Digitoxin

Digitoxin at a Glance

Digitoxin is a prescription heart-failure drug. It is a cardenolide glycoside — a steroid core with a sugar chain — that inhibits the sodium–potassium pump, and it belongs to the oldest drug class still in cardiological use.

For most of the twentieth century it was prescribed on inherited practice rather than trial evidence. That changed in 2025: DIGIT-HF randomised 1,240 patients with heart failure and reduced ejection fraction to 0.07 mg daily or placebo on top of guideline-directed therapy, and over a median 36 months the composite of death or first heart-failure hospitalisation fell from 44.1% to 39.5%, hazard ratio 0.82 (95% CI 0.69–0.98) ^{1Reference 1Bavendiek et al. · 2025RCTDigitoxin in Patients with Heart Failure and Reduced Ejection Fraction — randomised controlled trialView study →}. Neither component reached significance on its own. It is a modest, real result for a drug that had been used for two centuries without one.

What distinguishes digitoxin from its better-known relative digoxin is not what it does but how the body clears it. Digitoxin is eliminated largely independently of kidney function, with high and consistent oral bioavailability and an elimination half-life of four to seven days ^{3Reference 3Fender et al. · 2024ReviewFender, J., Klöcker, J., Boivin-Jahns, V., et al. (2024). “Cardiac glycosides”-quo vaditis?-past, present, and future? — review. Naunyn Schmiedebergs Arch Pharmacol. https://pubmed.ncbi.nlm.nih.gov/39007928/View study →}. That makes it the glycoside of choice where renal function is poor — and it also means that when exposure is too high, it stays too high for a week.

It comes from foxglove leaf, and that is where the plant story ends. The leaf is unassayable: total glycoside content swings several-fold with season, plant part, developmental stage and provenance ^{12Reference 12Ravi et al. · 2020High-resolution tandem mass spectrometry dataset reveals fragmentation patterns of cardiac glycosides in leaves of the foxglove plantsView study →}, so a weighed quantity is not a dose. Foxglove leaf was abandoned as a medicine once the glycosides could be purified, and nothing about the drug’s evidence transfers back to it.

Digitoxin vs. Digoxin

The two drugs share a mechanism, a therapeutic index and a toxidrome. They differ almost entirely in pharmacokinetics, and the difference is the reason both still exist.

	Digitoxin	Digoxin
Principal plant source	Digitalis purpurea leaf	Digitalis lanata leaf
Oral bioavailability	>90%, consistent	55–75%, variable
Elimination route	Hepatic metabolism + enterohepatic recirculation; largely independent of renal function	Predominantly renal excretion
Elimination half-life	~4–7 days	~30–50 hours
Plasma protein binding	High	Low
Practical consequence	Stable levels in renal impairment; slow to correct if too high	Levels track kidney function; faster to clear

Kinetics from a 2024 review of the class ^{3Reference 3Fender et al. · 2024ReviewFender, J., Klöcker, J., Boivin-Jahns, V., et al. (2024). “Cardiac glycosides”-quo vaditis?-past, present, and future? — review. Naunyn Schmiedebergs Arch Pharmacol. https://pubmed.ncbi.nlm.nih.gov/39007928/View study →}.

The clinical corollary is narrow and specific: in patients with reduced renal function, digitoxin may be considered where digoxin would accumulate unpredictably ^{3,4Reference 3Fender et al. · 2024ReviewFender, J., Klöcker, J., Boivin-Jahns, V., et al. (2024). “Cardiac glycosides”-quo vaditis?-past, present, and future? — review. Naunyn Schmiedebergs Arch Pharmacol. https://pubmed.ncbi.nlm.nih.gov/39007928/View study →Reference 4Whayne TF Jr · 2018Systematic reviewClinical Use of Digitalis: A State of the Art Review — systematic reviewView study →}. The corollary in the other direction is just as real. A four-to-seven-day half-life means an overdose does not wash out — the effect of stopping the drug is measured in days, not hours — and it is part of why digitoxin exposures reported to poison centres have risen year on year even as prescribing has fallen ^{9Reference 9Ecker et al. · 2026Critical analysis of digitalis glycosides: declining use but increasing poison-center exposure cases for digitoxinView study →}.

