Digoxin and the cardiac glycosides

Cardiac glycosides are natural sterols and constitute a group of secondary metabolites isolated from plants and animals. These cardiotonic agents are well recognised and accepted in the treatment of various cardiac diseases as they can increase the rate of cardiac contractions by acting on the cellular sodium potassium ATPase pump. However, there has also been recent interest in exploring the antitumour and antiviral potential of these compounds.¹

Cardiac glycosides include digoxin, digitoxin, digitalis and ouabain. Of these, only digoxin is in regular use in the UK.

How does digoxin work?

Digoxin acts by inhibiting cell membrane sodium/potassium ATPase which leads to reversal of the usual sodium/calcium exchange. An increased intracellular calcium level results which, in myocardial muscle, has the effect of enhancing the strength of contraction (positive inotropism). It also affects the electrical physiology of the heart, blocking atrioventricular (AV) conduction and reducing the heart rate by enhancing vagal nerve activity (negative chronotropy).

In what conditions should digoxin be considered?

Atrial fibrillation (AF)²

The principal indication is permanent/persistent AF with a fast ventricular rate - although it is not the preferred first-line medication (especially as digoxin prevents the normal rise in heart rate associated with exertion). Therefore, digoxin monotherapy should only be considered for initial rate control in patients with non-paroxysmal atrial fibrillation who are predominantly sedentary, or in those where other rate-limiting drugs are unsuitable.

Beta-blockers, diltiazem, or verapamil are recommended as first-choice drugs to control heart rate in AF patients with left ventricular ejection fraction (LVEF) of 40% or higher. Beta-blockers and/or digoxin are recommended to control heart rate in AF patients with LVEF below 40%.³

Digoxin has fallen out of favour due to studies reporting increases in all-cause mortality when given in AF - especially if no heart failure is present.⁴ Digoxin can be used when atrial fibrillation is accompanied by congestive heart failure.

For management of atrial fibrillation the maintenance dose of digoxin can usually be determined by the ventricular rate at rest, which should not usually be allowed to fall persistently below 60 beats per minute.

Digoxin is now rarely used for rapid control of heart rate. Even with intravenous administration, response may take many hours; persistence of tachycardia is, therefore, not an indication for exceeding the recommended dose. The intramuscular route is not recommended.

Supraventricular tachycardia²

Digoxin is a treatment option for paediatric supraventricular tachycardia.

Cardiac glycosides are contra-indicated in supraventricular arrhythmias associated with accessory conducting pathways (eg, Wolff- Parkinson-White syndrome).

Heart failure⁵

Digoxin is recommended by the National Institute for Health and Care Excellence (NICE) for worsening or severe heart failure with reduced ejection fraction despite first-line treatment for heart failure (eg, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and diuretic therapy). Lower doses and/or slower dose titration should be considered in patients with chronic kidney disease (GFR 45 ml/min/1.73 m² or below).

In patients with heart failure who are in sinus rhythm a loading dose is not required, and a satisfactory plasma-digoxin concentration can be achieved over a period of about a week.²

Monitoring²

Regular monitoring of plasma-digoxin concentration during maintenance treatment is not necessary unless problems are suspected. Hypokalaemia predisposes to digitalis toxicity, and is managed by giving a potassium-sparing diuretic or, if necessary, potassium supplementation. The plasma concentration alone cannot indicate toxicity reliably, but the likelihood of toxicity increases progressively through the range 1.5 to 3 micrograms/litre for digoxin. Digoxin should be used with special care in the elderly, who may be particularly susceptible to digitalis toxicity.

Features suggestive of toxicity include nausea, vomiting, diarrhoea, dyspnoea, confusion, dizziness, headache, blurred vision and diplopia. See the British National Formulary (BNF) for the full list.

For details of contra-indications and interactions, see the BNF.²