadministration (R/S ratio = 1.01 + or - 0.05). Urinary metabolite profiles indicated that O-demethylation and N-dealkylation were the major pathways of oxidative metabolism in the dog. alpha-Hydroxymetoprolol was a minor metabolite in urine. N-Dealkylation showed a strong preference for (S)-metoprolol, whereas O-demethylation and alpha-hydroxylation exhibited a modest selectivity toward (R)-metoprolol; hence, the slight (S)-enantioselectivity in the overall hepatic clearance. Comparison of metoprolol metabolite formation clearances in the absence or presence of verapamil coadministration showed that all three oxidative pathways were inhibited by 60-80%. The greater inhibition of hepatic clearance observed with (S)-metoprolol as compared to (R)-metoprolol was attributed to a significant (S)-enantioselective inhibition in the O-demethylation of metoprolol by verapamil.
Murthy SS et al; Drug Metab Dispos 19 (6): 1093-100 (1991)
The interaction between metoprolol and bromazepam and lorazepam was studied in 12 healthy male volunteers aged 21-37 years. Metoprolol had no significant effect on the pharmacokinetics of bromazepam or lorazepam. However, bromazepam area under the curve was 35% higher in the presence of metoprolol. Bromazepam enhanced the effect of metoprolol on systolic blood pressure but not on diastolic blood pressure or pulse rate. Lorazepam had no effect on either blood pressure or pulse. Metoprolol did not enhance the effect of bromazepam on the psychomotor tests used in this study. Metoprolol caused a small increase in critical flicker fusion threshold with lorazepam but had no effect on the other tests. Lorazepam (2 mg) was more potent than bromazepam (6 mg) in the doses used in this study. The interaction of metoprolol with bromazepam and lorazepam is unlikely to be of clinical significance. No change in dose is necessary when using these drugs together.
Scott AK et al; Eur J Clin Pharmacol 40 (4): 405-9 (1991)
In contrast to early work showing inhibition of the absorption of beta adrenergic blocking drugs by antacids, subsequent studies did not confirm a reduction in the bioavailability of either atenolol or propranolol during antacid treatment; indeed, they showed an increase in the plasma concentrations of metoprolol when the drug was coadministered with an antacid.
Gugler R, Allgayer H; Clin Pharmacokinet 18 (3): 210-9 (1990)
Caffeine and metoprolol have been reported to increase peak salicylic acid concentration following aspirin administration.
Miners JO; Clin Pharmacokine 17 (5): 327-44 (1989)
The effects of alcohol ingestion on the acute effects of metoprolol were compared with placebo in 8 healthy male volunteers aged 21-31 yr who received a single oral dose of 200 mg of metoprolol capsule or placebo 90 min after consuming 0.75 g/kg of alcohol in a randomized, controlled study. There was no significant difference in blood alcohol levels between the metoprolol and placebo phases of the study. Plasma metoprolol levels reached a peak of 688 ng/ml 3 hr after dosing. No acute rise in blood pressure was observed following alcohol ingestion during the placebo phase of the study. Metoprolol caused a significantly larger reduction in systolic blood pressure compared with placebo, although in both phases of the study blood pressure was falling at the time of alcohol consumption. Systolic blood pressure fell during the metoprolol phase and the rate of fall both before and after alcohol consumption seemed comparable. There was no significant difference in diastolic blood pressure during the metoprolol and placebo phases of the study. It was concluded that acute alcohol ingestion does not abolish the hypotensive effect of metoprolol.
Maheswaran R et al; J Clin Pharm Ther 15 (6): 405-10 (1990)
The ability of a series of antimalarial drugs to impair the metabolism of metoprolol tartrate in rat and Caucasian cadaver liver was examined. Chloroquine phosphate (chloroquine diphosphate) was a potent inhibitor in rat liver microsomes and a less potent inhibitor of metoprolol tartrate oxidation in human liver microsomes. Quinine was similar to chloroquine phosphate in potency, while quinidine, primaquine phosphate (primaquine diphosphate), and mefloquine hydrochloride were slightly less potent. It was concluded that antimalarial treatment might have contributed to a previously reported difference in the metabolic pattern of metoprolol tartrate between Caucasians and Nigerians.
Lancaster DL et al; J Pharm Pharmacol 42 (Apr): 267-71 (1990)
A study of the effects of 50 mg atenolol, 100 mg metoprolol and 80 mg propranolol on the metabolic clearance of 1,000 mg of oral antipyrine and 100 mg of intravenous phenytoin was conducted in 32 healthy male volunteers (aged 21-25 yr). ... Neither metoprolol nor placebo affected antipyrine clearance. Phenytoin clearance did not change during any of the treatments.
Perrild H et al; Br J Clin Pharmacol 28 (Nov): 551-4 (1989)
