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Mappings

MONDO

MONDO:0800388 cardiac glycoside intoxication Not Yet Curated

MONDO:0800388 is the direct parent of MONDO:0017863 and covers non-digitalis cardenolides and the bufadienolides. The relation is recorded as broadMatch because that is the ontological relation between the two terms, not because the entry's content stops at digitalis - it does not: the environmental block and the channel-block node both cover oleander cardenolides and toad bufadienolides, so the content sits between the two terms. Per CLAUDE.md a broadMatch is a cross-reference and does not retire MONDO:0800388 from the curation queue, which is correct here, since a genuine cardiac-glycoside entry would still have work to do on the non-digitalis agents.

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Subtypes

3

Acute poisoning

A single large ingestion by someone not already taking the drug - usually deliberate self-poisoning, or a plant or animal cardenolide exposure. Gastrointestinal and cardiac features dominate. Potassium leaves cells faster than the kidney can redistribute it, so hyperkalemia and the potassium-based prognostic thresholds are features of this presentation rather than of digitalis toxicity in general, which is why the hyperkalemia phenotype and the serum potassium entries below are scoped to it.

Show evidence (1 reference)

PMID:38505194 SUPPORT DIRECT BACKGROUND Human Clinical

"In acute toxicity, gastrointestinal symptoms of nausea, anorexia and vomiting, and cardiac manifestations dominates, whereas malaise, weakness and visual disturbances predominate in chronic toxicity."

States the split in presenting features between the two presentations. BACKGROUND because the sentence is the case report's framing of established clinical teaching rather than an observation it made.

Chronic toxicity

Accumulation at an unchanged dose over days to months, when renal clearance falls or a P-glycoprotein inhibitor is added. Malaise, weakness and visual disturbance predominate over the gastrointestinal and cardiac features of the acute form, and the slower onset makes it the harder of the two to recognise.

Show evidence (2 references)

PMID:38505194 SUPPORT DIRECT BACKGROUND Human Clinical

"In acute toxicity, gastrointestinal symptoms of nausea, anorexia and vomiting, and cardiac manifestations dominates, whereas malaise, weakness and visual disturbances predominate in chronic toxicity."

The same sentence read from the other side; it is the source for both subtype descriptions and is graded identically in each.

PMID:39219774 SUPPORT DIRECT BACKGROUND Human Clinical

"Chronic toxicity is more difficult to diagnose given a more protracted duration of onset: in the span of days to months."

Gives the time course and the diagnostic difficulty that separate this subtype from the acute one.

Acute-on-chronic toxicity

An extra dose, or an abrupt fall in clearance, on top of an existing body burden from chronic therapy. It presents much like the acute form but on a loaded compartment, and the entry curates it because the two cached cases of refractory toxicity after Fab both sit here.

Show evidence (2 references)

PMID:39219774 SUPPORT DIRECT BACKGROUND Human Clinical

"Acute on chronic digoxin toxicity are similar; however, there are important differences in presentation."

Establishes the third presentation as a recognised category rather than a curator's subdivision, while denying that it is simply the acute form.

PMID:41399569 SUPPORT DIRECT Human Clinical

"We present a unique case of a 73-year-old woman with acute-on-chronic digoxin toxicity in the setting of acute renal failure who exhibited persistent toxicity symptoms despite Fab therapy."

A worked instance, and the case behind this entry's plasma exchange treatment.

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Mechanistic Hypotheses

3

Pump inhibition causes arrhythmia through sodium-driven calcium overload and delayed afterdepolarizations

nka_calcium_overload_dad CANONICAL

The standard account, and the one the entry's chain follows: inhibition of the sodium-potassium pump raises intracellular sodium, which deprives the sodium-calcium exchanger of its driving gradient, which loads the sarcoplasmic reticulum with calcium, which releases it spontaneously in diastole, which the exchanger converts into a depolarizing current. It is supported by the fact that the same chain at lower occupancy is the drug's therapeutic inotropic mechanism.

Pathograph links

Systemic Cardiac Glycoside Excess -> Sodium-Potassium ATPase Inhibition DIRECT The glycoside binds the extracellular face of the pump's alpha subunit at a site it shares with potassium, which is why hypokalemia deepens the block.

Sodium-Potassium ATPase Inhibition -> Intracellular Sodium Accumulation DIRECT

Intracellular Sodium Accumulation -> Reduced Sodium-Calcium Exchanger Calcium Extrusion DIRECT The exchanger runs on the inward sodium gradient; collapsing the gradient removes the energy source for calcium export.

Reduced Sodium-Calcium Exchanger Calcium Extrusion -> Sarcoplasmic Reticulum Calcium Overload DIRECT

Sarcoplasmic Reticulum Calcium Overload -> Spontaneous Diastolic Calcium Release DIRECT

Spontaneous Diastolic Calcium Release -> Delayed Afterdepolarization DIRECT The exchanger extrudes the released calcium electrogenically, three sodium in for one calcium out, which is a net inward current during phase 4.

Delayed Afterdepolarization -> Triggered Automaticity DIRECT

Cardiac glycosides are also directly proarrhythmic through channel block independent of pump inhibition

nka_independent_channel_block EMERGING

Bufadienolides and cardenolides inhibit the L-type calcium current and the rapid delayed rectifier potassium current directly. The experiment that shows this is properly controlled for the canonical account - cytosolic calcium was chelated and the pump was already blocked with ouabain, so neither the calcium-overload arm nor pump inhibition can explain the effect. It is graded EMERGING rather than ALTERNATIVE because it adds a mechanism rather than displacing one, and because the effect was strongest for bufadienolides, which are the toad-derived glycosides rather than the pharmaceutical ones.

Pathograph links

Systemic Cardiac Glycoside Excess -> Direct Cardiac Ion Channel Block DIRECT A second, pump-independent action on the L-type calcium and rapid delayed rectifier currents.

Direct Cardiac Ion Channel Block -> Triggered Automaticity INDIRECT UNKNOWN INTERMEDIATES A second route to ectopy that does not run through calcium loading. The two currents pull in opposite directions in the source experiment - calcium-current block shortened the action potential at low micromolar concentrations, while potassium-current block prolonged it at 100 micromolar - so this edge asserts only that the glycoside is proarrhythmic by a pump-independent route, not which of the two currents carries it, and not that the resulting triggered activity is the same delayed-afterdepolarization mechanism as the canonical chain.

The non-cardiac features arise from inhibition of the same pump outside the heart

extracardiac_pump_inhibition EMERGING

Digitalis poisoning is not only a cardiac syndrome: nausea and vomiting, confusion, and yellow-tinged vision with haloes are all part of it, and the yellow vision is among its oldest recorded signs. The natural explanation is inhibition of the same sodium pump in the gut, the area postrema and the retina, since the pump is ubiquitous. The entry carries these as a hypothesis rather than as chain steps because the site-of-action evidence in humans is thin - the deep-research report this entry was built from marks the step "inferred" in its own causal chain, and no cached source localises the lesion. The symptoms themselves are well documented; what is hypothetical is where the drug acts to produce them.

Pathograph links

Systemic Cardiac Glycoside Excess -> Retinal Sodium-Potassium ATPase Inhibition INDIRECT UNKNOWN INTERMEDIATES The proposed basis of the visual disturbance, by the same pump in a different tissue.

Systemic Cardiac Glycoside Excess -> Central and Gastrointestinal Pump Inhibition INDIRECT UNKNOWN INTERMEDIATES The proposed basis of the gastrointestinal and neurological features.

Retinal Sodium-Potassium ATPase Inhibition -> Disturbed color vision INDIRECT UNKNOWN INTERMEDIATES

Central and Gastrointestinal Pump Inhibition -> Nausea INDIRECT UNKNOWN INTERMEDIATES

Central and Gastrointestinal Pump Inhibition -> Vomiting INDIRECT UNKNOWN INTERMEDIATES

Central and Gastrointestinal Pump Inhibition -> Confusion INDIRECT UNKNOWN INTERMEDIATES

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Discussions and Knowledge Gaps

3

Is intravenous calcium actually dangerous in digitalis-induced hyperkalemia, or is the contraindication inherited from older literature that controlled experiment does not support?

KNOWLEDGE GAP calcium_in_digitalis_hyperkalemia

Attached to

pathophysiology#Sarcoplasmic Reticulum Calcium Overload treatments#Supportive Care and Electrolyte Management

The mechanistic argument for withholding calcium is exactly this entry's canonical chain: the cell is already calcium-overloaded, so adding calcium should make the arrhythmia worse - the "stone heart" concern. It is a textbook contraindication. The only controlled test in the cached literature is a twelve-animal porcine study that found no difference in time to death, and its own background section describes the contraindication as resting on older literature rather than on controlled data. Twelve pigs do not overturn a contraindication, and the study reports a pilot; but the asymmetry is worth recording, because the reasoning behind the dogma is a mechanistic inference from the same model this entry curates, and mechanistic inference is precisely what an outcome study is supposed to check.

Show evidence (3 references)

PMID:15461240 SUPPORT DIRECT BACKGROUND Model Organism

"The administration of intravenous (IV) calcium to treat hyperkalemia resulting from digoxin poisoning is considered potentially dangerous, based on a body of older literature which, in sum, reported increased cardiac glycoside toxicity with calcium administration"

States the contraindication and, in the same sentence, what it rests on. BACKGROUND because the sentence is this paper's framing of prior belief, not its own result - its result is the REFUTE item below.

PMID:39219774 SUPPORT Human Clinical

"Research on this subject is conflicting, so it is imperative to approach it cautiously."

An independent source characterising the evidence on this question as conflicting rather than settled, which is the state this discussion records.

PMID:15461240 REFUTE DIRECT Model Organism

"The administration of intravenous CaCl in the setting of hyperkalemia from acute digoxin toxicity did not affect mortality or time to death at the dose administered."

Scoped to the claim that calcium worsens outcome in this setting, and only to the dose and model tested - six animals per arm, in swine. It does not establish that calcium is safe in patients.

Does a serum potassium above 5.5 mEq/L in acute digitalis poisoning really carry the near-certain mortality the classic stratification reports?

KNOWLEDGE GAP potassium_threshold_as_absolute_rule

Attached to

phenotypes#Hyperkalemia

The 0% / 50% / 100% stratification by potassium band is quoted throughout the clinical literature and drives the decision to give antidote. It comes from a pre-antidote era and, on its face, asserts a 100% mortality that a single survivor falsifies. The case report that restates the rule is itself such a survivor, treated without Fab. That does not make the threshold useless - it remains the best-validated marker available and the right trigger for treatment - but the entry records the figure and its counterexample together rather than the figure alone.

Show evidence (1 reference)

PMID:22737544 REFUTE DIRECT Human Clinical

"We present a case of acute digoxin toxicity with high potassium level and good outcome despite unavailability of digoxin-specific Fab fragments."

Scoped narrowly to the "100% mortality above 5.5" claim, which a single survivor is sufficient to refute as an absolute. It does not refute the association between potassium and mortality, which the prognostic series supports and this entry records.

Why is every randomised antidote trial for this poisoning in yellow oleander rather than in digoxin, and does that evidence transfer?

KNOWLEDGE GAP no_randomised_evidence_for_digoxin_itself

Attached to

treatments#Digoxin-Specific Antibody Fragments treatments#Multiple-Dose Activated Charcoal

Both randomised results this entry cites - charcoal on mortality, Fab on dysrhythmia - come from yellow oleander self-poisoning in South Asia, where the case numbers are large enough to run a trial and the antidote is too expensive to be standard. For pharmaceutical digoxin, where the antidote is standard of care, the evidence is observational. The systematic review states that no antidote studies in other cardenolides were identified at all. The transfer argument is mechanistic - the same pump, the same chain - which is the sort of argument the rest of this entry is built to make explicit rather than assume.

Show evidence (2 references)

PMID:17054261 SUPPORT DIRECT Human Clinical

"Studies assessing the effect of antidotes on other cardenolides were not identified."

The gap stated by the systematic review itself: the randomised evidence base covers yellow oleander and nothing else in this class.

PMID:17054261 REFUTE DIRECT Human Clinical

"Given pharmacokinetic differences between individual cardenolides, the effect of antidotes administered to patients with yellow oleander poisoning cannot be readily translated to those of other cardenolides."

Scoped to the transfer argument this discussion raises. The review the entry cites for the yellow-oleander trials says in so many words that their results do not readily translate to other cardenolides, which is the opposite of the mechanistic transfer argument, and is recorded here rather than left out.

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Pathophysiology

15

Systemic Cardiac Glycoside Excess

Tissue concentrations of digoxin or another cardiac glycoside above what the myocardium tolerates. Reached three ways that behave differently: a single large ingestion in someone not already taking the drug, an extra dose on top of chronic therapy, and slow accumulation at an unchanged dose when renal clearance falls or a P-glycoprotein inhibitor is added. The distinction matters clinically, and the mechanism predicts why: a sudden large inhibition redistributes potassium faster than the kidney can compensate, which is the usual explanation for hyperkalemia being described as an acute-pattern finding.

Cardiac glycosides are also directly proarrhythmic through channel block independent of pump inhibition Pump inhibition causes arrhythmia through sodium-driven calcium overload and delayed afterdepolarizations The non-cardiac features arise from inhibition of the same pump outside the heart

Downstream

Sodium-Potassium ATPase Inhibition The glycoside binds the extracellular face of the pump's alpha subunit at a site it shares with potassium, which is why hypokalemia deepens the block.

Direct Cardiac Ion Channel Block A second, pump-independent action on the L-type calcium and rapid delayed rectifier currents.

Increased Vagal Tone A separate action of the drug from its effect on the myocyte, and the limb responsible for slowing rather than for ectopy.

Retinal Sodium-Potassium ATPase Inhibition The proposed basis of the visual disturbance, by the same pump in a different tissue.

Central and Gastrointestinal Pump Inhibition The proposed basis of the gastrointestinal and neurological features.

Show evidence (2 references)

PMID:322907 SUPPORT DIRECT Human Clinical

"The main route of elimination is renal excretion of digoxin, which is closely correlated with the glomerular filtration rate."

Establishes renal clearance as the dominant elimination route, which is why declining glomerular filtration is the commonest route to chronic accumulation.

PMID:322907 SUPPORT DIRECT Human Clinical

"High concentrations are found in the heart and kidneys, but the skeletal muscles form the largest digoxin storage."

The tissue distribution that makes extracorporeal removal futile: almost none of the body burden is in the blood at any moment.

Sodium-Potassium ATPase Inhibition

Blockade of the sarcolemmal sodium pump. This is simultaneously the therapeutic mechanism and the toxic one - what changes with dose is the fraction of pumps occupied, not the kind of effect - which is the structural reason digitalis has no margin between efficacy and harm.

Pump inhibition causes arrhythmia through sodium-driven calcium overload and delayed afterdepolarizations

cardiac muscle cell CL:0000746

ATP1A1 hgnc:799

P-type sodium:potassium-exchanging transporter activity GO:0005391 ↓ DECREASED

Animal models

Guinea pig lethal digoxin infusion with monoclonal Fab rescue Guinea pig rescues Antibody fragments reverse otherwise lethal toxicity, which is the in vivo demonstration that sequestering the glycoside releases the lesion.

Downstream

Intracellular Sodium Accumulation

Extracellular Potassium Shift Potassium the pump would have returned to the cell stays outside, in every tissue rather than only the heart.

Show evidence (1 reference)

PMID:34159036 SUPPORT DIRECT BACKGROUND Human Clinical

"Digoxin's primary mechanism of action is to inhibit the sodium-potassium ATPase pump in the heart's myocardium."

Names the molecular lesion. Graded BACKGROUND because the sentence is in the introduction of a case report, restating established pharmacology rather than reporting this paper's own finding.

Intracellular Sodium Accumulation

Rising cytosolic sodium in the cardiomyocyte, the immediate consequence of a pump that is no longer extruding it.

Pump inhibition causes arrhythmia through sodium-driven calcium overload and delayed afterdepolarizations

cardiac muscle cell CL:0000746

Downstream

Reduced Sodium-Calcium Exchanger Calcium Extrusion The exchanger runs on the inward sodium gradient; collapsing the gradient removes the energy source for calcium export.

Show evidence (1 reference)

PMID:28550304 SUPPORT DIRECT BACKGROUND In Vitro

"In cardiac myocytes, NKA inhibition causes an accumulation of cytosolic Na+ which in turn activates the reverse-mode of Na+/Ca2+-exchanger."

States the pump-to-sodium-to-exchanger step in one sentence. Graded BACKGROUND because it is this paper's framing of established mechanism, not its own result - its own result is the pump-independent one cited elsewhere in this entry.

Reduced Sodium-Calcium Exchanger Calcium Extrusion

Loss of calcium export through NCX1, the exchanger that normally trades three sodium ions inward for one calcium ion outward. Nothing is wrong with the exchanger; its driving gradient has been spent.

Pump inhibition causes arrhythmia through sodium-driven calcium overload and delayed afterdepolarizations

SLC8A1 hgnc:11068

calcium:sodium antiporter activity involved in regulation of cardiac muscle cell membrane potential GO:0086038 ↓ DECREASED

Downstream

Sarcoplasmic Reticulum Calcium Overload

Calcium accumulating in the cytosol and, through SERCA, in the sarcoplasmic reticulum. At therapeutic occupancy this is the positive inotropic effect; past a threshold the store holds more than it can retain.

Pump inhibition causes arrhythmia through sodium-driven calcium overload and delayed afterdepolarizations

cardiac muscle cell CL:0000746

ATP2A2 hgnc:812

Downstream

Spontaneous Diastolic Calcium Release

Show evidence (1 reference)

PMID:34159036 SUPPORT DIRECT BACKGROUND Human Clinical

"Inhibition of this pump causes increased intracellular calcium, resulting in increased myocardial contractility and cardiac output while augmenting cardiac vagal tone"

Links pump inhibition to the calcium rise, and in the same sentence to the vagal limb, which is why it is cited on both nodes. BACKGROUND for the same reason as the pump node.

Spontaneous Diastolic Calcium Release

Unscheduled release of stored calcium through the ryanodine receptor after repolarization is complete - calcium arriving when the cell should be electrically quiet.

Pump inhibition causes arrhythmia through sodium-driven calcium overload and delayed afterdepolarizations

RYR2 hgnc:10484

release of sequestered calcium ion into cytosol by sarcoplasmic reticulum GO:0014808 ↑ INCREASED

Downstream

Delayed Afterdepolarization The exchanger extrudes the released calcium electrogenically, three sodium in for one calcium out, which is a net inward current during phase 4.

Delayed Afterdepolarization

A depolarizing hump after repolarization. Below threshold it is invisible; above it, the cell fires a beat nobody asked for.

Pump inhibition causes arrhythmia through sodium-driven calcium overload and delayed afterdepolarizations

Purkinje myocyte CL:0002068

cardiac muscle cell action potential GO:0086001 ↕ DYSREGULATED

Animal models

Canine Purkinje fibre strophanthidin preparation Dog recapitulates The oscillations and the spontaneous activity that follows them are directly recorded, which is the node itself rather than a proxy for it.

Downstream

Triggered Automaticity

Show evidence (1 reference)

PMID:1257581 SUPPORT DIRECT Model Organism

"In quiescent fibers, strophanthidin caused the membrane potential to depolarize and to develop oscillations of progressively larger magnitude which were followed by spontaneous activity."

The classical microelectrode experiment behind this node: a cardiac glycoside produces growing diastolic oscillations that end in spontaneous firing, in canine Purkinje fibres. The glycoside here is strophanthidin, not digoxin.

Triggered Automaticity

Ectopic beats arising from afterdepolarizations rather than from the sinus node. Named without a chamber because the foci are not confined to the ventricle: the same mechanism in the atrioventricular junction produces the accelerated junctional rhythm this entry also records, and the bound cell type CL:0002068 Purkinje myocyte spans the conduction system. When two foci with alternating exit pathways through the fascicles take turns, the result is bidirectional ventricular tachycardia. That pattern is a recognised presentation of this poisoning but is not specific to it; the phenotype entry of the same name records the differential and cites it.

Purkinje myocyte CL:0002068

Downstream

Bidirectional ventricular tachycardia

Premature ventricular contraction

Junctional ectopic tachycardia

Supraventricular tachycardia with atrioventricular block The atrial ectopy half of the pattern.

Hemodynamic Collapse

Show evidence (1 reference)

PMID:1257581 SUPPORT DIRECT Model Organism

"In quiescent fibers, strophanthidin caused the membrane potential to depolarize and to develop oscillations of progressively larger magnitude which were followed by spontaneous activity."

The classical microelectrode experiment behind this node: a cardiac glycoside produces growing diastolic oscillations that end in spontaneous firing, in canine Purkinje fibres. The glycoside here is strophanthidin, not digoxin.

Increased Vagal Tone

Enhanced parasympathetic outflow to the sinus and atrioventricular nodes, a separate action of the drug from its effect on the myocyte, and the half of the toxidrome responsible for slowing rather than for ectopy.

Downstream

Atrioventricular Conduction Block

Bradycardia

Atrioventricular Conduction Block

Slowed conduction and lengthened refractoriness at the atrioventricular node. Combined with the ectopy above this produces the entry's defining pattern: a heart firing too much in one place and conducting too little in another.

Purkinje myocyte of atrioventricular node CL:1000479

AV node cell action potential GO:0086016 ↕ DYSREGULATED

Downstream

Atrioventricular block

Supraventricular tachycardia with atrioventricular block The block half of the pattern; the atrial ectopy half comes from triggered automaticity, which is why this phenotype depends on both limbs at once.

Hemodynamic Collapse

Extracellular Potassium Shift

Potassium moving out of cells body-wide because the pump that returns it is inhibited. This is a systemic readout of how thoroughly the pump has been blocked, and it carries prognostic information: the cited series found death risk rising with serum potassium and more steeply with hyperkalemia that persisted. It is described as a feature of acute poisoning rather than of slow accumulation, where renal handling has time to compensate, though no cached source in this entry states that contrast directly.

potassium ion homeostasis GO:0055075 ↕ DYSREGULATED

Downstream

Hyperkalemia

Show evidence (1 reference)

PMID:7267327 SUPPORT DIRECT Human Clinical

"It increased with age, with digitoxin and potassium serum levels and even more with persistent hyperkalemia."

From a 179-patient series of digitoxin poisoning: death risk rose with serum potassium, and more steeply with hyperkalemia that persisted. Note the agent here is digitoxin rather than digoxin.

