View source for Digitoxin

{{Short description|Chemical compound}}
{{Distinguish|Digoxin}}
{{Drugbox| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 297417192
| IUPAC_name = (3β,5β)-3-[(O-2,6-dideoxy-<br />β-D-ribo-hexapyranosyl-(1->4)-<br />2,6-dideoxy-β-D-ribo-hexopyranosyl)oxy]-<br />14-hydroxycard-20(22)-enolide
| image = Digitoxin structure.svg
| width = 250px
<!--Clinical data-->
| tradename = Digalen, Digitaline, Digitmerck, others
| pregnancy_category = 
| legal_status = Rx-only
| routes_of_administration = [[Oral administration|By mouth]], [[Intravenous injection]]
<!--Pharmacokinetic data-->
| bioavailability = 98–100% (oral)
| protein_bound = 90–97%
| metabolism = Liver ([[CYP3A4]])
| elimination_half-life = 7–8 days
| excretion = 60% via urine, 40% via faeces
<!--Identifiers-->
| IUPHAR_ligand = 6782
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 71-63-6
| ATC_prefix = C01
| ATC_suffix = AA04
| PubChem = 441207
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB01396
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 389987
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = E90NZP2L9U
| KEGG_Ref = {{keggcite|changed|kegg}}
| KEGG = D00297
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 28544
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 254219
<!--Chemical data-->
| C=41 | H=64 | O=13
| smiles = O=C\1OC/C(=C/1)[C@H]2CC[C@@]8(O)[C@]2(C)CC[C@H]7[C@H]8CC[C@H]6[C@]7(C)CC[C@H](O[C@@H]5O[C@H](C)[C@@H](O[C@@H]4O[C@@H]([C@@H](O[C@@H]3O[C@@H]([C@@H](O)[C@@H](O)C3)C)[C@@H](O)C4)C)[C@@H](O)C5)C6
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = WDJUZGPOPHTGOT-XUDUSOBPSA-N
}}

'''Digitoxin''' is a [[cardiac glycoside]] used for the treatment of [[heart failure]] and certain kinds of [[arrhythmia|heart arrhythmia]]. It is a [[phytosteroid]] and is similar in [[chemical structure|structure]] and effects to [[digoxin]], though the effects are longer-lasting. Unlike digoxin, which is eliminated from the body via the kidneys, it is eliminated via the liver, and so can be used in patients with poor or erratic kidney function. While several controlled trials have shown digoxin to be effective in a proportion of patients treated for heart failure, the evidence base for digitoxin is not as strong, although it is presumed to be similarly effective.<ref name=Belz>{{cite journal | vauthors = Belz GG, Breithaupt-Grögler K, Osowski U | title = Treatment of congestive heart failure--current status of use of digitoxin | journal = European Journal of Clinical Investigation | volume = 31 | issue = Suppl 2 | pages = 10–7 | year = 2001 | pmid = 11525233 | doi = 10.1046/j.1365-2362.2001.0310s2010.x | doi-broken-date = 12 July 2025 | url = http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0014-2972&date=2001&volume=31&issue=&spage=10 | archive-url = https://archive.today/20130105085338/http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0014-2972&date=2001&volume=31&issue=&spage=10 | archive-date = 2013-01-05 | url-access = subscription }}</ref>

==Medical uses==
Digitoxin is used for the treatment of heart failure, especially in people with impaired kidney function. It is also used to treat certain kinds of [[heart arrhythmia]], such as [[atrial fibrillation]].<ref>{{cite book|editor=Erland Erdmann|title=Therapie mit Herzglykosiden|publisher=Springer|lang=de|year=2013|isbn=978-3-642-69046-4|page=43}}</ref><ref name="AC">{{cite book|title=Austria-Codex| veditors = Haberfeld H |at=Digimerck 0,07&nbsp;mg - Tabletten|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2021|language=German}}</ref>

==Contraindications==
Contraindications include<ref name="AC" />
* problems with the heart rhythm, such as severe [[bradycardia]] (slow heartbeat), [[ventricular tachycardia]] (fast heartbeat caused by the [[ventricle (heart)|ventricle]]s), [[ventricular fibrillation]], or first- to second-degree [[atrioventricular block]],
* and certain [[electrolyte imbalance]]s: [[hypokalemia]] (low blood potassium levels), [[hypomagnesemia]] (low magnesium), and [[hypercalcemia]] (high calcium).

