Bretylium

Identification

Summary

Bretylium is a norepinephrine release inhibitor used for the prophylaxis and therapy of ventricular fibrillation, as well as the treatment of life-threatening ventricular arrhythmias.

Generic Name
Bretylium
DrugBank Accession Number
DB01158
Background

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.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 243.163
Monoisotopic: 242.054437196
Chemical Formula
C11H17BrN
Synonyms
  • (2-bromobenzyl)ethyldimethylaminium
  • 2-bromo-N-ethyl-N,N-dimethylbenzenemethanaminium
  • Bretylium
  • N-ethyl-N,N-dimethyl-2-bromobenzenemethanaminium

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.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofVentricular fibrillation••••••••••••
Treatment ofVentricular tachycardia••••••••••••
Contraindications & Blackbox Warnings
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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
Humans
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

Adverse Effects
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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.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbaloparatideThe risk or severity of adverse effects can be increased when Bretylium is combined with Abaloparatide.
AcebutololBretylium may increase the arrhythmogenic activities of 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.
AcetyldigitoxinAcetyldigitoxin may increase the arrhythmogenic activities of Bretylium.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Bretylium tosylate78ZP3YR35361-75-6KVWNWTZZBKCOPM-UHFFFAOYSA-M
International/Other Brands
Anxyrex (Sanofi-Aventis) / Bretylol (ICI) / Bromidem (Nycomed) / Creosedin (AstraZeneca) / Darenthin (Burroughs Wellcome) / Lexotan (Roche) / Xionil (Novartis)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Bretylate Inj 50mg/mlLiquid50 mg / mLIntramuscular; IntravenousGlaxo Wellcome1980-12-312000-01-19Canada flag
Bretylium Tosylate Inj 50mg/mlSolution50 mg / mLIntramuscular; IntravenousAbbott1991-12-312007-07-31Canada flag
Bretylium Tosylate Injection USPSolution50 mg / mLIntramuscular; IntravenousSandoz Canada Incorporated1995-12-312021-04-21Canada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Bretylium TosylateInjection50 mg/1mLIntramuscular; IntravenousPharmaceutics International, Inc. (Pii)2019-06-302020-03-12US flag
Bretylium TosylateInjection50 mg/1mLIntramuscular; IntravenousANI Pharmaceuticals, Inc.2019-12-11Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Bretylium Tosylate 0.2% and Dextrose 5% InjBretylium tosylate (2 mg / mL) + Dextrose, unspecified form (50 mg / mL)SolutionIntravenousAbbott1988-12-312007-07-31Canada flag
Bretylium Tosylate 0.4% and Dextrose 5% InjBretylium tosylate (4 mg / mL) + Dextrose, unspecified form (50 mg / mL)SolutionIntravenousAbbott1988-12-312007-07-31Canada flag

Categories

ATC Codes
C01BD02 — Bretylium tosilate
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Amine / Aralkylamine / Aromatic homomonocyclic compound / Aryl bromide / Aryl halide / Benzylamine / Bromobenzene / Halobenzene / Hydrocarbon derivative / Organic cation
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
quaternary ammonium ion (CHEBI:3172)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
RZR75EQ2KJ
CAS number
59-41-6
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

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
Human Metabolome Database
HMDB0015289
KEGG Drug
D00645
KEGG Compound
C06855
PubChem Compound
2431
PubChem Substance
46505320
ChemSpider
2337
BindingDB
50239966
RxNav
19685
ChEBI
3172
ChEMBL
CHEMBL1199080
ZINC
ZINC000000001041
Therapeutic Targets Database
DAP000939
PharmGKB
PA448662
RxList
RxList Drug Page
Wikipedia
Bretylium
MSDS
Download (73 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
LiquidIntramuscular; Intravenous50 mg / mL
InjectionIntramuscular; Intravenous50 mg/1mL
SolutionIntravenous
SolutionIntramuscular; Intravenous50 mg / mL
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-MSsplash10-00or-9660000000-f1a790c5dc75745515bf
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-130.80302
predicted
DeepCCS 1.0 (2019)
[M+H]+133.19843
predicted
DeepCCS 1.0 (2019)
[M+Na]+141.28175
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
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. [Article]
  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. [Article]
  3. Dzimiri N, Almotrefi AA: Interaction of bretylium tosylate with guinea-pig myocardial Na(+)-K(+)-ATPase. Gen Pharmacol. 1991;22(5):935-8. [Article]
  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. [Article]

Drug created at June 13, 2005 13:24 / Updated at March 28, 2024 03:23