Metoprolol

Metoprolol
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Clinical data
Trade names	Lopressor, Toprol-xl
AHFS/Drugs.com	Monograph
MedlinePlus	a682864
[[Regulation of therapeutic goods \|Template:Engvar data]]	US FDA: Metoprolol;
Pregnancy; category	AU: C ; US: C (Risk not ruled out) ; ;
Routes of; administration	Oral, IV
ATC code	C07AB02 (WHO) ;
Legal status
Legal status	In general: ℞ (Prescription only);
Pharmacokinetic data
Bioavailability	12%
Metabolism	Hepatic via CYP2D6, CYP3A4
Elimination half-life	3-7 hours
Excretion	Renal
Identifiers
	IUPAC name (RS)-1-(Isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol;
CAS Number	51384-51-1 ;
PubChem CID	4171;
IUPHAR/BPS	553;
DrugBank	DB00264 ;
ChemSpider	4027 ;
UNII	GEB06NHM23;
KEGG	D02358 ;
ChEBI	CHEBI:6904 ;
ChEMBL	ChEMBL13 ;
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
Formula	C15H25NO3
Molar mass	267.364 g/mol
3D model (JSmol)	Interactive image;
Melting point	120 °C (248 °F)
	SMILES O(c1ccc(cc1)CCOC)CC(O)CNC(C)C;
	InChI 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 ; Key:IUBSYMUCCVWXPE-UHFFFAOYSA-N ;
(verify)

Metoprolol
Clinical data
Trade names	Lopressor, Toprol-xl
AHFS/Drugs.com	Monograph
MedlinePlus	a682864
[[Regulation of therapeutic goods \|Template:Engvar data]]	US FDA: Metoprolol;
Pregnancy; category	AU: C ; US: C (Risk not ruled out) ; ;
Routes of; administration	Oral, IV
ATC code	C07AB02 (WHO) ;
Legal status
Legal status	In general: ℞ (Prescription only);
Pharmacokinetic data
Bioavailability	12%
Metabolism	Hepatic via CYP2D6, CYP3A4
Elimination half-life	3-7 hours
Excretion	Renal
Identifiers
	IUPAC name (RS)-1-(Isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol;
CAS Number	51384-51-1 ;
PubChem CID	4171;
IUPHAR/BPS	553;
DrugBank	DB00264 ;
ChemSpider	4027 ;
UNII	GEB06NHM23;
KEGG	D02358 ;
ChEBI	CHEBI:6904 ;
ChEMBL	ChEMBL13 ;
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
Formula	C15H25NO3
Molar mass	267.364 g/mol
3D model (JSmol)	Interactive image;
Melting point	120 °C (248 °F)
	SMILES O(c1ccc(cc1)CCOC)CC(O)CNC(C)C;
	InChI 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 ; Key:IUBSYMUCCVWXPE-UHFFFAOYSA-N ;
(verify)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2]

For patient information, click here.

Synonyms / Brand Names: Lopressor^®, Toprol XL^®

Overview

Metoprolol (/mɛˈtoʊproʊlɑːl/, /mɛtoʊˈproʊlɑːl/) is a selective β₁ receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. 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 and the succinate is an extended-release formulation.^[1]

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.^[2]

Treatment of heart failure.^[3]
Vasovagal syncope^[4]
Adjunct in treatment of hyperthyroidism
Long QT syndrome, especially for patients with asthma, as metoprolol's β1 selectivity tends to interfere less with asthma drugs, which are often β2-adrenergic receptor-agonist drugs^{[citation needed]}

Due to its selectivity in blocking the beta₁ receptors in the heart, metoprolol is also prescribed for off-label use in performance anxiety, social anxiety disorder, and other anxiety disorders.

Adverse effects

Side-effects, especially with higher dosages, include the following: dizziness, drowsiness, fatigue, diarrhea, unusual dreams, ataxia, trouble sleeping, depression, and vision problems. It may also reduce blood flow to the hands and feet, causing them to feel numb and cold; smoking may worsen this effect.^[5] 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 and vivid dreams and nightmares.^[6]

Serious side-effects that are advised to be reported immediately include, but are not limited to, symptoms of bradycardia (a very slow heartbeat (less than 50 bpm)), persistent symptoms of dizziness, fainting and unusual fatigue, bluish discoloration of the fingers and toes, numbness/tingling/swelling of the hands or feet, sexual dysfunction, erectile dysfunction (impotence), hair loss, mental/mood changes, depression, trouble breathing, cough, dyslipidemia, and increased thirst. Other highly unlikely symptoms include easy bruising or bleeding, persistent sore throat or fever, yellowing skin or eyes, stomach pain, dark urine, and persistent nausea. Symptoms of an allergic reaction include: rash, itching, swelling, and severe dizziness. Taking it with alcohol might cause mild body rashes and therefore is not recommended.^[5]

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.^[7]

This medicine may cause changes in blood sugar levels or cover up signs of low blood sugar, such as a rapid pulse rate.^[7]

This medicine may cause some people to become less alert than they are normally, making it dangerous for them to drive, use machines, or do other things.^[7]

Overdosage

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 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.^[8]^[9]^[10]

Physical properties

Metoprolol has a very low melting point, tartrate around 120°C, succinate around 136°C. Because of this, metoprolol is always manufactured in a salt-based solution, as drugs with low melting points are difficult to work with in a manufacturing environment. The free base exists as a waxy white solid, and the tartrate salt is finer crystalline material.

