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Metoprolol


Pronunciation

 (me toe PROE lole)


U.S. Brand Names

 Lopressor®; Toprol-XL®


Synonyms

 Metoprolol Succinate; Metoprolol Tartrate


Generic Available

 Yes: Injection, tablet (nonextended release)


Canadian Brand Names

 Apo-Metoprolol®; Betaloc®; Betaloc® Durules®; Lopressor®; Novo-Metoprolol; Nu-Metop; PMS-Metoprolol; Toprol-XL®


Use

 Treatment of hypertension and angina pectoris; prevention of myocardial infarction, atrial fibrillation, flutter, symptomatic treatment of hypertrophic subaortic stenosis; to reduce mortality/hospitalization in patients with congestive heart failure (stable NYHA Class II or III) in patients already receiving ACE inhibitors, diuretics, and/or digoxin (sustained-release only)


Use - Unlabeled/Investigational

 Treatment of ventricular arrhythmias, atrial ectopy, migraine prophylaxis, essential tremor, aggressive behavior


Pregnancy Risk Factor

 C (manufacturer); D (2nd and 3rd trimesters - expert analysis)


Pregnancy Implications

 Metoprolol crosses the placenta. Beta-blockers have been associated with bradycardia, hypotension, and IUGR; IUGR is probably related to maternal hypertension. Available evidence suggests beta-blockers are generally safe during pregnancy (JNC 7). Cases of neonatal hypoglycemia have been reported following maternal use of beta-blockers at parturition or during breast-feeding. Monitor breast-fed infant for symptoms of beta-blockade.


Lactation

 Enters breast milk/use caution (AAP rates "compatible")


Contraindications

 Hypersensitivity to metoprolol or any component of the formulation; sinus bradycardia; heart block greater than first degree (except in patients with a functioning artificial pacemaker); cardiogenic shock; uncompensated cardiac failure; pregnancy (2nd and 3rd trimesters)


Warnings/Precautions

 Must use care in compensated heart failure and monitor closely for a worsening of the condition (efficacy has not been established for metoprolol). Beta-blocker therapy should not be withdrawn abruptly (particularly in patients with CAD), but gradually tapered to avoid acute tachycardia, hypertension, and/or ischemia. Beta-blockers may increase the risk of anaphylaxis (in predisposed patients) and blunt response to epinephrine. Use caution in patients with PVD (can aggravate arterial insufficiency). Use caution with concurrent use of beta-blockers and either verapamil or diltiazem; bradycardia or heart block can occur. Avoid concurrent I.V. use of both agents. In general, beta-blockers should be avoided in patients with bronchospastic disease. Metoprolol, with B1 selectivity, should be used cautiously in bronchospastic disease with close monitoring. Use cautiously in diabetics because it can mask prominent hypoglycemic symptoms. Can mask signs of thyrotoxicosis. Can cause fetal harm when administered in pregnancy. Use cautiously in the hepatically impaired. Use care with anesthetic agents which decrease myocardial function. The extended release formulation consists of drug within a nondeformable matrix; following drug release/absorption, the matrix/shell is expelled in the stool. The use of nondeformable products in patients with known stricture/narrowing of the GI tract has been associated with symptoms of obstruction.


Adverse Reactions

>10%:

Central nervous system: Drowsiness, insomnia

Endocrine & metabolic: Decreased sexual ability

1% to 10%:

Cardiovascular: Bradycardia, palpitation, edema, CHF, reduced peripheral circulation

Central nervous system: Mental depression

Gastrointestinal: Diarrhea or constipation, nausea, stomach discomfort

Respiratory: Bronchospasm

Miscellaneous: Cold extremities

<1% (Limited to important or life-threatening): Arrhythmias, arthralgia, chest pain, confusion (especially in the elderly), depression, dyspnea, hallucinations, headache, heart block (second- and third-degree), hepatic dysfunction, hepatitis, jaundice, leukopenia, nervousness, orthostatic hypotension, paresthesia, photosensitivity, thrombocytopenia, vomiting


Overdosage/Toxicology

 Symptoms of intoxication include cardiac disturbances, CNS toxicity, bronchospasm, hypoglycemia and hyperkalemia. The most common cardiac symptoms include hypotension and bradycardia. Atrioventricular block, intraventricular conduction disturbances, cardiogenic shock, and asystole may occur with severe overdose, especially with membrane-depressant drugs (eg, propranolol). CNS effects include convulsions, coma, and respiratory arrest. Treatment is symptom-directed and supportive.


