A condition in which the heart is unable to pump sufficient blood to meet the metabolic demand of the body and also unable to receive it back because every time after a systole.

1. Congestive Heart Failure

2. Introduction
A condition in which the heart is unable to pump
sufficient blood to meet the metabolic demand of the
body and also unable to receive it back because every
time after a systole.

3. Diagnos
ed
Echo
Chest X-
ray
ECG
Blood
tests

4. Classification..
1. Inotropic drugs:
(a)Cardiac glycosides: Digoxin, Digitoxin
(b)Sympathomimetics: Dobutamine, Dopamine
(c) Phosphodiesterase III inhibitors:Amrinone
2. Diuretics:
(a) High ceiling diuretics: Furosemide, Bumetanide
(b) Thiazide like diuretics: Hydrochlorothiazide,Metolazone.
3. Inhibitors of Renin-Angiotensin system-
(a) ACE-inhibitors: Enalapril, Ramipril
(b) Angiotensin (AT receptor) antagonists: Losartan
4. Aldosterone antagonist- Spironolactone, Eplerenone
5. Vasodilators-
(a) Venodilators: Glyceryl trinitrate
(b) Arteriolar dilator: Hydralazine
(c) Arteriolar + Venodilator: Sod.Nitroprusside

5.  Cardiotonic agents posses cardiac inotropic property, i.e. they increase
the force of contraction of the heart.
 They have a strengthening effect on the heart and increase cardiac
output
 Theses are cardiac glycoside
 They are used after myocardial infraction, cardiac surgical procedures or
in congestive heart failure.
 cardiac glycoside have following features-
 Cardiac glycosides are naturally occurring group of steroids found in 11
plant families.
 Depending on dosage cardiac glycosides may have beneficial or toxic
effects
 Digitalis found in digitalis lanata is used for treatment of heart condition
 Cardiac glycosides increase force of contraction of the heart muscle, by
increasing the availability of intracellular Ca++ ions.
 Toxic amount of cardiac glycosides decrease electric conductivity through
the heart causing irregular heart activity.

6. Chemistry Important structural element of cardiac glycosides / Chemistry of C. G.
 All Cardiac glycosides
 aglycone (genin) part (active
pharmacologically)
 sugar (glucose or digitoxose) attached
at Carbon 3 of nucleus
 Aglycone – Steroid ring
(cyclopentanoperhydrophenanth
rene ring) and lactone ring
attached at 17th position

8.  Cardiac glycosides show 2 major structural features-
 1- an aglycone steroid portion –
 The cardiac aglycone is a steroid compound
 The steroids have an unsaturated lactone ring attached to the C17 of the
steroid backbone
 Unusually plant sources provide a 5- membered unsaturated lactone ring
while animal sources give 6- membered unsaturated lactone ring.
 The steroid nucleus also carries, in most cases, two angular methyl groups at
C10 and C13
 Hydroxyl groups are located at C3, the site of the sugar attachment and at C14.
 2- Sugar:
 The hydroxyl group at C3 of the aglycone portion is usually conjugated to
sugar moieties with β 1,4 glucosidic linkages
 There are 1,5 sugar moieties in the sugar chain in most cardiac glycosides.
 The most commonly found sugar in the cardiac glycosides are β D- glucose, β
–D digitoxose, β D cymarose, β D- rhamnose
 There are three types of sugar found in cardiac glycosides- 2,6 dideoxysugar
moiety, 6-deoxysugar moeity and normal sugar moiety

9. SAR of cardiac glycoside
 Digitoxigenin is the prototype for SAR
 Naturally occurring cardenolides have a 5-memebered α β unsaturated lactone ring, while the
bufadienolides have 6-membered lactone ring at C17 of steroidal aglycone
 if the conjugation system in C17 side chain is extended, activity abolishes.
 The lactone ring is not essential for activity. The open chain analogues with α β unsaturated
function also active. The substitution can be of two types i.e. X may be oxygen or nitrogen

10.  The steroidal aglycones alone without sugar are usually less potent than
their glycoside forms and show rapid onset and reversal of enzyme
inhibitions.
 MOA of cardiac Glycosides: Digoxin
 The exact mechanism by which this exchanger works is unclear.
 Digitalis compounds are potent inhibitors of cellular Na+ / K+ -ATPase.
 By inhibiting the Na+ / K+ -ATPase, cardiac glycosides cause intracellular
sodium concentration to increase.
 By mechanism that are not fully understood, digitalis compounds also
increase vagal efferent activity to the heart.
 Pharmacokinetics and Toxicity:
 Therapeutic plasma level a special dosing regimen is required because of a
half life of 40 hours for digoxin and 160 hours for digitoxin.
 It is very important that therapeutic plasma level are not exceeded because
digitalis compounds have a relatively narrow therapeutic safety window.

11. Bosentan
4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(2-
methoxyphenoxy)
-2-(pyrimidin-2- yl)pyrimidin-4-yl]benzene-1-
sulfonamide
 Bosentan is a competitive antagonist of endothelin-
1 at the endothelin-A (ET-A) and endothelin-B (ET-
B) receptors.
 Under normal conditions, endothelin-1 binding
of ET-A receptors causes constriction of the
pulmonary blood vessels.
 Conversely, binding of endothelin-1 to ET-B
receptors has been associated with both
vasodilation and vasoconstriction of vascular
smooth muscle, depending on the ET-B subtype
(ET-B1 or ET-B2) and tissue.
 Bosentan blocks both ET-A and ET-B receptors,
but is thought to exert a greater effect on ET-
A receptors, causing a total decrease in
pulmonary vascular resistance

12. Mechanism of Action…
Normal
Endothelin -1 Endothelin -1
Endothelin –A Endothelin -B
VasoconstrictionVasodilationVasoconstriction
(Pulmonary Blood Vessels) (Vascular Smooth Muscles)
Bosentan

13. Tezosentan
1
5
13
4
4
3
5
2
6
62
1
3
4
5
6
2
3
4
5
6
1
2 3
N-(2-(2-(2H-tetrazol-5-yl)pyridin-4-yl)-6-(2-hydroxyethoxy)-5-(2-
methoxyphenoxy) pyrimidin-4-yl)-5-isopropylpyridine-2-
sulfonamide
4
2
5
2
Tezosentan is a non-selective ETA and
ETB

Receptor antagonist.
It acts as a vasodilator and was
designed
as a therapy for patients with acute
heart

14. Nesiritide
▪ Nesiritide (Natrecor) is the
recombinant form of the 32
amino acid human B-type
natriuretic peptide(BNP),
which is normally produced
by the ventricular
myocardium.
▪ Nesiritide works to
facilitate cardiovascular
fluid homeostasis through
counter regulation of the
renin–angiotensin–
aldosterone system,
stimulating cGMP, leading
to smooth muscle cell
relaxation.
Vasodilation
NPR-A
GTP
cGMP
▪ Recombinant human B-type natriuretic peptid
(BNP)
BNP
DiuresisNatriuresis
NO