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Identification
Name Disopyramide
Accession Number DB00280 (APRD00507)
Type small molecule
Groups approved
Description

A class I anti-arrhythmic agent (one that interferes directly with the depolarization of the cardiac membrane and thus serves as a membrane-stabilizing agent) with a depressant action on the heart similar to that of guanidine. It also possesses some anticholinergic and local anesthetic properties. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Disopiramida [INN-Spanish]
  • Disopyramide Free Base
  • Disopyramide Phosphate
  • Disopyramidum [INN-Latin]
Brand names
  • Dicorantil
  • Isorythm
  • Lispine
  • Norpace
  • Norpace CR
  • Ritmodan
  • Rythmodan
  • Rythmodan P
  • Rythmodan-La
  • Searle 703
  • Xi-Disopyramide
Brand name mixtures Not Available
Categories
  • Antiarrhythmic Agents
  • Anti-Arrhythmia Agents
CAS number 3737-09-5
Weight Average: 339.4745
Monoisotopic: 339.231062565
Chemical Formula C21H29N3O
InChI Key InChIKey=UVTNFZQICZKOEM-UHFFFAOYSA-N
InChI
InChI=1S/C21H29N3O/c1-16(2)24(17(3)4)15-13-21(20(22)25,18-10-6-5-7-11-18)19-12-8-9-14-23-19/h5-12,14,16-17H,13,15H2,1-4H3,(H2,22,25)
Plain Text
IUPAC Name
4-[bis(propan-2-yl)amino]-2-phenyl-2-(pyridin-2-yl)butanamide
SMILES
CC(C)N(CCC(C(N)=O)(C1=CC=CC=C1)C1=NC=CC=C1)C(C)C
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Pheniramines
Substructures
  • Pheniramines
  • Carbonyl Compounds
  • Amino Ketones
  • Pyridines and Derivatives
  • Benzene and Derivatives
  • Carbamates and Derivatives
  • Aliphatic and Aryl Amines
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Carboxamides and Derivatives
  • Phenylpropylamines
  • Imines
  • Carboxylic Acids and Derivatives
Pharmacology
Indication For the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, ventricular pre-excitation and cardiac dysrhythmias. It is a Class Ia antiarrhythmic drug.
Pharmacodynamics Disopyramide is an antiarrhythmic drug indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia that are life-threatening. In man, Disopyramide at therapeutic plasma levels shortens the sinus node recovery time, lengthens the effective refractory period of the atrium, and has a minimal effect on the effective refractory period of the AV node. Little effect has been shown on AV-nodal and His-Purkinje conduction times or QRS duration. However, prolongation of conduction in accessory pathways occurs.
Mechanism of action Disopyramide is a Type 1A antiarrhythmic drug (ie, similar to procainamide and quinidine). It inhibits the fast sodium channels. In animal studies Disopyramide decreases the rate of diastolic depolarization (phase 4) in cells with augmented automaticity, decreases the upstroke velocity (phase 0) and increases the action potential duration of normal cardiac cells, decreases the disparity in refractoriness between infarcted and adjacent normally perfused myocardium, and has no effect on alpha- or beta-adrenergic receptors.
Absorption Nearly complete
Volume of distribution Not Available
Protein binding 50%-65%
Metabolism

