Bisoprolol

Synonyms :
(+-)-1-((alpha-(2-Isopropoxyethoxy)-P-tolyl)oxy)-3-(isopropylamino)-2-propanol, (RS)-1-(4-(2-isopropoxyethoxymethyl)phenoxy)-3-(isopropylamino)-2-propanol, Bisoprolol, Bisoprololum

Status : approved

Category

Antihypertensive Agents

Therapeutic Classification

BETA BLOCKING AGENTS

CARDIOVASCULAR SYSTEM
BETA BLOCKING AGENTS
BETA BLOCKING AGENTS
Adrenergic beta-1 Receptor Antagonists

Description

Bisoprolol is a cardioselective β1-adrenergic blocking agent used for secondary prevention of myocardial infarction (MI), heart failure, angina pectoris and mild to moderate hypertension. Bisoprolol is structurally similar to metoprolol, acebutolol and atenolol in that it has two substituents in the para position of the benzene ring. The β1-selectivity of these agents is thought to be due in part to the large substituents in the para position. At lower doses (less than 20 mg daily), bisoprolol selectively blocks cardiac β1-adrenergic receptors with little activity against β2-adrenergic receptors of the lungs and vascular smooth muscle. Receptor selectivity decreases with daily doses of 20 mg or greater. Unlike propranolol and pindolol, bisoprolol does not exhibit membrane-stabilizing or sympathomimetic activity. Bisoprolol possesses a single chiral centre and is administered as a racemic mixture. Only l-bisoprolol exhibits significant β-blocking activity.

Used

For management of heart failure, angina pectoris, and mild to moderate hypertension and for secondary prevention of myocardial infarction (MI).

Mechanism Of Action

Bisoprolol selectively blocks catecholamine stimulation of β1-adrenergic receptors in the heart and vascular smooth muscle. This results in a reduction of heart rate, cardiac output, systolic and diastolic blood pressure, and possibly reflex orthostatic hypotension. At higher doses (e.g. 20 mg and greater) bisoprolol may competitively block β2-adrenergic receptors in bronchial and vascular smooth muscle causing bronchospasm and vasodilation.

Dosage

Form Route Strength
Tablet oral 10 mg
Tablet oral 5 mg
Tablet, coated oral 10 mg
Tablet, coated oral 5 mg
Tablet, film coated oral 10 mg
Tablet, film coated oral 5 mg
Tablet oral 10; 6.25 mg/1; mg
Tablet oral 2.5; 6.25 mg/1; mg
Tablet oral 5; 6.25 mg/1; mg
Tablet, coated oral 10; 6.25 mg/1; mg
Tablet, coated oral 2.5; 6.25 mg/1; mg
Tablet, coated oral 5; 6.25 mg/1; mg
Tablet, film coated oral 10; 6.25 mg/1; mg
Tablet, film coated oral 2.5; 6.25 mg/1; mg
Tablet, film coated oral 5; 6.25 mg/1; mg

Pharmacodynamics

Bisoprolol is a competitive, cardioselective β1-adrenergic antagonist. Activation of β1-receptors (located mainly in the heart) by epinephrine increases heart rate and the blood pressure causing the heart to consume more oxygen. β1-adrenergic blocking agents such as bisopolol lower the heart rate and blood pressure and may be used to reduce workload on the heart and hence oxygen demands. They are routinely prescribed in patients with ischemic heart disease. In addition, β1-selective blockers prevent the release of renin, a hormone produced by the kidneys causes constriction of blood vessels. Bisoprolol is lipophilic and exhibits no intrinsic sympathomimetic activity (ISA) or membrane-stabilizing activity.

Toxic Effect

Oral, mouse: LD50 = 100 mg/kg; Skin, rabbit: LD50 = 200 mg/kg; Skin, rat: LD50 = 500 mg/kg. Symptoms of overdose include congestive heart failure (marked by sudden weight gain, swelling of the legs, feet, and ankles, fatigue, and shortness of breath), difficult or labored breathing, low blood pressure, low blood sugar, and slow heartbeat.

Metabolism

Approximately 50% of the dose is metabolized primarily metabolized by CYP3A4 to inactive metabolites. In vitro studies have shown that bisoprolol is also metabolized by CYP2D6 though this does not appear to be clinically significant. Approximately half the administered dose is excreted in unchanged in urine.

