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] 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
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)
  (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] 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]

Metoprolol was first made in 1969, patented in 1970, and approved for medical use in 1982.[8][9] It is on the World Health Organization's List of Essential Medicines.[10] It is available as a generic drug.[3] In 2017, it was the sixth most commonly prescribed medication in the United States, with more than 68 million prescriptions.[11][12]

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[13]

The different salt versions of metoprolol, metoprolol tartrate and metoprolol succinate, are approved for different conditions and are not interchangeable.[14][15][16]

Off-label uses include supraventricular tachycardia and thyroid storm.[17]

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 per 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.[18][19] Metoprolol may also cause the hands and feet to feel cold.[20] 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.[21]

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.[17]

Precautions

Metoprolol may worsen the symptoms of heart failure in some patients, who may experience chest pain or discomfort, dilated neck veins, extreme fatigue, irregular breathing, an irregular heartbeat, shortness of breath, swelling of the face, fingers, feet, or lower legs, weight gain, or wheezing.[22]

This medicine may cause changes in blood sugar levels or cover up signs of low blood sugar, such as a rapid pulse rate.[22] It also may cause some people to become less alert than they are normally, making it dangerous for them to drive or use machines.[22]

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.[23][24][25]

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).[26] 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.[26]

Pharmacokinetics

It undergoes α-hydroxylation and O-demethylation as a substrate of the cytochrome liver enzymes CYP2D6.[27][28]

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.[29]

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:[30]

Enantiomers of metoprolol

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

Metoprolol was discovered in 1969 by Bengt Ablad and Enar Carlsson.[8] 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.[31]

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.[32]

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.[33] Metoprolol tartrate is a generic version of Lopressor, which was licensed and authorized on 6 June 1997 to Novartis Pharmaceuticals.[34]

In sport

Because beta blockers can be used to reduce heart rate and minimize tremors, which can enhance performance in sports such as archery,[35][36] 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.[37]

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.[38]

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.[39]

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