Why this poison is interesting

There is a pleasing circularity to opening the botanical band with foxglove. William Withering learned the use of Digitalis purpurea from a Shropshire herbalist in 1775, and the drug that became digoxin is a purified single glycoside pulled out of a leaf that contains dozens. The plant poisoning is therefore the parent of the drug poisoning, and the mechanism on the digoxin page applies here without amendment: inhibition of Na⁺/K⁺-ATPase, calcium overload through the sodium–calcium exchanger, increased automaticity, and a vagotonic slowing of the nodes.¹

So why a separate page? Because two things that are quiet conveniences with the pharmaceutical drug become active traps with the plant. The digoxin immunoassay reacts unpredictably with plant glycosides, so the one number a clinician reaches for to confirm the diagnosis can read low or absent while the patient is severely poisoned. And the plant does not come with a dose written on a box, so the estimation route that partly rescues digoxin management — vials from milligrams ingested — is unavailable. What is left is the clinical picture, the potassium, and an antidote that fortunately does not share the assay's calibration problem.

The toxic principle

Every clinically important plant cardiac glycoside is built on the same plan: a steroid nucleus, an unsaturated lactone ring that does the binding, and one or more sugars that modify potency and kinetics. That lactone-and-steroid core binds the extracellular face of Na⁺/K⁺-ATPase exactly as digoxin does, holding the pump in a conformation it cannot complete.¹

Because the mechanism is identical, so are the rhythms: premature ventricular contractions early, PR prolongation, bradyarrhythmias and AV block, and in severe poisoning the near-specific patterns — paroxysmal atrial tachycardia with block, bidirectional ventricular tachycardia, and regularised atrial fibrillation. The digoxin page describes each; nothing about them changes when the source is a leaf rather than a tablet.

Toxicokinetics

Plant glycosides are a family, not a molecule, so a single kinetic table is a simplification. The clinically important axis is that the foxglove glycosides — digitoxin in particular — are more lipid-soluble, more highly protein-bound and longer-acting than digoxin, cleared by the liver with a large enterohepatic component rather than renally. That has one practical implication and the table turns on it.

Foxglove glycosides against pharmaceutical digoxin — the differences that matter
Parameter	Therapeutic	In overdose	Why it changes
Absorption	Well absorbed orally; glycosides are heat-stable, so cooking, drying or brewing does not detoxify the plant	Unchanged in kind; a large leaf ingestion delivers a mixture of glycosides of differing potency	The heat stability matters because most botanical exposures are either accidental (foxglove mistaken for comfrey or borage) or deliberate herbal use — neither is protected by preparation.
Distribution	Large tissue distribution, as for digoxin, whose Vd is about 510 L⁴	Unchanged — and this is why extracorporeal removal fails	The poison lives in tissue, not plasma. The same structural fact that defeats dialysis for digoxin defeats it here.
Protein binding	Digitoxin is far more protein-bound than digoxin (of the order of 90% versus digoxin's ~25%)	Unchanged	High binding further argues against dialysis, and lengthens the elimination of the foxglove glycosides relative to digoxin.
Metabolism and elimination	Digitoxin is hepatically metabolised with marked enterohepatic recirculation, in contrast to digoxin's predominantly renal route⁴	Unchanged mechanism; the enterohepatic loop is the reason repeated-dose activated charcoal is invoked	The enterohepatic loop is the mechanistic rationale for multiple-dose activated charcoal in yellow-oleander poisoning — although, as below, the trial evidence for a mortality benefit is not there. Inferred
Half-life	Longer than digoxin's — digitoxin persists for days rather than the 30–40 h of digoxin⁴	Prolonged further in overdose	A longer half-life means the toxic effect and the risk of rebound outlast the initial presentation, and observation periods must reflect the specific glycoside where it is known.
Dialysability	—	No. Large volume of distribution and high protein binding, the same argument as digoxin	EXTRIP recommends against extracorporeal treatment for digoxin in any form regardless of severity, because a 510-litre volume of distribution does not change with severity.³ The foxglove glycosides, more protein-bound still, are no more removable.

Metabolism and the metabolites

As with digoxin, the parent glycoside is already the toxic species — there is no bioactivation to wait for. What the metabolism section adds for the plant is the enterohepatic loop, which is more prominent for the lipophilic foxglove glycosides than for digoxin and which shapes both the duration of toxicity and the decontamination argument.

