Metoprolol

Metoprolol is used for a number of conditions, including angina, acute myocardial infarction, high blood pressure, supraventricular tachycardia, ventricular tachycardia, congestive heart failure, and prevention of migraine headaches. It is an adjunct in the treatment of hyperthyroidism.{{cite journal | vauthors = Geffner DL, Hershman JM | title = Beta-adrenergic blockade for the treatment of hyperthyroidism | journal = The American Journal of Medicine | volume = 93 | issue = 1 | pages = 61–68 | date = July 1992 | pmid = 1352658 | doi = 10.1016/0002-9343(92)90681-Z }} Both oral and intravenous forms of metoprolol are available for administration.{{cite book | vauthors = Morris J, Dunham A | chapter = Metoprolol | title = StatPearls | location = Treasure Island (FL) | publisher = StatPearls Publishing |date=2023 |pmid=30422518 }} The different salt versions of metoprolol – metoprolol tartrate and metoprolol succinate – are approved for different conditions and are not interchangeable.{{cite web | title=Metoprolol vs Toprol-XL Comparison | website=Drugs.com | date=1 August 2019 | url=https://www.drugs.com/compare/metoprolol-vs-toprol-xl | access-date=24 September 2019}}{{cite web | vauthors = Eske J | title=Metoprolol tartrate vs. succinate: Differences in uses and effects | website=Medical News Today | date=25 September 2019 | url= https://www.medicalnewstoday.com/articles/324175.php | archive-url=https://web.archive.org/web/20190925030141/https://www.medicalnewstoday.com/articles/324175.php | archive-date=25 September 2019 | url-status=live | access-date=24 September 2019}}

Off-label uses include supraventricular tachycardia and thyroid storm.

Adverse effects, especially with higher doses, include dizziness, drowsiness, fatigue, diarrhea, unusual dreams, trouble sleeping, depression, and vision problems such as blurred vision or dry eyes. β-blockers, including metoprolol, reduce salivary flow via inhibition of the direct sympathetic innervation of the salivary glands.{{cite book | vauthors = Costanzo L | title = Physiology | edition = 3rd | publisher = Saunders Elsevier | year = 2009 | isbn = 978-1416023203 }}{{cite journal | vauthors = Turner MD | title = Hyposalivation and Xerostomia: Etiology, Complications, and Medical Management | journal = Dental Clinics of North America | volume = 60 | issue = 2 | pages = 435–443 | date = April 2016 | pmid = 27040294 | doi = 10.1016/j.cden.2015.11.003 }} Metoprolol may also cause the hands and feet to feel cold.{{ cite web | url = https://www.drugs.com/metoprolol.html | title = Metoprolol | publisher = Drugs.com | url-status = live | archive-url = https://web.archive.org/web/20100121160415/http://www.drugs.com/metoprolol.html | archive-date = 21 January 2010 | df=dmy-all }} Due to the high penetration across the blood–brain barrier, lipophilic beta blockers such as propranolol and metoprolol are more likely than other less lipophilic beta blockers to cause sleep disturbances such as insomnia, vivid dreams and nightmares.{{cite journal | vauthors = Cruickshank JM | title = Beta-blockers and heart failure | journal = Indian Heart Journal | volume = 62 | issue = 2 | pages = 101–110 | year = 2010 | pmid = 21180298 }} Patients should be cautious while driving or operating machinery due to its potential to cause decreased alertness.{{cite web|url=https://www.nhs.uk/medicines/metoprolol/common-questions-about-metoprolol/|title=Common questions about metoprolol | work = National Health Service (NHS) |date=15 March 2022 }}{{cite web |url=https://www.mayoclinic.org/drugs-supplements/metoprolol-oral-route/precautions/drg-20071141|title=Metoprolol (Oral Route)|website=Mayo Clinic }}

There may also be an impact on blood sugar levels, and it can potentially mask signs of low blood sugar.

