Bretylium

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Bretylium
Clinical data
MedlinePlus	a682861
Pregnancy; category	AU: C ; US: C (Risk not ruled out) ; ;
Routes of; administration	IV, IM
ATC code	C01BD02 (WHO) ;
Legal status
Legal status	US: ℞-only ;
Pharmacokinetic data
Bioavailability	NA
Protein binding	NA
Metabolism	None
Elimination half-life	7-8 hours
Excretion	Renal
Identifiers
	IUPAC name N-(2-bromobenzyl)-N,N-dimethylethanaminium;
CAS Number	59-41-6 ;
PubChem CID	2431;
DrugBank	DB01158 ;
ChemSpider	2337 ;
UNII	RZR75EQ2KJ;
KEGG	D00645 ;
ChEBI	CHEBI:3172 ;
ChEMBL	ChEMBL1199080 ;
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
Formula	C11H17BrN+
Molar mass	243.163 g/mol
3D model (JSmol)	Interactive image;
	SMILES Brc1ccccc1C[N+](CC)(C)C;
	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 ; Key:AAQOQKQBGPPFNS-UHFFFAOYSA-N ;
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Bretylium (also bretylium tosylate) is an antiarrhythmic agent.^[1] It blocks the release of noradrenaline from nerve terminals. In effect, it decreases output from the peripheral sympathetic nervous system. It also acts by blocking K⁺ channels and is considered a class III antiarrhythmic. The dose is 5–10 mg/kg and side effects are high blood pressure followed by low blood pressure and ventricular ectopy.

Originally introduced in 1959 for the treatment of hypertension.^[2] Its use as an antiarrhythmic for ventricular fibrilation was discovered and patented by Marvin Bacaner in 1969 at the University of Minnesota.^[3]

The American Heart Association removed Bretylium from their 2000 ECC/ACC guidelines due to its unproven efficacy and ongoing supply problems. Many have cited these supply problems as an issue of raw materials needed in the production of Bretylium. By the release of the AHA 2005 ECC/ACC guidelines there is no mention of Bretylium and it is virtually unavailable throughout most of the world.^[4]^[5]

As of June 8, 2011 Bretylium Tosylate is permanently no longer available in the US after request of Hospira Inc. to withdraw its NDA from the market. Bretylium will remain on the FDA's discontinued drug list since its withdrawal was not the result of a safety or effectiveness concern.^[6]

Uses

It was used in emergency medicine, cardiology, and other specialties throughout the 1980s-1990s for the acute management of ventricular tachycardia and ventricular fibrillation refractory to other first line treatments such as defibrillation or lidocaine.^[7]

It is contraindicated in patients with AV (atrioventricular) heart block or digoxin toxicity.

Bretylium should be used only in an ICU or Emergency Department setting and should not be used elsewhere due to its dramatic actions and its predominant side effect of hypotension.

Experimental Uses

It is used in physiological and pharmacological research as an inhibitor of sympathetic transmission. Its mechanism of action is the inhibition of neurotransmitter release from sympathetic nerve terminals, both by the inhibition of action potentials in the nerve terminals and by other mechanisms.^[8] Its specificity for sympathetic nerves is achieved because it is a substrate for the noradrenaline transporter;^[9] hence, it accumulates inside nerve terminals which have this transporter.

Synthesis

Quaternization of o-bromo-N,N-dimethylbenzylamine with ethyl-p-toluenesulfonate yields bretylium sulfonate.

References

↑ Tiku PE, Nowell PT (December 1991). "Selective inhibition of K(+)-stimulation of Na,K-ATPase by bretylium". Br. J. Pharmacol. 104 (4): 895–900. doi:10.1111/j.1476-5381.1991.tb12523.x. PMC 1908819. PMID 1667290.
↑ "the treatment of hypertension".
↑ "patent". Retrieved 2014-02-06.
↑ http://books.google.com/books?id=xco9aJ_Y9XIC&pg=PA221&lpg=PA221&dq=bretylium+raw+materials&source=bl&ots=fCgjx6lB2u&sig=UxuKAyXp6qKhKDG6riQM9gCG1hQ&hl=en&sa=X&ei=F0_lUveHAujjsASZv4DgCw&ved=0CDoQ6AEwBg#v=onepage&q=bretylium%20raw%20materials&f=false
↑ http://emedicine.medscape.com/article/770542-treatment
↑ https://www.federalregister.gov/articles/2011/12/19/2011-32367/determination-that-bretylium-tosylate-injection-50-milligramsmilliliter-was-not-withdrawn-from-sale
↑ "ACS". Retrieved 2008-09-23.^{[dead link]}
↑ K. L. Brain & T. C. Cunnane (2008). "Bretylium abolishes neurotransmitter release without necessarily abolishing the nerve terminal action potential in sympathetic terminals". British journal of pharmacology. 153 (4): 831–839. doi:10.1038/sj.bjp.0707623. PMC 2259200. PMID 18071295.
↑ A. L. BOURA, F. C. COPP, W. G. DUNCOMBE, A. F. GREEN & A. McCOUBREY (June 1960). "The selective accumulation of bretylium in sympathetic ganglia and their postganglionic nerves". British journal of pharmacology and chemotherapy. 15: 265–270. doi:10.1111/j.1476-5381.1960.tb01242.x. PMC 1481934. PMID 13803289.

