Digitoxin

Identification

Summary

Digitoxin is a cardiac glycoside used in the treatment and management of congestive cardiac insufficiency, arrhythmias and heart failure.

Generic Name
Digitoxin
DrugBank Accession Number
DB01396
Background

A cardiac glycoside sometimes used in place of digoxin. It has a longer half-life than digoxin; toxic effects, which are similar to those of digoxin, are longer lasting. (From Martindale, The Extra Pharmacopoeia, 30th ed, p665)

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 764.9391
Monoisotopic: 764.434692134
Chemical Formula
C41H64O13
Synonyms
  • Digitoksin
  • Digitoxin
  • Digitoxina
  • Digitoxine
  • Digitoxinum
  • Digitoxoside
External IDs
  • NSC-7529

Pharmacology

Indication

For the treatment and management of congestive cardiac insufficiency, arrhythmias and heart failure.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofAtrial fibrillation (af)••••••••••••••••••
Treatment ofAtrial fibrillation or flutter••••••••••••••••••
Treatment ofChronic heart failure (chf)••••••••••••••••••
Treatment ofFlutter, atrial••••••••••••••••••
Treatment ofTachyarrhythmia••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Digitoxin is a cardiac glycoside sometimes used in place of DIGOXIN. It has a longer half-life than digoxin; toxic effects, which are similar to those of digoxin, are longer lasting (From Martindale, The Extra Pharmacopoeia, 30th ed, p665). It is eliminated hepatically making it useful in patients with poor or erratic kidney function, although it is now rarely used in practice. Digitoxin lacks the strength of evidence that digoxin has in the management of heart failure.

Mechanism of action

Digitoxin inhibits the Na-K-ATPase membrane pump, resulting in an increase in intracellular sodium and calcium concentrations. Increased intracellular concentrations of calcium may promote activation of contractile proteins (e.g., actin, myosin). Digitoxin also acts on the electrical activity of the heart, increasing the slope of phase 4 depolarization, shortening the action potential duration, and decreasing the maximal diastolic potential.

TargetActionsOrganism
ASodium/potassium-transporting ATPase subunit alpha-1
inhibitor
Humans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Hepatic.

Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Digitoxin exerts similar toxic effects to digoxin including anorexia, nausea, vomiting, diarrhoea, confusion, visual disturbances, and cardiac arrhythmias.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Digitoxin can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Digitoxin can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Digitoxin.
AbrocitinibThe serum concentration of Digitoxin can be increased when it is combined with Abrocitinib.
AcalabrutinibThe metabolism of Digitoxin can be decreased when combined with Acalabrutinib.
Food Interactions
  • Avoid avocado. Persea americana (avocado) is a plant that affects the heart by interfering with the Na+, K+, ATPase, which may cause an additive effect with digitoxin.
  • Do not take with bran and high fiber foods. The absorption of digitoxin is more predictable than the absorption of digoxin in the presence of high-fiber food.

Products

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International/Other Brands
Crystodigin / Tardigal
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Digitaline Welcker Tab 0.1mgTablet.1 mg / tabOralWelcker Lyster Ltd., Division Of Technilab Inc.1951-12-312001-09-05Canada flag