Direct Cardiac Ion Channel Block

Inhibition of the L-type calcium current and of the rapid delayed rectifier potassium current by the glycoside itself, demonstrated with cytosolic calcium chelated and the sodium pump already blocked - so neither the calcium-overload chain nor pump inhibition accounts for it. The agent caveat is large enough to state plainly: the effect was measured mostly in bufadienolides, which are toad-derived, and the two cardenolides tested - ouabain and pecilocerin A, the class digoxin belongs to - showed around 10 to 15 per cent inhibition with IC50s above 100 micromolar, which is to say essentially none at attainable concentrations. Digoxin itself was not tested. The node is retained because the mechanism is real and this entry covers bufadienolide sources, but it should not be read as operating in ordinary digoxin poisoning.

Cardiac glycosides are also directly proarrhythmic through channel block independent of pump inhibition

voltage-gated calcium channel activity GO:0005245 ↓ DECREASED delayed rectifier potassium channel activity GO:0005251 ↓ DECREASED

Downstream

Triggered Automaticity A second route to ectopy that does not run through calcium loading. The two currents pull in opposite directions in the source experiment - calcium-current block shortened the action potential at low micromolar concentrations, while potassium-current block prolonged it at 100 micromolar - so this edge asserts only that the glycoside is proarrhythmic by a pump-independent route, not which of the two currents carries it, and not that the resulting triggered activity is the same delayed-afterdepolarization mechanism as the canonical chain.

Show evidence (3 references)

PMID:28550304 SUPPORT DIRECT In Vitro

"BF and CBG demonstrated a concentration-dependent (0.1 to100 µM) I Ca,L inhibition (maximal ≥50%) without and with the NKA activity blocked by 10 µM Oua"

The controlled result that makes this node separable from the canonical chain: the calcium-current inhibition is present both with and without the pump already blocked by ouabain, so pump inhibition cannot be producing it. The paper's conclusion sentence states this more directly but quotes a bracketed ion notation that the reference validator strips as a citation marker, so the result sentence is quoted instead.

PMID:28550304 SUPPORT DIRECT In Vitro

"BF and CBG at 100 µM demonstrated a strong inhibition (≥40%) of the rapidly activating component of the delayed rectifier K+ current (I Kr)"

The measured potassium-current inhibition behind this node. Note the concentration is far above the therapeutic range, which is why the node is grouped under an EMERGING hypothesis rather than the canonical chain.

PMID:28550304 REFUTE DIRECT In Vitro

"which were more remarkable than that of Oua and PEA (with maximized inhibition ~15% and ~10%, and estimated IC50s of way above 100 µM)"

Scoped to the claim that this mechanism operates at the digitalis cardenolides. In the same experiment the two cardenolides tested inhibited the current by about 10 to 15 per cent with IC50s above 100 micromolar, so the pump-independent effect is essentially a bufadienolide finding. It does not refute the mechanism, which the bufadienolide arm establishes.

Retinal Sodium-Potassium ATPase Inhibition

Proposed inhibition of the same pump in retinal cells, offered as the explanation for the yellow-tinged vision and haloes. Retained as a node because the visual signs are real and old; marked as a hypothesis because the human retinal-level evidence is not there.

The non-cardiac features arise from inhibition of the same pump outside the heart

P-type sodium:potassium-exchanging transporter activity GO:0005391 ↓ DECREASED

Downstream

Disturbed color vision

Central and Gastrointestinal Pump Inhibition

Proposed inhibition of the sodium pump in the gastrointestinal tract and in the area postrema, offered as the explanation for the nausea, vomiting and confusion. Modelled as a node so that the non-cardiac features are not left unexplained in the graph, and grouped under the extracardiac hypothesis because the site of action is inferred rather than shown.

The non-cardiac features arise from inhibition of the same pump outside the heart

P-type sodium:potassium-exchanging transporter activity GO:0005391 ↓ DECREASED

Downstream

Nausea

Vomiting

Confusion

Show evidence (1 reference)

PMID:34159036 SUPPORT INDIRECT Human Clinical

"Digoxin toxicity can manifest as a broad spectrum of symptoms such as nausea, vomiting, visual problems, altered mental status, and cardiac arrhythmias"

Documents the non-cardiac features as part of the toxidrome. Graded INDIRECT because it establishes that the symptoms occur, not that pump inhibition at these sites produces them, which is the part this node leaves hypothetical.

Hemodynamic Collapse

Failure of cardiac output from the combined bradyarrhythmia, block and ventricular tachyarrhythmia. The proximate cause of death in fatal digitalis poisoning; the myocardium is not structurally injured.

Downstream

Cardiac arrest

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Pathograph

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Phenotypes

12

Cardiovascular 7

Bidirectional ventricular tachycardia HP:0034040

Show evidence (2 references)

PMID:34159036 SUPPORT DIRECT Human Clinical

"Bidirectional ventricular tachycardia is an unusual arrhythmia wherein every other beat has a different QRS axis as it travels alternately down different conduction pathways."

Defines the arrhythmia, in a case report of digoxin-induced bidirectional ventricular tachycardia.

PMID:34159036 SUPPORT DIRECT Human Clinical

"The arrhythmia can be a manifestation of myocarditis, myocardial infarct, Andersen-Tawil syndrome, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia, herbal aconite poisoning, and digoxin toxicity."

The differential. Cited because it constrains the claim: an earlier draft of this description called the finding close to diagnostic, and this sentence names six other causes.

Premature ventricular contraction HP:0006682

Junctional ectopic tachycardia HP:0011716

The binding is imperfect and the mismatch is recorded rather than smoothed over. HPO has no accelerated-junctional-rhythm term - searched HP for "Junctional", which returns only HP:0011716 - and HP:0011716's own definition describes the congenital and post-surgical entity with narrow QRS and AV dissociation, which is a faster and clinically different arrhythmia from the slow accelerated junctional rhythm of digitalis toxicity. It is bound as the nearest available term, with the intended finding in preferred_term.

Supraventricular tachycardia with atrioventricular block HP:0004755

Bound to HP:0004755 Supraventricular tachycardia because HPO has no term for atrial tachycardia with block. Searched HP for "Atrial tachycardia", which returns only HP:0011701 Multifocal atrial tachycardia and HP:0011699 Atrial reentry tachycardia, neither of which is this; the block component is carried separately by the Atrioventricular block phenotype and in preferred_term here.

Show evidence (1 reference)

PMID:22737544 SUPPORT BACKGROUND Human Clinical

"Arrhythmogenesis and atrio-ventricular conduction arrhythmias such as paroxysmal atrial tachycardia with A-V block are diagnostic for digoxin toxicity."

Names the pattern and calls it diagnostic. Graded BACKGROUND because the sentence is in the introduction of a case report, restating established clinical teaching rather than reporting this paper's own observation.

Atrioventricular block HP:0001678

Show evidence (1 reference)

PMID:7267327 SUPPORT DIRECT Human Clinical

"the death risk was higher in males and in patients with A-V block"

Records atrioventricular block in the poisoning and establishes it as an adverse prognostic feature in a 179-patient series.

Bradycardia HP:0001662

Cardiac arrest HP:0001695

Digestive 2

Vomiting HP:0002013

Show evidence (1 reference)

PMID:7267327 SUPPORT Human Clinical

"previous heart disease and vomiting, were also significant in patients without heart block"

Records vomiting in the poisoning, and as a prognostic factor in the subgroup without heart block.

Nausea HP:0002018

Eye 1

Disturbed color vision Color vision defect HP:0000551

Bound to HP:0000551 Color vision defect, whose definition is "An anomaly in the ability to discriminate between or recognize colors" and whose synonyms include "Disturbed color vision". HP:0007641 Dyschromatopsia was rejected on positive grounds despite looking like the more specific term: its OLS definition is "A form of colorblindness in which only two of the three fundamental colors can be distinguished due to a lack of one of the retinal cone pigments", which describes congenital dichromacy, not an acquired drug effect. HPO has no xanthopsia term; the specific colour is carried in preferred_term.

Metabolism 1

Hyperkalemia HP:0002153

Show evidence (1 reference)

PMID:22737544 SUPPORT REVIEW SYNTHESIS Human Clinical

"mortality after digoxin toxicity have been reported to be zero in patients with acute digoxin toxicity and potassium levels less than 5.0 meq/dl, 50% in potassium levels between 5.0 and 5.5, and 100 percent in those with potassium levels above 5.5 meq/dl"

The classic stratification, quoted here from the case report that restates it rather than from the original series. Graded REVIEW_SYNTHESIS for that reason. The same paper is cited as a REFUTE against the 100% figure in the prognosis discussion, because its own patient survived above that threshold.

Nervous System 1

Confusion HP:0001289

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Genetic Associations

1

ABCB1

Gene: ABCB1 hgnc:40 relationship_type: MODIFIER

Show evidence (2 references)

PMID:21311904 SUPPORT INDIRECT Human Clinical

"Mutant genotype frequencies showed a positive relationship with post-mortem digoxin concentration for all SNPs."

Associates ABCB1 genotype with post-mortem digoxin concentration in 112 deceased subjects. Graded INDIRECT because a post-mortem concentration association is several steps from a clinical susceptibility claim, and the design cannot separate exposure from disposition.

PMID:12492608 REFUTE DIRECT Human Clinical

"AUC(0,4 h), Cmax and tmax, used as indices of digoxin absorption, were not significantly different in any of the genotype groups tested."

Scoped to the claim that ABCB1 genotype alters digoxin exposure. A negative pharmacokinetic result in fifty healthy volunteers, and the counterweight to the post-mortem association above; the two are not in direct conflict, since one measures single-dose absorption and the other a post-mortem concentration, but recording only the positive one would misstate the field. The paper's own title states the negative result, but a title is not quoted here as a finding - this is the result sentence from the abstract.

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Medical Actions

6

Digoxin-Specific Antibody Fragments

Action: Pharmacotherapy NCIT:C15986

Agent: ovine digoxin immune Fab NCIT:C80835

Platform: Other

Ovine Fab fragments that bind free glycoside and remove it from the pump. The only treatment here that acts on the lesion rather than on its consequences. It is one of two interventions in this entry with randomised evidence behind it, the other being multiple-dose activated charcoal; both trials were in yellow oleander poisoning rather than in digoxin.

Mechanism Target:

RESTORES Sodium-Potassium ATPase Inhibition — Binding free glycoside releases the pump, which is why the antidote reverses the dysrhythmias and the hyperkalemia together.

Show evidence (1 reference)

PMID:8492338 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"a strong toxicodynamic effect due to quick reversal of digitalis-induced dysrhythmias, hyperkalemia, and myocardial depression, by reactivation of membrane ATPases"

States the mechanism this edge asserts - reactivation of the pump - and names the three effects that reverse together, which is the signature of acting on the shared upstream lesion rather than on each downstream branch.

Show evidence (3 references)

PMID:17054261 SUPPORT DIRECT Human Clinical

"The second study found a beneficial effect of anti-digoxin Fab antitoxin on the presence of cardiac dysrhythmias at two hours post-administration; the RR was 0.60 (95% CI 0.44 to 0.81)."

The randomised evidence, from a systematic review. Note the endpoint is dysrhythmia at two hours, not mortality, and the trial was in yellow oleander poisoning.

PMID:1993775 SUPPORT DIRECT Human Clinical

"Fifty percent of patients were reported to have a complete response to treatment, 24% a partial response and 12% no response."

Response rates in 717 adults treated with the antidote in an observational surveillance study. Uncontrolled, and a complete response in half is a more measured picture than "antidote" suggests.

PMID:1993775 SUPPORT DIRECT Human Clinical

"Six patients (0.8%, 95% confidence interval 0.3% to 1.8%) had an allergic reaction to digoxin-specific antibody fragments."

The harm side of the same series: allergic reaction to an ovine product, with a confidence interval, which is what makes the rate usable.

Multiple-Dose Activated Charcoal

Action: multiple-dose activated charcoal Ontology label: Therapeutic Procedure NCIT:C49236

Agent: activated charcoal CHEBI:91090

Platform: Other

Repeated enteral charcoal, the only intervention in this entry with randomised evidence of a mortality benefit - again in yellow oleander poisoning rather than in digoxin.

Show evidence (1 reference)

PMID:17054261 SUPPORT DIRECT Human Clinical

"One trial investigated the effect of MDAC on mortality, the relative risk (RR) was 0.31 (95% confidence interval (CI) 0.12 to 0.83) indicating a beneficial effect."

A randomised mortality benefit, in yellow oleander poisoning. The confidence interval is wide and excludes 1 only just.

Atropine

Action: Pharmacotherapy NCIT:C15986

Agent: atropine CHEBI:16684

Platform: Small molecule

A temporising measure for bradyarrhythmia and block, directed at the vagal limb of the toxidrome rather than at the pump.

Mechanism Target:

INHIBITS Increased Vagal Tone — Muscarinic blockade opposes the vagal slowing of sinus rate and atrioventricular conduction. It does nothing about the ectopy.

Show evidence (1 reference)

PMID:8492338 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"First-line antiarrhythmic therapy is usually atropine, because of bradycardia-induced arrhythmia."

Places atropine as first-line and gives the indication - bradycardia-driven arrhythmia - which is the vagal limb this edge targets.

Therapeutic Plasma Exchange

Action: therapeutic plasma exchange Ontology label: Plasmapheresis NCIT:C15304

Platform: Other

Salvage for the specific case where the antidote is insufficient - a large tissue burden with renal failure, where Fab-glycoside complexes are cleared slowly and can dissociate. Not a treatment for ordinary poisoning, and conventional haemodialysis is ineffective for digoxin.

Show evidence (2 references)

PMID:41399569 SUPPORT DIRECT Human Clinical

"the delayed clearance of digoxin-Fab complexes can result in complex dissociation and rebound toxicity"

States the failure mode this salvage addresses. A single case report, which is the whole of the evidence for it.

PMID:41399569 SUPPORT DIRECT Human Clinical

"Conventional extracorporeal therapies such as hemodialysis are ineffective for removing digoxin or its antibody complexes due to their large molecular size and high volume of distribution"

Sources the statement that ordinary haemodialysis does not work here, and gives the reason - distribution volume and molecular size - rather than leaving it as an assertion.

Supportive Care and Electrolyte Management

Action: Supportive Care NCIT:C15747

Platform: Other

Correction of potassium and magnesium, rhythm monitoring, and avoidance of manoeuvres that make things worse - gastric lavage risks vagal stimulation in a patient already bradycardic, and cardioversion risks refractory ventricular fibrillation.

Temporary Cardiac Pacing

Action: temporary transvenous ventricular pacing Ontology label: Pacemaker Procedure NCIT:C99998

Platform: Device

Ventricular pacing for bradycardia and high-degree atrioventricular block when the antidote is unavailable or has not yet worked. The cited review recommends it and warns about it in the same breath, which is how it is recorded here: it addresses the conduction limb of the toxidrome without touching the pump inhibition that produces it, and it is technically awkward in a myocardium that is already irritable.

Mechanism Target:

BYPASSES Atrioventricular Conduction Block — Paces through the block rather than relieving it; the pump inhibition upstream is untouched.

Show evidence (1 reference)

PMID:8492338 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Ventricular pacing is a toxicodynamic treatment that may be helpful in both bradycardia-induced arrhythmia and high-degree atrioventricular block."

Names both indications, and classes pacing as toxicodynamic - acting on the consequence rather than on the toxin.

Show evidence (1 reference)

PMID:8492338 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Pacing is difficult to handle and can result in serious adverse effects."

The same review's warning, recorded beside the recommendation so the entry does not present pacing as a straightforward option.

🌍

Environmental Factors

1

Ingestion of a cardiac-glycoside-containing plant or animal product

Bound to the genus ECTO:0000537 exposure to toxin, after rejecting two nearer terms on positive grounds. Searched the pinned local build with `uv run runoak -i sqlite:obo:ecto search` for `l~glycoside`, `l~digital`, `l~cardenolide`, `l~oleander`, `l~digoxin`, `l~bufadienolide` and `l~ouabain` on 2026-09-19. `l~cardenolide`, `l~oleander`, `l~digoxin`, `l~bufadienolide` and `l~ouabain` return no ECTO exposure class. Two do exist and were rejected. ECTO:9000003 exposure to digitalin is a real digitalis-glycoside exposure class, but digitalin is one specific compound of Digitalis purpurea; this entry covers digoxin, digitoxin, oleandrin and bufadienolides, and almost no patient in it is exposed to digitalin, so the term would be precise and wrong. ECTO:9000436 exposure to glycoside is its parent and would cover the whole entry, but `RO:0002309` relates it to CHEBI:24400 glycoside, a chemical class whose other members include the aminoglycoside antibiotics; nothing about the toxicity follows from the glycosidic bond, so it names the wrong feature of the molecule. ECTO:0000524 exposure to mycotoxin is wrong on its face - these are plant and amphibian toxins, not fungal. ECTO:0000537 matches the pattern of Ciguatera_Fish_Poisoning and Acute_Ackee_Fruit_Intoxication, which bind it and carry the agent in preferred_term.

Foxglove, oleander, yellow oleander, lily-of-the-valley and toad-derived bufadienolide preparations all deliver cardiac glycosides and produce the same toxidrome by the same mechanism. In South Asia, yellow oleander seed ingestion is a major route of self-poisoning, and it is the setting in which the only randomised antidote trials for this class have been run.

Show evidence (1 reference)

PMID:17054261 SUPPORT BACKGROUND Human Clinical

"cardiotoxicity from other cardenolides such as the yellow oleander are also a major problem, with tens of thousands of cases of poisoning each year in South Asia"

Establishes the scale and geography of the non-pharmaceutical route. BACKGROUND rather than REVIEW_SYNTHESIS because the sentence sits in the review's background section, stating context rather than its own synthesis; the review's synthesis is quoted on the treatments, from its results.

Mechanism Target:

TRIGGERS Systemic Cardiac Glycoside Excess — Non-pharmaceutical glycoside sources reach the same systemic exposure node as a digoxin overdose.

Show evidence (1 reference)

PMID:17054261 SUPPORT BACKGROUND Human Clinical

"Because cardenolides from these plants are structurally similar, acute poisonings are managed using similar treatments."

States the structural and management equivalence that justifies routing plant exposures to the same mechanism node as pharmaceutical digoxin. BACKGROUND because it is the review's framing sentence. Note the same review elsewhere says antidote results do not readily translate between cardenolides, which this entry records as a REFUTE in the transfer discussion.

🔬

Biochemical Markers

1

Serum potassium (Increased)

Context: Prognostic stratification in acute poisoning, and the threshold on which the antidote decision is usually made.

Reference Ranges

– mEq/L (acute digitalis or cardiac glycoside poisoning, before antidote)

Below the antidote threshold (–5.0 mEq/L) Intermediate (5.0–5.5 mEq/L) → Hyperkalemia Above the antidote threshold (5.5– mEq/L) → Hyperkalemia

Below the antidote threshold: No deaths in the cited pre-Fab series. This is the band in which the potassium is not itself an indication for antidote.

Intermediate: Roughly 50% mortality without digoxin-specific Fab in the cited series.

Above the antidote threshold: 100% mortality in the cited pre-Fab series, but read this band together with the `potassium_threshold_as_absolute_rule` discussion, where the same publication reports its own patient surviving above the threshold without Fab. The band describes an untreated historical cohort, not a rule.

No normal interval is recorded here because no cached source in this entry states one; only the prognostic bands, which are what the cited sentence carries. `loinc_term` is likewise omitted, because LOINC has no adapter in `conf/oak_config.yaml` and no `cache/` membership file, so a LOINC code written here could not be validated by anything in the repository. The bands are recorded in mEq/L, the unit serum potassium is reported in; note that the quoted sentence prints "meq/dl", which is not a serum potassium unit, and the snippet preserves that as the source wrote it.

Show evidence (1 reference)

PMID:22737544 SUPPORT REVIEW SYNTHESIS Human Clinical

"mortality after digoxin toxicity have been reported to be zero in patients with acute digoxin toxicity and potassium levels less than 5.0 meq/dl, 50% in potassium levels between 5.0 and 5.5, and 100 percent in those with potassium levels above 5.5 meq/dl"

The source of all three bands. Graded exactly as the same sentence is graded on the Hyperkalemia phenotype, since evidence_source classifies the publication and cannot change because the quote moved.

Show evidence (1 reference)

PMID:8492338 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Previous assessment of outcome has shown that mortality increases in patients exhibiting five prognostic factors: 1) advanced age; 2) heart disease; 3) male sex; 4) high-degree atrioventricular block; 5) hyperkalemia."

Places potassium among five prognostic factors rather than above them, which is why the bands above are recorded as a stratification and not as a score.

🔬

Diagnosis

3

Serum potassium in acute poisoning

Not a diagnostic test for the poisoning but a prognostic measurement in it, and an indication for antidote. It is informative because it reports on the mechanism: potassium leaves cells in proportion to how much of the body's pump capacity has been switched off. The cited series ranks it alongside age, sex, atrioventricular block and prior heart disease rather than above them, and does not compare it with the serum drug level.

serum potassium measurement for risk stratification NCIT:C61030

Show evidence (1 reference)

PMID:7267327 SUPPORT DIRECT Human Clinical

"It increased with age, with digitoxin and potassium serum levels and even more with persistent hyperkalemia."

The prognostic association, in 179 patients. Persistent hyperkalemia carried more weight than the single value.

Serum digoxin concentration

Confirms exposure but is a poor guide to severity, and becomes uninterpretable once the antidote has been given because the assay cannot distinguish bound from free drug.

serum digoxin concentration measurement NCIT:C217390

NCIT has no digoxin measurement term. Searched the local build with `uv run runoak -i sqlite:obo:ncit search 'l~Digoxin'` and `'l~digoxin'` on 2026-09-19; the hits are digoxin the substance, digoxin immune Fab and the gene/transporter terms, with no measurement or assay among them, where the sibling potassium entry binds the specific NCIT:C61030 Serum Potassium Measurement. This was bound to the branch root NCIT:C18020 Diagnostic Procedure until review pointed out that NCIT:C217390 Diagnostic Blood Testing is strictly narrower and still correct for a serum assay; `ancestors -p i` confirms C217390 is a child of C18020 and reaches NCIT:C25218, the TreatmentActionTerm root.

Show evidence (1 reference)

PMID:37465455 SUPPORT REVIEW SYNTHESIS Human Clinical

"The current recommendations for monitoring digoxin, a narrow therapeutic index drug, are limited to confirming medication use or investigating suspicion of toxicity"

Describes what the level is actually used for, which is narrower than its reputation.

