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Digitoxin

PubChem CID
441207
Structure
Digitoxin_small.png
Molecular Formula
Synonyms
  • digitoxin
  • 71-63-6
  • Digitoxoside
  • Crystodigin
  • Digitoxinum
Molecular Weight
764.9 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-06-24
  • Modify:
    2024-12-07
Description
Digitoxin appears as odorless white or pale buff microcrystalline powder. Used as a cardiotonic drug. (EPA, 1998)
U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.
Digitoxin is a cardenolide glycoside in which the 3beta-hydroxy group of digitoxigenin carries a 2,6-dideoxy-beta-D-ribo-hexopyranosyl-(1->4)-2,6-dideoxy-beta-D-ribo-hexopyranosyl-(1->4)-2,6-dideoxy-beta-D-ribo-hexopyranosyl trisaccharide chain. It has a role as an EC 3.6.3.9 (Na(+)/K(+)-transporting ATPase) inhibitor. It is functionally related to a digitoxigenin. It is a conjugate acid of a digitoxin(1-).
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)
See also: Acetyldigitoxin (is active moiety of); Digitalis (annotation moved to).

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Digitoxin.png

1.2 3D Status

Conformer generation is disallowed since too many atoms

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

3-[(3S,5R,8R,9S,10S,13R,14S,17R)-3-[(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-14-hydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]-2H-furan-5-one
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 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
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

WDJUZGPOPHTGOT-XUDUSOBPSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

C[C@@H]1[C@H]([C@H](C[C@@H](O1)O[C@@H]2[C@H](O[C@H](C[C@@H]2O)O[C@@H]3[C@H](O[C@H](C[C@@H]3O)O[C@H]4CC[C@]5([C@@H](C4)CC[C@@H]6[C@@H]5CC[C@]7([C@@]6(CC[C@@H]7C8=CC(=O)OC8)O)C)C)C)C)O)O
Computed by OEChem 2.3.0 (PubChem release 2021.10.14)

2.2 Molecular Formula

C41H64O13
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

71-63-6

2.3.2 Deprecated CAS

1339-93-1, 1367-39-1, 1391-34-0, 82476-56-0

2.3.3 European Community (EC) Number

2.3.4 UNII

2.3.5 UN Number

2.3.6 ChEBI ID

2.3.7 ChEMBL ID

2.3.8 DrugBank ID

2.3.9 DSSTox Substance ID

2.3.10 HMDB ID

2.3.11 KEGG ID

2.3.12 Lipid Maps ID (LM_ID)

2.3.13 Metabolomics Workbench ID

2.3.14 NCI Thesaurus Code

2.3.15 Nikkaji Number

2.3.16 PharmGKB ID

2.3.17 Pharos Ligand ID

2.3.18 Wikidata

2.3.19 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • AWD, Digitoxin
  • Bürger, Digitoxin
  • Coramedan
  • Didier, Digitoxin
  • Digimed
  • Digimerck
  • Digitaline Nativelle
  • Digitoxin
  • Digitoxin AWD
  • Digitoxin Bürger
  • Digitoxin Didier
  • Digitoxin Philo
  • Digitoxin-Philo
  • Digophton
  • Nativelle, Digitaline

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
764.9 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3
Property Value
2.3
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
5
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
13
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
764.43469209 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
764.43469209 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
183Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
54
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
1410
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
20
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Digitoxin appears as odorless white or pale buff microcrystalline powder. Used as a cardiotonic drug. (EPA, 1998)
U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.
Solid

3.2.2 Color / Form

Very small elongated, rectangular plates from dilute alcohol
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 575
Prisms from dilute alcohol
Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 95th Edition. CRC Press LLC, Boca Raton: FL 2014-2015, p. 3-182
White or pale buff microcrystalline powder
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 792
White leaflets or powder
Larranaga, M.D., Lewis, R.J. Sr., Lewis, R.A.; Hawley's Condensed Chemical Dictionary 16th Edition. John Wiley & Sons, Inc. Hoboken, NJ 2016., p. 476
Solid
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 12th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2012., p. V3: 1576

3.2.3 Odor

Odorless
Larranaga, M.D., Lewis, R.J. Sr., Lewis, R.A.; Hawley's Condensed Chemical Dictionary 16th Edition. John Wiley & Sons, Inc. Hoboken, NJ 2016., p. 476

3.2.4 Taste

Bitter
Larranaga, M.D., Lewis, R.J. Sr., Lewis, R.A.; Hawley's Condensed Chemical Dictionary 16th Edition. John Wiley & Sons, Inc. Hoboken, NJ 2016., p. 476

3.2.5 Melting Point

493 to 495 °F when anhydrous (EPA, 1998)
U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.
255.5°C
PhysProp
255.5 °C
Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 95th Edition. CRC Press LLC, Boca Raton: FL 2014-2015, p. 3-182
MP: 256-257 °C (anhydrous)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 575

3.2.6 Solubility

3.9mg/L (at 25 °C)
YALKOWSKY,SH & DANNENFELSER,RM (1992)
In water, 3.9 mg/L at 25 °C
Yalkowsky, S.H., He, Yan, Jain, P. Handbook of Aqueous Solubility Data Second Edition. CRC Press, Boca Raton, FL 2010, p. 1346
Slightly soluble in water
Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 95th Edition. CRC Press LLC, Boca Raton: FL 2014-2015, p. 3-182
Practically insoluble in water (1 g/100 L at 20 °C)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 575
Very soluble in ethanol; soluble in ethyl ether, chloroform, methanol, pyridine
Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 95th Edition. CRC Press LLC, Boca Raton: FL 2014-2015, p. 3-182
1 g dissolves in about 40 mL chloroform, 60 mL alcohol, 400 mL ethyl acetate at 20 °C; soluble in acetate, amyl alcohol, pyridine; sparingly soluble in ether, petroleum ether
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 575
2.89e-02 g/L

3.2.7 LogP

1.85
SANGSTER (1993)
log Kow = 1.85
Sangster J; LOGKOW Databank. Sangster Res Lab, Montreal Quebec, Canada (1994)
1.85
SANGSTER (1993)

3.2.8 Stability / Shelf Life

Stable under recommended storage conditions.
Sigma-Aldrich; Material Safety Data Sheet for Digitoxin, Product Number: D5878, Version 4.5 (Revision Date 06/12/2018). Available from, as of October 31, 2018: https://www.sigmaaldrich.com/safety-center.html

3.2.9 Optical Rotation

Specific optical rotation: +4.8 deg at 20 C/D (concn by volume = 1.2 g in 100 mL dioxane)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 575
PURE DIGITOXIN HAS SPECIFIC OPTICAL ROTATION OF +18 TO +19 DEG IN CHLOROFORM
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 792

3.2.10 Decomposition

When heated to decomposition it emits acrid smoke and irritating fumes.
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1298

3.2.11 Collision Cross Section

275.61 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]
Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111

3.2.12 Other Experimental Properties

May contain 1/2 or 1 mole water or ethanol which is given up at 118 °C in vacuo.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 575
log Kow = 2.83 (pH= 7.4)
Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995., p. 192

3.3 Chemical Classes

3.3.1 Drugs

3.3.1.1 Human Drugs
Human drug -> Active ingredient (DIGITOXIN)
Human drug -> Discontinued
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

3.3.2 Lipids

Lipids -> Sterol Lipids [ST] -> Sterols [ST01] -> Cardanolides and derivatives [ST0112]

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 1H NMR Spectra

Source of Spectrum
Sigma-Aldrich Co. LLC.
Source of Sample
Sigma-Aldrich Co. LLC.
Catalog Number
851736
Copyright
Copyright © 2021-2024 Sigma-Aldrich Co. LLC. - Database Compilation Copyright © 2021 John Wiley & Sons, Inc. All Rights Reserved.
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4.1.2 13C NMR Spectra

1 of 2
Spectra ID
Frequency
50.18 MHz
Solvent
DMSO-d6
Shifts [ppm]:Intensity
40.62:458.00, 73.06:277.00, 67.42:378.00, 26.02:221.00, 20.76:256.00, 34.78:498.00, 116.15:306.00, 50.19:320.00, 18.25:557.00, 69.00:333.00, 81.52:312.00, 26.37:0.00, 66.02:306.00, 72.59:408.00, 83.68:488.00, 17.93:0.00, 176.16:424.00, 72.03:304.00, 49.35:482.00, 173.70:474.00, 32.15:277.00, 66.16:354.00, 15.65:450.00, 21.02:261.00, 17.93:1000.00, 34.83:376.00, 66.95:333.00, 36.21:293.00, 98.90:394.00, 26.37:338.00, 23.62:413.00, 37.75:312.00, 98.81:354.00, 67.54:317.00, 30.05:221.00, 81.79:312.00, 29.64:237.00, 95.25:362.00
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2 of 2
Source of Spectrum
Sigma-Aldrich Co. LLC.
Source of Sample
Sigma-Aldrich Co. LLC.
Catalog Number
851736
Copyright
Copyright © 2021-2024 Sigma-Aldrich Co. LLC. - Database Compilation Copyright © 2021 John Wiley & Sons, Inc. All Rights Reserved.
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4.2 Mass Spectrometry

4.2.1 LC-MS

1 of 7
View All
Authors
Nihon Waters K.K.
Instrument
ZQ, Waters
Instrument Type
LC-ESI-Q
MS Level
MS
Ionization Mode
POSITIVE
Ionization
ESI
Column Name
2.1 mm id - 3. 5{mu}m XTerra C18MS
Retention Time
16.480 min
Top 5 Peaks

113 999

131 498

339 129

375 125

787 94

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License
CC BY-NC
2 of 7
View All
Authors
Nihon Waters K.K.
Instrument
ZQ, Waters
Instrument Type
LC-ESI-Q
MS Level
MS
Ionization Mode
POSITIVE
Ionization
ESI
Column Name
2.1 mm id - 3. 5{mu}m XTerra C18MS
Retention Time
16.480 min
Top 5 Peaks

113 999

243 889

375 870

131 572

505 415

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License
CC BY-NC

4.2.2 Other MS

1 of 4
View All
Other MS
MASS: 3903 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63)
2 of 4
View All
MoNA ID
MS Category
Experimental
MS Type
Other
MS Level
MS2
Precursor Type
[M+Na]+
Precursor m/z
787.4239101
Ionization Mode
positive
Retention Time
2.2577377035470327
Top 5 Peaks

