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Identification
NameBretylium
Accession NumberDB01158  (APRD00830)
Typesmall molecule
Groupsapproved
Description

Bretylium blocks the release of noradrenaline from the peripheral sympathetic nervous system, and is used in emergency medicine, cardiology, and other specialties for the acute management of ventricular tachycardia and ventricular fibrillation. The primary mode of action for bretylium is thought to be inhibition of voltage-gated K(+) channels. Recent evidence has shown that bretylium may also inhibit the Na,K-ATPase by binding to the extracellular K-site.

Structure
Thumb
SynonymsNot Available
Salts
Name/CAS Structure Properties
Bretylium tosylate
Thumb Not applicable DBSALT001050
Brand names
NameCompany
AnxyrexSanofi-Aventis
BretylolICI
BromidemNycomed
CreosedinAstraZeneca
DarenthinBurroughs Wellcome
LexotanRoche
XionilNovartis
Brand mixturesNot Available
Categories
CAS number59-41-6
WeightAverage: 243.163
Monoisotopic: 242.054437196
Chemical FormulaC11H17BrN
InChI KeyInChIKey=AAQOQKQBGPPFNS-UHFFFAOYSA-N
InChI
InChI=1S/C11H17BrN/c1-4-13(2,3)9-10-7-5-6-8-11(10)12/h5-8H,4,9H2,1-3H3/q+1
IUPAC Name
[(2-bromophenyl)methyl](ethyl)dimethylazanium
SMILES
CC[N+](C)(C)CC1=CC=CC=C1Br
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassHalobenzenes
Direct parentBromobenzenes
Alternative parentsAryl Bromides; Polyamines; Organobromides
Substituentsaryl bromide; aryl halide; polyamine; organobromide; organohalogen; amine; organonitrogen compound
Classification descriptionThis compound belongs to the bromobenzenes. These are organic compounds containing a chlorine atom attached to a benzene ring.
Pharmacology
IndicationFor use in the prophylaxis and therapy of ventricular fibrillation. Also used in the treatment of life-threatening ventricular arrhythmias, such as ventricular tachycardia, that have failed to respond to adequate doses of a first-line antiarrhythmic agent, such as lidocaine.
PharmacodynamicsBretylium is a bromobenzyl quaternary ammonium compound which selectively accumulates in sympathetic ganglia and their postganglionic adrenergic neurons where it inhibits norepinephrine release by depressing adrenergic nerve terminal excitability. Bretylium also suppresses ventricular fibrillation and ventricular arrhythmias.
Mechanism of actionBretylium inhibits norepinephrine release by depressing adrenergic nerve terminal excitability. The mechanisms of the antifibrillatory and antiarrhythmic actions of bretylium are not established. In efforts to define these mechanisms, the following electrophysiologic actions of bretylium have been demonstrated in animal experiments: increase in ventricular fibrillation threshold, increase in action potential duration and effective refractory period without changes in heart rate, little effect on the rate of rise or amplitude of the cardiac action potential (Phase 0) or in resting membrane potential (Phase 4) in normal myocardium, decrease in the disparity in action potential duration between normal and infarcted regions, and increase in impulse formation and spontaneous firing rate of pacemaker tissue as well as increase ventricular conduction velocity.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

No metabolites have been identified following administration in man and laboratory animals.