The purpose of this study was to examine the influence of cigarette smoking and gender on the pharmacokinetics of metoprolol. Eighteen volunteers with no evidence of clinical disease each randomly received the following doses of metoprolol tartrate: 100 mg orally, 200 mg orally and 20 mg as a constant rate intravenous infusion over 20 min. The only significant difference between smokers and nonsmokers was that smokers had a larger steady state volume of distribution (3.3 vs 2.5 l/kg). There were no differences in half-life, systemic clearance or bioavailability. No differences were observed between males and females for any of the kinetic parameters examined. Systemic bioavailability varied markedly between subjects (range: 15 to 92%). In fifteen of the eighteen subjects, bioavailability was higher after the 200 mg dose compared to the 100 mg dose. These results suggest that metoprolol may be subject to saturable presystemic elimination and extend the previous observations that bioavailability increased from 31% to 46% when doses were increased from 20 to 100 mg. However, the difference in bioavailability as the dose is increased is unlikely to be clinically significant since the mean difference is smaller than the variation in bioavailability among subjects.
Schaaf LJ et al; Eur J Clin Pharmacol 33 (4): 355-62 (1987)
The pharmacokinetics of metoprolol tartrate assessed in terms of racemic metoprolol tartrate and the individual (R)- and (S)-enantiomers were studied in 12 male volunteers (aged 20-33 yrs) after three 8-day treatments of 100 mg oral metoprolol tartrate every 12 hr with concurrent once daily oral dose of 800 mg cimetidine or 300 mg ranitidine. Oral ranitidine had no effect on the pharmacodynamics or pharmacokinetics of metoprolol tartrate. Although not affecting the pharmacodynamics of metoprolol tartrate, cimetidine did not produce an increase in the bioavailability of metoprolol tartrate through inhibition of enzymes responsible for the first pass elimination of the beta-blocker. The effect was stereoselective, with the major effect being on the less pharmacologically active (R)-enantiomer.
Toon S et al; Clin Pharmacol Ther 43 (Mar): 283-89 (1988)
The plasma concentrations and urinary excretions of aspirin (acetylsalicylic acid) and metoprolol administered for 7 days alone and in combination to 6 healthy volunteers are described. Metoprolol kinetics remained uninfluenced whereas the maximal plasma concentrations of aspirin were significantly higher than in the aspirin control period.
Spahn H et al; Arzneim Forsch 6 (11): 1697-9 (1987)
The steady state plasma concentrations of metoprolol and propafenone were determined in patients being treated with one of these drugs alone and during combined treatment with both drugs. In addition, single dose studies with metoprolol, propafenone and the combination of both drugs were performed in healthy volunteers to determine the pharmacokinetics and the time course of beta adrenoceptor blocking activity. In four patients being treated with metoprolol first and subsequently with propafenone, steady state levels of metoprolol increased two to five fold with simultaneous treatment with propafenone. In four patients being treated with the drug combination first and thereafter with propafenone alone no changes in the steady state levels of propafenone were observed between both treatment periods. Adverse effects of the drug combination were observed in two patients (one patient experienced severe nightmares and the other left ventricular failure). When single oral doses of metoprolol (50 mg) and propafenone (150 mg) and the combination of both were administered to healthy subjects, an approximately two fold decrease of the oral clearance of metoprolol was seen when propafenone was given in addition. No conclusive changes in the pharmacokinetics of propafenone could be detected in the presence of metoprolol. Duration of beta adrenoceptor blocking activity of a single dose of metoprolol in healthy volunteers as measured by reduction of exercise induced tachycardia increased when propafenone was given in addition. The dose of metoprolol should be reduced when propafenone is given in addition.
Wagner F et al; Br J Clin Pharmacol 24 (2): 213-20 (1987)
This double blind, cross over study in healthy male subjects evaluated the pharmacokinetics of felodipine and metoprolol given both separately and in combination. ...None of the felodipine pharmacokinetic variables (tmax, Cmax, Cmin, area under the curve (0-12) and half-life) changed significantly when felodipine and metoprolol were given in combination. Cmax and area under the curve (0-12) for metoprolol increased significantly when metoprolol and felodipine were combined, although tmax, Cmin and half-life for metoprolol remained unchanged. The changes in metoprolol pharmacokinetics induced by felodipine are small and unlikely to be clinically important.
Smith SR et al; Eur J Clin Pharmacol 31 (5): 575-8 (1987)