555.292017037246 0.07

639.3542226140414 0.07

785.4111742392887 0.05

743.4330287561719 0.05

91.05695504691624 0.04

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4.3 UV Spectra

UV: 6-1256 (Organic Electronic Spectral Data, Phillips et al, John Wiley & Sons, New York)
Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V2: 2069

4.4 IR Spectra

IR Spectra
IR: 2588 (Sadtler Research Laboratories Prism Collection)

4.4.1 FTIR Spectra

1 of 2
Technique
KBr1 0.94mg
Source of Spectrum
Forensic Spectral Research
Source of Sample
Sigma-Aldrich, Inc.
Catalog Number
<a href=https://www.sigmaaldrich.com/US/en/product/sigma/D5878>D5878</a>
Lot Number
050M1500V
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. All Rights Reserved.
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2 of 2
Technique
KBr WAFER
Source of Sample
Eli Lilly & Company, Indianapolis, Indiana
Copyright
Copyright © 1980, 1981-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.4.2 ATR-IR Spectra

1 of 2
Instrument Name
Bio-Rad FTS
Technique
ATR-Neat (DuraSamplIR II)
Source of Spectrum
Forensic Spectral Research
Source of Sample
Sigma-Aldrich Inc.
Catalog Number
D5878
Lot Number
050M1500V
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. All Rights Reserved.
Thumbnail
Thumbnail
2 of 2
Source of Sample
Aldrich
Catalog Number
851736
Copyright
Copyright © 2018-2024 Sigma-Aldrich Co. LLC. - Database Compilation Copyright © 2018-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.5 Raman Spectra

Technique
FT-Raman
Source of Spectrum
Forensic Spectral Research
Source of Sample
Sigma-Aldrich Company LLC
Catalog Number
<a href=https://www.sigmaaldrich.com/US/en/product/sigma/D5878>D5878</a>
Lot Number
050M1500V
Copyright
Copyright © 2015-2024 John Wiley & Sons, Inc. All Rights Reserved.
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6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

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

7.2 FDA Approved Drugs

7.3 FDA Orange Book

7.4 Clinical Trials

7.4.1 ClinicalTrials.gov

7.4.2 EU Clinical Trials Register

7.5 Therapeutic Uses

Anti-Arrhythmia Agents; Cardiotonic Agents; Enzyme Inhibitors
National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)
MEDICATION (VET): cardiac tonic
Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989., p. 498
Cardiac glycosides are used principally in the prophylactic management and treatment of heart failure and to control the ventricular rate in patients with atrial fibrillation. ... Digoxin is the most commonly used cardiac glycoside, principally because it may be administered by various routes, has an intermediate duration of action, and has been extensively studied in patients with or without renal insufficiency. Some clinicians believe that digitoxin is the cardiac glycoside of choice in patients with renal failure because elimination half life in unchanged in these patients; however, digitoxin is no longer commercially available in the US. ...
American Society of Health-System Pharmacists; Drug Information 2018. Bethesda, MD. 2018, p. 1812
Cardiac glycosides are used, usually in conjunction with other agents, in the management of symptomatic congestive heart failure associated with left ventricular systolic dysfunction. /Cardiac glycosides/
American Society of Health-System Pharmacists; Drug Information 2018. Bethesda, MD. 2018, p. 1812
For more Therapeutic Uses (Complete) data for Digitoxin (14 total), please visit the HSDB record page.

7.6 Drug Warnings

Cardiac glycosides should be used with caution in patients with severe pulmonary disease, hypoxia, myxedema, acute myocardial infarction, severe heart failure, acute myocarditis (including rheumatic carditis) or an otherwise damaged myocardium, since the likelihood of cardiac glycoside-induced arrhythmias is increased in these patients. The possibility that use of cardiac lycosides in some patient with acute myocardial infarction may result in an undesirable increase in oxygen demand and associated ischemia should be considered. In patients with rheumatic carditis, dosage should be low initially and increased gradually until a beneficial effect is obtained or, if improvement does not occur in these patients, the drug should be discontinued. Cardiac glycosides should be used with caution in patient with chronic constrictive pericarditis since these patients may respond unfavorably. Cardiac glycosides should be administered with extreme caution in patients with acute glomerulonephritis and congestive heart failure; if the drugs are necessary, total daily dosage must be reduced and given in divided doses with constant ECG monitoring. These patients should be treated concomitantly with diuretics and hypotensive agents and the glycoside should be discontinued as soon as possible. Cardiac glycosides should also be used with extreme caution, if at all, in patients with idiopathic hypertrophic subaortic stenosis because increased obstruction to left ventricular outflow may result. Patients with certain ejection fraction (e.g., restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, acute cor pulmonale) may be particularly susceptible to the toxicity of cardiac glycosides. /Cardiac glycosides/
American Society of Health-System Pharmacists; Drug Information 2018. Bethesda, MD. 2018, p. 1814
Cardiac glycosides should be given iv with caution in hypertensive patients, since iv administration of these drugs may increase blood pressure transiently. /Cardiac glycosides/
American Society of Health-System Pharmacists; Drug Information 2018. Bethesda, MD. 2018, p. 1814
Safe use of cardiac glycosides during pregnancy has not been established. Although the drugs have been used in pregnant women without apparent harm to the mother or fetus, one neonatal death has been reported, allegedly due to digitoxin (no longer commercially available in the US) overdosage in utero.
American Society of Health-System Pharmacists; Drug Information 2018. Bethesda, MD. 2018, p. 1814
Cardiac glycosides should not be administered to patients with substantial sinus or atrioventricular (VA) block, unless the conduction block has been addressed with a permanent pacemaker. The drugs should be used cautiously with other drugs that can depress sinus or AV nodal function. /Cardiac glycosides/
American Society of Health-System Pharmacists; Drug Information 2018. Bethesda, MD. 2018, p. 1814
For more Drug Warnings (Complete) data for Digitoxin (24 total), please visit the HSDB record page.

8 Food Additives and Ingredients

8.1 Associated Foods

9 Pharmacology and Biochemistry

9.1 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.

9.2 MeSH Pharmacological Classification

Cardiotonic Agents
Agents that have a strengthening effect on the heart or that can increase cardiac output. They may be CARDIAC GLYCOSIDES; SYMPATHOMIMETICS; or other drugs. They are used after MYOCARDIAL INFARCT; CARDIAC SURGICAL PROCEDURES; in SHOCK; or in congestive heart failure (HEART FAILURE). (See all compounds classified as Cardiotonic Agents.)
Anti-Arrhythmia Agents
Agents used for the treatment or prevention of cardiac arrhythmias. They may affect the polarization-repolarization phase of the action potential, its excitability or refractoriness, or impulse conduction or membrane responsiveness within cardiac fibers. Anti-arrhythmia agents are often classed into four main groups according to their mechanism of action: sodium channel blockade, beta-adrenergic blockade, repolarization prolongation, or calcium channel blockade. (See all compounds classified as Anti-Arrhythmia Agents.)
Enzyme Inhibitors
Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)

9.3 ATC Code

C - Cardiovascular system

C01 - Cardiac therapy

C01A - Cardiac glycosides

C01AA - Digitalis glycosides

C01AA04 - Digitoxin

9.4 Absorption, Distribution and Excretion

Postmortem digitoxin levels in the choroid-retina and vitreous humor of patients who had undergone digitoxin therapy (therapeutic group) and in one case of suicidal digitoxin poisoning were measured and compared with levels in femoral vein blood, myocardium, kidney and liver. The results were interpreted in light of the medical history of each patient. The digitoxin level in the choroid-retina of the single case of suicidal poisoning was far higher than the choroid-retinal levels in the therapeutic group. In the latter, variation in choroid-retinal levels was comparable to that in the other tissues. In cases where the choroid-retina of the right and left eyes were examined, digitoxin levels in both eyes were essentially equal. There was no indication of significant changes in choroid-retinal levels due to postmortem diffusion of digitoxin into the vitreous body. Based on these results, determination of digitoxin levels in the choroid-retina could contribute to improving postmortem diagnosis of lethal digitoxin poisoning.
Ritz S et al; Int J Legal Med 105 (3): 155-9 (1992)
In cats ... 100% of digitoxin is absorbed in 80-100 min following duodenal admin ... digitalis glycosides are transported by blood ... bound to ... albumin, and in part free. ... Tissue distribution is not primarily to heart ... /highest concentration/ ... in excretory organs (liver, bile, intestinal tract, kidney) ... .
Jones, L.M., et al. Veterinary Pharmacology & Therapeutics. 4th ed. Ames: Iowa State University Press, 1977., p. 509
It is not predictably absorbed from gut of dogs... .
Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974., p. 173
...Prolonged biological half-life of digitoxin and its metabolites appears to depend on recirculation of free drug molecules after biliary excretion as glucuronide and sulfate conjugate.
Testa, B. and P. Jenner. Drug Metabolism: Chemical & Biochemical Aspects. New York: Marcel Dekker, Inc., 1976., p. 449
For more Absorption, Distribution and Excretion (Complete) data for Digitoxin (14 total), please visit the HSDB record page.

9.5 Metabolism / Metabolites

Hepatic.
Eliminated by hepatic degradation ...to inactive genins ...Stepwise hydrolysis of 3 molecules of digitoxose converts glycoside to aglycone digitoxigenin, which is ...converted to inactive epidigitoxigenin. Because enterohepatic recirculation occurs, approx 25% of metabolic end products appear in stool.
Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975., p. 674
Studies with various tissues of guinea pig showed that liver, kidney, and adrenal tissues converted digitoxin to digoxin.
Casarett, L.J., and J. Doull. Toxicology: The Basic Science of Poisons. New York: MacMillan Publishing Co., 1975., p. 119
Digitoxin in bile of rats was excreted largely in form of glucuronide of digitoxigenin monodigitoxoside.
Richards LG et al; Drug Metab Dispos 5 (5): 469-73 (1977)
Cardiac glycosides undergo varying degrees of hepatic metabolism, enterohepatic circulation, and renal filtration and reabsorption depending on their polarity and lipid solubility. ... Less polar glycosides such as digitoxin are metabolized extensively before they are excreted. Metabolism includes stepwise cleavage of the sugar molecules, hydroxylation, epimerization, and formation of glucuronide and sulfate conjugates. /Cardiac glycosides/
American Society of Health-System Pharmacists; Drug Information 2018. Bethesda, MD. 2018, p. 1819
For more Metabolism/Metabolites (Complete) data for Digitoxin (6 total), please visit the HSDB record page.

