BRETYLIUM TOSYLATE

US Previously Marketed

Details

Stereochemistry	ACHIRAL
Molecular Formula	C11H17BrN.C7H7O3S
Molecular Weight	414.357
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=CC=C(C=C1)S([O-])(=O)=O.CC[N+](C)(C)CC2=C(Br)C=CC=C2

InChI

InChIKey=KVWNWTZZBKCOPM-UHFFFAOYSA-M

InChI=1S/C11H17BrN.C7H8O3S/c1-4-13(2,3)9-10-7-5-6-8-11(10)12;1-6-2-4-7(5-3-6)11(8,9)10/h5-8H,4,9H2,1-3H3;2-5H,1H3,(H,8,9,10)/q+1;/p-1

HIDE SMILES / InChI

Molecular Formula	C11H17BrN
Molecular Weight	243.163
Charge	1
Count

Stereochemistry	RACEMIC
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	C7H7O3S
Molecular Weight	171.194
Charge	-1
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://www.rxlist.com/bretylium-drug.htm | https://www.ncbi.nlm.nih.gov/pubmed/386786

Bretylium (bretylium tosylate) is an antifibrillatory and antiarrhythmic agent. Bretylium is abromobenzyl 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. The drug has a direct positive inotropic effect on the myocardium and blocking effect on postganglionic sympathetic nerve transmission. The drug is poorly absorbed orally, requiring either i.m. or i.v. administration.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Sodium/potassium-transporting ATPase 39 Target ID: CHEMBL2095186 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15121098	Inhibitor 8297		4.5 mM [IC50]
norepinephrine secretion 9 Target ID: GO:0048243 Sources: http://www.rxlist.com/bretylium-drug.htm	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Ventricular fibrillation 4 Sources: http://www.rxlist.com/bretylium-drug.htm	Primary		Approved 8429	BRETYLIUM TOSYLATE Approved Use Bretylium (bretylium tosylate injection ) Tosylate is indicated in the prophylaxis and therapy of ventricular fibrillation. Bretylium (bretylium tosylate injection ) tosylate is also indicated 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. Use of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION should be limited to intensive care units, coronary care units or other facilities where equipment and personnel for constant monitoring of cardiac arrhythmias and blood pressure are available. Following injection of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION there may be a delay of 20 minutes to 2 hours in the onset of antiarrhythmic action, although it appears to act within minutes in ventricular fibrillation. The delay in effect appears to be longer after intramuscular than after intravenous injection.
Ventricular arrhythmia 50 Sources: http://www.rxlist.com/bretylium-drug.htm	Primary		Approved 8429	BRETYLIUM TOSYLATE Approved Use Bretylium (bretylium tosylate injection ) Tosylate is indicated in the prophylaxis and therapy of ventricular fibrillation. Bretylium (bretylium tosylate injection ) tosylate is also indicated 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. Use of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION should be limited to intensive care units, coronary care units or other facilities where equipment and personnel for constant monitoring of cardiac arrhythmias and blood pressure are available. Following injection of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION there may be a delay of 20 minutes to 2 hours in the onset of antiarrhythmic action, although it appears to act within minutes in ventricular fibrillation. The delay in effect appears to be longer after intramuscular than after intravenous injection.

C_max

Value	Dose	Co-administered	Analyte	Population
1100 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7104462/	100 mg single, intravenous dose: 100 mg route of administration: Intravenous experiment type: SINGLE co-administered:		BRETYLIUM plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
535 min EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7104462/	100 mg single, intravenous dose: 100 mg route of administration: Intravenous experiment type: SINGLE co-administered:		BRETYLIUM plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

Doses

Dose	Population	Adverse events
2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/7586312	unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: https://pubmed.ncbi.nlm.nih.gov/7586312	Other AEs: Hypotension, Heart block... Other AEs: Hypotension (32%) Heart block (4%) Congestive heart failure (5%) Proarrhythmia (3%) Nausea (6%) Confusion (4%) Thrombocytopenia (3%) Fever (1%) Diarrhea (5%) Sources: https://pubmed.ncbi.nlm.nih.gov/7586312