Drug Interactions

 Substrate of CYP2C19 (minor), 2D6 (major); Inhibits CYP2D6 (weak)

Alpha-blockers (prazosin, terazosin): Concurrent use of beta-blockers may increase risk of orthostasis.

AV conduction-slowing agents (digoxin): Effects may be additive with beta-blockers.

Clonidine: Hypertensive crisis after or during withdrawal of either agent.

CYP2D6 inhibitors: May increase the levels/effects of metoprolol. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

Fluoxetine may inhibit the metabolism of metoprolol resulting in cardiac toxicity.

Glucagon: Metoprolol may blunt the hyperglycemic action of glucagon.

Hydralazine may enhance the bioavailability of metoprolol.

Insulin and oral hypoglycemics: Metoprolol may mask tachycardia from hypoglycemia.

Metoprolol reduces antipyrine's clearance by 18%.

NSAIDs (ibuprofen, indomethacin, naproxen, piroxicam) may reduce the antihypertensive effects of beta-blockers.

Oral contraceptives may increase the AUC and Cmax of metoprolol.

Salicylates may reduce the antihypertensive effects of beta-blockers.

Sulfonylureas: Beta-blockers may alter response to hypoglycemic agents.

Verapamil or diltiazem may have synergistic or additive pharmacological effects when taken concurrently with beta-blockers; avoid concurrent I.V. use.


Ethanol/Nutrition/Herb Interactions

Food: Food increases absorption. Metoprolol serum levels may be increased if taken with food.

Herb/Nutraceutical: Avoid dong quai if using for hypertension (has estrogenic activity). Avoid ephedra, yohimbe, ginseng (may worsen hypertension). Avoid garlic (may have increased antihypertensive effect).


Stability

Injection: Do not store above 30°C (86°F); protect from light

Tablet: Store between 15°C to 30°C (59°F to 86°F)


Compatibility

 Stable in D5W, NS

Y-site administration: Compatible: Alteplase, meperidine, morphine. Incompatible: Amphotericin B cholesteryl sulfate complex


Mechanism of Action

 Selective inhibitor of beta1-adrenergic receptors; competitively blocks beta1-receptors, with little or no effect on beta2-receptors at doses <100 mg; does not exhibit any membrane stabilizing or intrinsic sympathomimetic activity


Pharmacodynamics/Kinetics

Onset of action: Peak effect: Antihypertensive: Oral: 1.5-4 hours

Duration: 10-20 hours

Absorption: 95%

Protein binding: 8%

Metabolism: Extensively hepatic; significant first-pass effect

Bioavailability: Oral: 40% to 50%

Half-life elimination: 3-4 hours; End-stage renal disease: 2.5-4.5 hours

Excretion: Urine (3% to 10% as unchanged drug)


Dosage

Children: Oral: 1-5 mg/kg/24 hours divided twice daily; allow 3 days between dose adjustments

Adults:

Hypertension: Oral: 100-450 mg/day in 2-3 divided doses, begin with 50 mg twice daily and increase doses at weekly intervals to desired effect; usual dosage range (JNC 7): 50-100 mg/day

Extended release: Same daily dose administered as a single dose

Angina, SVT, MI prophylaxis: Oral: 100-450 mg/day in 2-3 divided doses, begin with 50 mg twice daily and increase doses at weekly intervals to desired effect

Extended release: Same daily dose administered as a single dose

Hypertension/ventricular rate control: I.V. (in patients having nonfunctioning GI tract): Initial: 1.25-5 mg every 6-12 hours; titrate initial dose to response. Initially, low doses may be appropriate to establish response; however, up to 15 mg every 3-6 hours has been employed.

Congestive heart failure: Oral (extended release): Initial: 25 mg once daily (reduce to 12.5 mg once daily in NYHA class higher than class II); may double dosage every 2 weeks as tolerated, up to 200 mg/day

Myocardial infarction (acute): I.V.: 5 mg every 2 minutes for 3 doses in early treatment of myocardial infarction; thereafter give 50 mg orally every 6 hours 15 minutes after last I.V. dose and continue for 48 hours; then administer a maintenance dose of 100 mg twice daily.

Elderly: Oral: Initial: 25 mg/day; usual range: 25-300 mg/day

Extended release: 25-50 mg/day initially as a single dose; increase at 1- to 2-week intervals.

Hemodialysis: Administer dose posthemodialysis or administer 50 mg supplemental dose; supplemental dose is not necessary following peritoneal dialysis

Dosing adjustment/comments in hepatic disease: Reduced dose probably necessary


Administration

Oral: Do not crush or chew extended release tablets.