Most of the famous cardiac-glycoside literature is digoxin’s, not digitoxin’s. The DIG trial, the mortality meta-analyses, the atrial-fibrillation controversy and the cancer-epidemiology signal all concern digoxin ^{2Reference 2Digitalis Investigation Group · 1997RCTThe effect of digoxin on mortality and morbidity in patients with heart failure — randomised controlled trialView study →}. Treating the two as interchangeable is the standing error in this area, and it runs in both directions: digitoxin inherits digoxin’s reputation for harm and digoxin inherits digitoxin’s one positive randomised trial.

The Therapeutic Index — and the Antidote

Digitoxin has a narrow therapeutic range for a structural reason. It inhibits Na⁺/K⁺-ATPase, and that pump exists in every cell in the body. The rise in intracellular calcium that strengthens cardiac contraction is the same rise that, pushed a little further, produces spontaneous depolarisations and arrhythmia. There is no separate toxic mechanism to design around: therapy and poisoning are the same action a short distance apart ^{3Reference 3Fender et al. · 2024ReviewFender, J., Klöcker, J., Boivin-Jahns, V., et al. (2024). “Cardiac glycosides”-quo vaditis?-past, present, and future? — review. Naunyn Schmiedebergs Arch Pharmacol. https://pubmed.ncbi.nlm.nih.gov/39007928/View study →}.

The toxidrome is distinctive and easy to miss. Gastrointestinal symptoms first — nausea, vomiting, abdominal pain — then visual disturbance, classically xanthopsia, a yellow-green cast to vision with halos around lights, and confusion in older patients. The dangerous features are electrical and electrolytic: hyperkalaemia in acute overdose, because the poisoned pump is what moves potassium into cells; bradycardia and AV block; ventricular ectopy and, characteristically, bidirectional ventricular tachycardia. Myocardial injury with rising troponin is documented in severe cases ^{19Reference 19Tausendfreund et al. · 2026Case reportTausendfreund, O., Hoppe, J. M., Wörnle, M. (2026). [Dangerous Overdose: Myocardial Injury from Digitoxin Intoxication] — case report. Dtsch Med Wochenschr. https://pubmed.ncbi.nlm.nih.gov/42442727/View study →}.

Unlike colchicine, this poisoning has a real antidote. Digoxin-specific antibody fragments (Fab) bind circulating glycoside and reverse the toxicity; a 150-case multicentre study established their effectiveness for life-threatening digitalis intoxication ^{10Reference 10Antman et al. · 1990Clinical trialTreatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragmentsView study →}. Despite the name, they work for digitoxin too — cross-reactivity between the cardenolides is high enough that severe digitoxin poisoning has been treated successfully with the same product ^{11Reference 11Lignian et al. · 1984Case reportTreatment of severe digitoxin intoxication by digoxin-specific Fab antibody fragments — case reportView study →}. That single fact is why cardiac-glycoside poisoning is one of the more survivable serious plant poisonings, and it is the sharpest contrast available with the other drug in this group.

What It's Used For

The evidence divides cleanly: one adequately powered randomised trial in heart failure, one small early-phase trial in cystic fibrosis, and a body of laboratory work on the same Na⁺/K⁺-ATPase signalling that has not reached patients.

Evidence by IndicationStrength of support · Beta

01Heart Failure With Reduced Ejection FractionPromising68%DIGIT-HF, n=1,240, HR 0.82 on a composite; no component significant alone ^{1Reference 1Bavendiek et al. · 2025RCTDigitoxin in Patients with Heart Failure and Reduced Ejection Fraction — randomised controlled trialView study →}

02Rate Control in Atrial FibrillationShaky40%Class-level and guideline-based; the trial evidence is digoxin’s, not digitoxin’s ^{2,4Reference 2Digitalis Investigation Group · 1997RCTThe effect of digoxin on mortality and morbidity in patients with heart failure — randomised controlled trialView study →Reference 4Whayne TF Jr · 2018Systematic reviewClinical Use of Digitalis: A State of the Art Review — systematic reviewView study →}

