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Identification
NamePropafenone
Accession NumberDB01182  (APRD00261)
Typesmall molecule
Groupsapproved
Description

An antiarrhythmia agent that is particularly effective in ventricular arrhythmias. It also has weak beta-blocking activity. The drug is generally well tolerated. [PubChem]

Structure
Thumb
Synonyms
SynonymLanguageCode
PropafenonaSpanishINN
PropafenonumLatinINN
Salts
Name/CAS Structure Properties
Propafenone hydrochloride
34183-22-7
Thumb
  • InChI Key: XWIHRGFIPXWGEF-UHFFFAOYNA-N
  • Monoisotopic Mass: 377.175771474
  • Average Mass: 377.905
DBSALT000148
Brand names
NameCompany
RythmolNot Available
Rythmol SRNot Available
Brand mixturesNot Available
Categories
CAS number54063-53-5
WeightAverage: 341.444
Monoisotopic: 341.199093735
Chemical FormulaC21H27NO3
InChI KeyInChIKey=JWHAUXFOSRPERK-UHFFFAOYSA-N
InChI
InChI=1S/C21H27NO3/c1-2-14-22-15-18(23)16-25-21-11-7-6-10-19(21)20(24)13-12-17-8-4-3-5-9-17/h3-11,18,22-23H,2,12-16H2,1H3
IUPAC Name
1-{2-[2-hydroxy-3-(propylamino)propoxy]phenyl}-3-phenylpropan-1-one
SMILES
CCCNCC(O)COC1=CC=CC=C1C(=O)CCC1=CC=CC=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassPhenylpropanoids and Polyketides
ClassFlavonoids
SubclassChalcones and Dihydrochalcones
Direct parentChalcones and Dihydrochalcones
Alternative parentsButyrophenones; Acetophenones; Phenol Ethers; Benzoyl Derivatives; Alkyl Aryl Ethers; Ketones; Secondary Alcohols; 1,2-Aminoalcohols; Enolates; Polyamines; Dialkylamines
Substituentsbutyrophenone; acetophenone; benzoyl; phenol ether; alkyl aryl ether; benzene; ketone; 1,2-aminoalcohol; secondary alcohol; polyamine; enolate; ether; secondary aliphatic amine; secondary amine; carbonyl group; amine; alcohol; organonitrogen compound
Classification descriptionThis compound belongs to the chalcones and dihydrochalcones. These are organic compounds containing 1,3-Diphenylpropenone (benzylideneacetophenone), ArCH=CH(=O)Ar,or its derivatives formed by substitution.
Pharmacology
IndicationUsed to prolong the time to recurrence of paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms in patients without structural heart disease. Also used for the treatment of life-threatening documented ventricular arrhythmias, such as sustained ventricular tachycardia.
PharmacodynamicsPropafenone is a Class 1C antiarrhythmic drug with local anesthetic effects, and a direct stabilizing action on myocardial membranes. It is used in the treatment of atrial and ventricular arrhythmias. It works by slowing the influx of sodium ions into the cardiac muscle cells, causing a decrease in excitablity of the cells. Propafenone has local anesthetic activity approximately equal to procaine.
Mechanism of actionThe electrophysiological effect of propafenone manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and to a lesser extent myocardial fibers, propafenone reduces the fast inward current carried by sodium ions, which is responsible for the drugs antiarrhythmic actions. Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity. At very high concentrations in vitro, propafenone can inhibit the slow inward current carried by calcium but this calcium antagonist effect probably does not contribute to antiarrhythmic efficacy.
AbsorptionNearly completely absorbed following oral administration (90%). Systemic bioavailability ranges from 5 to 50%, due to significant first-pass metabolism. This wide range in systemic bioavailability is related to two factors: presence of food (food increases bioavailability) and dosage (bioavailability is 3.4% for a 150-mg tablet compared to 10.6% for a 300-mg tablet).
Volume of distribution
  • 252 L
Protein binding97%
Metabolism

Metabolized primarily in the liver where it is rapidly and extensively metabolized to two active metabolites, 5-hydroxypropafenone and N-depropylpropafenone. These metabolites have antiarrhythmic activity comparable to propafenone but are present in concentrations less than 25% of propafenone concentrations.

