Cardiac Glycosides

Cardiac glycosides inhibit the sodium-potassium ATPase pump, increasing intracellular calcium and cardiac contractility and slowing atrioventricular conduction through vagal effect. Digoxin is the member in routine use. It controls ventricular rate in atrial fibrillation and reduces hospitalisation in symptomatic heart failure with reduced ejection fraction, without a mortality benefit. The therapeutic window is narrow.

Members. Digoxin, digitoxin (where available) and ouabain (obsolete).

Mechanism. Pump inhibition raises intracellular sodium and reduces sodium-calcium exchanger extrusion of calcium, so calcium stores and release rise. Vagal tone rises and sympathetic outflow falls. At toxic levels, calcium overload produces delayed afterdepolarisations and ectopy.

Electrophysiology. Shortened atrial and ventricular refractory periods, prolonged atrioventricular nodal refractory period, slower sinus rate, and ECG changes of scooped ST depression, flattened T waves, shortened QT and longer PR interval. These changes show drug exposure, not toxicity.

Pharmacokinetics. Oral bioavailability of digoxin is 60% to 80%, with volume of distribution 5 to 7 L/kg and half-life 36 to 48 hours in normal kidney function. It is eliminated mainly by the kidney through P-glycoprotein, so impairment, older age and low body weight raise levels. Digitoxin is cleared by the liver with a half-life of about 7 days.

Target level. 0.5 to 0.9 ng/mL (0.6 to 1.2 nmol/L) in heart failure, drawn at least 6 hours after the last dose.

• Digoxin: oral and intravenous; renal clearance.
• Digitoxin: longer half-life; hepatic clearance; less affected by kidney failure.
• Digoxin-specific antibody fragments: the antidote.

• Atrial fibrillation rate control: digoxin as an add-on to a beta blocker or non-dihydropyridine calcium channel blocker, or alone in sedentary patients or when others are not tolerated. Loading: 500 micrograms intravenously over 30 to 60 minutes, then 250 micrograms after 4 to 6 hours up to a maximum of 1 mg in 24 hours, or oral 500 micrograms followed by 250 micrograms every 6 hours.
• Maintenance: 62.5 to 250 micrograms once daily. Start 62.5 to 125 micrograms daily in older adults and kidney impairment.
• Heart failure with reduced ejection fraction: 62.5 to 125 micrograms daily for persistent symptoms despite optimal therapy, aiming for the low target level.
• Dose reduction: reduce the dose by about half when amiodarone, quinidine or verapamil is started, and check levels.
• Selection: not first line for rate control. Use beta blockers first.

Contraindications. Ventricular tachycardia and fibrillation, second or third degree atrioventricular block without a pacemaker, atrial fibrillation with a pre-excitation syndrome (Wolff-Parkinson-White), hypertrophic obstructive cardiomyopathy, and hypokalaemia or hypercalcaemia until corrected.

Toxicity features. Gastrointestinal (anorexia, nausea, vomiting, abdominal pain), neurological (confusion, fatigue, yellow-green vision, halos) and cardiac (frequent ventricular ectopics, bigeminy, atrial tachycardia with block, junctional rhythm, bidirectional ventricular tachycardia, atrioventricular block, bradycardia). Hyperkalaemia suggests severe acute poisoning.

Precipitants. Hypokalaemia, hypomagnesaemia, hypercalcaemia, hypothyroidism, renal impairment, older age, low body weight, and interacting drugs (amiodarone, verapamil, quinidine, clarithromycin, erythromycin, itraconazole, propafenone, spironolactone, ciclosporin).

Treatment of toxicity. Stop digoxin, measure level, potassium, magnesium and creatinine, and monitor the rhythm. Correct potassium to 4 to 5 mmol/L and give magnesium sulphate 2 g intravenously for arrhythmia. Treat bradycardia with atropine. Use lidocaine for ventricular arrhythmia. Avoid cardioversion unless essential, using low energy.

For life-threatening arrhythmia, potassium over 5 mmol/L in acute poisoning, acute ingestion of over 10 mg in an adult, or level over 10 ng/mL, give digoxin-specific antibody fragments. Calculate vials as serum digoxin (ng/mL) multiplied by weight (kg), divided by 100. Without a level, give 10 vials for acute poisoning (20 in cardiac arrest) and 3 to 6 vials for chronic toxicity.

Activated charcoal 50 g applies in acute ingestion within 1 to 2 hours. Dialysis is ineffective because of the large volume of distribution.

Interactions. Amiodarone, verapamil, quinidine, propafenone, clarithromycin, erythromycin, itraconazole, spironolactone and ciclosporin raise digoxin levels. Loop and thiazide diuretics raise toxicity risk through hypokalaemia. Beta blockers and calcium channel blockers add atrioventricular block. Rifampicin and antacids lower levels.

Monitoring. Heart rate, rhythm, potassium, magnesium, creatinine, and digoxin levels after 1 week, after any interacting drug change and when toxicity is suspected.

Special groups. Renal impairment: reduce dose and extend interval. Older adults and low body weight: start at 62.5 micrograms daily. Pregnancy: used, with level monitoring. Children: weight-based dosing. Hypothyroidism: higher sensitivity.