In the treatment of patients with heart failure, it is extremely important to restore myocardial contractility. The basis of the molecular structure of cardiac glycosides is a steroid nucleus, to which an unsaturated lactone ring is attached at the C-17 position. Together they are united under the name aglikon or genin. It is this part of the molecule that determines the cardiotonic activity of cardiac glycosides. The addition of sucrose residues to this basic structure determines the solubility of a particular preparation in water and its pharmacokinetic properties.
Pharmacokinetics of cardiac glycosides
If there are no signs of severe malabsorption, most cardiac glycosides are well absorbed from the gastrointestinal tract even in the presence of vascular congestion due to heart failure. When taken orally, the drug is completely absorbed for about 2 hours. Bioavailability, i.e., the percentage of intravenously administered dose of the drug, when administered orally with glycosides varies. Significant variability of bioavailability was found in a number of commercial preparations of digoxin. Bioavailability of the elixir of Lanoxin is 70 – 85%, Lanoxin tablets – 60-80%, Lanoxin capsules-90-100%. Bioavailability of tablets digitoxin reaches 100%. Simultaneous use of funds that lower blood cholesterol levels, antidiarrheal drugs containing pectin and kaolin, nonabsorbable antacids and neomycin reduces the absorption of digoxin and digitoxin. The binding of glycosides to proteins in the blood is also different. Thus, for digitoxin it is 97%, for digoxin it is 25%. Despite the fact that these differences can affect the duration of action of different glycosides, they are not associated with the rate of manifestation of their effects. The plasma contains about 1% of the amount of digoxin that enters the body. Mostly it binds to the tissues of the body. That is why removal of the drug by dialysis, exchange blood transfusion or during an artificial circulation is ineffective. The main part of glycosides directly binds to various tissues, including the heart. After administration into the body, the digoxin concentration in the tissues is 30 times higher than in the plasma; digitoxin – 7 times higher. This drug is less polar and more soluble in fats than digoxin.
Digoxin, whose half-life is 1.6 days, is filtered in the glomeruli of the renal corpuscle and excreted by the renal tubules. About 85% of the administered dose is excreted in the urine mostly unchanged. Only 10-15% of digoxin is removed from the body with a stool in the bile-associated form, with normal kidney function. The ratio of clearance of digoxin to the clearance of endogenous creatinine is 0.8, and the percentage of digoxin in the body that can be lost per day can be calculated from the formula (14 ± 0.2) OCLC / ml, where Clk is the clearance of creatinine. In patients with normal renal function of the plateau, the concentration of the drug in the blood and tissues is achieved after 5 days of daily administration without a preload dose (see Figure 64-2). That is why a significant decrease in the glomerular filtration rate delays the elimination of digoxin, but not digitoxin. Consequently, the action of digoxin is prolonged, which can lead to its accumulation in toxic amounts if it is administered in these patients in the same way as in patients with normal renal function. Most diuretics do not significantly alter the excretion of digoxin. At the same time, spironolactone can inhibit the secretion of digoxin in the urine, leading to its pronounced accumulation. The levels of the drug in the blood serum and its pharmacokinetics do not change significantly with a significant loss of body weight. In approximately 10% of patients receiving digoxin, the bacterial flora of the gastrointestinal tract is able to form a large number of reconstituted digoxin products. Antibacterial therapy, changing the flora of the intestine, causes the conversion of digoxin into cardioactive compounds, which can lead to a drastic change in the digitalization process. Digitoxin, whose half-life is close to 5 days, is metabolized mainly in the liver. Only 15% of it is excreted in the urine in an unchanged state and the same with a stool. Such drugs as phenobarbital and phenylbutazone, increasing the activity of microsomal enzymes of the liver, accelerate the metabolism of digitoxin. In order to achieve a saturation state, maintenance doses of digitoxin should be administered within 3 to 4 weeks. Ouabain is a very fast acting drug. Its effect is manifested after 5 to 10 minutes after intravenous administration, and maximum activity is observed after 60 minutes. Due to poor absorption from the gastrointestinal tract, it is not suitable for oral administration. Ouabain is excreted by the kidneys, its half-life is 21 hours. This drug should be used in emergency situations.
The mechanism of action of cardiac glycosides
All cardiac glycosides have a similar effect on the heart. Clinical effects are a consequence of increased myocardial contractility, a decrease in heart rate and slowing of atrioventricular conduction.
The most important effect of glycosides is to shift the “force-velocity of the heart” curve upwards. The positive inotropic effect of the drug has both a healthy and hypertrophied myocardium without signs of insufficiency, and in the case of heart failure. The data that glycosides increase the contractility of the heart without signs of developing insufficiency allowed them to be used in patients with heart disease, but without heart failure before surgery or in other stressful situations such as severe infections, as well as with chronic high stress on the myocardium, for example, in the case of hypertension without heart failure. However, there is no convincing evidence of the effectiveness of glycoside administration in these circumstances.
Glycosides also increase the effective refractory period of the atrioventricular node, which is mainly due to the increased vagal effect on the heart. At the same time, these drugs shorten the refractory period of the musculature of the atria and ventricles. Small potentials of action, fading, spread in the atrioventricular connection. Most of them do not reach the ventricles. Some cells of the atrioventricular junction remain in the refractory state. This can explain the slowing of the rhythm of ventricular contractions with supraventricular tachycardia under the influence of glycosides. In atrial fibrillation, the slowing of the rhythm of ventricular contraction is explained by the prolongation of the effective refractory period of the atrioventricular node. Under the influence of the tone for the vagus nerve, and possibly also the direct action of cardiac glycosides on the atrial-ventricular junction, latent conductance, carried out by a small number of pulses passing through the atrioventricular junction, becomes more important.