Route of eliminationNot Available
Half lifeThe terminal half-life in four normal volunteers averaged 7.8±0.6 hours (range 6.9-8.1). During hemodialysis, this patient's arterial and venous bretylium concentrations declined rapidly, resulting in a half-life of 13 hours.
ClearanceNot Available
ToxicityOral, mouse: LD50 = 400 mg/kg. In the presence of life-threatening arrhythmias, underdosing with bretylium probably presents a greater risk to the patient than potential overdosage. However, one case of accidental overdose has been reported in which a rapidly injected intravenous bolus of 30 mg/kg was given instead of an intended 10 mg/kg dose during an episode of ventricular tachycardia. Marked hypertension resulted, followed by protracted refractory hypotension. The patient expired 18 hours later in asystole, complicated by renal failure and aspiration pneumonitis. Bretylium serum levels were 8000 ng/mL.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption - 0.8406
Blood Brain Barrier + 0.9484
Caco-2 permeable + 0.6831
P-glycoprotein substrate Substrate 0.5105
P-glycoprotein inhibitor I Non-inhibitor 0.9789
P-glycoprotein inhibitor II Non-inhibitor 0.8742
Renal organic cation transporter Non-inhibitor 0.6279
CYP450 2C9 substrate Non-substrate 0.861
CYP450 2D6 substrate Non-substrate 0.6999
CYP450 3A4 substrate Substrate 0.5132
CYP450 1A2 substrate Non-inhibitor 0.6973
CYP450 2C9 substrate Non-inhibitor 0.8505
CYP450 2D6 substrate Non-inhibitor 0.8475
CYP450 2C19 substrate Non-inhibitor 0.8038
CYP450 3A4 substrate Non-inhibitor 0.9752
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6854
Ames test Non AMES toxic 0.9045
Carcinogenicity Carcinogens 0.5905
Biodegradation Not ready biodegradable 0.9157
Rat acute toxicity 2.6214 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9291
hERG inhibition (predictor II) Inhibitor 0.6322
Pharmacoeconomics
Manufacturers
  • Abraxis pharmaceutical products
  • Astrazeneca lp
  • Baxter healthcare corp anesthesia and critical care
  • Hospira inc
  • International medication system
  • Luitpold pharmaceuticals inc
  • Abbott laboratories pharmaceutical products div
  • B braun medical inc
  • Baxter healthcare corp
PackagersNot Available
Dosage forms
FormRouteStrength
LiquidIntramuscular
SolutionIntramuscular
PricesNot Available
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point238Fryer, R.I., Schmidt, R.A. and Sternbach, L.H.; U.S. Patent 3,100,770; August 13, 1963; assigned to Hoffmann-LaRoche Inc. Fryer, R.I., Schmidt, R.A. and Sternbach, L.H.; U.S. Patent 3,182,065; May 4, 1965; assigned to Hoffmann-LaRoche Inc. Fryer, R.I., Schmidt, R.A. and Sternbach, L.H.; US. Patent 3,182,067; May 4, 1965; assigned to Hoffmann-LaRoche Inc.
water solubilityFreely solubleNot Available
Predicted Properties
PropertyValueSource
water solubility1.54e-04 g/lALOGPS
logP-1.4ALOGPS
logP-1.1ChemAxon
logS-6.3ALOGPS
pKa (strongest acidic)17.58ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count0ChemAxon
hydrogen donor count0ChemAxon
polar surface area0ChemAxon
rotatable bond count3ChemAxon
refractivity72.89ChemAxon
polarizability23.24ChemAxon
number of rings1ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Copp, F.C. and Stephenson, D.; US. Patent 3,038,004; June 5, 1962; assigned to Burroughs
Wellcome & Co.

US3038004
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00645
PubChem Compound2431
PubChem Substance46505320
ChemSpider2337
ChEBI3172
ChEMBLCHEMBL1199080
Therapeutic Targets DatabaseDAP000939
PharmGKBPA448662
Drug Product Database2185377
RxListhttp://www.rxlist.com/cgi/generic3/bretosy.htm
WikipediaBretylium
ATC CodesC01BD02
AHFS Codes
  • 24:04.04.20
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(73 KB)
Interactions
Drug Interactions
Drug
CisaprideIncreased risk of cardiotoxicity and arrhythmias
ClarithromycinIncreased risk of cardiotoxicity and arrhythmias
ErythromycinIncreased risk of cardiotoxicity and arryhthmias
GatifloxacinIncreased risk of cardiotoxicity and arrhythmias
GrepafloxacinIncreased risk of cardiotoxicity and arrhythmias
LevofloxacinIncreased risk of cardiotoxicity and arrhythmias
MesoridazineIncreased risk of cardiotoxicity and arrhythmias
MoxifloxacinIncreased risk of cardiotoxicity and arrhythmias
RanolazinePossible additive effect on QT prolongation
TelithromycinIncreased risk of cardiotoxicity and arrhythmias
ThioridazineIncreased risk of cardiotoxicity and arrhythmias
Food InteractionsNot Available

1. Sodium/potassium-transporting ATPase subunit alpha-1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sodium/potassium-transporting ATPase subunit alpha-1 P05023 Details

References:

  1. Dzimiri N, Almotrefi AA: Inhibition of myocardial Na()-K()-ATPase activity by bretylium: role of potassium. Arch Int Pharmacodyn Ther. 1992 Jul-Aug;318:76-85. Pubmed
  2. Helms JB, Arnett KL, Gatto C, Milanick MA: Bretylium, an organic quaternary amine, inhibits the Na,K-ATPase by binding to the extracellular K-site. Blood Cells Mol Dis. 2004 May-Jun;32(3):394-400. Pubmed
  3. Dzimiri N, Almotrefi AA: Interaction of bretylium tosylate with guinea-pig myocardial Na()-K()-ATPase. Gen Pharmacol. 1991;22(5):935-8. Pubmed
  4. Tiku PE, Nowell PT: Selective inhibition of K(+)-stimulation of Na,K-ATPase by bretylium. Br J Pharmacol. 1991 Dec;104(4):895-900. Pubmed

Comments
Drug created on June 13, 2005 07:24 / Updated on April 01, 2014 14:23