Cardiac
Glycosides

Sections

Congestive
Heart Failure

Cardiac
Glycosides

Structure

Structure-Activity
Relationships

Biochemical
Mechanism of Action

Questionnaire

Congestive Heart Failure

Heart
diseases can be primarily grouped into three major disorders: cardiac failure,
ischemia and cardiac arrhythmia.

Cardiac
failure can be described as the inability of the heart to pump blood effectively
at a rate that meets the needs of the metabolizing tissues. This occurs when the
muscles that perform contraction and force the blood out of heart are performing
weakly. Thus cardiac failures primarily arise from the reduced contractility of
heart muscles, especially the ventricles. Reduced contraction of heart leads to
reduced heart output but new blood keeps coming in resulting in the increase in
heart blood volume. The heart feels congested. Hence the term congestive heart
failure.

Congested
heart leads to lowered blood pressure and poor renal blood flow. This results in
the development of edema in the lower extremities and the lung (pulmonary edema)
as well as renal failure.

Cardiac Glycosides

Increasing the force of contraction of the heart (positive inotropic activity)
is very important for most heart failure patients. There are several mechanisms
by which this could be achieved. Cardiac steroids are perhaps the most useful
and are being discussed here. Phosphodiesterase inhibitors, such as amrinone and
milrinone, have also been explored and so are direct adenylate cyclase
stimulants, such as forskolin. These drugs all
act by affecting the availability of intracellular Ca+2 for myocardial
contraction or increasing the sensitivity of myocardial contractile
proteins.

The
cardiac glycosides are an important class of naturally occurring drugs whose
actions include both beneficial and toxic effects on the heart. Plants
containing cardiac steroids have been used as poisons and heart drugs at least
since 1500 B.C. Throughout history these plants or their extracts have been
variously used as arrow poisons, emetics, diuretics, and heart tonics. Cardiac
steroids are widely used in the modern treatment of congestive heart failure and
for treatment of atrial fibrillation and flutter. Yet their toxicity remains a
serious problem.

Structure

Cardiac
glycosides are composed of two structural features : the sugar (glycoside) and
the non-sugar (aglycone - steroid) moieties. (figure below)

The R
group at the 17-position defines the class of cardiac glycoside. Two classes
have been observed in Nature - the cardenolides and the bufadienolides (see
figure below). The cardenolides have an unsaturated butyrolactone ring while the
bufadienolides have an a-pyrone ring.

Nomenclature : The cardiac glycosides occur mainly in
plants from which the names have been derived. Digitalis purpurea, Digitalis
lanata, Strophanthus grtus, and Strophanthus kombe are the major sources of the
cardiac glycosides. The term 'genin' at the end refers to only the aglycone
portion (without the sugar). Thus the word digitoxin refers to a agent
consisting of digitoxigenin (aglycone) and
sugar moieties (three). The aglycone portion (figure below) of cardiac
glycosides is more important than the glycone portion.

Click the following links to view the three dimensional
structures of digitoxigenin,
digoxigenin,
gitoxigenin,
strophanthidin
and bufalin.
Let us discuss some of the important
characteristics of each structural feature.

The
aglycone moiety: The steroid nucleus has a unique
set of fused ring system that makes the aglycone moiety structurally distinct
from the other more common steroid ring systems. Rings A/B and C/D are cis fused
while rings B/C are trans fused. Such ring fusion give the aglycone nucleus of
cardiac glycosides the characteristic 'U' shape as
shown below. To view the 3-dimensional structure of the aglycone moiety click on
the figure.

The steroid nucleus has hydroxyls at
3- and 14- positions of which the sugar attachment uses the 3-OH group. 14-OH is
normally unsubstituted. Many genins have OH groups at 12- and 16- positions.
These additional hydroxyl groups influence the partitioning of the cardiac
glycosides into the aqueous media and greatly affect the duration of
action.

The lactone moiety at C-17 position
is an important structural feature. The size and degree of unsaturation varies
with the source of the glycoside. Normally plant sources provide a 5-membered
unsaturated lactone while animal sources give a 6-membered unsaturated
lactone.

Sugar moiety : One to 4 sugars are found to be present in most cardiac
glycosides attached to the 3b-OH group. The sugars most commonly used
include L-rhamnose, D-glucose, D-digitoxose, D-digitalose, D-digginose, D-sarmentose, L-vallarose, and D-fructose. These sugars
predominantly exist in the cardiac glycosides in the b-conformation. The
presence of acetyl group on the sugar affects the lipophilic character and the
kinetics of the entire glycoside.  Because the order of sugars appears to
have little to do with biological activity Nature has synthesized a repertoire
of numerous cardiac glycosides with differing sugar skeleton but relatively few
aglycone structures.