03Airway Inflammation in Cystic FibrosisShaky24%One completed Phase II safety/PK/dose-finding study ^{5Reference 5Zeitlin et al. · 2017RCTDigitoxin for Airway Inflammation in Cystic Fibrosis: Preliminary Assessment of Safety, Pharmacokinetics, and Dose Finding — randomised controlled trialView study →}

04Antiproliferative ActivityShaky14%Cell lines only; HIF-1α/STAT3 in KRAS-mutant colon cancer ^{6,7Reference 6Mi et al. · 2022Digitoxin promotes apoptosis and inhibits proliferation and migration by reducing HIF-1α and STAT3 in KRAS mutant human colon cancer cellsView study →Reference 7Bejček et al. · 2021ReviewNa(+)/K(+)-ATPase Revisited: On Its Mechanism of Action, Role in Cancer, and Activity Modulation — reviewView study →}

05Antiviral ActivityShaky10%In vitro, class-level repurposing reviews; no human data ^{8Reference 8Škubník et al. · 2021ReviewRepurposing Cardiac Glycosides: Drugs for Heart Failure Surmounting Viruses — reviewView study →}

Mechanisms

The sugar chain is not the pharmacophore. Digitoxigenin, the aglycone core, is what docks into the pump; the three digitoxose sugars govern potency, protein binding and pharmacokinetics rather than the binding event itself ^{3,7Reference 3Fender et al. · 2024ReviewFender, J., Klöcker, J., Boivin-Jahns, V., et al. (2024). “Cardiac glycosides”-quo vaditis?-past, present, and future? — review. Naunyn Schmiedebergs Arch Pharmacol. https://pubmed.ncbi.nlm.nih.gov/39007928/View study →Reference 7Bejček et al. · 2021ReviewNa(+)/K(+)-ATPase Revisited: On Its Mechanism of Action, Role in Cancer, and Activity Modulation — reviewView study →}. That is why the Digitalis glycosides all share one mechanism and differ mainly in how the body handles them.

Pharmacokinetics

The kinetics are what make digitoxin a distinct drug rather than a variant of digoxin. Oral bioavailability is above 90% and consistent between doses and patients — unusually so for a glycoside. It is highly bound to plasma protein, metabolised in the liver, and subject to enterohepatic recirculation, which together give an elimination half-life of about four to seven days. Critically, elimination is largely independent of renal function, in contrast to digoxin’s predominantly renal clearance ^{3Reference 3Fender et al. · 2024ReviewFender, J., Klöcker, J., Boivin-Jahns, V., et al. (2024). “Cardiac glycosides”-quo vaditis?-past, present, and future? — review. Naunyn Schmiedebergs Arch Pharmacol. https://pubmed.ncbi.nlm.nih.gov/39007928/View study →}.

Three consequences follow. Steady state takes weeks rather than days, so dose changes take effect slowly. Renal impairment does not force a dose adjustment the way it does for digoxin, which is the drug’s clinical niche ^{3,4Reference 3Fender et al. · 2024ReviewFender, J., Klöcker, J., Boivin-Jahns, V., et al. (2024). “Cardiac glycosides”-quo vaditis?-past, present, and future? — review. Naunyn Schmiedebergs Arch Pharmacol. https://pubmed.ncbi.nlm.nih.gov/39007928/View study →Reference 4Whayne TF Jr · 2018Systematic reviewClinical Use of Digitalis: A State of the Art Review — systematic reviewView study →}. And an overdose cannot be waited out — a week of exposure remains after the last tablet, which is the practical argument for Fab fragments rather than observation in significant poisoning ^{10,11Reference 10Antman et al. · 1990Clinical trialTreatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragmentsView study →Reference 11Lignian et al. · 1984Case reportTreatment of severe digitoxin intoxication by digoxin-specific Fab antibody fragments — case reportView study →}. Maintenance-dose metabolism studies established the same picture from the other direction, showing how slowly the body turns the drug over on a stable regimen ^{20Reference 20Storstein · 1977Studies on digitalisView study →}.

