Metoprolol

Last updated

Metoprolol
Metoprolol structure.svg
Metoprolol ball-and-stick.png
Clinical data
Pronunciation /mɛˈtoʊproʊlɑːl/ , /mɛtoʊˈproʊlɑːl/
Trade names Lopressor, Metolar XR, Toprol XL, others
AHFS/Drugs.com Monograph
MedlinePlus a682864
License data
Pregnancy
category
  • AU:C
Routes of
administration 		By mouth, intravenous
Drug class Beta blocker
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 50% (single dose) [2]
70% (repeated administration) [3]
Protein binding 12%
Metabolism Liver via CYP2D6, CYP3A4
Elimination half-life 3–7 hours
Excretion Kidney
Identifiers
  • (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 InfoCard 100.051.952 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C15H25NO3
Molar mass 267.369 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
Melting point 120 °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 Yes check.svgY
  • Key:IUBSYMUCCVWXPE-UHFFFAOYSA-N Yes check.svgY
   (verify)

Metoprolol, sold under the brand name Lopressor among others, is a medication used to treat high blood pressure, angina, and a number of conditions involving an abnormally fast heart rate. [4] It is also used to prevent further heart problems after myocardial infarction and to prevent headaches in those with migraines. [4] It is a selective β1 receptor blocker medication. [4] It is taken by mouth or is given intravenously. [4]

Contents

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] or CYP2D6 polymorphism. [10]

Metoprolol was first made in 1969, patented in 1970, and approved for medical use in 1978. [11] [12] [13] It is on the World Health Organization's List of Essential Medicines. [14] It is available as a generic medication. [4] In 2021, it was the sixth most commonly prescribed medication in the United States, with more than 65 million prescriptions. [15] [16]

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. [4] It is an adjunct in the treatment of hyperthyroidism. [17] Both oral and intravenous forms of metoprolol are available for administration. [18] The different salt versions of metoprolol – metoprolol tartrate and metoprolol succinate – are approved for different conditions and are not interchangeable. [19] [20]

Off-label uses include supraventricular tachycardia and thyroid storm. [18]

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. [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]

Precautions

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]

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. [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]

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). [7] It appears to be safe in breastfeeding. [8]

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. [34] [35] [36]

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. [37]

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:

  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. [38]
  2. Reduction of the force of contraction, i.e., decrease in contractility (negative inotropic effect), which lessens how hard each heartbeat contracts. [38]
  3. 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]
  4. Lowering of blood pressure. [38]
  5. Antiarrhythmic effects, such as supraventricular tachycardia prevention. Metoprolol also prevents electrical wave propagation. [38]

Pharmacokinetics

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 neuropsychiatric side 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]

Chemistry

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]

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: [42]

Enantiomers of metoprolol
(R)-Metoprolol Structural Formula V1.svg
CAS-Nummer: 81024-43-3		 (S)-Metoprolol Structural Formula V1.svg
CAS-Nummer: 81024-42-2

Society and culture

Metoprolol was approved for medical use in the United States in August 1978. [11]

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$ 11 million. [43] [ better source needed ]

Sport

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]

Related Research Articles

<span class="mw-page-title-main">Beta blocker</span> Class of medications used to manage abnormal heart rhythms

Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms (arrhythmia), and to protect the heart from a second heart attack after a first heart attack. They are also widely used to treat high blood pressure, although they are no longer the first choice for initial treatment of most patients.

<span class="mw-page-title-main">Propranolol</span> Beta blocker drug

Propranolol, sold under the brand name Inderal among others, is a medication of the beta blocker class. It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, capillary hemangiomas, performance anxiety, and essential tremors, as well to prevent migraine headaches, and to prevent further heart problems in those with angina or previous heart attacks. It can be taken orally or by intravenous injection. The formulation that is taken orally comes in short-acting and long-acting versions. Propranolol appears in the blood after 30 minutes and has a maximum effect between 60 and 90 minutes when taken orally.

