Identification

Name
Bretylium
Accession Number
DB01158  (APRD00830)
Type
Small Molecule
Groups
Approved
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
Product Ingredients
IngredientUNIICASInChI Key
Bretylium tosylate78ZP3YR35361-75-6KVWNWTZZBKCOPM-UHFFFAOYSA-M
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Bretylate Inj 50mg/mlLiquid50 mgIntramuscular; IntravenousGlaxo Wellcome1980-12-312000-01-19Canada
Bretylium Tosylate Inj 50mg/mlSolution50 mgIntramuscular; IntravenousAbbott1991-12-312007-07-31Canada
Bretylium Tosylate Injection USPSolution50 mgIntramuscular; IntravenousSandoz Canada Incorporated1995-12-31Not applicableCanada
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Bretylium Tosylate 0.2% and Dextrose 5% InjBretylium tosylate (2 mg) + Dextrose, unspecified form (50 mg)SolutionIntravenousAbbott1988-12-312007-07-31Canada
Bretylium Tosylate 0.4% and Dextrose 5% InjBretylium tosylate (4 mg) + Dextrose, unspecified form (50 mg)SolutionIntravenousAbbott1988-12-312007-07-31Canada
International/Other Brands
Anxyrex (Sanofi-Aventis) / Bretylol (ICI) / Bromidem (Nycomed) / Creosedin (AstraZeneca) / Darenthin (Burroughs Wellcome) / Lexotan (Roche) / Xionil (Novartis)
Categories
UNII
RZR75EQ2KJ
CAS number
59-41-6
Weight
Average: 243.163
Monoisotopic: 242.054437196
Chemical Formula
C11H17BrN
InChI Key
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

Pharmacology

Indication

For 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.

Associated Conditions
Pharmacodynamics

Bretylium 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 action

Bretylium 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.

TargetActionsOrganism
ASodium/potassium-transporting ATPase subunit alpha-1
inhibitor
Human
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

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

Route of elimination
Not Available
Half life

The 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.

Clearance
Not Available
Toxicity

Oral, 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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidBretylium may increase the hypotensive activities of 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid.
4-MethoxyamphetamineThe therapeutic efficacy of 4-Methoxyamphetamine can be decreased when used in combination with Bretylium.
AbediterolThe therapeutic efficacy of Abediterol can be decreased when used in combination with Bretylium.
AbexinostatThe risk or severity of QTc prolongation can be increased when Bretylium is combined with Abexinostat.
AcebutololThe risk or severity of QTc prolongation can be increased when Bretylium is combined with Acebutolol.
AceclofenacThe therapeutic efficacy of Bretylium can be decreased when used in combination with Aceclofenac.
AcemetacinThe therapeutic efficacy of Bretylium can be decreased when used in combination with Acemetacin.
AceprometazineThe risk or severity of QTc prolongation can be increased when Bretylium is combined with Aceprometazine.
AcetyldigoxinThe risk or severity of QTc prolongation can be increased when Bretylium is combined with Acetyldigoxin.
Acetylsalicylic acidThe therapeutic efficacy of Bretylium can be decreased when used in combination with Acetylsalicylic acid.
Food Interactions
Not 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 References
Not Available
External Links
Human Metabolome Database
HMDB0015289
KEGG Drug
D00645
KEGG Compound
C06855
PubChem Compound
2431
PubChem Substance
46505320
ChemSpider
2337
ChEBI
3172
ChEMBL
CHEMBL1199080
Therapeutic Targets Database
DAP000939
PharmGKB
PA448662
RxList
RxList Drug Page
Wikipedia
Bretylium
AHFS Codes
  • 24:04.04.20 — Class III Antiarrythmics
MSDS
Download (73 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
LiquidIntramuscular; Intravenous50 mg
SolutionIntravenous
SolutionIntramuscular; Intravenous50 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)238Fryer, 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 FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Phenylmethylamines
Direct Parent
Phenylmethylamines
Alternative Parents
Benzylamines / Bromobenzenes / Aralkylamines / Aryl bromides / Tetraalkylammonium salts / Organopnictogen compounds / Organobromides / Organic salts / Hydrocarbon derivatives / Organic cations
Substituents
Benzylamine / Phenylmethylamine / Aralkylamine / Bromobenzene / Halobenzene / Aryl bromide / Aryl halide / Tetraalkylammonium salt / Quaternary ammonium salt / Amine
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
quaternary ammonium ion (CHEBI:3172)

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 th...
Gene Name
ATP1A1
Uniprot ID
P05023
Uniprot Name
Sodium/potassium-transporting ATPase subunit alpha-1
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]

Drug created on June 13, 2005 07:24 / Updated on December 18, 2018 05:46