Glycosides: chemical and clinical aspects of digoxin and other digitalis glycosides

1. Md. Imran Nur Manik
Lecturer
Department of Pharmacy
Northern University Bangladesh

5. Cardiotonics:
Cardiotonics are drugs that acts by increasing the force of contraction of
myocardial fiber improve cardiac excitability, automaticity, conduction velocity and refractory
period.
In another words, cardiotonics increase the tonicity of the heart i.e. increases the cardiac
muscle tone.
Indications of cardiotonics:
1. Congestive cardiac failure.
2. Atrial fibrillation (The atrial contractions are rapid and irregular. The atrial contraction occurs
at a rate of 300-400/minute).
3. Atrial flutter (The atrial contractions are rapid but regular. The atrial rate can rise to 250-350/
min. Paroxysmal atrial tachycardia (a suddenly occurring arrhythmia where the atrial rate
becomes higher – usually 160-200 beats per minute). It is also known as Paroxysmal
supraventricular tachycardia.

6. The cardiotonics increase the force of
contraction of myocardial fibers. By doing this a
cardiotonic drug –Increases cardiac output (the volume
of blood pumped out by any ventricle per minute).
Increased cardiac output also leads to increased
diuresis. Lowers venous pressure and venous blood
volume.In CCF, the pumping is improper and blood
volume in heart increases leading to edema in heart.
This increases the size of the heart. The cardiotonic
counteracts this and decreases the size of heart to
normal.

7. Generally the cardiac glycosides are considered as cardiotonics. There are also
some synthetic drugs that may be used for positive inotropic effect.
In acute conditions (acute ventricular failure, tachyarrythmia) synthetic
drugs (or ouabain, deslanoside) are used for rapid response. For less acute,
chronic or stabilized cardiac failure cardiac glycosides are used. Then, digitalis leaf
or digitoxin is 1st choice, digoxin is 2nd choice.
Cardiac glycosides:
Introduction:
Glycosides:
Glycosides are compounds which upon hydrolysis yield a glycone (sugar)
part (such as glucose, rhamnose, digitoxose, ribose, cymarose) and an aglycone
(also called genin, the non-sugar part) part.

8. Cardiac glycosides are glycosides containing a steroidal aglycone and have highly
specific and powerful action on cardiac muscle.
They are also called cardio-active glycosides and cardiotonic glycosides.
The principle sources of cardiac glycosides are –
– Digitalis
– Strophanthus
– Squill
Digitalis glycosides:
There are about 80 species of Digitalis but only Digitalis purpurea and
D. lanata are main sources of cardiac glycosides.
The digitalis leaf refers to dried leaves of Digitalis purpurea. Digitoxin is
obtained from these leaves. Digoxin is obtained from dried leaves of D. lanata.
Digitoxin and digoxin are the glycosides which are frequently employed as medicine.

9. • Increased intracellular concentrations of
calcium may promote
activation of contractile proteins to increase
the force of contraction.
• Cardiac glycosides also stimulate the vagus
nerve which decreases heart rate.
The definite
mechanism of action is not
known. Some hypotheses have
been postulated –
Cardiac glycosides inhibit Na/K
adenosine triphosphatase, the
“sodium pump” which causes
more Na to remain inside
myocardial cells
Increased intracellular Na
stimulates Na/Ca exchange
that brings more Ca inside
heart cells.

10. Structure of cardiac glycosides:
The following structural features of cardiac glycosides are deemed
important –
1. Steroidal aglycones known as genins
2. Sugars: Attached to the genins in sequence.
Most common sugars are D-galactose,
D-glucose and L-rhamnose.
3. 14 β-OH group.
4. 17-α, β-unsaturated lactone ring (6-membere
d or five membered). If the lactone ring is
5-membered then they are called cardenolides
(aka butenolides); if the lactone ring is
6-membered then they are called
bufadienolides (aka pentadienolides).

11. Two drugs digoxin and digitoxin are commercially available for administration.
Digoxin:
Source: Obtained from the dried leaves of D. lanata (family Scrophulariaceace).
It has not been successfully synthesized in laboratory yet.
Use: It is the most widely used cardiac glycoside for the treatment of congestive
heart failure and most supraventricular tachyarrythmias.
It is given in oral or IV route.
Dose: Dose is individualized. The average loading dose (the initial dose) is
0.75-1.5mg in 1 day when orally given and 0.5-1mg when given in IV route. The
maintenance dose (the dose given to maintain the plasma concentration of the drug
to therapeutic level) is smaller.

12. Source:
Obtained from the dried leaves of D. purpurea and D. lanata (family
Scrophulariaceace).
Use:
It is used in the treatment of congestive heart failure and most
supraventricular tachyarrythmias.
Dosage:
Dose is individualized. The general loading dose is 1-1.5mg in 1 day; or
200µg twice daily for 4 days; or 400µg/day for 2-3 days.
Maintenance dose is smaller. Generally 100µg daily or once in two days.
The dose may be raised to 200µg/day if necessary.