6 Environmental Fate & Exposure

6.1 Environmental Fate / Exposure Summary

Metoprolol's production and use as an antihypertensive, antianginal, and antiarrhythmic drug may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 2.8X10-7 mm Hg at 25 °C indicates metoprolol will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase metoprolol will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 0.22 days. Particulate-phase metoprolol will be removed from the atmosphere by wet and dry deposition. If released to soil, metoprolol is expected to have high mobility based upon an estimated Koc of 62. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 2.1X10-11 atm-cu m/mole. An estimated pKa of metoprolol is 9.6, indicating that this compound will primarily exist in the protonated form in the environment and cations generally adsorb to organic carbon and clay more strongly than their neutral counterparts. Metoprolol is not expected to volatilize from dry soil surfaces based upon its vapor pressure. If released into water, metoprolol is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon metoprolol's estimated Henry's Law constant. An estimated BCF of 1.3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to metoprolol may occur through inhalation and dermal contact with this compound at workplaces where metoprolol is produced or used. Monitoring data indicate that the general population may be exposed to metoprolol by ingestion of this compound as a drug or by contact with wastewater or surface water contaminated with metoprolol. (SRC)

6.2 Probable Routes of Human Exposure (Complete)

NIOSH (NOES Survey 1981-1983) has statistically estimated that 340 workers (180 of these are female) are potentially exposed to metoprolol in the US(1). Occupational exposure to metoprolol may occur through inhalation and dermal contact with this compound at workplaces where metoprolol is produced or used(SRC). Monitoring data indicate that the general population may be exposed to metoprolol by ingestion of this compound as a drug or by contact with wastewater or surface water contaminated with metoprolol(SRC).
(1) NIOSH; National Occupational Exposure Survey (NOES) (1983)

6.3 Artificial Pollution Sources (Complete)

Metoprolol's production and use as an antihypertensive, antianginal, and antiarrhythmic drug(1) may result in its release to the environment through various waste streams(SRC).
(1) Budavari S, ed; The Merck Index. 13th ed Whitehouse Station, NJ: Merck and Co., Inc., p. 1096 (2001)

6.4 Environmental Fate (Complete)

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 62(SRC), determined from a structure estimation method(2), indicates that metoprolol is expected to have high mobility in soil(SRC). Volatilization of metoprolol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.1X10-11 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Metoprolol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.9X10-7 mm Hg(SRC), determined from a fragment constant method(4).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992)
(3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(4) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 62.24(SRC), determined from a structure estimation method(2), indicates that metoprolol is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.1X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). An estimated pKa of metoprolol is 9.6(9), indicating that this compound will primarily exist in cation form in the environment and cations generally adsorb to organic carbon and clay more strongly than their neutral counterparts(5). According to a classification scheme(6), an estimated BCF of 1.252(SRC), from its log Kow of 1.88(7) and a regression-derived equation(8), suggests the potential for bioconcentration in aquatic organisms is low(SRC).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992)
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990)
(4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(5) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
(6) Franke C et al; Chemosphere 29: 1501-14 (1994)
(7) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 137 (1995)
(8) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999)
(9) Hilal SH et al; pp. 291-353 in Quantitative Treatments of Solute/Solvent Interactions: Theoretical and Computational Chemistry Vol. 1 NY, NY: Elsevier (1994)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), metoprolol, which has an estimated vapor pressure of 2.9X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase metoprolol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 0.22 days(SRC), calculated from its rate constant of 1.58X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
(3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)