I.V.: When administered acutely for cardiac treatment, monitor ECG and blood pressure. May administer by rapid infusion (I.V. push) over 1 minute or by slow infusion (ie, 5-10 mg of metoprolol in 50 mL of fluid) over ~30 minutes. Necessary monitoring for surgical patients who are unable to take oral beta-blockers (prolonged ileus) has not been defined. Some institutions require monitoring of baseline and postinfusion heart rate and blood pressure when a patient's response to beta-blockade has not been characterized (ie, the patient's initial dose or following a change in dose). Consult individual institutional policies and procedures.


Monitoring Parameters

 Acute cardiac treatment: Monitor ECG and blood pressure with I.V. administration; heart rate and blood pressure with oral administration


Dietary Considerations

 Regular tablets should be taken with food. Extended release tablets may be taken without regard to meals.


Patient Education

 I.V. use in emergency situations: Patient information is appropriate to patient condition.

Oral: Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take exactly as directed. Do not change dosage or discontinue without consulting prescriber. Take pulse daily, prior to medication and follow prescriber's instruction about holding medication. Do not take with antacids. If you have diabetes, monitor serum sugar closely (drug may alter glucose tolerance or mask signs of hypoglycemia). May cause fatigue, dizziness, or postural hypotension (use caution when changing position from lying or sitting to standing, when driving, or when climbing stairs until response to medication is known); or alteration in sexual performance (reversible). Report unresolved swelling of extremities, respiratory difficulty or new cough, unresolved fatigue, unusual weight gain, unresolved constipation, or unusual muscle weakness. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.


Anesthesia and Critical Care Concerns/Other Considerations

 Symptomatic bradycardia may be treated with atropine.

Surgery: Atenolol has also been shown to improve cardiovascular outcomes when used in the perioperative period in patients with underlying cardiovascular disease who are undergoing noncardiac surgery. Bisoprolol in high-risk patients undergoing vascular surgery reduced the perioperative incidence of death from cardiac causes and nonfatal myocardial infarction.

Withdrawal: Beta-blocker therapy should not be withdrawn abruptly, but gradually tapered to avoid acute tachycardia and hypertension.


Cardiovascular Considerations

Hypertension: Beta-blocker therapy in the treatment of hypertension has been associated with improved cardiovascular outcomes. This class of drug is beneficial for elderly patients with hypertension. A recent UKPDS study showed that beta-blocker therapy (atenolol) was as effective as an ACE inhibitor in reducing cardiovascular events and that the benefits of therapy were related more to the degree of antihypertensive efficacy rather than the class of drug used.

Myocardial infarction: Beta-blockers, in general without intrinsic sympathomimetic activity (ISA), have been shown to decrease morbidity and mortality when initiated in the acute treatment of myocardial infarction and continued long-term. In this setting, therapy should be avoided in patients with hypotension, cardiogenic shock, or heart block.

Surgery: Atenolol has also been shown to improve cardiovascular outcomes when used in the perioperative period in patients with underlying cardiovascular disease who are undergoing noncardiac surgery. Bisoprolol in high-risk patients undergoing vascular surgery reduced the perioperative incidence of death from cardiac causes and nonfatal myocardial infarction.

Atrial fibrillation: Beta-blocker therapy provides effective rate control in patients with atrial fibrillation.

Angina: Beta-blockers are effective in the treatment of angina as monotherapy or when combined with nitrates and/or calcium channel blockers. In patients with severe intractable angina requiring negative cardiac chronotropic medications, pacemaker placement has been carried out to maintain heart rate in the setting of large doses of beta-blockers and/or calcium channel blockers. Beta-blockers are ineffective in the treatment of pure vasospastic (Prinzmetal) angina.

Unstable angina/non-ST-segment elevation MI: In the treatment of unstable angina/non-ST-segment elevation MI, a beta-blocker, with the first dose administered intravenously if there is ongoing chest pain, followed by oral administration, is recommended (in the absence of contraindications).

Withdrawal: Beta-blocker therapy should not be withdrawn abruptly, but gradually tapered to avoid acute tachycardia and hypertension.

Heart failure: There is emerging evidence that beta-blocker therapy, without intrinsic sympathomimetic activity (ISA), should be initiated in select patients with stable congestive heart failure (NYHA Class II-III). To date, carvedilol, sustained release metoprolol, and bisoprolol have demonstrated a beneficial effect on morbidity and mortality. It is important that beta-blocker therapy be instituted initially at very low doses with gradual and very careful titration.

