PharmacologyTier 1Medical Sciences concept

Digoxin mechanism of action (Na+/K+-ATPase inhibition)

Core concept

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dec Na+/K+-ATPase

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Separate and clinically dominant effect: increased vagal tone
- Central vagomimetic action + inc baroreceptor sensitivity
- -> dec AV nodal conduction, inc AV refractory period -> rate control in AF
Digoxin and potassium compete for the same binding site on the ATPase
- Hypokalaemia -> more digoxin binding -> toxicity at a "therapeutic" level
- In acute overdose, HYPERkalaemia is the marker of severity - the pump is poisoned and K leaks out of cells

Narrow therapeutic index: target 0.5-0.9 nanograms/mL (0.6-1.2 nmol/L) in heart failure; sample >=6 h after the dose and at steady state (~7 days)
Pharmacokinetics - fe ~70-80% renal, Vd ~7 L/kg, t-half ~36 h (much longer in renal failure) -> not dialysable
Toxicity precipitants
- Renal impairment (the commonest)
- dec K, dec Mg, inc Ca
- Drugs: amiodarone, verapamil, dronedarone, quinidine, clarithromycin, itraconazole, ciclosporin (P-gp inhibition -> halve the digoxin dose); diuretics via hypokalaemia; spironolactone
Features of toxicity
- GI - anorexia, nausea, vomiting (earliest)
- Visual - xanthopsia (yellow-green haloes), blurred vision
- Neuro - confusion, delirium, weakness
- Arrhythmia - "any arrhythmia except a rapidly conducted supraventricular one"
  - Classic: atrial tachycardia with AV block, bidirectional VT, junctional rhythms, frequent ectopy
"Reverse tick" / sagging ST depression is a therapeutic effect, not toxicity
Digoxin Fab indications: potassium >5-5.5, life-threatening arrhythmia, haemodynamic compromise, large ingestion
- After Fab, the serum digoxin assay measures bound drug and is uninterpretable
- Avoid calcium in digoxin-related hyperkalaemia (theoretical "stone heart")

Roles
- Rate control in AF, particularly in heart failure or hypotension where beta-blockers and verapamil are poorly tolerated
- Poor at controlling exertional rate - it is a vagal drug, and exercise withdraws vagal tone
- Symptomatic benefit in HFrEF (DIG trial: dec hospitalisation, no mortality benefit); ESC 2026 upgraded its role in selected chronic HF
Reduce the dose in the elderly - dec renal clearance and dec lean mass (dec Vd) both apply
Check U&E, magnesium and renal function whenever toxicity is suspected, and think of the drug chart
Avoid in WPW with AF (shortens accessory pathway refractoriness), HOCM, and second/third-degree block without a pacemaker
Withhold before DC cardioversion where practical, or ensure a normal potassium

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