6.5 Environmental Abiotic Degradation (Complete)

The rate constant for the vapor-phase reaction of metoprolol with photochemically-produced hydroxyl radicals has been estimated as 1.5X10-10 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 0.22 dayss at an atmospheric concentration of 5.5X10+5 hydroxyl radicals per cu cm(1). Metoprolol is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(3) nor to directly photolyze due to the lack of absorption in the environmental UV spectrum (>290 nm)(SRC).
(1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(2) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02- 4254. Menlo Park, CA: SRI International (1987)
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990)

6.6 Environmental Bioconcentration (Complete)

An estimated BCF of 1.2 was calculated for metoprolol(SRC), using a log Kow of 1.88(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).
(1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 137 (1995)
(2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999)
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

6.7 Soil Adsorption / Mobility (Complete)

Using a structure estimation method based on molecular connectivity indices(1), the Koc for metoprolol can be estimated to be 62(SRC). According to a classification scheme(2), this estimated Koc value suggests that metoprolol is expected to have high mobility in soil. An estimated pKa of metoprolol is 9.6(3), indicating that this compound will primarily exist in the protonated form in the environment and cations generally adsorb to organic carbon and clay more strongly than their neutral counterparts(4).
(1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992)
(2) Swann RL et al; Res Rev 85: 17-28 (1983)
(3) Hilal SH et al; pp. 291-353 in Quantitative Treatments of Solute/Solvent Interactions: Theoretical and Computational Chemistry Vol. 1 NY, NY: Elsevier (1994)
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)

6.8 Volatilization from Water / Soil (Complete)

The Henry's Law constant for metoprolol is estimated as 2.1X10-11 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that metoprolol is expected to be essentially nonvolatile from water surfaces(2). Metoprolol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.9X10-7 mm Hg(SRC), determined from a fragment constant method(3).
(1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)

6.9 Environmental Water Concentrations (Complete)

SURFACE WATER: Composite water samples (n=45) were taken from various rivers (n=23) in Germany and metoprolol concentrations were 0.045 ug/l (median), 1.2 ug/l (90th percentile) and 2.2 ug/l (maximum)(1). Metoprolol concentrations in surface water in Germany were reported ranging from <0.003 to 1.54 ug/l(2).
(1) Ternes TA et al; Wat Res 32: 3245-60 (1998)
(2) Stan HJ et al; Analusis 25: M20-M23 (1997)

6.10 Effluent Concentrations (Complete)

Effluent from sewage treatment plants (n=29) in Germany 1996-1998 contained metoprolol concentrations of 0.73 ug/l (median), 1.3 ug/l (90th percentile) and 2.2 ug/l (maximum)(1). Removal efficiency for metoprolol from sewage treatment plants was 83%(1). Metoprolol concentrations in sewage effluent in Germany were reported ranging from <0.025 to 2.20 ug/l (2). Mean concentration and loads of metoprolol in the effluent of a municipal sewage treatment plant close to Frankfurt/Main, June 24-30, 1996 were 7.2 ug/l (mean concn influent), 2.08 ug/l (mean concn effluent), 374 g/day (load influent), 108 g/day (load effluent)(3). The percent removal for metoprolol was 67% and the mean flow rate for the plant was 63,190 cu m/day(3).
(1) Ternes TA et al; Wat Res 32: 3245-60 (1998)
(2) Stan HJ et al; Analusis 25: M20-M23 (1997)
(3) Ternes T; In Amer Chem Soc ACS Symp Ser 2001 Pharmaceuticals and Personal Care Products in the Environment pp.39-54