Clinical Trials

Last checked: September 2026.

Isolate vs. Plant Studies

All of it is the isolate, and that is not an oversight.

Every result above used pharmaceutical digitoxin at a measured dose — 0.07 mg daily in DIGIT-HF, a dose-finding range in the cystic-fibrosis study ^{1,5Reference 1Bavendiek et al. · 2025RCTDigitoxin in Patients with Heart Failure and Reduced Ejection Fraction — randomised controlled trialView study →Reference 5Zeitlin et al. · 2017RCTDigitoxin for Airway Inflammation in Cystic Fibrosis: Preliminary Assessment of Safety, Pharmacokinetics, and Dose Finding — randomised controlled trialView study →}. No modern controlled trial has tested a foxglove leaf preparation, and none will. The leaf’s total glycoside content is low and varies several-fold with season, plant part, developmental stage and provenance ^{12Reference 12Ravi et al. · 2020High-resolution tandem mass spectrometry dataset reveals fragmentation patterns of cardiac glycosides in leaves of the foxglove plantsView study →}, so a weighed quantity of dried leaf is not a reproducible dose. Before chemical assay was possible, pharmacies standardised digitalis leaf by biological assay — measuring the dose needed to arrest a frog’s or a pigeon’s heart, and calibrating batches against a reference ^{14Reference 14Norn et al. · 2004Norn, S., Kruse, P. R. (2004). [Cardiac glycosides: From ancient history through Withering’s foxglove to endogeneous cardiac glycosides]. Dan Medicinhist Arbog. https://pubmed.ncbi.nlm.nih.gov/15685783/View study →}. That a drug required a live animal to establish its strength is the clearest statement of the problem, and once the glycosides could be purified and measured directly the crude preparations were displaced entirely.

The plant-side literature that exists is toxicological. Foxglove poisoning follows misidentification — the non-flowering first-year rosette is soft, downy and grey-green, and is taken for comfrey, borage or mullein; one published case is a spring “wild herb smoothie” ^{15Reference 15Kingma et al. · 2020Case reportKingma, J. S., Frenay, I. M., Meinders, A. J., et al. (2020). [A poisonous spring smoothie with wild herbs: accidental intoxication with foxglove (Digitalis purpurea)] — case report. Ned Tijdschr Geneeskd. https://pubmed.ncbi.nlm.nih.gov/33331728/View study →}. Modern analytical work on foxglove leaf is about detecting the glycosides in poisonings and distinguishing the species, not about preparing a medicine ^{12,13Reference 12Ravi et al. · 2020High-resolution tandem mass spectrometry dataset reveals fragmentation patterns of cardiac glycosides in leaves of the foxglove plantsView study →Reference 13Kwon et al. · 2011HPLC method validation for Digitalis and its analogue by pulsed amperometric detectionView study →}.

Prevalence in Nature

Digitoxin is the principal cardenolide of Digitalis purpurea leaf, alongside gitoxin and the characteristic formyl derivative gitaloxin — the latter being the best chemical marker separating purpurea from lanata ^{12,13Reference 12Ravi et al. · 2020High-resolution tandem mass spectrometry dataset reveals fragmentation patterns of cardiac glycosides in leaves of the foxglove plantsView study →Reference 13Kwon et al. · 2011HPLC method validation for Digitalis and its analogue by pulsed amperometric detectionView study →}. It also occurs in Digitalis lanata and other Digitalis species, in which digoxin rather than digitoxin dominates. Cardenolides of the same class occur far beyond the genus — in Convallaria, Nerium, Strophanthus and Urginea, and as bufadienolides in toad skin — but digitoxin itself is a Digitalis molecule.