Categories

ATC Codes
C01AA04 — Digitoxin
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as cardenolide glycosides and derivatives. These are compounds containing a carbohydrate glycosidically bound to the cardenolide moiety.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Steroid lactones
Direct Parent
Cardenolide glycosides and derivatives
Alternative Parents
Steroidal glycosides / Oligosaccharides / 14-hydroxysteroids / O-glycosyl compounds / Oxanes / Butenolides / Tertiary alcohols / Enoate esters / Secondary alcohols / Cyclic alcohols and derivatives
show 7 more
Substituents
14-hydroxysteroid / 2-furanone / Acetal / Alcohol / Aliphatic heteropolycyclic compound / Alpha,beta-unsaturated carboxylic ester / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester / Cardanolide-glycoside
show 19 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
cardenolide glycoside (CHEBI:28544) / cardanolide, Cardanolides and derivatives, Cardanolide and derivatives, Cardiac glycosides (C06955) / Cardanolides and derivatives (LMST01120018)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
E90NZP2L9U
CAS number
71-63-6
InChI Key
WDJUZGPOPHTGOT-XUDUSOBPSA-N
InChI
InChI=1S/C41H64O13/c1-20-36(46)29(42)16-34(49-20)53-38-22(3)51-35(18-31(38)44)54-37-21(2)50-33(17-30(37)43)52-25-8-11-39(4)24(15-25)6-7-28-27(39)9-12-40(5)26(10-13-41(28,40)47)23-14-32(45)48-19-23/h14,20-22,24-31,33-38,42-44,46-47H,6-13,15-19H2,1-5H3/t20-,21-,22-,24-,25+,26-,27+,28-,29+,30+,31+,33+,34+,35+,36-,37-,38-,39+,40-,41+/m1/s1
IUPAC Name
4-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-7-{[(2R,4S,5S,6R)-5-{[(2S,4S,5S,6R)-5-{[(2S,4S,5S,6R)-4,5-dihydroxy-6-methyloxan-2-yl]oxy}-4-hydroxy-6-methyloxan-2-yl]oxy}-4-hydroxy-6-methyloxan-2-yl]oxy}-3a-hydroxy-9a,11a-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-1-yl]-2,5-dihydrofuran-2-one
SMILES
[H][C@@]1(CC[C@]2(O)[C@]3([H])CC[C@]4([H])C[C@H](CC[C@]4(C)[C@@]3([H])CC[C@]12C)O[C@H]1C[C@H](O)[C@H](O[C@H]2C[C@H](O)[C@H](O[C@H]3C[C@H](O)[C@H](O)[C@@H](C)O3)[C@@H](C)O2)[C@@H](C)O1)C1=CC(=O)OC1

