Metoprolol

Metoprolol, sold under the brand name Lopressor, among others, is a selective β1 receptor blocker medication.[3] It is used to treat high blood pressure, chest pain due to poor blood flow to the heart, and a number of conditions involving an abnormally fast heart rate.[3] By working on the beta-1 receptor of the cardiac muscle cells, it yields both a chronotropic and inotropic effect. It is also used to prevent further heart problems after myocardial infarction and to prevent headaches in those with migraines.[3]

Metoprolol
Clinical data
Pronunciation/mɛˈtoʊproʊlɑːl/, /mɛtoʊˈproʊlɑːl/
Trade namesLopressor, Metolar XR, Toprol XL, others
AHFS/Drugs.comMonograph
MedlinePlusa682864
License data
Pregnancy
category
  • AU: C
Routes of
administration		By mouth, intravenous (IV)
Drug classBeta blocker
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability50% (single dose)[1]
70% (repeated administration)[2]
Protein binding12%
MetabolismLiver via CYP2D6, CYP3A4
Elimination half-life3–7 hours
ExcretionKidney
Identifiers
IUPAC name
  • (RS)-1-[4-(2-Methoxyethyl)phenoxy]-3-[(propan-2-yl)amino]propan-2-ol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.051.952
Chemical and physical data
FormulaC15H25NO3
Molar mass267.369 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
Melting point120 °C (248 °F)
  • O(c1ccc(cc1)CCOC)CC(O)CNC(C)C
  • InChI=1S/C15H25NO3/c1-12(2)16-10-14(17)11-19-15-6-4-13(5-7-15)8-9-18-3/h4-7,12,14,16-17H,8-11H2,1-3H3 Y
  • Key:IUBSYMUCCVWXPE-UHFFFAOYSA-N Y
  (verify)

Metoprolol is sold in formulations that can be taken by mouth or given intravenously.[3] The medication is often taken twice a day.[3] The extended-release formulation is taken once per day.[3] Metoprolol may be combined with hydrochlorothiazide (a diuretic) in a single tablet.[3]

Common side effects include trouble sleeping, feeling tired, feeling faint, and abdominal discomfort.[3] Large doses may cause serious toxicity.[4][5] Risk in pregnancy has not been ruled out.[3][6] It appears to be safe in breastfeeding.[7] The metabolism of metoprolol can vary widely between patients, often as a result of hepatic impairment[8] or CYP2D6 polymorphism.[9] Care should be taken in patients with asthma; metoprolol should only be used in these patients when the benefits outweigh the risks, for example in heart failure.[10] Stopping this drug should be done slowly to decrease the risk of further health problems.[3]

Metoprolol was first made in 1969, patented in 1970, and approved for medical use in 1982.[11][12] It is on the World Health Organization's List of Essential Medicines.[13] It is available as a generic drug.[3] In 2020, it was the sixth most commonly prescribed medication in the United States, with more than 66 million prescriptions.[14][15]

Medical uses

Metoprolol is used for a number of conditions, including hypertension, angina, acute myocardial infarction, supraventricular tachycardia, ventricular tachycardia, congestive heart failure, and prevention of migraine headaches.[3] It is an adjunct in the treatment of hyperthyroidism.[16]

The different salt versions of metoprolol – metoprolol tartrate and metoprolol succinate – are approved for different conditions and are not interchangeable.[17][18][19]

Off-label uses include supraventricular tachycardia and thyroid storm.[20]

Available forms

Metoprolol is sold in formulations that can be taken by mouth or given intravenously.[3] The medication is often taken twice a day.[3] The extended-release formulation is taken once a day.[3] Metoprolol may be combined with hydrochlorothiazide (a diuretic) in a single tablet.[3]

Adverse effects

Adverse effects, especially with higher doses, include dizziness, drowsiness, fatigue, diarrhea, unusual dreams, trouble sleeping, depression, and vision problems. β-blockers, including metoprolol, reduce salivary flow via inhibition of the direct sympathetic innervation of the salivary glands.[21][22] Metoprolol may also cause the hands and feet to feel cold.[23] 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.[24]

Serious side effects that are advised to be reported immediately include symptoms of bradycardia (resting heart rate slower than 60 beats per minute), persistent symptoms of dizziness, fainting and unusual fatigue, bluish discoloration of the fingers and toes and/or lips, numbness/tingling/swelling of the hands or feet, sexual dysfunction, erectile dysfunction, hair loss, mental/mood changes, depression, breathing difficulty, cough, dyslipidemia and increased thirst. Consuming alcohol while taking metoprolol may cause mild body rashes and is not advised.[20]

