TOCAINIDE HYDROCHLORIDE

US Previously Marketed

Details

Stereochemistry	RACEMIC
Molecular Formula	C11H16N2O.ClH
Molecular Weight	228.718
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.CC(N)C(=O)NC1=C(C)C=CC=C1C

InChI

InChIKey=AMZACPWEJDQXGW-UHFFFAOYSA-N

InChI=1S/C11H16N2O.ClH/c1-7-5-4-6-8(2)10(7)13-11(14)9(3)12;/h4-6,9H,12H2,1-3H3,(H,13,14);1H

HIDE SMILES / InChI

Description
Sources: https://www.drugs.com/cons/tocainide.html
Curator's Comment: description was created based on several sources, including https://www.drugbank.ca/drugs/DB01056 | https://www.ncbi.nlm.nih.gov/pubmed/2499645 | https://www.ncbi.nlm.nih.gov/pubmed/3107988 | https://www.ncbi.nlm.nih.gov/pubmed/2108835 | https://www.ncbi.nlm.nih.gov/pubmed/3161487

Tocainide is a primary amine analog of lidocaine with antiarrhythmic properties useful in the treatment of ventricular arrhythmias. Tocainide, like lidocaine, produces dose-dependent decreases in sodium and potassium conductance, thereby decreasing the excitability of myocardial cells. In experimental animal models, the dose-related depression of sodium current is more pronounced in ischemic tissue than in normal tissue. Tocainide is a Class I antiarrhythmic compound with electrophysiologic properties in man similar to those of lidocaine, but dissimilar from quinidine, procainamide, and disopyramide. The recommended initial dosage is 400 mg every 8 hours. The usual adult dosage is between 1200 and 1800 mg/day in a three-dose daily divided regimen. Doses beyond 2400 mg per day have been administered infrequently. Patients who tolerate the t.i.d. the regimen may be tried on a twice-daily regimen with careful monitoring. Tocainide commonly produces minor, transient, nervous system and gastrointestinal adverse reactions, but is otherwise generally well tolerated.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Sodium channel alpha subunit 76 Target ID: CHEMBL2331043 Sources: https://www.ncbi.nlm.nih.gov/pubmed/2451117	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Ventricular arrhythmia 50 Sources: https://www.ncbi.nlm.nih.gov/pubmed/2108835	Primary		Approved 8429	TONOCARD Approved Use Unknown Launch Date 1984

C_max

Value	Dose	Co-administered	Analyte	Population
3.2 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3116834	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:		TOCAINIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
7.8 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2127569	200 mg single, intravenous dose: 200 mg route of administration: Intravenous experiment type: SINGLE co-administered:	R(-)-TOCAINIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
11.7 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2127569	200 mg single, intravenous dose: 200 mg route of administration: Intravenous experiment type: SINGLE co-administered:	(S)-TOCAINIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
84 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3116834	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:	TOCAINIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
11.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2127569	200 mg single, intravenous dose: 200 mg route of administration: Intravenous experiment type: SINGLE co-administered:	R(-)-TOCAINIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
17.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/2127569	200 mg single, intravenous dose: 200 mg route of administration: Intravenous experiment type: SINGLE co-administered:	(S)-TOCAINIDE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED
15 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/3116834	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered:	TOCAINIDE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
250 mg 2 times / day single, intravenous (starting) Dose: 250 mg, 2 times / day Route: intravenous Route: single Dose: 250 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6439023	unhealthy, 34 - 75 years n = 50 Health Status: unhealthy Condition: Acute Ventricular Arrhythmias Age Group: 34 - 75 years Sex: M+F Population Size: 50 Sources: https://pubmed.ncbi.nlm.nih.gov/6439023	Disc. AE: Hypotension... Other AEs: Nausea, Vomiting... AEs leading to discontinuation/dose reduction: Hypotension (3 patients) Other AEs: Nausea (1 patient) Vomiting (1 patient) Junctional rhythm (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/6439023
600 mg 2 times / day multiple, oral Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/3931448	unhealthy, 59 years (range: 28-83 years) n = 67 Health Status: unhealthy Condition: benign and potentially lethal ventricular arrhythmias Age Group: 59 years (range: 28-83 years) Sex: M+F Population Size: 67 Sources: https://pubmed.ncbi.nlm.nih.gov/3931448	Disc. AE: Ataxia, Tremor... AEs leading to discontinuation/dose reduction: Ataxia (8 patients) Tremor (8 patients) Dizzy (8 patients) Rash (4 patients) Diarrhea (1 patient) Nausea (1 patient) Vomiting (1 patient) Anorexia (1 patient) Congestive heart failure (1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/3931448