9.6 Biological Half-Life

The digitoxin half-life in elderly patients in the eight and ninth decade was more prolonged (mean +/- SD: 25 +/- 9 days) than in younger people (6.7 +/- 1.7). These elderly patients accumulated digitoxin even on a dose of 0.05 mg/ day. The symptoms of digitoxin intoxication disappeared on discontinuation of medication. When digitoxin is used in the treatment for heart failure in the very elderly patients, one should be aware of the possibility of digitoxin intoxication, even on a low dose.
Bohmer T1, Roseth A; Age Ageing 27 (2): 222-4 (1998)
After administration of 0.6 mg digitoxin mean serum digitoxin half-life of 4.3 days and 8.1 days respectively observed in cholecystectomized heart patients and control subjects.
Storstein L; Clin Pharmacol Ther 17 (3): 313-20 (1975)
The elimination half-life of digitoxin is usually 5-7 days, but may range from 4-14 days. The elimination half-life of digitoxin is generally unchanged in patients with renal failure. In patients with biliary fistulas, plasma half-life is decreased by about 50%. Variability among patients in the degree of enterohepatic recycling of digitoxin may account for part of the variability in plasma half-life in some patients. The elimination half-life of digitoxin is prolonged in hypothyroid patients and decreased in hyperthyroid patients.
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 893

9.7 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.
AIMS: Recent studies suggest that proarrhythmic effects of cardiac glycosides (CGs) on cardiomyocyte Ca(2+) handling involve generation of reactive oxygen species (ROS). However, the specific pathway(s) of ROS production and the subsequent downstream molecular events that mediate CG-dependent arrhythmogenesis remain to be defined. METHODS AND RESULTS: We examined the effects of digitoxin (DGT) on Ca(2+) handling and ROS production in cardiomyocytes using a combination of pharmacological approaches and genetic mouse models. Myocytes isolated from mice deficient in NADPH oxidase type 2 (NOX2KO) and mice transgenically overexpressing mitochondrial superoxide dismutase displayed markedly increased tolerance to the proarrhythmic action of DGT as manifested by the inhibition of DGT-dependent ROS and spontaneous Ca(2+) waves (SCW). Additionally, DGT-induced mitochondrial membrane potential depolarization was abolished in NOX2KO cells. DGT-dependent ROS was suppressed by the inhibition of PI3K, PKC, and the mitochondrial KATP channel, suggesting roles for these proteins, respectively, in activation of NOX2 and in mitochondrial ROS generation. Western blot analysis revealed increased levels of oxidized CaMKII in WT but not in NOX2KO hearts treated with DGT. The DGT-induced increase in SCW frequency was abolished in myocytes isolated from mice in which the Ser 2814 CaMKII phosphorylation site on RyR2 is constitutively inactivated. CONCLUSION: These results suggest that the arrhythmogenic adverse effects of CGs on Ca(2+) handling involve PI3K- and PKC-mediated stimulation of NOX2 and subsequent NOX2-dependent ROS release from the mitochondria; mitochondria-derived ROS then activate CaMKII with consequent phosphorylation of RyR2 at Ser 2814.
Ho HT et al; Cardiovasc Res 101 (1):165-74 (2014)
Pro-inflammatory processes initiated in the endothelium represent a crucial step in the pathogenesis of inflammatory cardiovascular disease, such as atherosclerosis. Recent observations pointed to potential anti-inflammatory properties of the cardiac glycoside digitoxin. Therefore, the present study investigated potential anti-inflammatory and vasoprotective properties of digitoxin as well as the underlying signaling pathways affected in endothelial cells (EC). Digitoxin, employing therapeutical concentrations used in patients (3-30 nM), potently inhibited the IL-1beta-induced expression of MCP-1 and VCAM-1 in EC and the capacity of corresponding cell culture supernatants on monocyte migration as well as monocyte adhesion to endothelial monolayers, respectively. Furthermore, digitoxin prevented the IL-1beta-induced activation of p44/42-MAPK and NF-kappaB without affecting activation of JNK and p38-MAPK. Inhibition of NF-kappaB signaling but not p44/42-MAPK mimicked the observed inhibitory effects of digitoxin on MCP-1 expression and monocyte migration. Moreover, digitoxin inhibited NF-kappaB signaling at the level of TAK-1/IKK. Additionally, digitoxin prevented TNF-alpha-induced apoptosis in EC accompanied by activation of Akt. Blockade of PI-3-kinase, activator of Akt, prevented the anti-apoptotic properties of digitoxin and impaired its inhibitory action on NF-kappaB signaling and MCP-1 expression. Finally, digitoxin activated endothelial NO-synthase, which was blocked by inhibition of PI-3-kinase, Ca(2+)/Calmodulin-dependent-proteinkinase-II and chelation of intracellular calcium. Digitoxin elicits anti-inflammatory and vasoprotective properties by blocking NF-kappaB and activating PI-3-kinase/Akt signaling as well as Ca(2+)/Calmodulin-dependent-proteinkinase-II in EC. These observations indicate a potential therapeutical application of digitoxin in the treatment of cardiovascular diseases, such as atherosclerosis.
Jagielska J et al; Atherosclerosis 206 (2): 390-6 (2009)
Cardiac glycosides have been used in the treatment of arrhythmias for more than 200 years. Two-pore-domain (K2P) potassium channels regulate cardiac action potential repolarization. Recently, K2P3.1 [tandem of P domains in a weak inward rectifying K+ channel (TWIK)-related acid-sensitive K+ channel (TASK)-1] has been implicated in atrial fibrillation pathophysiology and was suggested as an atrial-selective antiarrhythmic drug target. We hypothesized that blockade of cardiac K2P channels contributes to the mechanism of action of digitoxin and digoxin. All functional human K2P channels were screened for interactions with cardiac glycosides. Human K2P channel subunits were expressed in Xenopus laevis oocytes, and voltage clamp electrophysiology was used to record K+ currents. Digitoxin significantly inhibited K2P3.1 and K2P16.1 channels. By contrast, digoxin displayed isolated inhibitory effects on K2P3.1. K2P3.1 outward currents were reduced by 80% (digitoxin, 1 Hz) and 78% (digoxin, 1 Hz). Digitoxin inhibited K2P3.1 currents with an IC50 value of 7.4 uM. Outward rectification properties of the channel were not affected. Mutagenesis studies revealed that amino acid residues located at the cytoplasmic site of the K2P3.1 channel pore form parts of a molecular binding site for cardiac glycosides. In conclusion, cardiac glycosides target human K2P channels. The antiarrhythmic significance of repolarizing atrial K2P3.1 current block by digoxin and digitoxin requires validation in translational and clinical studies.
Schmidt C et al; J Pharmacol Exp Ther 365 (3): 614-623 (2018)
Cardiac glycosides inhibit the activity of sodium-potassium-activated adenosine triphosphatase (Na+-K+-ATPase), an enzyme required for active transport of sodium across myocardial cell membranes. Inhibition of this enzyme in cardiac cells results in an increase in the contractile state of the heart and it was believed that benefits of cardiac glycosides in heart failure were mainly associated with inotropic action. However, it has been suggested that benefits of cardiac glycosides may be in part related to enzyme inhibition in noncardiac tissues. Inhibition of Na+-K+-ATPase in vagal afferents acts to sensitize cardiac baroreceptors which may in turn decrease sympathetic outflow from the CNS. In addition, by inhibiting Na+-K+-ATPase in the kidney, cardiac glycosides decrease the renal tubular reabsorption of sodium; the resulting increase in the delivery of sodium to the distal tubules leads to the suppression of renin secretion from the kidneys. These observations led to the hypothesis that cardiac glycosides act in heart failure principally by attenuating the activation of the neurohormonal system, rather than by a positive inotropic action. Toxic doses of cardiac glycosides cause efflux of potassium from the myocardium and concurrent influx of sodium. Toxicity results in part from loss of intracellular potassium associated with inhibition of Na+-K+-ATPase. With therapeutic doses, augmentation of calcium influx to the contractile proteins with resultant enhancement of excitation-contraction coupling is involved in the positive inotropic action of cardiac glycosides; the role of Na+-K+-ATPase in this effect is controversial. /Cardiac glycosides/
American Society of Health-System Pharmacists; Drug Information 2018. Bethesda, MD. 2018, p. 1818
Low concentrations of cardiac glycosides including ouabain, digoxin, and digitoxin block cancer cell growth without affecting Na+,K+-ATPase activity, but the mechanism underlying this anti-cancer effect is not fully understood. Volume-regulated anion channel (VRAC) plays an important role in cell death signaling pathway in addition to its fundamental role in the cell volume maintenance. Here, we report cardiac glycosides-induced signaling pathway mediated by the crosstalk between Na+,K+-ATPase and VRAC in human cancer cells. Submicromolar concentrations of ouabain enhanced VRAC currents concomitantly with a deceleration of cancer cell proliferation. The effects of ouabain were abrogated by a specific inhibitor of VRAC (DCPIB) and knockdown of an essential component of VRAC (LRRC8A), and they were also attenuated by the disruption of membrane microdomains or the inhibition of NADPH oxidase. Digoxin and digitoxin also showed anti-proliferative effects in cancer cells at their therapeutic concentration ranges, and these effects were blocked by DCPIB. In membrane microdomains of cancer cells, LRRC8A was found to be co-immunoprecipitated with Na+,K+-ATPase a1-isoform. These ouabain-induced effects were not observed in non-cancer cells. Therefore, cardiac glycosides were considered to interact with Na+,K+-ATPase to stimulate the production of reactive oxygen species, and they also apparently activated VRAC within membrane microdomains, thus producing anti-proliferative effects.
Fujii T et al; Biochim Biophys Acta Mol Basis Dis 1864 (11): 3792-3804 (2018)

9.8 Human Metabolite Information

9.8.1 Cellular Locations

  • Extracellular
  • Membrane

10 Use and Manufacturing

10.1 Uses

MEDICATION
For digitoxin (USEPA/OPP Pesticide Code: 097002) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./
National Pesticide Information Retrieval System's Database on Digitoxin (71-63-6). Available from, as of January 28, 2019: https://npirspublic.ceris.purdue.edu/ppis/
For the treatment and management of congestive cardiac insufficiency, arrhythmias and heart failure.

