Na+–K+exchange, which occurs before each heart contraction. The inhibition of Na+
extrusion increases the Na+concentration, which in turn triggers greater Ca^2 +mobilization
and controls the contraction of the heart. If, however, the Na+pump is further inhibited,
toxic effects appear; indeed, cardiac steroids show considerable toxicity that, unfortu-
nately, is due to the same mechanism as their beneficial effect. Nevertheless, it has been
shown that the inotropic effect of these drugs is possible without pump inhibition. The
mechanisms involved are complex, and there are several possible interpretations. The
major difficulties in firmly correlating steroid glycoside action with Na+–K+–ATPase
activity are the lack of a specific antagonist and the fact that many other compounds
inhibit the enzyme without showing cardiac activity. In order to form a complex with a
drug, the ATPase must be in the proper conformation. This conformation exists only
immediately after the enzyme has transported Na+and is ready to bind K+.
Cardiac steroids, or cardenolides, are steroid glycosides. Their effect has been known
since the time of the ancient Egyptians. In more recent times, the foxglove (Digitalis
purpurea) and its effect were described in 1785 by William Withering, who knew of its
use in folk medicine.
Types of Cardiac Glycoside. Three groups of plants produce cardenolides: the
Digitalisspecies, growing in temperate climates; the Strophanthus species, of tropical
provenance; and Scilla(sea onion or squill), a Mediterranean plant.
TheDigitalisglycosides are the most widely used cardenolids. The aglycones (the
steroid parts) of the molecule differ from the usual steroid structure in several points.
The anellation of the A–B and C–D rings is cis(Z), the 3-OH is axial (β), and all of
these steroids carry a 14β-OH group. The C17 side chain is an unsaturated lactone ring.
The sugar part, binding to the 3-OH, is a tri- or tetrasaccharide consisting mainly of dig-
itoxose (2,6-dideoxy-β-D-allose) and glucose. The strophanthin aglycones have a 5β-OH
group in addition to other hydroxyls, up to a maximum of six in ouabain. The 19-methyl
is replaced by an aldehyde or primary alcohol and the sugars are the unusual rhamnose
or cymarose. The squillaglycones carry a six-membered lactone ring with two double
bonds, and are closely related to some toad venoms (bufotalin). None is used therapeu-
tically since all are highly toxic.
Structure–Activity Correlations. The structure–activity relationships of cardenolides
have been thoroughly investigated, and have undergone considerable revision on the
basis of crystallographic work and potential energy calculations. The correlations are
summarized as follows:
- The A–B cisfused rings, the axial methyl group, and ring C form the rigid essential
backbone of the structure. - Ring D has conformational flexibility, influenced by the nature of the 17βside
group. The C–D cis junction and 14βconformation are essential. - The 14-OH group, previously considered essential, can be omitted in some struc-
tures or can be replaced by a 14β-NH 2 group. - The ∆20–22double bond serves to properly orient the carbonyl oxygen. The ring itself is
not as essential as previously thought, and some derivatives with side chains instead
of a ring have even higher activity. However, the side chains must be coplanar, and
are much less flexible than one would expect.
ENDOGENOUS MACROMOLECULES 493