Precautions

It’s well documented that metoprolol reduces long-term mortality and hospitalisation due to worsening heart failure.[25] A meta-analysis further supports reduced incidence of heart failure worsening in patients treated with beta-blockers compared to placebo.[26] 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.[27] Patients should monitor for swelling of extremities, fatigue, and shortness of breath.[28]

This medicine may cause changes in blood sugar levels or cover up signs of low blood sugar, such as a rapid pulse rate.[28] It also may cause some people to become less alert than they are normally, making it dangerous for them to drive or use machines.[28]

Greater care is required with use in those with liver problems or asthma.[3] Stopping this drug should be done slowly to decrease the risk of further health problems.[3]

Pregnancy and breastfeeding

Risk for the fetus has not been ruled out, per being rated pregnancy category C in the United States.[3][6] Metoprolol is category C in Australia, meaning that it may be suspected of causing harmful effects on the human fetus (but no malformations).[6] It appears to be safe in breastfeeding.[7]

Overdose

Excessive doses of metoprolol can cause severe hypotension, bradycardia, 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.[29][30][31]

Pharmacology

General pharmacological principles of metoprolol:

  • beta-1 selective
  • moderately lipophilic
  • without intrinsic sympathomimetic activity
  • with weak membrane stabilizing activity
  • decreases heart rate, contractility, and cardiac output, therefore decreasing blood pressure

Mechanism of action

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).[32] 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.[32]

Pharmacokinetics

It undergoes α-hydroxylation and O-demethylation as a substrate of the cytochrome liver enzymes CYP2D6.[33][34]

Chemistry

The active substance metoprolol is employed either as metoprolol succinate or as metoprolol tartrate (where 100 mg metoprolol tartrate corresponds to 95 mg metoprolol succinate). The tartrate is an immediate-release formulation and the succinate is an extended-release formulation.[35]

Stereochemistry

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:[36]

Enantiomers of metoprolol

CAS-Nummer: 81024-43-3
CAS-Nummer: 81024-42-2

Metoprolol was discovered in 1969 by Bengt Ablad and Enar Carlsson.[11] Within the UK it is classified as a prescription-only drug in the beta blocker class and is regulated by the Medicines and Healthcare products Regulatory Agency (MHRA). The MHRA is a government body set up in 2003 and is responsible for regulating medicines, medical devices, and equipment used in healthcare. The MHRA acknowledges that no product is completely risk free but takes into account research and evidence to ensure that any risks associated are minimal.[37]

The use of beta blockers such as metoprolol was approved in the U.S. by the Food and Drug Administration (FDA) in 1967. The FDA has approved beta blockers for the treatment of cardiac arrhythmias, hypertension, migraines, and others. Prescribers may choose to prescribe beta blockers for other treatments if there is just cause even though it is not approved by the FDA. Drug manufacturers, however, are unable to advertise beta blockers for other purposes that have not been approved by the FDA. Since the FDA does not regulate the practice of medicine after the drug has been approved, it is legal to prescribe beta blockers for other treatments such as performance anxiety.[38]

Legislation

On 23 September 2011, the Medicines and Healthcare products Regulatory Agency (MHRA) granted the Intas Pharmaceuticals Limited marketing authorization (licences) for metoprolol tartrate (50 mg and 100 mg tablets) for medicinal prescription only; this was after it was established that there were no new or unexpected safety concerns and that the benefits of metoprolol tartrate were greater than the risks.[39] Metoprolol tartrate is a generic version of Lopressor, which was licensed and authorized on 6 June 1997 to Novartis Pharmaceuticals.[40]

In sport

Because beta blockers can be used to reduce heart rate and minimize tremors, which can enhance performance in sports such as archery,[41][42] Metoprolol is banned by the world anti-doping agency in some sports. Some bans, as in all forms of billiards, darts, and golf, apply during competition only. In others, such as riflery competition, any form of beta blocker is banned by the National Collegiate Athletic Association.[43]

Urine tests are used to detect if beta blockers are present. Uncharged drugs and/or metabolites of beta blockers can be analysed by gas chromatography-mass spectrometry in selected ion monitoring (GC-MS-SIM). However, in modern times it is increasingly difficult to detect the presence of beta blockers used for sports doping purposes. A disadvantage to using GC-MS-SIM is that prior knowledge of the molecular structure of the target drugs/metabolites is required. Modern times have shown a variance in structures and hence novel beta blockers can go undetected.[44]