10.1.1 Use Classification

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients
Hazard Classes and Categories ->
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

10.2 Methods of Manufacturing

Secondary glycoside from Digitalis purpurea L., Scrophulariaceae. Extracted from the dried leaves with 50% alcohol.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 575

10.3 Consumption Patterns

The chief therapeutic use for /digitoxin/ is in the treatment of low output congestive heart failure (1985)
GENNARO. REMINGTON'S PHARM SCI 17TH ED 1985 p.855

10.4 U.S. Production

(1975) PROBABLY GREATER THAN 4.54X10+5 G
SRI

10.5 U.S. Imports

(1984) 4.54X10+3 g /Digitalis or purpurea/
BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.1-364

10.6 U.S. Exports

(1972) 2.7X10+7 G (GLYCOSIDES, DERIVATIVES)
SRI
(1984) 5.10X10+7 g /Glycosides, Natural or reproduced by synthesis, bulk/
BUREAU OF THE CENSUS. U.S. EXPORTS, SCHEDULE E, 1984 p.2-101

10.7 General Manufacturing Information

EPA TSCA Commercial Activity Status
Card-20(22)-enolide, 3-[(O-2,6-dideoxy-.beta.-D-ribo-hexopyranosyl-(1.fwdarw.4)-O-2,6-dideoxy-.beta.-D-ribo-hexopyranosyl-(1.fwdarw.4)-2,6-dideoxy-.beta.-D-ribo-hexopyranosyl)oxy]-14-hydroxy-, (3.beta.,5.beta.)-: ACTIVE
Most active glycoside of Digitalis purpurea.
Larranaga, M.D., Lewis, R.J. Sr., Lewis, R.A.; Hawley's Condensed Chemical Dictionary 16th Edition. John Wiley & Sons, Inc. Hoboken, NJ 2016., p. 476

11 Identification

11.1 Analytic Laboratory Methods

Analyte: digitoxin; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p612 (2003)
Analyte: digitoxin; matrix: chemical identification; procedure: retention time of liquid chromatogram with comparison to standards
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p612 (2003)
Analyte: digitoxin; matrix: chemical identification; procedure: thin-layer chromatography with detection using long-wavelength ultraviolet light and comparison to standards
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p612 (2003)
Analyte: digitoxin; matrix: chemical purity; procedure: liquid chromatography with detection at 218 nm and comparison to standards
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p612 (2003)
For more Analytic Laboratory Methods (Complete) data for Digitoxin (15 total), please visit the HSDB record page.

12 Safety and Hazards

12.1 Hazards Identification

12.1.1 GHS Classification

1 of 4
View All
Pictogram(s)
Acute Toxic
Health Hazard
Signal
Danger
GHS Hazard Statements

H300 (12%): Fatal if swallowed [Danger Acute toxicity, oral]

H301 (88%): Toxic if swallowed [Danger Acute toxicity, oral]

H331 (100%): Toxic if inhaled [Danger Acute toxicity, inhalation]

H373 (98%): May causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]

Precautionary Statement Codes

P260, P261, P264, P270, P271, P301+P316, P304+P340, P316, P319, P321, P330, P403+P233, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 50 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

12.1.2 Hazard Classes and Categories

Acute Tox. 2 (12%)

Acute Tox. 3 (88%)

Acute Tox. 3 (100%)

STOT RE 2 (98%)

Acute toxicity - category 3

Acute toxicity - category 3

Specific target organ toxicity (repeated exposure) - category 2

12.1.3 Health Hazards

Material is bioactive and capable of causing cardiac arrythmias and electrolyte imbalances that may be fatal. Death is due to ventricular fibrillation or cardiac standstill. Material has a high toxicity hazard rating; it may cause death or permanent injury after a very short exposure. It is classified as super toxic; an estimated single lethal dose is 3-10 mg. (EPA, 1998)
U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.

12.1.4 Fire Hazards

When heated to decomposition, it emits acrid smoke and irritating fumes. (EPA, 1998)
U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.

12.2 First Aid Measures

12.2.1 First Aid

Warning: Digitoxin may cause death or permanent injury after a very short exposure. Effects may be delayed up to 12 hours. Caution is advised. Vital signs should be monitored closely.

Signs and Symptoms of Digitoxin Exposure: Acute digitoxin ingestion may produce the following signs and symptoms: nausea, vomiting, headache, lethargy, fatigue, weakness, drowsiness, confusion, slowed pulse, varying degrees of heart block, heart arrhythmias, delirium, and halucinations. Convulsions, coma, respiratory failure, and heart failure may also occur.

Emergency Life-Support Procedures: Acute exposure to digitoxin may require decontamination and life support for the victims. Emergency personnel should wear protective clothing appropriate to the type and degree of contamination. Air-purifying or supplied-air respiratory equipment should also be worn, as necessary. Rescue vehicles should carry supplies such as plastic sheeting and disposable plastic bags to assist in preventing spread of contamination.

Inhalation Exposure:

1. Move victims to fresh air. Emergency personnel should avoid self-exposure to digitoxin.

2. Evaluate vital signs including pulse and respiratory rate, and note any trauma. If no pulse is detected, provide CPR. If not breathing, provide artificial respiration. If breathing is labored, administer oxygen or other respiratory support.

3. Obtain authorization and/or further instructions from the local hospital for administration of an antidote or performance of other invasive procedures.

4. Transport to a health care facility.

Dermal/Eye Exposure:

1. Remove victims from exposure. Emergency personnel should avoid self-exposure to digitoxin.

2. Evaluate vital signs including pulse and respiratory rate, and note any trauma. If no pulse is detected, provide CPR. If not breathing, provide artificial respiration. If breathing is labored, administer oxygen or other respiratory support.

3. Remove and isolate contaminated clothing as soon as possible.

4. If eye exposure has occurred, eyes must be flushed with lukewarm water for at least 15 minutes.

5. Wash exposed skin areas thoroughly with water.

6. Obtain authorization and/or further instructions from the local hospital for administration of an antidote or performance of other invasive procedures.

7. Transport to a health care facility.

Ingestion Exposure:

1. Evaluate vital signs including pulse and respiratory rate, and note any trauma. If no pulse is detected, provide CPR. If not breathing, provide artificial respiration. If breathing is labored, administer oxygen or other respiratory support.

2. Obtain authorization and/or further instructions from the local hospital for administration of an antidote or performance of other invasive procedures.

3. Vomiting may be induced with syrup of Ipecac. If elapsed time since ingestion of digitoxin is unknown or suspected to be greater than 30 minutes, do not induce vomiting and proceed to Step

4. Ipecac should not be administered to children under 6 months of age.Warning: Ingestion of digitoxin may result in sudden onset of seizures or loss of consciousness. Syrup of Ipecac should be administered only if victims are alert, have an active gag reflex, and show no signs of impending seizure or coma. If ANY uncertainty exists, proceed to Step

4.The following dosages of Ipecac are recommended: children up to 1 year old, 10 mL (1/3 oz); children 1 to 12 years old, 15 mL (1/2 oz); adults, 30 mL (1 oz). Ambulate (walk) the victims and give large quantities of water. If vomiting has not occurred after 15 minutes, Ipecac may be readministered. Continue to ambulate and give water to the victims. If vomiting has not occurred within 15 minutes after second administration of Ipecac, administer activated charcoal.

4. Activated charcoal may be administered if victims are conscious and alert. Use 15 to 30 g (1/2 to 1 oz) for children, 50 to 100 g (1-3/4 to 3-1/2 oz) for adults, with 125 to 250 mL (1/2 to 1 cup) of water.

5. Promote excretion by administering a saline cathartic or sorbitol to conscious and alert victims. Children require 15 to 30 g (1/2 to 1 oz) of cathartic; 50 to 100 g (1-3/4 to 3-1/2 oz) is recommended for adults.

6. Rush to a health care facility. (EPA, 1998)

U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.

12.3 Fire Fighting

(Non-Specific -- Drugs or Medicines, Solid, n.o.s.) Avoid breathing dusts and fumes from burning material. Keep upwind. Wear boots, protective gloves, and goggles.

(Non-Specific -- Drugs or Medicines, Solid, n.o.s.) Extinguish fire using agent suitable for type of surrounding fire (material itself burns with difficulty.) Use water in flooding quantities as fog. Use alcohol foam, carbon dioxide or dry chemical. (EPA, 1998)

U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.

12.3.1 Fire Fighting Procedures

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.
Sigma-Aldrich; Material Safety Data Sheet for Digitoxin, Product Number: D5878, Version 4.5 (Revision Date 06/12/2018). Available from, as of October 31, 2018: https://www.sigmaaldrich.com/safety-center.html
Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary.
Sigma-Aldrich; Material Safety Data Sheet for Digitoxin, Product Number: D5878, Version 4.5 (Revision Date 06/12/2018). Available from, as of October 31, 2018: https://www.sigmaaldrich.com/safety-center.html

12.4 Accidental Release Measures

12.4.1 Isolation and Evacuation

Excerpt from ERG Guide 154 [Substances - Toxic and/or Corrosive (Non-Combustible)]:

IMMEDIATE PRECAUTIONARY MEASURE: Isolate spill or leak area in all directions for at least 50 meters (150 feet) for liquids and at least 25 meters (75 feet) for solids.

SPILL: Increase the immediate precautionary measure distance, in the downwind direction, as necessary.

FIRE: If tank, rail tank car or highway tank is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. (ERG, 2024)

12.4.2 Cleanup Methods

ACCIDENT RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.
Sigma-Aldrich; Material Safety Data Sheet for Digitoxin, Product Number: D5878, Version 4.5 (Revision Date 06/12/2018). Available from, as of October 31, 2018: https://www.sigmaaldrich.com/safety-center.html

12.4.3 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product.
Sigma-Aldrich; Material Safety Data Sheet for Digitoxin, Product Number: D5878, Version 4.5 (Revision Date 06/12/2018). Available from, as of October 31, 2018: https://www.sigmaaldrich.com/safety-center.html

12.4.4 Preventive Measures

ACCIDENT RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.
Sigma-Aldrich; Material Safety Data Sheet for Digitoxin, Product Number: D5878, Version 4.5 (Revision Date 06/12/2018). Available from, as of October 31, 2018: https://www.sigmaaldrich.com/safety-center.html
Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.
Sigma-Aldrich; Material Safety Data Sheet for Digitoxin, Product Number: D5878, Version 4.5 (Revision Date 06/12/2018). Available from, as of October 31, 2018: (Revision Date 06/30/2014). Available from, as of September 11, 2018: https://www.sigmaaldrich.com/safety-center.html
Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.
Sigma-Aldrich; Material Safety Data Sheet for Digitoxin, Product Number: D5878, Version 4.5 (Revision Date 06/12/2018). Available from, as of October 31, 2018: https://www.sigmaaldrich.com/safety-center.html
Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.
Sigma-Aldrich; Material Safety Data Sheet for Digitoxin, Product Number: D5878, Version 4.5 (Revision Date 06/12/2018). Available from, as of October 31, 2018: https://www.sigmaaldrich.com/safety-center.html
SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

12.5 Handling and Storage

12.5.1 Nonfire Spill Response

(Non-Specific -- Drugs or Medicines, Solids, n.o.s.) Keep upwind. Avoid bodily contact with the material. Wear full protective clothing. Wash away any material which may have contacted the body with copious amounts of water or soap and water. (EPA, 1998)
U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.

