excitability of the cell membrane. Since membrane excitability is crucial both to the
spread of electrical activity throughout the heart and to the contraction of muscle cells
within the heart, it is not surprising that the Na+/K+ATPase protein is a key molecular
player in the clinical phenomenology of CHF.
In view of the central importance of the Na+/K+ATPase protein to CHF, it is reasonable
that drugs that target Na+/K+ATPase may be clinically useful in the treatment of CHF.
Thecardiac glycosidesare such agents. Cardiac glycosides (also called cardiotonic gly-
cosides, cardiosteroids, or digitalis-like compounds) are an important class of naturally
occurring drugs. They may be isolated from either plant sources (e.g.,Digitalis pur-
purea[foxglove],Digitalis lanata, Strophanthus gratus, Strophanthus kombe) or more
rarely from animal sources (e.g., skin glands of certain poisonous toads); the glycosides
isolated from plants are cardenolides, whilst those from the toad are bufadienolides.
The cardiac glycosides exert their therapeutic effects via inhibition of the function of
the Na+/K+ATPase protein, thereby increasing cardiac output and altering the electrical
function of the heart. This therapeutic goal is achieved primarily by an augmentation of
cardiac contractility (producing a so-called positive inotropic action).
Because of their significant clinical importance, the interaction between cardiac
glycoside and Na+/K+ATPase has been studied in detail at the molecular–atomic level
of structural resolution, using computer modeling and computer-aided drug design.
Such studies have revealed that the αdimer of Na+/K+ATPase contains a deep cleft that
constitutes the cardiac glycoside binding zone. These in silico molecular modeling
studies have also shown that cardiac glycosides are not rigid molecules; rather, they are
dynamic entities. Therefore, considerations of conformation are crucial to the drug–
receptor interaction.
Chemically, cardiac glycosides are composed of two segments: the sugar and the
non-sugar (or aglycone) moieties. This structural arrangement is shown in figure 7.4.
The aglycone segment is a steroid nucleus with a unique combination of fused rings
that differentiates these cardiosteroids from other steroids. The A–B and C–D rings are cis
fused, while the B–C rings are in a transconfiguration. Frequently, there are two angular
methyl groups at C-10 and C-13. The lactone ring at C-17 is the other important struc-
tural feature. In cardenolides, this ring at C-17 is a five-membered α,β-unsaturated
lactone ring, while in bufadienolides it is a six-membered lactone ring with two
conjugated double bonds, forming an α-pyrone structure. The hydroxyl group at the
C-3 site of the aglycone is conjugated to either a monosaccharide sugar moiety or to a
polysaccharide via β-1,4-glucosidic covalent linkages. The number and type of sugar
varies from glycoside to glycoside, with the most commonly occurring sugars being
D-glucose, D-digitoxose, L-rhamnose, or D-cymarose. The nature of the sugar does
influence biological properties. For example, adding an OH group to the 5′-CH 3 of
rhamnose produces mannose and substantially changes bioactivity. Stereochemically,
these sugars exist predominantly in the β-conformation—another variable which influ-
ences bioactivity. Structure–activity studies indicate that both the steroid ring system
and the lactone ring are optimal, but not essential, for bioactivity as mediated via a
pharmacodynamic interaction; pregnane steroids, which lack the C-17 lactone ring,
exhibit acceptable binding to Na+/K+ATPase. The sugar moiety at the C-3 position
influences pharmacokinetic properties such as absorption and half-life. As discussed
ENDOGENOUS CELLULAR STRUCTURES 435