6.11 Milk Concentrations (Complete)

Metoprolol is distributed into milk in a concentration about 3-4 times that of maternal plasma concentrations, but the actual amount distributed into milk appears to be very small.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1770

7 Environmental Standards & Regulations

7.1 FDA Requirements (Complete)

Metoprolol tartrate, used as a beta adrenergic blocking agent, was approved by FDA for marketing in the United States 12/84.
U.S. Department of Health and Human Services. Public Health Service. FDA. Drug Utilization in the United States: 1989. Eleventh Annual Review. p.23 (April, 1991)
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed drug products, incl metaprolol, metoprolol tartrate, and metoprolol succinate approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act. /Metaprolol, metoprolol tartrate, and metoprolol succinate/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of July 1, 2003: https://www.fda.gov/cder/ob/
Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).
21 CFR 200-299, 300-499, 820, and 860; U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of July 1, 2003: https://www.ecfr.gov

8 Chemical / Physical Properties

8.1 Molecular Formula

C15-H25-N-O3
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1096

8.2 Molecular Weight

267.36
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1096

8.3 LogP

log Kow = 1.88
Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995., p. 137

8.4 Solubility (Complete)

Solubility (mg/ml) @ 25 °C: water >1000; methanol >500; chloroform 496; acetone 1.1; acetonitrile 0.89; hexane 0.001; UV max (water): 223 nm (E 23400) /Tartrate/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1096

8.5 Other Experimental Properties (Complete)

White crystalline powder; freely soluble in water; soluble in methanol; sparingly soluble in ethanol; slightly soluble in dichloromethane and 2-propanol; practically insoluble in ethyl acetate, acetone, diethylether and heptane /Metoprolol succinate/
Physicians' Desk Reference. 57th ed. Montvale, NJ: Medical Economics Co., Inc., p. 645 (2002)
White crystalline powder /Metoprolol tartrate/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1770
Bitter taste; pKa = 9.68; very sol in water and freely sol in alc. /Metoprolol tartrate/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2002. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2002 (Plus Supplements)., p. 1679

9 Chemical Safety & Handling

9.1 Storage Conditions (Complete)

Commercially available preparations of metoprolol tartrate should be protected from light. Metoprolol tartrate tablets should be stored in tight, light-resistant containers at 15-30 °C and metoprolol tartrate injection should be stored at a temperature of 30 °C or less, preferably at 15-30 °C, freezing of the injection should be avoided.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 1770

9.2 Disposal Methods (Complete)

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

10 Manufacturing / Use Information

10.1 Uses (Complete)

MEDICATION

10.2 Manufacturers

Geneva Pharmaceuticals, Inc., 506 Carnegie Center, Suite 400, Princeton, NJ 08540, (800) 525-8747
Physicians' Desk Reference. 57th ed. Montvale, NJ: Thompson PDR p. 1417 (2003)

10.3 Formulations / Preparations (Complete)

O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1096
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1096

11 Laboratory Methods

11.1 Clinical Laboratory Methods (Complete)

A simple and rapid thin layer chromatographic method with derivatization and fluorimetric determination of enantiomers of metoprolol tartrate ... in urine samples is described. ...
Pflugmann G et al; J Chromatog Biomed Appl 416: 331-9 (1987)
Aa beta-adrenoreceptor subtype specific radioreceptor assay procedure was developed and compared with an enantiospecific high performance liquid chromatographic liquid chromatographic method to determine metoprolol tartrate blood levels in healthy volunteers. ...
Spahn H et al; Pharm Res 6: 152-5 (1989)