Atenolol is a beta blocker medication primarily used to treat high blood pressure and heart-associated chest pain. Atenolol, however, does not seem to improve mortality in those with high blood pressure. Other uses include the prevention of migraines and treatment of certain irregular heart beats. It is taken orally or by intravenous injection. It can also be used with other blood pressure medications.

<span class="mw-page-title-main">Sotalol</span> Medication

Sotalol, sold under the brand name Betapace among others, is a medication used to treat and prevent abnormal heart rhythms. Evidence does not support a decreased risk of death with long term use. It is taken by mouth or given by injection into a vein.

<span class="mw-page-title-main">Nadolol</span> Non-selective beta blocker used in the treatment of high blood pressure and chest pain

Nadolol, sold under the brand name Corgard among others, is a medication used to treat high blood pressure, heart pain, atrial fibrillation, and some inherited arrhythmic syndromes. It has also been used to prevent migraine headaches and complications of cirrhosis. It is taken orally.

<span class="mw-page-title-main">Esmolol</span> Class II antiarrhythmic drug

Esmolol, sold under the brand name Brevibloc, is a cardio selective beta1 receptor blocker with rapid onset, a very short duration of action, and no significant intrinsic sympathomimetic or membrane stabilising activity at therapeutic dosages.

<span class="mw-page-title-main">Isoprenaline</span> Medication for slow heart rate

Isoprenaline, or isoproterenol, is a medication used for the treatment of bradycardia, heart block, and rarely for asthma. It is a non-selective β adrenoceptor agonist that is the isopropylamine analog of epinephrine (adrenaline).

<span class="mw-page-title-main">Phentolamine</span> An α-adrenergic antagonist medication

Phentolamine, sold under the brand name Regitine among others, is a reversible nonselective α-adrenergic antagonist.

<span class="mw-page-title-main">Labetalol</span> Medication used to treat high blood pressure

Labetalol is a medication used to treat high blood pressure and in long term management of angina. This includes essential hypertension, hypertensive emergencies, and hypertension of pregnancy. In essential hypertension it is generally less preferred than a number of other blood pressure medications. It can be given by mouth or by injection into a vein.

<span class="mw-page-title-main">Bisoprolol</span> Beta-1 selective adrenenergic blocker medication used to treat cardiovascular diseases

Bisoprolol, sold under the brand name Zebeta among others, is a beta blocker which is selective for the beta-1 receptor and used for cardiovascular diseases, including tachyarrhythmias, high blood pressure, angina, and heart failure. It is taken by mouth.

<span class="mw-page-title-main">Carvedilol</span> Blood pressure medication

Carvedilol, sold under the brand name Coreg among others, is a medication used to treat high blood pressure, congestive heart failure (CHF), and left ventricular dysfunction in people who are otherwise stable. For high blood pressure, it is generally a second-line treatment. It is taken by mouth.

<span class="mw-page-title-main">Penbutolol</span> Chemical compound

Penbutolol is a medication in the class of beta blockers, used in the treatment of high blood pressure. Penbutolol is able to bind to both beta-1 adrenergic receptors and beta-2 adrenergic receptors, thus making it a non-selective β blocker. Penbutolol is a sympathomimetic drug with properties allowing it to act as a partial agonist at β adrenergic receptors.

<span class="mw-page-title-main">Beta-1 adrenergic receptor</span> Protein-coding gene in the species Homo sapiens

The beta-1 adrenergic receptor, also known as ADRB1, can refer to either the protein-encoding gene or one of the four adrenergic receptors. It is a G-protein coupled receptor associated with the Gs heterotrimeric G-protein that is expressed predominantly in cardiac tissue. In addition to cardiac tissue, beta-1 adrenergic receptors are also expressed in the cerebral cortex.

<span class="mw-page-title-main">Nebivolol</span> Chemical compound

Nebivolol is a beta blocker used to treat high blood pressure and heart failure. As with other β-blockers, it is generally a less preferred treatment for high blood pressure. It may be used by itself or with other blood pressure medication. It is taken by mouth.

