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Identification
Name Propafenone
Accession Number DB01182 (APRD00261)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Propafenona [INN-Spanish]
Propafenonum [INN-Latin]
Salts
  • Propafenone hydrochloride
Brand names
Name Company
Rythmol
Rythmol SR
Brand mixtures Not Available
Categories
  • Anti-Arrhythmia Agents
CAS number 54063-53-5
Weight Average: 341.444
Monoisotopic: 341.199093735
Chemical Formula C21H27NO3
InChI Key InChIKey=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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phenols and Derivatives
  • Ethers
  • Anisoles
  • Benzoyl Derivatives
  • Acetophenones and Derivatives
Substructures
  • Hydroxy Compounds
  • Aliphatic and Aryl Amines
  • Phenols and Derivatives
  • Ethers
  • Benzene and Derivatives
  • Amino Alcohols
  • Aromatic compounds
  • Anisoles
  • Benzoyl Derivatives
  • Alcohols and Polyols
  • Acetophenones and Derivatives
  • Phenyl Esters
  • Ketones
Pharmacology
Indication Used 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.
Pharmacodynamics Propafenone 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 action The 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.
Absorption Nearly 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 binding 97%
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.
Route of elimination Approximately 50% of propafenone metabolites are excreted in the urine following administration of immediate release tablets.
Half life 2-10 hours
Clearance Not Available
Toxicity Symptoms 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
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Glaxosmithkline llc
  • Kv pharmaceutical co
  • Mutual pharmaceutical co inc
  • Pliva inc
  • Vintage pharmaceuticals inc
  • Watson laboratories
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Rythmol SR 325 mg 12 Hour Capsule 8.9 USD capsule
Rythmol SR 425 mg 12 Hour Capsule 8.9 USD capsule
Rythmol sr 325 mg capsule 8.56 USD capsule
Rythmol sr 425 mg capsule 8.56 USD capsule
Rythmol SR 225 mg 12 Hour Capsule 7.02 USD capsule
Rythmol sr 225 mg capsule 6.75 USD capsule
Rythmol 225 mg tablet 6.2 USD tablet
Rythmol 300 mg tablet 5.05 USD tablet
Rythmol 150 mg tablet 3.95 USD tablet
Propafenone hcl 300 mg tablet 3.03 USD tablet
Propafenone hcl 225 mg tablet 2.38 USD tablet
Rythmol 300 mg Tablet 2.09 USD tablet
Propafenone hcl 150 mg tablet 1.64 USD tablet
Rythmol 150 mg Tablet 1.18 USD tablet
Apo-Propafenone 300 mg Tablet 0.79 USD tablet
Pms-Propafenone 300 mg Tablet 0.79 USD tablet
Apo-Propafenone 150 mg Tablet 0.45 USD tablet
Pms-Propafenone 150 mg Tablet 0.45 USD tablet
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Patents
Country Patent Number Approved Expires (estimated)
United States 5681588 1994-10-28 2014-10-28
Properties
State solid
Experimental Properties
Property Value Source
water solubility Slightly soluble Not Available
logP 3.2 Not Available
Predicted Properties
Property Value Source
water solubility 7.58e-03 g/l ALOGPS
logP 3.1 ALOGPS
logP 3.54 ChemAxon
logS -4.7 ALOGPS
pKa (strongest acidic) 14.09 ChemAxon
pKa (strongest basic) 9.63 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 4 ChemAxon
hydrogen donor count 2 ChemAxon
polar surface area 58.56 ChemAxon
rotatable bond count 11 ChemAxon
refractivity 100.21 ChemAxon
polarizability 39.75 ChemAxon
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Compound C07381 Link_out
PubChem Compound 4932 Link_out
PubChem Substance 46504529 Link_out
ChemSpider 4763 Link_out
BindingDB 50067133 Link_out
Therapeutic Targets Database DAP000497 Link_out
PharmGKB PA451131 Link_out
IUPHAR 2561 Link_out
Guide to Pharmacology 2561 Link_out
Drug Product Database 2243728 Link_out
RxList http://www.rxlist.com/cgi/generic3/propafen.htm Link_out
Drugs.com http://www.drugs.com/cdi/propafenone.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/ryt1392.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Propafenone Link_out
ATC Codes
  • C01BC03
AHFS Codes
  • 24:04.04.12
PDB Entries Not Available
FDA label show (91.1 KB)
MSDS show (73.7 KB)
Interactions
Drug Interactions
Drug Interaction
Acenocoumarol Propafenone may increase the anticoagulant effect of acenocoumarol.
Aminophylline Propafenone increases the effect of theophylline
Anisindione Propafenone may increase the anticoagulant effect of anisindione.
Artemether Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Cisapride Increased risk of cardiotoxicity and arrhythmias
Cyclosporine Propafenone increases the effect and toxicity of cyclosporine
Dicumarol Propafenone may increase the anticoagulant effect of dicumarol.
Digoxin Propafenone increases the effect of digoxin
Dihydroquinidine barbiturate Quinidine increases the effect of propafenone
Duloxetine Possible increase in the levels of this agent when used with duloxetine
Dyphylline Propafenone increases the effect of theophylline
Fluoxetine Additive 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.
Lumefantrine Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Mesoridazine Increased risk of cardiotoxicity and arrhythmias.
Metoprolol Propafenone may increase the effect of beta-blocker, metoprolol.
Mexiletine Propafenone may increase the effect and toxicity of mexilitine.
Oxtriphylline Propafenone increases the effect of theophylline
Paroxetine Paroxetine may increase the effect and toxicity of propafenone.
Propranolol Propafenone may increase the effect of the beta-blocker, propranolol.
Quinidine Quinidine increases the effect of propafenone
Quinidine barbiturate Quinidine increases the effect of propafenone
Rifabutin Rifampin decreases the effect of propafenone
Rifampin Rifampin decreases the effect of propafenone
Ritonavir Ritonavir increases the effect and toxicity of propafenone
Sertraline Fluoxetine increases the effect and toxicity of propafenone
Tacrolimus Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Terbinafine Terbinafine 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.
Terfenadine Increased risk of cardiotoxicity and arrhythmias.
Theophylline Propafenone increases the effect of theophylline
Thiopental Thiopental may increase the metabolism and clearance of Propafenone. Monitor for decreased therapeutic effect of Propafenone if Thiopental is initiated.
Thioridazine Increased risk of cardiotoxicity and arrhythmias.
Thiothixene May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
Tipranavir Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Propafenone. Concomitant therapy is contraindicated.
Tizanidine Propafenone may decrease the metabolism and clearance of Tizanidine. Consider alternate therapy or use caution during co-administration.
Toremifene Additive 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.
Trimipramine Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Venlafaxine Propafenone increases the effect and toxicity of venlafaxine
Voriconazole Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Vorinostat Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Warfarin Propafenone may increase the anticoagulant effect of warfarin.
Ziprasidone Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
Zuclopenthixol Additive 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

Pharmacological action: yes
Actions: inhibitor

This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential in the electrocardiogram

Organism class: human
UniProt ID: Q14524 Link_out
Gene: SCN5A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Pharmacological action: yes
Actions: inhibitor

Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr). Isoform 3 has no channel activity by itself, but modulates channel characteristics when associated with isoform 1

Organism class: human
UniProt ID: Q12809 Link_out
Gene: KCNH2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate, inhibitor

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol)

UniProt ID: P10632 Link_out
Gene: CYP2C8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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 February 08, 2013 16:19