Electrocardiography and continuous cardiac monitoring

The front-line test, and the one that carries this entry's cardiac phenotypes: seven of them - atrioventricular block, bidirectional ventricular tachycardia, atrial tachycardia with block, junctional ectopic tachycardia, premature ventricular contractions, sinus bradycardia and ventricular fibrillation - are ECG diagnoses and had no diagnostic modality behind them until this entry was reviewed. It is not specific: no ECG pattern here is unique to digitalis, so the ECG localises and grades the rhythm disturbance while the history, the potassium and the drug level establish the cause.

12-lead electrocardiography and continuous cardiac monitoring NCIT:C217427

NCIT:C217427 was offered in review and verified before binding: it resolves in the local NCIT build with that exact label, and `ancestors -p i` puts it under NCIT:C18020 Diagnostic Procedure and NCIT:C25218 Clinical Intervention or Procedure, so it is inside the TreatmentActionTerm root that diagnosis_term requires.

Show evidence (2 references)

PMID:8492338 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The intensity of gastrointestinal and visual symptoms together with hyperkalemia and the characteristic ECG features make diagnosis of acute digitalis intoxication relatively easy."

Names the ECG as one of the three findings that make the diagnosis, and scopes that statement to acute intoxication, which is why the sentence also supports the Acute subtype above.

PMID:34159036 SUPPORT DIRECT Human Clinical

"An electrocardiogram (EKG) revealed a wide complex tachycardia with alternating QRS axis, suggestive of bidirectional ventricular tachycardia (BDVT)"

A worked instance of the modality making the rhythm diagnosis this entry curates as a phenotype.

📊

Prevalence

2

United States, National Poison Control Center data 2012-2020

Unknown Not yet documented

An absolute annual death count, not a rate - there is no denominator here, so no prevalence class can honestly be assigned. Recorded because it is the clearest available statement of the current burden in a country with comprehensive poison-centre reporting.

Show evidence (1 reference)

PMID:37465455 SUPPORT DIRECT Human Clinical

"Data from the United States National Poison Control Center (2012-2020) show annual deaths due to digoxin of 18-36"

The annual death count this record exists to capture.

Patients hospitalised after absorbing more than 2 mg of digitoxin

Unknown Not yet documented

Case fatality in a defined poisoned cohort, not a population rate. The agent is digitoxin rather than digoxin, and the series predates the antidote.

Show evidence (1 reference)

PMID:7267327 SUPPORT DIRECT Human Clinical

"The mortality rate in this series was 17%."

Case fatality in the 179-patient series.

🔬

Clinical Trials

1

ISRCTN71018309 COMPLETED

Fructose-1,6-diphosphate as a candidate antidote in yellow oleander poisoning - a double-blind randomised placebo-controlled trial in Sri Lanka, target 240 patients. Recorded as a registered trial rather than as a treatment: the only cached publication for it (PMID:20587052) is the study protocol, which reports no results, so there is nothing here that could support an efficacy claim. Recorded because review asked why FDP was absent from the treatments, and this is the honest answer - the intervention was tested, and this entry has no result to cite.

Show evidence (2 references)

ICTRP:ISRCTN71018309 SUPPORT Other

"Study design | Double-blind randomised placebo controlled trial (Treatment)"

WHO ICTRP registration record establishing the trial's design and identity. OTHER because a registration document is not study evidence.

ICTRP:ISRCTN71018309 SUPPORT Other

"Recruitment status | Completed"

The trial completed recruitment, which is why its absence from the treatment section is a missing result rather than a missing trial.

🐁

Animal Models

2

Canine Purkinje fibre strophanthidin preparation

Isolated canine Purkinje fibres exposed to strophanthidin under microelectrode recording, the classical preparation in which the diastolic oscillations that became known as delayed afterdepolarizations were characterised. It is an ex vivo tissue preparation from a dog rather than a whole-animal poisoning model.

Species

Dog

Publication

PMID:1257581

Pathograph links

Delayed Afterdepolarization recapitulates fidelity: high observes: cellular The oscillations and the spontaneous activity that follows them are directly recorded, which is the node itself rather than a proxy for it.

Limitations: The glycoside is strophanthidin, not digoxin, and the preparation is isolated tissue with no autonomic input, so it models the myocyte limb of this entry and says nothing about the vagal limb.

Show evidence (1 reference)

PMID:1257581 SUPPORT Model Organism

"Transmembrane potentials of quiescent, spontaneously active, or electrically driven fibers were recorded in the presence and absence of strophanthidin"

The recording method, which is what makes this a direct observation of the node.

Guinea pig lethal digoxin infusion with monoclonal Fab rescue

Whole-animal digoxin poisoning taken to an otherwise lethal endpoint and reversed with digoxin-specific antibody fragments - the model that established the antidote concept before it reached patients.

Species

Guinea pig

Publication

PMID:6707937

Pathograph links

Sodium-Potassium ATPase Inhibition rescues fidelity: moderate observes: organism Antibody fragments reverse otherwise lethal toxicity, which is the in vivo demonstration that sequestering the glycoside releases the lesion.

Limitations: The antibody here is monoclonal, whereas the clinical product is polyclonal ovine Fab, and guinea pig myocardial glycoside sensitivity is not identical to human.

Show evidence (1 reference)

PMID:6707937 SUPPORT Model Organism

"reversal of advanced, otherwise lethal digoxin toxicity in guinea pigs"

States the model and the rescue endpoint.

{ }

Source YAML

click to show

name: Digitalis Poisoning
creation_date: '2026-09-19T22:00:00Z'
description: >-
  Poisoning by digoxin or another cardiac glycoside. One molecular lesion accounts
  for nearly all of it: the drug binds the extracellular face of the
  sodium-potassium pump and stops it. That is also how the drug works at
  therapeutic dose, so unlike most poisonings there is no separate toxic mechanism
  to describe - only more of the intended one, in a drug whose therapeutic window
  is narrow enough that the two overlap.

  What follows is a chain of ion-gradient failures. Sodium accumulates inside the
  myocyte, which starves the sodium-calcium exchanger of the gradient it uses to
  pump calcium out, so calcium accumulates too. An overloaded sarcoplasmic
  reticulum releases calcium spontaneously after repolarization, the exchanger
  turns that release into an inward current, and the resulting afterdepolarization
  fires an unscheduled beat. Meanwhile the same drug raises vagal tone and slows
  conduction through the atrioventricular node. The combination - ectopic firing
  from below, block from above - is the classic description of the toxidrome as
  increased automaticity with decreased conduction, and it is why the
  electrocardiogram can show a fast rhythm and a blocked one at once.

  Two features set the clinical problem apart. Potassium leaks out of every cell
  whose pump is inhibited, so in acute poisoning the serum potassium is a readout
  of how comprehensively the pump has been shut down, and it carries prognostic
  information. And the poison is not confined to pharmacy shelves: foxglove, oleander, lily-of-the-valley and toad bufadienolides produce
  the same syndrome by the same mechanism.
categories:
- Toxic Exposure Disorder
- Treatment Toxicity
- Foodborne Toxin Exposure
category: Complex
parents:
- Poisoning
synonyms:
- digoxin toxicity
- digitalis intoxication
- cardiac glycoside poisoning
- digitalis glycoside overdose
disease_term:
  preferred_term: digitalis poisoning
  term:
    id: MONDO:0017863
    label: digitalis poisoning
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0800388
      label: cardiac glycoside intoxication
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO:0800388 is the direct parent of MONDO:0017863 and covers non-digitalis
      cardenolides and the bufadienolides. The relation is recorded as broadMatch
      because that is the ontological relation between the two terms, not because
      the entry's content stops at digitalis - it does not: the environmental block
      and the channel-block node both cover oleander cardenolides and toad
      bufadienolides, so the content sits between the two terms. Per CLAUDE.md a
      broadMatch is a cross-reference and does not retire MONDO:0800388 from the
      curation queue, which is correct here, since a genuine cardiac-glycoside
      entry would still have work to do on the non-digitalis agents.
notes: >-
  The clinical picture is the same whichever glycoside delivers it, so the entry
  is written around the shared mechanism and names digoxin where a source is
  specifically about digoxin. Plant and animal sources are modelled in the
  `environmental:` block rather than as separate entries.

  `just check-genereviews` reports GeneReviews NO_CHAPTER, correct for an acquired
  poisoning with no genetic cause. It also reports StatPearls CITED_UNTAGGED,
  naming PMID:29262029 'Digoxin Toxicity' and PMID:29083729 'Cardiac Glycoside and
  Digoxin Toxicity'. Both chapters exist and neither is cited as evidence: the
  checker matches them through this entry's `digoxin toxicity` synonym, which is
  correct, and counts them as cited because this paragraph names their PMIDs - the
  `references:` block has three entries and neither PMID is among them. StatPearls
  is never a phenotype baseline in this repository, so nothing is missing here.
  This paragraph read UNTAGGED_CHAPTER until review pointed out that the class had
  changed; re-running `just check-genereviews` on this file confirms
  CITED_UNTAGGED.

  Twenty-two further references are committed because the deep-research report
  cites them, and are not cited by this entry. They fall into four groups:
  pharmacogenomic studies of ABCB1 and SLCO1B3 beyond the two already cited here,
  one positive and one negative (PMID:17377214, PMID:26531821, PMID:28208135);
  veterinary and wildlife cardenolide toxicity, which is a different host
  (PMID:31349685, PMID:32722138, PMID:23108514, PMID:40660117); endogenous
  digoxin-like immunoreactive substances as an assay interference, a real gap in
  the `diagnosis:` section rather than a screened-out topic
  (DOI:10.7326/0003-4819-99-5-604, DOI:10.1111/j.1651-2227.1989.tb11093.x,
  DOI:10.1007/BF02343220); and epidemiological, pharmacokinetic and
  mechanism-adjacent material not used for a specific claim (the remainder,
  including DOI:10.1126/sciadv.ady9596 on NCX1 Na-dependent inactivation, which
  would strengthen the exchanger node and was left for a later pass).
  PMID:20587052 is a study protocol with no results, so it cannot support an
  efficacy claim and is not cited as evidence for one. Review asked why
  fructose-1,6-diphosphate was absent; the protocol carries the trial's
  registration number, so the trial is now recorded in `clinical_trials:` against
  ICTRP:ISRCTN71018309, and the absence of a treatment entry for it is explicit
  rather than silent. PMID:28904341 is a
  non-substantive erratum to PMID:28550304 and does not change the quotes taken
  from it.

  The autonomic branch is curated on its parasympathetic limb only. Review asked
  for the sympathetic limb - enhanced central sympathetic outflow and inhibition of
  norepinephrine reuptake, which the deep-research report lists as step 8b - and it
  is deliberately still absent. The two cached sentences that state it are both in
  veterinary oleander papers (PMID:32722138, PMID:31349685), a different host,
  which this entry screens out for exactly that reason, and model-organism evidence
  should not be the sole support for a human mechanism node. A PubMed search for a
  human source ('digoxin sympathetic nerve activity humans', 2026-09-19) returns
  heart-failure pharmacology in which digoxin is sympatho-inhibitory at therapeutic
  concentrations, which is the opposite direction to the toxic-dose claim, so
  binding one of those would assert the wrong sign. The limb stays out until a
  human or experimental source for sympathoexcitation at toxic concentrations is in
  the cache.

  `GO:0055075 potassium ion homeostasis` sits on the ORGANISM-scale Extracellular
  Potassium Shift node, which review flagged as borderline against the
  GO-is-molecular-or-cellular expectation. Left as it is, on a second look: GO's
  only alternative is `GO:0030007 intracellular potassium ion homeostasis`, which
  asserts the wrong compartment for a node about potassium leaving cells, so
  GO:0055075 is the most specific term that is also accurate.
has_subtypes:
- name: Acute
  display_name: Acute poisoning
  description: >-
    A single large ingestion by someone not already taking the drug - usually
    deliberate self-poisoning, or a plant or animal cardenolide exposure.
    Gastrointestinal and cardiac features dominate. Potassium leaves cells faster
    than the kidney can redistribute it, so hyperkalemia and the potassium-based
    prognostic thresholds are features of this presentation rather than of
    digitalis toxicity in general, which is why the hyperkalemia phenotype and the
    serum potassium entries below are scoped to it.
  evidence:
  - reference: PMID:38505194
    reference_title: "Digoxin and Symptomatic Bradyarrhythmia: the 'demon' or a 'red herring'."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "In acute toxicity, gastrointestinal symptoms of nausea, anorexia and vomiting, and cardiac manifestations dominates, whereas malaise, weakness and visual disturbances predominate in chronic toxicity."
    explanation: >-
      States the split in presenting features between the two presentations.
      BACKGROUND because the sentence is the case report's framing of established
      clinical teaching rather than an observation it made.
- name: Chronic
  display_name: Chronic toxicity
  description: >-
    Accumulation at an unchanged dose over days to months, when renal clearance
    falls or a P-glycoprotein inhibitor is added. Malaise, weakness and visual
    disturbance predominate over the gastrointestinal and cardiac features of the
    acute form, and the slower onset makes it the harder of the two to recognise.
  evidence:
  - reference: PMID:38505194
    reference_title: "Digoxin and Symptomatic Bradyarrhythmia: the 'demon' or a 'red herring'."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "In acute toxicity, gastrointestinal symptoms of nausea, anorexia and vomiting, and cardiac manifestations dominates, whereas malaise, weakness and visual disturbances predominate in chronic toxicity."
    explanation: >-
      The same sentence read from the other side; it is the source for both
      subtype descriptions and is graded identically in each.
  - reference: PMID:39219774
    reference_title: "Stone heart syndrome: A curious case of digoxin toxicity and calcium infusion."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Chronic toxicity is more difficult to diagnose given a more protracted duration of onset: in the span of days to months."
    explanation: >-
      Gives the time course and the diagnostic difficulty that separate this
      subtype from the acute one.
- name: Acute-on-chronic
  display_name: Acute-on-chronic toxicity
  description: >-
    An extra dose, or an abrupt fall in clearance, on top of an existing body
    burden from chronic therapy. It presents much like the acute form but on a
    loaded compartment, and the entry curates it because the two cached cases of
    refractory toxicity after Fab both sit here.
  evidence:
  - reference: PMID:39219774
    reference_title: "Stone heart syndrome: A curious case of digoxin toxicity and calcium infusion."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Acute on chronic digoxin toxicity are similar; however, there are important differences in presentation."
    explanation: >-
      Establishes the third presentation as a recognised category rather than a
      curator's subdivision, while denying that it is simply the acute form.
  - reference: PMID:41399569
    reference_title: "Digoxin Toxicity in Renal Failure: Resolution With Plasma Exchange After Fab Therapy Failure."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present a unique case of a 73-year-old woman with acute-on-chronic digoxin toxicity in the setting of acute renal failure who exhibited persistent toxicity symptoms despite Fab therapy."
    explanation: >-
      A worked instance, and the case behind this entry's plasma exchange
      treatment.
mechanistic_hypotheses:
- hypothesis_group_id: nka_calcium_overload_dad
  hypothesis_label: Pump inhibition causes arrhythmia through sodium-driven calcium overload and delayed afterdepolarizations
  status: CANONICAL
  description: >-
    The standard account, and the one the entry's chain follows: inhibition of the
    sodium-potassium pump raises intracellular sodium, which deprives the
    sodium-calcium exchanger of its driving gradient, which loads the
    sarcoplasmic reticulum with calcium, which releases it spontaneously in
    diastole, which the exchanger converts into a depolarizing current. It is
    supported by the fact that the same chain at lower occupancy is the drug's
    therapeutic inotropic mechanism.
- hypothesis_group_id: nka_independent_channel_block
  hypothesis_label: Cardiac glycosides are also directly proarrhythmic through channel block independent of pump inhibition
  status: EMERGING
  description: >-
    Bufadienolides and cardenolides inhibit the L-type calcium current and the
    rapid delayed rectifier potassium current directly. The experiment that shows
    this is properly controlled for the canonical account - cytosolic calcium was
    chelated and the pump was already blocked with ouabain, so neither the
    calcium-overload arm nor pump inhibition can explain the effect. It is graded
    EMERGING rather than ALTERNATIVE because it adds a mechanism rather than
    displacing one, and because the effect was strongest for bufadienolides, which
    are the toad-derived glycosides rather than the pharmaceutical ones.
- hypothesis_group_id: extracardiac_pump_inhibition
  hypothesis_label: The non-cardiac features arise from inhibition of the same pump outside the heart
  status: EMERGING
  description: >-
    Digitalis poisoning is not only a cardiac syndrome: nausea and vomiting,
    confusion, and yellow-tinged vision with haloes are all part of it, and the
    yellow vision is among its oldest recorded signs. The natural explanation is
    inhibition of the same sodium pump in the gut, the area postrema and the
    retina, since the pump is ubiquitous. The entry carries these as a hypothesis
    rather than as chain steps because the site-of-action evidence in humans is
    thin - the deep-research report this entry was built from marks the step
    "inferred" in its own causal chain, and no cached source localises the lesion.
    The symptoms themselves are well documented; what is hypothetical is where the
    drug acts to produce them.
pathophysiology:
- name: Systemic Cardiac Glycoside Excess
  role: trigger
  biological_scale: ORGANISM
  description: >-
    Tissue concentrations of digoxin or another cardiac glycoside above what the
    myocardium tolerates. Reached three ways that behave differently: a single
    large ingestion in someone not already taking the drug, an extra dose on top of
    chronic therapy, and slow accumulation at an unchanged dose when renal
    clearance falls or a P-glycoprotein inhibitor is added. The distinction matters
    clinically, and the mechanism predicts why: a sudden large inhibition
    redistributes potassium faster than the kidney can compensate, which is the
    usual explanation for hyperkalemia being described as an acute-pattern finding.
  chemical_entities:
  - preferred_term: digoxin
    term:
      id: CHEBI:4551
      label: digoxin
    modifier: INCREASED
  evidence:
  - reference: PMID:322907
    reference_title: Clinical pharmacokinetics of digoxin.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main route of elimination is renal excretion of digoxin, which is closely correlated with the glomerular filtration rate."
    explanation: >-
      Establishes renal clearance as the dominant elimination route, which is why
      declining glomerular filtration is the commonest route to chronic accumulation.
  - reference: PMID:322907
    reference_title: Clinical pharmacokinetics of digoxin.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "High concentrations are found in the heart and kidneys, but the skeletal muscles form the largest digoxin storage."
    explanation: >-
      The tissue distribution that makes extracorporeal removal futile: almost none
      of the body burden is in the blood at any moment.
  downstream:
  - target: Sodium-Potassium ATPase Inhibition
    causal_link_type: DIRECT
    hypothesis_groups:
    - nka_calcium_overload_dad
    description: >-
      The glycoside binds the extracellular face of the pump's alpha subunit at a
      site it shares with potassium, which is why hypokalemia deepens the block.
  - target: Direct Cardiac Ion Channel Block
    causal_link_type: DIRECT
    hypothesis_groups:
    - nka_independent_channel_block
    description: >-
      A second, pump-independent action on the L-type calcium and rapid delayed
      rectifier currents.
  - target: Increased Vagal Tone
    causal_link_type: DIRECT
    description: >-
      A separate action of the drug from its effect on the myocyte, and the limb
      responsible for slowing rather than for ectopy.
    evidence:
    - reference: PMID:34159036
      reference_title: 'A Visual Resolution of Cardiotoxicity: A Case Report of Digoxin-Induced Bidirectional Ventricular Tachycardia.'
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Inhibition of this pump causes increased intracellular calcium, resulting in increased myocardial contractility and cardiac output while augmenting cardiac vagal tone"
      explanation: >-
        Attributes the vagal augmentation to the drug, which is the edge this
        asserts. Without it the whole bradycardia and block limb hung off nothing.
  - target: Retinal Sodium-Potassium ATPase Inhibition
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - extracardiac_pump_inhibition
    description: >-
      The proposed basis of the visual disturbance, by the same pump in a different
      tissue.
  - target: Central and Gastrointestinal Pump Inhibition
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - extracardiac_pump_inhibition
    description: >-
      The proposed basis of the gastrointestinal and neurological features.
- name: Sodium-Potassium ATPase Inhibition
  biological_scale: MOLECULAR
  description: >-
    Blockade of the sarcolemmal sodium pump. This is simultaneously the
    therapeutic mechanism and the toxic one - what changes with dose is the
    fraction of pumps occupied, not the kind of effect - which is the structural
    reason digitalis has no margin between efficacy and harm.
  molecular_functions:
  - preferred_term: P-type sodium:potassium-exchanging transporter activity
    term:
      id: GO:0005391
      label: P-type sodium:potassium-exchanging transporter activity
    modifier: DECREASED
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  genes:
  - preferred_term: ATP1A1
    term:
      id: hgnc:799
      label: ATP1A1
  evidence:
  - reference: PMID:34159036
    reference_title: 'A Visual Resolution of Cardiotoxicity: A Case Report of Digoxin-Induced Bidirectional Ventricular Tachycardia.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Digoxin's primary mechanism of action is to inhibit the sodium-potassium ATPase pump in the heart's myocardium."
    explanation: >-
      Names the molecular lesion. Graded BACKGROUND because the sentence is in the
      introduction of a case report, restating established pharmacology rather than
      reporting this paper's own finding.
  downstream:
  - target: Intracellular Sodium Accumulation
    causal_link_type: DIRECT
    hypothesis_groups:
    - nka_calcium_overload_dad
  - target: Extracellular Potassium Shift
    causal_link_type: DIRECT
    description: >-
      Potassium the pump would have returned to the cell stays outside, in every
      tissue rather than only the heart.
- name: Intracellular Sodium Accumulation
  biological_scale: CELLULAR
  description: >-
    Rising cytosolic sodium in the cardiomyocyte, the immediate consequence of a
    pump that is no longer extruding it.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:28550304
    reference_title: Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "In cardiac myocytes, NKA inhibition causes an accumulation of cytosolic Na+ which in turn activates the reverse-mode of Na+/Ca2+-exchanger."
    explanation: >-
      States the pump-to-sodium-to-exchanger step in one sentence. Graded BACKGROUND
      because it is this paper's framing of established mechanism, not its own
      result - its own result is the pump-independent one cited elsewhere in this entry.
  downstream:
  - target: Reduced Sodium-Calcium Exchanger Calcium Extrusion
    causal_link_type: DIRECT
    hypothesis_groups:
    - nka_calcium_overload_dad
    description: >-
      The exchanger runs on the inward sodium gradient; collapsing the gradient
      removes the energy source for calcium export.
    evidence:
    - reference: PMID:28550304
      reference_title: Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "In cardiac myocytes, NKA inhibition causes an accumulation of cytosolic Na+ which in turn activates the reverse-mode of Na+/Ca2+-exchanger."
      explanation: Covers this edge specifically - rising cytosolic sodium acting on the exchanger.
- name: Reduced Sodium-Calcium Exchanger Calcium Extrusion
  biological_scale: CELLULAR
  description: >-
    Loss of calcium export through NCX1, the exchanger that normally trades three
    sodium ions inward for one calcium ion outward. Nothing is wrong with the
    exchanger; its driving gradient has been spent.
  molecular_functions:
  - preferred_term: calcium:sodium antiporter activity involved in regulation of cardiac muscle cell membrane potential
    term:
      id: GO:0086038
      label: calcium:sodium antiporter activity involved in regulation of cardiac muscle cell membrane potential
    modifier: DECREASED
  genes:
  - preferred_term: SLC8A1
    term:
      id: hgnc:11068
      label: SLC8A1
  downstream:
  - target: Sarcoplasmic Reticulum Calcium Overload
    causal_link_type: DIRECT
    hypothesis_groups:
    - nka_calcium_overload_dad
- name: Sarcoplasmic Reticulum Calcium Overload
  biological_scale: CELLULAR
  description: >-
    Calcium accumulating in the cytosol and, through SERCA, in the sarcoplasmic
    reticulum. At therapeutic occupancy this is the positive inotropic effect; past
    a threshold the store holds more than it can retain.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  genes:
  - preferred_term: ATP2A2
    term:
      id: hgnc:812
      label: ATP2A2
  evidence:
  - reference: PMID:34159036
    reference_title: 'A Visual Resolution of Cardiotoxicity: A Case Report of Digoxin-Induced Bidirectional Ventricular Tachycardia.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Inhibition of this pump causes increased intracellular calcium, resulting in increased myocardial contractility and cardiac output while augmenting cardiac vagal tone"
    explanation: >-
      Links pump inhibition to the calcium rise, and in the same sentence to the
      vagal limb, which is why it is cited on both nodes. BACKGROUND for the same
      reason as the pump node.
  downstream:
  - target: Spontaneous Diastolic Calcium Release
    causal_link_type: DIRECT
    hypothesis_groups:
    - nka_calcium_overload_dad
- name: Spontaneous Diastolic Calcium Release
  biological_scale: CELLULAR
  description: >-
    Unscheduled release of stored calcium through the ryanodine receptor after
    repolarization is complete - calcium arriving when the cell should be
    electrically quiet.
  biological_processes:
  - preferred_term: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    term:
      id: GO:0014808
      label: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    modifier: INCREASED
  genes:
  - preferred_term: RYR2
    term:
      id: hgnc:10484
      label: RYR2
  downstream:
  - target: Delayed Afterdepolarization
    causal_link_type: DIRECT
    hypothesis_groups:
    - nka_calcium_overload_dad
    description: >-
      The exchanger extrudes the released calcium electrogenically, three sodium in
      for one calcium out, which is a net inward current during phase 4.
- name: Delayed Afterdepolarization
  biological_scale: CELLULAR
  description: >-
    A depolarizing hump after repolarization. Below threshold it is invisible;
    above it, the cell fires a beat nobody asked for.
  cell_types:
  - preferred_term: Purkinje myocyte
    term:
      id: CL:0002068
      label: Purkinje myocyte
  biological_processes:
  - preferred_term: cardiac muscle cell action potential
    term:
      id: GO:0086001
      label: cardiac muscle cell action potential
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:1257581
    reference_title: On the mechanisms underlying digitalis toxicity in cardiac Purkinje fibers.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "In quiescent fibers, strophanthidin caused the membrane potential to depolarize and to develop oscillations of progressively larger magnitude which were followed by spontaneous activity."
    explanation: >-
      The classical microelectrode experiment behind this node: a cardiac glycoside
      produces growing diastolic oscillations that end in spontaneous firing, in
      canine Purkinje fibres. The glycoside here is strophanthidin, not digoxin.
  downstream:
  - target: Triggered Automaticity
    causal_link_type: DIRECT
    hypothesis_groups:
    - nka_calcium_overload_dad
- name: Triggered Automaticity
  biological_scale: TISSUE
  description: >-
    Ectopic beats arising from afterdepolarizations rather than from the sinus
    node. Named without a chamber because the foci are not confined to the
    ventricle: the same mechanism in the atrioventricular junction produces the
    accelerated junctional rhythm this entry also records, and the bound cell type
    CL:0002068 Purkinje myocyte spans the conduction system. When two foci with alternating exit pathways through the fascicles take
    turns, the result is bidirectional ventricular tachycardia. That pattern is a
    recognised presentation of this poisoning but is not specific to it; the
    phenotype entry of the same name records the differential and cites it.
  cell_types:
  - preferred_term: Purkinje myocyte
    term:
      id: CL:0002068
      label: Purkinje myocyte
  evidence:
  - reference: PMID:1257581
    reference_title: On the mechanisms underlying digitalis toxicity in cardiac Purkinje fibers.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "In quiescent fibers, strophanthidin caused the membrane potential to depolarize and to develop oscillations of progressively larger magnitude which were followed by spontaneous activity."
    explanation: >-
      The classical microelectrode experiment behind this node: a cardiac glycoside
      produces growing diastolic oscillations that end in spontaneous firing, in
      canine Purkinje fibres. The glycoside here is strophanthidin, not digoxin.
  downstream:
  - target: Bidirectional ventricular tachycardia
    causal_link_type: DIRECT
  - target: Premature ventricular contraction
    causal_link_type: DIRECT
  - target: Junctional ectopic tachycardia
    causal_link_type: DIRECT
  - target: Supraventricular tachycardia with atrioventricular block
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: The atrial ectopy half of the pattern.
  - target: Hemodynamic Collapse
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Increased Vagal Tone
  biological_scale: ORGANISM
  description: >-
    Enhanced parasympathetic outflow to the sinus and atrioventricular nodes, a
    separate action of the drug from its effect on the myocyte, and the half of the
    toxidrome responsible for slowing rather than for ectopy.
  downstream:
  - target: Atrioventricular Conduction Block
    causal_link_type: DIRECT
  - target: Bradycardia
    causal_link_type: DIRECT
- name: Atrioventricular Conduction Block
  biological_scale: TISSUE
  description: >-
    Slowed conduction and lengthened refractoriness at the atrioventricular node.
    Combined with the ectopy above this produces the entry's defining pattern: a
    heart firing too much in one place and conducting too little in another.
  cell_types:
  - preferred_term: Purkinje myocyte of atrioventricular node
    term:
      id: CL:1000479
      label: Purkinje myocyte of atrioventricular node
  biological_processes:
  - preferred_term: AV node cell action potential
    term:
      id: GO:0086016
      label: AV node cell action potential
    modifier: DYSREGULATED
  downstream:
  - target: Atrioventricular block
    causal_link_type: DIRECT
  - target: Supraventricular tachycardia with atrioventricular block
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The block half of the pattern; the atrial ectopy half comes from triggered
      automaticity, which is why this phenotype depends on both limbs at once.
  - target: Hemodynamic Collapse
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Extracellular Potassium Shift
  biological_scale: ORGANISM
  description: >-
    Potassium moving out of cells body-wide because the pump that returns it is
    inhibited. This is a systemic readout of how thoroughly the pump has been
    blocked, and it carries prognostic information: the cited series found death
    risk rising with serum potassium and more steeply with hyperkalemia that
    persisted. It is described as a feature of acute poisoning rather than of slow
    accumulation, where renal handling has time to compensate, though no cached
    source in this entry states that contrast directly.
  biological_processes:
  - preferred_term: potassium ion homeostasis
    term:
      id: GO:0055075
      label: potassium ion homeostasis
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:7267327
    reference_title: '[Prognostic factors in acute digitalis poisoning (author''s transl)].'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "It increased with age, with digitoxin and potassium serum levels and even more with persistent hyperkalemia."
    explanation: >-
      From a 179-patient series of digitoxin poisoning: death risk rose with serum
      potassium, and more steeply with hyperkalemia that persisted. Note the agent
      here is digitoxin rather than digoxin.
  downstream:
  - target: Hyperkalemia
    causal_link_type: DIRECT
- name: Direct Cardiac Ion Channel Block
  biological_scale: MOLECULAR
  description: >-
    Inhibition of the L-type calcium current and of the rapid delayed rectifier
    potassium current by the glycoside itself, demonstrated with cytosolic calcium
    chelated and the sodium pump already blocked - so neither the calcium-overload
    chain nor pump inhibition accounts for it.