12.5.2 Storage Conditions

Keep container tightly closed in a dry and well-ventilated place. Keep in a dry place.
Sigma-Aldrich; Material Safety Data Sheet for Digitoxin, Product Number: D5878, Version 4.5 (Revision Date 06/12/2018). Available from, as of October 31, 2018: https://www.sigmaaldrich.com/safety-center.html

12.6 Exposure Control and Personal Protection

12.6.1 Personal Protective Equipment (PPE)

For emergency situations, wear a positive pressure, pressure-demand, full facepiece self-contained breathing apparatus (SCBA) or pressure- demand supplied air respirator with escape SCBA and a fully-encapsulating, chemical resistant suit. (EPA, 1998)
U.S. Environmental Protection Agency. 1998. Extremely Hazardous Substances (EHS) Chemical Profiles and Emergency First Aid Guides. Washington, D.C.: U.S. Government Printing Office.
Eye/face protection: Face shield and safety glasses. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).
Sigma-Aldrich; Material Safety Data Sheet for Digitoxin, Product Number: D5878, Version 4.5 (Revision Date 06/12/2018). Available from, as of October 31, 2018: https://www.sigmaaldrich.com/safety-center.html
Skin protection: Handle with gloves.
Sigma-Aldrich; Material Safety Data Sheet for Digitoxin, Product Number: D5878, Version 4.5 (Revision Date 06/12/2018). Available from, as of October 31, 2018: https://www.sigmaaldrich.com/safety-center.html
Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.
Sigma-Aldrich; Material Safety Data Sheet for Digitoxin, Product Number: D5878, Version 4.5 (Revision Date 06/12/2018). Available from, as of October 31, 2018: https://www.sigmaaldrich.com/safety-center.html
Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face respirator with multipurpose combination (US) or type ABEK (EN 14387) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).
Sigma-Aldrich; Material Safety Data Sheet for Digitoxin, Product Number: D5878, Version 4.5 (Revision Date 06/12/2018). Available from, as of October 31, 2018: https://www.sigmaaldrich.com/safety-center.html

12.7 Stability and Reactivity

12.7.1 Air and Water Reactions

No rapid reaction with air. No rapid reaction with water.

12.7.2 Reactive Group

Alcohols and Polyols

Esters, Sulfate Esters, Phosphate Esters, Thiophosphate Esters, and Borate Esters

Ethers

Hydrocarbons, Aliphatic Unsaturated

12.7.3 Hazardous Reactivities and Incompatibilities

Incompatible materials: Strong oxidizing agents.
Sigma-Aldrich; Material Safety Data Sheet for Digitoxin, Product Number: D5878, Version 4.5 (Revision Date 06/12/2018). Available from, as of October 31, 2018: https://www.sigmaaldrich.com/safety-center.html

12.8 Transport Information

12.8.1 DOT Label

Poison

12.9 Regulatory Information

New Zealand EPA Inventory of Chemical Status
Digitoxin: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.

12.9.1 CERCLA Reportable Quantities

Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Digitoxin is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 100 or 10,000 lbs. Extremely hazardous substances that are solids are subject to either of two threshold planning quantities ... The lower quantity applies only if the solid exists in powdered form and has a particle size less than 100 microns; or is handled in solution or in molten form; or meets the criteria for a National Fire Protection Association (NFPA) rating of 2, 3 or 4 for reactivity. If the solid does not meet any of these criteria, it is subject to the upper ... threshold planning quantity ... .
40 CFR 355 (USEPA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of January 28, 2019: https://www.ecfr.gov

12.9.2 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently discontinued drug products, including digitoxin, on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of January 28, 2019: https://www.fda.gov/cder/ob/

12.10 Other Safety Information

12.10.1 Toxic Combustion Products

Hazardous decomposition products formed under fire conditions. - Carbon oxides.
Sigma-Aldrich; Material Safety Data Sheet for Digitoxin, Product Number: D5878, Version 4.5 (Revision Date 06/12/2018). Available from, as of October 31, 2018: https://www.sigmaaldrich.com/safety-center.html

12.10.2 Special Reports

Allen NM, Dunham GD; Treatment of Digitalis Intoxication with Emphasis on the Clinical Use of Digoxin Immune Fab. DICP Ann Pharmacother 24: 991-8 (1990). Efficacy, safety, indications, mechanism of action, dosage, administration and pharmacokinetics of digoxin immune Fab (Digibind) in reversing digitalis toxicity from digoxin, digitoxin and other compounds are reviewed.
Bhatia SJ, Smith TW; Digitalis toxicity: Mechanisms, Diagnosis, and Management. Card Surg 2 (4): 453-65 (1987). This review focuses primarily on toxicity produced by digoxin and discusses the mechanisms, clinical manifestations, and current management of digitalis toxicity. The appropriate methodology for measurement and interpretation of serum digoxin levels is emphasized.

13 Toxicity

13.1 Toxicological Information

13.1.1 Toxicity Summary

IDENTIFICATION AND USE: Digitoxin is a cardiac glycoside, which was used is in the treatment of low output congestive heart failure. HUMAN STUDIES: Digitoxin applied in eyedrops or ointment in sufficient concentration to reduce intraocular pressure, tends to cause corneal edema and clouding. One neonatal death has been reported, allegedly due to digitoxin overdosage in utero. The widespread use of cardiac glycosides and the very narrow margin between effective therapeutic and toxic dosages contributed to the high incidence of toxicity and the relatively high associated mortality rate. Overdosage of cardiac glycosides is manifested by a wide variety of signs and symptoms that are difficult to distinguish from effects associated with cardiac disease. The extracardiac manifestations of cardiac glycoside intoxication are similar in both acute and chronic intoxication. However, GI effects and, to a lesser extent, CNS and visual disturbances may be more pronounced following acute overdosage. Acute toxicity may cause hyperkalemia, whereas patients with chronic toxicity may be hypokalemic or normokalemic. Anorexia, nausea, and vomiting are common early signs of toxicity and may precede or follow evidence of cardiotoxicity. Headache, fatigue, malaise, drowsiness, and generalized muscle weakness are common nervous system signs of cardiac glycoside toxicity. Dizziness, vertigo, syncope, apathy, lethargy, excitement, euphoria, insomnia, irritability, agitation, hiccups, restlessness, nervousness, seizures, opisthotonos, stupor, and coma have also occurred. Visual disturbances induced by toxic doses of cardiac glycosides probably result from a direct effect on the retina (cones are affected more than rods). Transient retrobulbar neuritis has been reported to cause visual changes in cardiac glycoside intoxication. Cardiac glycosides have caused almost every kind of cardiac arrhythmia, and various combinations of arrhythmias may occur in the same patient. In addition, arrhythmias associated with cardiac glycoside intoxication may result in worsening of congestive heart failure. Otherwise healthy individuals with acute toxicity frequently present with atrioventricular conduction disturbances and supraventricular arrhythmias, such as sinus bradycardia. Ventricular arrhythmias are uncommon in these individuals; however, when present, they are associated with severe toxicity and high mortality. Pediatric patients with healthy hearts often present with sinus bradycardia and conduction disturbances; ventricular arrhythmias also occur but are less common than in adults. In neonates, premonitory signs of toxicity may include sinus bradycardia, sinoatrial arrest, or prolongation of the PR interval. Paroxysmal and nonparoxysmal atrioventricular junctional rhythms, especially nonparoxysmal atrioventricular junctional tachycardia, atrioventricular dissociation (with or without some degree of atrioventricular block), and paroxysmal atrial tachycardia with variable atrioventricular block, are common in both adults and children. Cardiac glycoside toxicity may also cause various atrial and sinoatrial nodal arrhythmias and conduction disorders including atrial tachycardia, atrial fibrillation, atria flutter, atrial premature complexes, wandering atrial pacemaker, sinus bradycardia, sinoatrial arrest, sinoatrial exit block, and sinus tachycardia. Hypersensitivity reactions to cardiac glycosides are rare but may occur, usually within 6-10 days after initiating therapy. Skin reactions may be erythematous, scarlatiniform. papular, vesicular, or bullous. Rashes are usually accompanied by eosinophilia; eosinophilia also may occur without skin reactions. Urticaria; fever; pruritus; facial, angioneurotic, or laryngeal edema; alopecia of the scalp; shedding of finger and toe nails; and desquamation have been reported. Rarely, thrombocytopenic purpura has been reported to occur during administration of cardiac glycosides, particularly digitoxin. ANIMAL STUDIES: ECG monitoring of adult and 1 week old rats during severe acute digitoxin toxicity showed lack of cardiotoxicity despite marked neurotoxicity in both age groups. High adrenal concentration noted in all animals.
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.

13.1.2 Carcinogen Classification

Carcinogen Classification
No indication of carcinogenicity to humans (not listed by IARC).