References

General References
  1. Belz GG, Breithaupt-Grogler K, Osowski U: Treatment of congestive heart failure--current status of use of digitoxin. Eur J Clin Invest. 2001;31 Suppl 2:10-7. [Article]
  2. Kurowski V, Iven H, Djonlagic H: Treatment of a patient with severe digitoxin intoxication by Fab fragments of anti-digitalis antibodies. Intensive Care Med. 1992;18(7):439-42. [Article]
  3. Johansson S, Lindholm P, Gullbo J, Larsson R, Bohlin L, Claeson P: Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells. Anticancer Drugs. 2001 Jun;12(5):475-83. [Article]
  4. Hippius M, Humaid B, Sicker T, Hoffmann A, Gottler M, Hasford J: Adverse drug reaction monitoring--digitoxin overdosage in the elderly. Int J Clin Pharmacol Ther. 2001 Aug;39(8):336-43. [Article]
Human Metabolome Database
HMDB0015468
KEGG Drug
D00297
KEGG Compound
C06955
PubChem Compound
441207
PubChem Substance
46506035
ChemSpider
389987
BindingDB
46356
RxNav
3403
ChEBI
28544
ChEMBL
CHEMBL254219
ZINC
ZINC000095862733
Therapeutic Targets Database
DAP000120
PharmGKB
PA449316
PDBe Ligand
F9R
Wikipedia
Digitoxin
PDB Entries
7ddi
MSDS
Download (73.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentCystic Fibrosis (CF)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Spectrum Pharmaceuticals
Dosage Forms
FormRouteStrength
TabletOral0.1 mg/1
TabletOral
Injection, solutionParenteral
TabletOral0.07 mg/1
TabletOral0.05 mg/1
TabletOral.1 mg / tab
TabletOral0.07 MG
TabletOral0.1 mg
Prices
Unit descriptionCostUnit
Digitoxin powder486.85USD g
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)255.5 °CPhysProp
water solubility3.9 mg/L (at 25 °C)YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP1.85SANGSTER (1993)
Predicted Properties
PropertyValueSource
Water Solubility0.0289 mg/mLALOGPS
logP2.33ALOGPS
logP3.6Chemaxon
logS-4.4ALOGPS
pKa (Strongest Acidic)7.18Chemaxon
pKa (Strongest Basic)0.24Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count12Chemaxon
Hydrogen Donor Count5Chemaxon
Polar Surface Area182.83 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity191.72 m3·mol-1Chemaxon
Polarizability83.54 Å3Chemaxon
Number of Rings8Chemaxon
Bioavailability0Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9718
Blood Brain Barrier-0.557
Caco-2 permeable-0.8386
P-glycoprotein substrateSubstrate0.8528
P-glycoprotein inhibitor IInhibitor0.5557
P-glycoprotein inhibitor IINon-inhibitor0.6021
Renal organic cation transporterNon-inhibitor0.8473
CYP450 2C9 substrateNon-substrate0.8687
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.7407
CYP450 1A2 substrateNon-inhibitor0.8902
CYP450 2C9 inhibitorNon-inhibitor0.9082
CYP450 2D6 inhibitorNon-inhibitor0.9412
CYP450 2C19 inhibitorNon-inhibitor0.9258
CYP450 3A4 inhibitorNon-inhibitor0.901
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9381
Ames testNon AMES toxic0.9233
CarcinogenicityNon-carcinogens0.9637
BiodegradationNot ready biodegradable0.9671
Rat acute toxicity4.4764 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9812
hERG inhibition (predictor II)Inhibitor0.7759
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (12.6 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Mass Spectrum (Electron Ionization)MSsplash10-052g-9620000000-5ddc0df4702d2f0b8581
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-00kb-0001001900-b1c97ad124188f2437cd
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-03di-0201014900-bef9cc4c4d5b115a6e85
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-03fs-0500013900-0ee99076b34282c9b133
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-014i-0940001700-06e92e34a9c51b1a91f8
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-01si-0420227900-4fb4c255b7f8af3a188a
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-014r-2912027600-75a2f63447cff9fa6611
13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-292.538183
predicted
DarkChem Lite v0.1.0
[M-H]-294.102883
predicted
DarkChem Lite v0.1.0
[M-H]-293.705983
predicted
DarkChem Lite v0.1.0
[M-H]-295.985983
predicted
DarkChem Lite v0.1.0
[M-H]-262.88226
predicted
DeepCCS 1.0 (2019)
[M+H]+299.683883
predicted
DarkChem Lite v0.1.0
[M+H]+297.357883
predicted
DarkChem Lite v0.1.0
[M+H]+293.358983
predicted
DarkChem Lite v0.1.0
[M+H]+298.888383
predicted
DarkChem Lite v0.1.0
[M+H]+264.55496
predicted
DeepCCS 1.0 (2019)
[M+Na]+292.096583
predicted
DarkChem Lite v0.1.0
[M+Na]+294.944983
predicted
DarkChem Lite v0.1.0
[M+Na]+293.280983
predicted
DarkChem Lite v0.1.0
[M+Na]+296.802983
predicted
DarkChem Lite v0.1.0
[M+Na]+270.71182
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Steroid hormone binding
Specific Function
This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates th...
Gene Name
