Digitalis

The terms “cardiac glycoside” and “digitalis” are used interchangably because these drugs were traditionally obtained from the foxglove Digitalis purpurea (digitoxin) or D. lanata (digoxin). D. purpurea is a common weed in NZ and an occasional cause of poisoning (although much rarer than overdose by vets as it tastes disgusting).

Sources

They are complex molecules present in a variety of plants, a number of which have been used therapeutically including digoxin (the only one available in NZ), digitoxin, oubain (which is probably the endogenous ligand) and lanatoside C. Other cardiac glycosides are usually only encountered as toxins: convallotoxin (from lily of the valley), oleandrin and neriine (from oleander) and squill (from sea onion; previously used as rat poison).

Structure

Cardiac glycosides consist of a steroid nucleus with a lactone ring (responsible for activity) to which are attached three sugars (different with the different toxins) which influence solubility and binding.

Toxicity

Overdosage of digoxin used to treat congestive heart failure in dogs is relatively common.

Dosage with cardiac glycosides will vary considerably with the following factors:

age: as older animals have less skeletal muscle and therefore less binding of drug. Glomerular filtration rate decreases with age and with decreased cardiac output
obesity: as digoxin is not very lipid soluble, then dosage must be based on lean bodyweight. Conversely, digitoxin is lipid soluble so dosage is unchanged
electrolyte imbalances: because these drugs compete with K⁺ for binding to the Na/K ATPase, in hypokalaemia the dose must be reduced and visa versa for hyperkalaemia. Dosage should also be reduced for hypernatraemia and hypercalcaemia.
concurrent drug administration
myocardial failure: If the animal is in myocardial failure or is hypoxaemic they are more sensitive to digitalis.

Digitalis has a very low therapeutic ratio. Sudden calcium influx can cause arrhthymias due to electrical instability in myocardial cells, so work up to a steady state on a maintenance schedule and do not use loading doses.

Pathophysiology

Digitalis exerts a positive inotropic and negative chronotropic effect.

positive inotropic effect: Digitalis glycosides bind to the K⁺ binding site of the sodium pump. This inhibits Na⁺ being pumped out of the cell; the extra Na⁺ is exchanged for Ca⁺⁺ resulting in an increased intracellular Ca⁺⁺ concentration which increases contractility. Numerous other mechanisms have been proposed but this is currently thought to be the main one.
negative chronotropic effects: Thought to be due to stimulation of central vagal nuclei and potentiation of the effects of acetylcholine in atrial myocardium and in AV conducting tissue. Together this results in an increase of vagal tone. In the atria this increased parasympathetic tone decreases atrial automaticity, depresses atrial conduction and increases the effective and functional refractory periods. At the AV node, increased parasympathetic tone decreases atrio ventricular conduction slowing ventricular response to atrial fibrillation and flutter. The most pronounced ECG change therefore, is prolongation of the P R interval (first degree heart block), although total heart block can occur.

Digoxin

Absorption may be decreased by food. Time to peak plasma concentrations vary depending on the formulation and dose
Distribution digoxin is approximately 20% bound to serum proteins (species dependent) and the remainder is free in the serum. Digoxin is strongly bound to skeletal muscle but is also distributed widely, with the highest concentration in kidney, heart, intestine, liver and skeletal muscle. Lowest concentrations are found in the plasma and brain. The half life in the dog varies between 14-56 hours, in the cat it is between 33-58 hours, ie plasma concentrations take several days to stabilise.
Metabolism approximately 15% is metabolised by the liver. (remember there is decreased hepatic function in both right and left sided heart failure) In some people, metabolism by gut bacteria is important, and antibiotic induced changes in gut bacteria may lead to digoxin toxicity.

Elimination the remaining 85% is excreted renally by glomerular filtration and tubular secretion so be careful with patients in renal failure and adjust the dose appropriately using therapeutic drug monitoring.

Severe heart disease will affect all aspects of pharmacokinetics care is required!

Digitoxin

Digitoxin is similar to digoxin but it is primarily metabolised in the liver. It is 70 - 90% protein bound (cf. digoxin which is only 20% protein bound) and has a much shorter half life of between 8 12 hours in the dog. The half life in the cat is >100 hours. It also has a long half life in man.

Clinical signs

Mild toxicity anorexia, nausea, vomiting, and diarrhoea. Digoxin can be directly irritant to the gastric mucosa, causing vomiting. This is worse with the tablet formulations, and can be difficult to clinically differentiate from toxicity due to high plasma concentrations. Try using elixir formulations if tablets are causing irritation.

Serious toxicity increased excitability ventricular ectopic beats, especially bigeminy, ventricular tachycardia.

Post mortem signs

Diagnosis

Plasma levels of digoxin can be measured. Steady state peak and trough concentrations should be maintained between 1.0 - 2.5ng/mL (dog) and 0.9 - 2.0ng/mL (cat) for therapeutic purposes. Mild toxicity is seen at concentrations of 2.5 - 6 ng/mL. Severe toxicity is seen at > 6 ng/mL.

Differential diagnosis

Other causes of heart failure.

Treatment

Mild toxicity appropriate treatment is to withdraw digoxin for 24 hours, then give maintenance at 50% of the initial dose for 12 hours. Use therapeutic drug monitoring to check.

Serious toxicity atropine will help to block the increased vagal tone. Antiarrhthymic drugs may be used: phenytoin or lignocaine are the drugs of choice. Procainamide or propanolol may also be useful. Digoxin antibodies which mop up the drug are available but difficult to obtain and extremely expensive.

Prevention

Calculate digoxin doses extremely carefully. Do not confuse microgrammes with milligrammes.

Prognosis

Reasonable if treatment started in time.