No content figure is quotable, and that is the finding rather than a gap in the data. Leaf total-glycoside content is low and swings several-fold with season, plant part, developmental stage and provenance ^{12Reference 12Ravi et al. · 2020High-resolution tandem mass spectrometry dataset reveals fragmentation patterns of cardiac glycosides in leaves of the foxglove plantsView study →}. High-resolution tandem mass spectrometry has characterised the fragmentation patterns that identify these glycosides in leaf material ^{12Reference 12Ravi et al. · 2020High-resolution tandem mass spectrometry dataset reveals fragmentation patterns of cardiac glycosides in leaves of the foxglove plantsView study →}, and validated HPLC methods exist for the isolated compounds ^{13Reference 13Kwon et al. · 2011HPLC method validation for Digitalis and its analogue by pulsed amperometric detectionView study →} — the analytical chemistry is not the limitation; the plant’s variability is.

Biosynthesis proceeds from a steroid precursor through the cardenolide pathway, with a 3β-hydroxysteroid dehydrogenase among the characterised enzymes converting pregnenolone-type intermediates on the route to digitoxin ^{16Reference 16Han et al. · 2024Han, Y., Xia, M., Zhang, Y. F., et al. (2024). [Cloning and functional analysis of 3β-hydroxysteroid dehydrogenase gene involved in biosynthesis of digitoxin]. Zhongguo Zhong Yao Za Zhi. https://pubmed.ncbi.nlm.nih.gov/38403313/View study →}. The pathway is not fully elucidated, and commercial supply has never depended on understanding it.

Discovery & Synthesis

Foxglove leaf entered orthodox medicine through William Withering’s Account of the Foxglove in 1785, a graded case series in 163 patients with dropsy that established the plant had to be titrated against the individual ^{14Reference 14Norn et al. · 2004Norn, S., Kruse, P. R. (2004). [Cardiac glycosides: From ancient history through Withering’s foxglove to endogeneous cardiac glycosides]. Dan Medicinhist Arbog. https://pubmed.ncbi.nlm.nih.gov/15685783/View study →}. The chemistry came a century later. Digitoxin was isolated from Digitalis purpurea in the 1860s–70s and obtained as a pure crystalline substance by the 1890s — the first of the Digitalis glycosides to be purified, decades before digoxin was isolated from D. lanata in 1930 ^{14Reference 14Norn et al. · 2004Norn, S., Kruse, P. R. (2004). [Cardiac glycosides: From ancient history through Withering’s foxglove to endogeneous cardiac glycosides]. Dan Medicinhist Arbog. https://pubmed.ncbi.nlm.nih.gov/15685783/View study →}.

Purification is what ended the plant’s medical career. Once the glycoside could be weighed and assayed, biological standardisation against animal hearts became unnecessary and crude leaf preparations became indefensible ^{14Reference 14Norn et al. · 2004Norn, S., Kruse, P. R. (2004). [Cardiac glycosides: From ancient history through Withering’s foxglove to endogeneous cardiac glycosides]. Dan Medicinhist Arbog. https://pubmed.ncbi.nlm.nih.gov/15685783/View study →}.

Manufacture today is still extraction. Digitoxin is obtained from Digitalis leaf rather than synthesised — the cardenolide skeleton with its three digitoxose sugars is a poor target for economical total synthesis, and the plant makes it well. Prescribing has declined sharply across Europe over the past three decades, while poison-centre exposure reports involving digitoxin have risen year on year, a divergence quantified for Germany between 1990 and 2023 ^{9Reference 9Ecker et al. · 2026Critical analysis of digitalis glycosides: declining use but increasing poison-center exposure cases for digitoxinView study →}.

Patents: not yet researched.

Toxicity & Safety

Digitoxin is flagged poisonous. This describes the purified drug, not only the plant: a therapeutic dose and a dangerous one are close together, and the long half-life means a mistake persists.