SubstrateEnzymesProduct
Propafenone
N-desalkylpropafenoneDetails
Propafenone
5-hydroxypropafenoneDetails
Propafenone
    N-depropylpropafenoneDetails
    Route of eliminationApproximately 50% of propafenone metabolites are excreted in the urine following administration of immediate release tablets.
    Half life2-10 hours
    ClearanceNot Available
    ToxicitySymptoms of propafenone overdose (usually most severe within the first 3 hours) may include convulsions (rarely), heartbeat irregularities, low blood pressure, and sleepiness.
    Affected organisms
    • Humans and other mammals
    PathwaysNot Available
    SNP Mediated EffectsNot Available
    SNP Mediated Adverse Drug ReactionsNot Available
    ADMET
    Predicted ADMET features
    Property Value Probability
    Human Intestinal Absorption + 0.996
    Blood Brain Barrier - 0.958
    Caco-2 permeable - 0.5433
    P-glycoprotein substrate Substrate 0.8548
    P-glycoprotein inhibitor I Inhibitor 0.8565
    P-glycoprotein inhibitor II Inhibitor 0.874
    Renal organic cation transporter Non-inhibitor 0.7204
    CYP450 2C9 substrate Non-substrate 0.7897
    CYP450 2D6 substrate Substrate 0.8919
    CYP450 3A4 substrate Non-substrate 0.5499
    CYP450 1A2 substrate Inhibitor 0.9106
    CYP450 2C9 substrate Non-inhibitor 0.9071
    CYP450 2D6 substrate Inhibitor 0.8932
    CYP450 2C19 substrate Non-inhibitor 0.9026
    CYP450 3A4 substrate Inhibitor 0.7066
    CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8931
    Ames test Non AMES toxic 0.8446
    Carcinogenicity Non-carcinogens 0.8879
    Biodegradation Not ready biodegradable 0.803
    Rat acute toxicity 2.3795 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Weak inhibitor 0.5383
    hERG inhibition (predictor II) Inhibitor 0.8915
    Pharmacoeconomics
    Manufacturers
    • Glaxosmithkline llc
    • Kv pharmaceutical co
    • Mutual pharmaceutical co inc
    • Pliva inc
    • Vintage pharmaceuticals inc
    • Watson laboratories
    Packagers
    Dosage forms
    FormRouteStrength
    TabletOral
    Prices
    Unit descriptionCostUnit
    Rythmol SR 325 mg 12 Hour Capsule8.9USDcapsule
    Rythmol SR 425 mg 12 Hour Capsule8.9USDcapsule
    Rythmol sr 325 mg capsule8.56USDcapsule
    Rythmol sr 425 mg capsule8.56USDcapsule
    Rythmol SR 225 mg 12 Hour Capsule7.02USDcapsule
    Rythmol sr 225 mg capsule6.75USDcapsule
    Rythmol 225 mg tablet6.2USDtablet
    Rythmol 300 mg tablet5.05USDtablet
    Rythmol 150 mg tablet3.95USDtablet
    Propafenone hcl 300 mg tablet3.03USDtablet
    Propafenone hcl 225 mg tablet2.38USDtablet
    Rythmol 300 mg Tablet2.09USDtablet
    Propafenone hcl 150 mg tablet1.64USDtablet
    Rythmol 150 mg Tablet1.18USDtablet
    Apo-Propafenone 300 mg Tablet0.79USDtablet
    Pms-Propafenone 300 mg Tablet0.79USDtablet
    Apo-Propafenone 150 mg Tablet0.45USDtablet
    Pms-Propafenone 150 mg Tablet0.45USDtablet
    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
    Patents
    CountryPatent NumberApprovedExpires (estimated)
    United States56815881994-10-282014-10-28
    Properties
    Statesolid
    Experimental Properties
    PropertyValueSource
    water solubilitySlightly solubleNot Available
    logP3.2Not Available
    Predicted Properties
    PropertyValueSource
    water solubility7.58e-03 g/lALOGPS
    logP3.1ALOGPS
    logP3.54ChemAxon
    logS-4.7ALOGPS
    pKa (strongest acidic)14.09ChemAxon
    pKa (strongest basic)9.63ChemAxon
    physiological charge1ChemAxon
    hydrogen acceptor count4ChemAxon
    hydrogen donor count2ChemAxon
    polar surface area58.56ChemAxon
    rotatable bond count11ChemAxon
    refractivity100.21ChemAxon
    polarizability39.75ChemAxon
    number of rings2ChemAxon
    bioavailability1ChemAxon
    rule of fiveYesChemAxon
    Ghose filterYesChemAxon
    Veber's ruleNoChemAxon
    MDDR-like ruleNoChemAxon
    Spectra
    SpectraNot Available
    References
    Synthesis Reference

    Helmut Lietz, “Preparation of propafenone.” U.S. Patent US4474986, issued May, 1974.