Lawsuit

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 such action by the pharmaceutical companies AstraZeneca AB, AstraZeneca LP, AstraZeneca Pharmaceuticals LP, and Aktiebolaget Hassle violated antitrust and consumer protection law. A settlement was reached in 2012, with the above manufacturers paying out $11 million in damages.[45]

Environmental presence

In 2021, metoprolol was one of the 12 compounds identified in sludge samples taken from 12 wastewater treatment plants in California that were associated with estrogenic activity in in vitro.[46]

References
  1. "Metolar 25/50 (metoprolol tartrate) tablet" (PDF). Food and Drug Administration (FDA). Archived (PDF) from the original on 3 March 2016. Retrieved 5 May 2015.
  2. Jasek, W, ed. (2007). Austria-Codex (in German) (62nd ed.). Vienna: Österreichischer Apothekerverlag. pp. 916–919. ISBN 978-3852001814.
  3. "Metoprolol". The American Society of Health-System Pharmacists. Archived from the original on 12 March 2014. Retrieved 21 April 2014.
  4. Pillay VV (2012). "Diuretics, Antihypertensives, and Antiarrhythmics". Modern Medical Toxicology. Jaypee Brothers Publishers. p. 303. ISBN 978-9350259658. Archived from the original on 7 July 2017.
  5. Marx JA (2014). "Chapter 152: Cardiovascular Drugs". Rosen's emergency medicine : concepts and clinical practice (8th ed.). Philadelphia, PA: Elsevier/Saunders. ISBN 978-1455706051.
  6. "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. Archived from the original on 8 April 2014. Retrieved 22 April 2014.
  7. Medical Toxicology. Lippincott Williams & Wilkins. 2004. p. 684. ISBN 978-0781728454. Archived from the original on 7 July 2017.
  8. Regardh C, Jordo L, Ervik M, Lundborg P, Olsson R, Ronn O. "Pharmacokinetics of metoprolol in patients with hepatic cirrhosis." Clinical Pharmacokinetics. 1981: 6; 375–388.
  9. Blake C, Kharasch E, Schwab M, Nagele P. "A meta-analysis of CYP2D6 metabolizer phenotype and metoprolol pharmacokinetics". Clinical Pharmacology and Therapeutics. 2013: 94(3); 394–399
  10. Timothy H, Wallace J, Soberman J. "Cardioselective beta-blocker treatment of hypertension in patients with asthma: when do benefits outweigh risks?" Journal of Asthma. 2012: 49(9); 947–951
  11. Carlsson B, ed. (1997). Technological systems and industrial dynamics. Dordrecht: Kluwer Academic. p. 106. ISBN 978-0792399728. Archived from the original on 3 March 2017.
  12. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 461. ISBN 978-3527607495.
  13. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  14. "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  15. "Metoprolol – Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  16. Geffner DL, Hershman JM (July 1992). "Beta-adrenergic blockade for the treatment of hyperthyroidism". Am. J. Med. 93 (1): 61–68. doi:10.1016/0002-9343(92)90681-Z. PMID 1352658.
  17. "Metoprolol vs Toprol-XL Comparison". Drugs.com. 1 August 2019. Retrieved 24 September 2019.
  18. "Metoprolol Tartrate vs. Metoprolol Succinate: A Comparison". Healthline. 28 February 2018. Archived from the original on 25 September 2019. Retrieved 24 September 2019.
  19. Eske J (25 September 2019). "Metoprolol tartrate vs. succinate: Differences in uses and effects". Medical News Today. Archived from the original on 25 September 2019. Retrieved 24 September 2019.
  20. Morris J, Dunham A (2020). "Metoprolol". Statpearls. PMID 30422518.
  21. Costanzo L (2009). Physiology (3rd ed.). Saunders Elsevier. ISBN 978-1416023203.
  22. Turner MD (April 2016). "Hyposalivation and Xerostomia: Etiology, Complications, and Medical Management". Dent. Clin. North Am. 60 (2): 435–443. doi:10.1016/j.cden.2015.11.003. PMID 27040294.
  23. "Metoprolol". Drugs.com. Archived from the original on 21 January 2010.
  24. Cruickshank JM (2010). "Beta-blockers and heart failure". Indian Heart Journal. 62 (2): 101–110. PMID 21180298.
  25. Hjalmarson Å, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, et al. "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)". JAMA 2000;283(10):1295–1302.