Safety at a Glance

☠️ PoisonousCardiac cautionOverdose riskDrug interactions

• Narrow therapeutic index. Therapy and toxicity are the same pump inhibition at slightly different exposures — there is no separate toxic mechanism to avoid ^{3Reference 3Fender et al. · 2024ReviewFender, J., Klöcker, J., Boivin-Jahns, V., et al. (2024). “Cardiac glycosides”-quo vaditis?-past, present, and future? — review. Naunyn Schmiedebergs Arch Pharmacol. https://pubmed.ncbi.nlm.nih.gov/39007928/View study →}.
• Cardiac toxidrome. Bradycardia, AV block, ventricular ectopy and bidirectional ventricular tachycardia; myocardial injury in severe cases ^{19Reference 19Tausendfreund et al. · 2026Case reportTausendfreund, O., Hoppe, J. M., Wörnle, M. (2026). [Dangerous Overdose: Myocardial Injury from Digitoxin Intoxication] — case report. Dtsch Med Wochenschr. https://pubmed.ncbi.nlm.nih.gov/42442727/View study →}.
• Hyperkalaemia in acute overdose — the poisoned pump cannot move potassium into cells, and serum potassium was the classic predictor of death before Fab fragments existed ^{3Reference 3Fender et al. · 2024ReviewFender, J., Klöcker, J., Boivin-Jahns, V., et al. (2024). “Cardiac glycosides”-quo vaditis?-past, present, and future? — review. Naunyn Schmiedebergs Arch Pharmacol. https://pubmed.ncbi.nlm.nih.gov/39007928/View study →}.
• A 4–7 day half-life means an overdose does not wash out. Stopping the drug takes days to matter ^{3Reference 3Fender et al. · 2024ReviewFender, J., Klöcker, J., Boivin-Jahns, V., et al. (2024). “Cardiac glycosides”-quo vaditis?-past, present, and future? — review. Naunyn Schmiedebergs Arch Pharmacol. https://pubmed.ncbi.nlm.nih.gov/39007928/View study →}.
• A real antidote exists. Digoxin-specific Fab fragments reverse life-threatening digitalis toxicity and cross-react well enough to treat digitoxin poisoning ^{10,11Reference 10Antman et al. · 1990Clinical trialTreatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragmentsView study →Reference 11Lignian et al. · 1984Case reportTreatment of severe digitoxin intoxication by digoxin-specific Fab antibody fragments — case reportView study →}.
• Xanthopsia — a yellow-green cast to vision with halos — is characteristic, easily dismissed, and often the first non-gastrointestinal sign ^{3Reference 3Fender et al. · 2024ReviewFender, J., Klöcker, J., Boivin-Jahns, V., et al. (2024). “Cardiac glycosides”-quo vaditis?-past, present, and future? — review. Naunyn Schmiedebergs Arch Pharmacol. https://pubmed.ncbi.nlm.nih.gov/39007928/View study →}.
• Interactions are transporter-mediated, not CYP450. Quinidine, verapamil, amiodarone, macrolides and ketoconazole raise levels; potassium-losing diuretics potentiate toxicity without changing the level at all ^{3,18Reference 3Fender et al. · 2024ReviewFender, J., Klöcker, J., Boivin-Jahns, V., et al. (2024). “Cardiac glycosides”-quo vaditis?-past, present, and future? — review. Naunyn Schmiedebergs Arch Pharmacol. https://pubmed.ncbi.nlm.nih.gov/39007928/View study →Reference 18Fenster et al. · 1980Digitoxin-quinidine interaction: pharmacokinetic evaluationView study →}.
• Poison-centre exposures are rising even as prescribing falls, with elderly patients over-represented ^{9Reference 9Ecker et al. · 2026Critical analysis of digitalis glycosides: declining use but increasing poison-center exposure cases for digitoxinView study →}.

Full Safety & Interactions Detail

The toxidrome and its sequence. Poisoning opens with nausea, vomiting and abdominal pain, progresses to visual disturbance — xanthopsia, halos, blurring — and confusion, and becomes dangerous in the cardiac and electrolyte findings: hyperkalaemia, profound bradycardia and heart block, ventricular arrhythmias including the characteristic bidirectional ventricular tachycardia. Troponin rise and documented myocardial injury occur in severe intoxication ^{19Reference 19Tausendfreund et al. · 2026Case reportTausendfreund, O., Hoppe, J. M., Wörnle, M. (2026). [Dangerous Overdose: Myocardial Injury from Digitoxin Intoxication] — case report. Dtsch Med Wochenschr. https://pubmed.ncbi.nlm.nih.gov/42442727/View study →}. Because the drug’s half-life is measured in days, clinical improvement after withdrawal alone is slow, and severity should be judged on the rhythm and the potassium rather than on how the patient looks at presentation ^{3,9Reference 3Fender et al. · 2024ReviewFender, J., Klöcker, J., Boivin-Jahns, V., et al. (2024). “Cardiac glycosides”-quo vaditis?-past, present, and future? — review. Naunyn Schmiedebergs Arch Pharmacol. https://pubmed.ncbi.nlm.nih.gov/39007928/View study →Reference 9Ecker et al. · 2026Critical analysis of digitalis glycosides: declining use but increasing poison-center exposure cases for digitoxinView study →}.