The safety of metoprolol during pregnancy is not fully established.{{cite book|pmid=30000215| chapter = Metoprolol|date=2006 |title = Drugs and Lactation Database (LactMed®) | location = Bethesda (MD) | publisher = National Institute of Child Health and Human Development }}{{cite book|pmid=35952115| chapter = Metoprolol|date=1994 |title = Drugs and Lactation Database (LactMed®) | location = Bethesda (MD) | publisher = National Institute of Child Health and Human Development}}

Metoprolol reduces long-term mortality and hospitalisation due to worsening heart failure.{{cite journal | vauthors = Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, Wikstrand J, El Allaf D, Vítovec J, Aldershvile J, Halinen M, Dietz R, Neuhaus KL, Jánosi A, Thorgeirsson G, Dunselman PH, Gullestad L, Kuch J, Herlitz J, Rickenbacher P, Ball S, Gottlieb S, Deedwania P | display-authors = 6 | title = Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group | journal = JAMA | volume = 283 | issue = 10 | pages = 1295–1302 | date = March 2000 | pmid = 10714728 | doi = 10.1001/jama.283.10.1295 }} A meta-analysis further supports reduced incidence of heart failure worsening in patients treated with beta-blockers compared to placebo.{{cite journal | vauthors = Barron AJ, Zaman N, Cole GD, Wensel R, Okonko DO, Francis DP | title = Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: recommendations for patient information | journal = International Journal of Cardiology | volume = 168 | issue = 4 | pages = 3572–3579 | date = October 2013 | pmid = 23796325 | pmc = 3819624 | doi = 10.1016/j.ijcard.2013.05.068 }} However, in some circumstances, particularly when initiating metoprolol in patients with more symptomatic disease, an increased prevalence of hospitalisation and mortality has been reported within the first two months of starting.{{cite journal | vauthors = Gottlieb SS, Fisher ML, Kjekshus J, Deedwania P, Gullestad L, Vitovec J, Wikstrand J | title = Tolerability of beta-blocker initiation and titration in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) | journal = Circulation | volume = 105 | issue = 10 | pages = 1182–1188 | date = March 2002 | pmid = 11889011 | doi = 10.1161/hc1002.105180 | s2cid = 24119608 | collaboration = John Wikstrand; MERIT-HF Investigators }} Patients should monitor for swelling of extremities, fatigue, and shortness of breath.{{ cite web | publisher = Mayo Clinic | work = Drug Information | url = http://www.mayoclinic.com/health/drug-information/DR602483/DSECTION=precautions- | title = Metoprolol (Oral Route) Precautions | url-status = live | archive-url = https://web.archive.org/web/20090416020036/http://www.mayoclinic.com/health/drug-information/DR602483/DSECTION%3Dprecautions- | archive-date = 16 April 2009 }}

A Cochrane Review concluded that although metoprolol reduces the risk of atrial fibrillation recurrence, it is unclear whether the long-term benefits outweigh the risks.{{cite journal | vauthors = Lafuente-Lafuente C, Valembois L, Bergmann J, Belmin J | title= Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation | journal= The Cochrane Database of Systematic Reviews | issue=3 | pages=CD005049 | year=2015 | doi= 10.1002/14651858.CD005049.pub4 | pmid=25820938}}

This medicine may cause changes in blood sugar levels or cover up signs of low blood sugar, such as a rapid pulse rate. It also may cause some people to become less alert than they are normally, making it dangerous for them to drive or use machines.

Risk for the fetus has not been ruled out, per being rated pregnancy category C in Australia, meaning that it may be suspected of causing harmful effects on the human fetus (but no malformations). It appears to be safe in breastfeeding.

Excessive doses of metoprolol can cause bradycardia, hypotension, metabolic acidosis, seizures, and cardiorespiratory arrest. Blood or plasma concentrations may be measured to confirm a diagnosis of overdose or poisoning in hospitalized patients or to assist in a medicolegal death investigation. Plasma levels are usually less than 200 μg/L during therapeutic administration, but can range from 1–20 mg/L in overdose victims.{{cite journal | vauthors = Page C, Hacket LP, Isbister GK | title = The use of high-dose insulin-glucose euglycemia in beta-blocker overdose: a case report | journal = Journal of Medical Toxicology | volume = 5 | issue = 3 | pages = 139–143 | date = September 2009 | pmid = 19655287 | pmc = 3550395 | doi = 10.1007/bf03161225 }}{{cite journal | vauthors = Albers S, Elshoff JP, Völker C, Richter A, Läer S | title = HPLC quantification of metoprolol with solid-phase extraction for the drug monitoring of pediatric patients | journal = Biomedical Chromatography | volume = 19 | issue = 3 | pages = 202–207 | date = April 2005 | pmid = 15484221 | doi = 10.1002/bmc.436 }}{{ cite book | vauthors = Baselt R | title = Disposition of Toxic Drugs and Chemicals in Man | edition = 8th | publisher = Biomedical Publications | location = Foster City, CA | year = 2008 | pages = 1023–1025 }}

Metoprolol is a beta blocker, or an antagonist of the β-adrenergic receptors. It is specifically a selective antagonist of the β₁-adrenergic receptor and has no intrinsic sympathomimetic activity.

