CARDIAC GLYCOSIDES

Pharmacological Effects
Cardiac glycosides exert positive inotropic effects and thus are also used in heart failure (see
Chapter 33). Their inotropic action results from increased intracellular
Ca2, which also forms the basis for arrhythmias related to cardiac glycoside intoxication. Cardiac
glycosides increase phase 4 slope (i.e., increase the rate of automaticity), especially if [K]o is low.
They also exert prominent vagotonic actions, resulting in inhibition of Ca 2currents in the AV
node
and activation of acetylcholine-mediated Kcurrents in the atrium. Thus, the major indirect
electrophysiological effects of cardiac glycosides are hyperpolarization, shortening of atrial
action
potentials, and increases in AV nodal refractoriness. The latter action accounts for the utility of
digitalis
in terminating reentrant arrhythmias involving the AV node and in controlling ventricular
response in patients with atrial fibrillation. Cardiac glycosides may be especially useful in the
latter
situation because many such patients have heart failure, which can be exacerbated by other AV
nodal blocking drugs such as Ca 2channel blockers or b adrenergic receptor antagonists.
However,
sympathetic drive is increased markedly in many patients with advanced heart failure, so
digitalis
is not very effective in decreasing the rate; on the other hand, even a modest decrease in rate
can
ameliorate heart failure. Similarly, in other conditions in which high sympathetic tone drives
rapid
atrioventricular conduction (e.g., chronic lung disease and thyrotoxicosis), digitalis therapy may
be
only marginally effective in slowing the rate. In heart transplant patients, in whom innervation
has
been ablated, cardiac glycosides are ineffective for rate control. Increased sympathetic activity
and
hypoxia can potentiate digitalis-induced changes in automaticity and DADs, thus increasing the
risk of digitalis toxicity. A further complicating feature in thyrotoxicosis is increased digoxin
clearance.
The major ECG effects of cardiac glycosides are PR prolongation and a nonspecific alteration
in ventricular repolarization (manifested by depression of the ST segment), whose underlying
mechanism is not well understood.
Adverse Effects
Because of the low therapeutic index of cardiac glycosides, toxicity is
common, including arrhythmias, nausea, disturbances of cognitive function, and blurred or
yellow
vision. Elevated serum concentrations of digitalis, hypoxia, and electrolyte abnormalities (e.g.,
hypokalemia, hypomagnesemia, and hypercalcemia) predispose patients to digitalis-induced
arrhythmias. While digitalis intoxication can cause virtually any arrhythmia, arrhythmias that
should raise a strong suspicion of digitalis intoxication are those in which DAD-related
tachycardias
occur along with impairment of sinus node or AV nodal function. Atrial tachycardia with AV
block is classic, but ventricular bigeminy (sinus beats alternating with beats of ventricular
origin),
bidirectional ventricular tachycardia, AV junctional tachycardias, and various degrees of AV
block also can occur. With severe intoxication (e.g., with suicidal ingestion), severe hyperkalemia
owing to poisoning of Na,KATPase and profound bradyarrhythmias are seen. In patients with
elevated serum digitalis levels, the risk of precipitating ventricular fibrillation by DC
cardioversion
probably is increased; in those with therapeutic blood levels, DC cardioversion can be used
safely.
Minor forms of cardiac glycoside intoxication may require no specific therapy beyond monitoring
cardiac rhythm until symptoms and signs of toxicity resolve. Sinus bradycardia and AV block
often
respond to intravenous atropine, but the effect is transient. Mg 2has been used successfully in
some
cases of digitalis-induced tachycardia. Any serious arrhythmia should be treated with antidigoxin
Fab fragments (DIGIBIND), which bind digoxin and digitoxin and greatly enhance their renal
excretion.
Temporary cardiac pacing may be required for advanced sinus node or AV node dysfunction.
Digitalis exerts direct arterial vasoconstrictor effects, and mesenteric and coronary ischemia can

occur, especially in patients with advanced atherosclerosis who receive intravenous drug.