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Identification
NameFlecainide
Accession NumberDB01195  (APRD00129)
TypeSmall Molecule
GroupsApproved, Withdrawn
Description

A potent anti-arrhythmia agent, effective in a wide range of ventricular and atrial arrhythmias and tachycardias. Paradoxically, however, in myocardial infarct patients with either symptomatic or asymptomatic arrhythmia, flecainide exacerbates the arrhythmia and is not recommended for use in these patients. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
(+-)-FlecainideNot AvailableNot Available
CCRIS 313Not AvailableNot Available
FlecaineNot AvailableNot Available
FlecainidaSpanishINN
FlecainidumLatinINN
N-(2-Piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamideNot AvailableNot Available
Salts
Name/CAS Structure Properties
Flecainide acetate
Thumb
  • InChI Key: RKXNZRPQSOPPRN-UHFFFAOYNA-N
  • Monoisotopic Mass: 474.158941118
  • Average Mass: 474.3947
DBSALT000086
Brand names
NameCompany
AlmarytmNot Available
ApocardNot Available
Tambocor3M pharmaceuticals
Brand mixturesNot Available
Categories
CAS number54143-55-4
WeightAverage: 414.3427
Monoisotopic: 414.137811746
Chemical FormulaC17H20F6N2O3
InChI KeyDJBNUMBKLMJRSA-UHFFFAOYSA-N
InChI
InChI=1S/C17H20F6N2O3/c18-16(19,20)9-27-12-4-5-14(28-10-17(21,22)23)13(7-12)15(26)25-8-11-3-1-2-6-24-11/h4-5,7,11,24H,1-3,6,8-10H2,(H,25,26)
IUPAC Name
N-(piperidin-2-ylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide
SMILES
FC(F)(F)COC1=CC(C(=O)NCC2CCCCN2)=C(OCC(F)(F)F)C=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassBenzoic Acid and Derivatives
Direct parentSalicylamides
Alternative parentsBenzamides; Benzoyl Derivatives; Phenol Ethers; Alkyl Aryl Ethers; Piperidines; Secondary Carboxylic Acid Amides; Dialkylamines; Carboxylic Acids; Polyamines; Enolates; Alkyl Fluorides; Organofluorides
Substituentsphenol ether; benzoyl; alkyl aryl ether; piperidine; secondary carboxylic acid amide; carboxamide group; polyamine; enolate; secondary aliphatic amine; secondary amine; carboxylic acid derivative; carboxylic acid; ether; organohalogen; organofluoride; amine; alkyl halide; alkyl fluoride; organonitrogen compound
Classification descriptionThis compound belongs to the salicylamides. These are carboxamide derivatives of salicylic acid.
Pharmacology
IndicationFlecainide is is a class Ic antiarrhythmic agent and as such, it is used for the prevention of paroxysmal supraventricular tachycardias (PSVT), including atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia and other supraventricular tachycardias of unspecified mechanism associated with disablin.
PharmacodynamicsFlecainide has local anesthetic activity and belongs to the membrane stabilizing (Class 1) group of antiarrhythmic agents; it has electrophysiologic effects characteristic of the IC class of antiarrhythmics.
Mechanism of actionFlecainide acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation. The antiarrhythmic actions are mediated through effects on sodium channels in Purkinje fibers. Flecainide is a sodium channel blocker, binding to voltage gated sodium channels. It stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses. Ventricular excitability is depressed and the stimulation threshold of the ventricle is increased during diastole.
AbsorptionNearly complete following oral administration.
Volume of distributionNot Available
Protein binding40%
Metabolism

Hepatic. Flecainide does not undergo any consequential presystemic biotransformation. The two major urinary metabolites are meta-O-dealkylated flecainide (active, but about one-fifth as potent) and the meta-O-dealkylated lactam of flecainide (non-active metabolite).

