Metoprolol, sold under the brand names Lopressor and Toprol-XL among others, is a medication used to treat angina, Hypertension and a number of conditions involving an Tachyarrhythmia.[ It is also used to prevent further heart problems after myocardial infarction and to prevent headaches in those with .][ It is a beta blocker, specifically a selective β1 receptor blocker, and is taken by mouth or is given intravenously.][
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Common side effects include trouble sleeping, feeling tired, feeling faint, and abdominal discomfort.[ Large doses may cause serious toxicity.]
Metoprolol was first made in 1969, patented in 1970, and approved for medical use in 1978.[ In 2022, it was the sixth most commonly prescribed medication in the United States, with more than 65million prescriptions.]
Medical uses
Metoprolol is used for a number of conditions, including angina, acute myocardial infarction, Hypertension, supraventricular tachycardia, ventricular tachycardia, congestive heart failure, and prevention of migraine headaches.[ It is an adjunct in the treatment of hyperthyroidism.]
Off-label uses include supraventricular tachycardia and thyroid storm.
Adverse effects
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.
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.
Precautions
Metoprolol reduces long-term mortality and hospitalisation due to worsening heart failure.
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.
This medicine may cause changes in blood sugar levels or cover up signs of low blood sugar, such as a rapid pulse rate.
Pregnancy and breastfeeding
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).
Overdose
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.
Pharmacology
Mechanism of action
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 Neurotransmitter, specifically adrenaline and Norepinephrine. 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 gland, 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 Kidney. 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 cardiomyocytes, 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).
Through this mechanism of selective blockade at β1 receptors, metoprolol exerts the following effects:
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Heart rate reduction, i.e., decrease of the resting heart rate (negative chronotropic effect) and reduction of excessive elevations resulting from exercise or stress.
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Reduction of the force of contraction, i.e., decrease in contractility (negative inotropic effect), which lessens how hard each heartbeat contracts.
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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.
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Lowering of blood pressure.
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Antiarrhythmic effects, such as supraventricular tachycardia prevention. Metoprolol also prevents electrical wave propagation.
Pharmacokinetics
Metoprolol is mostly absorbed from the intestine with an absorption fraction of 0.95. The systemic bioavailability after oral administration is approximately 50%.
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 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.
Chemistry
The experimental log P of metoprolol is 1.6 to 2.15.
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:[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, , S. 200.]
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CAS-Number: 81024-43-3 |
CAS-Number: 81024-42-2 |
Formulations
Metoprolol was synthesized and its activity discovered in 1969.
Metoprolol tartrate was first developed by Novartis and this dosage form received approval in the US in 1978.[Curt H. Appelgren, Eva C. Eskilsson US Patent 5081154A, Metoprolol succinate]
Society and culture
Legal status
Metoprolol was approved for medical use in the United States in August 1978.
Economics
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.
Sports
Because beta blockers can be used to reduce heart rate and minimize tremors, which can enhance performance in sports such as archery,
Further reading