Absorption

Well absorbed. Bioavailability > 80%. Absorption is not affected by food. Peak plasma concentrations occur within 2-4 hours.

Half Life

9-12 hours; prolonged in the elderly and those with decreased renal function

Protein Binding

Binding to serum proteins is approximately 30%

Elimination Route

Eliminated equally by renal and non-renal pathways. Approximately 50% of the total orally administered dose is excreted unchanged in urine with the remainder appearing as inactive metabolites. Less than 2% of the dose is excreted in the feces.

Chemical Classification

This compound belongs to the class of organic compounds known as benzylethers. These are aromatic ethers with the general formula ROCR’ (R = alkyl, aryl; R’=benzene).

Benzylethers

Organic compounds

Benzenoids

Benzene and substituted derivatives

Benzylethers

Salt : Bisoprolol Fumarate

Chemical Name

(+-)-1-((alpha-(2-Isopropoxyethoxy)-P-tolyl)oxy)-3-(isopropylamino)-2-propanol

Brands

name Dosage form Country
Apo-bisoprolol tablet Canada
Apo-bisoprolol tablet Canada
Ava-bisoprolol tablet Canada
Ava-bisoprolol tablet Canada
Bisoprolol tablet Canada
Bisoprolol tablet Canada
Bisoprolol tablet Canada
Bisoprolol tablet Canada
Bisoprolol tablet Canada
Bisoprolol tablet Canada
Bisoprolol Fumarate tablet, film coated US
Bisoprolol Fumarate tablet, film coated US
Bisoprolol Fumarate tablet US
Bisoprolol Fumarate tablet US
Bisoprolol Fumarate tablet US
Bisoprolol Fumarate tablet, coated US
Bisoprolol Fumarate tablet, coated US
Bisoprolol Fumarate tablet, film coated US
Bisoprolol Fumarate tablet, film coated US
Bisoprolol Fumarate tablet, film coated US
Bisoprolol Fumarate tablet US
Bisoprolol Fumarate tablet, film coated US
Bisoprolol Fumarate tablet, film coated US
Bisoprolol Fumarate tablet, film coated US
Bisoprolol Fumarate tablet, film coated US
Bisoprolol Fumarate tablet, film coated US
Bisoprolol Fumarate tablet, coated US
Bisoprolol Fumarate tablet US
Bisoprolol Fumarate tablet US
Bisoprolol Fumarate and Hydrochlorothiazide tablet US
Bisoprolol Fumarate and Hydrochlorothiazide tablet US
Bisoprolol Fumarate and Hydrochlorothiazide tablet US
Bisoprolol Fumarate and Hydrochlorothiazide tablet, coated US
Bisoprolol Fumarate and Hydrochlorothiazide tablet US
Bisoprolol Fumarate and Hydrochlorothiazide tablet, coated US
Bisoprolol Fumarate and Hydrochlorothiazide tablet, coated US
Bisoprolol Fumarate and Hydrochlorothiazide tablet, coated US
Bisoprolol Fumarate and Hydrochlorothiazide tablet, coated US
Bisoprolol Fumarate and Hydrochlorothiazide tablet, coated US
Bisoprolol Fumarate and Hydrochlorothiazide tablet, coated US
Bisoprolol Fumarate and Hydrochlorothiazide tablet, film coated US
Bisoprolol Fumarate and Hydrochlorothiazide tablet, film coated US
Bisoprolol Fumarate and Hydrochlorothiazide tablet, film coated US
Bisoprolol Fumarate and Hydrochlorothiazide tablet, film coated US
Bisoprolol Fumarate and Hydrochlorothiazide tablet US
Bisoprolol Fumarate and Hydrochlorothiazide tablet US
Bisoprolol Fumarate and Hydrochlorothiazide tablet, coated US
Bisoprolol Fumarate and Hydrochlorothiazide tablet, coated US
Bisoprolol Fumarate and Hydrochlorothiazide tablet, coated US
Bisoprolol Fumarate and Hydrochlorothiazide tablet US
Bisoprolol Fumarate and Hydrochlorothiazide tablet, coated US
Bisoprolol Fumarate and Hydrochlorothiazide tablet, film coated US
Dom-bisoprolol tablet Canada
Dom-bisoprolol tablet Canada
Monocor -(10mg) tablet Canada
Monocor -(5mg) tablet Canada
Mylan-bisoprolol tablet Canada
Mylan-bisoprolol tablet Canada
Nu-bisoprolol tablet Canada
Nu-bisoprolol tablet Canada
PHL-bisoprolol tablet Canada
PHL-bisoprolol tablet Canada
PMS-bisoprolol tablet Canada
PMS-bisoprolol tablet Canada
Pro-bisoprolol – 10 tablet Canada
Pro-bisoprolol – 5 tablet Canada
Sandoz Bisoprolol tablet Canada
Sandoz Bisoprolol tablet Canada
Teva-bisoprolol tablet Canada
Teva-bisoprolol tablet Canada
Zebeta tablet US
Zebeta tablet US
Ziac tablet, film coated US
Ziac tablet, film coated US
Ziac tablet, film coated US