SubstrateEnzymesProduct
Flecainide
Not Available
Meta-O-dealkylated flecainideDetails
Flecainide
Not Available
Meta-o-dealkylated lactamDetails
Route of eliminationIn healthy subjects, about 30% of a single oral dose (range, 10 to 50%) is excreted in urine as unchanged drug. Several minor metabolites (3% of the dose or less) are also found in urine; only 5% of an oral dose is excreted in feces. In patients, free (unconjugated) plasma levels of the two major metabolites are very low (less than 0.05 μg/mL).
Half life20 hours (range 12-27 hours)
ClearanceNot Available
ToxicityOral LD50 is 50-498 mg/kg in rat. Symptoms of overdose include nausea and vomiting, convulsions, hypotension, bradycardia, syncope, extreme widening of the QRS complex, widening of the QT interval, widening of the PR interval, ventricular tachycardia, AV nodal block, asystole, bundle branch block, cardiac failure, and cardiac arrest.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Flecainide Action PathwayDrug actionSMP00331
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9856
Blood Brain Barrier + 0.8605
Caco-2 permeable + 0.8867
P-glycoprotein substrate Substrate 0.7773
P-glycoprotein inhibitor I Inhibitor 0.5307
P-glycoprotein inhibitor II Non-inhibitor 0.7716
Renal organic cation transporter Non-inhibitor 0.6687
CYP450 2C9 substrate Non-substrate 0.8921
CYP450 2D6 substrate Substrate 0.8918
CYP450 3A4 substrate Non-substrate 0.5957
CYP450 1A2 substrate Inhibitor 0.9106
CYP450 2C9 substrate Non-inhibitor 0.6853
CYP450 2D6 substrate Non-inhibitor 0.6556
CYP450 2C19 substrate Inhibitor 0.5307
CYP450 3A4 substrate Non-inhibitor 0.8309
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.5538
Ames test Non AMES toxic 0.672
Carcinogenicity Non-carcinogens 0.8821
Biodegradation Not ready biodegradable 0.9968
Rat acute toxicity 2.5680 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9409
hERG inhibition (predictor II) Inhibitor 0.8474
Pharmacoeconomics
Manufacturers
  • Amneal pharmaceutical
  • Apotex inc
  • Barr laboratories inc
  • Ranbaxy laboratories ltd
  • Roxane laboratories inc
  • Sandoz inc
  • Graceway pharmaceuticals llc
Packagers
Dosage forms
FormRouteStrength
TabletOral
Prices
Unit descriptionCostUnit
Tambocor 150 mg tablet5.75USDtablet
Tambocor 100 mg tablet4.27USDtablet
Flecainide acetate 150 mg tablet3.83USDtablet
Flecainide acetate 100 mg tablet2.95USDtablet
Tambocor 50 mg tablet2.72USDtablet
Flecainide acetate 50 mg tablet1.95USDtablet
Tambocor 100 mg Tablet1.19USDtablet
Apo-Flecainide 100 mg Tablet0.83USDtablet
Tambocor 50 mg Tablet0.6USDtablet
Apo-Flecainide 50 mg Tablet0.41USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point228-229Bmitt, E.H. and Brown, W.R.; U.S. Patent 3,900,481; August 19,1975; assigned to Riker Laboratories, Inc.
water solubility48.4 mg/mL at 37 °C (acetate form)Not Available
logP3.78MANNHOLD,R ET AL. (1990)
pKa9.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0324ALOGPS
logP2.98ALOGPS
logP3.19ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)13.68ChemAxon
pKa (Strongest Basic)9.62ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area59.59 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity88.4 m3·mol-1ChemAxon
Polarizability35.92 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
Spectra
References
Synthesis Reference

Bmitt, E.H. and Brown, W.R.; U.S. Patent 3,900,481; August 19,1975; assigned to Riker Laboratories, Inc.