Metoprolol has also been used in the treatment of vasovagal (neurogenic) syncope.


Dental Health: Effects on Dental Treatment

 Metoprolol is a cardioselective beta-blocker. Local anesthetic with vasoconstrictor can be safely used in patients medicated with metoprolol. Nonselective beta-blockers (ie, propranolol, nadolol) enhance the pressor response to epinephrine, resulting in hypertension and bradycardia; this has not been reported for metoprolol. Many nonsteroidal anti-inflammatory drugs, such as ibuprofen and indomethacin, can reduce the hypotensive effect of beta-blockers after 3 or more weeks of therapy with the NSAID. Short-term NSAID use (ie, 3 days) requires no special precautions in patients taking beta-blockers.


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 Sedation and dizziness are common; may cause depression; may rarely cause insomnia, confusion, amnesia, or nightmares


Mental Health: Effects on Psychiatric Treatment

 Barbiturates may decrease the effects of metoprolol; beta-blockers may increase the effects of psychotropics; monitor clinical status for potential changes


Dosage Forms

Injection, solution, as tartrate (Lopressor®): 1 mg/mL (5 mL)

Tablet, as tartrate 25 mg, 50 mg, 100 mg

Lopressor®: 50 mg, 100 mg

Tablet, extended release, as succinate (Toprol-XL®): 25 mg, 50 mg, 100 mg, 200 mg [expressed as mg equivalent to tartrate]


Extemporaneously Prepared

 A mixture of metoprolol 10 mg/mL plus hydrochlorothiazide 5 mg/mL was found to be stable for 60 days in a refrigerator in a 1:1 preparation of Ora-Sweet® and Ora-Plus®, in Ora-Sweet® SF and Ora-Plus®, and in cherry syrup

Allen LV and Erickson III MA, "Stability of Labetalol Hydrochloride, Metoprolol Tartrate, Verapamil Hydrochloride, and Spironolactone With Hydrochlorothiazide in Extemporaneously Compounded Oral Liquids," Am J Health Syst Pharm , 1996, 53:2304-9.


References

"American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics , 2001, 108(3):776-89.

Antman EM, Anbe SC, Alpert JS, et al, "ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction)," Circulation , 2004, 110:588-636. Available at: http://www.circulationaha.org/cgi/content/full/110/5/588. Last accessed August 26, 2004.

Braunwald E, Antman EM, Beasley JW, et al, "ACC/AHA 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction - Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina)," J Am Coll Cardiol , 2002, 40(7):1366-74. Available at: http://www.acc.org/clinical/guidelines/unstable/incorporated/index.htm. Accessed May 20, 2003.

Chobanian AV, Bakris GL, Black HR, et al, "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report," JAMA , 2003, 289(19):2560-71.

"Consensus Recommendations for the Management of Chronic Heart Failure. On Behalf of the Membership of the Advisory Council to Improve Outcomes Nationwide in Heart Failure," Am J Cardiol , 1999, 83(2A):1A-38A.

"Effect of Metoprolol CR/XL in Chronic Heart Failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)," Lancet , 1999, 353(9169):2001-7.

Gibbons RJ, Abrams J, Chatterjee K, et al, "ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina - Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina)," J Am Coll Cardiol , 2003, 41(1):159-68.

Herlitz J, Dellborg M, Karlson BW, et al, "Similar Risk Reducing Effect of Extended Release Metoprolol Once Daily and Immediate Release Metoprolol Twice Daily During 5 Years After Myocardial Infarction," Cardiovasc Drugs Ther , 1999 (in press).

Kukin ML, Kalman J, Charney RH, et al, "Prospective, Randomized Comparison of Effect of Long-Term Treatment With Metoprolol or Carvedilol on Symptoms, Exercise, Ejection Fraction, and Oxidative Stress in Heart Failure," Circulation , 1999, 99(2):2645-51.

Mokhlesi B, Leikin JB, Murray P, et al, "Adult Toxicology in Critical Care: Part II: Specific Poisonings," Chest , 2003, 123(3):897-922.

Waagstein F, Bristow MR, Swedberg K, et al, "Beneficial Effects of Metoprolol in Idiopathic Dilated Cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group," Lancet , 1993, 342(8885):1441-6.


