Common side effects include trouble sleeping, feeling tired, feeling faint, and abdominal discomfort.[4] Large doses may cause serious toxicity.[5][6] Risk in pregnancy has not been ruled out.[4][7] It appears to be safe in breastfeeding.[8] The metabolism of metoprolol can vary widely among patients, often as a result of hepatic impairment[9]orCYP2D6 polymorphism.[10]
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.[21] β-blockers, including metoprolol, reduce salivary flow via inhibition of the direct sympathetic innervation of the salivary glands.[22][23] Metoprolol may also cause the hands and feet to feel cold.[24] 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.[25]
Patients should be cautious while driving or operating machinery due to its potential to cause decreased alertness.[26][21]
There may also be an impact on blood sugar levels and it can potentially mask signs of low blood sugar.[21]
The safety of metoprolol during pregnancy is not fully established.[27][28]
Metoprolol reduces long-term mortality and hospitalisation due to worsening heart failure.[29] A meta-analysis further supports reduced incidence of heart failure worsening in patients treated with beta-blockers compared to placebo.[30] 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.[31] Patients should monitor for swelling of extremities, fatigue, and shortness of breath.[32]
ACochrane Review concluded that although metoprolol reduces the risk of atrial fibrillation recurrence, it is unclear whether the long-term benefits outweigh the risks.[33]
This medicine may cause changes in blood sugar levels or cover up signs of low blood sugar, such as a rapid pulse rate.[32] It also may cause some people to become less alert than they are normally, making it dangerous for them to drive or use machines.[32]
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).[7] It appears to be safe in breastfeeding.[8]
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.[34][35][36]
Metoprolol exerts its effects by blocking the action of certain neurotransmitters, specifically adrenaline and noradrenaline. It does this by selectively binding to and antagonizing β-1 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 β-1 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 β-1 receptors. By occupying these receptor sites without activating them, metoprolol blocks or inhibits their activation by endogenous catecholamines like adrenaline or noradrenaline.[38]
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).[39][non-primary source needed] 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.[39][non-primary source needed]
Through this mechanism of selective blockade at beta-(β)-1 receptors, metoprolol exerts the following effects:
Heart rate reduction, i.e., decrease of the resting heart rate (negative chronotropic effect) and reduction of excessive elevations resulting from exercise or stress.[38]
Reduction of the force of contraction, i.e., decrease in contractility (negative inotropic effect), which lessens how hard each heartbeat contracts.[38]
Decrease in cardiac output, i.e., decrease in both heart rate and contractility within myocardium cells, where beta-(β)-1 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.[38]
Metoprolol is mostly absorbed from the intestine with an absorption fraction of 0.95. The systemic bioavailability after oral administration is approximately 50%.[38] 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.[38]
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.[38][40][10]
Metoprolol is classified as a moderately lipophilic beta blocker.[37] 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 neuropsychiatricside effects.[37] 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.[38]
Metoprolol was synthesized and its activity discovered in 1969.[12] 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).[41]
This section needs expansion with: a statement from secondary sources of the importance/relevance of this information. You can help by adding to it. (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:[42]
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$ 11million.[43][better source needed]
Because beta blockers can be used to reduce heart rate and minimize tremors, which can enhance performance in sports such as archery,[44][45] metoprolol is banned by the world anti-doping agency in some sports.[45]
^World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
^Geffner DL, Hershman JM (July 1992). "Beta-adrenergic blockade for the treatment of hyperthyroidism". The American Journal of Medicine. 93 (1): 61–68. doi:10.1016/0002-9343(92)90681-Z. PMID1352658.
^ abMorris J, Dunham A (2023). "Metoprolol". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID30422518.
^Costanzo L (2009). Physiology (3rd ed.). Saunders Elsevier. ISBN978-1416023203.
^Turner MD (April 2016). "Hyposalivation and Xerostomia: Etiology, Complications, and Medical Management". Dental Clinics of North America. 60 (2): 435–443. doi:10.1016/j.cden.2015.11.003. PMID27040294.
^"Metoprolol". Drugs and Lactation Database (LactMed®). Bethesda (MD): National Institute of Child Health and Human Development. 2006. PMID30000215.
^"Metoprolol". Drugs and Lactation Database (LactMed®). Bethesda (MD): National Institute of Child Health and Human Development. 1994. PMID35952115.
^Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, et al. (March 2000). "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". JAMA. 283 (10): 1295–1302. doi:10.1001/jama.283.10.1295. PMID10714728.
^Albers S, Elshoff JP, Völker C, Richter A, Läer S (April 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. PMID15484221.
^Baselt R (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 1023–1025.
^ abcdefghijZamir A, Hussain I, Ur Rehman A, Ashraf W, Imran I, Saeed H, et al. (August 2022). "Clinical Pharmacokinetics of Metoprolol: A Systematic Review". Clinical Pharmacokinetics. 61 (8): 1095–1114. doi:10.1007/s40262-022-01145-y. PMID35764772. S2CID250094483.
^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. PMID16176119. S2CID1570605.
^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, ISBN978-3946057109, S. 200.
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