13.1.3 Acute Effects

13.1.4 Interactions

BACKGROUND: The cardiac glycoside digitoxin preferentially inhibits the growth of breast cancer cells and targets the Erk pathway. Digitoxin alters the expression of genes that mediate calcium metabolism and IAP genes. PURPOSE: Since the optimal treatment for cancer involves the use of agents in combination, we assessed the growth inhibitory effects of digitoxin combined with agents that alter calcium metabolism, thapsigargin, a sarcoplasmic/ER Ca(2+)-ATPase inhibitor, and the statin simvastatin, as well as digitoxin's effect on the IAP pathway of apoptosis. METHODS: To reveal signaling pathways, we treated human cancer cells with digitoxin, alone or combined with thapsigargin or simvastatin, and measured cell growth using the MTT and colony formation assays. We used histology and Western blot analysis of HEK293 cells to assay effects on IAPs. RESULTS: Digitoxin inhibited the growth of breast, colon and ovarian cancer cells. Consistent with an effect on calcium metabolism, digitoxin exhibited synergy with thapsigargin and simvastatin on ER-negative breast cancer cells. Digitoxin activates expression of Erk pathway genes and suppresses expression of IAP genes. The growth inhibitory effects on HEK293 cells are not blocked by the pancaspase inhibitor zVAD-FMK, indicating that digitoxin may act by a caspase independent pathway of apoptosis. Furthermore, digitoxin does not have an effect on XIAP protein, a major anti-apoptotic protein. CONCLUSION: Digitoxin appears to act through the Erk and stress response pathways and is worthwhile to study to prevent and treat cancer. Our findings warn of possible safety issues for cardiac patients who take a combination of digitoxin and statins.
Einbond LS et al; Fitoterapia 109: 146-54 (2016)
The effects of concomitant drug therapy on the absorption, distribution, and elimination of digoxin and digitoxin are reviewed. A number of agents can increase or decrease the absorption of digoxin and digitoxin from the gastrointestinal tract by altering GI motility, binding the drugs through physical adsorption, altering the properties of the intestinal wall, or altering the bacterial flora of the intestine. The steady-state serum concentrations of digoxin and digitoxin can be affected if the changes in absorption are of sufficient magnitude, and adjustments in digoxin or digitoxin dosage may be required. A reduction in digoxin and digitoxin protein binding has occurred during concomitant administration of heparin and cardiac glycosides. Since digitoxin is more highly protein bound than digoxin, interactions that involve changes in protein binding are of much greater clinical importance with digitoxin. A number of drugs increase or decrease the elimination of digoxin and digitoxin, and subtherapeutic or toxic concentrations of the cardiac glycosides often result. Drugs that induce hepatic microsomal enzymes can increase the elimination of digitoxin, which is eliminated mainly by hepatic biotransformation. Digoxin is eliminated mainly by renal excretion; renal clearance of digoxin may be increased by vasodilators and thyroid hormones and decreased by quinidine, verapamil, amiodarone, and potassium-sparing diuretics. The clinical importance of changes in serum concentrations of the cardiac glycosides that result from alterations in glycoside elimination requires further study, as does the importance of preliminary reports of interactions between cardiac glycosides and diazepam, captopril, and combination therapy with quinidine-pentobarbital or quinidine-rifampin. Because the cardiac glycosides have a narrow therapeutic range, patients receiving concomitant therapy with agents that might affect the absorption, distribution, or elimination of the cardiac glycosides should be monitored carefully for symptoms of digitalis toxicity or undertreatment.
Hooymans PM, Merkus FW; Clin Pharm 4 (4): 404-13 (1985)
Metabolism of digitoxin is accelerated by cholestyramine... .
The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 144
Cardiac glycoside toxicity may also cause various atrial and sinoatrial nodal arrhythmias and conduction disorders including atrial tachycardia, atrial fibrillation, atria flutter, atrial premature complexes, wandering atrial pacemaker, sinus bradycardia, sinoatrial arrest, sinoatrial exit block, and sinus tachycardia. Junctional premature complexes may also occur. Excessive slowing of the pulse rate may be a sign of cardiac glycoside toxicity, but mild resting bradycardia in the absence of other manifestations of toxicity may not necessitate withholding the glycoside. In patients with sinus node disease (ie, sick sinus syndrome), cardiac glycosides may worsen sinus bradycardia or sinoatrial block, particularly in combination with other drugs that depress sinus node or AV conduction, such a beta-adrenergic blocking agents (beta-blockers) and certain nondihydropyridine calcium-channel blockers. /Cardiac glycosides/
American Society of Health-System Pharmacists; Drug Information 2018. Bethesda, MD. 2018, p. 1815
For more Interactions (Complete) data for Digitoxin (18 total), please visit the HSDB record page.

13.1.5 Antidote and Emergency Treatment

Digoxin-immune Fab has been used to treat approximately 150 adults and children with life-threatening cardiac arrhythmias and/or hyperkalemia due to digoxin or digitoxin toxicity. In most cases, the patient failed to respond to conventional therapy, including atropine, lidocaine (xylocaine, and others), and phenytoin (dilantin and others). The pharmacokinetics /indicate that/ free serum digoxin or digitoxin concentrations drop to unmeasurable levels (< 0.2 ng/mL) less than one minute after iv injection of digoxin-immune Fab. Favorable changes in cardiac rhythm or serum potassium concn occur within 15 to 30 minutes. The antibody fragments and bound drug are excreted mainly by the kidneys, with an elimination half-life of about 15-20 hr in patients with normal renal function. Excretion may be slower in patients with renal impairment. ... In most patients, signs of toxicity disappeared within a few hours. The deaths that occurred were attributed mainly to inadequate amounts of antibody fragments available or irreversible heart failure. Since clinical use has been limited and the effects of repeated exposure are unknown, digoxin-immune Fab is not indicated for mild digitalis toxicity. It is recommended for patients in shock or cardiac arrest, or with ventricular arrhythmias such as ventricular tachycardia or fibrillation, progressive bradyarrhythmias, or second- or third-degree atrioventricular blocks not responsive to atropine.
Medical Letter 28 (722): 87-8 (1986)
Emergency and supportive measures. 1. Maintain on open airway and assist ventilation if necessary. 2. Monitor the patient closely for at least 12-24 hours after significant ingestion because of delayed tissue distribution. 3. Treat hyperkalemia with digoxin-specific antibodies; calcium (calcium gluconate 10% ... sodium bicarbonate ... and/or sodium polystyrene sulfonate (Kayexalate ... . a. NOTE: Although it is widely recommended that calcium be avoided inpatients with cardiac glycoside toxicity because of concern that it will worsen ventricular arrhythmias, this warning is based on old and very weak case reports and is not substantiated by animal studies. Calcium is the drug of choice for life-threatening cardiac toxicity due to hyperkalemia. b. Mild hyperkalemia may actually protect against tachyarrhythmias. 4. Hypokalemia and hypomagnesemia should be corrected, as these may contribute to cardiac toxicity. 5. Treat bradycardia or heart block with atropine, ... . temporary transvenous cardiac pacemaker amy be needed for persistent symptomatic bradycardia, but because a pacemaker may trigger serious arrhythmias in patients with digitalis toxicity, pacing is recommended only after failure or unavailability of digoxin-specific antibodies. 6. Ventricular tachyarrhythmias may respond to correction of low potassium or magnesium. Lidocaine and phenytoin have been used, but digoxin-specific antibody is the preferred treatment for life-threatening arrhythmias. Avoid quinidine, procainamide, and other type 1a or 1c antiarrhythmic drugs. /Digoxin and other cardiac glycosides/
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Seventh Edition. McGraw-Hill, New York, NY 2018, p. 223
Specific drugs and antidotes. Fab fragments of digoxin-specific antibodies (eg, DigiFab) are highly effective in reversing digoxin toxicity and are indicated for significant poisoning. This includes hyperkalemia (>mEq/L), symptomatic arrhythmias, high degree AV block, ventricular arrhythmias, and hemodynamic instability. Digoxin antibodies should also be considered in digoxin-toxic patients with renal failure and for prophylactic treatment in a patient with massive oral overdose and high serum levels. Digoxin antibodies rapidly bind to digoxin and, to a lesser extent, digitoxin and other cardiac glycoside. The inactive complex that is formed in excreted rapidly in the urine. ... /Digoxin and other cardiac glycosides/
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Seventh Edition. McGraw-Hill, New York, NY 2018, p. 224
Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly. /Digoxin and other cardiac glycosides/
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Seventh Edition. McGraw-Hill, New York, NY 2018, p. 224
For more Antidote and Emergency Treatment (Complete) data for Digitoxin (8 total), please visit the HSDB record page.

13.1.6 Human Toxicity Excerpts

/SIGNS AND SYMPTOMS/ The toxic effects of cardiac glycosides that are excreted relatively rapidly (eg, digoxin) usually dissipate more rapidly than those of glycosides that are excreted slowly (eg, digitoxin). The toxicities of cardiac glycosides are additive and when toxicity is caused by one cardiac glycoside, administration of all others is contraindicated. Most cases of cardiac glycoside toxicity occur following multiple doses and result, at least in part, from the cumulative effects of the drug. ... /Cardiac glycosides/
American Society of Health-System Pharmacists; Drug Information 2018. Bethesda, MD. 2018, p. 1814
/SIGNS AND SYMPTOMS/ Overdosage of cardiac glycosides is manifested by a wide variety of signs and symptoms that are difficult to distinguish from effects associated with cardiac disease (eg, adverse GI effects, arrhythmias). Before further doses of the drug are administered, attempts should be made to determine whether these manifestations are glycoside induced. However, this may be difficult since signs of intoxication do not occur in regular sequence, and subjective signs of toxicity are frequently less easily recognized in infants and children than in adults /Cardiac glycosides/
American Society of Health-System Pharmacists; Drug Information 2018. Bethesda, MD. 2018, p. 1814
/SIGNS AND SYMPTOMS/ The extracardiac manifestations of cardiac glycoside intoxication are similar in both acute and chronic intoxication. However, GI effects and, to a lesser extent, CNS and visual disturbances may be more pronounced following acute overdosage. Acute toxicity may cause hyperkalemia, whereas patients with chronic toxicity may be hypokalemic or normokalemic. In addition, patients receiving chronic cardiac glycoside therapy may be hyperkalemic, normokalemic, or hypokalemic if acute intoxication occurs. In pediatric patients, drowsiness and vomiting are often the most prominent extracardiac effects. However, life-threatening cardiac arrhythmias have developed suddenly in children without evidence of any extracardiac signs of intoxication. /Cardiac glycosides/
American Society of Health-System Pharmacists; Drug Information 2018. Bethesda, MD. 2018, p. 1814-5
/SIGNS AND SYMPTOMS/ Anorexia, nausea, and vomiting are common early signs of toxicity and may precede or follow evidence of cardiotoxicity. ... GI effects probably are at least partially mediated by the area postrema of the medulla since they occur following administration by all routes. Large doses of cardiac glycosides may also produce emesis by direct GI irritation. Episodes of nausea and vomiting may start and stop abruptly. Other GI effects include salivation, epigastric or abdominal pain, abdominal distention, diarrhea, constipation, and weight loss. Acute hemorrhage and intestinal, esophageal, and gastric necrosis have occurred rarely in patients receiving cardiac glycosides. /Cardiac glycosides/
American Society of Health-System Pharmacists; Drug Information 2018. Bethesda, MD. 2018, p. 1815
For more Human Toxicity Excerpts (Complete) data for Digitoxin (26 total), please visit the HSDB record page.

