Cardiac glycoside

The cardiac glycosides, also called cardiotonic glycosides, are heteroside glycosides with activity on cardiac muscle, composed of a steroid genin and sugars. Genin, in turn, has a lactone that can be pentagonal or hexagonal. When the lactone is hexagonal, the glycosides are known as bufadienolides, while when it is pentagonal, they are called cardenolides. The former are typical of toads of the Bufo genus and the latter of plants of the Digitalis genus such as Digitalis purpurea, formerly used in medicine for the treatment of heart failure.

Background

Digital or foxglove (Digitalis spp.) is a source of cardiac glycoside compounds and has been used for centuries, even though the true causes of these effects are not clear. William Withering described that foxglove had a capacity to act on the movement of the heart in a way not previously observed with other medicines and that there were good expectations if used for medicinal purposes. The effects of digitalis on the heart have been known since the late 16th century when John Ferriar first described it. The veracity of the clinical value of the substance for the treatment of congestive heart failure was not scientifically established until the beginning of the 20th century. Today, digitalis preparations continue to be part of medical treatments due to their inotropic action and because they are orally administered. The final description of the chemical structure of digitalis was made by Arthur Stoll in 1933.

Chemistry

Being glycosides, these drugs have a sugar molecule that can be mono-, di- or trisaccharides and a component called aglycone or genin. The simplest genin is digitoxigenin, which is the aglycone of one of the main glycosides of Digitalis lanata, Lanatoside A. The sugar component, attached to the hydroxyl of carbon 3 (C3) of the steroid structure, is in both cases a polysaccharide composed of glucose and three molecules of D-digitoxose.

Cardioactive glycosides (digalic glycosides, cardioactive steroids) consist of a genine or aglycona and a rest of sugarated through an oxygen atom (cardenolide).

Pharmacology

Cardiac glycosides include mixtures of digitalis leaf glycosides such as digitoxin, derived from D. purpurea and digoxin and lanatoside A, derived from D. lanata. Although they differ in their chemical structure and pharmacokinetics, in the heart they have very similar therapeutic properties.

Effects

The effects of cardiac glycosides on cardiac muscle are dose-related and encompass both direct and indirect mechanisms. Among the direct drugs, the drugs increase the force and speed of myocardial contractility, increase the refractory period of the atrioventricular node, and increase peripheral resistance. At high doses, they come to favor the sympathetic influence. They indirectly depress the sinoatrial node and prolong conduction to the atrioventricular node. In patients with heart failure, the force of contraction induced by cardiac glycosides increases cardiac output, improves systolic emptying, and even decreases the size of the heart in diastole (see the article on the cardiac cycle). They also reduce the rise in ventricular end-diastolic pressure, and due to this action, pulmonary pressure and systemic venous pressure are lowered.

The increase in cardiac contractility and cardiac output reflexly reduces sympathetic tone, thus compensating for the vasoconstrictor effect of the drugs with a total reduction in peripheral resistance.

Another effect of cardiac glycosides, and one of the first things that was noticed in these drugs, is diuresis in edematous patients.

In congestive heart failure

In patients with congestive heart failure, cardiac glycosides cause minimal heart rate retardation resulting from vagal cholinergic and sympatholytic effects on the sinoatrial node.

Clinical indications

Cardiac glycosides are used in the following conditions:

• Heart failure.
• Disrhythmias.
• paroxystical atrial tachycardia.
• Acute myocardial infarction.
• Heart rate in patients with pulmonary edema and/or atrial fibrillation.
• Breast angina.
• Cardiomegaly and heart failure.

Adverse reactions and toxicity

With toxic doses, a reduction in heart rate is noted, caused by a direct depression of the automatism of the sinoatrial node. Toxic doses increase automaticity (spontaneous dystolic depolarization) of all cardiac regions except the sinoatrial node.

Cardiac glycosides have a very narrow therapeutic index and the signs and symptoms of the disease to be treated can be difficult to distinguish from those that indicate toxicity. Some of the signs of toxicity may be anorexia, nausea, vomiting. Discomforts such as abdominal pain and diarrhea may be included. Dysrhythmias ranging from various degrees of atrioventricular block to complex ventricular ectopy have also been noted. Gynecomastia has been reported with chronic use of the drugs. Although rare, hypersensitivity reactions characterized by eosinophilia, rash, and thrombocytopenia may occur.

General considerations

Children older than one month may require higher doses than those given to adults, so cardiologists should be alert for any signs of toxicity. Cardiac glycosides are excreted in breast milk so special care should be taken in lactating mothers.