Hepatic

Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 3A4 mono-isopropyl-disopyramide N-dealkylation 1637 637
Route of elimination In healthy men, about 50% of a given dose of disopyramide is excreted in the urine as the unchanged drug, about 20% as the mono-N-dealkylated metabolite and 10% as the other metabolites.
Half life 6.7 hours (range 4-10 hours)
Clearance Not Available
Toxicity LD50=580 mg/kg in rats
Affected organisms
  • Humans and other mammals
Pathways
Pathway Name SMPDB ID
Smp00325 Disopyramide Pathway SMP00325
Pharmacoeconomics
Manufacturers
  • Kv pharmaceutical co
  • Gd searle llc
  • Interpharm inc
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Mutual pharmaceutical co inc
  • Mylan pharmaceuticals inc
  • Sandoz inc
  • Superpharm corp
  • Teva pharmaceuticals usa inc
  • Watson laboratories inc
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Tablet, extended release Oral
Prices
Unit description Cost Unit
Norpace CR 150 mg 12 Hour Capsule 2.35 USD capsule
Norpace cr 150 mg capsule 2.26 USD capsule
Norpace CR 100 mg 12 Hour Capsule 1.98 USD capsule
Norpace 150 mg capsule 1.94 USD capsule
Norpace cr 100 mg capsule 1.91 USD capsule
Norpace 100 mg capsule 1.62 USD capsule
Disopyramide Phosphate 150 mg capsule 0.96 USD capsule
Disopyramide 150 mg capsule 0.82 USD capsule
Disopyramide Phosphate 100 mg capsule 0.72 USD capsule
Disopyramide 100 mg capsule 0.69 USD capsule
Rythmodan 150 mg Capsule 0.43 USD capsule
Rythmodan 100 mg Capsule 0.3 USD capsule
Patents Not Available
Properties
State solid
Melting point 94.5-95 oC
Experimental Properties
Property Value Source
water solubility 44.9 mg/L PhysProp
logP 3.5 PhysProp
Predicted Properties
Property Value Source
water solubility 4.93e-02 g/l ALOGPS
logP 3.21 ALOGPS
logP 3.47 ChemAxon Molconvert
logS -3.84 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 3 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 59.22 ChemAxon Molconvert
rotatable bond count 8 ChemAxon Molconvert
refractivity 102.30 ChemAxon Molconvert
polarizability 38.66 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00303 Link_out
KEGG Compound C06965 Link_out
PubChem Compound 3114 Link_out
PubChem Substance 46508226 Link_out
ChemSpider 3002 Link_out
ChEBI 4657 Link_out
ChEMBL 4657 Link_out
Therapeutic Targets Database DAP000504 Link_out
PharmGKB PA449373 Link_out
Drug Product Database 2224828 Link_out
RxList http://www.rxlist.com/cgi/generic2/disopyr.htm Link_out
Drugs.com http://www.drugs.com/cdi/disopyramide.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Disopyramide Link_out
ATC Codes
  • C01BA03
AHFS Codes
  • 24:04.04.04
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions
  • Avoid alcohol.
  • Take without regard to meals.
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. Sugao M, Fujiki A, Nishida K, Sakabe M, Tsuneda T, Iwamoto J, Mizumaki K, Inoue H: Repolarization dynamics in patients with idiopathic ventricular fibrillation: pharmacological therapy with bepridil and disopyramide. J Cardiovasc Pharmacol. 2005 Jun;45(6):545-9. Pubmed
  2. Fujiki A, Sugao M, Nishida K, Sakabe M, Tsuneda T, Mizumaki K, Inoue H: Repolarization abnormality in idiopathic ventricular fibrillation: assessment using 24-hour QT-RR and QaT-RR relationships. J Cardiovasc Electrophysiol. 2004 Jan;15(1):59-63. Pubmed
  3. 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
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Muscarinic acetylcholine receptor M1

Pharmacological action: unknown
Actions: antagonist

The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover

Organism class: human
UniProt ID: P11229 Link_out
Gene: CHRM1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Yamamoto N, Ozaki T, Keida Y, Ohtsuka M, Goto T: A comparison of the binding characteristics of class I antiarrhythmic agents for human muscarinic m1-m3 receptors. J Cardiovasc Pharmacol. 1999 Jul;34(1):53-9. Pubmed
  2. Ishida Y, Mizukami M, Taniguchi T, Satake N, Fujiwara M, Shibata S: Anticholinergic action of disopyramide in intestinal smooth muscle of the guinea pig: inhibition of muscarinic receptors (M1 and M2). Jpn J Pharmacol. 1990 Feb;52(2):363-70. Pubmed

3. Muscarinic acetylcholine receptor M2

Pharmacological action: unknown
Actions: antagonist

The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is adenylate cyclase inhibition

Organism class: human
UniProt ID: P08172 Link_out
Gene: CHRM2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Yamamoto N, Ozaki T, Keida Y, Ohtsuka M, Goto T: A comparison of the binding characteristics of class I antiarrhythmic agents for human muscarinic m1-m3 receptors. J Cardiovasc Pharmacol. 1999 Jul;34(1):53-9. Pubmed
  2. Ishida Y, Mizukami M, Taniguchi T, Satake N, Fujiwara M, Shibata S: Anticholinergic action of disopyramide in intestinal smooth muscle of the guinea pig: inhibition of muscarinic receptors (M1 and M2). Jpn J Pharmacol. 1990 Feb;52(2):363-70. Pubmed

4. Muscarinic acetylcholine receptor M3

Pharmacological action: unknown
Actions: antagonist

The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover

Organism class: human
UniProt ID: P20309 Link_out
Gene: CHRM3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Yamamoto N, Ozaki T, Keida Y, Ohtsuka M, Goto T: A comparison of the binding characteristics of class I antiarrhythmic agents for human muscarinic m1-m3 receptors. J Cardiovasc Pharmacol. 1999 Jul;34(1):53-9. Pubmed

5. Potassium voltage-gated channel subfamily D member 2

Pharmacological action: unknown
Actions: inhibitor

Pore-forming (alpha) subunit of voltage-gated rapidly inactivating A-type potassium channels. May contribute to I(To) current in heart and I(Sa) current in neurons. Channel properties are modulated by interactions with other alpha subunits and with regulatory subunits

Organism class: human
UniProt ID: Q9NZV8 Link_out
Gene: KCND2 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Casis O, Sanchez-Chapula JA: Disopyramide, imipramine, and amitriptyline bind to a common site on the transient outward K+ channel. J Cardiovasc Pharmacol. 1998 Oct;32(4):521-6. Pubmed

6. Potassium voltage-gated channel subfamily D member 3

Pharmacological action: unknown
Actions: inhibitor

Pore-forming (alpha) subunit of voltage-gated rapidly inactivating A-type potassium channels. May contribute to I(To) current in heart and I(Sa) current in neurons. Channel properties are modulated by interactions with other alpha subunits and with regulatory subunits