Template:Potassium channel blockers Template:Antiarrhythmic agents

[pmid1667290-1] Tiku PE, Nowell PT (December 1991). "Selective inhibition of K(+)-stimulation of Na,K-ATPase by bretylium". Br. J. Pharmacol. 104 (4): 895–900. doi:10.1111/j.1476-5381.1991.tb12523.x. PMC 1908819. PMID 1667290.

[2] "the treatment of hypertension".

[3] "patent". Retrieved 2014-02-06.

[4] ttp://books.google.com/books?id=xco9aJ_Y9XIC&pg=PA221&lpg=PA221&dq=bretylium+raw+materials&source=bl&ots=fCgjx6lB2u&sig=UxuKAyXp6qKhKDG6riQM9gCG1hQ&hl=en&sa=X&ei=F0_lUveHAujjsASZv4DgCw&ved=0CDoQ6AEwBg#v=onepage&q=bretylium%20raw%20materials&f=false

[5] ttp://emedicine.medscape.com/article/770542-treatment

[Determination_that_Bretylium_Tosylate_Injection,_50_Milligrams/Milliliter,_Was_Not_Withdrawn_From_Sale_for_Reasons_of_Safety_or_Effectiveness-6] ttps://www.federalregister.gov/articles/2011/12/19/2011-32367/determination-that-bretylium-tosylate-injection-50-milligramsmilliliter-was-not-withdrawn-from-sale

[urlACS-7] "ACS". Retrieved 2008-09-23.^{[dead link]}

[8] K. L. Brain & T. C. Cunnane (2008). "Bretylium abolishes neurotransmitter release without necessarily abolishing the nerve terminal action potential in sympathetic terminals". British journal of pharmacology. 153 (4): 831–839. doi:10.1038/sj.bjp.0707623. PMC 2259200. PMID 18071295.

[9] A. L. BOURA, F. C. COPP, W. G. DUNCOMBE, A. F. GREEN & A. McCOUBREY (June 1960). "The selective accumulation of bretylium in sympathetic ganglia and their postganglionic nerves". British journal of pharmacology and chemotherapy. 15: 265–270. doi:10.1111/j.1476-5381.1960.tb01242.x. PMC 1481934. PMID 13803289.

