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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
Synonyms
SynonymLanguageCode
(2-Bromobenzyl)ethyldimethylaminiumNot AvailableNot Available
2-Bromo-N-ethyl-N,N-dimethylbenzenemethanaminiumNot AvailableNot Available
N-Ethyl-N,N-dimethyl-2-bromobenzenemethanaminiumNot AvailableNot Available
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
AnxyrexSanofi-Aventis
BretylolICI
BromidemNycomed
CreosedinAstraZeneca
DarenthinBurroughs Wellcome
LexotanRoche
XionilNovartis
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Bretylium tosylate
ThumbNot applicableDBSALT001050
Categories
CAS number59-41-6
WeightAverage: 243.163
Monoisotopic: 242.054437196
Chemical FormulaC11H17BrN
InChI KeyAAQOQKQBGPPFNS-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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phenylmethylamines. These are compounds containing a phenylmethtylamine moiety, which consists of a phenyl group substituted by an methanamine.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassPhenylmethylamines
Direct ParentPhenylmethylamines
Alternative Parents
Substituents
  • Phenylmethylamine
  • Benzylamine
  • Aralkylamine
  • Halobenzene
  • Bromobenzene
  • Aryl halide
  • Aryl bromide
  • Quaternary ammonium salt
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Organobromide
  • Organohalogen compound
  • Amine
  • Organic cation
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors
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
PropertyValueProbability
Human Intestinal Absorption-0.8406
Blood Brain Barrier+0.9484
Caco-2 permeable+0.6831
P-glycoprotein substrateSubstrate0.5105
P-glycoprotein inhibitor INon-inhibitor0.9789
P-glycoprotein inhibitor IINon-inhibitor0.8742
Renal organic cation transporterNon-inhibitor0.6279
CYP450 2C9 substrateNon-substrate0.861
CYP450 2D6 substrateNon-substrate0.6999
CYP450 3A4 substrateSubstrate0.5132
CYP450 1A2 substrateNon-inhibitor0.6973
CYP450 2C9 substrateNon-inhibitor0.8505
CYP450 2D6 substrateNon-inhibitor0.8475
CYP450 2C19 substrateNon-inhibitor0.8038
CYP450 3A4 substrateNon-inhibitor0.9752
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.6854
Ames testNon AMES toxic0.9045
CarcinogenicityCarcinogens 0.5905
BiodegradationNot ready biodegradable0.9157
Rat acute toxicity2.6214 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9291
hERG inhibition (predictor II)Inhibitor0.6322
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
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 Solubility0.000154 mg/mLALOGPS
logP-1.4ALOGPS
logP-1.1ChemAxon
logS-6.3ALOGPS
pKa (Strongest Acidic)17.58ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count0ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area0 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity72.89 m3·mol-1ChemAxon
Polarizability23.24 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
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
ATC CodesNot Available
AHFS Codes
  • 24:04.04.20
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (73 KB)
Interactions
Drug Interactions
Drug
AcebutololMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
AmiodaroneMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
AtenololMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
BendroflumethiazideMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
BeractantMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
BisoprololMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
ButabarbitalMay enhance the hypotensive effect of Hypotensive Agents.
ButethalMay enhance the hypotensive effect of Hypotensive Agents.
CalfactantMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
CarteololMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
CarvedilolMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
ClonidineMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
CrizotinibMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
DigoxinMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
DiltiazemMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
DonepezilMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
DronedaroneMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
DuloxetineHypotensive Agents may enhance the orthostatic hypotensive effect of DULoxetine.
EsmololMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
FingolimodMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
GalantamineMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
GuanfacineMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
HeptabarbitalMay enhance the hypotensive effect of Hypotensive Agents.
HexobarbitalMay enhance the hypotensive effect of Hypotensive Agents.
LabetalolMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
LanreotideMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
LevobunololMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
LucinactantMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
MethohexitalMay enhance the hypotensive effect of Hypotensive Agents.
MethyldopaMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
MetipranololMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
MetoprololMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
NadololMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
NebivololMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
OctreotideMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
PasireotideMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
PenbutololMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
PentobarbitalMay enhance the hypotensive effect of Hypotensive Agents.
PindololMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
PrimidoneMay enhance the hypotensive effect of Hypotensive Agents.
PropafenoneMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
PropranololMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
RisperidoneHypotensive Agents may enhance the hypotensive effect of RisperiDONE.
RivastigmineMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
SecobarbitalMay enhance the hypotensive effect of Hypotensive Agents.
SotalolMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
SufentanilMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
TimololMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
TizanidineMay enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents.
Food InteractionsNot Available

Targets

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

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