Digoxin

Why this drug is interesting

Digoxin is a survivor. Derived from foxglove, in clinical use since the eighteenth century, repeatedly written off, and still named in the RCUK 2025 rate-control options at every level of ventricular function — including below an ejection fraction of 40%, where verapamil and diltiazem drop off the list entirely.³

The reason is simple and clinically important: digoxin slows the ventricular rate without negative inotropy or vasodilatation. In a patient whose blood pressure will not tolerate a beta-blocker or a calcium channel blocker, it is often the only rate-control option left.

Its weaknesses are equally clear. It works slowly, it controls rate poorly during exertion, and its therapeutic index is among the narrowest of any drug in common use — narrow enough that toxicity is a recognisable clinical syndrome with its own antidote.

Pharmacology

Mechanism — two distinct effects

Digoxin inhibits the Na⁺/K⁺-ATPase in cardiac myocytes. Intracellular sodium rises, which reduces the gradient driving the sodium–calcium exchanger, so less calcium is extruded and intracellular calcium rises — producing positive inotropy without increasing myocardial oxygen demand in the way catecholamines do.

Separately, and more relevant to emergency use, digoxin has a vagotonic action: it increases parasympathetic tone at the AV node, slowing conduction and prolonging refractoriness. This is what controls the ventricular rate in atrial fibrillation.

Why potassium matters so much

Kinetics

Onset, IV

Within 30 minutes; peak effect 2–6 hours — this is not a fast drug

Half-life

Approximately 36–48 hours with normal renal function; considerably longer in renal impairment

Excretion

Predominantly renal, largely unchanged

Distribution

Very large volume of distribution — which is why dialysis does not remove it

Loading requirement

The long half-life means a loading dose is needed to reach effect within hours rather than days

Indications and dosing

Licensed indications

• Chronic cardiac failure where the dominant problem is systolic dysfunction — particularly with ventricular dilatation, and especially with concurrent atrial fibrillation¹
• Certain supraventricular arrhythmias, particularly chronic atrial flutter and fibrillation¹

Intravenous loading

Maintenance

• Most patients: 125–250 micrograms daily
• Increased sensitivity, the elderly, or renal impairment: 62.5 micrograms daily or less
• The SmPC bases maintenance on daily loss estimated as 14 + (creatinine clearance ÷ 5) percent
• Reduce both loading and maintenance doses in the elderly and in reduced renal clearance

Therapeutic monitoring

• Optimal range 0.5–1.0 ng/mL, based on the Digitalis Investigation Group findings¹
• Toxicity commonly above 2.0 ng/mL, but the SmPC is explicit that concentration must be interpreted clinically and that toxicity may occur at lower levels
• Sample at least 6 hours after a dose, or the result reflects the distribution phase and reads misleadingly high

Rate control in the RCUK algorithm

Digoxin appears as an option at both levels of ventricular function — beta-blocker, verapamil, diltiazem or digoxin at EF above 40%; beta-blocker or digoxin at EF below 40%.³ See Verapamil, Diltiazem and Metoprolol.

Contraindications

• Intermittent complete heart block or second-degree AV block, especially with a history of Stokes-Adams attacks
• Arrhythmias caused by cardiac glycoside intoxication
• Supraventricular arrhythmias associated with an accessory pathway, as in Wolff-Parkinson-White syndrome — the SmPC qualifies this as "unless the electrophysiological characteristics of the accessory pathway and any possible deleterious effect of digoxin on these characteristics have been evaluated". In an undifferentiated emergency presentation that evaluation has not happened, so treat it as absolute
• Ventricular tachycardia or ventricular fibrillation
• Hypertrophic obstructive cardiomyopathy, unless there is concomitant atrial fibrillation and heart failure
• Hypersensitivity to digoxin or other digitalis glycosides

Toxicity

Digoxin toxicity is a clinical diagnosis supported by a level, not the other way round. The SmPC's description is worth knowing because the rhythms are distinctive.

Cardiac features

• Multiple rhythm disturbances in the same patient are common — this combination is itself the clue
• Paroxysmal atrial tachycardia with variable AV block — the classic
• Accelerated junctional rhythm
• Slow atrial fibrillation — a regularised or inappropriately slow ventricular response in known AF
• Bidirectional ventricular tachycardia — rare, and close to pathognomonic
• Premature ventricular contractions — the earliest sign
• Sinus bradycardia and other bradyarrhythmias are very common

Non-cardiac features

• Gastrointestinal symptoms are very common in both acute and chronic toxicity — nausea, vomiting and anorexia in up to 80% of cases
• Visual disturbance, classically aberration of colour vision with a predominance of yellow-green (xanthopsia)
• Confusion, delirium, weakness and fatigue — easily attributed to age or to the underlying illness

Potassium in toxicity

Chronic toxicity is typically associated with hypokalaemia, usually from concurrent diuretics — and the hypokalaemia is part of the cause. Acute poisoning instead produces hyperkalaemia, as Na⁺/K⁺-ATPase inhibition drives potassium out of cells; the degree of hyperkalaemia is a recognised marker of severity in acute overdose.

Interactions

Digoxin's narrow margin makes its interactions clinically significant rather than theoretical. The SmPC recommends checking the serum concentration whenever doubt exists.¹

Critical appraisal

1. The DIG trial is the pivotal evidence and its result is nuanced. In heart failure with reduced ejection fraction and sinus rhythm, digoxin reduced hospitalisation but had no effect on mortality. That is a real but limited benefit, and it is the basis for the lower target concentration now recommended.
2. Observational data associating digoxin with increased mortality in AF are heavily confounded. Digoxin is preferentially given to older, frailer, more renally impaired patients with worse heart failure — precisely those who die sooner. Whether the drug contributes causally is genuinely unresolved, and the honest position is uncertainty rather than either reassurance or alarm.
3. Its niche is narrower than its prescribing. Digoxin is well suited to the sedentary patient with AF and heart failure who cannot tolerate other agents. It is poorly suited to the active patient who needs exertional rate control, and it is often continued indefinitely without anyone revisiting whether it is still the right choice.
4. Monotherapy rarely achieves adequate rate control in the acute setting. Onset takes hours, so a patient needing rate control now generally needs something else as well — which is worth stating plainly, because digoxin's presence in the algorithm can imply an acuity it does not possess.
5. Level interpretation is routinely mishandled. Sampling within 6 hours of a dose, or reading a level without the potassium and renal function alongside it, produces confident wrong answers in both directions.

References

1. 1
   Digoxin 250 microgram/ml solution for injection/infusion — Summary of Product Characteristics. electronic Medicines Compendium. Sections 4.1–4.5, 4.9. Verified 20 Aug 2026.
2. 2
   Digoxin — dosing, monitoring and safety monograph. BNF, NICE. bnf.nice.org.uk
3. 3
   Resuscitation Council UK. Adult tachyarrhythmia algorithm, 2025. resus.org.uk — mirrored at lifesupport.resusdoc.uk. Digoxin appears as a rate-control option both above and below an ejection fraction of 40%.
4. 4
   The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997;336(8):525–33.
5. 5
   Rathore SS, Curtis JP, Wang Y, et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003;289(7):871–78.
6. 6
   NICE NG196. Atrial fibrillation: diagnosis and management. National Institute for Health and Care Excellence.
7. 7
   TOXBASE — digoxin and cardiac glycoside poisoning. National Poisons Information Service. toxbase.org (NHS login required.)