    US4474986
    General ReferenceNot Available
    External Links
    ResourceLink
    KEGG CompoundC07381
    PubChem Compound4932
    PubChem Substance46504529
    ChemSpider4763
    BindingDB50067133
    Therapeutic Targets DatabaseDAP000497
    PharmGKBPA451131
    IUPHAR2561
    Guide to Pharmacology2561
    Drug Product Database2243728
    RxListhttp://www.rxlist.com/cgi/generic3/propafen.htm
    Drugs.comhttp://www.drugs.com/cdi/propafenone.html
    PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/ryt1392.shtml
    WikipediaPropafenone
    ATC CodesC01BC03
    AHFS Codes
    • 24:04.04.12
    PDB EntriesNot Available
    FDA labelshow(91.1 KB)
    MSDSshow(73.7 KB)
    Interactions
    Drug Interactions
    Drug
    AcenocoumarolPropafenone may increase the anticoagulant effect of acenocoumarol.
    AminophyllinePropafenone increases the effect of theophylline
    AnisindionePropafenone may increase the anticoagulant effect of anisindione.
    ArtemetherAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
    CisaprideIncreased risk of cardiotoxicity and arrhythmias
    CyclosporinePropafenone increases the effect and toxicity of cyclosporine
    DicoumarolPropafenone may increase the anticoagulant effect of dicumarol.
    DigoxinPropafenone increases the effect of digoxin
    Dihydroquinidine barbiturateQuinidine increases the effect of propafenone
    DuloxetinePossible increase in the levels of this agent when used with duloxetine
    DyphyllinePropafenone increases the effect of theophylline
    EtravirinePropafenone, when used concomitantly with Etravirine, may experience a decrease in serum concentration. It is recommended to monitor for continued efficacy of propafenone therapy.
    FluoxetineAdditive QTc-prolongation may occur increasing the risk of serious life-threatening arrhythmias. Fluoxetine may also increase the serum concentration of propafenone. Use caution during concomitant therapy and monitor for QTc-prolongation.
    LumefantrineAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
    MesoridazineIncreased risk of cardiotoxicity and arrhythmias.
    MetoprololPropafenone may increase the effect of beta-blocker, metoprolol.
    MexiletinePropafenone may increase the effect and toxicity of mexilitine.
    Mirabegron Mirabegron is a moderate CYP2D6 inhibitor and may cause an increase in exposure of CYP2D6 substrates. Monitor concomitant therapy closely.
    OxtriphyllinePropafenone increases the effect of theophylline
    ParoxetineParoxetine may increase the effect and toxicity of propafenone.
    PropranololPropafenone may increase the effect of the beta-blocker, propranolol.
    QuinidineQuinidine increases the effect of propafenone
    Quinidine barbiturateQuinidine increases the effect of propafenone
    RifabutinRifampin decreases the effect of propafenone
    RifampicinRifampin decreases the effect of propafenone
    RitonavirRitonavir increases the effect and toxicity of propafenone
    SertralineFluoxetine increases the effect and toxicity of propafenone
    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 Propafenone. Consider alternate therapy or monitor for therapeutic/adverse effects of Propafenone if Terbinafine is initiated, discontinued or dose changed.
    TerfenadineIncreased risk of cardiotoxicity and arrhythmias.
    TheophyllinePropafenone increases the effect of theophylline
    ThiopentalThiopental may increase the metabolism and clearance of Propafenone. Monitor for decreased therapeutic effect of Propafenone if Thiopental is initiated.
    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 Propafenone. Concomitant therapy is contraindicated.
    TizanidinePropafenone may decrease the metabolism and clearance of Tizanidine. Consider alternate therapy or use caution during co-administration.
    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.
    VenlafaxinePropafenone increases the effect and toxicity of venlafaxine
    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).
    WarfarinPropafenone may increase the anticoagulant effect of warfarin.
    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).
    Zuclopenthixol acetateAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
    Zuclopenthixol decanoateAdditive 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
    • Always take at the same time in regard to meals.
    • Grapefruit and grapefruit juice should be avoided throughout treatment. Grapefruit can increase serum levels of this product.