Foxglove glycosides — the enterohepatic loop is the point

Plant glycoside (ingested leaf, flower or tea)Already the toxic species. Heat-stable — not destroyed by cooking or brewing
Absorption; binds Na⁺/K⁺-ATPase in every tissueNo metabolic activation required
Hepatic metabolism and biliary excretionGlycoside in bile → gutReabsorbed from the gut lumen — the enterohepatic loop that prolongs the digitoxin-type poisoning
Renal excretion (variable by glycoside)Glycoside in urineA minor route for the lipophilic foxglove glycosides, unlike digoxin

Elimination and accumulation

The elimination story for the foxglove glycosides is the mirror of digoxin's in one respect: hepatic, not renal, with a substantial enterohepatic component. That has two consequences. First, renal function — the variable that turns a stable digoxin prescription into a chronic poisoning — is far less relevant to the foxglove glycosides. Second, the longer half-life and the recirculating pool mean the poison persists, and a patient who has stabilised is not necessarily finished.

Target organs — and why those

The target-organ logic is digoxin's: Na⁺/K⁺-ATPase is everywhere, and what differs between tissues is how visibly a partially inhibited pump matters. The heart dominates because it converts a small change in intracellular calcium directly into a rhythm.

Myocardium and conducting system

TargetNa⁺/K⁺-ATPase in cardiomyocytes; vagal input to the SA and AV nodes

Why hereThe heart concentrates and responds to the glycosides for the same reasons it does with digoxin: calcium overload generates afterdepolarisations and therefore automaticity, while vagotonia suppresses the nodes. The combination of a slow node and an irritable ventricle is the signature, and it is glycoside-class, not molecule-specific. Established

At the bedsideBradyarrhythmias, AV block, ventricular ectopy and, in severe poisoning, the near-specific patterns; hyperkalaemia tracks severity in acute ingestion.²

Gut and area postrema

TargetPump inhibition in enteric tissue plus chemoreceptor trigger zone stimulation

Why hereThe area postrema sits outside the blood–brain barrier and samples plasma directly, so profound vomiting occurs even though the glycosides penetrate the CNS poorly. Vomiting is usually the first symptom and, unlike with mushrooms, arrives early. Inferred

At the bedsideNausea, vomiting and abdominal pain, often within hours; the plant material itself is intensely bitter and irritant.

Skeletal muscle

TargetThe same pump, in the largest tissue mass in the body

Why hereAs in digoxin poisoning, skeletal muscle holds a large share of the body burden and is a principal source of the potassium that appears in serum when the pump is inhibited. Inferred

At the bedsideContributes to the hyperkalaemia of acute poisoning, which is a marker of severity rather than a renal phenomenon.

Timeline of effects

Acute foxglove or oleander ingestion — early vomiting, then the cardiac phase

Time

What you seeWhat is happening

0–2 hGastrointestinal onset
What you seeNausea, vomiting, abdominal pain. Unlike amatoxin mushrooms, the gut symptoms come early.
What is happeningDirect enteric irritation plus area postrema stimulation. Glycoside absorption is under way; tissue uptake beginning.
2–12 hCardiac phase
What you seeBradyarrhythmias, AV block, ventricular ectopy; hyperkalaemia in significant ingestions.
What is happeningNa⁺/K⁺-ATPase inhibition established across the myocardium; calcium overload produces afterdepolarisations, vagotonia suppresses the nodes.
12–24 h+Plateau and slow decline
What you seeArrhythmia may persist for a day or more, longer with the lipophilic foxglove glycosides.
What is happeningThe long half-life and enterohepatic recirculation of the foxglove-type glycosides mean the body burden falls slowly, with no rapid clearance route.