    The agent caveat is large enough to state plainly: the effect was measured
    mostly in bufadienolides, which are toad-derived, and the two cardenolides
    tested - ouabain and pecilocerin A, the class digoxin belongs to - showed
    around 10 to 15 per cent inhibition with IC50s above 100 micromolar, which is
    to say essentially none at attainable concentrations. Digoxin itself was not
    tested. The node is retained because the mechanism is real and this entry
    covers bufadienolide sources, but it should not be read as operating in
    ordinary digoxin poisoning.
  molecular_functions:
  - preferred_term: voltage-gated calcium channel activity
    term:
      id: GO:0005245
      label: voltage-gated calcium channel activity
    modifier: DECREASED
  - preferred_term: delayed rectifier potassium channel activity
    term:
      id: GO:0005251
      label: delayed rectifier potassium channel activity
    modifier: DECREASED
  evidence:
  - reference: PMID:28550304
    reference_title: Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "BF and CBG demonstrated a concentration-dependent (0.1 to100 µM) I Ca,L inhibition (maximal ≥50%) without and with the NKA activity blocked by 10 µM Oua"
    explanation: >-
      The controlled result that makes this node separable from the canonical
      chain: the calcium-current inhibition is present both with and without the
      pump already blocked by ouabain, so pump inhibition cannot be producing it.
      The paper's conclusion sentence states this more directly but quotes a
      bracketed ion notation that the reference validator strips as a citation
      marker, so the result sentence is quoted instead.
  - reference: PMID:28550304
    reference_title: Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "BF and CBG at 100 µM demonstrated a strong inhibition (≥40%) of the rapidly activating component of the delayed rectifier K+ current (I Kr)"
    explanation: >-
      The measured potassium-current inhibition behind this node. Note the
      concentration is far above the therapeutic range, which is why the node is
      grouped under an EMERGING hypothesis rather than the canonical chain.
  - reference: PMID:28550304
    reference_title: Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides.
    supports: REFUTE
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "which were more remarkable than that of Oua and PEA (with maximized inhibition ~15% and ~10%, and estimated IC50s of way above 100 µM)"
    explanation: >-
      Scoped to the claim that this mechanism operates at the digitalis
      cardenolides. In the same experiment the two cardenolides tested inhibited
      the current by about 10 to 15 per cent with IC50s above 100 micromolar, so
      the pump-independent effect is essentially a bufadienolide finding. It does
      not refute the mechanism, which the bufadienolide arm establishes.
  downstream:
  - target: Triggered Automaticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - nka_independent_channel_block
    description: >-
      A second route to ectopy that does not run through calcium loading. The two
      currents pull in opposite directions in the source experiment - calcium-current
      block shortened the action potential at low micromolar concentrations, while
      potassium-current block prolonged it at 100 micromolar - so this edge asserts
      only that the glycoside is proarrhythmic by a pump-independent route, not which
      of the two currents carries it, and not that the resulting triggered activity
      is the same delayed-afterdepolarization mechanism as the canonical chain.
- name: Retinal Sodium-Potassium ATPase Inhibition
  biological_scale: CELLULAR
  description: >-
    Proposed inhibition of the same pump in retinal cells, offered as the
    explanation for the yellow-tinged vision and haloes. Retained as a node because
    the visual signs are real and old; marked as a hypothesis because the human
    retinal-level evidence is not there.
  molecular_functions:
  - preferred_term: P-type sodium:potassium-exchanging transporter activity
    term:
      id: GO:0005391
      label: P-type sodium:potassium-exchanging transporter activity
    modifier: DECREASED
  downstream:
  - target: Disturbed color vision
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - extracardiac_pump_inhibition
- name: Central and Gastrointestinal Pump Inhibition
  biological_scale: CELLULAR
  description: >-
    Proposed inhibition of the sodium pump in the gastrointestinal tract and in the
    area postrema, offered as the explanation for the nausea, vomiting and
    confusion. Modelled as a node so that the non-cardiac features are not left
    unexplained in the graph, and grouped under the extracardiac hypothesis because
    the site of action is inferred rather than shown.
  molecular_functions:
  - preferred_term: P-type sodium:potassium-exchanging transporter activity
    term:
      id: GO:0005391
      label: P-type sodium:potassium-exchanging transporter activity
    modifier: DECREASED
  evidence:
  - reference: PMID:34159036
    reference_title: 'A Visual Resolution of Cardiotoxicity: A Case Report of Digoxin-Induced Bidirectional Ventricular Tachycardia.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Digoxin toxicity can manifest as a broad spectrum of symptoms such as nausea, vomiting, visual problems, altered mental status, and cardiac arrhythmias"
    explanation: >-
      Documents the non-cardiac features as part of the toxidrome. Graded INDIRECT
      because it establishes that the symptoms occur, not that pump inhibition at
      these sites produces them, which is the part this node leaves hypothetical.
  downstream:
  - target: Nausea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - extracardiac_pump_inhibition
  - target: Vomiting
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - extracardiac_pump_inhibition
  - target: Confusion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - extracardiac_pump_inhibition
- name: Hemodynamic Collapse
  biological_scale: ORGANISM
  description: >-
    Failure of cardiac output from the combined bradyarrhythmia, block and
    ventricular tachyarrhythmia. The proximate cause of death in fatal digitalis
    poisoning; the myocardium is not structurally injured.
  downstream:
  - target: Cardiac arrest
    causal_link_type: DIRECT
phenotypes:
- category: Cardiovascular
  name: Bidirectional ventricular tachycardia
  description: >-
    Beat-to-beat alternation of QRS axis, produced by ectopic foci whose impulses
    travel alternately down different conduction pathways. It is an unusual
    arrhythmia and a recognised presentation of digoxin toxicity, but it is not
    specific to it: the same pattern occurs in myocarditis, myocardial infarction,
    Andersen-Tawil syndrome, arrhythmogenic right ventricular cardiomyopathy,
    catecholaminergic polymorphic ventricular tachycardia and aconite poisoning,
    the last of which this knowledge base curates as Aconitine_Poisoning.
  phenotype_term:
    preferred_term: Bidirectional ventricular tachycardia
    term:
      id: HP:0034040
      label: Bidirectional ventricular tachycardia
  evidence:
  - reference: PMID:34159036
    reference_title: 'A Visual Resolution of Cardiotoxicity: A Case Report of Digoxin-Induced Bidirectional Ventricular Tachycardia.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bidirectional ventricular tachycardia is an unusual arrhythmia wherein every other beat has a different QRS axis as it travels alternately down different conduction pathways."
    explanation: >-
      Defines the arrhythmia, in a case report of digoxin-induced bidirectional
      ventricular tachycardia.
  - reference: PMID:34159036
    reference_title: 'A Visual Resolution of Cardiotoxicity: A Case Report of Digoxin-Induced Bidirectional Ventricular Tachycardia.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The arrhythmia can be a manifestation of myocarditis, myocardial infarct, Andersen-Tawil syndrome, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia, herbal aconite poisoning, and digoxin toxicity."
    explanation: >-
      The differential. Cited because it constrains the claim: an earlier draft of
      this description called the finding close to diagnostic, and this sentence
      names six other causes.
- category: Cardiovascular
  name: Premature ventricular contraction
  phenotype_term:
    preferred_term: Premature ventricular contraction
    term:
      id: HP:0006682
      label: Premature ventricular contraction
- category: Cardiovascular
  name: Junctional ectopic tachycardia
  description: >-
    Accelerated junctional rhythm - an ectopic focus at the atrioventricular
    junction outpacing the sinus node.
  phenotype_term:
    preferred_term: accelerated junctional rhythm
    term:
      id: HP:0011716
      label: Junctional ectopic tachycardia
  notes: >-
    The binding is imperfect and the mismatch is recorded rather than smoothed
    over. HPO has no accelerated-junctional-rhythm term - searched HP for
    "Junctional", which returns only HP:0011716 - and HP:0011716's own definition
    describes the congenital and post-surgical entity with narrow QRS and AV
    dissociation, which is a faster and clinically different arrhythmia from the
    slow accelerated junctional rhythm of digitalis toxicity. It is bound as the
    nearest available term, with the intended finding in preferred_term.
- category: Cardiovascular
  name: Supraventricular tachycardia with atrioventricular block
  description: >-
    Paroxysmal atrial tachycardia with block - a fast atrial rate that the
    atrioventricular node does not conduct one-for-one. It is the combination that
    makes it characteristic: ectopy and block together are hard to produce by any
    other mechanism, which is why the classical literature calls it diagnostic.
  phenotype_term:
    preferred_term: paroxysmal atrial tachycardia with atrioventricular block
    term:
      id: HP:0004755
      label: Supraventricular tachycardia
  notes: >-
    Bound to HP:0004755 Supraventricular tachycardia because HPO has no term for
    atrial tachycardia with block. Searched HP for "Atrial tachycardia", which
    returns only HP:0011701 Multifocal atrial tachycardia and HP:0011699 Atrial
    reentry tachycardia, neither of which is this; the block component is carried
    separately by the Atrioventricular block phenotype and in preferred_term here.
  evidence:
  - reference: PMID:22737544
    reference_title: Good outcome after digoxin toxicity despite very high serum potassium level.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Arrhythmogenesis and atrio-ventricular conduction arrhythmias such as paroxysmal atrial tachycardia with A-V block are diagnostic for digoxin toxicity."
    explanation: >-
      Names the pattern and calls it diagnostic. Graded BACKGROUND because the
      sentence is in the introduction of a case report, restating established
      clinical teaching rather than reporting this paper's own observation.
- category: Cardiovascular
  name: Atrioventricular block
  phenotype_term:
    preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
  evidence:
  - reference: PMID:7267327
    reference_title: '[Prognostic factors in acute digitalis poisoning (author''s transl)].'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "the death risk was higher in males and in patients with A-V block"
    explanation: >-
      Records atrioventricular block in the poisoning and establishes it as an
      adverse prognostic feature in a 179-patient series.
- category: Cardiovascular
  name: Bradycardia
  phenotype_term:
    preferred_term: Bradycardia
    term:
      id: HP:0001662
      label: Bradycardia
- category: Cardiovascular
  name: Cardiac arrest
  phenotype_term:
    preferred_term: Cardiac arrest
    term:
      id: HP:0001695
      label: Cardiac arrest
- category: Metabolic
  name: Hyperkalemia
  subtype: Acute
  description: >-
    A feature of acute poisoning specifically, reflecting the scale of pump
    inhibition. Rising potassium is associated with death in the prognostic series
    cited below, and a raised potassium is used as an indication for antidote.
  phenotype_term:
    preferred_term: Hyperkalemia
    term:
      id: HP:0002153
      label: Hyperkalemia
  evidence:
  - reference: PMID:22737544
    reference_title: Good outcome after digoxin toxicity despite very high serum potassium level.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "mortality after digoxin toxicity have been reported to be zero in patients with acute digoxin toxicity and potassium levels less than 5.0 meq/dl, 50% in potassium levels between 5.0 and 5.5, and 100 percent in those with potassium levels above 5.5 meq/dl"
    explanation: >-
      The classic stratification, quoted here from the case report that restates it
      rather than from the original series. Graded REVIEW_SYNTHESIS for that
      reason. The same paper is cited as a REFUTE against the 100% figure in the
      prognosis discussion, because its own patient survived above that threshold.
- category: Gastrointestinal
  name: Vomiting
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:7267327
    reference_title: '[Prognostic factors in acute digitalis poisoning (author''s transl)].'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "previous heart disease and vomiting, were also significant in patients without heart block"
    explanation: >-
      Records vomiting in the poisoning, and as a prognostic factor in the subgroup
      without heart block.
- category: Gastrointestinal
  name: Nausea
  phenotype_term:
    preferred_term: Nausea
    term:
      id: HP:0002018
      label: Nausea
- category: Neurologic
  name: Confusion
  phenotype_term:
    preferred_term: Confusion
    term:
      id: HP:0001289
      label: Confusion
- category: Ophthalmologic
  name: Disturbed color vision
  description: >-
    Xanthopsia - objects appearing yellow-tinged - and haloes around lights. One of
    the oldest recorded signs of the toxicity and a feature of the chronic pattern
    in particular.
  phenotype_term:
    preferred_term: xanthopsia
    term:
      id: HP:0000551
      label: Color vision defect
  notes: >-
    Bound to HP:0000551 Color vision defect, whose definition is "An anomaly in the
    ability to discriminate between or recognize colors" and whose synonyms include
    "Disturbed color vision". HP:0007641 Dyschromatopsia was rejected on positive
    grounds despite looking like the more specific term: its OLS definition is "A
    form of colorblindness in which only two of the three fundamental colors can be
    distinguished due to a lack of one of the retinal cone pigments", which
    describes congenital dichromacy, not an acquired drug effect. HPO has no
    xanthopsia term; the specific colour is carried in preferred_term.
biochemical:
- name: Serum potassium
  subtype: Acute
  presence: Increased
  context: >-
    Prognostic stratification in acute poisoning, and the threshold on which the
    antidote decision is usually made.
  biomarker_term:
    preferred_term: Potassium
    term:
      id: NCIT:C765
      label: Potassium
  reference_ranges:
  - unit: mEq/L
    population: acute digitalis or cardiac glycoside poisoning, before antidote
    notes: >-
      No normal interval is recorded here because no cached source in this entry
      states one; only the prognostic bands, which are what the cited sentence
      carries. `loinc_term` is likewise omitted, because LOINC has no adapter in
      `conf/oak_config.yaml` and no `cache/` membership file, so a LOINC code
      written here could not be validated by anything in the repository. The bands
      are recorded in mEq/L, the unit serum potassium is reported in; note that the
      quoted sentence prints "meq/dl", which is not a serum potassium unit, and the
      snippet preserves that as the source wrote it.
    evidence:
    - reference: PMID:22737544
      reference_title: Good outcome after digoxin toxicity despite very high serum potassium level.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "mortality after digoxin toxicity have been reported to be zero in patients with acute digoxin toxicity and potassium levels less than 5.0 meq/dl, 50% in potassium levels between 5.0 and 5.5, and 100 percent in those with potassium levels above 5.5 meq/dl"
      explanation: >-
        The source of all three bands. Graded exactly as the same sentence is
        graded on the Hyperkalemia phenotype, since evidence_source classifies the
        publication and cannot change because the quote moved.
    interpretation_bands:
    - name: Below the antidote threshold
      upper_bound: 5.0
      unit: mEq/L
      abnormal_flag: NORMAL
      interpretation: >-
        No deaths in the cited pre-Fab series. This is the band in which the
        potassium is not itself an indication for antidote.
    - name: Intermediate
      lower_bound: 5.0
      upper_bound: 5.5
      unit: mEq/L
      abnormal_flag: HIGH
      severity: MODERATE
      phenotype_term:
        preferred_term: Hyperkalemia
        term:
          id: HP:0002153
          label: Hyperkalemia
      interpretation: >-
        Roughly 50% mortality without digoxin-specific Fab in the cited series.
    - name: Above the antidote threshold
      lower_bound: 5.5
      unit: mEq/L
      abnormal_flag: CRITICAL_HIGH
      severity: SEVERE
      phenotype_term:
        preferred_term: Hyperkalemia
        term:
          id: HP:0002153
          label: Hyperkalemia
      interpretation: >-
        100% mortality in the cited pre-Fab series, but read this band together
        with the `potassium_threshold_as_absolute_rule` discussion, where the same
        publication reports its own patient surviving above the threshold without
        Fab. The band describes an untreated historical cohort, not a rule.
  evidence:
  - reference: PMID:8492338
    reference_title: Clinical features and management of digitalis poisoning--rationale for immunotherapy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Previous assessment of outcome has shown that mortality increases in patients exhibiting five prognostic factors: 1) advanced age; 2) heart disease; 3) male sex; 4) high-degree atrioventricular block; 5) hyperkalemia."
    explanation: >-
      Places potassium among five prognostic factors rather than above them, which
      is why the bands above are recorded as a stratification and not as a score.
  notes: >-
    Added in review. The bands were already quoted on the Hyperkalemia phenotype;
    this block is what makes them queryable. Review attributed them to
    PMID:7267327, which does not carry them - that abstract reports a 17%
    overall mortality and a 2-74% range across four clinical factors, and never
    names a potassium threshold. The bands come from PMID:22737544, which this
    entry already cited for exactly this sentence.
environmental:
- name: Ingestion of a cardiac-glycoside-containing plant or animal product
  description: >-
    Foxglove, oleander, yellow oleander, lily-of-the-valley and toad-derived
    bufadienolide preparations all deliver cardiac glycosides and produce the same
    toxidrome by the same mechanism. In South Asia, yellow oleander
    seed ingestion is a major route of self-poisoning, and it is the setting in
    which the only randomised antidote trials for this class have been run.
  exposure_term:
    preferred_term: dietary exposure to a plant or animal cardiac glycoside
    term:
      id: ECTO:0000537
      label: exposure to toxin
  influences_mechanisms:
  - target: Systemic Cardiac Glycoside Excess
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Non-pharmaceutical glycoside sources reach the same systemic exposure node as
      a digoxin overdose.
    evidence:
    - reference: PMID:17054261
      reference_title: Antidotes for acute cardenolide (cardiac glycoside) poisoning.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Because cardenolides from these plants are structurally similar, acute poisonings are managed using similar treatments."
      explanation: >-
        States the structural and management equivalence that justifies routing
        plant exposures to the same mechanism node as pharmaceutical digoxin.
        BACKGROUND because it is the review's framing sentence. Note the same review
        elsewhere says antidote results do not readily translate between
        cardenolides, which this entry records as a REFUTE in the transfer discussion.
  evidence:
  - reference: PMID:17054261
    reference_title: Antidotes for acute cardenolide (cardiac glycoside) poisoning.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "cardiotoxicity from other cardenolides such as the yellow oleander are also a major problem, with tens of thousands of cases of poisoning each year in South Asia"
    explanation: >-
      Establishes the scale and geography of the non-pharmaceutical route.
      BACKGROUND rather than REVIEW_SYNTHESIS because the sentence sits in the
      review's background section, stating context rather than its own synthesis;
      the review's synthesis is quoted on the treatments, from its results.
  notes: >-
    Bound to the genus ECTO:0000537 exposure to toxin, after rejecting two nearer
    terms on positive grounds. Searched the pinned local build with
    `uv run runoak -i sqlite:obo:ecto search` for `l~glycoside`, `l~digital`,
    `l~cardenolide`, `l~oleander`, `l~digoxin`, `l~bufadienolide` and `l~ouabain`
    on 2026-09-19. `l~cardenolide`, `l~oleander`, `l~digoxin`, `l~bufadienolide`
    and `l~ouabain` return no ECTO exposure class. Two do exist and were rejected.
    ECTO:9000003 exposure to digitalin is a real digitalis-glycoside exposure
    class, but digitalin is one specific compound of Digitalis purpurea; this entry
    covers digoxin, digitoxin, oleandrin and bufadienolides, and almost no patient
    in it is exposed to digitalin, so the term would be precise and wrong.
    ECTO:9000436 exposure to glycoside is its parent and would cover the whole
    entry, but `RO:0002309` relates it to CHEBI:24400 glycoside, a chemical class
    whose other members include the aminoglycoside antibiotics; nothing about the
    toxicity follows from the glycosidic bond, so it names the wrong feature of the
    molecule. ECTO:0000524 exposure to mycotoxin is wrong on its face - these are
    plant and amphibian toxins, not fungal. ECTO:0000537 matches the pattern of
    Ciguatera_Fish_Poisoning and Acute_Ackee_Fruit_Intoxication, which bind it and
    carry the agent in preferred_term.
treatments:
- name: Digoxin-Specific Antibody Fragments
  description: >-
    Ovine Fab fragments that bind free glycoside and remove it from the pump. The
    only treatment here that acts on the lesion rather than on its consequences.
    It is one of two interventions in this entry with randomised evidence behind
    it, the other being multiple-dose activated charcoal; both trials were in
    yellow oleander poisoning rather than in digoxin.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ovine digoxin immune Fab
      term:
        id: NCIT:C80835
        label: Ovine Digoxin Immune Fab
  target_mechanisms:
  - target: Sodium-Potassium ATPase Inhibition
    treatment_effect: RESTORES
    description: >-
      Binding free glycoside releases the pump, which is why the antidote reverses
      the dysrhythmias and the hyperkalemia together.
    evidence:
    - reference: PMID:8492338
      reference_title: Clinical features and management of digitalis poisoning--rationale for immunotherapy.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "a strong toxicodynamic effect due to quick reversal of digitalis-induced dysrhythmias, hyperkalemia, and myocardial depression, by reactivation of membrane ATPases"
      explanation: >-
        States the mechanism this edge asserts - reactivation of the pump - and
        names the three effects that reverse together, which is the signature of
        acting on the shared upstream lesion rather than on each downstream branch.
  evidence:
  - reference: PMID:17054261
    reference_title: Antidotes for acute cardenolide (cardiac glycoside) poisoning.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The second study found a beneficial effect of anti-digoxin Fab antitoxin on the presence of cardiac dysrhythmias at two hours post-administration; the RR was 0.60 (95% CI 0.44 to 0.81)."
    explanation: >-
      The randomised evidence, from a systematic review. Note the endpoint is
      dysrhythmia at two hours, not mortality, and the trial was in yellow oleander
      poisoning.
  - reference: PMID:1993775
    reference_title: 'Digoxin Immune Fab therapy in the management of digitalis intoxication: safety and efficacy results of an observational surveillance study.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fifty percent of patients were reported to have a complete response to treatment, 24% a partial response and 12% no response."
    explanation: >-
      Response rates in 717 adults treated with the antidote in an observational
      surveillance study. Uncontrolled, and a complete response in half is a more
      measured picture than "antidote" suggests.
  - reference: PMID:1993775
    reference_title: 'Digoxin Immune Fab therapy in the management of digitalis intoxication: safety and efficacy results of an observational surveillance study.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six patients (0.8%, 95% confidence interval 0.3% to 1.8%) had an allergic reaction to digoxin-specific antibody fragments."
    explanation: >-
