It should be emphasized that this narrow therapeutic margin is directly related to the
mechanism of action which involves inhibition of Na+/K+ATPase. For instance, the CNS
side effects of cardiac glycosides are due to binding to neural Na+/K+ATPases; this, in
turn, leads to disturbances of colour vision as well as to stimulation of the area postrema
within the brain, leading to nausea and vomiting. Accordingly, the pharmacophore and
toxicophore are congruent, and re-engineering the molecule to remove toxicities becomes
essentially impossible.
Since the Na+/K+ATPase enzyme is seemingly so crucial to heart function and thus
to CHF, it is tempting to speculate that there must exist chemicals within the human
heart (endogenous ligands) which bind to and regulate Na+/K+ATPase. The high affin-
ity of cardiac glycosides for Na+/K+ATPase and the fact that Na+/K+ATPases occur nat-
urally in plants and animals suggests that this endogenous ligand may in fact be an
endogenous cardiac glycoside. Although the ring stereochemistry is quite different from
that of typical cholesterol derivatives, the cardiac glycosides are centered on a steroid
nucleus, much like the adrenocortical hormones. Over the past decade, some researchers,
using sensitive immunochemical techniques, have suggested that the cardiac glycoside
ouabain is synthesized in the human adrenals and perhaps in the human brain. These
speculations remain somewhat controversial, but nevertheless underline the importance
of the Na+/K+ATPase protein to the molecular–clinical interface in the pathogenesis and
treatment of CHF.
438 MEDICINAL CHEMISTRY