AEs

AE	Significance	Dose	Population
Junctional rhythm	1 patient	250 mg 2 times / day single, intravenous (starting) Dose: 250 mg, 2 times / day Route: intravenous Route: single Dose: 250 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6439023	unhealthy, 34 - 75 years n = 50 Health Status: unhealthy Condition: Acute Ventricular Arrhythmias Age Group: 34 - 75 years Sex: M+F Population Size: 50 Sources: https://pubmed.ncbi.nlm.nih.gov/6439023
Nausea	1 patient	250 mg 2 times / day single, intravenous (starting) Dose: 250 mg, 2 times / day Route: intravenous Route: single Dose: 250 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6439023	unhealthy, 34 - 75 years n = 50 Health Status: unhealthy Condition: Acute Ventricular Arrhythmias Age Group: 34 - 75 years Sex: M+F Population Size: 50 Sources: https://pubmed.ncbi.nlm.nih.gov/6439023
Vomiting	1 patient	250 mg 2 times / day single, intravenous (starting) Dose: 250 mg, 2 times / day Route: intravenous Route: single Dose: 250 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6439023	unhealthy, 34 - 75 years n = 50 Health Status: unhealthy Condition: Acute Ventricular Arrhythmias Age Group: 34 - 75 years Sex: M+F Population Size: 50 Sources: https://pubmed.ncbi.nlm.nih.gov/6439023
Hypotension	3 patients Disc. AE	250 mg 2 times / day single, intravenous (starting) Dose: 250 mg, 2 times / day Route: intravenous Route: single Dose: 250 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/6439023	unhealthy, 34 - 75 years n = 50 Health Status: unhealthy Condition: Acute Ventricular Arrhythmias Age Group: 34 - 75 years Sex: M+F Population Size: 50 Sources: https://pubmed.ncbi.nlm.nih.gov/6439023
Anorexia	1 patient Disc. AE	600 mg 2 times / day multiple, oral Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/3931448	unhealthy, 59 years (range: 28-83 years) n = 67 Health Status: unhealthy Condition: benign and potentially lethal ventricular arrhythmias Age Group: 59 years (range: 28-83 years) Sex: M+F Population Size: 67 Sources: https://pubmed.ncbi.nlm.nih.gov/3931448
Congestive heart failure	1 patient Disc. AE	600 mg 2 times / day multiple, oral Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/3931448	unhealthy, 59 years (range: 28-83 years) n = 67 Health Status: unhealthy Condition: benign and potentially lethal ventricular arrhythmias Age Group: 59 years (range: 28-83 years) Sex: M+F Population Size: 67 Sources: https://pubmed.ncbi.nlm.nih.gov/3931448
Diarrhea	1 patient Disc. AE	600 mg 2 times / day multiple, oral Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/3931448	unhealthy, 59 years (range: 28-83 years) n = 67 Health Status: unhealthy Condition: benign and potentially lethal ventricular arrhythmias Age Group: 59 years (range: 28-83 years) Sex: M+F Population Size: 67 Sources: https://pubmed.ncbi.nlm.nih.gov/3931448
Nausea	1 patient Disc. AE	600 mg 2 times / day multiple, oral Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/3931448	unhealthy, 59 years (range: 28-83 years) n = 67 Health Status: unhealthy Condition: benign and potentially lethal ventricular arrhythmias Age Group: 59 years (range: 28-83 years) Sex: M+F Population Size: 67 Sources: https://pubmed.ncbi.nlm.nih.gov/3931448
Vomiting	1 patient Disc. AE	600 mg 2 times / day multiple, oral Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/3931448	unhealthy, 59 years (range: 28-83 years) n = 67 Health Status: unhealthy Condition: benign and potentially lethal ventricular arrhythmias Age Group: 59 years (range: 28-83 years) Sex: M+F Population Size: 67 Sources: https://pubmed.ncbi.nlm.nih.gov/3931448
Rash	4 patients Disc. AE	600 mg 2 times / day multiple, oral Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/3931448	unhealthy, 59 years (range: 28-83 years) n = 67 Health Status: unhealthy Condition: benign and potentially lethal ventricular arrhythmias Age Group: 59 years (range: 28-83 years) Sex: M+F Population Size: 67 Sources: https://pubmed.ncbi.nlm.nih.gov/3931448
Ataxia	8 patients Disc. AE	600 mg 2 times / day multiple, oral Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/3931448	unhealthy, 59 years (range: 28-83 years) n = 67 Health Status: unhealthy Condition: benign and potentially lethal ventricular arrhythmias Age Group: 59 years (range: 28-83 years) Sex: M+F Population Size: 67 Sources: https://pubmed.ncbi.nlm.nih.gov/3931448
Dizzy	8 patients Disc. AE	600 mg 2 times / day multiple, oral Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/3931448	unhealthy, 59 years (range: 28-83 years) n = 67 Health Status: unhealthy Condition: benign and potentially lethal ventricular arrhythmias Age Group: 59 years (range: 28-83 years) Sex: M+F Population Size: 67 Sources: https://pubmed.ncbi.nlm.nih.gov/3931448
Tremor	8 patients Disc. AE	600 mg 2 times / day multiple, oral Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/3931448	unhealthy, 59 years (range: 28-83 years) n = 67 Health Status: unhealthy Condition: benign and potentially lethal ventricular arrhythmias Age Group: 59 years (range: 28-83 years) Sex: M+F Population Size: 67 Sources: https://pubmed.ncbi.nlm.nih.gov/3931448