Metoprolol exerts its effects by blocking the action of certain neurotransmitters, specifically adrenaline and noradrenaline. It does this by selectively binding to and antagonizing β₁ adrenergic receptors in the body. When adrenaline (epinephrine) or noradrenaline (norepinephrine) are released from nerve endings or secreted by the adrenal glands, they bind to β₁ adrenergic receptors found primarily in cardiac tissues such as the heart. This binding activates these receptors, leading to various physiological responses, including an increase in heart rate, force of contraction (inotropic effect), conduction speed through electrical pathways in the heart, and release of renin from the kidneys. Metoprolol competes with adrenaline and noradrenaline for binding sites on these β₁ receptors. By occupying these receptor sites without activating them, metoprolol blocks or inhibits their activation by endogenous catecholamines like adrenaline or noradrenaline.

Metoprolol blocks β₁-adrenergic receptors in heart muscle cells, thereby decreasing the slope of phase 4 in the nodal action potential (reducing Na⁺ uptake) and prolonging repolarization of phase 3 (slowing down K⁺ release).{{cite journal | vauthors = Suita K, Fujita T, Hasegawa N, Cai W, Jin H, Hidaka Y, Prajapati R, Umemura M, Yokoyama U, Sato M, Okumura S, Ishikawa Y | display-authors = 6 | title = Norepinephrine-Induced Adrenergic Activation Strikingly Increased the Atrial Fibrillation Duration through β1- and α1-Adrenergic Receptor-Mediated Signaling in Mice | journal = PLOS ONE | volume = 10 | issue = 7 | pages = e0133664 | date = 23 July 2015 | pmid = 26203906 | pmc = 4512675 | doi = 10.1371/journal.pone.0133664 | doi-access = free | bibcode = 2015PLoSO..1033664S }}{{primary source inline|date = November 2022}} It also suppresses the norepinephrine-induced increase in the sarcoplasmic reticulum (SR) Ca²⁺ leak and the spontaneous SR Ca²⁺ release, which are the major triggers for atrial fibrillation.{{primary source inline|date = November 2022}}

Through this mechanism of selective blockade at β₁ receptors, metoprolol exerts the following effects:

1. Heart rate reduction, i.e., decrease of the resting heart rate (negative chronotropic effect) and reduction of excessive elevations resulting from exercise or stress.
2. Reduction of the force of contraction, i.e., decrease in contractility (negative inotropic effect), which lessens how hard each heartbeat contracts.
3. Decrease in cardiac output, i.e., decrease in both heart rate and contractility within myocardium cells, where β₁ is predominantly located, overall blood output per minute lowers called cardiac output/dysfunction, allowing decreased demands placed onto impaired hearts, reducing oxygen demand-supply mismatch.
4. Lowering of blood pressure.
5. Antiarrhythmic effects, such as supraventricular tachycardia prevention. Metoprolol also prevents electrical wave propagation.

Metoprolol is mostly absorbed from the intestine with an absorption fraction of 0.95. The systemic bioavailability after oral administration is approximately 50%. Less than 5% of an orally administered dose of metoprolol is excreted unchanged in urine; most of it is eliminated in metabolized form through feces via bile secretion into the intestines.

Metoprolol undergoes extensive metabolism in the liver, mainly α-hydroxylation and O-demethylation through various cytochrome P450 enzymes such as CYP2D6 (primary), CYP3A4, CYP2B6, and CYP2C9. The primary metabolites formed are α-hydroxymetoprolol and O-demethylmetoprolol.{{cite journal | vauthors = Zamir A, Hussain I, Ur Rehman A, Ashraf W, Imran I, Saeed H, Majeed A, Alqahtani F, Rasool MF | display-authors = 6 | title = Clinical Pharmacokinetics of Metoprolol: A Systematic Review | journal = Clinical Pharmacokinetics | volume = 61 | issue = 8 | pages = 1095–1114 | date = August 2022 | pmid = 35764772 | doi = 10.1007/s40262-022-01145-y | s2cid = 250094483 }}{{cite journal | vauthors = Swaisland HC, Ranson M, Smith RP, Leadbetter J, Laight A, McKillop D, Wild MJ | title = Pharmacokinetic drug interactions of gefitinib with rifampicin, itraconazole and metoprolol | journal = Clinical Pharmacokinetics | volume = 44 | issue = 10 | pages = 1067–1081 | year = 2005 | pmid = 16176119 | doi = 10.2165/00003088-200544100-00005 | s2cid = 1570605 }}

