Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C11H17BrN |
| Molecular Weight | 243.163 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 1 |
SHOW SMILES / InChI
SMILES
CC[N+](C)(C)CC1=C(Br)C=CC=C1
InChI
InChIKey=AAQOQKQBGPPFNS-UHFFFAOYSA-N
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
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.
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: CHEMBL2095186 |
4.5 mM [IC50] | ||
Target ID: GO:0048243 |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | BRETYLIUM TOSYLATE Approved UseBretylium (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. |
|||
| Primary | BRETYLIUM TOSYLATE Approved UseBretylium (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. |
Cmax
| 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 |
T1/2
| 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: |
unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: |
Other AEs: Hypotension, Heart block... Other AEs: Hypotension (32%) Sources: Heart block (4%) Congestive heart failure (5%) Proarrhythmia (3%) Nausea (6%) Confusion (4%) Thrombocytopenia (3%) Fever (1%) Diarrhea (5%) |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Fever | 1% | 2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: |
unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: |
| Proarrhythmia | 3% | 2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: |
unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: |
| Thrombocytopenia | 3% | 2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: |
unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: |
| Hypotension | 32% | 2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: |
unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: |
| Confusion | 4% | 2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: |
unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: |
| Heart block | 4% | 2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: |
unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: |
| Congestive heart failure | 5% | 2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: |
unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: |
| Diarrhea | 5% | 2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: |
unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: |
| Nausea | 6% | 2500 mg multiple, intravenous Dose: 2500 mg Route: intravenous Route: multiple Dose: 2500 mg Sources: |
unhealthy, 66±12 years n = 103 Health Status: unhealthy Age Group: 66±12 years Sex: M+F Population Size: 103 Sources: |
Overview
| CYP3A4 | CYP2C9 | CYP2D6 | hERG |
|---|---|---|---|
OverviewOther
| Other Inhibitor | Other Substrate | Other Inducer |
|---|---|---|
Drug as perpetrator
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
| likely | ||||
| likely |
Drug as victim
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
| no |
Tox targets
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
PubMed
| Title | Date | PubMed |
|---|---|---|
| Treatment of acute systemic toxicity after the rapid intravenous injection of ropivacaine and bupivacaine in the conscious dog. | 1991 Oct |
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| Inhibition of the Na,K-ATPase by the antiarrhythmic drug, Bretylium. | 2003 Apr |
|
| Carotid-sinus baroreflex modulation of core and skin temperatures in rats: an open-loop approach. | 2003 Dec |
|
| How do Belgian mobile intensive care units deal with cardiovascular emergencies? | 2003 Jun |
|
| Strategies for reversing shock-resistant ventricular fibrillation. | 2003 Jun |
|
| Cutaneous vasoconstrictor response to whole body skin cooling is altered by time of day. | 2003 Mar |
|
| Effects of reboxetine on sympathetic neuroeffector transmission in rabbit carotid artery. | 2003 Sep |
|
| Altered neurotransmitter control of reflex vasoconstriction in aged human skin. | 2004 Jul 15 |
|
| [Particular features of the impact of certain vegetotropic drugs on the excitability of cholinergic structures, contractile myocardial function and electromotive stomach activity]. | 2005 |
|
| Sympathetic, sensory, and nonneuronal contributions to the cutaneous vasoconstrictor response to local cooling. | 2005 Apr |
|
| Cholinergic innervation of the mouse isolated vas deferens. | 2005 Dec |
|
| Electrical storms in Brugada syndrome: review of pharmacologic and ablative therapeutic options. | 2005 Jan 1 |
|
| Active cutaneous vasodilation in resting humans during mild heat stress. | 2005 Mar |
|
| Ca2+ sensitization and the regulation of contractility in rat anococcygeus and retractor penis muscle. | 2005 May 15 |
|
| Solute attributes and molecular interactions contributing to "U-shape" retention on a fluorinated high-performance liquid chromatography stationary phase. | 2005 May 6 |
|
| Decreased microvascular nitric oxide-dependent vasodilation in postural tachycardia syndrome. | 2005 Oct 25 |
|
| Peripheral mechanisms involved in gastric mucosal protection by intracerebroventricular and intraperitoneal nociceptin in rats. | 2005 Sep |
|
| Effect of defocused CO2 laser on equine tissue perfusion. | 2006 |