Organism class: human
UniProt ID: Q9UK17 Link_out
Gene: KCND3 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Casis O, Sanchez-Chapula JA: Disopyramide, imipramine, and amitriptyline bind to a common site on the transient outward K+ channel. J Cardiovasc Pharmacol. 1998 Oct;32(4):521-6. Pubmed
Enzymes

1. 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. Echizen H, Tanizaki M, Tatsuno J, Chiba K, Berwick T, Tani M, Gonzalez FJ, Ishizaki T: Identification of CYP3A4 as the enzyme involved in the mono-N-dealkylation of disopyramide enantiomers in humans. Drug Metab Dispos. 2000 Aug;28(8):937-44. 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
  3. Zhang L, Fitzloff JF, Engel LC, Cook CS: Species difference in stereoselective involvement of CYP3A in the mono-N-dealkylation of disopyramide. Xenobiotica. 2001 Feb;31(2):73-83. Pubmed
Transporters

1. Solute carrier family 22 member 1

Actions: inhibitor

Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnicotinamide (NMN), 4-(4-(dimethylamino)styryl)- N-methylpyridinium (ASP), the endogenous compounds choline, guanidine, histamine, epinephrine, adrenaline, noradrenaline and dopamine, and the drugs quinine, and metformin. The transport of organic cations is inhibited by a broad array of compounds like tetramethylammonium (TMA), cocaine, lidocaine, NMDA receptor antagonists, atropine, prazosin, cimetidine, TEA and NMN, guanidine, cimetidine, choline, procainamide, quinine, tetrabutylammonium, and tetrapentylammonium. Translocates organic cations in an electrogenic and pH-independent manner. Translocates organic cations across the plasma membrane in both directions. Transports the polyamines spermine and spermidine. Transports pramipexole across the basolateral membrane of the proximal tubular epithelial cells. The choline transport is activated by MMTS. Regulated by various intracellular signaling pathways including inhibition by protein kinase A activation, and endogenously activation by the calmodulin complex, the calmodulin- dependent kinase II and LCK tyrosine kinase

UniProt ID: O15245 Link_out
Gene: SLC22A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zhang L, Schaner ME, Giacomini KM: Functional characterization of an organic cation transporter (hOCT1) in a transiently transfected human cell line (HeLa). J Pharmacol Exp Ther. 1998 Jul;286(1):354-61. Pubmed
  2. Urakami Y, Okuda M, Masuda S, Akazawa M, Saito H, Inui K: Distinct characteristics of organic cation transporters, OCT1 and OCT2, in the basolateral membrane of renal tubules. Pharm Res. 2001 Nov;18(11):1528-34. Pubmed

2. Solute carrier family 22 member 2

Actions: inhibitor

Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creatinine, amantadine, memantine, acriflavine, 4-[4-(dimethylamino)-styryl]-N-methylpyridinium ASP, amiloride, metformin, N-1-methylnicotinamide (NMN), tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, cisplatin and oxaliplatin. Cisplatin may develop a nephrotoxic action. Transport of creatinine is inhibited by fluoroquinolones such as DX-619 and LVFX. This transporter is a major determinant of the anticancer activity of oxaliplatin and may contribute to antitumor specificity

UniProt ID: O15244 Link_out
Gene: SLC22A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Urakami Y, Okuda M, Masuda S, Akazawa M, Saito H, Inui K: Distinct characteristics of organic cation transporters, OCT1 and OCT2, in the basolateral membrane of renal tubules. Pharm Res. 2001 Nov;18(11):1528-34. Pubmed
Carriers

1. Alpha-1-acid glycoprotein 1

Actions: other/unknown

Appears to function in modulating the activity of the immune system during the acute-phase reaction

UniProt ID: P02763 Link_out
Gene: ORM1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chu JS, Kishion S, Nomura A, Miyazaki K: Serum alpha 1-acid glycoprotein, sialic acid, and protein binding of disopyramide in normal subjects and cardiac patients. Zhongguo Yao Li Xue Bao. 1997 Sep;18(5):408-10. Pubmed
  2. Hanada K, Ohta T, Hirai M, Arai M, Ogata H: Enantioselective binding of propranolol, disopyramide, and verapamil to human alpha(1)-acid glycoprotein. J Pharm Sci. 2000 Jun;89(6):751-7. Pubmed
  3. Nakagawa T, Kishino S, Itoh S, Sugawara M, Miyazaki K: Differential binding of disopyramide and warfarin enantiomers to human alpha(1)-acid glycoprotein variants. Br J Clin Pharmacol. 2003 Dec;56(6):664-9. Pubmed
  4. Haughey DB, Steinberg I, Lee MH: Protein binding of disopyramide—displacement by mono-N-dealkyldisopyramide and variation with source of alpha-1-acid glycoprotein. J Pharm Pharmacol. 1985 Apr;37(4):285-8. Pubmed
  5. Brunner F, Muller WE: Prazosin binding to human alpha 1-acid glycoprotein (orosomucoid), human serum albumin, and human serum. Further characterization of the ‘single drug binding site’ of orosomucoid. J Pharm Pharmacol. 1985 May;37(5):305-9. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:02

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.