==Adverse effects and toxicity==
Digitoxin exhibits similar toxic effects to [[digoxin]], namely: [[anorexia]], [[nausea]], vomiting, diarrhea, confusion, visual disturbances, and cardiac [[arrhythmias]]. Antidigoxin [[antibody fragment]]s, the specific treatment for digoxin poisoning, are also effective in serious digitoxin toxicity.<ref name=Kurowsky>{{cite journal | vauthors = Kurowski V, Iven H, Djonlagic H | title = Treatment of a patient with severe digitoxin intoxication by Fab fragments of anti-digitalis antibodies | journal = Intensive Care Medicine | volume = 18 | issue = 7 | pages = 439–42 | year = 1992 | pmid = 1469187 | doi = 10.1007/BF01694351 | s2cid = 2324996 }}</ref>

==Interactions==
Drugs that can increase digitoxin toxicity include:<ref name="AC" />
* calcium
* substances that lower potassium or magnesium levels, such as [[diuretic]]s and [[corticosteroid]]s
* [[enzyme inhibitor|inhibitors]] of the liver enzyme [[CYP3A4]], which slow down digitoxin [[metabolism]]; examples are the antibiotic [[clarithromycin]], the antifungal [[itraconazole]], and [[grapefruit juice]]
* inhibitors of the transporter protein [[P-gp]], such as clarithromycin
* [[Beta blocker]]s add to the [[bradycardia]] (slow heartbeat) caused by digitoxin.

Drugs that can decrease the effectivity of digitoxin include:<ref name="AC" />
* substances that increase potassium levels, such as [[Potassium-sparing diuretic]]s
* [[enzyme inducer|inducers]] of CYP3A4 or P-gp, such as [[phenytoin]], [[rifampicin]] and [[St John's Wort]]
* substances that bind digitoxin in the gut, such as aluminium containing [[antacid]]s or [[colestyramine]]

==Pharmacology==
===Mechanism of action===
{{main|Cardiac glycoside#Mechanism of action}}
Digitoxin inhibits the [[sodium-potassium ATPase]] in heart muscle cells, resulting in increased force of contractions (positive [[inotropic]]), reduced speed of electric conduction (negative [[dromotropic]]), increased excitability (positive [[bathmotropic]]), and reduced frequency of heartbeat (negative [[chronotropic]]).<ref name="AC" />

===Pharmacokinetics===
The drug is almost completely absorbed from the gut. When in the bloodstream, 90 to 97% are bound to [[plasma protein]]s. Digitoxin undergoes [[enterohepatic circulation]]. It is [[metabolized]] in part by CYP3A4; metabolites include [[digitoxigenin]], [[digoxin]] (>2%), and [[conjugation (biochemistry)|conjugate esters]]. In healthy people, 60% are eliminated via the kidneys and 40% via the faeces. In people with impaired kidney function, elimination via the faeces is increased. The [[biological half-life]] is 7 to 8 days except when kidney ''and'' liver functions are impaired, in which case it is usually longer.<ref name="AC" /><ref>{{cite web|url=https://www.mediq.ch/|title=mediQ: Digitoxin|access-date=2021-09-14}}</ref>

==History==
The first description of the use of [[Digitalis purpurea|foxglove]] dates back to 1775.<ref>{{cite book | url = https://archive.org/details/b21517356 | title = An Account of the Foxglove and Some of its Medical Uses: With Practical Remarks on Dropsy and other Diseases | publisher = Classics of Medicine Library | last = Withering | first = William | name-list-style = vanc | year = 1785 }}</ref> For quite some time, the active compound was not isolated. [[Oswald Schmiedeberg]] was able to obtain a pure sample in 1875. The modern therapeutic use of this molecule was made possible by the works of the pharmacist and the French chemist [[Claude-Adolphe Nativelle]] (1812–1889). The first structural analysis was done by [[Adolf Otto Reinhold Windaus]] in 1925, but the full structure with an exact determination of the sugar groups was not accomplished until 1962.<ref>{{cite journal | vauthors = Diefenbach WC, Meneely JK | title = Digitoxin; a critical review | journal = The Yale Journal of Biology and Medicine | volume = 21 | issue = 5 | pages = 421–31 | date = May 1949 | pmid = 18127991 | pmc = 2598854 }}</ref><ref>{{cite book | url = https://books.google.com/books?id=mYQxRY9umjcC&pg=PA107 | page = 107 | title = Drug discovery: A history | isbn = 978-0-471-89980-8 | last = Sneader | first = Walter | name-list-style = vanc | year = 2005| publisher = Wiley }}</ref>

== Use as a weapon ==
Digitoxin has been used for at least 7,000 years as an [[arrow poison]].<ref>{{cite journal |last=Bradfield |first=Justin |date=January 23, 2025  |title=Discovery in South Africa holds oldest evidence of mixing ingredients to make arrow poison |url=https://theconversation.com/discovery-in-south-africa-holds-oldest-evidence-of-mixing-ingredients-to-make-arrow-poison-247250 |journal=The Conversation |access-date=January 24, 2025}}</ref> [[Marie Alexandrine Becker]], a Belgian serial killer, was sentenced to death for poisoning eleven people with digitoxin.{{fact|reason=Her article only says digitalis, not specifically digitoxin.|date=September 2021}}

=== In fiction ===
Digitoxin is used as a poison or murder weapon in:
* [[Agatha Christie]]'s ''[[Appointment with Death]]''
* [[Elizabeth Peters]]' ''[[Die For Love]]''
* ''[[CSI: Crime Scene Investigation|CSI]]'', season 9, episode 19: "The Descent of Man"
* ''[[Rosewood (TV series)|Rosewood]]'' season 2, episode 20: ''[[Rosewood (TV series)#ep42|Calliphoridae and Country Roads]]''
* "Casino Royale" (2006)
* "Uneasy Lies the Crown" on ''Columbo'', season 9, episode 5 (1990)
* "Affair of the Heart" on ''McMillan and Wife'', season 6, episode 5 (1977)
* ''Murder 101'': "College can be a Murder"
* Several episodes of Murder She Wrote.
* [[Private Practice (season 4)|Private Practice]], season 4, episode 18: "The Hardest Part"

In [[The Decemberists]]'s song, "The Rake's Song" on ''[[The Hazards of Love]]'' album, the narrator murders his daughter by feeding her foxglove.