Drug Drug Interactions

  •  Acetylcholine  : Beta-Blockers may enhance the adverse/toxic effect of Cholinergic Agonists. Of particular concern are the potential for cardiac conduction abnormalities and bronchoconstriction.
  •  Amifostine  : Antihypertensives may enhance the hypotensive effect of Amifostine.
  •  Amiodarone  : May enhance the bradycardic effect of Beta-Blockers. Possibly to the point of cardiac arrest. Amiodarone may increase the serum concentration of Beta-Blockers.
  •  Aprepitant  : May increase the serum concentration of CYP3A4 Substrates.
  •  Bosentan  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Bretylium  : May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
  •  Bupivacaine  : Beta-Blockers may increase the serum concentration of Bupivacaine.
  •  Butabarbital  : May decrease the serum concentration of Beta-Blockers.
  •  Butethal  : May decrease the serum concentration of Beta-Blockers.
  •  Carbachol  : Beta-Blockers may enhance the adverse/toxic effect of Cholinergic Agonists. Of particular concern are the potential for cardiac conduction abnormalities and bronchoconstriction.
  •  Ceritinib  : Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib.
  •  Conivaptan  : May increase the serum concentration of CYP3A4 Substrates.
  •  Dabrafenib  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Dasatinib  : May increase the serum concentration of CYP3A4 Substrates.
  •  Deferasirox  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Diazoxide  : May enhance the hypotensive effect of Antihypertensives.
  •  Dipyridamole  : May enhance the bradycardic effect of Beta-Blockers.
  •  Disopyramide  : May enhance the bradycardic effect of Beta-Blockers. Beta-Blockers may enhance the negative inotropic effect of Disopyramide.
  •  Dronedarone  : May enhance the bradycardic effect of Beta-Blockers. Dronedarone may increase the serum concentration of Beta-Blockers. This likely applies only to those agents that are metabolized by CYP2D6.
  •  Duloxetine  : Hypotensive Agents may enhance the orthostatic hypotensive effect of Duloxetine.
  •  Fingolimod  : Beta-Blockers may enhance the bradycardic effect of Fingolimod.
  •  Floctafenine  : May enhance the adverse/toxic effect of Beta-Blockers.
  •  Fosaprepitant  : May increase the serum concentration of CYP3A4 Substrates.
  •  Heptabarbital  : May decrease the serum concentration of Beta-Blockers.
  •  Hexobarbital  : May decrease the serum concentration of Beta-Blockers.
  •  Idelalisib  : May increase the serum concentration of CYP3A4 Substrates.
  •  Ivabradine  : Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine.
  •  Ivacaftor  : May increase the serum concentration of CYP3A4 Substrates.
  •  Lacosamide  : Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide.
  •  Levodopa  : Hypotensive Agents may enhance the orthostatic hypotensive effect of Levodopa.
  •  Luliconazole  : May increase the serum concentration of CYP3A4 Substrates.
  •  Mepivacaine  : Beta-Blockers may increase the serum concentration of Mepivacaine.
  •  Methacholine  : Beta-Blockers may enhance the adverse/toxic effect of Methacholine.
  •  Methohexital  : May decrease the serum concentration of Beta-Blockers.
  •  Methylphenidate  : May diminish the antihypertensive effect of Antihypertensives.
  •  Midodrine  : Beta-Blockers may enhance the bradycardic effect of Midodrine.
  •  Mifepristone  : May increase the serum concentration of CYP3A4 Substrates.
  •  Mitotane  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Netupitant  : May increase the serum concentration of CYP3A4 Substrates.
  •  Nifedipine  : May enhance the hypotensive effect of Beta-Blockers. Nifedipine may enhance the negative inotropic effect of Beta-Blockers.
  •  Obinutuzumab  : Antihypertensives may enhance the hypotensive effect of Obinutuzumab.
  •  Palbociclib  : May increase the serum concentration of CYP3A4 Substrates.
  •  Pentobarbital  : May decrease the serum concentration of Beta-Blockers.
  •  Pentoxifylline  : May enhance the hypotensive effect of Antihypertensives.
  •  Primidone  : May decrease the serum concentration of Beta-Blockers.
  •  Propafenone  : May increase the serum concentration of Beta-Blockers. Propafenone possesses some independent beta blocking activity.
  •  Regorafenib  : May enhance the bradycardic effect of Beta-Blockers.
  •  Reserpine  : May enhance the hypotensive effect of Beta-Blockers.
  •  Risperidone  : Hypotensive Agents may enhance the hypotensive effect of Risperidone.
  •  Rituximab  : Antihypertensives may enhance the hypotensive effect of Rituximab.
  •  Rivastigmine  : May enhance the bradycardic effect of Beta-Blockers.
  •  Ruxolitinib  : May enhance the bradycardic effect of Bradycardia-Causing Agents.
  •  Secobarbital  : May decrease the serum concentration of Beta-Blockers.
  •  Siltuximab  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Simeprevir  : May increase the serum concentration of CYP3A4 Substrates.
  •  Stiripentol  : May increase the serum concentration of CYP3A4 Substrates.
  •  Tadalafil  : May enhance the antihypertensive effect of Antihypertensives.
  •  Tocilizumab  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Tofacitinib  : May enhance the bradycardic effect of Bradycardia-Causing Agents.
  •  Vardenafil  : May enhance the antihypertensive effect of Antihypertensives.
  •  Yohimbine  : May diminish the antihypertensive effect of Antihypertensives.

