Digoxin and Cardiac Glycosides — Mechanism, Toxicity and Digoxin Immune Fab

Cardiac glycosides are naturally occurring compounds made of a steroid nucleus, a lactone ring and a sugar moiety. They are found in plants and in amphibians. Digoxin is isolated from the foxglove Digitalis lanata, and it is one of the oldest drugs still in use in cardiology. William Withering first used foxglove for dropsy (oedema) in 1775, and digoxin itself was isolated in 1930.

Digoxin is the only cardioactive glycoside approved for human use. Other glycosides share the same structure and the same mechanism, which is why they cause the same kind of poisoning: ouabain (from Acokanthera, no clinical use), oleandrin (from Nerium oleander) and bufalin (from toads). Differences in the lactone ring and sugar change the kinetics and the arrhythmia pattern, not the basic mechanism.

Digoxin has two linked actions that explain nearly every exam question on it. The first is on the myocyte, the second on the conduction system.

1. Reversible inhibition of the Na+/K+ ATPase pump on the myocyte membrane, so intracellular sodium rises.
2. The raised sodium reduces calcium extrusion through the sodium–calcium exchanger, so intracellular calcium rises.
3. More calcium means a positive inotropic effect: stronger contraction, higher cardiac output and lower ventricular filling pressures.
4. Separately, digoxin increases vagal (parasympathetic) tone. This slows conduction through the SA and AV nodes and lengthens the AV nodal refractory period, which slows the ventricular rate.

Digoxin is now a second-line or add-on drug. Beta blockers and calcium-channel blockers have largely replaced it for rate control because they have a better safety profile. Its approved indications are chronic atrial fibrillation and symptomatic heart failure.

Digoxin was also used off-label to induce fetal death before second-trimester abortion and to treat fetal supraventricular tachyarrhythmia. Concerns over efficacy and safety have limited the abortion use. If you meet this in a question, remember that digoxin can cause uterine contractions, so the lowest effective dose is used in pregnancy.

• Absorption: oral bioavailability is about 75%; high-fibre meals can reduce it, and some gut bacteria convert digoxin to inactive dihydro-digoxin.
• Distribution: very large volume of distribution (about 475–500 L, roughly 6 L/kg) with a distribution phase of 6–8 hours. About 25% is protein bound.
• Elimination: mainly renal and unchanged, in proportion to GFR. Half-life is 36–48 hours and can reach a week in renal failure.
• Steady state: 7–10 days in normal renal function.
• Narrow therapeutic index: the usual range is 0.8–2.0 ng/mL, with levels above about 2.4 ng/mL regarded as toxic, but toxicity can occur inside the range.

Because of the large volume of distribution, a blood sample taken within 6 hours of a dose gives a falsely high level. Because the drug is deep in tissues, haemodialysis does not remove digoxin; this is a classic exam point.

Toxicity may be acute (no prior use), acute on chronic (extra bolus in a regular user) or chronic (reduced clearance, usually renal). Most symptoms are non-specific, which is why the diagnosis is mainly clinical.

At therapeutic doses the ECG shows the digitalis effect: T-wave flattening or inversion and a scooped ST segment with ST depression in lateral leads. This is not toxicity. Left or right bundle branch block is rarely seen because digoxin has little effect on the His bundle and bundle branches. For rhythm recognition, revise ECG interpretation alongside the antiarrhythmic drugs.

1. Stabilise: continuous cardiac monitoring, serial ECGs, check renal function, potassium, magnesium and calcium.
2. Decontaminate after acute ingestion with activated charcoal. Gastric lavage is not recommended because vagal stimulation can worsen bradycardia.
3. Digoxin immune Fab (digoxin-specific antibody fragments, trade name Digibind) is considered first-line for life-threatening arrhythmias such as AV block or ventricular tachycardia caused by suspected toxicity.
4. Treat arrhythmias: atropine for bradycardia, lidocaine for ventricular arrhythmias, short-acting beta blockers or phenytoin for supraventricular and digoxin-induced tachyarrhythmias.
5. Correct electrolytes and monitor potassium, which often falls after Fab.

Related pharmacology that is often asked in the same block: pharmacokinetics for volume of distribution and half-life, diuretics for the hypokalaemia link, and plant irritant poisons for oleander and other plant toxins.