cardiac glycosides

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cardiac glycosides The introduction of the cardiac glycosides into medicine was inextricably linked to William Withering (1741–99), who studied medicine in Edinburgh and then practised in Birmingham. Like many educated people of his time, his interests were wide, and he made significant contributions to chemistry, mineralogy, and particularly botany. In 1776, he published A botanical Arrangement of all the Vegetables naturally growing in Great Britain, in two volumes which went through several later editions. His expertise in botany was put to good use when in 1775 his opinion was asked about a family recipe for the cure of dropsy, which had been kept secret by an old woman in Shropshire. He wrote:
‘I was informed that the effects produced were violent vomiting and purging … This medicine was composed of twenty or more different herbs; but it was not difficult for one conversant in these subjects to perceive that the active herb could be none other than the Foxglove.’

He found that foxglove was a powerful diuretic, but he then heard that a colleague in Oxford had cured an accumulation of fluid in the chest with it. This made him undertake a comprehensive study of foxglove, which led to the conclusion that it cured dropsy (the term then used to describe an accumulation of fluid in the tissues) due to cardiac failure, and that it led to a brisk diuresis. He published his findings on 163 cases in An account of Foxglove and some of its medical uses in 1785, in which he gave a full account of the botany, preparations, actions, and toxic effects. Of course, the poisonous actions of foxglove were already well known. Leonhard Fuchs had given a good description of the plant in 1542 and noted its action as a diuretic and laxative. However, the focus on the action in heart failure was entirely due to Withering, and represents the best early account of a rational therapeutic approach.

The main active substance in the purple foxglove Digitalis purpurea is digitoxin, a steroid (17 lactone with a trisaccharide attached at the 3 position). It is active at nanomolar concentration. Related active substances are found in D.lanata (digoxin, which is more widely used in current medical practice because of its shorter duration of action), and in Strophanthus gratus (ouabain), squill, convallaria, hellebore, and many other plants. The main effects on the heart are an increase in contractile force, especially in the failing heart, and a slowing of the rate. The slowing is particularly marked in people with atrial fibrillation, and the heartbeat is also made more regular.

All the active cardiac glycosides are inhibitors of the enzyme Na/K ATPase, present in cell membranes, which is responsible for pumping sodium out of the cell and pumping potassium in. It is generally believed that the inhibition of this enzyme is mainly responsible for the strengthening of the contraction of the heart (the resulting rise in intracellular sodium inhibits the sodium/calcium exchanger, which is the main mechanism concerned with extruding calcium from the cell; thus intracellular calcium increases, and this enhances the contractile force of the cardiac muscle). However, the action of the glycosides are complex and involve also the effects of acetylcholine and noradrenaline released from the cardiac nerves: this may be the main mechanism for reducing the heart rate. Reduction in the rate of beating of the ventricles when there is atrial fibrillation is due to a number of actions: raising of the excitation threshold at the atrio-ventricular node is probably most important (allowing fewer of the disordered waves of atrial activity to be conducted to the ventricles.) The diuretic action is probably due to inhibition of the ATPase in the kidney tubules, resulting in reduced reabsorption of sodium — and therefore also of water — from the tubular fluid, thus increasing the volume of urine.

Toxic effects include anorexia, nausea, vomiting, headache, drowsiness, and visual disturbances, as well as extrasystoles and excessive slowing of the heart rate. The dose range between therapeutic and toxic levels is small: if this were a new drug today, it is very doubtful whether it would receive approval! However, even after 200 years, cardiac glycosides remain of major importance in the treatment of heart failure.

Arnold Burgen

See also cardiac muscle; heart; heart failure.