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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 KeyJWHAUXFOSRPERK-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
Not Available
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.
MirabegronMirabegron 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.

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. 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

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. 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

Transporters

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

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