BRETYLIUM TOSYLATE

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	C7H7O3S
Molecular Weight	171.194
Charge	-1
Count

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

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

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 35 Target ID: CHEMBL2095186 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15121098	Inhibitor 8228		4.5 mM [IC50]
norepinephrine secretion 9 Target ID: GO:0048243 Sources: http://www.rxlist.com/bretylium-drug.htm	Inhibitor 8228

Conditions

Condition	Modality	Targets	Highest Phase	Product
Ventricular fibrillation 4 Sources: http://www.rxlist.com/bretylium-drug.htm	Primary		Approved 8360	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 8360	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 1599

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
Ca2+ channels 41 K+ channels 56	CYP 266

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
Ca2+ channels 44	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/18071295/	likely
K+ channels 56	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/15121098/	likely

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP 266	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/12688833/	no

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1632	inhibitor 1613 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

Baroreceptor modulation of active cutaneous vasodilation during dynamic exercise in humans.	2001 Apr	11247948
Acute cold exposure induces vagally mediated Fos expression in gastric myenteric neurons in conscious rats.	2001 Aug	11447037
Dependence of reversed-phase retention of ionizable analytes on pH, concentration of organic solvent and silanol activity.	2001 Aug 3	11519817
Intravenous antiarrhythmic agents.	2001 Jan	11124714
Localized abdominal pain following sympathetic blockade with bretylium for the management of complex regional pain syndrome.	2002 Feb	11999600
Advanced cardiac life support antiarrhythmic drugs.	2002 Feb	11845546
Evidence that the human cutaneous venoarteriolar response is not mediated by adrenergic mechanisms.	2002 Jan 15	11790822
Electrical stimulation-induced alpha1- and alpha2-adrenoceptors-mediated contractions of isolated canine lymph nodes.	2002 Mar 18	11958481
Potentially significant drug interactions of class III antiarrhythmic drugs.	2003	12688833
Inhibition of the Na,K-ATPase by the antiarrhythmic drug, Bretylium.	2003 Apr	12763901
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
Bretylium in the treatment of complex regional pain syndrome: uncommon side-effect of a common drug.	2003 Feb	12562438
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
Cutaneous active vasodilation in humans during passive heating postexercise.	2003 Sep	12777407
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
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
Sympathetic, sensory, and nonneuronal contributions to the cutaneous vasoconstrictor response to local cooling.	2005 Apr	15576441
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
Active cutaneous vasodilation in resting humans during mild heat stress.	2005 Mar	15489258
Ca2+ sensitization and the regulation of contractility in rat anococcygeus and retractor penis muscle.	2005 May 15	15857612
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
Effect of defocused CO2 laser on equine tissue perfusion.	2006	16722304
Delayed threshold for active cutaneous vasodilation in patients with Type 2 diabetes mellitus.	2006 Feb	16210432
Rate dependency and role of nitric oxide in the vascular response to direct cooling in human skin.	2006 Jan	16179403
Different vascular responses in glabrous and nonglabrous skin with increasing core temperature during exercise.	2006 Jul	16767440
Ventricular tachyarrhythmias (out of hospital cardiac arrests).	2006 Jun	16973013
Adrenergic control of venous capacitance during moderate hypoxia in the rainbow trout (Oncorhynchus mykiss): role of neural and circulating catecholamines.	2006 Sep	16741138
Leptin inhibits gastric emptying in rats: role of CCK receptors and vagal afferent fibers.	2007	16792473
Systemic hypoxia causes cutaneous vasodilation in healthy humans.	2007 Aug	17510298
Determination of adenosine effects and adenosine receptors in murine corpus cavernosum.	2007 Aug	17494861
Role of sensory nerves in the cutaneous vasoconstrictor response to local cooling in humans.	2007 Jul	17468334
The effect of the sympathetic and sensory nervous system on active eustachian tube function in the rat.	2007 Mar	17364363
Relationship among amiodarone, new class III antiarrhythmics, miscellaneous agents and acquired long QT syndrome.	2008	18651412
Anti-arrhythmic and vasopressor medications for the treatment of ventricular fibrillation in severe hypothermia: a systematic review of the literature.	2008 Jul	18406039
Plasma hyperosmolality elevates the internal temperature threshold for active thermoregulatory vasodilation during heat stress in humans.	2009 Dec	19812357
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
Investigation of the role of adrenergic and non-nitrergic, non-adrenergic neurotransmission in the sheep isolated internal anal sphincter.	2009 Mar	19254355
[Recurrent refractory ventricular fibrillation: how many times is it necessary to defibrillate?].	2010 Apr	19819591
Cold-induced vasoconstriction at forearm and hand skin sites: the effect of age.	2010 Jul	20300768

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 `Wed Jul 05 22:30:19 UTC 2023` Edited by `admin` on `Wed Jul 05 22:30:19 UTC 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