Structure -
Activity Relationships

The sugar moiety appears to be
important only for the partitioning and kinetics of action. (see section on pharmacokinetics
of cardiac glycosides) It possesses no biological activity. For example,
elimination of the aglycone moiety eliminates the activity of alleviating
symptoms associated with cardiac failure.

The "backbone" U shape of the
steroid nucleus appears to be very important. Structures with C/D trans
fusion are inactive.

Conversion to A/B trans
system leads to a marked drop in activity. Thus although not mandatory A/B
cis fusion is important.

The 14b-OH
groups is now believed to be dispensible. A skeleton without 14b-OH group but retaining the C/D cis ring fusion was
found to retain activity.

Lactones alone, when not attached
to the steroid skeleton, are not active. Thus the activity rests in the
steroid skeleton.

The unsaturated 17-lactone plays
an important role in receptor binding. Saturation of the lactone ring
dramatically reduced the biological activity.

The lactone ring is not absolutely
required. For example, using a,b-unsaturated
nitrile (C=C-CN group) the lactone could be replaced with little or no loss in
biological activity.

Pharmacokinetics of Cardiac
Glycosides

The commercially available cardiac
steroids differ markedly in their degree of absorption, half-life, and the time
to maximal effect (see table below).

Agent

GI
absorption

Onset (m)

Peak (h)

Half-life

Ouabain

Unreliable

5-10

0.5-2

21 h

Deslanoside

Unreliable

10-30

1-2

33 h

Digoxin

55-75%

15-30

1.5-5

36 h

Digitoxin

90-100%

25-120

4-12

4-6
days

Usually this is due to the polarity
differences caused by the number of sugars at C-3 and the presence of additional
hydroxyls on the cardenolide. Although two cardiac glycosides may differ by only
one sugar residue their partition co-efficients may be significantly different
resulting in different pharmacokinetics. For example, lanatoside C and digoxin
differ only by a glucose residue and yet the partition co-efficient measured in
CHCl3/16% aqueous MeOH are 16.2 and 81.5, respectively.

Glycoside

Partition Coefficient

Lanatoside C
(glucose-3-acetyldigitoxose-digitoxose2-digoxigenin)

16.2

Digoxin
(digitoxose3-digoxigenin)

81.5

Digitoxin
(digitoxose3-digitoxigenin)

96.5

Acetyldigoxin
(3-acetyldigitoxose-digitoxose2-digoxigenin)

98.0

G-Strophanthin (rhamnose-ouabagein)

very
low

In general, cardiac glycosides with
more lipophilic character are absorbed faster and exhibit longer duration of
action as a result of slower urinary exretion rate. Lipophilicity is markely
influenced by the number of sugar residues and the number of hydroxyl groups on
the aglycone part of the glycoside. Comparison of digitoxin and digoxin
structures reveals that they differ only by an extra OH group in digoxin at
C-12, yet their partition coefficients differ by as much as 15 %
points.

Biochemical
Mechanism of Action

The mechanism whereby cardiac
glycosides cause a positive inotropic effect and electrophysiologic changes is
still not completely clear. Several mechanisms have been proposed, but the most
widely accepted involves the ability of cardiac glycosides to inhibit the
membrane bound Na+-K+-ATPase pump responsible for
Na+-K+ exchange.

The process of muscle contraction
can be pictured as shown below.

The process of membrane
depolarization / repolarization is controlled by the movement of three cations,
Na+, Ca+2, and K+, in and out of the cell. At
the resting stage, the concentration of Na+ is high on the outside.
On membrane depolarization sodium fluxes-in leading to an immediate elevation of
the action potential. Elevated intracellular Na+ triggers the influx
of free of Ca++ that occurs more slowly. The higher intracellular
[Ca++] results in the efflux of K+. The reestablishment of
the action potential occurs later by the reverse of the
Na+-K+ exchange.

The Na+ / K+
exchange requires energy which is provided by an enzyme
Na+-K+-ATPase. Cardiac glycosides are proposed to inhibit
this enzyme with a net result of reduced sodium exchange with potassium that
leaves increased intracellular Na+. This results in increased
intracellular [Ca++]. Elevated intracellular calcium concentration
triggers a series of intracellular biochemical events that ultimately result in
an increase in the force of the myocardial contraction or a positive inotropic
effect.

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©2000 VCU School of Pharmacy
Revised: January 5,
2000
Questions or Comments : Dr. Umesh
R. Desai