Food Interactions

  • Take without regard to meals.

Calculated Property

kind Value Source
logP 2.3 ALOGPS
logS -3.7 ALOGPS
Water Solubility 7.07e-02 g/l ALOGPS
logP 2.2 ChemAxon
IUPAC Name 1-[(propan-2-yl)amino]-3-(4-{[2-(propan-2-yloxy)ethoxy]methyl}phenoxy)propan-2-ol ChemAxon
Traditional IUPAC Name 1-{4-[(2-isopropoxyethoxy)methyl]phenoxy}-3-(isopropylamino)propan-2-ol ChemAxon
Molecular Weight 325.443 ChemAxon
Monoisotopic Weight 325.225308485 ChemAxon
SMILES CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 ChemAxon
Molecular Formula C18H31NO4 ChemAxon
InChI InChI=1S/C18H31NO4/c1-14(2)19-11-17(20)13-23-18-7-5-16(6-8-18)12-21-9-10-22-15(3)4/h5-8,14-15,17,19-20H,9-13H2,1-4H3 ChemAxon
InChIKey InChIKey=VHYCDWMUTMEGQY-UHFFFAOYSA-N ChemAxon
Polar Surface Area (PSA) 59.95 ChemAxon
Refractivity 92.15 ChemAxon
Polarizability 38.5 ChemAxon
Rotatable Bond Count 12 ChemAxon
H Bond Acceptor Count 5 ChemAxon
H Bond Donor Count 2 ChemAxon
pKa (strongest acidic) 14.09 ChemAxon
pKa (strongest basic) 9.67 ChemAxon
Physiological Charge 1 ChemAxon
Number of Rings 1 ChemAxon
Bioavailability 1 ChemAxon
Rule of Five 1 ChemAxon
Ghose Filter 1 ChemAxon
MDDR-Like Rule 0 ChemAxon

Affected organism

Humans and other mammals

Target within organism

  • Beta-1 adrenergic receptor : in Human
  • Beta-2 adrenergic receptor : in Human