13.1.7 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Acute Exposure/ ECG monitoring of adult and 1 week old rats during severe acute digitoxin toxicity showed lack of cardiotoxicity despite marked neurotoxicity in both age groups. High adrenal concentration in all animals.
Boor PJ et al; Arch Int Pharmacodyn Ther 224 (1): 4-12 (1976)
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The effects of chronic treatment with digitoxin on arterial baroreceptor sensitivity for heart rate (HR) and renal sympathetic nerve activity (rSNA) control, cardiopulmonary reflex, and autonomic HR control in an animal model of heart failure (HF) were evaluated. Wistar rats were treated with digitoxin, which was administered in their daily feed (1 mg/kg per day) for 60 days. The following 3 experimental groups were evaluated: sham, HF, and HF treated with digitoxin (HF + DIG). We observed an increase in rSNA in the HF group (190 +/- 29 pps, n = 5) compared with the sham group (98 +/- 14 pps, n = 5). Digitoxin treatment prevented an increase in rSNA (98 +/- 14 pps, n = 7). Therefore, arterial baroreceptor sensitivity was decreased in the HF group (-1.24 +/- 0.07 bpm/mm Hg, n = 8) compared with the sham group (-2.27 +/- 0.23 bpm/mm Hg, n = 6). Digitoxin did not alter arterial baroreceptor sensitivity in the HF + DIG group. Finally, the HF group showed an increased low frequency band (LFb: 23 +/- 5 ms(2), n = 8) and a decreased high frequency band (HFb: 77 +/- 5 ms(2), n = 8) compared with the sham group (LFb: 14 +/- 3 ms(2); HFb: 86 +/- 3 ms(2), n = 9); the HF+DIG group exhibited normalized parameters (LFb: 15 +/- 3 ms(2); HFb: 85 +/- 3 ms(2), n = 9). In conclusion, the benefits of decreasing rSNA are not directly related to improvements in peripheral cardiovascular reflexes; such occurrences are due in part to
Fardin NM et al; Can J Physiol Pharmacol 94 (6): 643-50 (2016)
/ENDOCRINE MODULATION/ Both in vivo and in vitro experiments were conducted to determined the effects of digitoxin on the secretion of testosterone, and its underlying mechanisms including testicular adenosine 3':5'-cyclic monophosphate (cAMP), and the activities of steroidogenic enzymes. Male rats were injected with digitoxin, human chorionic gonadotropin (hCG), or hCG plus digitoxin via a jugular catheter. Blood samples were collected immediately before and at 30 and 60 min after the challenge, and analyzed for testosterone by radioimmunoassay. In an in vitro study, rat testicular interstitial cells were isolated and incubated with digitoxin, hCG, 8-bromo-cAMP (8-Br-cAMP), digitoxin plus hCG, or digitoxin plus 8-Br-cAMP at 34 degrees C for 1 hr. The media were collected and analyzed for testosterone. For studying cAMP accumulation, testicular interstitial cells were incubated for 1 hr in the medium containing isobutyl-1-methylxanthine (IBMX) and different doses of digitoxin with the absence or presence of hCG. After incubation, cells were processed for determining cAMP content. Intravenous injection of digitoxin decreased hCG-stimulated, but not basal, plasma testosterone levels. Administration of digitoxin in vitro resulted in an inhibition of both basal and hCG- as well as 8-Br-cAMP-stimulated release of testosterone. In addition, digitoxin diminished hCG-stimulated cAMP accumulation in rat testicular interstitial cells. Furthermore, digitoxin inhibited the activity of cytochrome P450 side chain cleavage enzyme (P450scc) but failed to affect the activities of other steroidogenic enzymes. Taken together, these results suggest that the acute inhibitory effect of digitoxin on the testosterone production in testicular interstitial cells involves, at least partly, an inefficiency of post-cAMP events, and a decrease of P450scc activity.
Wang SW et al; J Cell Biochem 74 (1): 74-80 (1999)
/ENDOCRINE MODULATION// Previous studies have shown that digoxin decreases testosterone secretion in testicular interstitial cells. However, the effect of digoxin on progesterone secretion in luteal cells is unclear. Progesterone is known as an endogenous digoxin-like hormone (EDLH). This study investigates how digitalis affected progesterone production and whether progesterone antagonized the effects of digitalis. Digoxin or digitoxin, but not ouabain, decreased the basal and human chorionic gonadotropin (hCG)-stimulated progesterone secretion as well as the activity of cytochrome P450 side chain cleavage enzyme (P450scc) in luteal cells. 8-Br-cAMP and forskolin did not affect the reduction. Neither the amount of P450scc, the amount of steroidogenic acute regulatory (StAR) protein, nor the activity of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) was affected by digoxin or digitoxin. Moreover, in testicular interstitial and luteal cells, progesterone partially attenuated the reduction of pregnenolone by digoxin or digitoxin and the progesterone antagonist, RU486, blocked this attenuation. These new findings indicated that (1) digoxin or digitoxin inhibited pregnenolone production by decreasing the activity of P450scc enzyme, but not Na(+)-K(+)-ATPase, resulting in a decrease on progesterone secretion in rat luteal cells, and (2) the inhibitory effect on pregnenolone production by digoxin or digitoxin was reversed partially by progesterone. In conclusion, digoxin or digitoxin decreased progesterone production via the inhibition of pregnenolone by decreasing P450scc activity. Progesterone, an EDLH, could antagonize the effects of digoxin or digitoxin in luteal cells.
Chen JJ et al; J Cell Biochem 86 (1): 107-17 (2002)
For more Non-Human Toxicity Excerpts (Complete) data for Digitoxin (6 total), please visit the HSDB record page.

13.1.8 Non-Human Toxicity Values

LD50 Rat iv 3900 ug/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1298
LD50 Mouse ip 3900 ug/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1298
LD50 Mouse sc 22,180 ug/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1298
LD50 Mouse siv 4100 ug/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1298
For more Non-Human Toxicity Values (Complete) data for Digitoxin (8 total), please visit the HSDB record page.

13.1.9 Ongoing Test Status

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of February 4, 2019: http://actor.epa.gov/dashboard/]

13.1.10 Populations at Special Risk

BACKGROUND: Although the value of digitalis glycosides in the treatment of heart failure is limited, approximately 255 million DDDs of digitalis glycosides (DGs) were prescribed in Germany in 2004. METHOD: The authors analyzed data from adverse drug reactions (ADRs) resulting in hospitalization in the four German Pharmacovigilance Centers (PVCs) associated with DGs between 2000 and 2004. All patients with an at least "probable" ADR were included. RESULTS: Out of 3,092 ADR patients, in 314 patients (10.2%, 244 women) admission was caused by a DG-related ADR. Patients with DG-related ADR had a significantly lower body weight and were significantly older than patients with other ADRs. Per 1,000 patients exposed to DGs the incidence [95% CI] was calculated to 1.9 [1.0; 3.3] ADRs per 3 months exposition. Oral digitoxin was involved in 296 patients (228 women). 70.6% of women but only 29.3% of men were overdosed (> 1 ug/kg body weight per day). Women received significantly higher body weight-related digitoxin doses and had significantly higher digitoxin plasma levels than men. ADRs in patients with nonelevated digitoxin serum level were mainly caused by pharmacodynamic drug-drug interactions (e.g., beta-blockers). Overall, 42.4% of the ADRs were supposed to be preventable. CONCLUSION: Body weight-adapted dosing of digitoxin is essential for preventing DG-ADRs, particularly in elderly women with low body weight. Beyond giving attention to pharmacodynamic and pharmakokinetic drug-drug interactions, regular measurements of digitoxin plasma concentrations are crucial accounting for the increased half-life of digitoxin in the very old.
Schmiedl S et al; Med Klin (Munich) 102 (8): 603-11 (2007)
Drug-related illness is an everlasting universal problem and also an important cause of admissions to hospitals. Adverse reactions are still grossly underreported by medical professions. Little information is available regarding the frequency or type of ADRs managed in hospitals. Since January 1997, we have taken part in a study, supported by the German Federal Institute for Drugs and Medical Device to improve the spontaneous drug information reporting system in Germany. Three German regionalized Departments of Clinical Pharmacology--Jena, Dresden, Rostock--serve as Pharmacovigilance Centers in collaboration with the Pharmacoepidemiology Research Group of the University of Munich. Since January 1997, the regional group in Jena has been monitoring the University Clinic of Internal Medicine for admissions caused by adverse drug reactions. All emergency cases and patients on intensive care units were checked for adverse drug reactions. We present our results, including clinical and demographic data, concerning intoxications and especially those involving digitoxin in 210 patients with ADR. Forty patients with digitoxin toxicity had an average age of 81 years (81.1 +/- 6.3), a low body weight (59.7 +/- 12.7 kg) and 3 out of 4 were women. 75% of all patients with digitoxin side effects had elevated serum digitoxin levels with concentrations higher than 25 ug/mL. The relatively high frequency of digitoxin intoxications in our hospital may reflect the advanced age and low body weight of patients. Patients received digitoxin regardless of age, weight and, sometimes, clinical indication. Physicians should be aware of drugs having a high risk when used in elderly patients. The use of digitoxin assays and keeping serum levels within or near the therapeutic range will diminish the incidence of overdoses.
Hippius M et al; Int J Clin Pharmacol Ther 39 (8): 336-43 (2001)
The digitoxin half-life in elderly patients in the eight and ninth decade was more prolonged (mean +/- SD: 25 +/- 9 days) than in younger people (6.7 +/- 1.7). These elderly patients accumulated digitoxin even on a dose of 0.05 mg/ day. The symptoms of digitoxin intoxication disappeared on discontinuation of medication. When digitoxin is used in the treatment for heart failure in the very elderly patients, one should be aware of the possibility of digitoxin intoxication, even on a low dose.
Bohmer T1, Roseth A; Age Ageing 27 (2): 222-4 (1998)
Neuropsychiatric disturbances are especially likely to develop in geriatric patients with atherosclerotic disease and are easily overlooked in patients receiving chronic cardiac glycoside therapy. These effects include disorientation, confusion, depression, memory impairment, amnesia, aphasia, bad dreams, delirium, delusions, illusions, and hallucinations. /Cardiac glycosides/
American Society of Health-System Pharmacists; Drug Information 2018. Bethesda, MD. 2018, p. 1815
For more Populations at Special Risk (Complete) data for Digitoxin (9 total), please visit the HSDB record page.

