Description
DRUGS USED IN CONGESTIVE HEART
FAILURE
10.1.1. Introduction
When a heart fails to pump blood in a quantity sufficient to fulfil the body
requirements, a condition of Congestive Heart Failure (CHF) occurs, which is
also known as a Heart Failure (HF). CHF is caused due to:
1) Narrowing of the arteries, supplying blood to the heart muscles,
2) The patient suffered in the past with myocardial infarction or heart attack with
the injured tissue that obstructs the normal functioning of heart,
3) Any congenital heart defects,
4) Endocarditis (infection in heart valve) or myocarditis (infection of heart muscles),
5) Any heart valve disease (due to past rheumatic fever or other causes) and high
blood pressure, for long-term, and
6) Cardiomyopathy (disease of the heart muscles).
10.1.2. Classification
The drugs used in CHF are classified as follows:
1) Drugs with Positive Inotropic Effects
i) Cardiac Glycosides: Digoxin, Digitoxin, and Ouabain.
ii) Bipyridines/Phosphodiesterase Inhibitors: Amrinone and Milrinone.
iii) β-Adrenergic Agonists: Dobutamine and Dopamine.
2) Drugs without Positive Inotropic Effects
i) Diuretics: Thiazides, Furosemide, and Spironolactone.
ii) Angiotensin Antagonists: ACE inhibitors and Losartan.
iii) β-Adrenergic Antagonists: Bisoprolol, Carvedilol, and Metoprolol.
iv) Vasodilators: Nitrates and Hydralazine.
10.1.3. Cardiac Glycosides
Cardiac glycosides are derived from the foxglove plant ( Digitalis purpurea ).
William Withering described the therapeutic benefits of digitalis in 1785.
Primarily, digitalis was used for treating dropsy, an old word for oedema. Further
investigations established that digitalis was most helpful for oedema caused by
weakened heart (i.e., heart failure). The natural sources of cardiotonic agents are
foxgloves (Digitalis spp.) and related plants. Foxgloves contain several cardiac
glycosides with similar actions. The cardiac glycosides and their sources are
given in 4) Normally, the concentration of Ca 2+ ions around the myofilaments is lowered
by the calcium pump in the Sarcoplasmic Reticulum (SR). The energy for
driving this pump is obtained by ATP hydrolysis carried out by Na +
-K
+
–
ATPase.
However, digitalis inhibits this enzyme and hence less energy is available for
driving the calcium pump. Thus, the supply of Ca 2+ ions from SR around the
myofilaments increases, which in turn activates the contractile machinery
[figure 9.1 (d and e)].
5) The binding of digitalis to sodium pump is inhibited by K+
ions present in the
serum. Hence, conditions of hypokalaemia facilitate the action of digitalis.
On the other hand, conditions of hyperkalaemia can decrease cardiac
toxicity. Arrhythmia, induced by digitalis, is increased by conditions of
hypercalcaemia or hypomagnesaemia.
10.1.3.3. Uses
Amongst digoxin and digitoxin, the former is favoured whose therapeutic
uses include:
1) Treatment of Cardiac Failure: It modifies cardiac function and declines
the frequency of hospitalisations; however, mortality is not delayed. The
direct effect of digoxin on blood vessels is vasoconstriction, and when given
to patients in heart failure, the systemic vascular resistance falls.
2) Treatment of Atrial Fibrillation and Flutter: These conditions lead to a
rapid ventricular rate that can impair ventricular filling (due to decreased
filling time) and reduce cardiac output. Furthermore, chronic ventricular
tachycardia can lead to heart failure.
Digoxin reduces ventricular rate by its ability to activate vagal efferent
nerves to the heart (parasympathomimetic effect). Vagal activation reduces
the conduction of electrical impulses within the atrioventricular node to the
point where some of the impulses will be blocked. When this occurs, fewer
impulses reach the ventricles and the ventricular rate falls.
b) By reducing the C-17 side chain double bond, the activity reduces.
c) The compounds show higher activity if CH═CHCH═NH side
chain (A═N) is present at C-17.
d) The activity of a compounds is eradicated if the conjugation system
in C-17 side-chain is extended, i.e., CH═CH–CH═CHCH═A.
e) The H-bonding between the side chain and K +
-binding site of Na +
–
K
+
-ATPase enzyme det ermines the degree of Na +
-K
+
-ATPase
inhibition, thus, the dipole of a molecule is an important parameter.
ii) Steroid Nucleus
a) The compound is efficient in activity if lactone ring is present at C-17.
b) The presence of hydroxyl group at C -14 is not essential for
compound’s activity because some compounds without C -14
hydroxyl group have not shown activity.
2) Sugar Portion: There is no direct cardiotonic role of sugars; however, their
presence in the steroid at C -3 contributes to the pharmacodynamic and
pharmacokinetic parameters of cardiac glycosides. The absorption and
distribution of free genins is more than the corresponding glycosides. Thus,
they are rapidly metabolised into less active 3-epimers, and then excreted via
sulphates and glucuronides formation at fre e C-3 OH group. The free genins
are not utilised as therapeutic agents due to their unstable nature.
Pharmacodynamically, the genins are less potent than their glycosidic forms.
Their onset is also rapid and they are capable of reversing enzyme
inhibitions. On the contrary, the glycosides combine with Na +
-K
+
-ATPase
enzyme to form complexes of high stability. By replacing the sugar moieties
with side chains containing nitrogen, potent analogues of digitalis can be
obtained. For example, the affinity of N-(4-amino- n-butyl)-3-amino acetyl
derivative of strophanthidine towards Na +
-K
+
-ATPase enzyme is about 60
times greater than that of the parent genin. The sugar moieties and the
enzyme interact with each other via H-bonding. The 3-OH and 5-CH3 groups
are considered the binding group in 2,6-deoxy sugars.
10.1.3.5. Recent Developments
Cardiac glycosides should fulfil the following prerequisites in order to be
successfully used:
1) The inotropically active component should be se parable from the toxically –
active component.
2) The structure-activity relationships and/or indispensable structural features of
the compounds should be known.
Subject:- Medicinal chemistry 2
Semester:- Sem 5
Course:- Bachelor of pharmacy
