Digoxin and the Cardiac Glycosides

Cardiac glycosides act by increasing sodium/calcium exchange. This has the effect of increasing intracellular calcium levels which in turn enhances the strength of contraction of myocardial muscle (positive ionotropism). It also affects the electrical physiology of the heart, blocking AV conduction, and reducing the heart rate by enhancing vagal nerve activity (negative chronotropy). Members of this group include digoxin, digitoxin, digitalis and oubaine. Of these, only digoxin is in regular use in the UK.

Atrial fibrillation

The principle indication is permanent/persistent atrial fibrillation with a fast ventricular rate. The target should be a resting ventricular rate of approximately 90/minute. It should be considered as monotherapy primarily for sedentary patients. Beta-blockers or rate-limiting calcium-channel blockers are more effective for monotherapy in patients likely to undergo exertion.¹

Supraventricular tachycardia

Digoxin is most commonly used in this situation in children with congenital heart disease. It is given intravenously in the acute situation to slow the heart rate.

Heart Failure

NICE guidance suggests that digoxin should be used as first-line in patients with co-existing heart failure. In all other cases due to left ventricular dysfunction it should be reserved for patients in whom the condition has worsened despite the use of ACE inhibitors, beta-blockers and diuretic therapy.²

Initiation

Digoxin is usually given orally and rarely intravenously. It should not be given intramuscularly as absorption will be erratic. A loading dose should be given of 15mcg/kg of lean body weight, in three divided doses at 6 hourly intervals. For a woman with a lean body weight of 50kg this would work out at a total dose of 15x50=750mcg. Lean body weight is defined as total body mass minus fat mass. There are a number of methods of determining this but where it is clinically significant the simplest method in primary care is the use of skin calipers.⁴ Divide the total by three to give an individual dose of 250mcg. If the ventricular rate does not reduce to the desired target, an additional dose of 5mcg/kg can be given, providing there are no symptoms or signs of toxicity (see below). If the rate does not come down after a further dose another drug should be given.
Patients given a loading dose need to be monitored carefully for symptoms of toxicity and the development of arrhythmias. There are no indications in the guidelines as to how frequently patients on a loading dose should be monitored, so this will have to be determined by the clinical state of the patient. If regular monitoring is not possible a starting dose can be given of 5mcg/kg adjusted pro rata according to renal function (see below).

Maintenance

The maintenance dose is calculated as a fraction of the effective loading dose, adjusted for renal function.

• Recent myocardial infarction - The concern here is that digoxin can increase utilisation of oxygen by the myocardium, so although it is not contra-indicated, it should be used with caution.
• Hypokalaemia - This sensitises the actions of digoxin on the myocardium.
• Sick sinus syndrome - Digoxin may be unpredictable in its chronotropic actions and may cause all sorts of arrhythmias. In Sick sinus syndrome, digoxin may provoke or aggravate sinus bradycardia or cause sinoatrial block.
• Pregnancy - No significant adverse effects on the developing fetus have been demonstrated but the dosage response may be more unpredictable than in non-pregnant women. The risks and benefits of treatment need to be carefully considered in pregnant women with heart disease. There is no contraindication to breast-feeding.
• Thyroid disorders - The dosage may need to be reduced in myxoedema and increased in thyrotoxicosis (until the patient becomes euthyroid).
• The elderly - This group of patients tend to have a lower BMI and reduced renal function, both of which increase the risk of toxicity. Dosage should be initiated at the lower end of the range.
• Driving and operating machinery - The effects on the central nervous system and eyesight mean that patients should be warned about these activities.
• Intravenous administration - This should be carried out slowly.

• Intermittent complete heart block or 2nd degree heart block - Digoxin should be avoided, particularly if there is a history of Stokes-Adams attacks.
• Ventricular fibrillation or tachycardia - The negative chronotropic effect of digoxin would be dangerous in these conditions.
• Arrythmias with accessory pathways - Wolff-parkinson-white syndrome is a common example of these conditions. Digoxin is contra-indicated because it will impair conduction in the normal pathways without affecting the accessory pathways.
• Left ventricular outflow obstruction - Examples here include aortic stenosis and hypertrophic obstructive cardiomyopathy. The positive ionotropic effect would aggravate the demand on the ventricular myocardium to contract against the obstruction. The exception may be some patients with co-existent atrial fibrillation or heart failure, but specialist advice would be required.

• Arrythmias - Common arrythmias include ventricular ectopics, atrial premature beats, ventricular bigeminy / trigeminy and atrial tachycardia with complete heart block
• Visual disturbance - yellow vision (xanthopsia), blurred vision, photophobia
• Gastrointestinal effects - abdominal pain, poor appetite, nausea, diarrhoea
• Gynaecomastia
• Central nervous system effects - Weakness, dizziness, confusion, apathy, fatigue, malaise, headache, depression, psychosis
• Rare effects - Bowel ischaemia, thrombocytopaenia, skin rashes

Monitoring is important both to ensure that the correct dosage is being given and also that factors which might provoke toxicity - e.g. renal dysfunction and hypokalaemia - are not developing. Urea and electrolytes should be monitored. In stable patients this may be done annually, but if there is any change in dosage or clinical status more regular monitoring should be performed.

The best monitor of response to treatment in atrial fibrillation is ventricular rate. Plasma concentrations can however be helpful when initiating therapy, checking compliance or detecting toxicity. A target range of 1.0-1.5nml/l should be aimed for but concentrations of 2nm/l may be required in atrial fibrillation. Levels above 2nm/l suggest toxicity. Plasma potassium should be measured in all cases of suspected toxicity. If hypokalaemia is evident, the drug should be withheld irrespective of the digoxin level.

• Drugs causing potassium depletion - Potassium-sparing diuretics should be used. Apart from diuretics, lithium salts, carbenoxolone and corticosteroids can also cause potassium depletion.
• Drugs causing an increase in digoxin level - These include amiodarone, diltiazem, verapamil, itraconazole, quinidine, and spironolactone. Amiodarone has the greatest effect of this group and some authorities recommend avoiding it altogether. In all cases, digoxin levels should be monitored closely.
• Drugs affecting the breakdown of digoxin in the gut - In about 10% of patients, digoxin is metabolised by the gut intestinal bacteria, mainly Eubacterium glenum. Antibiotics such as erythromycin, clarithromycin, and tetracycline can inhibit this breakdown and thus increase the systemic availability of digoxin.