What the mechanism predicts at the bedside

Do not use a digoxin level to exclude a plant glycoside ingestion. The immunoassay is calibrated for digoxin and reacts unpredictably with plant glycosides; a low or absent result is consistent with severe poisoning. The DigiFab label states in vitro binding affinities are similar for digoxin and plant glycoside analogues, which is why the antidote works even though the assay does not.¹ Established
Potassium is the most informative single number, as in digoxin poisoning — it estimates the fraction of pump inhibited, and in yellow-oleander poisoning it is associated with serious arrhythmia and marks severity.²
Dialysis is futile, for the same reason as digoxin: large volume of distribution, high protein binding, negligible plasma fraction. EXTRIP recommends against it for digoxin in any form.³
An irregularly irregular rhythm becoming regular is usually a deterioration — complete AV block with a junctional escape, not restored sinus rhythm — exactly as on the digoxin page.⁴
Digoxin-specific Fab is the specific treatment and it cross-reacts, but the dose cannot be estimated from an ingested milligram figure the way it can for a tablet count; the label carries a separate scheme for non-pharmaceutical glycoside poisoning and management is set with NPIS.¹

The antidote, from the poison's side

The antidote is the same digoxin-specific antibody fragment used for the pharmaceutical drug, and the reason it works on a leaf poisoning is a happy accident of immunology: the antibody was raised against digoxin, but its binding site recognises the shared steroid-lactone core, so it grips plant glycosides too.

How an antidote confined to plasma empties tissue is explained on the digoxin page: binding free plasma glycoside reverses the concentration gradient across every cell membrane, and tissue glycoside flows back into plasma to be bound in turn. Total measured 'digoxin' rises after Fab and the free active fraction falls — a rising level after antidote is expected and is not treatment failure. Because the foxglove glycosides are longer-acting, the observation window after apparent recovery should be longer than for a pharmaceutical-digoxin patient.

Critical appraisal

The immunoassay cross-reactivity is qualitative, not quantitative. That a digoxin immunoassay may detect a plant glycoside is established; the degree of cross-reactivity varies by glycoside and by assay platform, so a positive result confirms exposure but a number should not be trusted as a body-burden estimate.¹ Established
Multiple-dose activated charcoal has a sound mechanism and mixed outcomes. The enterohepatic loop justifies it in principle, and de Silva's yellow-oleander trial showed fewer cardiac complications,⁵ but Eddleston's larger trial found no mortality benefit across mixed self-poisonings.⁶ The recommendation is not settled and is a TOXBASE decision, not a mechanistic one. Traditional teaching
Fab dosing for plant glycosides is an extrapolation. The label provides a scheme, but the vial calculations for pharmaceutical digoxin rest on a known neutralisation capacity per vial against digoxin; applied to a mixture of plant glycosides of differing molar potency, they are an approximation, which is one reason NPIS involvement is advised.¹ Inferred
Yellow-oleander data may not transfer wholesale to UK foxglove. Most large outcome studies come from South Asian yellow-oleander self-poisoning, a high-dose deliberate exposure; UK foxglove and lily-of-the-valley cases are more often accidental and smaller, and the prognostic thresholds should be read with that in mind.

References

1
DigiFab 40 mg/vial digoxin immune Fab (ovine) — Summary of Product Characteristics. electronic medicines compendium, product 102213. Sections 4.2 (Posology, including cardiac glycosides other than digoxin) and 4.4 (immunoassay interference). medicines.org.uk/emc/product/102213
2
Eddleston M, Ariaratnam CA, Sjöström L, et al. Acute yellow oleander (Thevetia peruviana) poisoning: cardiac arrhythmias, electrolyte disturbances, and serum cardiac glycoside concentrations on presentation to hospital. Heart 2000;83(3):301–6. PMID 10677410. (Hyperkalaemia associated with serious arrhythmia in cardiac glycoside plant poisoning.)
3
EXTRIP Workgroup. Digoxin — recommendations. Extracorporeal Treatments in Poisoning Workgroup. extrip-workgroup.org/digoxin
4
Digoxin 0.25 mg Tablets — Summary of Product Characteristics. electronic medicines compendium, product 5465. Sections 4.9 and 5.2 (pharmacokinetics; comparison with the plant glycosides). medicines.org.uk/emc/product/5465
5
de Silva HA, Fonseka MM, Pathmeswaran A, et al. Multiple-dose activated charcoal for treatment of yellow oleander poisoning: a single-blind, randomised, placebo-controlled trial. The Lancet 2003;361(9373):1935–8. PMID 12801736.
6
Eddleston M, Juszczak E, Buckley NA, et al. Multiple-dose activated charcoal in acute self-poisoning: a randomised controlled trial. The Lancet 2008;371(9612):579–87. PMID 18280328.

Foxglove and the cardiac-glycoside plants

At a glance