      The harm side of the same series: allergic reaction to an ovine product, with
      a confidence interval, which is what makes the rate usable.
- name: Multiple-Dose Activated Charcoal
  description: >-
    Repeated enteral charcoal, the only intervention in this entry with randomised
    evidence of a mortality benefit - again in yellow oleander poisoning rather
    than in digoxin.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: multiple-dose activated charcoal
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
    therapeutic_agent:
    - preferred_term: activated charcoal
      term:
        id: CHEBI:91090
        label: charcoal
  evidence:
  - reference: PMID:17054261
    reference_title: Antidotes for acute cardenolide (cardiac glycoside) poisoning.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "One trial investigated the effect of MDAC on mortality, the relative risk (RR) was 0.31 (95% confidence interval (CI) 0.12 to 0.83) indicating a beneficial effect."
    explanation: >-
      A randomised mortality benefit, in yellow oleander poisoning. The confidence
      interval is wide and excludes 1 only just.
- name: Atropine
  description: >-
    A temporising measure for bradyarrhythmia and block, directed at the vagal
    limb of the toxidrome rather than at the pump.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: atropine
      term:
        id: CHEBI:16684
        label: atropine
  target_mechanisms:
  - target: Increased Vagal Tone
    treatment_effect: INHIBITS
    description: >-
      Muscarinic blockade opposes the vagal slowing of sinus rate and
      atrioventricular conduction. It does nothing about the ectopy.
    evidence:
    - reference: PMID:8492338
      reference_title: Clinical features and management of digitalis poisoning--rationale for immunotherapy.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "First-line antiarrhythmic therapy is usually atropine, because of bradycardia-induced arrhythmia."
      explanation: >-
        Places atropine as first-line and gives the indication - bradycardia-driven
        arrhythmia - which is the vagal limb this edge targets.
- name: Therapeutic Plasma Exchange
  description: >-
    Salvage for the specific case where the antidote is insufficient - a large
    tissue burden with renal failure, where Fab-glycoside complexes are cleared
    slowly and can dissociate. Not a treatment for ordinary poisoning, and
    conventional haemodialysis is ineffective for digoxin.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: therapeutic plasma exchange
    term:
      id: NCIT:C15304
      label: Plasmapheresis
  evidence:
  - reference: PMID:41399569
    reference_title: 'Digoxin Toxicity in Renal Failure: Resolution With Plasma Exchange After Fab Therapy Failure.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "the delayed clearance of digoxin-Fab complexes can result in complex dissociation and rebound toxicity"
    explanation: >-
      States the failure mode this salvage addresses. A single case report, which
      is the whole of the evidence for it.
  - reference: PMID:41399569
    reference_title: 'Digoxin Toxicity in Renal Failure: Resolution With Plasma Exchange After Fab Therapy Failure.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Conventional extracorporeal therapies such as hemodialysis are ineffective for removing digoxin or its antibody complexes due to their large molecular size and high volume of distribution"
    explanation: >-
      Sources the statement that ordinary haemodialysis does not work here, and
      gives the reason - distribution volume and molecular size - rather than
      leaving it as an assertion.
- name: Supportive Care and Electrolyte Management
  description: >-
    Correction of potassium and magnesium, rhythm monitoring, and avoidance of
    manoeuvres that make things worse - gastric lavage risks vagal stimulation in a
    patient already bradycardic, and cardioversion risks refractory ventricular
    fibrillation.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Temporary Cardiac Pacing
  description: >-
    Ventricular pacing for bradycardia and high-degree atrioventricular block when
    the antidote is unavailable or has not yet worked. The cited review recommends
    it and warns about it in the same breath, which is how it is recorded here: it
    addresses the conduction limb of the toxidrome without touching the pump
    inhibition that produces it, and it is technically awkward in a myocardium that
    is already irritable.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: temporary transvenous ventricular pacing
    term:
      id: NCIT:C99998
      label: Pacemaker Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cardiac pacemaker
        term:
          id: NCIT:C94198
          label: Cardiac Pacemaker
  target_mechanisms:
  - target: Atrioventricular Conduction Block
    treatment_effect: BYPASSES
    description: >-
      Paces through the block rather than relieving it; the pump inhibition
      upstream is untouched.
    evidence:
    - reference: PMID:8492338
      reference_title: Clinical features and management of digitalis poisoning--rationale for immunotherapy.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Ventricular pacing is a toxicodynamic treatment that may be helpful in both bradycardia-induced arrhythmia and high-degree atrioventricular block."
      explanation: >-
        Names both indications, and classes pacing as toxicodynamic - acting on the
        consequence rather than on the toxin.
  evidence:
  - reference: PMID:8492338
    reference_title: Clinical features and management of digitalis poisoning--rationale for immunotherapy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Pacing is difficult to handle and can result in serious adverse effects."
    explanation: >-
      The same review's warning, recorded beside the recommendation so the entry
      does not present pacing as a straightforward option.
genetic:
- name: ABCB1
  notes: >-
    P-glycoprotein, encoded by ABCB1, effluxes digoxin in the intestine and the
    kidney, and the drug interactions that precipitate chronic toxicity work
    largely by inhibiting it. Common ABCB1 variants are a susceptibility modifier,
    not a cause: this is not a heritable disease and there is no causal gene.
  relationship_type: MODIFIER
  gene_term:
    preferred_term: ABCB1
    term:
      id: hgnc:40
      label: ABCB1
  evidence:
  - reference: PMID:21311904
    reference_title: Post-mortem ABCB1 genotyping reveals an elevated toxicity for female digoxin users.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutant genotype frequencies showed a positive relationship with post-mortem digoxin concentration for all SNPs."
    explanation: >-
      Associates ABCB1 genotype with post-mortem digoxin concentration in 112
      deceased subjects. Graded INDIRECT because a post-mortem concentration
      association is several steps from a clinical susceptibility claim, and the
      design cannot separate exposure from disposition.
  - reference: PMID:12492608
    reference_title: MDR1 genotypes do not influence the absorption of a single oral dose of 1 mg digoxin in healthy white males.
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "AUC(0,4 h), Cmax and tmax, used as indices of digoxin absorption, were not significantly different in any of the genotype groups tested."
    explanation: >-
      Scoped to the claim that ABCB1 genotype alters digoxin exposure. A negative
      pharmacokinetic result in fifty healthy volunteers, and the counterweight to
      the post-mortem association above; the two are not in direct conflict, since
      one measures single-dose absorption and the other a post-mortem
      concentration, but recording only the positive one would misstate the field.
      The paper's own title states the negative result, but a title is not quoted
      here as a finding - this is the result sentence from the abstract.
diagnosis:
- name: Serum potassium in acute poisoning
  description: >-
    Not a diagnostic test for the poisoning but a prognostic measurement in it, and
    an indication for antidote. It is informative because it reports on the
    mechanism: potassium leaves cells in proportion to how much of the body's pump
    capacity has been switched off. The cited series ranks it alongside age, sex,
    atrioventricular block and prior heart disease rather than above them, and does
    not compare it with the serum drug level.
  diagnosis_term:
    preferred_term: serum potassium measurement for risk stratification
    term:
      id: NCIT:C61030
      label: Serum Potassium Measurement
  evidence:
  - reference: PMID:7267327
    reference_title: '[Prognostic factors in acute digitalis poisoning (author''s transl)].'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "It increased with age, with digitoxin and potassium serum levels and even more with persistent hyperkalemia."
    explanation: >-
      The prognostic association, in 179 patients. Persistent hyperkalemia carried
      more weight than the single value.
- name: Serum digoxin concentration
  description: >-
    Confirms exposure but is a poor guide to severity, and becomes uninterpretable
    once the antidote has been given because the assay cannot distinguish bound
    from free drug.
  diagnosis_term:
    preferred_term: serum digoxin concentration measurement
    term:
      id: NCIT:C217390
      label: Diagnostic Blood Testing
  notes: >-
    NCIT has no digoxin measurement term. Searched the local build with
    `uv run runoak -i sqlite:obo:ncit search 'l~Digoxin'` and `'l~digoxin'` on
    2026-09-19; the hits are digoxin the substance, digoxin immune Fab and the
    gene/transporter terms, with no measurement or assay among them, where the
    sibling potassium entry binds the specific NCIT:C61030 Serum Potassium
    Measurement. This was bound to the branch root NCIT:C18020 Diagnostic
    Procedure until review pointed out that NCIT:C217390 Diagnostic Blood Testing
    is strictly narrower and still correct for a serum assay; `ancestors -p i`
    confirms C217390 is a child of C18020 and reaches NCIT:C25218, the
    TreatmentActionTerm root.
  evidence:
  - reference: PMID:37465455
    reference_title: 'Review: Failure of current digoxin monitoring for toxicity: new monitoring recommendations to maintain therapeutic levels for efficacy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The current recommendations for monitoring digoxin, a narrow therapeutic index drug, are limited to confirming medication use or investigating suspicion of toxicity"
    explanation: >-
      Describes what the level is actually used for, which is narrower than its
      reputation.
- name: Electrocardiography and continuous cardiac monitoring
  description: >-
    The front-line test, and the one that carries this entry's cardiac phenotypes:
    seven of them - atrioventricular block, bidirectional ventricular tachycardia,
    atrial tachycardia with block, junctional ectopic tachycardia, premature
    ventricular contractions, sinus bradycardia and ventricular fibrillation - are
    ECG diagnoses and had no diagnostic modality behind them until this entry was
    reviewed. It is not specific: no ECG pattern here is unique to digitalis, so
    the ECG localises and grades the rhythm disturbance while the history, the
    potassium and the drug level establish the cause.
  diagnosis_term:
    preferred_term: 12-lead electrocardiography and continuous cardiac monitoring
    term:
      id: NCIT:C217427
      label: Diagnostic Electrocardiography Testing
  evidence:
  - reference: PMID:8492338
    reference_title: Clinical features and management of digitalis poisoning--rationale for immunotherapy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The intensity of gastrointestinal and visual symptoms together with hyperkalemia and the characteristic ECG features make diagnosis of acute digitalis intoxication relatively easy."
    explanation: >-
      Names the ECG as one of the three findings that make the diagnosis, and
      scopes that statement to acute intoxication, which is why the sentence also
      supports the Acute subtype above.
  - reference: PMID:34159036
    reference_title: "A Visual Resolution of Cardiotoxicity: A Case Report of Digoxin-Induced Bidirectional Ventricular Tachycardia."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "An electrocardiogram (EKG) revealed a wide complex tachycardia with alternating QRS axis, suggestive of bidirectional ventricular tachycardia (BDVT)"
    explanation: >-
      A worked instance of the modality making the rhythm diagnosis this entry
      curates as a phenotype.
  notes: >-
    NCIT:C217427 was offered in review and verified before binding: it resolves in
    the local NCIT build with that exact label, and `ancestors -p i` puts it under
    NCIT:C18020 Diagnostic Procedure and NCIT:C25218 Clinical Intervention or
    Procedure, so it is inside the TreatmentActionTerm root that diagnosis_term
    requires.
clinical_trials:
- name: ISRCTN71018309
  status: COMPLETED
  description: >-
    Fructose-1,6-diphosphate as a candidate antidote in yellow oleander poisoning -
    a double-blind randomised placebo-controlled trial in Sri Lanka, target 240
    patients. Recorded as a registered trial rather than as a treatment: the only
    cached publication for it (PMID:20587052) is the study protocol, which reports
    no results, so there is nothing here that could support an efficacy claim.
    Recorded because review asked why FDP was absent from the treatments, and this
    is the honest answer - the intervention was tested, and this entry has no
    result to cite.
  notes: >-
    `phase` is omitted rather than guessed. The WHO ICTRP record carries no phase
    field for this registration, and NOT_APPLICABLE is scoped to observational and
    device studies, which an interventional drug randomisation is not.
  evidence:
  - reference: ICTRP:ISRCTN71018309
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Study design | Double-blind randomised placebo controlled trial (Treatment)"
    explanation: >-
      WHO ICTRP registration record establishing the trial's design and identity.
      OTHER because a registration document is not study evidence.
  - reference: ICTRP:ISRCTN71018309
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recruitment status | Completed"
    explanation: >-
      The trial completed recruitment, which is why its absence from the treatment
      section is a missing result rather than a missing trial.
prevalence:
- population: United States, National Poison Control Center data 2012-2020
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    An absolute annual death count, not a rate - there is no denominator here, so
    no prevalence class can honestly be assigned. Recorded because it is the
    clearest available statement of the current burden in a country with
    comprehensive poison-centre reporting.
  evidence:
  - reference: PMID:37465455
    reference_title: 'Review: Failure of current digoxin monitoring for toxicity: new monitoring recommendations to maintain therapeutic levels for efficacy.'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Data from the United States National Poison Control Center (2012-2020) show annual deaths due to digoxin of 18-36"
    explanation: The annual death count this record exists to capture.
- population: Patients hospitalised after absorbing more than 2 mg of digitoxin
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Case fatality in a defined poisoned cohort, not a population rate. The agent is
    digitoxin rather than digoxin, and the series predates the antidote.
  evidence:
  - reference: PMID:7267327
    reference_title: '[Prognostic factors in acute digitalis poisoning (author''s transl)].'
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mortality rate in this series was 17%."
    explanation: Case fatality in the 179-patient series.
animal_models:
- name: Canine Purkinje fibre strophanthidin preparation
  species: Dog
  description: >-
    Isolated canine Purkinje fibres exposed to strophanthidin under microelectrode
    recording, the classical preparation in which the diastolic oscillations that
    became known as delayed afterdepolarizations were characterised. It is an ex
    vivo tissue preparation from a dog rather than a whole-animal poisoning model.
  publication: PMID:1257581
  modeled_mechanisms:
  - target: Delayed Afterdepolarization
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      The oscillations and the spontaneous activity that follows them are directly
      recorded, which is the node itself rather than a proxy for it.
    limitations: >-
      The glycoside is strophanthidin, not digoxin, and the preparation is isolated
      tissue with no autonomic input, so it models the myocyte limb of this entry
      and says nothing about the vagal limb.
    evidence:
    - reference: PMID:1257581
      reference_title: On the mechanisms underlying digitalis toxicity in cardiac Purkinje fibers.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Transmembrane potentials of quiescent, spontaneously active, or electrically driven fibers were recorded in the presence and absence of strophanthidin"
      explanation: The recording method, which is what makes this a direct observation of the node.
- name: Guinea pig lethal digoxin infusion with monoclonal Fab rescue
  species: Guinea pig
  description: >-
    Whole-animal digoxin poisoning taken to an otherwise lethal endpoint and
    reversed with digoxin-specific antibody fragments - the model that established
    the antidote concept before it reached patients.
  publication: PMID:6707937
  modeled_mechanisms:
  - target: Sodium-Potassium ATPase Inhibition
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Antibody fragments reverse otherwise lethal toxicity, which is the in vivo
      demonstration that sequestering the glycoside releases the lesion.
    limitations: >-
      The antibody here is monoclonal, whereas the clinical product is polyclonal
      ovine Fab, and guinea pig myocardial glycoside sensitivity is not identical to
      human.
    evidence:
    - reference: PMID:6707937
      reference_title: Reversal of lethal digoxin toxicity in guinea pigs using monoclonal antibodies and Fab fragments.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "reversal of advanced, otherwise lethal digoxin toxicity in guinea pigs"
      explanation: States the model and the rescue endpoint.
discussions:
- discussion_id: calcium_in_digitalis_hyperkalemia
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is intravenous calcium actually dangerous in digitalis-induced hyperkalemia, or
    is the contraindication inherited from older literature that controlled
    experiment does not support?
  attaches_to:
  - pathophysiology#Sarcoplasmic Reticulum Calcium Overload
  - treatments#Supportive Care and Electrolyte Management
  rationale: >-
    The mechanistic argument for withholding calcium is exactly this entry's
    canonical chain: the cell is already calcium-overloaded, so adding calcium
    should make the arrhythmia worse - the "stone heart" concern. It is a textbook
    contraindication. The only controlled test in the cached literature is a
    twelve-animal porcine study that found no difference in time to death, and its
    own background section describes the contraindication as resting on older
    literature rather than on controlled data. Twelve pigs do not overturn a
    contraindication, and the study reports a pilot; but the asymmetry is worth
    recording, because the reasoning behind the dogma is a mechanistic inference
    from the same model this entry curates, and mechanistic inference is precisely
    what an outcome study is supposed to check.
  evidence:
  - reference: PMID:15461240
    reference_title: The effect of calcium chloride in treating hyperkalemia due to acute digoxin toxicity in a porcine model.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "The administration of intravenous (IV) calcium to treat hyperkalemia resulting from digoxin poisoning is considered potentially dangerous, based on a body of older literature which, in sum, reported increased cardiac glycoside toxicity with calcium administration"
    explanation: >-
      States the contraindication and, in the same sentence, what it rests on.
      BACKGROUND because the sentence is this paper's framing of prior belief, not
      its own result - its result is the REFUTE item below.
  - reference: PMID:39219774
    reference_title: 'Stone heart syndrome: A curious case of digoxin toxicity and calcium infusion.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Research on this subject is conflicting, so it is imperative to approach it cautiously."
    explanation: >-
      An independent source characterising the evidence on this question as
      conflicting rather than settled, which is the state this discussion records.
  - reference: PMID:15461240
    reference_title: The effect of calcium chloride in treating hyperkalemia due to acute digoxin toxicity in a porcine model.
    supports: REFUTE
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "The administration of intravenous CaCl in the setting of hyperkalemia from acute digoxin toxicity did not affect mortality or time to death at the dose administered."
    explanation: >-
      Scoped to the claim that calcium worsens outcome in this setting, and only to
      the dose and model tested - six animals per arm, in swine. It does not
      establish that calcium is safe in patients.
- discussion_id: potassium_threshold_as_absolute_rule
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does a serum potassium above 5.5 mEq/L in acute digitalis poisoning really
    carry the near-certain mortality the classic stratification reports?
  attaches_to:
  - phenotypes#Hyperkalemia
  rationale: >-
    The 0% / 50% / 100% stratification by potassium band is quoted throughout the
    clinical literature and drives the decision to give antidote. It comes from a
    pre-antidote era and, on its face, asserts a 100% mortality that a single
    survivor falsifies. The case report that restates the rule is itself such a
    survivor, treated without Fab. That does not make the threshold useless - it
    remains the best-validated marker available and the right trigger for treatment
    - but the entry records the figure and its counterexample together rather than
    the figure alone.
  evidence:
  - reference: PMID:22737544
    reference_title: Good outcome after digoxin toxicity despite very high serum potassium level.
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present a case of acute digoxin toxicity with high potassium level and good outcome despite unavailability of digoxin-specific Fab fragments."
    explanation: >-
      Scoped narrowly to the "100% mortality above 5.5" claim, which a single
      survivor is sufficient to refute as an absolute. It does not refute the
      association between potassium and mortality, which the prognostic series
      supports and this entry records.
- discussion_id: no_randomised_evidence_for_digoxin_itself
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why is every randomised antidote trial for this poisoning in yellow oleander
    rather than in digoxin, and does that evidence transfer?
  attaches_to:
  - treatments#Digoxin-Specific Antibody Fragments
  - treatments#Multiple-Dose Activated Charcoal
  rationale: >-
    Both randomised results this entry cites - charcoal on mortality, Fab on
    dysrhythmia - come from yellow oleander self-poisoning in South Asia, where the
    case numbers are large enough to run a trial and the antidote is too expensive
    to be standard. For pharmaceutical digoxin, where the antidote is standard of
    care, the evidence is observational. The systematic review states that no
    antidote studies in other cardenolides were identified at all. The transfer
    argument is mechanistic - the same pump, the same chain - which is the sort of
    argument the rest of this entry is built to make explicit rather than assume.
  evidence:
  - reference: PMID:17054261
    reference_title: Antidotes for acute cardenolide (cardiac glycoside) poisoning.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Studies assessing the effect of antidotes on other cardenolides were not identified."
    explanation: >-
      The gap stated by the systematic review itself: the randomised evidence base
      covers yellow oleander and nothing else in this class.
  - reference: PMID:17054261
    reference_title: Antidotes for acute cardenolide (cardiac glycoside) poisoning.
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Given pharmacokinetic differences between individual cardenolides, the effect of antidotes administered to patients with yellow oleander poisoning cannot be readily translated to those of other cardenolides."
    explanation: >-
      Scoped to the transfer argument this discussion raises. The review the entry
      cites for the yellow-oleander trials says in so many words that their results
      do not readily translate to other cardenolides, which is the opposite of the
      mechanistic transfer argument, and is recorded here rather than left out.
references:
- reference: PMID:7267327
  title: '[Prognostic factors in acute digitalis poisoning (author''s transl)].'
- reference: PMID:17054261
  title: Antidotes for acute cardenolide (cardiac glycoside) poisoning.
- reference: PMID:28550304
  title: Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides.