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A1 110 CYP1A2 1524

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/10215663/	yes [Inhibition 2000 uM]
CYP1A1 218	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/8689940/	yes [Ki 12400 uM]

Sourcing

Vendor/Aggregator	ID	URL
Alfa Chemistry	35891-93-1	https://www.alfa-chemistry.com/cas_35891-93-1.htm
Ambinter	Amb22336892	http://www.ambinter.com/reference/22336892
Aurora Fine Chemicals LLC	A17.901.147	http://online.aurorafinechemicals.com/info?ID=A17.901.147
Avantor Inc	101094-176	https://us.vwr.com/store/catalog/product.jsp?catalog_number=101094-176
Chem Scene	CS-0013838	http://www.chemscene.com/71395-14-7.html
ChemMol	99074262	http://www.chemmol.com/chemmol/99074262.html
Chemspace	CSSS00015314419	https://chem-space.com/CSSS00015314419
Clearsynth	CS-T-87276	https://www.clearsynth.com/en/CST87276.html
LGC Standards	LGCFOR3323.00	https://www.lgcstandards.com/US/en/p/LGCFOR3323.00
MedChem Express	HY-B1798A	https://www.medchemexpress.com/tocainide-hydrochloride.html
MolPort	MolPort-046-647-173	https://www.molport.com/shop/molecule-link/MolPort-046-647-173
MuseChem	R062387	https://www.musechem.com/product/R062387.html
Sigma-Aldrich	T0202_SIGMA	https://www.sigmaaldrich.com/catalog/product/sigma/t0202?utm_source=pubchem&utm_campaign=pubchem_2017&utm_medium=referral
Sigma-Aldrich	1667552_USP	https://www.sigmaaldrich.com/catalog/product/usp/1667552?utm_source=pubchem&utm_campaign=pubchem_2017&utm_medium=referral

PubMed

Title	Date	PubMed
Open clinical studies at a referral center: chronic maintenance tocainide therapy in patients with recurrent sustained ventricular tachycardia refractory to conventional antiarrhythmic agents.	1980 Dec	6778190
Tocainide-induced ventricular fibrillation.	1981 Apr	6782848
New drugs for treating cardiac arrhythmias.	1981 Jan	6780988
Severe paranoia with concomitant tocainide and propranolol therapy.	1982 Mar-Apr	6821034
Nodal bradycardia induced by tocainide.	1983 Apr	6408628
Paranoid psychosis induced by tocainide.	1984 Feb 25	6421396
Paranoid psychoses induced by tocainide.	1984 Mar 31	6423157
Facilitation of ventricular tachyarrhythmia induction by isoproterenol.	1984 Oct 1	6486026
Efficacy and safety of oral tocainide in refractory ventricular arrhythmia: a preliminary report on an open label study.	1986 Apr	2424347
Aplastic anemia due to tocainide.	1986 Feb 27	3080682
A seizure induced by concurrent lidocaine-tocainide therapy--is it just a case of additive toxicity?	1986 Jan	3080299
Effect on the seizure threshold in dogs of tocainide/lidocaine administration.	1987 Jul	3109286
Possible proarrhythmic effects of tocainide in dilated cardiomyopathy.	1988 Jul	2457881
Congestive heart failure induced by six of the newer antiarrhythmic drugs.	1989 Nov 1	2509529
Sinoatrial block due to tocainide.	1989 Oct	2508453
Pulmonary fibrosis associated with tocainide: report of a case with literature review.	1990 Feb	2137316
[Na channel myotonia].	2001	11555893
Effect of acidity on the enantiomeric resolution of thyroxine and tocainide by HPLC on a (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid column.	2002 Dec 31	12543515
Optimal requirements for high affinity and use-dependent block of skeletal muscle sodium channel by N-benzyl analogs of tocainide-like compounds.	2003 Oct	14500750
High-speed chiral separations on a microchip with UV detection.	2003 Sep	14518050
[Pharmacological treatment of trigeminal neuralgia: systematic review and metanalysis.].	2004 Dec	19471799
New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse.	2004 Jul	15210163
Synthesis, structure and pharmacology of acyl-2,6-xylidines.	2004 May-Jun	15481248
Chiral separations on multichannel microfluidic chips.	2005 Dec	16278920
Ventricular tachycardia induced by biventricular pacing in patient with severe ischemic cardiomyopathy.	2005 Jun	15946367
Systemic administration of local anesthetic agents to relieve neuropathic pain.	2005 Oct 19	16235318
Robust randomised control trials needed for drug treatments for trigeminal neuralgia.	2006	17187047
Non-antiepileptic drugs for trigeminal neuralgia.	2006 Jul 19	16856027
Quantitative structure-pharmacokinetic relationships for drug clearance by using statistical learning methods.	2006 Mar	16290201
Synthesis and biological evaluation of chiral alpha-aminoanilides with central antinociceptive activity.	2007 Apr 19	17373780
[Eulenburg's paramyotonia congenita].	2007 Nov	18033047
Constrained analogues of tocainide as potent skeletal muscle sodium channel blockers towards the development of antimyotonic agents.	2008 Nov	18342401
Liquid chromatographic direct resolution of tocainide and its analogs on a (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6-based chiral stationary phase containing residual silanol protecting n-octyl groups.	2009 Jan	18506839
Update on methodologies available for ciguatoxin determination: perspectives to confront the onset of ciguatera fish poisoning in Europe.	2010 Jun 14	20631873