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v t e Adrenergic receptor modulators
α₁	Agonists: 6-FNE Amidephrine Anisodine Buspirone Cirazoline Corbadrine Desglymidodrine Dexisometheptene Dipivefrine Dopamine Droxidopa (L-DOPS) Ephedrine Epinephrine Etilefrine Etilevodopa Ethylnorepinephrine Indanidine Isometheptene L-DOPA (levodopa) L-Phenylalanine L-Tyrosine Melevodopa Metaraminol Methoxamine Methyldopa Midodrine Naphazoline Norepinephrine Octopamine (drug) Oxymetazoline Phenylephrine Phenylpropanolamine Pseudoephedrine Synephrine Tetryzoline Tiamenidine XP21279 Xylometazoline Antagonists: Abanoquil Adimolol Ajmalicine Alfuzosin Amosulalol Anisodamine Arotinolol Atiprosin Atypical antipsychotics (e.g., brexpiprazole, clozapine, olanzapine, quetiapine, risperidone) Benoxathian Buflomedil Bunazosin Carvedilol Corynanthine Dapiprazole Domesticine Doxazosin Ergolines (e.g., ergotamine, dihydroergotamine, lisuride, terguride) Etoperidone Eugenodilol Fenspiride Hydroxyzine Indoramin Ketanserin L-765,314 Labetalol mCPP Mepiprazole Metazosin Monatepil Moxisylyte Naftopidil Nantenine Neldazosin Niaprazine Nicergoline Niguldipine Pardoprunox Pelanserin Perlapine Phendioxan Phenoxybenzamine Phentolamine Phenylpiperazine antidepressants (e.g., hydroxynefazodone, nefazodone, trazodone, triazoledione) Piperoxan Prazosin Quinazosin Quinidine Ritanserin Silodosin Spiperone Talipexole Tamsulosin Terazosin Tiodazosin Tolazoline Tetracyclic antidepressants (e.g., amoxapine, maprotiline, mianserin) Tricyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin, imipramine, trimipramine) Trimazosin Typical antipsychotics (e.g., chlorpromazine, fluphenazine, loxapine, thioridazine) Urapidil WB-4101 Zolertine
α₂	Agonists: (R)-3-Nitrobiphenyline 4-NEMD 6-FNE Amitraz Apraclonidine Brimonidine Cannabivarin Clonidine Corbadrine Detomidine Dexmedetomidine Dihydroergotamine Dipivefrine Dopamine Droxidopa (L-DOPS) Etilevodopa Ephedrine Ergotamine Epinephrine Etilefrine Ethylnorepinephrine Guanabenz Guanfacine Guanoxabenz L-DOPA (levodopa) L-Phenylalanine L-Tyrosine Lofexidine Medetomidine Melevodopa Methyldopa Mivazerol Naphazoline Norepinephrine Oxymetazoline Phenylpropanolamine Piperoxan Pseudoephedrine Rezatomidine Rilmenidine Romifidine Talipexole Tasipimidine Tetrahydrozoline Tiamenidine Tizanidine Tolonidine Urapidil Vatinoxan XP21279 Xylazine Xylometazoline Antagonists: 1-PP Adimolol Amesergide Aptazapine Atipamezole Atypical antipsychotics (e.g., asenapine, brexpiprazole, clozapine, lurasidone, paliperidone, quetiapine, risperidone, zotepine) Azapirones (e.g., buspirone, gepirone, ipsapirone, tandospirone) BRL-44408 Buflomedil Cirazoline Efaroxan Esmirtazapine Fenmetozole Fluparoxan Idazoxan mCPP Mianserin Mirtazapine NAN-190 Olanzapine Pardoprunox Phentolamine Phenoxybenzamine Piperoxan Piribedil Rauwolscine Rotigotine SB-269970 Setiptiline Spiroxatrine Sunepitron Tolazoline Typical antipsychotics (e.g., chlorpromazine, fluphenazine, loxapine, thioridazine) Yohimbine
β	Agonists: Abediterol Alifedrine Amibegron Arbutamine Arformoterol Arotinolol BAAM Bambuterol Befunolol Bitolterol Broxaterol Buphenine Carbuterol Carmoterol Cimaterol Clenbuterol Colterol Corbadrine Denopamine Dipivefrine Dobutamine Dopamine Dopexamine Droxidopa (L-DOPS) Ephedrine Epinephrine Etafedrine Etilefrine Etilevodopa Ethylnorepinephrine Fenoterol Formoterol Hexoprenaline Higenamine Indacaterol Isoetarine Isoprenaline Isoxsuprine L-DOPA (levodopa) L-Phenylalanine L-Tyrosine Levosalbutamol Mabuterol Melevodopa Methoxyphenamine Methyldopa Mirabegron Norepinephrine Orciprenaline Oxyfedrine PF-610355 Phenylpropanolamine Pirbuterol Prenalterol Ractopamine Procaterol Pseudoephedrine Reproterol Rimiterol Ritodrine Salbutamol Salmeterol Solabegron Terbutaline Tretoquinol Tulobuterol Vilanterol Xamoterol XP21279 Zilpaterol Zinterol Antagonists: Acebutolol Adaprolol Adimolol Afurolol Alprenolol Alprenoxime Amosulalol Ancarolol Arnolol Arotinolol Atenolol Befunolol Betaxolol Bevantolol Bisoprolol Bopindolol Bornaprolol Brefonalol Bucindolol Bucumolol Bufetolol Bufuralol Bunitrolol Bunolol Bupranolol Butaxamine Butidrine Butofilolol Capsinolol Carazolol Carpindolol Carteolol Carvedilol Celiprolol Cetamolol Cicloprolol Cinamolol Cloranolol Cyanopindolol Dalbraminol Dexpropranolol Diacetolol Dichloroisoprenaline Dihydroalprenolol Dilevalol Diprafenone Draquinolol Ecastolol Epanolol Ericolol Ersentilide Esatenolol Esprolol Eugenodilol Exaprolol Falintolol Flestolol Flusoxolol Hydroxycarteolol Hydroxytertatolol ICI-118,551 Idropranolol Indenolol Indopanolol Iodocyanopindolol Iprocrolol Isoxaprolol Isamoltane Labetalol Landiolol Levobetaxolol Levobunolol Levomoprolol Medroxalol Mepindolol Metipranolol Metoprolol Moprolol Nadolol Nadoxolol Nebivolol Nifenalol Nipradilol Oxprenolol Pacrinolol Pafenolol Pamatolol Pargolol Penbutolol Pindolol Practolol Primidolol Procinolol Pronethalol Propafenone Propranolol Ridazolol Ronactolol Soquinolol Sotalol Spirendolol SR 59230A Sulfinalol Talinolol Tazolol Tertatolol Tienoxolol Tilisolol Timolol Tiprenolol Tolamolol Toliprolol Xibenolol Xipranolol

Clinical data

MedlinePlus	a682861
Pregnancy category	AU: C US: C (Risk not ruled out)
Routes of administration	IV, IM
ATC code	C01BD02 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	NA
Protein binding	NA
Metabolism	None
Elimination half-life	7-8 hours
Excretion	Renal
Identifiers
IUPAC name N-(2-bromobenzyl)-N,N-dimethylethanaminium
CAS Number	59-41-6^Y
PubChem CID	2431
DrugBank	DB01158^Y
ChemSpider	2337^Y
UNII	RZR75EQ2KJ
KEGG	D00645^N
ChEBI	CHEBI:3172^Y
ChEMBL	ChEMBL1199080^N
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
Formula	C₁₁H₁₇BrN⁺
Molar mass	243.163 g/mol
3D model (JSmol)	Interactive image
SMILES Brc1ccccc1C[N+](CC)(C)C
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^Y Key:AAQOQKQBGPPFNS-UHFFFAOYSA-N^Y
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