International Brand Names

 Apo-Metoprolol® (CA, CZ); Azumetop® (DE); Beloc® (AR, AT, CH, CO, DE, TR); Beloc COR® (CH); Beloc ZOK® (CH, DE); Beloc-Zok® (TR); Beloken® (ES); Betaloc® (AU, CA, CO, CZ, GB, HK, HU, IE, IN, NZ, PL, RO, SG, TH); Betaloc CR® (NZ); Betaloc® Durules® (CA); Betaloc Durules® (CY, EG, JO, KW, LB, MT, SY); Betaloc SA® (GB); Betaloc Zok® (BG, CO, CZ, HK, HU, PL, RO, RU, SG); Betaprol® (RO); Betazok® (IE); Betoprolol® (CO); Bloxan® (CZ, HR, RO, SI); Cardeloc® (TH); Cardiosel® (ID); Cardoxone® (CY, JO); Cardoxone R® (TH); Corvitol® (RU); Denex® (SG); Dura-Zok® (DK); Egiloc® (RU); Egilok® (CZ, PL, RO); Huma-Metoprol® (HU); Jeprolol® (DE); Jutabloc® (DE); Lanoc® (AT); Lopresor® (AR, AT, AU, BE, CH, CL, CO, DE, ES, GB, ID, IE, IT, LU, MX, NL, NZ, PT, TR, ZA); Lopresor Divitabs® (IL); Lopresor OROS® (CH, IL, LU, NL, ZA); Lopresor SR® (GB); Lopressor® (AU, BR, CA, FR, NZ); Maintate® (ID); Melol® (TH); Meprolol® (DE, DO); Mepronet® (DK); Metblock® (FI); Meto AbZ® (DE); Meto APS® (DE); Metobeta® (DE); Meto Biochemie® (DE); Metoblock® (TH); Metocar® (DK); Metocard® (PL, RU); Metocor® (IE); Metodoc® (DE); Metodura® (DE); Meto-Hennig® (DE); Metohexal® (AT, AU, DE, LU, PL); Meto-Isis® (DE); Metok AbZ® (DE); Metolar® (IN); Metolol® (AT, AU, TH); MetoMed® (AT); Metomerck® (DE); Meto-phamos® (DE); Metophar® (BE); Metop® (IE); Metopress® (CH); Metopress Retard® (IL); Metoprogamma® (DE); Metoprolin® (FI); Metoprolol 1A Farma® (DK); Metoprolol 1A Pharma® (DE); Metoprolol acis® (DE); Metoprolol AL® (CZ, DE, RO); Metoprolol Apogepha® (DE); Metoprolol Atid® (DE); Metoprolol Basics® (DE); Metoprolol-BC (AU); Metoprolol-B® (HU); metoprolol-corax® (DE); Metoprolol® (CZ, DK, NO, PL, RO, YU); Metoprolol.d.a.v.i.d® (DE); Metoprolol Gea® (DK); Metoprolol GEA Retard® (SE); Metoprolol Genericon® (AT); Metoprolol-GRY® (DE); Metoprolol Heumann® (DE); Metoprolol KSK® (DE); Metoprolol Lindo® (DE); Metoprolol Merck® (CO); Metoprolol NOK Sandoz® (DE); Metoprololo EG® (IT); Metoprololo Hexan® (IT); Metoprolol PB® (DE); Metoprolol ratiopharm® (AT); Metoprolol-ratiopharm® (DE, HU, RU); Metoprolol Retard® (NO); Metoprolol-rpm® (LU); Metoprolol Sandoz® (DE); Metoprolol Stada® (AT, DE, TH); Metoprolol Tartrate® (GB); Metoprolol Verla® (DE); metoprolol von ct® (DE); Metoprolol-Wolff® (DE); Meto-Puren® (DE); Meto-Tablinen® (DE); Metotyrol® (AT); Metovim® (RO); Metozoc® (FI, NO); Minax® (AU, TH); Neobloc® (IL); Novo-Metoprolol (CA); Nu-Metop (CA); PMS-Metoprolol (CA); Prelis® (DE); Presolol® (YU); Proken M® (MX); Prolaken® (MX); Ritmetol® (HU); Ritmolol® [tabs] (MX); Selectadril® [tabs] (MX); Selokeen® (NL); Selokeen ZOC® (NL); Seloken® (AT, BE, BR, DK, ES, FI, FR, ID, IT, JP, MX, NO, SE); SelokenZOC® (FI, SE); Selopral® (FI); Selozok® (BE); Selo-Zok® (DK); Selozok® (FR, LU); Selo-Zok® (NO); Sigaprolol® (DE); Slow-Lopresor® (LU); Spesicor Dos® (FI); Spesicor® (FI); Toprol-XL® (CA); Vasocardin® (CZ, RO, RU)


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