US3900481A
General Reference
  1. Gill JS, Mehta D, Ward DE, Camm AJ: Efficacy of flecainide, sotalol, and verapamil in the treatment of right ventricular tachycardia in patients without overt cardiac abnormality. Br Heart J. 1992 Oct;68(4):392-7. Pubmed
  2. Sakurada H, Hiyoshi Y, Tejima T, Yanase O, Tokuyasu Y, Watanabe K, Motomiya T, Sugiura M, Hiraoka M: [Effects of oral flecainide treatment of refractory tachyarrhythmias] Kokyu To Junkan. 1990 May;38(5):471-6. Pubmed
  3. Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL, et al.: Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991 Mar 21;324(12):781-8. Pubmed
  4. Greenberg HM, Dwyer EM Jr, Hochman JS, Steinberg JS, Echt DS, Peters RW: Interaction of ischaemia and encainide/flecainide treatment: a proposed mechanism for the increased mortality in CAST I. Br Heart J. 1995 Dec;74(6):631-5. Pubmed
  5. Gasparini M, Priori SG, Mantica M, Napolitano C, Galimberti P, Ceriotti C, Simonini S: Flecainide test in Brugada syndrome: a reproducible but risky tool. Pacing Clin Electrophysiol. 2003 Jan;26(1 Pt 2):338-41. Pubmed
External Links
ResourceLink
KEGG DrugD07962
KEGG CompoundC07001
PubChem Compound3356
PubChem Substance46508078
ChemSpider3239
BindingDB50131434
Therapeutic Targets DatabaseDAP000518
PharmGKBPA449646
IUPHAR2560
Guide to Pharmacology2560
Drug Product Database1966197
RxListhttp://www.rxlist.com/cgi/generic2/flecainide.htm
Drugs.comhttp://www.drugs.com/cdi/flecainide.html
WikipediaFlecainide
ATC CodesC01BC04
AHFS Codes
  • 24:04.04.12
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(77.1 KB)
Interactions
Drug Interactions
Drug
AmiodaroneAmiodarone may increase the effect and toxicity of flecainide
ArtemetherAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
CimetidineCimetidine, a moderate CYP2D6 inhibitor, may decrease the metabolism of flecainide.
CisaprideIncreased risk of cardiotoxicity and arrhythmias
DuloxetinePossible increase in the levels of this agent when used with duloxetine
EtravirineFlecainide, when administered concomitantly with etravirine, may experience a decrease in serum concentration. It is recommended to monitor flecainide therapy.
LumefantrineAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
MesoridazineIncreased risk of cardiotoxicity and arrhythmias
MirabegronMirabegron is a moderate CYP2D6 inhibitor and may cause an increase in exposure of CYP2D6 substrates. Monitor concomitant therapy closely.
QuinupristinThis combination presents an increased risk of toxicity
RitonavirRitonavir increases the toxicity of the anti-arrhythmic
TacrolimusAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
TerbinafineTerbinafine may reduce the metabolism and clearance of Flecainide. Consider alternate therapy or monitor for therapeutic/adverse effects of Flecainide if Terbinafine is initiated, discontinued or dose changed.
TerfenadineIncreased risk of cardiotoxicity and arrhythmias
ThioridazineIncreased risk of cardiotoxicity and arrhythmias
ThiothixeneMay cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
TipranavirTipranavir, co-administered with Ritonavir, may increase the plasma concentration of Flecainide. Concomitant therapy is contraindicated.
ToremifeneAdditive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.
TrimipramineAdditive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
VoriconazoleAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
VorinostatAdditive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
ZiprasidoneAdditive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
ZuclopenthixolAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Food Interactions
  • Take without regard to meals.

Targets

1. Sodium channel protein type 5 subunit alpha

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sodium channel protein type 5 subunit alpha Q14524 Details

References:

  1. Nagatomo T, January CT, Makielski JC: Preferential block of late sodium current in the LQT3 DeltaKPQ mutant by the class I© antiarrhythmic flecainide. Mol Pharmacol. 2000 Jan;57(1):101-7. Pubmed
  2. Benhorin J, Taub R, Goldmit M, Kerem B, Kass RS, Windman I, Medina A: Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome? Circulation. 2000 Apr 11;101(14):1698-706. Pubmed
  3. Priori SG, Napolitano C, Schwartz PJ, Bloise R, Crotti L, Ronchetti E: The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge. Circulation. 2000 Aug 29;102(9):945-7. Pubmed
  4. Cerrone M, Crotti L, Faggiano G, De Michelis V, Napolitano C, Schwartz PJ, Priori SG: [Long QT syndrome and Brugada syndrome: 2 aspects of the same disease?] Ital Heart J Suppl. 2001 Mar;2(3):253-7. Pubmed
  5. Viswanathan PC, Bezzina CR, George AL Jr, Roden DM, Wilde AA, Balser JR: Gating-dependent mechanisms for flecainide action in SCN5A-linked arrhythmia syndromes. Circulation. 2001 Sep 4;104(10):1200-5. Pubmed
  6. Ramos E, O’leary ME: State-dependent trapping of flecainide in the cardiac sodium channel. J Physiol. 2004 Oct 1;560(Pt 1):37-49. Epub 2004 Jul 22. Pubmed
  7. Shimizu W, Antzelevitch C, Suyama K, Kurita T, Taguchi A, Aihara N, Takaki H, Sunagawa K, Kamakura S: Effect of sodium channel blockers on ST segment, QRS duration, and corrected QT interval in patients with Brugada syndrome. J Cardiovasc Electrophysiol. 2000 Dec;11(12):1320-9. Pubmed
  8. Liu H, Atkins J, Kass RS: Common molecular determinants of flecainide and lidocaine block of heart Na+ channels: evidence from experiments with neutral and quaternary flecainide analogues. J Gen Physiol. 2003 Mar;121(3):199-214. Pubmed
  9. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Sodium channel protein type 4 subunit alpha

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Sodium channel protein type 4 subunit alpha P35499 Details

References:

  1. Desaphy JF, De Luca A, Didonna MP, George AL Jr, Camerino Conte D: Different flecainide sensitivity of hNav1.4 channels and myotonic mutants explained by state-dependent block. J Physiol. 2004 Jan 15;554(Pt 2):321-34. Epub 2003 Nov 7. Pubmed

Enzymes

1. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 2C9

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C9 P11712 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on April 22, 2014 15:34