<span class="mw-page-title-main">Adrenergic antagonist</span> Type of drug

An adrenergic antagonist is a drug that inhibits the function of adrenergic receptors. There are five adrenergic receptors, which are divided into two groups. The first group of receptors are the beta (β) adrenergic receptors. There are β1, β2, and β3 receptors. The second group contains the alpha (α) adrenoreceptors. There are only α1 and α2 receptors. Adrenergic receptors are located near the heart, kidneys, lungs, and gastrointestinal tract. There are also α-adreno receptors that are located on vascular smooth muscle.

<span class="mw-page-title-main">Beta-adrenergic agonist</span> Medications that relax muscles of the airways

Beta adrenergic agonists or beta agonists are medications that relax muscles of the airways, causing widening of the airways and resulting in easier breathing. They are a class of sympathomimetic agents, each acting upon the beta adrenoceptors. In general, pure beta-adrenergic agonists have the opposite function of beta blockers: beta-adrenoreceptor agonist ligands mimic the actions of both epinephrine- and norepinephrine- signaling, in the heart and lungs, and in smooth muscle tissue; epinephrine expresses the higher affinity. The activation of β1, β2 and β3 activates the enzyme, adenylate cyclase. This, in turn, leads to the activation of the secondary messenger cyclic adenosine monophosphate (cAMP); cAMP then activates protein kinase A (PKA) which phosphorylates target proteins, ultimately inducing smooth muscle relaxation and contraction of the cardiac tissue.

<span class="mw-page-title-main">Landiolol</span> Chemical compound

Landiolol (INN) is an ultra short-acting, β1-superselective intravenous adrenergic antagonist, which decreases the heart rate effectively with less negative effect on blood pressure or myocardial contractility. In comparison to other beta blockers, landiolol has the shortest elimination half-life, ultra-rapid onset of effect, and predictable effectiveness with inactive metabolites. The pure S-enantiomer structure of landiolol is believed to develop less hypotensive side effects in comparison to other β-blockers. This has a positive impact on the treatment of patients when reduction of heart rate without decrease in arterial blood pressure is desired. Landiolol was developed by modifying the chemical structure of esmolol to produce a compound with a higher rate of cardioselectivity and a greater potency without increasing its duration of action. It is sold as landiolol hydrochloride. Based on its positive benefit risk profile, landiolol has been granted the marketing authorization and introduced to the European markets under the brand names Rapibloc, Raploc, Runrapiq, Landibloc mid 2016. Landiolol is available in Japan under the brand names Onoact (50 mg) and Corbeta.

<span class="mw-page-title-main">Discovery and development of beta-blockers</span>

β adrenergic receptor antagonists were initially developed in the 1960s, for the treatment of angina pectoris but are now also used for hypertension, congestive heart failure and certain arrhythmias. In the 1950s, dichloroisoproterenol (DCI) was discovered to be a β-antagonist that blocked the effects of sympathomimetic amines on bronchodilation, uterine relaxation and heart stimulation. Although DCI had no clinical utility, a change in the compound did provide a clinical candidate, pronethalol, which was introduced in 1962.

Autonomic drugs can either inhibit or enhance the functions of the parasympathetic and sympathetic nervous systems. This type of drug can be used to treat a wide range of diseases, such as glaucoma, asthma, urinary, gastrointestinal and cardiopulmonary disorders.

Adrenergic blocking agents are a class of drugs that exhibit its pharmacological action through inhibiting the action of the sympathetic nervous system in the body. The sympathetic nervous system(SNS) is an autonomic nervous system that we cannot control by will. It triggers a series of responses after the body releases chemicals named noradrenaline and epinephrine. These chemicals will act on adrenergic receptors, with subtypes Alpha-1, Alpha-2, Beta-1, Beta-2, Beta-3, which ultimately allow the body to trigger a "fight-or-flight" response to handle external stress. These responses include vessel constriction in general vessels whereas there is vasodilation in vessels that supply skeletal muscles or in coronary vessels. Additionally, the heart rate and contractile force increase when SNS is activated, which may be harmful to cardiac function as it increases metabolic demand.

References

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Further reading

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