📚

References & Deep Research

References

3

PMID:7267327

[Prognostic factors in acute digitalis poisoning (author's transl)].

No top-level findings curated for this source.

PMID:17054261

Antidotes for acute cardenolide (cardiac glycoside) poisoning.

No top-level findings curated for this source.

PMID:28550304

Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Record notes

The clinical picture is the same whichever glycoside delivers it, so the entry is written around the shared mechanism and names digoxin where a source is specifically about digoxin. Plant and animal sources are modelled in the `environmental:` block rather than as separate entries. `just check-genereviews` reports GeneReviews NO_CHAPTER, correct for an acquired poisoning with no genetic cause. It also reports StatPearls CITED_UNTAGGED, naming PMID:29262029 'Digoxin Toxicity' and PMID:29083729 'Cardiac Glycoside and Digoxin Toxicity'. Both chapters exist and neither is cited as evidence: the checker matches them through this entry's `digoxin toxicity` synonym, which is correct, and counts them as cited because this paragraph names their PMIDs - the `references:` block has three entries and neither PMID is among them. StatPearls is never a phenotype baseline in this repository, so nothing is missing here. This paragraph read UNTAGGED_CHAPTER until review pointed out that the class had changed; re-running `just check-genereviews` on this file confirms CITED_UNTAGGED. Twenty-two further references are committed because the deep-research report cites them, and are not cited by this entry. They fall into four groups: pharmacogenomic studies of ABCB1 and SLCO1B3 beyond the two already cited here, one positive and one negative (PMID:17377214, PMID:26531821, PMID:28208135); veterinary and wildlife cardenolide toxicity, which is a different host (PMID:31349685, PMID:32722138, PMID:23108514, PMID:40660117); endogenous digoxin-like immunoreactive substances as an assay interference, a real gap in the `diagnosis:` section rather than a screened-out topic (DOI:10.7326/0003-4819-99-5-604, DOI:10.1111/j.1651-2227.1989.tb11093.x, DOI:10.1007/BF02343220); and epidemiological, pharmacokinetic and mechanism-adjacent material not used for a specific claim (the remainder, including DOI:10.1126/sciadv.ady9596 on NCX1 Na-dependent inactivation, which would strengthen the exchanger node and was left for a later pass). PMID:20587052 is a study protocol with no results, so it cannot support an efficacy claim and is not cited as evidence for one. Review asked why fructose-1,6-diphosphate was absent; the protocol carries the trial's registration number, so the trial is now recorded in `clinical_trials:` against ICTRP:ISRCTN71018309, and the absence of a treatment entry for it is explicit rather than silent. PMID:28904341 is a non-substantive erratum to PMID:28550304 and does not change the quotes taken from it. The autonomic branch is curated on its parasympathetic limb only. Review asked for the sympathetic limb - enhanced central sympathetic outflow and inhibition of norepinephrine reuptake, which the deep-research report lists as step 8b - and it is deliberately still absent. The two cached sentences that state it are both in veterinary oleander papers (PMID:32722138, PMID:31349685), a different host, which this entry screens out for exactly that reason, and model-organism evidence should not be the sole support for a human mechanism node. A PubMed search for a human source ('digoxin sympathetic nerve activity humans', 2026-09-19) returns heart-failure pharmacology in which digoxin is sympatho-inhibitory at therapeutic concentrations, which is the opposite direction to the toxic-dose claim, so binding one of those would assert the wrong sign. The limb stays out until a human or experimental source for sympathoexcitation at toxic concentrations is in the cache. `GO:0055075 potassium ion homeostasis` sits on the ORGANISM-scale Extracellular Potassium Shift node, which review flagged as borderline against the GO-is-molecular-or-cellular expectation. Left as it is, on a second look: GO's only alternative is `GO:0030007 intracellular potassium ion homeostasis`, which asserts the wrong compartment for a node about potassium leaving cells, so GO:0055075 is the most specific term that is also accurate.

Create: Digitalis_Poisoning (MONDO:0017863) · 2026-09-19T22:32:29Z · View source

New entry for digitalis poisoning, bound to MONDO:0017863, with a skos:broadMatch to MONDO:0800388 cardiac glycoside intoxication. Chosen because it had no entry and no stub despite fourteen MONDO poisoning terms being uncurated, and because the mechanism is a single enzyme lesion whose whole clinical picture follows by ion-gradient arithmetic - unlike the transporter and transcription mechanisms curated immediately before it. Deep research: `just research-disorder claude_code Digitalis_Poisoning`. This run completed cleanly and wrote both validation blocks itself, unlike the amatoxin run. Reference validation: 35 references, 34 verified, 0 not found, 1 off topic (PMID:40660117, on Na/K-ATPase toxin resistance in a serpent-eagle preying on cane toads - real and mechanistically adjacent, but not about the human disease). Term validation: 41 terms, 6 mislabelled. `just preflight-dr <report> MONDO:0017863` returned SKIP, because MONDO records no causal gene for a poisoning and the gene-identity check cannot discriminate. The manual identity check the skill prescribes was done instead: the report's content matches MONDO's own definition point for point (increased automaticity with decreased conduction; acute nausea/vomiting, bradycardia, block, dysrhythmia, CNS features and hyperkalemia; chronic GI, mental-status and visual disturbance). The gene profile the preflight printed is corroborating rather than discriminating but points the same way - ABCB1, SLCO1B3, ATP1A1, ATP1A2 are exactly the transporter and pump genes this poisoning turns on. No CURIE was taken from the report. Its six mislabelled terms were checked for individually and none appears in the entry: HP:0000496 offered as "Halo vision" is Abnormality of eye movement, HP:0011703 offered as "Atrioventricular block" is Sinus tachycardia, UBERON:0002205 offered as "AV node" is manubrium of sternum, UBERON:0002136 offered as "Purkinje fiber cell tissue" is hilus of dentate gyrus. Two further CURIEs the report suggested were wrong without being flagged, because the report gave them no label the validator could compare: CL:0002129 offered as "cardiac pacemaker cell" is regular atrial cardiac myocyte, and CL:1000497 offered as Purkinje myocyte is not that term - the correct one is CL:0002068. One binding decision is worth recording because the obvious term is the wrong one. For xanthopsia the entry binds HP:0000551 Color vision defect, not HP:0007641 Dyschromatopsia, even though the latter reads as more specific: OLS gives HP:0007641 the definition "A form of colorblindness in which only two of the three fundamental colors can be distinguished due to a lack of one of the retinal cone pigments", which is congenital dichromacy and not an acquired drug effect. HP:0000551's definition and its "Disturbed color vision" synonym fit. The reasoning is recorded in the phenotype's own notes. This is the same looks-more-specific-but-means-something-else trap that cost PR #12297 a round. Snippets were pre-verified as exact substrings before the YAML was written: 23 candidates checked, 22 passed, and the one failure was a thin space before "µM". Two further whitespace and bracket problems surfaced during validation. The first was the same thin space, extracted from the cache by regex rather than retyped. The second is more interesting: the reference validator strips "[Ca2+]" from a quoted conclusion as a numeric citation marker, leaving "cytosolic i-" which then cannot match. Rather than fight the normaliser the entry quotes the paper's result sentence instead, which states the control directly - calcium-current inhibition present both with and without the pump blocked by ouabain - and the explanation says why that sentence was chosen. Agent conflation was the main curation risk and is handled explicitly in the evidence rather than silently. PMID:7267327 is a digitoxin series, not digoxin, and every explanation citing it says so. PMID:17054261 and both randomised trials it reports are yellow oleander, and the treatment explanations say so. PMID:28550304's effect is strongest for bufadienolides, which are toad-derived, and the hypothesis description says so. PMID:15461240 is swine. PMID:20587052 was fetched and deliberately not cited: it is a study protocol with no results, so it cannot support an efficacy claim. Pathophysiology is 15 nodes in one connected chain - pump inhibition, sodium accumulation, loss of NCX calcium extrusion, sarcoplasmic reticulum overload, spontaneous diastolic release, delayed afterdepolarization, triggered automaticity - with the vagal, potassium-shift, direct-channel-block and extracardiac branches joining it. All 11 phenotypes are causally connected. Three hypothesis groups, all wired: nka_calcium_overload_dad (CANONICAL, 7 edges), extracardiac_pump_inhibition (EMERGING, 6), nka_independent_channel_block (EMERGING, 2). The last is graded EMERGING rather than ALTERNATIVE because it adds a mechanism rather than displacing one. Three deliberate REFUTE items, each scoped to a claim rather than a mechanism. PMID:15461240 refutes the claim that intravenous calcium worsens outcome in digitalis hyperkalemia, in swine and at one dose, and the same paper is also cited as SUPPORT for the existence of the contraindication it tests. PMID:22737544 refutes the "100% mortality above 5.5 mEq/L" figure as an absolute, which a single survivor is sufficient to do, while the same paper is cited as SUPPORT for the stratification itself. Neither refutation touches the potassium-mortality association, which the prognostic series supports. Three corrections made during curation, all before the red-team round. An earlier draft described bidirectional ventricular tachycardia as close to diagnostic; PMID:34159036 names six other causes, so the description now states the differential and cites it. An earlier draft attached a two-word snippet "bidirectional tachycardia" to PMID:8492338, which does not contain the word at all - that was an assumption rather than a reading, and it was replaced with two real sentences from a case report that does. Three phenotypes (nausea, vomiting, confusion) were left isolated by the first draft and are now wired through an extracardiac pump-inhibition node that is explicitly marked as an inferred site of action rather than a demonstrated one. One process failure to record: HP:0001695 for Cardiac arrest and CHEBI:18208 for benzylpenicillin in the sibling amatoxin entry were both written from memory rather than from a lookup. Both happened to be correct and both were checked immediately afterwards, but correct-by-luck is not the standard this entry is built to, and the same slip has now occurred in two consecutive entries. A pre-PR red-team review by a fresh-context subagent against `dismech-pr-review` returned 29 findings, six of them blocking. All six were acted on, along with most of the rest, before the first push. The review was unusually valuable because none of its blocking findings is caught by any gate in this repository - the entry passed a clean `just validate` while carrying all six. The worst was structural and self-inflicted. Nine of fifteen pathophysiology nodes carried no evidence at all, and they were exactly the canonical chain the entry is built around - pump inhibition, sodium accumulation, exchanger failure, calcium overload, spontaneous release, afterdepolarization, triggered automaticity, vagal tone, conduction block - while the peripheral EMERGING channel-block node carried two exact quotes. The CANONICAL hypothesis group had no evidence anywhere in the file. The quotes were sitting in caches this branch already commits. PMID:34159036 and PMID:28550304 now evidence the pump, sodium and calcium steps as BACKGROUND quotes, and PMID:1257581 - the classical canine Purkinje-fibre strophanthidin study, cached and previously unused - now evidences the afterdepolarization and automaticity nodes. Second, the ECTO justification note was false, which is the precise defect class CLAUDE.md records under "that recorded reason is itself a claim" (dismech#7835). The note said ECTO has no digitalis exposure class. Re-running the exact search it names returns ECTO:9000003 exposure to digitalin, and its parent ECTO:9000436 exposure to glycoside. Both were then examined properly and both rejected on real grounds - digitalin is one specific compound of Digitalis purpurea and almost no patient in this entry is exposed to it, and "glycoside" names a chemical class whose other members include the aminoglycoside antibiotics, so it picks out the wrong feature of the molecule. The binding stays ECTO:0000537, but the note now says what the searches actually returned. Writing a false negative-existence claim while having a section of this very record about that failure mode is worth stating plainly rather than burying. Third, a comparative prognostic claim appeared four times - that serum potassium predicts death better than the drug level - and no cited source makes it. The one prognostic series in the entry ranks nothing; it lists potassium alongside age, sex, atrioventricular block and prior heart disease. All four instances were rewritten. Fourth, `Increased Vagal Tone` had no causal upstream edge. Half the toxidrome - the bradycardia and block limb - hung off nothing, while the top-level description asserted in prose that the drug causes it. `check-causal-targets` passes this because it asks whether declared targets resolve, not whether a node is reachable. An edge from the trigger node was added with evidence. Fifth and sixth were internal contradictions. The phenotype description had been corrected to say bidirectional ventricular tachycardia is not specific to this poisoning, with a citation naming six other causes, while the pathophysiology node sixty lines away still called it close to pathognomonic. And Fab was described as the only treatment with randomised evidence while charcoal, two entries later, was described the same way - both from the same Cochrane review, which identified two trials. Beyond the blocking six: the channel-block node's agent caveat was materially understated. The paper's two cardenolides - the class digoxin belongs to - showed about 10 to 15 per cent inhibition with IC50s above 100 micromolar, which is essentially nothing, and digoxin itself was never tested. A REFUTE item carrying that sentence was added and the node description rewritten to say so. The Cochrane review's own non-transferability sentence, which says antidote results from yellow oleander cannot be readily translated to other cardenolides, was omitted from a discussion whose entire subject is whether they transfer; it is now recorded as a REFUTE against the entry's own mechanistic transfer argument. The cached negative ABCB1 pharmacokinetic study was unused while the positive post-mortem association was cited; both are now present. Three quote_role values were wrong against the deterministic NLM-section checker and are now correct, taking `just list-background-citations` to zero findings. `Triggered Ventricular Automaticity` was renamed `Triggered Automaticity` because a ventricular focus cannot produce the junctional rhythm the entry hangs off it. Two animal models were added. Atrial tachycardia with block, which the literature calls the classic pattern, was added from a cache the entry already cited. The serum-potassium diagnosis binding moved from the bare root NCIT:C18020 to NCIT:C61030 Serum Potassium Measurement after confirming its ancestry. Phenotype connectivity went from 11/11 to 12/12 and no pathophysiology node is now unreachable. Validation: `just validate-disorders` reports 44/44 snippets verified, schema and term validation passing. Clean: check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-snippet-grading, check-title-snippets, check-snippet-length, check-folded-hyphens, check-environmental-evidence, check-case-collisions, check-reference-titles, check-not4curation, validate-history. All 12 distinct reference titles were written programmatically from cache frontmatter and re-checked after assembly.

Claude Code ▸

Digitalis (Digoxin/Cardiac Glycoside) Poisoning — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 70 citations 2026-09-19T22:04:51.213671

Digitalis (Digoxin/Cardiac Glycoside) Poisoning — Comprehensive Research Report

1. Disease Information

Overview. Digitalis poisoning (digoxin toxicity, cardiac glycoside toxicity) is a potentially life-threatening intoxication produced by excessive exposure to digoxin or related cardiac glycosides (digitoxin, oleandrin, bufalin/bufadienolides, ouabain). It results from Na⁺/K⁺-ATPase pump inhibition and manifests as a triad of gastrointestinal, neurologic/visual, and cardiac-conduction disturbances, the last being the dominant cause of morbidity and mortality (StatPearls NBK459165; Medscape). Toxicity is classically divided into acute (single large ingestion, often suicidal or accidental, in a previously non-exposed person), acute-on-chronic (an extra dose/overdose superimposed on chronic therapy), and chronic (gradual accumulation from impaired clearance, drug interactions, or dose creep in a patient already on maintenance therapy) — these three patterns differ substantially in electrolyte pattern (hyperkalemia is typically an acute-poisoning finding; chronic toxicity does not usually cause hyperkalemia) and prognosis (LITFL Digoxin Toxicity; StatPearls).

Key identifiers | System | ID | |---|---| | MONDO | MONDO:0017863 ("digitalis poisoning") (Wikidata Q151350; NORD/Mondo mirror) | | MeSH | "Digoxin" (D004077); toxicity subheading; related "Cardiac Glycosides/poisoning" | | ATC | C01AA05 (digoxin, cardiac glycoside class C01A); V03AB24 (digoxin immune Fab antidote) | | ChEBI | CHEBI:4551 (digoxin) — cardenolide glycoside from Digitalis lanata, a steroid nucleus + unsaturated lactone ring + trisaccharide (ChEBI) | | PubChem CID | 2724385 (digoxin, C₄₁H₆₄O₁₄) (PubChem) | | ICD-10-CM | T46.0X1– (poisoning by cardiac-stimulant glycosides, accidental), with intent-based 5th/6th character extensions |

Synonyms/alternative names: digoxin toxicity, digitalis intoxication, cardiac glycoside toxicity/poisoning, digitalis glycoside overdose; plant-source variants are named for the source (oleander/yellow oleander poisoning, foxglove poisoning, toad-venom/bufadienolide poisoning).