ATP1A1
Uniprot ID
P05023
Uniprot Name
Sodium/potassium-transporting ATPase subunit alpha-1
Molecular Weight
112895.01 Da
References
  1. Chen JJ, Wang PS, Chien EJ, Wang SW: Direct inhibitory effect of digitalis on progesterone release from rat granulosa cells. Br J Pharmacol. 2001 Apr;132(8):1761-8. [Article]
  2. Marcus FI, Ryan JN, Stafford MG: The reactivity of derivatives of digoxin and digitoxin as measured by the Na-K-atpase displacement assay and by radioimmunoassay. J Lab Clin Med. 1975 Apr;85(4):610-20. [Article]
  3. Prignitz R, Frohlich D, Hoffmeister G: [Influence of roentgen rays on electrolyte changes and metabolism of the myocardium. VII. Radiation-induced inhibition of the sodium- and potassium--activated microscomal-trasport ATPase]. Strahlentherapie. 1976 Apr;151(4):356-65. [Article]
  4. Bluschke V, Bonn R, Greeff K: Increase in the (Na+ + K+)-ATPase activity in heart muscle after chronic treatment with digitoxin or potassium deficient diet. Eur J Pharmacol. 1976 May;37(1):189-91. [Article]
  5. Fricke U: [New aspects on the mode of action of cardiac glycosides]. Fortschr Med. 1976 Nov 11;94(32):1037-45. [Article]
  6. Hauck C, Potter T, Bartz M, Wittwer T, Wahlers T, Mehlhorn U, Scheiner-Bobis G, McDonough AA, Bloch W, Schwinger RH, Muller-Ehmsen J: Isoform specificity of cardiac glycosides binding to human Na+,K+-ATPase alpha1beta1, alpha2beta1 and alpha3beta1. Eur J Pharmacol. 2009 Nov 10;622(1-3):7-14. doi: 10.1016/j.ejphar.2009.08.039. Epub 2009 Sep 12. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, nad(p)h as one donor, and incorporation of one atom of oxygen
Specific Function
Catalyzes the side-chain cleavage reaction of cholesterol to pregnenolone.
Gene Name
CYP11A1
Uniprot ID
P05108
Uniprot Name
Cholesterol side-chain cleavage enzyme, mitochondrial
Molecular Weight
60101.87 Da
References
  1. Wang SW, Lin H, Hwang JJ, Wang PS: Inhibition of testosterone secretion by digitoxin in rat testicular interstitial cells. J Cell Biochem. 1999 Jul 1;74(1):74-80. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Eberhart DC, Gemzik B, Halvorson MR, Parkinson A: Species differences in the toxicity and cytochrome P450 IIIA-dependent metabolism of digitoxin. Mol Pharmacol. 1991 Nov;40(5):859-67. [Article]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Hage DS, Sengupta A: Characterisation of the binding of digitoxin and acetyldigitoxin to human serum albumin by high-performance affinity chromatography. J Chromatogr B Biomed Sci Appl. 1999 Mar 5;724(1):91-100. [Article]
  2. Dasgupta A, Vega AE, Wells A, Datta P: Sensitive methods for determination of free digitoxin concentration using digitoxin immunoassays: demonstration of elevated free digitoxin concentration caused by digitoxin-phenytoin interaction by applying these new techniques. Ther Drug Monit. 1999 Dec;21(6):625-30. [Article]
  3. Datta P, Dasgupta A: Interactions between drugs and Asian medicine: displacement of digitoxin from protein binding site by bufalin, the constituent of Chinese medicines Chan Su and Lu-Shen-Wan. Ther Drug Monit. 2000 Apr;22(2):155-9. [Article]
  4. Dasgupta A, Paul A, Wells A: Uremic sera contain inhibitors that block digitoxin-valproic acid interaction. Am J Med Sci. 2001 Oct;322(4):204-8. [Article]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity). Selectively inhibit...
Gene Name
SLCO1A2
Uniprot ID
P46721
Uniprot Name
Solute carrier organic anion transporter family member 1A2
Molecular Weight
74144.105 Da
References
  1. Bossuyt X, Muller M, Hagenbuch B, Meier PJ: Polyspecific drug and steroid clearance by an organic anion transporter of mammalian liver. J Pharmacol Exp Ther. 1996 Mar;276(3):891-6. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Organic anion transporter, capable of transporting pharmacological substances such as digoxin, ouabain, thyroxine, methotrexate and cAMP. May participate in the regulation of membrane transport of ...
Gene Name
SLCO4C1
Uniprot ID
Q6ZQN7
Uniprot Name
Solute carrier organic anion transporter family member 4C1
Molecular Weight
78947.525 Da
References
  1. Mikkaichi T, Suzuki T, Onogawa T, Tanemoto M, Mizutamari H, Okada M, Chaki T, Masuda S, Tokui T, Eto N, Abe M, Satoh F, Unno M, Hishinuma T, Inui K, Ito S, Goto J, Abe T: Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3569-74. Epub 2004 Mar 1. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Pauli-Magnus C, Murdter T, Godel A, Mettang T, Eichelbaum M, Klotz U, Fromm MF: P-glycoprotein-mediated transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin. Naunyn Schmiedebergs Arch Pharmacol. 2001 Mar;363(3):337-43. [Article]

Drug created at July 08, 2007 17:03 / Updated at February 21, 2021 18:51