|
| Intracellular cGMP may promote Ca2+-dependent and Ca2+-independent release of catecholamines from sympathetic nerve terminals. | 2006 Aug |
|
| The involvement of nitric oxide in the cutaneous vasoconstrictor response to local cooling in humans. | 2006 Aug 1 |
|
| Rate dependency and role of nitric oxide in the vascular response to direct cooling in human skin. | 2006 Jan |
|
| Differences in the postexercise threshold for cutaneous active vasodilation between men and women. | 2006 Jan |
|
| Noradrenergic and cholinergic neural pathways mediate stress-induced reactivation of colitis in the rat. | 2006 Jan 30 |
|
| Different vascular responses in glabrous and nonglabrous skin with increasing core temperature during exercise. | 2006 Jul |
|
| Local regulation of skin blood flow during cooling involving presynaptic P2 purinoceptors in rats. | 2006 Jul |
|
| Nitric oxide and noradrenaline contribute to the temperature threshold of the axon reflex response to gradual local heating in human skin. | 2006 May 1 |
|
| LC/MS/MS analysis of quaternary ammonium drugs and herbicides in whole blood. | 2006 Oct 2 |
|
| Adrenergic control of venous capacitance during moderate hypoxia in the rainbow trout (Oncorhynchus mykiss): role of neural and circulating catecholamines. | 2006 Sep |
|
| Modification of cutaneous vasodilator response to heat stress by daytime exogenous melatonin administration. | 2006 Sep |
|
| Leptin inhibits gastric emptying in rats: role of CCK receptors and vagal afferent fibers. | 2007 |
|
| Determination of adenosine effects and adenosine receptors in murine corpus cavernosum. | 2007 Aug |
|
| Cholinergic innervation of the guinea-pig isolated vas deferens. | 2007 Dec |
|
| The effect of the sympathetic and sensory nervous system on active eustachian tube function in the rat. | 2007 Mar |
|
| Pharmacotherapy options for complex regional pain syndrome. | 2007 May |
|
| Relationship among amiodarone, new class III antiarrhythmics, miscellaneous agents and acquired long QT syndrome. | 2008 |
|
| Prediction of oral absorption in humans by experimental immobilized artificial membrane chromatography indices and physicochemical descriptors. | 2008 Aug 6 |
|
| Bretylium abolishes neurotransmitter release without necessarily abolishing the nerve terminal action potential in sympathetic terminals. | 2008 Feb |
|
| The involvement of norepinephrine, neuropeptide Y, and nitric oxide in the cutaneous vasodilator response to local heating in humans. | 2008 Jul |
|
| Anti-arrhythmic and vasopressor medications for the treatment of ventricular fibrillation in severe hypothermia: a systematic review of the literature. | 2008 Jul |
|
| Nervous and humoral control of cardiac performance in the winter flounder (Pleuronectes americanus). | 2009 Apr |
|
| Plasma hyperosmolality elevates the internal temperature threshold for active thermoregulatory vasodilation during heat stress in humans. | 2009 Dec |
|
| Plasma ATP concentration and venous oxygen content in the forearm during dynamic handgrip exercise. | 2009 Dec 15 |
|
| The involvement of heating rate and vasoconstrictor nerves in the cutaneous vasodilator response to skin warming. | 2009 Jan |
|
| The diagnosis of brain death. | 2009 Jan-Mar |
|
| Investigation of the role of adrenergic and non-nitrergic, non-adrenergic neurotransmission in the sheep isolated internal anal sphincter. | 2009 Mar |
|
| Tetrahydrobiopterin does not affect end-organ responsiveness to norepinephrine-mediated vasoconstriction in aged skin. | 2010 Dec |
|
| Nitric oxide-induced vasorelaxation in response to PnTx2-6 toxin from Phoneutria nigriventer spider in rat cavernosal tissue. | 2010 Dec |
|
| Cold-induced vasoconstriction at forearm and hand skin sites: the effect of age. | 2010 Jul |
|
| Evidence based guidelines for complex regional pain syndrome type 1. | 2010 Mar 31 |
|
| 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 |
Patents
Sample Use Guides
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
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NCI_THESAURUS |
C29713
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DTXSID3046958
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394
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BRETYLIUM
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100000085141
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RZR75EQ2KJ
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19685
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C77300
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C045166
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Bretylium
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7130
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SUB00867MIG
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DB01158
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2431
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59-41-6
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SALT/SOLVATE (PARENT)
SUBSTANCE RECORD