  26. Barron AJ, Zaman N, Cole GD, Wensel R, Okonko DO, Francis DP. "Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: Recommendations for patient information". International Journal of Cardiology 2013;168(4):3572–3579.
  27. Gottlieb SS, Fisher ML, Kjekshus J, Deedwania P, Gullestad L, Vitovec J, et al. "Tolerability of B-Blocker Initiation and Titration in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF)". Circulation 2002;105(10):1182–1188.
  28. "Metoprolol (Oral Route) Precautions". Drug Information. Mayo Clinic. Archived from the original on 16 April 2009.
  29. Page C, Hacket LP, Isbister GK (2009). "The use of high-dose insulin-glucose euglycemia in beta-blocker overdose: a case report". Journal of Medical Toxicology. 5 (3): 139–143. doi:10.1007/bf03161225. PMC 3550395. PMID 19655287.
  30. Albers S, Elshoff JP, Völker C, Richter A, Läer S (2005). "HPLC quantification of metoprolol with solid-phase extraction for the drug monitoring of pediatric patients". Biomedical Chromatography. 19 (3): 202–207. doi:10.1002/bmc.436. PMID 15484221.
  31. Baselt R (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 1023–1025.
  32. Suita K, Fujita T, Hasegawa N, Cai W, Jin H, Hidaka Y, et al. (23 July 2015). "Norepinephrine-Induced Adrenergic Activation Strikingly Increased the Atrial Fibrillation Duration through β1- and α1-Adrenergic Receptor-Mediated Signaling in Mice". PLOS ONE. 10 (7): e0133664. Bibcode:2015PLoSO..1033664S. doi:10.1371/journal.pone.0133664. PMC 4512675. PMID 26203906.
  33. Swaisland HC, Ranson M, Smith RP, Leadbetter J, Laight A, McKillop D, Wild MJ (2005). "Pharmacokinetic drug interactions of gefitinib with rifampicin, itraconazole and metoprolol". Clinical Pharmacokinetics. 44 (10): 1067–1081. doi:10.2165/00003088-200544100-00005. PMID 16176119. S2CID 1570605.
  34. Blake CM, Kharasch ED, Schwab M, Nagele P (September 2013). "A meta-analysis of CYP2D6 metabolizer phenotype and metoprolol pharmacokinetics". Clin Pharmacol Ther. 94 (3): 394–399. doi:10.1038/clpt.2013.96. PMC 3818912. PMID 23665868.
  35. Cupp M (2009). "Alternatives for Metoprolol Succinate" (PDF). Pharmacist's Letter / Prescriber's Letter. 25 (250302). Retrieved 6 July 2012.
  36. 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.
  37. The Medicines and Healthcare products Regulatory Agency (2018). Medicines & Medical Devices Regulation. London, pp. 1–24.
  38. Engelke LC, Ewell TB (2011). "The Ethics and Legality of Beta Blockers for Performance Anxiety: What Every Educator Should Know". College Music Symposium. 51. doi:10.18177/sym.2011.51.sr.18. ISSN 2330-2011. JSTOR 26513061.
  39. "PAR Metoprolol Tartrate 50 mg and 100 mg tablets" (PDF). Medicines and Healthcare products Regulatory Agency (MHRA). PL 30139/0017-18; UK/H/4414/001-2/DC.
  40. "UKPAR Metoprolol Tartrate 50 mg and 100 mg Film-coated Tablets" (PDF). Medicines and Healthcare products Regulatory Agency (MHRA). PL 17907/0129-30.
  41. Hughes D (October 2015). "The World Anti-Doping Code in sport: Update for 2015". Aust Prescr. 38 (5): 167–170. doi:10.18773/austprescr.2015.059. PMC 4657305. PMID 26648655.
  42. World Anti-Doping Agency (2017). Prohibited List. Montreal: WADA's Executive Committee.
  43. Barnes KP, Rainbow CR (September 2013). "Update on banned substances 2013". Sports Health. 5 (5): 442–447. doi:10.1177/1941738113478546. PMC 3752189. PMID 24427415.
  44. Politi L, Groppi A, Polettini A (2005). "Applications of liquid chromatography-mass spectrometry in doping control". J Anal Toxicol. 29 (1): 1–14. doi:10.1093/jat/29.1.1. PMID 15808007.
  45. "$11 Million Settlement Reached in Lawsuit Involving the Heart Medication, Toprol XL®, and its generic equivalent, metoprolol succinate". www.prnewswire.com.
  46. Black GP (2021). "Using Estrogenic Activity and Nontargeted Chemical Analysis to Identify Contaminants in Sewage Sludge". Environmental Science & Technology. 55 (10): 6729–6739. Bibcode:2021EnST...55.6729B. doi:10.1021/acs.est.0c07846. PMC 8378343. PMID 33909413.

Further reading
  • "Metoprolol". Drug Information Portal. U.S. National Library of Medicine.
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