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CHAPTER 13 Drugs Used in Heart Failure 219

NSR PVB NSR PVB BIPYRIDINES

Milrinone is a bipyridine compound that inhibits phosphodies-
V 6 terase 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An older congener, inamrinone, has been withdrawn in the USA.
ST
Pharmacodynamics
FIGURE 13–6 Electrocardiographic record showing digitalis-
induced bigeminy. The complexes marked NSR are normal sinus The bipyridines increase myocardial contractility by increasing
rhythm beats; an inverted T wave and depressed ST segment are inward calcium flux in the heart during the action potential; they
present. The complexes marked PVB are premature ventricular beats may also alter the intracellular movements of calcium by influ-
and are the electrocardiographic manifestations of depolarizations encing the SR. In addition, they have an important vasodilating
evoked by delayed oscillatory afterpotentials as shown in Figure 13–5. effect. Inhibition of phosphodiesterase results in an increase in
(Adapted, with permission, from Goldman MJ: Principles of Clinical Electrocardiogra- cAMP and the increase in contractility and vasodilation.
phy, 12th ed. Lange, 1986. Copyright © The McGraw-Hill Companies, Inc.) 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,
second-degree atrioventricular blockade. However, it is claimed this drug has been withdrawn. Milrinone appears less likely to
that digitalis can cause virtually any arrhythmia. cause bone marrow and liver toxicity, but it does cause arrhyth-
mias. Milrinone is now used only intravenously and only for acute
B. Effects on Other Organs heart failure or severe exacerbation of chronic heart failure.
Cardiac glycosides affect all excitable tissues, including smooth mus-
cle and the CNS. The gastrointestinal tract is the most common site
of digitalis toxicity outside the heart. The effects include anorexia, BETA-ADRENOCEPTOR AGONISTS
nausea, vomiting, and diarrhea. This toxicity is caused in part by
direct effects on the gastrointestinal tract and in part by CNS actions. The general pharmacology of these agents is discussed in Chapter 9.
CNS effects include vagal and chemoreceptor trigger zone The selective β agonist that has been most widely used in patients
1
stimulation. Less often, disorientation and hallucinations— with heart failure is dobutamine. This parenteral drug produces an
especially in the elderly—and visual disturbances are noted. The lat- increase in cardiac output together with a decrease in ventricular
ter effect may include aberrations of color perception. Gynecomastia filling pressure. Some tachycardia and an increase in myocardial
is a rare effect reported in men taking digitalis. oxygen consumption have been reported. Therefore, the potential
for producing angina or arrhythmias in patients with coronary
C. Interactions with Potassium, Calcium, and Magnesium artery disease is significant, as is the tachyphylaxis that accompanies
Potassium and digitalis interact in two ways. First, they inhibit each the use of any β stimulant. Intermittent dobutamine infusion may
benefit some patients with chronic heart failure.
+
+
other’s binding to Na /K -ATPase; therefore, hyperkalemia reduces Dopamine has also been used in acute heart failure and may
the enzyme-inhibiting actions of cardiac glycosides, whereas hypoka- be particularly helpful if there is a need to raise blood pressure.
lemia 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. INVESTIGATIONAL POSITIVE
Calcium ion facilitates the toxic actions of cardiac glycosides INOTROPIC DRUGS
by accelerating the overloading of intracellular calcium stores that
appears to be responsible for digitalis-induced abnormal automa- Istaroxime is an investigational steroid derivative that increases
ticity. Hypercalcemia therefore increases the risk of a digitalis- contractility by inhibiting Na /K -ATPase (like cardiac glycosides)
+
+
induced arrhythmia. The effects of magnesium ion are opposite to but in addition appears to facilitate sequestration of Ca by the
2+
those of calcium. These interactions mandate careful evaluation of SR. The latter action may render the drug less arrhythmogenic
serum electrolytes in patients with digitalis-induced arrhythmias. than digitalis.
Levosimendan, a drug that sensitizes the troponin system to cal-
OTHER POSITIVE INOTROPIC cium, also appears to inhibit phosphodiesterase and to cause some
DRUGS USED IN HEART FAILURE vasodilation in addition to its inotropic effects. Some clinical trials
suggest that this drug may be useful in patients with heart failure,
Major efforts are being made to find safer positive inotropic and the drug has been approved in some countries (not the USA).
agents because cardiac glycosides have an extremely narrow Omecamtiv mecarbil is an investigational parenteral agent
therapeutic window and may not decrease mortality in chronic that activates cardiac myosin and prolongs systole without increas-
heart failure. ing oxygen consumption of the heart. It has been shown to reduce