AEs

AE	Significance	Dose	Population
Fever	1%	2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/7586312	unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: https://pubmed.ncbi.nlm.nih.gov/7586312
Proarrhythmia	3%	2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/7586312	unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: https://pubmed.ncbi.nlm.nih.gov/7586312
Thrombocytopenia	3%	2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/7586312	unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: https://pubmed.ncbi.nlm.nih.gov/7586312
Hypotension	32%	2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/7586312	unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: https://pubmed.ncbi.nlm.nih.gov/7586312
Confusion	4%	2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/7586312	unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: https://pubmed.ncbi.nlm.nih.gov/7586312
Heart block	4%	2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/7586312	unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: https://pubmed.ncbi.nlm.nih.gov/7586312
Congestive heart failure	5%	2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/7586312	unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: https://pubmed.ncbi.nlm.nih.gov/7586312
Diarrhea	5%	2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/7586312	unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: https://pubmed.ncbi.nlm.nih.gov/7586312
Nausea	6%	2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/7586312	unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: https://pubmed.ncbi.nlm.nih.gov/7586312

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
			inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
Ca2+ channels 57 K+ channels 70	CYP 270

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
Ca2+ channels 60	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/18071295/	likely
K+ channels 70	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/15121098/	likely

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP 270	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/12688833/	no

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/18651412/

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:3172	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:3172
ChemicalBook	CB31178143	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB31178143
ZINC	ZINC000000001041	http://zinc15.docking.org/substances/ZINC000000001041

