FIGURE 13–6 Electrocardiographic record showing digitalis-induced bigeminy. The complexes marked NSR are normal sinus rhythm beats; an inverted T wave and depressed ST segment are present. The complexes marked PVB are premature ventricular beats and are the electrocardiographic manifestations of depolarizations evoked by delayed oscillatory afterpotentials as shown in Figure 13–5. (Adapted, with permission, from Goldman MJ: Principles of Clinical Electrocardiogra phy, 12th ed. Lange, 1986. Copyright © The McGraw-Hill Companies, Inc.) second-degree atrioventricular blockade. However, it is claimed that digitalis can cause virtually any arrhythmia.
B. Effects on Other Organs
Cardiac glycosides affect all excitable tissues, including smooth muscle and the CNS. The gastrointestinal tract is the most common site of digitalis toxicity outside the heart. The effects include anorexia, nausea, vomiting, and diarrhea. This toxicity is caused in part by direct effects on the gastrointestinal tract and in part by CNS actions.
CNS effects include vagal and chemoreceptor trigger zone stimulation. Less often, disorientation and hallucinations— especially in the elderly—and visual disturbances are noted. The latter effect may include aberrations of color perception. Gynecomastia is a rare effect reported in men taking digitalis.
C. Interactions with Potassium, Calcium, and Magnesium
Potassium and digitalis interact in two ways. First, they inhibit each other’s binding to Na+/K+-ATPase; therefore, hyperkalemia reduces the enzyme-inhibiting actions of cardiac glycosides, whereas hypokalemia facilitates these actions. Second, increased cardiac automaticity is inhibited by hyperkalemia (see Chapter 14). Moderately increased extracellular K+ therefore reduces the toxic effects of digitalis.
Calcium ion facilitates the toxic actions of cardiac glycosides by accelerating the overloading of intracellular calcium stores that appears to be responsible for digitalis-induced abnormal automaticity. Hypercalcemia therefore increases the risk of a digitalis-induced arrhythmia. The effects of magnesium ion are opposite to those of calcium. These interactions mandate careful evaluation of serum electrolytes in patients with digitalis-induced arrhythmias.
Major efforts are being made to find safer positive inotropic agents because cardiac glycosides have an extremely narrow therapeutic window and may not decrease mortality in chronic heart failure.
Milrinone is a bipyridine compound that inhibits phosphodiesterase isozyme 3 (PDE-3). It is active orally as well as parenterally but is available only in parenteral form. It has an elimination half-life of 3–6 hours, with 10–40% being excreted in the urine. An older congener, inamrinone, has been withdrawn in the USA.
The bipyridines increase myocardial contractility by increasing inward calcium flux in the heart during the action potential; they may also alter the intracellular movements of calcium by influencing the SR. In addition, they have an important vasodilating effect. Inhibition of phosphodiesterase results in an increase in cAMP and the increase in contractility and vasodilation.
The toxicity of inamrinone includes nausea and vomiting; arrhythmias, thrombocytopenia, and liver enzyme changes have also been reported in a significant number of patients. As noted, this drug has been withdrawn. Milrinone appears less likely to cause bone marrow and liver toxicity, but it does cause arrhythmias. Milrinone is now used only intravenously and only for acute heart failure or severe exacerbation of chronic heart failure.