Nature of source data. Because this is a toxidrome rather than a Mendelian or classically epidemiologic disease, most of the evidence base is: (a) aggregated case series and poison-control/registry data (individual case reports contribute mechanistic and phenotype detail but are not population-representative); (b) the large RCT evidence base for therapeutic digoxin use in heart failure/atrial fibrillation (the DIG trial and its post-hoc analyses), which is the source of dose–toxicity relationship data; and (c) basic-science/model-organism electrophysiology studies establishing mechanism. There is essentially no disease-specific EHR-derived cohort literature distinct from these three streams.

2. Etiology

Disease causal factor

Digitalis poisoning is fundamentally a pharmacologic/toxicologic disease, not a genetic one: it is caused by supratherapeutic tissue concentrations of a cardiac glycoside, reaching a level at which Na⁺/K⁺-ATPase inhibition exceeds the myocardium's compensatory capacity ("mechanistic" causal factor). There is no single-gene or chromosomal cause of the disease itself; genetic contributions are limited to pharmacokinetic/pharmacogenomic modifiers of individual susceptibility (below).

Risk factors

Environmental / iatrogenic / mechanistic: - Narrow therapeutic index. Therapeutic total digoxin is 0.8–2.0 ng/mL (older target) or, per contemporary heart-failure guidance, 0.5–1.0 ng/mL (lower is now preferred because higher levels raise morbidity/mortality without added benefit); toxicity is generally associated with levels >2.4 ng/mL, but ~10% of toxic patients have levels below 2 ng/mL, especially with hypokalemia, hypomagnesemia, hypoxia, or hypercalcemia (PMC10350506; StatPearls NBK459165). - Renal impairment — the leading cause of chronic toxicity; ~50–70% of a digoxin dose is excreted unchanged by the kidney, closely tracking GFR, so renal decline (common with age) markedly prolongs half-life (1.5–2.0 days with normal renal function → 3.5–5 days in anuric patients) (Clinical Pharmacokinetics of Digoxin, PMID:322907; StatPearls NBK556025). - Electrolyte disturbance: hypokalemia and hypomagnesemia (digoxin competes with K⁺ at the ATPase binding site, so low K⁺ increases glycoside binding/effect), hypercalcemia (potentiates the arrhythmogenic Ca²⁺-overload mechanism), hypoxemia, acid–base disturbance. - Drug–drug interactions: >100–400 reported interacting drugs; the clinically dominant mechanism is inhibition of P-glycoprotein (ABCB1)-mediated renal/biliary clearance and reduced volume of distribution — amiodarone, verapamil, quinidine, macrolides (clarithromycin, erythromycin), itraconazole, cyclosporine — each of which can roughly double serum digoxin concentration (StatPearls NBK459165; uspharmacist.com). - Age and sex: advanced age (renal decline, lower muscle mass → smaller volume of distribution, polypharmacy) and female sex are independently associated with higher toxicity risk and, in post-mortem genotyping series, greater lethality for a given exposure (PMID:21311904). - Plant/zootoxin exposure (non-iatrogenic route): ingestion of foxglove (Digitalis purpurea/lanata), oleander (Nerium oleander), yellow oleander (Thevetia peruviana), lily-of-the-valley (Convallaria majalis), or toad-derived bufadienolide preparations produces an identical clinical/ECG toxidrome via the same Na⁺/K⁺-ATPase mechanism (PMC3721620; PMC7472096). - Intentional self-poisoning is a major global route, dominated in South/Southeast Asia by yellow oleander seed ingestion (see §9 Epidemiology).

Genetic risk/modifier factors (pharmacogenomic, not causal): - ABCB1 (MDR1, P-glycoprotein, HGNC gene ABCB1) polymorphisms (notably 2677G>T/A and 3435C>T) modestly alter digoxin serum concentration via effects on P-gp–mediated intestinal absorption and renal/biliary excretion; results across studies are mixed — several show no clinically meaningful pharmacokinetic effect (PMID:12492608), while others link variant ABCB1 alleles to increased sudden-cardiac-death risk in digoxin users and to sex-differential post-mortem toxicity (PMID:26531821; PMID:21311904 "Post-mortem ABCB1 genotyping reveals an elevated toxicity for female digoxin users"; PMID:28208135; review PMID: Clin Pharmacokinet 2016). - SLCO1B3 (organic anion transporter) variants have also been examined as modifiers of digoxin disposition alongside ABCB1 in the Tunisian AF cohort study above. - There is no known primary Mendelian causal gene for digitalis poisoning; it is not a heritable disease.

Protective factors: - No genetic protective variant is described specifically against digitalis poisoning (unlike, e.g., predator/herbivore cardiac-glycoside-resistance alleles in other species — see §14). - Environmental/clinical protective factors: routine therapeutic drug monitoring, dose reduction with declining renal function, avoidance of known P-gp inhibitors, potassium/magnesium repletion, and (in the modern heart-failure era) preference for lower target concentrations (0.5–0.8 ng/mL) have reduced population-level toxicity incidence (StatPearls NBK459165).

Gene–environment interaction: The clearest G×E pattern is genotype (ABCB1)–drug interaction: a P-gp inhibitor (environmental exposure) produces a larger rise in serum digoxin in a patient whose ABCB1 genotype already confers reduced transporter efficiency, and this combination is proposed to explain some of the sex-based differences in fatal toxicity reported in post-mortem series (PMID:21311904).

3. Phenotypes

Digitalis poisoning presents with a fairly stereotyped triad. Frequencies below are drawn from case-series/registry literature; most are qualitative ("common," "most common") rather than precisely quantified in a single denominator study.

Phenotype	Type	HPO suggestion	Onset/course	Notes
Nausea and vomiting	Symptom (GI)	HP:0002018 (Nausea and vomiting); HP:0002017 (Nausea)	Earliest sign in both acute and chronic toxicity	Often the presenting complaint; anorexia frequently precedes it
Anorexia	Symptom	HP:0002039 (Anorexia)	Early	—
Abdominal pain	Symptom	HP:0002027 (Abdominal pain)	Variable	—
Diarrhea	Symptom	HP:0002014 (Diarrhea)	Variable	Less prominent than nausea/vomiting
Xanthopsia / chromatopsia (yellow-tinged vision)	Symptom (visual)	HP:0025590 or closest available "abnormality of color vision" term; no exact HPO term for xanthopsia exists — consider free text with SNOMED CT grounding	Chronic toxicity predominant	Classically described as "Van Gogh's yellow" vision; near-pathognomonic
Halo vision / photopsia / scotoma	Symptom (visual)	HP:0000496 (Halo vision)	Chronic toxicity	—
Diminished visual acuity	Sign	HP:0000505 (Visual impairment)	Chronic	—
Headache	Symptom	HP:0002315 (Headache)	Variable	—
Confusion / altered mental status	Symptom	HP:0001289 (Confusion)	More prominent in elderly/chronic toxicity	—
Malaise / weakness	Symptom	HP:0033834 (Fatigue) / HP:0001324 (weakness)	Variable	—
Insomnia	Symptom	HP:0100785 (Insomnia)	Variable	—
Premature ventricular complexes	Lab/ECG sign	Not HPO-mapped directly; consider EKG-specific ontologies (LOINC/SNOMED)	Cardiac	Most common dysrhythmia in digoxin toxicity
AV nodal (junctional) block, varying degree	ECG/clinical sign	HP:0011703 (Atrioventricular block)	Cardiac; 30–40% of toxic cases	"AV junctional blocks... are the most common manifestations of digoxin toxicity, occurring in 30-40% of cases" (Medscape/StatPearls synthesis)
Bidirectional ventricular tachycardia	ECG sign	HP:0004756 (Ventricular tachycardia) as parent term	Cardiac	Near pathognomonic for digoxin toxicity — alternating QRS axis beat-to-beat (LITFL)
Atrial tachycardia with block (esp. 2:1 AV block)	ECG sign	HP:0001700 (parent: Cardiac arrhythmia)	Cardiac	Classic pattern
Sinus bradycardia	Sign	HP:0001662 (Sinus bradycardia)	Cardiac	Vagotonic effect
Hyperkalemia	Lab abnormality	HP:0002153 (Hyperkalemia)	Acute poisoning predominant; usually absent in chronic toxicity	Strong severity/mortality marker (see §11)
"Scooped"/sagging ST depression, T-wave flattening/inversion, short QT, prominent U wave, PR prolongation	ECG (lab) finding	— (ECG morphology, not an HPO phenotype per se)	Chronic "digitalis effect," not toxicity per se	Reflects therapeutic exposure, distinct from toxic arrhythmia

Severity/progression: Acute poisoning tends to be more abrupt and life-threatening (vomiting, hyperkalemia, brady-/tachyarrhythmias progressing rapidly to hemodynamic collapse), whereas chronic toxicity is insidious, dominated by GI/CNS/visual symptoms with bradyarrhythmia and increased automaticity evolving over days (LITFL). Nearly any arrhythmia can occur — "almost any type of arrhythmia has been reported," making digoxin toxicity a classic diagnostic mimicker (Healio).

Quality-of-life impact: Not separately studied with EQ-5D/SF-36 instruments for the acute poisoning entity (as opposed to chronic digoxin-treated heart failure, where instrument data exist but reflect the underlying heart failure rather than glycoside toxicity itself). This is a data gap.

4. Genetic/Molecular Information

Digitalis poisoning is not a monogenic disease — there is no OMIM causal-gene entry, no ClinVar pathogenic-variant catalog, and no chromosomal-abnormality association analogous to a Mendelian disorder. The molecular information relevant to this entry is instead:

The molecular target: Na⁺/K⁺-ATPase (sodium pump), specifically the α-subunit's extracellular cardiac-glycoside binding pocket. In humans this is encoded chiefly by ATP1A1 (HGNC:799, the ubiquitously expressed catalytic α1 isoform, the principal cardiac isoform relevant to glycoside binding) and ATP1A2/ATP1A3 in other tissues. Digoxin binds a highly conserved extracellular pocket involving residues homologous to Q111, N122, F786, and T797 across species (eLife 48224; PMID:8385116).
Pharmacogenomic modifier genes — ABCB1 (P-glycoprotein) and SLCO1B3 (organic-anion transporter), discussed in §2, which alter systemic exposure but do not cause the disease.
Endogenous digoxin-like immunoreactive substances (DLIS/"endobain"/"endoxin") — an important molecular confounder rather than a causal factor: uncharacterized endogenous Na⁺/K⁺-ATPase-inhibiting factors cross-react with anti-digoxin immunoassays and are elevated in renal failure, liver failure, pregnancy, and especially neonates (with an inverse relationship to gestational/postnatal age and possibly linked to bilirubin level), producing falsely elevated "digoxin" levels in patients who have never taken the drug (Ann Intern Med, DOI:10.7326/0003-4819-99-5-604; Acta Paediatrica DLIS neonates; Eur J Pediatr). "As long as the chemical structure, origin and physiological properties of DLIS remain unknown, clinicians must be cautious in interpreting the serum levels of digoxin."
Somatic/epigenetic/chromosomal information: not applicable — no evidence of epigenetic dysregulation or chromosomal abnormality contributing to susceptibility beyond the pharmacogenomic SNP-level effects above.

Ontology note for a KB entry: since there is no causal Mendelian gene, genetic: entries (if used at all) should be scoped as modifier/susceptibility relationships (ABCB1, SLCO1B3) rather than causal, and the molecular target (ATP1A1, GO:0005391 sodium:potassium-exchanging ATPase activity) belongs in pathophysiology as the affected molecular function, not in a causal genetic: block.

5. Environmental Information

Iatrogenic/pharmaceutical exposure: digoxin prescribed for heart failure or atrial fibrillation rate control is the dominant real-world exposure route in high-income settings.
Toxins/plants (the classic "digitalis" exposure route and origin of the disease name): Digitalis purpurea and D. lanata (foxglove — original glycoside source), Nerium oleander (oleander) and Thevetia peruviana (yellow oleander), Convallaria majalis (lily of the valley), Kalanchoe spp., and toad venom (bufadienolides, e.g., from Bufo species used in some traditional Chinese medicines) — all inhibit the same Na⁺/K⁺-ATPase target and produce a clinically indistinguishable toxidrome (PMC3721620 Cardiotoxicity of plants in South Africa; VETgirl; StatPearls, bufalin/toad section).
Occupational/accidental exposure: pediatric accidental ingestion of ornamental plants or grandparents' medications; livestock grazing on oleander (documented outbreak in dairy cattle with food-safety implications for milk/meat, PMC7472096; PMC6723884 fatal cattle case).
Lifestyle factors: none specific to the causal mechanism; comorbid heart failure/AF (which drive prescription) are lifestyle-modifiable but the toxicity itself is dose/clearance-driven, not lifestyle-driven, apart from alcohol/renal-toxin exposures that worsen renal clearance.
Infectious agents: not applicable — this is not an infectious disease.

6. Mechanism / Pathophysiology

Ordered causal chain

Excess systemic exposure to a cardiac glycoside (supratherapeutic dose, impaired renal clearance, P-gp–inhibiting drug interaction, or ingestion of a glycoside-containing plant/toad product) leads to cardiac-glycoside tissue concentrations that exceed the therapeutic window.
Digoxin binds the extracellular K⁺-binding site of the Na⁺/K⁺-ATPase (Na,K-ATPase; sodium pump) α-subunit on the cardiomyocyte sarcolemma, which inhibits the enzyme's Na⁺-extrusion/K⁺-uptake activity in a manner that is competitively worsened by hypokalemia (digoxin and K⁺ compete for the same site) (StatPearls; PMID:322907; Deranged Physiology).
Na,K-ATPase inhibition causes a rise in intracellular Na⁺ concentration, which collapses the transmembrane Na⁺ gradient that the Na⁺/Ca²⁺ exchanger (NCX1) normally uses to extrude Ca²⁺.
Reduced Ca²⁺ extrusion via NCX1 leads to intracellular (and, specifically, sarcoplasmic-reticulum) Ca²⁺ accumulation — "calcium overload." (At therapeutic concentrations this same step, more modestly engaged, is the basis of digoxin's positive inotropic effect; recent work shows the mechanism critically depends on a specific allosteric state of NCX1 called Na⁺-dependent inactivation — Science Advances, sciadv.ady9596.)
At toxic (but not therapeutic) degrees of Na,K-ATPase inhibition, SR Ca²⁺ overload exceeds the SR's sequestering capacity, causing spontaneous, oscillatory Ca²⁺ release from the SR after normal repolarization.
Spontaneous Ca²⁺ release activates the electrogenic 3Na⁺/1Ca²⁺ exchanger in the Ca²⁺-extrusion direction, generating a net inward (depolarizing) current during phase 4 — a delayed afterdepolarization (DAD) (PMC5446409; PMC5597635 erratum).
If the DAD reaches threshold, it triggers spontaneous, non-driven action potentials (triggered automaticity/aftercontractions), which manifest as ectopic beats and, when they arise from independent foci with alternating exit pathways through the ventricular conduction system, produce the near-pathognomonic bidirectional ventricular tachycardia, as well as PVCs, accelerated junctional rhythms, and atrial tachycardia with block.
In parallel, digoxin increases vagal (parasympathetic) tone and enhances central sympathetic outflow / inhibits norepinephrine reuptake at adrenergic terminals, which branches to two further effects: (a) increased vagal tone slows SA-node discharge and prolongs AV-nodal conduction/refractoriness, producing sinus bradycardia and AV block (the basis of the classic "increased automaticity + decreased conduction" toxidrome description); (b) enhanced sympathetic tone contributes to the ectopic/triggered-automaticity burden above.
Independently, Na,K-ATPase inhibition causes a shift of intracellular K⁺ into the extracellular space, producing hyperkalemia — this branch is most evident in acute massive ingestion (where the sudden, large-magnitude pump inhibition rapidly redistributes total-body K⁺) and is typically absent in slowly accumulating chronic toxicity (StatPearls; LITFL). Serum K⁺ is therefore both a downstream biomarker of pump-inhibition severity and, empirically, the single best prognostic marker in acute poisoning (§11).
The combined arrhythmia burden (bradyarrhythmia, AV block, and/or ventricular tachyarrhythmia) culminates in hemodynamic instability, and, when untreated or severe, cardiac arrest/death — the proximate cause of most digitalis-poisoning mortality.
A separate, less-defined branch: digoxin's Na,K-ATPase inhibition in the area postrema/CNS and GI tract contributes to the nausea/vomiting and the visual-pathway effects (color-vision disturbance, xanthopsia), inferred rather than fully mechanistically demonstrated at the retinal/cortical level in humans; retinal Na,K-ATPase inhibition affecting photoreceptor signal processing is the leading hypothesis but retinal-level human mechanistic data are limited (inferred step).

Category detail

Molecular pathway/function: GO:0005391 (P-type Na⁺/K⁺-exchanging ATPase activity, sodium/potassium-transporting ATPase complex) inhibition is the initiating molecular lesion; downstream engagement of the Na⁺/Ca²⁺ exchanger (NCX1, gene SLC8A1) and SR Ca²⁺-handling machinery (SERCA2a/ATP2A2, ryanodine receptor RyR2) is the amplifying pathway.
Cellular process: GO:0086036 (regulation of cardiac muscle cell membrane potential), GO:0086013 (membrane repolarization in ventricular cardiac muscle cell), and triggered-automaticity/afterdepolarization processes; increased cardiomyocyte contractility (positive inotropy at sub-toxic levels) versus disordered automaticity at toxic levels.
Protein dysfunction: not a structural protein-misfolding disease — the "dysfunction" is pharmacologic inhibition of a normally functioning enzyme (Na,K-ATPase), not a mutant/misfolded protein.
Metabolic/biochemical: net cellular ion-homeostasis derangement (↑ intracellular Na⁺, ↑ intracellular Ca²⁺, ↑ extracellular K⁺); no primary energy-metabolism or lipid-metabolism lesion.
Immune involvement: none intrinsic to the toxicity; immune mechanisms are only relevant to the antidote (ovine anti-digoxin Fab fragments) and to rare Fab-associated serum-sickness/anaphylaxis reactions.
Tissue damage mechanisms: primarily electrophysiologic/functional (arrhythmia) rather than structural cell death; myocardial injury markers are not classically part of the toxidrome (unlike ischemic injury).
Cell types involved: cardiomyocyte (CL:0000746, cardiac muscle myoblast/cardiac muscle cell), cardiac Purkinje fiber cell/cardiac conduction system cells, SA-node and AV-node pacemaker cells, and (for the extracardiac symptoms) enteric/vagal afferent neurons and retinal photoreceptor/bipolar cells (visual symptoms).
Molecular profiling / advanced technologies: no transcriptomic, proteomic, single-cell, or spatial-omics signature is established for this toxidrome in humans — mechanistic knowledge derives almost entirely from classical electrophysiology (voltage-clamp, sharp-electrode recording in isolated Purkinje fibers and whole-heart preparations), not omics.

Suggested GO terms: GO:0005391 (Na⁺/K⁺-ATPase activity), GO:0086036 (cardiac membrane potential regulation), GO:0060402 (calcium ion transport into cytosol via sarcoplasmic reticulum), GO:0086016 (AV node cell action potential). Suggested CL terms: CL:0000746 (cardiac muscle cell), CL:1000497 (Purkinje myocyte), CL:0002129 (cardiac pacemaker cell).

7. Anatomical Structures Affected

Organ level: heart (primary organ); secondary/systemic effects on GI tract (nausea/vomiting), CNS (confusion, headache), and visual system (retina/optic pathway — xanthopsia, halos).
Body systems: cardiovascular system (primary), digestive system, nervous system (CNS and autonomic/vagal), visual system.
Tissue/cell level: the cardiac conduction system specifically — SA node, AV node, His-Purkinje fibers — plus ventricular and atrial myocardium generally. UBERON suggestions: UBERON:0002018 (SA node), UBERON:0002205 (AV node), UBERON:0002136 (Purkinje fiber cell tissue), UBERON:0000948 (heart).
Subcellular level: sarcolemma (site of Na,K-ATPase inhibition; GO cellular component GO:0005890 Na⁺/K⁺-ATPase complex), sarcoplasmic reticulum (Ca²⁺ overload site, GO:0033017 sarcoplasmic reticulum membrane), mitochondria (secondary Ca²⁺ handling, not primary).
Localization: diffuse/systemic rather than focal; no lateralization applicable (bilateral/systemic toxicity).

8. Temporal Development

Onset: any age; timing depends on exposure route. Acute ingestion → symptom onset typically within hours (GI symptoms first, cardiac effects following the ~6–8-hour distribution phase). Chronic toxicity develops insidiously over days to weeks as clearance declines or dose/interacting drugs accumulate.
Progression/stages: pre-symptomatic supratherapeutic level → GI prodrome → neurologic/visual symptoms (chronic pattern) → cardiac conduction/arrhythmia phase → (if untreated) hemodynamic collapse/cardiac arrest.
Course pattern: acute poisoning is typically a self-limited event (resolves with elimination/antidote) unless fatal; chronic toxicity may recur if the precipitating renal/drug-interaction/dosing problem is not corrected.
Critical period for intervention: the first ~1 hour post-acute-ingestion is the window for GI decontamination (activated charcoal); the diagnostic/therapeutic window for digoxin-specific antibody (Fab) therapy is essentially the entire symptomatic period, since Fab does not depend on the same narrow timing constraint as charcoal (StatPearls NBK459165; RebelEM).
Remission: recovery typically follows drug clearance/discontinuation and, when indicated, Fab administration; recurrence is possible if the underlying cause (renal failure, ongoing interacting drug) persists.

9. Inheritance and Population

Inheritance: not applicable — digitalis poisoning is an acquired toxicologic disease, not a Mendelian condition. No inheritance pattern, penetrance, expressivity, anticipation, mosaicism, founder-effect, or carrier-frequency concept applies to the disease itself (only to the minor ABCB1/SLCO1B3 pharmacogenomic modifiers described in §4).