11.2 Analytic Laboratory Methods (Complete)

Analyte: metoprolol tartrate; matrix: chemical purity; procedure: potentiometric titration with comparison to standards /Metoprolol tartrate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1222 (2003)
Analyte: metoprolol tartrate; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /Metoprolol tartrate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1222 (2003)
Analyte: metoprolol succinate; matrix: chemical purity; procedure: potentiometric titration with comparison to standards /Metoprolol succinate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1220 (2003)
Analyte: metoprolol succinate; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /Metoprolol succinate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1220 (2003)
Analyte: metoprolol tartrate; matrix: pharmaceutical preparation (injection solution); procedure: infrared absorption spectrophotometry with comparison to standards (chemical identification)/Metoprolol tartrate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1223 (2003)
Analyte: metoprolol tartrate; matrix: pharmaceutical preparation (injection solution); procedure: liquid chromatography with detection at 254 nm and comparison to standards (assay purity)/Metoprolol tartrate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1223 (2003)
Analyte: metoprolol tartrate; matrix: pharmaceutical preparation (tablet); procedure: infrared absorption spectrophotometry with comparison to standards (chemical identification) /Metoprolol tartrate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1223 (2003)
Analyte: metoprolol tartrate; matrix: pharmaceutical preparation (tablet); procedure: retention time of liquid chromatogram with comparison to standards (chemical identification) /Metoprolol tartrate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1223 (2003)
Analyte: metoprolol tartrate; matrix: pharmaceutical preparation (tablet); procedure: liquid chromatography with detection at 254 nm and comparison to standards (assay purity) /Metoprolol tartrate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1223 (2003)
Analyte: metoprolol succinate; matrix: pharmaceutical preparation (extended release tablet); procedure: infrared absorption spectrophotometry with comparison to standards (chemical identification) /Metoprolol succinate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1221 (2003)
Analyte: metoprolol succinate; matrix: pharmaceutical preparation (extended release tablet); procedure: liquid chromatography with detection at 280 nm and comparison to standards (assay purity) /Metoprolol succinate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p1221 (2003)

12 Special References

12.1 Special Reports (Complete)

Benfield P et al; Metoprolol. An Updated Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy, in Hypertension, Ischaemic Heart Disease and Related Cardiovascular Disorders; Drugs 31 (5): 376-429 (1986).

13 Synonyms and Identifiers

13.1 Substance Title

METOPROLOL

13.2 Associated Chemicals (Complete)

14 Administrative Information

14.1 Hazardous Substances DataBank Number

6531

14.2 Last Revision Date

20040225

14.3 Last Review Date

Reviewed by SRP on 10/2/2003

14.4 Update History

Field Update on 2012-03-14, 1 fields added/edited/deleted

Complete Update on 2004-02-25, 37 fields added/edited/deleted

Field Update on 2003-06-10, 0 fields added/edited/deleted

Field Update on 02/14/2003, 1 field added/edited/deleted.

Complete Update on 11/08/2002, 1 field added/edited/deleted.

Complete Update on 01/14/2002, 1 field added/edited/deleted.

Complete Update on 08/09/2001, 1 field added/edited/deleted.

Complete Update on 05/15/2001, 1 field added/edited/deleted.

Complete Update on 09/12/2000, 1 field added/edited/deleted.

Complete Update on 06/12/2000, 1 field added/edited/deleted.

Complete Update on 02/08/2000, 1 field added/edited/deleted.

Complete Update on 02/02/2000, 1 field added/edited/deleted.

Complete Update on 09/21/1999, 1 field added/edited/deleted.

Complete Update on 08/27/1999, 1 field added/edited/deleted.

Complete Update on 06/07/1999, 6 fields added/edited/deleted.

Field Update on 09/11/1998, 1 field added/edited/deleted.

Field Update on 06/03/1998, 1 field added/edited/deleted.

Field Update on 11/01/1997, 1 field added/edited/deleted.

Field Update on 05/09/1997, 1 field added/edited/deleted.

Complete Update on 03/17/1997, 1 field added/edited/deleted.

Complete Update on 02/03/1997, 1 field added/edited/deleted.

Complete Update on 10/20/1996, 1 field added/edited/deleted.

Complete Update on 02/01/1996, 1 field added/edited/deleted.

Complete Update on 11/09/1995, 1 field added/edited/deleted.

Complete Update on 08/21/1995, 1 field added/edited/deleted.

Complete Update on 03/31/1993, 31 fields added/edited/deleted.

Created 19910802 by GCF

CONTENTS