PubMed

Title	Date	PubMed
Potentially significant drug interactions of class III antiarrhythmic drugs.	2003	12688833
Carotid-sinus baroreflex modulation of core and skin temperatures in rats: an open-loop approach.	2003 Dec	15038844
Survival and normal neurological outcome after CPR with periodic Gz acceleration and vasopressin.	2003 Feb	12589997
How do Belgian mobile intensive care units deal with cardiovascular emergencies?	2003 Jun	12789062
Strategies for reversing shock-resistant ventricular fibrillation.	2003 Jun	12771668
Amiodarone and bretylium in the treatment of hypothermic ventricular fibrillation in a canine model.	2003 Mar	12615580
Cutaneous vasoconstrictor response to whole body skin cooling is altered by time of day.	2003 Mar	12571128
Effects of reboxetine on sympathetic neuroeffector transmission in rabbit carotid artery.	2003 Sep	12754319
Effects of ovariectomy and steroid hormones on vaginal smooth muscle contractility.	2004 Feb	14963470
Altered neurotransmitter control of reflex vasoconstriction in aged human skin.	2004 Jul 15	15181162
Bretylium, an organic quaternary amine, inhibits the Na,K-ATPase by binding to the extracellular K-site.	2004 May-Jun	15121098
Prevention of ventricular fibrillation, acute myocardial infarction (myocardial necrosis), heart failure, and mortality by bretylium: is ischemic heart disease primarily adrenergic cardiovascular disease?	2004 Sep-Oct	15356432
[Particular features of the impact of certain vegetotropic drugs on the excitability of cholinergic structures, contractile myocardial function and electromotive stomach activity].	2005	16518920
Sympathetic, sensory, and nonneuronal contributions to the cutaneous vasoconstrictor response to local cooling.	2005 Apr	15576441
Exogenous melatonin delays gastric emptying rate in rats: role of CCK2 and 5-HT3 receptors.	2005 Dec	16391413
Electrical storms in Brugada syndrome: review of pharmacologic and ablative therapeutic options.	2005 Jan 1	16943940
Complex regional pain syndrome: which treatments show promise?	2005 Jul	16009087
Decreased microvascular nitric oxide-dependent vasodilation in postural tachycardia syndrome.	2005 Oct 25	16230486
Peripheral mechanisms involved in gastric mucosal protection by intracerebroventricular and intraperitoneal nociceptin in rats.	2005 Sep	15919744
Rate dependency and role of nitric oxide in the vascular response to direct cooling in human skin.	2006 Jan	16179403
Differences in the postexercise threshold for cutaneous active vasodilation between men and women.	2006 Jan	16123228
Noradrenergic and cholinergic neural pathways mediate stress-induced reactivation of colitis in the rat.	2006 Jan 30	16464645
Ventricular tachyarrhythmias (out of hospital cardiac arrests).	2006 Jun	16973013
Refractory Electrical Storm suppression by bretylium.	2006 Nov 18	16904769
Adrenergic control of venous capacitance during moderate hypoxia in the rainbow trout (Oncorhynchus mykiss): role of neural and circulating catecholamines.	2006 Sep	16741138
Determination of adenosine effects and adenosine receptors in murine corpus cavernosum.	2007 Aug	17494861
Cholinergic innervation of the guinea-pig isolated vas deferens.	2007 Dec	17992517
Influence of hyperoxia on skin vasomotor control in normothermic and heat-stressed humans.	2007 Dec	17885027
Reducing myocardial injury by minimizing imbalance between oxygen supply and demand.	2007 Jul	17585228
The effect of the sympathetic and sensory nervous system on active eustachian tube function in the rat.	2007 Mar	17364363
[Electrical storm].	2007 Nov	17920558
Bretylium abolishes neurotransmitter release without necessarily abolishing the nerve terminal action potential in sympathetic terminals.	2008 Feb	18071295
Criteria for arrhythmogenicity in genetically-modified Langendorff-perfused murine hearts modelling the congenital long QT syndrome type 3 and the Brugada syndrome.	2008 Jan	17805561
Influence of intravesicular pH drift and membrane binding on the liposomal release of a model amine-containing permeant.	2008 Jan	17694543
The involvement of norepinephrine, neuropeptide Y, and nitric oxide in the cutaneous vasodilator response to local heating in humans.	2008 Jul	18483164
EANM procedure guidelines for 131I-meta-iodobenzylguanidine (131I-mIBG) therapy.	2008 May	18274745
Plasma hyperosmolality elevates the internal temperature threshold for active thermoregulatory vasodilation during heat stress in humans.	2009 Dec	19812357
Plasma ATP concentration and venous oxygen content in the forearm during dynamic handgrip exercise.	2009 Dec 15	20003530
Neural reflex hypotension induced by very small dose of hypertonic NaCl solution in rats.	2009 Feb 28	19764348
The involvement of heating rate and vasoconstrictor nerves in the cutaneous vasodilator response to skin warming.	2009 Jan	19011042
The diagnosis of brain death.	2009 Jan-Mar	19881172
A resuscitation of bretylium?	2009 Nov-Dec	19940608
[Recurrent refractory ventricular fibrillation: how many times is it necessary to defibrillate?].	2010 Apr	19819591
Amiodarone for the treatment and prevention of ventricular fibrillation and ventricular tachycardia.	2010 Aug 9	20730062
Tetrahydrobiopterin does not affect end-organ responsiveness to norepinephrine-mediated vasoconstriction in aged skin.	2010 Dec	20926766
Nitric oxide-induced vasorelaxation in response to PnTx2-6 toxin from Phoneutria nigriventer spider in rat cavernosal tissue.	2010 Dec	20722794
Survival after prolonged resuscitation with 99 defibrillations due to Torsade De Pointes cardiac electrical storm: a case report.	2010 Feb 6	20137096
Cold-induced vasoconstriction at forearm and hand skin sites: the effect of age.	2010 Jul	20300768
Evidence based guidelines for complex regional pain syndrome type 1.	2010 Mar 31	20356382
Increased excitability and spontaneous activity of rat sensory neurons following in vitro stimulation of sympathetic fiber sprouts in the isolated dorsal root ganglion.	2010 Nov	20800969

