Glycosides-Medicinal Chemistry MANIK

and
PHARM 3127: Medicinal Chemistry
Cardiac Glycosides
Md. Imran Nur Manik
Lecturer
Department of Pharmacy
Northern University Bangladesh

Natural Products and Secondary Metabolites: Cardiac glycosides
Prepared By: Md. Imran Nur Manik; B.Pharm; M.Pharm Page 1
manikrupharmacy@gmail.com; Lecturer; Department of Pharmacy; Northern University Bangladesh.
Cardiac glycosides
Syllabus for Glycosides: chemical and clinical aspects of digoxin and other digitalis glycosides.
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.
Automaticity:
It is the unique property of cardiac muscles to contract without nervous
stimulation.
Conduction velocity:
The heart is capable of producing electrical impulse for the contraction of muscle.
There are specialized myocytes which depolarize spontaneously and rythmitically to
generate the electrical impulse which is conducted throughout the heart. If the conduction
velocity is increased then, the heart rate will be increased (?). In different parts of heart
conduction velocity is different as below –
 Atrial muscle fibers: 0.3m/sec
 Internodal fibers: 1m/sec
 AV node: 0.05m/sec
 Bundle of His: 0.12m/sec
 Purkinje fibers: 4m/sec
 Ventricular muscle fibers: 0.5m/sec
Tone:
The state of functioning normally. Muscle tone is defined as the resistance of
muscle to stretch
Refractory period:
It is the period of time during which cardiac muscle doesn't respond to the
electrical impulse.
Cardiac excitability:
It is the ability of cardiac muscle to excite i.e. to contract in response to a stimulus
(electrical impulse).
Inotropic effect:
It is the effect on the force of muscle contraction. If the force of muscle contraction
is increased then it is called positive inotropic effect.
Md.
Imran
Nur
Manik

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/minute).
4. 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.
Effect of cardiotonics:
The cardiotonics increase the force of contraction of myocardial fibers. By doing
this a cardiotonic drug –
1. Increases cardiac output (the volume of blood pumped out by any ventricle per
minute). Increased cardiac output also leads to increased diuresis.
2. Lowers venous pressure and venous blood volume.
3. 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.
Md.
Imran
Nur
Manik

Cardiotonic drugs:
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.
Cardiac glycosides
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.
Md.
Imran
Nur
Manik

Mechanism of action of cardiac glycosides:
General pharmacology:
The definite mechanism of action is not known. Some hypotheses have been
postulated –
1. The glycosides interfere with the movement of 
/KNa across the myocardial
membrane causing a loss of intracellular 
K .
2. They exert a direct action on contractile proteins in cardiac muscle i.e. actin and
myosin.
3. They raise the intracellular conc. of 
Ca by releasing it from its binding sites and
facilitating its entry into the cytosol. It is postulated that they inhibit the
ATPase
/KNa which normally maintains the gradient of the two ions across
membranes. Thus when it is inhibited the cell undergoes depolarization. So the ion
permeability is changed and 
Ca enters the cell. Thus the intracellular 
Ca conc.
is increased. Then 
Ca interacts with actin and myosin leading to contraction of
the myocardial fiber. Repolarization reverses this situation.
This theory is most accepted thus far.
Structure of cardiac glycosides:
The following structural features of cardiac glycosides are deemed important –
2
3
4
5
10
1
6
7
8
9 14
13
12
11
17
16
15
O O
CH3
CH3
O
OH
H
Sugars
OH
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-membered 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).
Md.
Imran
Nur
Manik

2
3
4
5
10
1
6
7
8
9 14
13
12
11 17
16
15
O
OH
H
CH3
CH3
O
HO
H
H
Digitoxigenin
(Cardenolide)
O O
HO
H
CH3 CH3
HO
2
3
4
5
10
1
6
7
8
9 14
13
12
11 17
16
15
OH
H
CH3
CH3
HO
H
H
Bufogenin
(bufadienolide)
HO
H
CH3 CH3
HO
O O
OH
O
OH
SAR of cardiac glycosides:
The following features are (or were) considered important for pharmacological
activity –
1. α, β-unsaturated lactone ring at 17-β position.
2. Hydroxyl group at 14 –β position.
3. cis configuration between the A & B rings and C & D rings.
The following model has been postulated for the binding of cardiac glycoside with the
ATPase
/KNa .
O O
HO
H
CH3
CH3
OH3C
O
Sugar
O
H
Site C
Site B
Site A
Site D


Green = Hydrophobic binding Violet = Hydrogen bonding
Blue = Electrostatic attraction Indigo = 1 sugar moeity involved in binding
Md.
Imran
Nur
Manik

According to this model –
1. First a long range attraction between the lactone ring and site A is initiated.
2. Then the steroid part undergoes short-range interaction with site B via
hydrophobic bond.
3. The sugar unit attached directly with the steroid interacts with the site C which
further enhances overall binding.
4. This causes receptor to change as follows –
C
B
A
D
Drug
CBA
D
Drug
Drug-receptor
complex
An allosteric effect is thus produced and ATP can’t bind to the protein receptor.
Problems with administration of cardiac glycosides:
1. Narrow therapeutic index: The therapeutic index of cardiotonics is very low.
Infact it is lowest of all drugs. Their effective dose is 50-60% of the toxic dose.
Thus life-threatening poisoning is very common. Such a condition is called
“digitalis poisoning.
2. Hypakalemia
3. Anorexia
4. Vomiting
5. Salivation
6. Diarrhea
7. Nausea
Countering problems:
The antidote for digitalis poisoning is Digoxin immune Fab (commercial name
Digibind –GSK). It consists of antigen-binding fragments of a specific antidigoxin
antibody isolated from immunized sheep.
Other side-effects can be relieved by adjusting the dose.
Md.
Imran
Nur
Manik

Commercial preparations of glycosides:
Two drugs digoxin and digitoxin are commercially available for administration.
Digoxin:
2
3
4
5
10
1
6
7
8
9 14
13
12
11
17
16
15
O O
CH3
CH3
O
OH
O
OO
OO
OH
OH
OH
OH
CH3
CH3
CH3
Digoxin
OH
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.
Md.
Imran
Nur
Manik

Digitoxin:
2
3
4
5
10
1
6
7
8
9 14
13
12
11
17
16
15
O O
CH3
CH3
O
OH
O
OO
OO
OH
OH
OH
OH
CH3
CH3
CH3
Digitoxin
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.
Md.
Imran
Nur
Manik

Glycosides-Medicinal Chemistry MANIK

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