Metoprolol is classified as a moderately lipophilic beta blocker.{{cite journal | vauthors = Cojocariu SA, Maștaleru A, Sascău RA, Stătescu C, Mitu F, Leon-Constantin MM | title = Neuropsychiatric Consequences of Lipophilic Beta-Blockers | journal = Medicina | volume = 57 | issue = 2 | page = 155 | date = February 2021 | pmid = 33572109 | pmc = 7914867 | doi = 10.3390/medicina57020155 | doi-access = free }} More lipophilic beta blockers tend to cross the blood–brain barrier more readily, with greater potential for effects in the central nervous system as well as associated neuropsychiatric side effects. Metoprolol binds mainly to human serum albumin with an unbound fraction of 0.88. It has a large volume of distribution at steady state (3.2 L/kg), indicating extensive distribution throughout the body.

Metoprolol was synthesized and its activity discovered in 1969. The specific agent in on-market formulations of metoprolol is either metoprolol tartrate or metoprolol succinate, where tartrate is an immediate-release formulation and the succinate is an extended-release formulation (with 100 mg metoprolol tartrate corresponding to 95 mg metoprolol succinate).{{cite journal | vauthors = Cupp M | title = Alternatives for Metoprolol Succinate | journal = Pharmacist's Letter / Prescriber's Letter | year = 2009 | volume = 25 | issue = 250302 | url = http://www.ncbop.org/PDF/MetoprololShortageMarch2009.pdf | access-date = 6 July 2012 | archive-date = 20 September 2016 | archive-url = https://web.archive.org/web/20160920200624/http://www.ncbop.org/PDF/MetoprololShortageMarch2009.pdf | url-status = dead }}

{{expand section | with = a statement from secondary sources of the importance/relevance of this information | small = no | date = November 2022}}

Metoprolol contains a stereocenter and consists of two enantiomers. This is a racemate, i.e. a 1:1 mixture of (R)- and the (S)-form:Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, {{ISBN|978-3946057109}}, S. 200.

Metoprolol was approved for medical use in the United States in August 1978.{{cite web | title=Lopressor: FDA-Approved Drugs | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=017963 | access-date=20 June 2023}}

In the 2000s, a lawsuit was brought against the manufacturers of Toprol XL (a time-release formula version of metoprolol) and its generic equivalent (metoprolol succinate) claiming that to increase profits, lower cost generic versions of Toprol XL were intentionally kept off the market. It alleged that the pharmaceutical companies AstraZeneca AB, AstraZeneca LP, AstraZeneca Pharmaceuticals LP, and Aktiebolaget Hassle violated antitrust and consumer protection law. In a settlement by the companies in 2012, without admission to the claims, they agreed to a settlement pay-out of US$ 11{{nbsp}}million.{{cite press release |title=$11 Million Settlement Reached in Lawsuit Involving the Heart Medication, Toprol XL, and its generic equivalent, metoprolol succinate |url=https://www.prnewswire.com/news-releases/11-million-settlement-reached-in-lawsuit-involving-the-heart-medication-toprol-xl-and-its-generic-equivalent-metoprolol-succinate-177848501.html |website=www.prnewswire.com }}{{better source|date = November 2022}}

Because beta blockers can be used to reduce heart rate and minimize tremors, which can enhance performance in sports such as archery,{{cite journal | vauthors = Hughes D | title = The World Anti-Doping Code in sport: Update for 2015 | journal = Australian Prescriber | volume = 38 | issue = 5 | pages = 167–170 | date = October 2015 | pmid = 26648655 | pmc = 4657305 | doi = 10.18773/austprescr.2015.059 }}{{cite web | title=The Prohibited List | website=World Anti Doping Agency | date=3 January 2023 | url=https://www.wada-ama.org/en/prohibited-list | access-date=20 June 2023}} metoprolol is banned by the world anti-doping agency in some sports.

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• {{cite book | title=Medical Genetics Summaries | chapter=Metoprolol Therapy and CYP2D6 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK425389/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=National Center for Biotechnology Information (NCBI) | year=2017 | pmid=28520381 | id=Bookshelf ID: NBK425389 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }}

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