13.2 Ecological Information

13.2.1 Environmental Fate / Exposure Summary

Digitoxin's production and administration as a human and veterinary cardiotonic may result in its release to the environment through various waste streams. It is a natural product from Digitalis purpurea (foxglove) leaves. If released to air, an estimated vapor pressure of 1.1X10-27 mm Hg at 25 °C indicates digitoxin will exist solely in the particulate phase in the atmosphere. Particulate-phase digitoxin will be removed from the atmosphere by wet and dry deposition. Digitoxin contains chromophores that absorb at wavelengths >290 nm and, therefore, may be susceptible to direct photolysis by sunlight. If released to soil, digitoxin is expected to be immobile based upon an estimated Koc of 6.0X10+4. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 1.3X10-25 atm-cu m/mole. Digitoxin is not expected to volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation data in soil or water were not available. If released into water, digitoxin is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 7 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is expected to be an important environmental fate process since this compound contains functional groups that hydrolyze under environmental conditions (pH 5 to 9). Occupational exposure should be low or non-existent since digitoxin is not produced in the US. The general public is not likely to be exposed to digitoxin unless by direct medical treatment with digitoxin or with the parent drug digoxin. (SRC)

13.2.2 Natural Pollution Sources

Digitoxin is a natural product from Digitalis purpurea (foxglove) leaves(1,2).
(1) Larranaga MD et al, eds; Hawley's Condensed Chemical Dictionary. 16th ed., Hoboken, NJ: John Wiley & Sons, Inc., p. 476 (2016)
(2) Dr. Duke's Phytochemical and Ethnobotanical Databases. Digitoxin. Available from, as of Sept 20, 2018: https://phytochem.nal.usda.gov/phytochem/search
Cardiac glycosides of medicinal importance are obtained from Digitalis purpurea Linne (Fam. Scrophulariaceae) (digitoxin, digitalis) and Digitalis lanata Ehrhart (Fam. Scrophulariaceae) (digoxin, digitoxin, deslanoside). /Cardiac glycosides/
McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 886

13.2.3 Artificial Pollution Sources

Digitoxin's production and administration as a human and veterinary cardiotonic(1) may result in its release to the environment through various waste streams(SRC).
(1) O'Neil MJ, ed; The Merck Index. 15th ed., Cambridge, UK: Royal Society of Chemistry, p. 575 (2013)

13.2.4 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 6.0X10+4(SRC), determined from a structure estimation method(2), indicates that digitoxin is expected to be immobile in soil(SRC). Volatilization of digitoxin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.3X10-25 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). Digitoxin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.1X10-27 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2018).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.11. Nov, 2012. Available from, as of Sept 30, 2018: https://www2.epa.gov/tsca-screening-tools
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 6.0X10+4(SRC), determined from a structure estimation method(2), indicates that digitoxin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.3X10-25 atm-cu m/mole(SRC), developed using a fragment constant estimation method(2). According to a classification scheme(4), an estimated BCF of 7(SRC), from its log Kow of 1.85(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2018).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.11. Nov, 2012. Available from, as of Sept 30, 2018: https://www2.epa.gov/tsca-screening-tools
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(4) Franke C et al; Chemosphere 29: 1501-14 (1994)
(5) Sangster J; LOGKOW Databank. Sangster Res Lab, Montreal Quebec, Canada (1994)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), digitoxin, which has an estimated vapor pressure of 1.1X10-27 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase digitoxin may be removed from the air by wet and dry deposition(SRC). Digitoxin contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.11. Nov, 2012. Available from, as of Sept 20, 2018: https://www2.epa.gov/tsca-screening-tools
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990)

13.2.5 Environmental Abiotic Degradation

Digitoxin is expected to undergo hydrolysis in the environment due to the presence of functional groups that hydrolyze under environmental conditions(1). Acid hydrolysis of digitoxin yields 1 mol digitoxigenin + 3 mol digitoxose. The sugar residue is attached to the hydroxyl group at C-3 of the aglycon(2). Digitoxin contains chromophores that absorb at wavelengths >290 nm(1) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).
(1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5, 8-12, 8-13 (1990)
(2) O'Neil MJ, ed; The Merck Index. 15th ed., Cambridge, UK: Royal Society of Chemistry, p. 575 (2013)

13.2.6 Environmental Bioconcentration

An estimated BCF of 7 was calculated in fish for digitoxin(SRC), using a log Kow of 1.85(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).
(1) Sangster J; LOGKOW Databank. Sangster Res Lab, Montreal Quebec, Canada (1994)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.11. Nov, 2012. Available from, as of Sept 30, 2018: https://www2.epa.gov/tsca-screening-tools
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

13.2.7 Soil Adsorption / Mobility

Using a structure estimation method based on molecular connectivity indices(1), the Koc of digitoxin can be estimated to be 6.0X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that digitoxin is expected to be immobile in soil(SRC).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.11. Nov, 2012. Available from, as of Sept 20, 2018: https://www2.epa.gov/tsca-screening-tools
(2) Swann RL et al; Res Rev 85: 17-28 (1983)

13.2.8 Volatilization from Water / Soil

The Henry's Law constant for digitoxin is estimated as 1.3X10-25 atm-cu m/mole(SRC) developed using a fragment constant estimation method(1). This Henry's Law constant indicates that digitoxin is expected to be essentially nonvolatile from water and moist soil surfaces(2). Digitoxin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.1X10-27 mm Hg(SRC), determined from a fragment constant method(1).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.11. Nov, 2012. Available from, as of Sept 20, 2018: https://www2.epa.gov/tsca-screening-tools
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)

13.2.9 Plant Concentrations

Digitoxin occurrence in plants(1).
Genus species
Digitalis purpurea
Family
Scrophulariaceae
Common name(s)
Purple Foxglove
Part
Leaf
Concn (ppm)
3000
Genus species
Digitalis lanata
Family
Scrophulariaceae
Common name(s)
Grecian Foxglove
Part
Leaf
Concn (ppm)
200
(1) Dr. Duke's Phytochemical and Ethnobotanical Databases. Digitoxin. Available from, as of Sept 20, 2018: https://phytochem.nal.usda.gov/phytochem/search

13.2.10 Probable Routes of Human Exposure

NIOSH (NOES Survey 1981-1983) has statistically estimated that 2,173 workers (1,302 of these are female) are potentially exposed to digitoxin in the US(1). Occupational exposure should be low or non-existent since digitoxin is not produced in the US. The general public is not likely to be exposed to digitoxin unless by direct medical treatment with digitoxin or with the parent drug digoxin(SRC),
(1) NIOSH; National Occupational Exposure Survey (NOES) (1983)

14 Associated Disorders and Diseases

15 Literature

15.1 Consolidated References

15.2 NLM Curated PubMed Citations

15.3 Springer Nature References

15.4 Chemical Co-Occurrences in Literature

15.5 Chemical-Gene Co-Occurrences in Literature

15.6 Chemical-Disease Co-Occurrences in Literature

16 Patents

16.1 Depositor-Supplied Patent Identifiers

16.2 WIPO PATENTSCOPE

16.3 Chemical Co-Occurrences in Patents

16.4 Chemical-Disease Co-Occurrences in Patents

16.5 Chemical-Gene Co-Occurrences in Patents

17 Interactions and Pathways

17.1 Protein Bound 3D Structures

17.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

17.2 Chemical-Target Interactions

17.3 Drug-Drug Interactions

17.4 Drug-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.

18 Biological Test Results

18.1 BioAssay Results

19 Taxonomy

The LOTUS Initiative for Open Natural Products Research: frozen dataset union wikidata (with metadata) | DOI:10.5281/zenodo.5794106
S29 | PHYTOTOXINS | Toxic Plant Phytotoxin (TPPT) Database | DOI:10.5281/zenodo.2652993

20 Classification

20.1 MeSH Tree

20.2 NCI Thesaurus Tree

20.3 ChEBI Ontology

20.4 LIPID MAPS Classification

20.5 KEGG: Metabolite

20.6 KEGG: Lipid

20.7 KEGG: Phytochemical Compounds

20.8 KEGG: Natural Toxins

20.9 KEGG: ATC

20.10 KEGG: Target-based Classification of Drugs

20.11 KEGG: Drug Groups

20.12 KEGG : Glycosides

20.13 WHO ATC Classification System

20.14 ChemIDplus

20.15 CAMEO Chemicals

20.16 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

20.17 ChEMBL Target Tree

20.18 UN GHS Classification

20.19 NORMAN Suspect List Exchange Classification

20.20 CCSBase Classification

20.21 EPA DSSTox Classification

20.22 EPA TSCA and CDR Classification

20.23 LOTUS Tree

20.24 EPA Substance Registry Services Tree

20.25 MolGenie Organic Chemistry Ontology

21 Information Sources

  1. BindingDB
    LICENSE
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  3. DrugBank
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    https://www.guidetopharmacology.org/about.jsp#license
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    https://cameochemicals.noaa.gov/help/reference/terms_and_conditions.htm?d_f=false
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    Card-20(22)-enolide, 3-[(O-2,6-dideoxy-.beta.-D-ribo-hexopyranosyl-(1.fwdarw.4)-O-2,6-dideoxy-.beta.-D-ribo-hexopyranosyl-(1.fwdarw.4)-2,6-dideoxy-.beta.-D-ribo-hexopyranosyl)oxy]-14-hydroxy-, (3.beta.,5.beta.)-
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    https://lotus.nprod.net/
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    https://platform-docs.opentargets.org/licence
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    http://www.ebi.ac.uk/Information/termsofuse.html
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  26. NORMAN Suspect List Exchange
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    Digitoxin
    NORMAN Suspect List Exchange Classification
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  29. Regulation (EC) No 1272/2008 of the European Parliament and of the Council
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    Anatomical Therapeutic Chemical (ATC) classification
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CONTENTS