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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
(2-Bromobenzyl)ethyldimethylaminium
2-Bromo-N-ethyl-N,N-dimethylbenzenemethanaminium
N-Ethyl-N,N-dimethyl-2-bromobenzenemethanaminium
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Bretylate Inj 50mg/mlliquid50 mgintramuscular; intravenousGlaxo Wellcome Inc.1980-12-312000-01-19Canada
Bretylium Tosylate Inj 50mg/mlsolution50 mgintramuscular; intravenousAbbott Laboratories, Limited1991-12-312007-07-31Canada
Bretylium Tosylate Injection USPsolution50 mgintramuscular; intravenousSandoz Canada Incorporated1995-12-31Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
AnxyrexSanofi-Aventis
BretylolICI
BromidemNycomed
CreosedinAstraZeneca
DarenthinBurroughs Wellcome
LexotanRoche
XionilNovartis
Brand mixtures
NameLabellerIngredients
Bretylium Tosylate 0.2% and Dextrose 5% InjAbbott Laboratories, Limited
Bretylium Tosylate 0.4% and Dextrose 5% InjAbbott Laboratories, Limited
Salts
Name/CASStructureProperties
Bretylium tosylate
ThumbNot applicableDBSALT001050
Categories
UNIIRZR75EQ2KJ
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
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.
Related Articles
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 inhibitorNon-inhibitor0.8505
CYP450 2D6 inhibitorNon-inhibitor0.8475
CYP450 2C19 inhibitorNon-inhibitor0.8038
CYP450 3A4 inhibitorNon-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
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Liquidintramuscular; intravenous50 mg
Solutionintravenous
Solutionintramuscular; intravenous50 mg
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 ReferencesNot 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
AcebutololBretylium may increase the bradycardic activities of Acebutolol.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Bretylium.
AmiodaroneBretylium may increase the bradycardic activities of Amiodarone.
AtenololBretylium may increase the bradycardic activities of Atenolol.
BeractantBretylium may increase the bradycardic activities of Beractant.
BetaxololBretylium may increase the bradycardic activities of Betaxolol.
BisoprololBretylium may increase the bradycardic activities of Bisoprolol.
ButabarbitalButabarbital may increase the hypotensive activities of Bretylium.
ButethalButethal may increase the hypotensive activities of Bretylium.
CalfactantBretylium may increase the bradycardic activities of Calfactant.
CarteololBretylium may increase the bradycardic activities of Carteolol.
CarvedilolBretylium may increase the bradycardic activities of Carvedilol.
CeritinibBretylium may increase the bradycardic activities of Ceritinib.
ClonidineBretylium may increase the bradycardic activities of Clonidine.
CrizotinibBretylium may increase the bradycardic activities of Crizotinib.
DexmedetomidineBretylium may increase the bradycardic activities of Dexmedetomidine.
DigoxinBretylium may increase the bradycardic activities of Digoxin.
DiltiazemBretylium may increase the bradycardic activities of Diltiazem.
DonepezilBretylium may increase the bradycardic activities of Donepezil.
DronedaroneBretylium may increase the bradycardic activities of Dronedarone.
DuloxetineBretylium may increase the orthostatic hypotensive activities of Duloxetine.
EsmololBretylium may increase the bradycardic activities of Esmolol.
FingolimodBretylium may increase the bradycardic activities of Fingolimod.
GalantamineBretylium may increase the bradycardic activities of Galantamine.
GuanfacineBretylium may increase the bradycardic activities of Guanfacine.
HeptabarbitalHeptabarbital may increase the hypotensive activities of Bretylium.
HexobarbitalHexobarbital may increase the hypotensive activities of Bretylium.
IvabradineBretylium may increase the bradycardic activities of Ivabradine.
LabetalolBretylium may increase the bradycardic activities of Labetalol.
LanreotideBretylium may increase the bradycardic activities of Lanreotide.
LevobunololBretylium may increase the bradycardic activities of Levobunolol.
LevodopaBretylium may increase the orthostatic hypotensive activities of Levodopa.
LucinactantBretylium may increase the bradycardic activities of Lucinactant.
MethohexitalMethohexital may increase the hypotensive activities of Bretylium.
MethyldopaBretylium may increase the bradycardic activities of Methyldopa.
MetipranololBretylium may increase the bradycardic activities of Metipranolol.
MetoprololBretylium may increase the bradycardic activities of Metoprolol.
NadololBretylium may increase the bradycardic activities of Nadolol.
NebivololBretylium may increase the bradycardic activities of Nebivolol.
NicorandilNicorandil may increase the hypotensive activities of Bretylium.
OctreotideBretylium may increase the bradycardic activities of Octreotide.
PasireotideBretylium may increase the bradycardic activities of Pasireotide.
PenbutololBretylium may increase the bradycardic activities of Penbutolol.
PentobarbitalPentobarbital may increase the hypotensive activities of Bretylium.
PhenelzinePhenelzine may increase the orthostatic hypotensive activities of Bretylium.
PindololBretylium may increase the bradycardic activities of Pindolol.
Poractant alfaBretylium may increase the bradycardic activities of Poractant alfa.
PrimidonePrimidone may increase the hypotensive activities of Bretylium.
PropafenoneBretylium may increase the bradycardic activities of Propafenone.
PropranololBretylium may increase the bradycardic activities of Propranolol.
RisperidoneBretylium may increase the hypotensive activities of Risperidone.
RivastigmineBretylium may increase the bradycardic activities of Rivastigmine.
SecobarbitalSecobarbital may increase the hypotensive activities of Bretylium.
SotalolBretylium may increase the bradycardic activities of Sotalol.
SufentanilBretylium may increase the bradycardic activities of Sufentanil.
TimololBretylium may increase the bradycardic activities of Timolol.
TizanidineBretylium may increase the bradycardic activities of Tizanidine.
TranylcypromineTranylcypromine may increase the orthostatic hypotensive activities of Bretylium.
ValsartanThe risk or severity of adverse effects can be increased when Valsartan is combined with Bretylium.
VerapamilBretylium may increase the bradycardic activities of Verapamil.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Steroid hormone binding
Specific Function:
This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients.
Gene Name:
ATP1A1
Uniprot ID:
P05023
Molecular Weight:
112895.01 Da
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:1334399 ]
  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:15121098 ]
  3. Dzimiri N, Almotrefi AA: Interaction of bretylium tosylate with guinea-pig myocardial Na(+)-K(+)-ATPase. Gen Pharmacol. 1991;22(5):935-8. [PubMed:1662173 ]
  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:1667290 ]
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23