In [[Metal Gear Solid V: The Phantom Pain]], Venom Snake uses digitalis to obtain digoxin for tranquilizer rounds to incapacitate enemies.

== Research ==
Digitoxin and related cardenolides display anticancer activity against a range of human [[cancer]] cell lines in vitro but the clinical use of digitoxin to treat [[cancer]] has been restricted by its narrow [[therapeutic index]].<ref>{{cite journal | vauthors = Menger L, Vacchelli E, Kepp O, Eggermont A, Tartour E, Zitvogel L, Kroemer G, Galluzzi L | display-authors = 6 | title = Trial watch: Cardiac glycosides and cancer therapy | journal = Oncoimmunology | volume = 2 | issue = 2 | article-number = e23082 | date = February 2013 | pmid = 23525565 | pmc = 3601180 | doi = 10.4161/onci.23082 }}</ref><ref>{{cite journal | vauthors = Elbaz HA, Stueckle TA, Tse W, Rojanasakul Y, Dinu CZ | title = Digitoxin and its analogs as novel cancer therapeutics | journal = Experimental Hematology & Oncology | volume = 1 | issue = 1 | article-number = 4 | date = April 2012 | pmid = 23210930 | pmc = 3506989 | doi = 10.1186/2162-3619-1-4 | doi-access = free }}</ref> Digitoxin [[glycorandomization]] led to the discovery of novel [[digitoxigenin]] neoglycosides which displayed improved anticancer potency and reduced inotropic activity (the perceived mechanism of general toxicity).<ref>{{cite journal | vauthors = Langenhan JM, Peters NR, Guzei IA, Hoffmann FM, Thorson JS | title = Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 35 | pages = 12305–10 | date = August 2005 | pmid = 16105948 | pmc = 1194917 | doi = 10.1073/pnas.0503270102 | bibcode = 2005PNAS..10212305L | doi-access = free }}</ref>

== References ==
{{reflist|35em}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Johansson S, Lindholm P, Gullbo J, Larsson R, Bohlin L, Claeson P | title = Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells | journal = Anti-Cancer Drugs | volume = 12 | issue = 5 | pages = 475–83 | date = June 2001 | pmid = 11395576 | doi = 10.1097/00001813-200106000-00009 | s2cid = 19894541 }}
* {{cite journal | vauthors = Hippius M, Humaid B, Sicker T, Hoffmann A, Göttler M, Hasford J | title = Adverse drug reaction monitoring--digitoxin overdosage in the elderly | journal = International Journal of Clinical Pharmacology and Therapeutics | volume = 39 | issue = 8 | pages = 336–43 | date = August 2001 | pmid = 11515708 | doi = 10.5414/cpp39336 }}
* {{cite journal | vauthors = Haux J, Klepp O, Spigset O, Tretli S | title = Digitoxin medication and cancer; case control and internal dose-response studies | journal = BMC Cancer | volume = 1 | article-number = 11 | year = 2001 | pmid = 11532201 | pmc = 48150 | doi = 10.1186/1471-2407-1-11 | doi-access = free }}
* {{cite journal | vauthors = Srivastava M, Eidelman O, Zhang J, Paweletz C, Caohuy H, Yang Q, Jacobson KA, Heldman E, Huang W, Jozwik C, Pollard BS, Pollard HB | display-authors = 6 | title = Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from cystic fibrosis lung epithelial cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 20 | pages = 7693–8 | date = May 2004 | pmid = 15136726 | pmc = 419668 | doi = 10.1073/pnas.0402030101 | bibcode = 2004PNAS..101.7693S | doi-access = free }}
{{refend}}

== External links ==
{{commonscatinline}}
* Comparing the Toxicity of Digoxin and Digitoxin in a Geriatric Population: Should an Old Drug Be Rediscovered? on [https://www.medscape.com/viewarticle/410488 Medscape] {{registration required}}, a convenience link from the [https://sma.org/southern-medical-journal/article/comparing-the-toxicity-of-digoxin-and-digitoxin-in-a-geriatric-population-should-an-old-drug-be-rediscovered-2/ original]. {{subscription required}}

{{Glycosides}}
{{Cardiac glycosides}}
{{Estrogen receptor modulators}}

[[Category:Cardenolides]]
[[Category:Estrogens]]
[[Category:Drugs developed by Merck]]