The antidote. Digoxin-specific antibody fragments bind circulating glycoside and reverse toxicity; the definitive multicentre series covered 150 cases of life-threatening digitalis intoxication ^{10Reference 10Antman et al. · 1990Clinical trialTreatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragmentsView study →}. Cross-reactivity across the cardenolides is sufficient that severe digitoxin poisoning has been treated with the same product, including in children ^{11Reference 11Lignian et al. · 1984Case reportTreatment of severe digitoxin intoxication by digoxin-specific Fab antibody fragments — case reportView study →}. Supportive care addresses the hyperkalaemia and the rhythm. (The long-taught warning that intravenous calcium causes a fatal “stone heart” in digitalis toxicity is widely repeated and contested in the modern literature — it is disputed rather than settled.)

Interactions run through transporters, not cytochromes. This is the commonest labelling error in the class. Quinidine raises digitoxin levels through a documented pharmacokinetic interaction ^{18Reference 18Fenster et al. · 1980Digitoxin-quinidine interaction: pharmacokinetic evaluationView study →}; verapamil, amiodarone, macrolide antibiotics and ketoconazole act similarly. Separately and more insidiously, potassium-depleting diuretics, laxatives and corticosteroids potentiate toxicity without changing the drug level at all — a normal serum concentration in a hypokalaemic patient is not reassurance. Hypomagnesaemia and hypercalcaemia act in the same direction.

Populations. Renal impairment is the one setting where digitoxin has an advantage over digoxin, since its elimination does not depend on the kidney ^{3,4Reference 3Fender et al. · 2024ReviewFender, J., Klöcker, J., Boivin-Jahns, V., et al. (2024). “Cardiac glycosides”-quo vaditis?-past, present, and future? — review. Naunyn Schmiedebergs Arch Pharmacol. https://pubmed.ncbi.nlm.nih.gov/39007928/View study →Reference 4Whayne TF Jr · 2018Systematic reviewClinical Use of Digitalis: A State of the Art Review — systematic reviewView study →}. Elderly patients are over-represented in poison-centre exposure reports, and the German 1990–2023 analysis found digitoxin exposures rising by 4.65% a year on a population-adjusted basis — 11.8% a year per million defined daily doses — while prescribing fell, which the authors read as a problem of patient selection and monitoring rather than of the drug itself ^{9Reference 9Ecker et al. · 2026Critical analysis of digitalis glycosides: declining use but increasing poison-center exposure cases for digitoxinView study →}.

Reproductive findings. A 2026 study reported that digitoxin induces apoptosis in ovarian granulosa cells, reducing granulosa-cell viability to about 15% and proliferation to 3% at 100 nM over 48 hours in porcine follicle culture, with disrupted follicular development and impaired reproductive performance in a mouse model ^{17Reference 17Jiang et al. · 2026Digitoxin-induced apoptosis in ovarian granulosa cells disrupts follicular development and impairs reproductive performanceView study →}. This is cell-culture and rodent work on the isolated molecule, not a human finding, and its relevance to therapeutic exposure is unestablished — but it is the only dedicated reproductive-toxicity dataset for this glycoside and it points one way. Pregnancy and lactation decisions belong to the prescribing context, not to a molecule page.

Dosage

Prescription-only. The figures below are the doses used in the trials, recorded for reference and not a recommendation.

Two features of the dosing are worth stating plainly. The therapeutic dose is seventy micrograms — a quantity no domestic measurement can approach. And with a four-to-seven-day half-life, steady state takes weeks, so the drug is not titrated by immediate response the way Withering titrated his leaf.