    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. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
    2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

    2. Potassium voltage-gated channel subfamily H member 2

    Kind: protein

    Organism: Human

    Pharmacological action: yes

    Actions: inhibitor

    Components

    Name UniProt ID Details
    Potassium voltage-gated channel subfamily H member 2 Q12809 Details

    References:

    1. Mergenthaler J, Haverkamp W, Huttenhofer A, Skryabin BV, Musshoff U, Borggrefe M, Speckmann EJ, Breithardt G, Madeja M: Blocking effects of the antiarrhythmic drug propafenone on the HERG potassium channel. Naunyn Schmiedebergs Arch Pharmacol. 2001 Apr;363(4):472-80. Pubmed
    2. Arias C, Gonzalez T, Moreno I, Caballero R, Delpon E, Tamargo J, Valenzuela C: Effects of propafenone and its main metabolite, 5-hydroxypropafenone, on HERG channels. Cardiovasc Res. 2003 Mar;57(3):660-9. Pubmed
    3. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

    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. Botsch S, Gautier JC, Beaune P, Eichelbaum M, Kroemer HK: Identification and characterization of the cytochrome P450 enzymes involved in N-dealkylation of propafenone: molecular base for interaction potential and variable disposition of active metabolites. Mol Pharmacol. 1993 Jan;43(1):120-6. Pubmed
    3. 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 3A4

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Cytochrome P450 3A4 P08684 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

    3. Cytochrome P450 1A2

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate inhibitor

    Components

    Name UniProt ID Details
    Cytochrome P450 1A2 P05177 Details

    References:

    1. Botsch S, Gautier JC, Beaune P, Eichelbaum M, Kroemer HK: Identification and characterization of the cytochrome P450 enzymes involved in N-dealkylation of propafenone: molecular base for interaction potential and variable disposition of active metabolites. Mol Pharmacol. 1993 Jan;43(1):120-6. Pubmed
    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

    4. 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

    5. Cytochrome P450 2C8

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: inhibitor

    Components

    Name UniProt ID Details
    Cytochrome P450 2C8 P10632 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

    1. Multidrug resistance protein 1

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: inhibitor

    Components

    Name UniProt ID Details
    Multidrug resistance protein 1 P08183 Details

    References:

    1. Schmid D, Ecker G, Kopp S, Hitzler M, Chiba P: Structure-activity relationship studies of propafenone analogs based on P-glycoprotein ATPase activity measurements. Biochem Pharmacol. 1999 Nov 1;58(9):1447-56. Pubmed
    2. Bachmakov I, Rekersbrink S, Hofmann U, Eichelbaum M, Fromm MF: Characterisation of (R/S)-propafenone and its metabolites as substrates and inhibitors of P-glycoprotein. Naunyn Schmiedebergs Arch Pharmacol. 2005 Mar;371(3):195-201. Epub 2005 Apr 15. Pubmed
    3. Singh P, Paul K: Studies of interactions between uracil-based hybrid molecules and P-glycoprotein—search for multidrug resistance modulators. Bioorg Med Chem. 2006 Nov 1;14(21):7183-6. Epub 2006 Jul 14. Pubmed
    4. Woodland C, Verjee Z, Giesbrecht E, Koren G, Ito S: The digoxin-propafenone interaction: characterization of a mechanism using renal tubular cell monolayers. J Pharmacol Exp Ther. 1997 Oct;283(1):39-45. Pubmed
    5. Tmej C, Chiba P, Huber M, Richter E, Hitzler M, Schaper KJ, Ecker G: A combined Hansch/Free-Wilson approach as predictive tool in QSAR studies on propafenone-type modulators of multidrug resistance. Arch Pharm (Weinheim). 1998 Jul-Aug;331(7-8):233-40. Pubmed

    Comments
    Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13