Metabolism

Metoprolol undergoes a-hydroxylation and O-demethylation as a substrate of the cytochrome liver enzymes CYP2D6 ^[11] and a small percentage by CYP3A4.

Pharmacology

Selective
Moderately lipophilic
Without intrinsic sympathomimetic activity (ISA)
With weak membrane stabilizing activity
Short half-life, therefore must be taken at least twice daily or as a slow-release preparation
Decreases heart rate, contractility and cardiac output, therefore decreasing blood pressure
Metabolized in the liver to inactive metabolite

Chemistry

Metoprolol, 1-(iso-propylamino)-3-[4′(2-methoxyethyl)phenoxy]-2-propanol, is synthesized by reacting 4-(2-methoxyethyl)phenol with epichlorohydrin in the presence of a base, isolating 1,2-epoxy-3-[4′(2-methoxyethyl)phenoxy]propane, the subsequent reaction with isopropylamine, gives an opening of the epoxide ring and leads to the formation of metoprolol.

P. A. E. Carlsson, S. A. I. Carlsson, H. R. Corrodi, L. Ek, B. A. H. Ablad, A. E. Brandstrom, Template:US Patent (1975).
A. E. Brandstrom, P. A. E. Carlsson, S. A. I. Carlsson, H. R. Corrodi, L. Ek, DE 2106209 (1971).

Brand names

Amlong MT combination of Amlodipine and Metoprolol with 25 and 50 mg claim for Metoproplol(Micro Labs-India)

Toprol XL 50 mg

It is marketed under the brand name Lopressor by Novartis, and Toprol-XL (in the USA); Selokeen (in the Netherlands); as Minax by Alphapharm (in Australia), Metrol by Arrow Pharmaceuticals (in Australia), as Betaloc by AstraZeneca, as Bloxan by Krka (company) (in Slovenia), as Neobloc by Unipharm (in Israel), Presolol by Hemofarm (in Serbia) and as Corvitol by Berlin-Chemie AG (in Germany). In India, this drug is available under the brand names of Met-XL, Metolar and Starpress,Restopress. A number of generic products are available as well.

FDA Package Insert

Mechanism of Action

References

↑ Cupp M (2009). "Alternatives for Metoprolol Succinate" (pdf). Pharmacist's Letter / Prescriber's Letter. 25 (250302). Retrieved 2012-07-06.
↑ "Metoprolol". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
↑ MERIT-HF Study Group (1999). "Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)". Lancet. 353 (9169): 2001–2007. doi:10.1016/S0140-6736(99)04440-2. PMID 10376614.
↑ Zhang Q, Jin H, Wang L, Chen J, Tang C, Du J (2008). "Randomized comparison of metoprolol versus conventional treatment in preventing recurrence of vasovagal syncope in children and adolescents". Medical Science Monitor. 14 (4): CR199–CR203. PMID 18376348.
↑ ^5.0 ^5.1 "Metoprolol". Drugs.com.
↑ Cruickshank JM (2010). "Beta-blockers and heart failure". Indian Heart Journal. 62 (2): 101–110. PMID 21180298.
↑ ^7.0 ^7.1 ^7.2 "Metoprolol (Oral Route) Precautions". Drug Information. Mayo Clinic.
↑ 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. PMID 19655287.
↑ 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.
↑ Baselt R (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 1023–1025.
↑ 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. PMID 16176119.

[1] Cupp M (2009). "Alternatives for Metoprolol Succinate" (pdf). Pharmacist's Letter / Prescriber's Letter. 25 (250302). Retrieved 2012-07-06.

[AHFS-2] "Metoprolol". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.

[Lancet-MERIT-HF-3] MERIT-HF Study Group (1999). "Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)". Lancet. 353 (9169): 2001–2007. doi:10.1016/S0140-6736(99)04440-2. PMID 10376614.

[pmid18376348-4] Zhang Q, Jin H, Wang L, Chen J, Tang C, Du J (2008). "Randomized comparison of metoprolol versus conventional treatment in preventing recurrence of vasovagal syncope in children and adolescents". Medical Science Monitor. 14 (4): CR199–CR203. PMID 18376348.

[drugs-5] 5.0 ^5.1 "Metoprolol". Drugs.com.

[pmid21180298-6] Cruickshank JM (2010). "Beta-blockers and heart failure". Indian Heart Journal. 62 (2): 101–110. PMID 21180298.

[mayoclinic-7] 7.0 ^7.1 ^7.2 "Metoprolol (Oral Route) Precautions". Drug Information. Mayo Clinic.

[8] 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. PMID 19655287.

[9] 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.

[10] Baselt R (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 1023–1025.

[11] 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. PMID 16176119.

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