No plant-material equivalent can be given. Foxglove leaf glycoside content varies several-fold with season, part and provenance ^{12Reference 12Ravi et al. · 2020High-resolution tandem mass spectrometry dataset reveals fragmentation patterns of cardiac glycosides in leaves of the foxglove plantsView study →}, and a conversion figure on a molecule with this therapeutic index would be an invitation rather than an estimate.

References

1. Bavendiek, U., Großhennig, A., Schwab, J., et al. (2025). Digitoxin in Patients with Heart Failure and Reduced Ejection Fraction — randomised controlled trial. N Engl J Med. https://pubmed.ncbi.nlm.nih.gov/40879434/
2. Digitalis Investigation Group (1997). The effect of digoxin on mortality and morbidity in patients with heart failure — randomised controlled trial. N Engl J Med. https://pubmed.ncbi.nlm.nih.gov/9036306/
3. Fender, J., Klöcker, J., Boivin-Jahns, V., et al. (2024). “Cardiac glycosides”-quo vaditis?-past, present, and future? — review. Naunyn Schmiedebergs Arch Pharmacol. https://pubmed.ncbi.nlm.nih.gov/39007928/
4. Whayne TF Jr (2018). Clinical Use of Digitalis: A State of the Art Review — systematic review. Am J Cardiovasc Drugs. https://pubmed.ncbi.nlm.nih.gov/30066080/
5. Zeitlin, P. L., Diener-West, M., Callahan, K. A., et al. (2017). Digitoxin for Airway Inflammation in Cystic Fibrosis: Preliminary Assessment of Safety, Pharmacokinetics, and Dose Finding — randomised controlled trial. Ann Am Thorac Soc. https://pubmed.ncbi.nlm.nih.gov/28006108/
6. Mi, C., Cao, X., Ma, K., et al. (2022). Digitoxin promotes apoptosis and inhibits proliferation and migration by reducing HIF-1α and STAT3 in KRAS mutant human colon cancer cells. Chem Biol Interact. https://pubmed.ncbi.nlm.nih.gov/34717917/
7. Bejček, J., Spiwok, V., Kmoníčková, E., et al. (2021). Na(+)/K(+)-ATPase Revisited: On Its Mechanism of Action, Role in Cancer, and Activity Modulation — review. Molecules. https://pubmed.ncbi.nlm.nih.gov/33800655/
8. Škubník, J., Bejček, J., Pavlíčková, V. S., et al. (2021). Repurposing Cardiac Glycosides: Drugs for Heart Failure Surmounting Viruses — review. Molecules. https://pubmed.ncbi.nlm.nih.gov/34577097/
9. Ecker, P. A. M., Schaper, A., Bräunig, H. J., et al. (2026). Critical analysis of digitalis glycosides: declining use but increasing poison-center exposure cases for digitoxin. Eur J Clin Pharmacol. https://pubmed.ncbi.nlm.nih.gov/42334625/
10. Antman, E. M., Wenger, T. L., Butler VP Jr, et al. (1990). Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Final report of a multicenter study — clinical trial. Circulation. https://pubmed.ncbi.nlm.nih.gov/2188752/
11. Lignian, H., Vincent, J. L., Hallemans, R. (1984). Treatment of severe digitoxin intoxication by digoxin-specific Fab antibody fragments — case report. Acta Cardiol. https://pubmed.ncbi.nlm.nih.gov/6333127/
12. Ravi, B. G., Guardian, M. G. E., Dickman, R., et al. (2020). High-resolution tandem mass spectrometry dataset reveals fragmentation patterns of cardiac glycosides in leaves of the foxglove plants. Data Brief. https://pubmed.ncbi.nlm.nih.gov/32300626/
13. Kwon, H. J., Sim, H. J., Lee, S. I., et al. (2011). HPLC method validation for Digitalis and its analogue by pulsed amperometric detection. J Pharm Biomed Anal. https://pubmed.ncbi.nlm.nih.gov/20800985/
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