Patents

Sample Use Guides

In Vivo Use Guide

BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION is to be used clinically only for treatment of life-threatening ventricular arrhythmias under constant electrocardiographic monitoring. The clinical use of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION is for short-term use only. Patients should either be kept supine during the course of bretylium (bretylium tosylate injection ) therapy or be closely observed for postural hypotension. The optimal dose schedule for parenteral administration of the drug has not been determined. There is comparatively little experience with dosages greater than 40mg/kg/day, although such doses have been used without apparent adverse effects. The following schedules are suggested: A. For immediately Life-threatening Ventricular Arrhythmias such as Ventricular Fibrillation or Hemodynamically Unstable Ventricular Tachycardia: Administer undiluted BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION at a dosage of 5mg/kg of body weight by rapid intravenous injection. Other usual cardiopulmonary resuscitative procedures, including electrical cardioversion, should be employed prior to and following the injection in accordance with good medical practice. If ventricular fibrillation persists, the dosage may be increased to 10mg/kg and repeated as necessary. For continuous suppression, dilute Bretylium (bretylium tosylate injection ) Tosylate Injection with Dextrose Injection, USP or Sodium Chloride Injection, USP using the table below and administer the diluted solution as a constant infusion of 1 to 2mg Bretylium (bretylium tosylate injection ) Tosylate Injection per minute, (see Table below). When administering Bretylium (bretylium tosylate injection ) Tosylate Injection (or any potent medication) by continuous intravenous infusion, it is advisable to use a precision volume control device. An alternative maintenance schedule is to infuse the diluted solution at a dosage of 5 to 10mg Bretylium (bretylium tosylate injection ) Tosylate per kg body weight, over a period greater than 8 minutes, every 6 hours. More rapid infusion may cause nausea and vomiting, and in patients older than 65 years, may increase the risk of developing orthostatic hypotension. B. Other ventricular arrhythmias: 1) Intravenous Use: Bretylium (bretylium tosylate injection ) tosylate injection must be diluted as described above before intravenous use. Administer the diluted solution at a dosage of 5 to 10mg bretylium (bretylium tosylate injection ) tosylate per kg of body weight by intravenous infusion over a period greater than 8 minutes. More rapid infusion may cause nausea and vomiting, and in patients older than 65 years, may increase the risk of developing orthostatic hypotension. Subsequent doses may be given at 1 to 2 hour intervals if the arrhythmia persists. 2) For Intramuscular Injection: DO NOT DILUTE BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION PRIOR TO INTRAMUSCULAR INJECTION. Inject 5 to 10mg bretylium (bretylium tosylate injection ) tosylate per kg of body weight. Subsequent doses may be given at 1 to 2 hour intervals if the arrhythmia persists. Thereafter, maintain the same dosage every 6 to 8 hours. Intramuscular injection should not be made directly into or near a major nerve, and the site of injection should be varied on repeated injection. Not more than 5mL should be injected intramuscularly in one site. (See PRECAUTONS) As soon as possible, and when indicated, patients should be changed to an oral antiarrhythmic agent for maintenance therapy.

Route of Administration: Other

In Vitro Use Guide

bretylium at 1-100 uM prolonged the action potentials of the Wistar Kyoto normotensive rat left ventricular strip.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 14:58:13 GMT 2023` Edited by `admin` on `Fri Dec 15 14:58:13 GMT 2023`
Record UNII	78ZP3YR353
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

BRETYLIUM TOSYLATE

Official Name

English

BRETYLIUM TOSILATE [MART.]

Common Name

English

BENZENEMETHANAMINIUM, 2-BROMO-N-ETHYL-N,N-DIMETHYL-, SALT WITH 4-METHYLBENZENESULFONIC ACID (1:1)

Common Name

English

BRETYLIUM TOSYLATE [USAN]

Common Name

English

bretylium tosilate [INN]

Common Name

English

(O-BROMOBENZYL)ETHYLDIMETHYLAMMONIUM P-TOLUENESULPHONATE

Common Name

English

BRETYLIUM TOSYLATE [ORANGE BOOK]

Common Name

English

BRETYLIUM TOSYLATE [USP-RS]

Common Name

English

NSC-62164

Code

English

BRETYLIUM TOSYLATE [USP MONOGRAPH]

Common Name

English

BRETYLOL

Brand Name

English

BRETYLIUM TOSILATE

Official Name

English

Bretylium tosilate [WHO-DD]

Common Name

English

ASL-603

Code

English

BRETYLIUM TOSYLATE [MI]

Common Name

English

(O-BROMOBENZYL)ETHYLDIMETHYLAMMONIUM P-TOLUENESULFONATE

Common Name

English

BRETYLIUM TOSYLATE [VANDF]

Common Name

English

Classification Tree Code System Code

WHO-VATC

QC01BD02