Epidemiology: - United States: an estimated ~8,000 hospital visits annually for digitalis toxicity; in 2011 the US Poison Control system recorded 2,513 cases, of which 27 resulted in death (Medscape/StatPearls synthesis). - Age-stratified ED burden: digoxin toxicity accounted for ~1% of adverse-drug-event ED visits in patients ≥40 years, rising to 3.3% in patients ≥85 years, and 5.9% of adverse-drug-event hospitalizations in patients ≥85 years; ED admissions for digoxin toxicity were 3.5-fold greater in patients >85 years than in a younger comparison cohort (CDC report). - Historical elderly-specific series: up to a quarter of all drug poisonings in elderly cohorts have historically been attributed to digitalis toxicity in some series (ScienceDirect PMID:073567579190161C). - Prescribing trend: digoxin use in heart failure has declined substantially (to roughly ~8% of HF patients started on it at discharge in recent practice), which has correspondingly reduced toxicity incidence over the past decade (StatPearls NBK459165). - Global/plant-poisoning burden: Yellow oleander (Thevetia peruviana) seed self-poisoning is a major cause of digitalis-like toxicity in South Asia, with "thousands of cases each year" in northern Sri Lanka alone, and an estimated tens of thousands of cases and probably thousands of deaths per year across South Asia; in some Sri Lankan regions up to 40% of self-poisoning cases are oleander-related, with annual incidence >150/100,000 in affected districts, disproportionately affecting adolescents/young adults; overall mortality ~10% in Sri Lankan series, and oleander plus paraquat together caused 74% of poisoning deaths in patients <25 years old (Trop Med Int Health 1999; PMID:16319413; Sci Total Environ review, ScienceDirect 0379073888901508). - Sex distribution: females are disproportionately represented in ED visits for digoxin toxicity relative to outpatient prescription frequency (CDC report); in the Sri Lankan oleander series, 61% of admitted cases were women, and 46% were <21 years old (oleander case series). - Geographic distribution: iatrogenic digoxin toxicity is globally distributed wherever digoxin is prescribed (highest absolute case counts in older, higher-income populations with heart failure/AF); plant-glycoside poisoning is concentrated in regions where the causative plants grow and are used for self-harm (South Asia for yellow oleander; parts of Africa for other cardiotoxic plants — PMC3721620).

10. Diagnostics

Laboratory tests - Serum digoxin concentration: therapeutic 0.8–2.0 ng/mL (older range) / 0.5–1.0 ng/mL (contemporary HF target); toxic threshold >2.4 ng/mL, but diagnosis is clinical, since levels do not reliably correlate with toxicity — deaths have occurred within the "therapeutic" range, and atrial-fibrillation patients show increased mortality risk even at >1.2 ng/mL (StatPearls NBK459165; PMC10350506). Timing matters: levels must be drawn ≥6 hours post-dose/ingestion (after the distribution phase) to avoid falsely elevated readings. - Free (unbound) digoxin: therapeutic 0.4–0.9 ng/mL; toxicity associated with ≥3.0 ng/mL free digoxin (droracle summary). - Serum potassium — the single best-validated severity/prognostic biomarker in acute poisoning (see §11); also magnesium, calcium, and renal function (creatinine/GFR) — essential because renal impairment is the dominant chronic-toxicity risk factor. - Assay caveats: endogenous digoxin-like immunoreactive substances (DLIS) cause false-positive "digoxin" levels in renal failure, hepatic failure, pregnancy, and neonates (§4); Fab therapy itself invalidates standard immunoassay readings post-treatment because bound digoxin-Fab complex cross-reacts, giving falsely high apparent levels (StatPearls NBK459165).

Electrophysiology / imaging - 12-lead ECG and continuous cardiac monitoring are the primary and most time-sensitive diagnostic tools: look for PVCs (most common), AV block of any degree, sinus bradycardia, atrial tachycardia with block, and — near-pathognomonic — bidirectional ventricular tachycardia (LITFL; PMC8212916 case report). - "Digitalis effect" (as opposed to toxicity) — scooped/sagging ST depression, T-wave flattening/inversion, short QT, prominent U-wave, PR prolongation — reflects therapeutic exposure and is distinct from a toxic arrhythmia and must not itself be mistaken for toxicity. - No specific imaging modality is diagnostic; echocardiography may be used to assess the underlying cardiac disease (not the toxicity per se).

Clinical criteria / differential diagnosis - Diagnosis is clinical, integrating exposure history, ECG pattern, and (supportively) serum level; differential includes other causes of AV block/bradyarrhythmia (beta-blocker or calcium-channel-blocker toxicity, hyperkalemia from other causes, sick sinus syndrome), other toxidromes causing GI+neuro symptoms, and — importantly — other cardiac glycoside exposures (oleander, foxglove, toad venom) which may or may not cross-react on a digoxin immunoassay depending on the specific assay (StatPearls NBK459165).

Screening: no population screening program exists; this is an acute/subacute event rather than a screenable condition. The nearest analog is therapeutic drug monitoring protocol in patients on chronic digoxin (checking level after dose change, with new renal impairment, or with initiation of an interacting drug).

Genetic testing: not indicated for the disease itself. ABCB1 genotyping remains a research tool rather than a validated clinical decision aid for digoxin dosing at this time.

11. Outcome/Prognosis

Mortality: severe digoxin toxicity carries an estimated ~20% mortality in historical series predating widespread Fab availability (StatPearls NBK459165); more recent in-hospital mortality estimates range 3–20% depending on population and era (search synthesis, various). US Poison Control 2011 data show a case-fatality of ~1.1% (27/2,513) across the broad (including less-severe) reported case population (Medscape overview).
Best-validated prognostic marker — serum potassium in acute ingestion: a classic series of 91 patients (pre-Fab era) found serum K⁺ >5.5 mEq/L associated with 100% mortality, 5.0–5.5 mEq/L with ~50% mortality, and <5.0 mEq/L with 0% mortality, and potassium outperformed both initial ECG changes and serum digoxin level as a predictor of death (synthesis of the classic Bismuth series, cited via StatPearls/PMC3372009). Expert consensus treats serum K⁺ ≥6 mEq/L (with other causes of hyperkalemia excluded) as an indication for Fab therapy.
Complications: refractory bradyarrhythmia/heart block, ventricular arrhythmia and cardiac arrest (leading direct cause of death), hyperkalemia-related complications, and — as a treatment complication — anaphylaxis or serum sickness from ovine Fab fragments.
Recovery potential: generally good with prompt recognition and Fab therapy where indicated; digoxin's positive inotropic/toxic effects are reversible once free drug is neutralized or eliminated, and no long-term structural cardiac sequelae are described from the toxicity itself (as opposed to the underlying heart disease that led to digoxin prescription).
Prognostic factors overall: age, degree/type of arrhythmia (heart block or new arrhythmia worsens prognosis), renal function, timing of presentation, and (per the above) serum potassium at presentation.

12. Treatment

Decontamination - Activated charcoal (single or multi-dose) is first-line for recent (~within 1 hour) acute ingestion; multi-dose charcoal can interrupt enterohepatic recirculation. By the time cardiac symptoms manifest, most patients are outside this window (RebelEM; StatPearls NBK459165). - Gastric lavage is avoided — vagal stimulation from the procedure risks worsening bradyarrhythmia.

Definitive antidote — Digoxin Immune Fab (ovine) - Digoxin Immune Fab (brand names Digibind, DigiFab) — ovine polyclonal Fab fragments raised against a digoxin derivative (digoxindicarboxymethoxylamine, DDMA) that rapidly bind and neutralize free digoxin (DigiFab prescribing info, FDA; Wikipedia). - Indications: life-threatening arrhythmia (especially AV block or ventricular tachyarrhythmia), acute ingestion ≥10 mg in a previously healthy adult (≥4 mg or >0.1 mg/kg in a child), serum digoxin >10 ng/mL, or serum K⁺ ≥5 mEq/L in the setting of digoxin toxicity (mdcalc; StatPearls NBK459165). - Dosing: one 40 mg vial neutralizes ~0.5 mg digoxin; empiric dosing of 10 vials (adult)/5 vials (pediatric) is used when the ingested dose/level is unknown; a weight-and-level-based formula (vials = [serum level (ng/mL) × weight (kg)] / 100) is used when data are available. - Practical consequences: after Fab administration, standard digoxin immunoassays become clinically uninterpretable (falsely high, reflecting bound complex) until Fab is cleared; hypokalemia commonly follows successful Fab therapy as the pump is "released," requiring close K⁺ monitoring (StatPearls NBK459165). - Adverse effects: hypersensitivity/anaphylaxis (screen for known sheep-protein, papain/papaya allergy) and serum sickness.

Supportive/electrolyte management - Hyperkalemia: standard measures (insulin/glucose, sodium bicarbonate, binding resins); IV calcium is classically considered relatively contraindicated in digoxin toxicity because it can precipitate ventricular arrhythmia by further raising already-elevated intracellular Ca²⁺ ("stone heart" concern) — though this theoretical concern lacks strong clinical-outcome data supporting an absolute contraindication, per recent reviews (StatPearls NBK459165); Fab is preferred over calcium when K⁺ ≥5 mEq/L is due to digoxin. - Bradyarrhythmia/AV block: atropine as a temporizing measure (excess vagal tone); temporary transvenous pacing may be considered but pacing/beta-agonists risk provoking ventricular tachyarrhythmia and are used cautiously. - Ventricular arrhythmia: lidocaine or phenytoin have been used for digoxin-induced ventricular ectopy/tachyarrhythmia; magnesium is generally avoided if it will worsen bradycardia/AV block; cardioversion is avoided where possible (risk of precipitating refractory ventricular fibrillation) — defibrillation per ACLS protocol is reserved for pulseless arrest. - Hemodialysis/hemofiltration: not effective for digoxin removal because of its very large volume of distribution (~6 L/kg) and extensive tissue binding (only ~0.5% of total-body digoxin is in the blood at steady state); the digoxin-Fab complex is likewise not cleared by conventional hemodialysis. Continuous venovenous hemodialysis/plasma exchange have been reported in refractory renal-failure cases as salvage options (Pharmacy Times summary; PMC12702486 plasma exchange after Fab failure).

Yellow-oleander-specific note: fructose-1,6-diphosphate has been trialed as a low-cost antidote for yellow-oleander cardiotoxicity in resource-limited settings where Fab is unaffordable, given cost barriers to Fab access in South Asia (PMC2912827 FDP RCT).

Suggested NCIT terms: NCIT:C15747 (Supportive Care) for general management; NCIT:C15986 (Pharmacotherapy) with therapeutic_agent bound to the Fab product (no confirmed NCIT code identified in this search — verify via OAK/NCIT lookup before curation); a device/procedure term (e.g., transvenous pacing) would use the standard NCIT clinical-intervention/device pattern already established elsewhere in this KB.

13. Prevention

Primary prevention (iatrogenic): careful patient selection, renal-function-adjusted dosing, preference for lower target serum concentrations (0.5–0.8/1.0 ng/mL) in heart failure, avoidance/careful monitoring when co-prescribing known P-gp inhibitors (amiodarone, verapamil, macrolides, azole antifungals), and electrolyte optimization (avoid/correct hypokalemia, hypomagnesemia).
Secondary prevention: routine therapeutic drug monitoring in at-risk patients (elderly, renal impairment, new interacting drug, dose change), with digoxin levels drawn correctly (≥6 h post-dose).
Primary prevention (plant/environmental): public-health messaging around the toxicity of foxglove, oleander, lily-of-the-valley, and related ornamental plants for households with children/pets; means-restriction approaches (reducing accessibility of yellow oleander seeds) have been proposed as a suicide-prevention strategy in South Asia, analogous to pesticide means-restriction, though this is less developed in the literature than pesticide restriction programs.
Public health/behavioral: recognition that self-poisoning with a lethal, locally accessible plant agent (yellow oleander) is closely tied to impulsive self-harm in young people in endemic regions, making rapid access to antidote (Fab) and emergency care — rather than exposure elimination alone — a key tertiary-prevention lever given the plant's ubiquity.
Veterinary/agricultural prevention: removing oleander and other cardiotoxic ornamentals from livestock-accessible pasture/hedgerows to prevent grazing-animal poisoning outbreaks and downstream food-safety concerns (contaminated milk/meat) (PMC7472096).
Prophylaxis: no chemoprophylactic agent exists; prevention is entirely a matter of dosing/monitoring practice and exposure avoidance.
Genetic counseling: not applicable (no heritable component to counsel about).

14. Other Species / Natural Disease

Companion animals: dogs and cats are frequently poisoned by ingestion of foxglove, oleander, lily-of-the-valley, or Kalanchoe houseplants; clinical signs mirror the human toxidrome — drooling, vomiting/diarrhea, bradyarrhythmia, "nearly any type of dysrhythmia," tremors, and sudden death with few premonitory signs (Pet Poison Helpline; VETgirl). Dog-toad (bufadienolide) poisoning from Bufo species interaction is a recognized veterinary presentation, especially where toads/frogs and dogs cohabit outdoor spaces.
Livestock: cattle are poisoned by grazing on oleander, with documented outbreak-level mortality in dairy herds and secondary food-safety concerns about oleandrin residues in milk/meat (PMC7472096; PMC6723884).
NCBI Taxon references: Canis lupus familiaris (NCBITaxon:9615), Felis catus (NCBITaxon:9685), Bos taurus (NCBITaxon:9913), Equus caballus (NCBITaxon:9796) are all reported natural hosts of cardiac-glycoside plant poisoning.
Comparative/evolutionary biology — a genuinely distinctive feature of this "disease": several vertebrate and invertebrate lineages that specialize on cardiac-glycoside-containing diets or prey have independently evolved target-site resistance in the Na,K-ATPase α-subunit. Rodents (Cricetidae and Muridae) have convergently evolved substitutions Q111L + A119S in ATP1A2 and Q111R in ATP1A1, reducing cardiac-glycoside binding affinity at the same pocket digoxin exploits in humans (eLife 48224); the crested serpent-eagle preying on invasive toxic cane toads in Okinawa shows analogous Na,K-ATPase-mediated resistance (PMID:40660117); milkweed-specialist insect predators/parasites show the same convergent pattern (ScienceDirect S0960982221014147). This is directly relevant to why rodents used as toxicology/pest-control models are relatively insensitive to cardiac glycosides, a key consideration in interpreting rodent-model data for this entry.
Zoonotic potential: none — this is a toxicologic, not infectious, process, so it is not "transmissible," though secondary human poisoning via contaminated animal products (milk/meat from oleander-grazing livestock) is a real, documented food-safety pathway.

15. Model Organisms

Digitalis poisoning is modeled almost entirely through acute pharmacologic/electrophysiologic challenge, not through genetic (knockout/transgenic) disease models, because the "disease" is drug/toxin exposure rather than a genetic lesion.

Guinea pig (whole-animal, in vivo): slow IV digoxin infusion in the anesthetized guinea pig reliably provokes extrasystoles, ventricular tachyarrhythmia, and cardiac arrest, and has been used classically to test antidote efficacy — e.g., a loading dose of 500 µg/kg digoxin was used to establish otherwise-lethal toxicity before testing monoclonal anti-digoxin antibody/Fab reversal (PMID:6707937 "Reversal of lethal digoxin toxicity in guinea pigs using monoclonal antibodies and Fab fragments"). Standardized "Electrocardiographic Toxicity in the Guinea Pig" protocols exist for this purpose (Curr Protoc Pharmacol).
Dog (whole-animal and isolated Purkinje fiber): canine Purkinje fiber preparations, using the cardiac glycoside strophanthidin as a pharmacologic proxy, are the classical system for demonstrating glycoside-induced enhancement of diastolic depolarization slope and spontaneous automaticity, and abnormal Ca²⁺ cycling as the source of non-driven depolarizations in conduction tissue (PMID:1257581 "On the mechanisms underlying digitalis toxicity in cardiac Purkinje fibers"; JACC 1985, S0735-1097(85)80460-5). Selective AV-block induction with physostigmine has been used in dogs to terminate digoxin-induced ventricular arrhythmia experimentally (PMID:512919).
Rodent limitation (mouse/rat): as noted in §14, rodents have evolved reduced-affinity Na,K-ATPase isoforms (ATP1A1 Q111R; ATP1A2 Q111L/A119S), making them comparatively insensitive to cardiac glycosides relative to humans/dogs/guinea pigs — an important translational caveat for any rodent-based mechanistic or antidote study, and part of why guinea pig and dog (not mouse/rat) are the historical gold-standard toxicity models.
Cell-based/isolated-tissue systems: isolated cardiac Purkinje fiber and ventricular myocyte preparations (sharp-electrode/voltage-clamp) remain the primary reductionist system for dissecting the DAD/triggered-automaticity mechanism; no major organoid, iPSC-cardiomyocyte, or CRISPR-screen literature specific to digoxin toxicity was identified in this search (a plausible gap/opportunity area rather than an established resource).
Model translational fidelity: guinea pig and dog models recapitulate the core arrhythmia phenotype (ectopy, tachyarrhythmia, AV block) and were historically used to validate Fab-fragment antidote efficacy prior to human licensure, giving them high fidelity for the cardiac-electrophysiology endpoint; they do not model the human GI/visual symptom complex, which remains characterized almost exclusively from human case reports and case series.

Summary for Knowledge-Base Curation

Digitalis poisoning is best curated as an acquired/toxicologic disease entry (MONDO:0017863) with: - Pathophysiology nodes: Na⁺/K⁺-ATPase inhibition (molecular) → intracellular Na⁺/Ca²⁺ overload (molecular) → NCX1-mediated delayed afterdepolarization (cellular) → triggered automaticity/AV block (cellular→tissue) → arrhythmia/hemodynamic collapse (systemic), plus a parallel autonomic (vagal/sympathetic) branch and a hyperkalemia branch specific to acute massive exposure. - No causal genetic: entries in the Mendelian sense; ABCB1/SLCO1B3 belong, if included at all, as modifier/susceptibility relationships, and ATP1A1 as the pathophysiology-node molecular target. - Environmental entries for iatrogenic overdose, drug–drug interaction (P-gp inhibitors), and plant/zootoxin exposure (foxglove, oleander, yellow oleander, lily of the valley, toad bufadienolides), each with influences_mechanisms linking to the Na⁺/K⁺-ATPase inhibition node. - Treatments: Digoxin Immune Fab as the flagship targeted antidote (with therapeutic_agent/NCIT binding to be resolved via OAK lookup), activated charcoal, atropine/pacing, and explicit notes on the calcium-contraindication controversy and hemodialysis ineffectiveness. - Animal models: guinea pig and dog (RECAPITULATES, high fidelity for the cardiac phenotype), with an explicit divergence note for rodent Na,K-ATPase target-site insensitivity if a mouse/rat model is ever added.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	35
Resolved	34
Unresolved (possible confabulation)	0
Unverifiable	1
References weighed for topical relevance	34
On topic	11
Off topic	1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

PMID:40660117 (5 mentions) - Evolutionary insights into Na(+)/K(+)-ATPase-mediated toxin resistance in the Crested Serpent-eagle preying on introduced cane toads in Okinawa, Japan.
shared terms: atpase

Weighed against this report's own most characteristic terms: digoxin, toxicity, cardiac, poisoning, digitalis, glycoside, disease, drug, exposure, fab, failure, effect, oleander, atpase, patient, heart, renal, ventricular, acute, arrhythmia.

34 of 35 references resolved; the rest could not be looked up either way. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	41
Resolved	40
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	32
Terms named correctly	17
Terms named as a different term	6
Terms whose name is worth a second look	9

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0017863 (3 mentions) - the report calls it "digitalis poisoning", "acquired/toxicologic disease entry"; MONDO calls it digitalis poisoning
HP:0000496 (1 mention) - the report calls it "Halo vision"; HP calls it Abnormality of eye movement
HP:0011703 (1 mention) - the report calls it "Atrioventricular block"; HP calls it Sinus tachycardia
HP:0001700 (1 mention) - the report calls it "parent: Cardiac arrhythmia"; HP calls it Myocardial necrosis
UBERON:0002205 (1 mention) - the report calls it "AV node"; UBERON calls it manubrium of sternum
UBERON:0002136 (1 mention) - the report calls it "Purkinje fiber cell tissue"; UBERON calls it hilus of dentate gyrus

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0001662 (1 mention) - the report calls it "Sinus bradycardia"; HP calls it Bradycardia
GO:0005391 (3 mentions) - the report calls it "P-type Na⁺/K⁺-exchanging ATPase activity, sodium/potassium-transporting ATPase complex", "Na⁺/K⁺-ATPase activity"; GO calls it P-type sodium:potassium-exchanging transporter activity, and lists "P-type sodium:potassium-exchanging ATPase activity" among its other names
GO:0086036 (2 mentions) - the report calls it "regulation of cardiac muscle cell membrane potential", "cardiac membrane potential regulation"; GO calls it regulation of cardiac muscle cell membrane potential
GO:0086013 (1 mention) - the report calls it "membrane repolarization in ventricular cardiac muscle cell"; GO calls it membrane repolarization during cardiac muscle cell action potential
GO:0060402 (1 mention) - the report calls it "calcium ion transport into cytosol via sarcoplasmic reticulum"; GO calls it calcium ion transport into cytosol
CL:1000497 (1 mention) - the report calls it "Purkinje myocyte"; CL calls it kidney cell
CL:0002129 (1 mention) - the report calls it "cardiac pacemaker cell"; CL calls it regular atrial cardiac myocyte, and lists "atrial cardiac muscle cell" among its other names
UBERON:0002018 (1 mention) - the report calls it "SA node"; UBERON calls it synovial membrane of synovial joint, and lists "stratum synoviale" among its other names
NCBITaxon:9615 (1 mention) - the report calls it "Canis lupus familiaris", "NCBI Taxon references: *Canis lupus familiaris"; NCBITaxon calls it Canis lupus familiaris**

Terms named inconsistently

The report gives these identifiers more than one name of its own:

MONDO:0017863 - called "digitalis poisoning", "acquired/toxicologic disease entry"
GO:0005391 - called "P-type Na⁺/K⁺-exchanging ATPase activity, sodium/potassium-transporting ATPase complex", "Na⁺/K⁺-ATPase activity"
GO:0086036 - called "regulation of cardiac muscle cell membrane potential", "cardiac membrane potential regulation"
NCBITaxon:9615 - called "Canis lupus familiaris", "NCBI Taxon references*: Canis lupus familiaris"

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Digitalis (Digoxin/Cardiac Glycoside) Poisoning — Comprehensive Research Report

1. Disease Information

2. Etiology

Disease causal factor

Risk factors

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

Category detail

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary for Knowledge-Base Curation

Sources

Reference Validation

References that may not be about this subject

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently