Digoxin

Digoxin is a cardiac glycoside. It slows the ventricular rate in atrial fibrillation by increasing vagal tone and slowing atrioventricular conduction, and it gives a small increase in contractility in heart failure with reduced ejection fraction. It has no mortality benefit, a narrow therapeutic range, and many interactions. It remains in wide use in East Africa for atrial fibrillation with rheumatic mitral stenosis, where beta blockers and rate limiting calcium channel blockers are sometimes poorly tolerated.

Classification. Cardiac glycoside; positive inotrope; rate control agent.

Mechanism. Inhibits the sodium potassium ATPase pump in myocytes, raising intracellular sodium and, through the sodium calcium exchanger, intracellular calcium, which increases contractility. It also increases vagal tone and slows conduction at the atrioventricular node.

Pharmacodynamics. Oral onset within 1 to 2 hours, peak at 2 to 6 hours. IV onset within 5 to 30 minutes, peak at 1 to 4 hours. Works poorly in high sympathetic states (for example fever, sepsis, thyrotoxicosis, exercise).

Pharmacokinetics. Oral bioavailability 60 to 80% (tablets), 70 to 85% (solution). Half life 36 to 48 hours (longer, up to 4 to 6 days, in kidney impairment). Volume of distribution 5 to 7 L/kg; use lean body weight. About 70% excreted unchanged in urine, so the dose depends on kidney function. P-glycoprotein substrate.

Atrial fibrillation or flutter with rapid ventricular rate, adult.

• Loading (when rapid effect is needed): oral 10 to 15 micrograms/kg lean body weight in divided doses over 24 hours (usually 0.75 to 1.5 mg total): half as the first dose, then quarter doses at 6 hour intervals, with a check of heart rate and ECG before each.

• IV loading: 500 micrograms over at least 30 minutes, repeated after 4 to 8 hours if needed; total in 24 hours up to 1 mg in patients with normal kidney function; use half in older or kidney impairment.

• Maintenance 125 to 250 micrograms once daily orally (62.5 to 125 micrograms in older adults, low body weight or eGFR under 50 mL/min).

• Therapeutic level 0.5 to 0.9 ng/mL (heart failure) or up to 2.0 ng/mL (atrial fibrillation), measured at least 6 hours after the dose.

Heart failure with reduced ejection fraction (add-on), adult. 62.5 to 125 micrograms once daily without loading; aim for a level of 0.5 to 0.9 ng/mL; adjust for kidney function and age.

Children. Specialist only. Weight and age based. Typical oral loading 20 to 40 micrograms/kg in divided doses over 24 hours (higher in neonates and infants up to 30 to 50 micrograms/kg), then maintenance 5 to 10 micrograms/kg daily in 2 divided doses; IV doses are about 75% of oral.

Contraindications. Ventricular tachycardia or fibrillation; second or third degree atrioventricular block without a pacemaker; Wolff Parkinson White syndrome with atrial fibrillation; hypertrophic obstructive cardiomyopathy; digoxin toxicity; uncorrected hypokalaemia, hypomagnesaemia or hypercalcaemia; sick sinus syndrome without a pacemaker.

Warnings. Narrow therapeutic range. Toxicity features: nausea, vomiting, anorexia, diarrhoea, confusion, yellow or green visual halos, blurred vision, bradycardia, atrioventricular block, atrial tachycardia with block, ventricular ectopy, ventricular tachycardia. Hypokalaemia, hypomagnesaemia, hypercalcaemia, hypothyroidism, hypoxia and acute kidney injury all raise the risk of toxicity. Direct current cardioversion on digoxin can cause ventricular arrhythmia. Dose in acute myocardial ischaemia with care.

Adverse effects. Nausea, vomiting, diarrhoea, anorexia, visual disturbance, confusion, dizziness, bradycardia, heart block, atrial and ventricular arrhythmias, rarely gynaecomastia.

Interactions. Amiodarone, verapamil, diltiazem (small), dronedarone, quinidine, clarithromycin, erythromycin, itraconazole, ciclosporin, spironolactone and trimethoprim: raised digoxin levels (halve the digoxin dose with amiodarone and check levels). Loop and thiazide diuretics: hypokalaemia raises toxicity. Rifampicin, St John's wort and antacids reduce levels. Suxamethonium: arrhythmias. Calcium given IV in a digitalised patient: dangerous. Beta blockers: additive bradycardia.

Toxicity treatment. Stop digoxin. Monitor ECG. Correct potassium to 4.0 to 5.0 mmol/L and magnesium. Treat bradycardia with atropine 500 micrograms to 1 mg IV (maximum 3 mg). Use digoxin specific antibody fragments for life threatening arrhythmias (dose based on the serum level or the estimated amount ingested); if unavailable, use magnesium and supportive care. Hyperkalaemia from acute poisoning: treat with insulin and glucose; avoid calcium.

Special groups.

• Pregnancy: can be used for maternal and foetal tachyarrhythmias; clearance rises, so levels are needed.

• Breastfeeding: small amounts in milk; compatible.

• Patients of African ancestry: no dose change; used in rheumatic atrial fibrillation.

• Older adults: low body mass and reduced kidney function: start 62.5 micrograms daily.

• Kidney impairment: reduce the dose; eGFR 10 to 50 mL/min: 62.5 to 125 micrograms daily; below 10 mL/min: 62.5 micrograms on alternate days; no loading unless essential.

• Liver impairment: no adjustment.

Formulations. Tablets 62.5 and 250 micrograms (0.0625 and 0.25 mg); oral solution 50 micrograms/mL; injection 250 micrograms/mL.

Administration. Oral once daily with or without food. IV: dilute in 5% glucose or 0.9% sodium chloride and infuse over at least 30 minutes (rapid IV can cause coronary vasoconstriction); do not give IM.

Baseline. ECG, heart rate, potassium, magnesium, calcium, creatinine and eGFR, thyroid function, lean body weight.

Monitoring. Heart rate and rhythm at each visit. Resting heart rate target below 110 beats/minute in atrial fibrillation (below 80 in symptomatic patients). Digoxin level 6 hours after a dose when toxicity is suspected, after dose changes, with new interacting drugs, and with changing kidney function; do not rely on levels alone. Potassium, magnesium and creatinine at baseline, after 1 to 2 weeks, then every 6 months.

Stopping. No taper. Stopping suddenly may increase heart rate in atrial fibrillation.

Common prescribing errors. Loading in an older patient with kidney impairment; omitting the dose reduction when starting amiodarone; using a total body weight rather than lean weight; giving it with uncorrected hypokalaemia; not checking a level when nausea appears; confusing 62.5 microgram and 250 microgram tablets; giving IV calcium to a digitalised patient.