Patents

Sample Use Guides

In Vivo Use Guide

Initial dose: 400 mg orally every 8 hours. Maintenance dose: 1200-1800 mg/day in 3 divided doses.

Route of Administration: Oral

In Vitro Use Guide

Cardiac myocytes were isolated from adult male Sprague-Dawley rats. Myocytes (6 x 10^5) in 50 mkl of incubation buffer were incubated with 1.3 mkM sea anemone toxin II, 13 nM [3H] BTXB (50 Ci/mmol), and 0.13 mM tetrodotoxin for 45-60 mm at 37C. Tetrodotoxin was added to prevent depolarization induced by sodium influx; without tetrodotoxin, no specific binding is observed. Various concentrations of tocainide enantiomers were included in the incubations. Assays were done in parallel with tubes containing 0.2 mM aconitine to define nonspecific binding. Concentration-response curves for both stereoisomers were performed on common preparations of cells and toxins. Reactions were terminated by adding 10 ml of KHS buffer (Krebs-Henseleit-BSA; 127 mM NaCl, 2.33 mM KC1, 1.30 mM KH2PO4, 1.23 mM MgSO4, 25 mM NaHCO3, 10 mM glucose, 50 mkM CaCl2, 1% BSA) equilibrated with 95% 02/5% CO2 and incubated at 3C for 1 min, then filtered through a Whatman GF-C 24-mm filter and washed five times with 5 ml of rinse buffer (25 mM Tris-Cl, pH 7.4, 130 mM NaCl, 5.5 mM KC1, 0.8 mM MgSO4, 5.5 mM glucose, 50 mkM CaCl2.) The filters were then dried and counted in Econofluor scintillation fluid. The retained radioactivity represents [3H]BTXB bound to the myocyte.

Name

Type

Language

TOCAINIDE HYDROCHLORIDE

Common Name

English

PROPANAMIDE, 2-AMINO-N-(2,6-DIMETHYLPHENYL)-, MONOHYDROCHLORIDE

Common Name

English

TOCAINIDE HCL

Common Name

English

Tocainide hydrochloride [WHO-DD]

Common Name

English

2-AMINO-N-(2,6-DIMETHYLPHENYL)PROPANAMIDE MONOHYDROCHLORIDE

Systematic Name

English

TOCAINIDE HYDROCHLORIDE [USP IMPURITY]

Common Name

English

TOCAINIDE MONOHYDROCHLORIDE

Common Name

English

TOCAINIDE HYDROCHLORIDE [VANDF]

Common Name

English

TOCAINIDE (±)-FORM HYDROCHLORIDE [MI]

Common Name

English

TOCAINIDE HYDROCHLORIDE [MART.]

Common Name

English

TOCAINIDE HYDROCHLORIDE [ORANGE BOOK]

Common Name

English

TOCAINIDE (±)-FORM HYDROCHLORIDE

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C47793