CHF.pptx

1
DRUGS FOR HEART FAILURE
Congestive heart failure CHF is a complex clinical syndrome
characterized by impaired ventricular performance (impaired
cardiac output), exercise intolerance, a high incidence of
ventricular arrhythmias, and shortened life expectancy.
The signs and symptoms of heart failure include tachycardia,
decreased exercise tolerance and shortness of breath,
peripheral and pulmonary edema, and cardiac hypertrophy.
Virtually all forms of heart disease can lead to heart failure, with
coronary artery disease, hypertension, and diabetes mellitus
being the most common.
The primary goal in treating heart failure is to improve the
patient's quality of life by reliving the symptoms and to
decrease the mortality rate.

2
Positive Inotropic Drugs
HEART FAILURE
Decreased
Cardiac Output
Decreased tissue
perfusion
Symp.NS activation RAS activation
Vasoconstriction Na & water retention
Increased afterload
Increased venous
volume & pressure
Congestion & Edema
ACEIs
VDs
VDs
Diuretics
Diuretics
Neuroendocrine
system activation

3
Three categories of drugs are used in the treatment of CHF:
1. Positively Inotropic Drugs:
a. Cardiac Glycosides.
b. Adrenergic Receptors Agonists.
c. Phosphodiestrase Inhibitors
2. Vasodilators:
a. ACEIs.
b. CCBs (vasoselective only, why?).
c. Organic Nitrates.
d. Human B-type natriuretic peptide (BNP) Analogues
3. Diuretics (mainly potassium sparing).
1. Positively Inotropic Drugs (Cardiotonics)
O
OH
H
O
OH
H
H
O
Dig3
Digoxin, Lanoxine®
a. Cardiac Glycosides
O
OH
O
H
O
H
Digitoxose (Dig)
• The cardiac glycosides inhibit the Na+/K+ - ATPase
pump, which causes an increase in intracellular Na+,
slowing the rate of the Na+/Ca++-exchanger, thereby
causing an increase in intracellular Ca++ leading to
greater myofibril shortening (contraction).

4
Sugar Portion
Aglycone Portion
R defines the class
OH
O
O
H
O
OH
O
O
OH
O
O
H
OH
H
H
R

Nomenclature:
5
• The cardiac glycosides occur mainly in plants from
which the names have been derived:
– Digitalis purpurea,
– Digitalis lanata,
– Strophanthus gratus, 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 of cardiac glycosides is more
important than the glycone portion.

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 gives the
aglycone nucleus of cardiac
glycosides the characteristic
'U' shape. 7

8
• 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:
9
• One to 4 sugars are found to be present in most cardiac
glycosides attached to the 3β-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 β-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
10
• The sugar moiety appears to be important only for the partitioning
and kinetics of action. 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.
• A skeleton without 14β-OH group but retaining the C/D cis ring
fusion was found to retain activity.
 The 14β-OH groups are now believed to be dispensable.
• Lactones alone, when not attached to the steroid skeleton, are not
active. Thus the activity rests in the steroid skeleton.
• Saturation of the lactone ring dramatically reduced the biological
activity.
 The unsaturated 17-lactone plays an important role in receptor binding.
• The lactone ring is not absolutely required.
 For example, using α, β-unsaturated nitrile (C=C-CN group) the lactone could be
replaced with little or no loss in biological activity.

Biochemical Mechanism of Action
• The mechanism whereby
cardiac glycosides cause a
positive inotropic effect 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.
11

12
• 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.
Mechanism of action

 Causes Digitalis toxicity which is manifests as:
 GI – nausea, vomiting, anorexia etc
 CNS – headache, hallucination, delirium, visual disturbances etc
 Cardiac – Heart block, arrhythmias
 Drug interaction:
 Digoxin –drug interactions are common.
 Both digoxin and quinidine are actively secreted by renal p-gp ( -60%)
 Verapamil, unlike quinidine ,inhibit intestinal pgp and thereby inhibit
the efflux of digoxin from lumen to intestine. On the other hand
Rifampin induce the expression of intestinal p-gp and enhance the
secretion of digoxin and many more drugs!
Side effect

 Management of digitalis toxicity
 If mild GI or Visual disturbances - reduce the dose
 If cardiac arrhythmias occur check serum levels of
K+, Digoxin, Ca++ & Mg++
Correct electrolytes, potassium salt
Use anti arrhythmic agents like Lidocaine
Administer digitalis antibodies

15
B - b-Adrenergic Agonists
O
H
O
H
NH2
Dopamine, Intoropin®
N
H
O
H
OH
O
H
Dobutamine, Dobutrex®
 Dobutamine – a racemic mixture
At therapeutic doses it has positive Inotropic effect
Increases myocardial contractility (β1 effect)
Adverse effects; excessive tachycardia or arrhythmias
 Dopamine
Action mediated through Dopamine receptors.
Used for systolic HF along with shock e.g. hemorrhage, dehydration

C- Phosphodiesterase Inhibitors
N
N
O
H
N
H2
Amirinone, Inocor®
Milrinone, Primacor®
Available for parenteral use only
Selective inhibitors of type III PDEastrase enzyme in the heart & smooth
muscles
Increase the concentration of cAMP & cGMP
Increase Ca++ influx  increased cardiac contractility
Vasodilatation
Used for the treatment of acute heart failure & acute exacerbation of
chronic heart failure
N
N
O
H
NC

Human B-type natriuretic peptide
(BNP) Analogues
Nesiritide
• Nesiritide is a recombinant human B-type natriuretic peptide (BNP).
• It is identical to the endogenous hormone produced in E. coli.
• It is a new drug class for the treatment of congestive heart failure.
Mechanism of action
• Human B-type natriuretic peptide (BNP) is normally produced by the
ventricular cardiomyocytes.
• Human BNP binds to the particulate guanylate cyclase receptor of vascular
smooth muscle and endothelial cells, leading to increased intracellular
concentrations of guanosine 3', 5'-cyclic monophosphate (cGMP) and
smooth muscle cell relaxation.
• cGMP serves as a second messenger to dilate veins and arteries.

• Nesiritide mimics the actions of endogenous BNP by
binding to and stimulating receptors in the heart,
kidney and vasculature.
• Nesiritide has venous, arterial, and coronary
vasodilatory properties that reduce preload and
afterload, and increase cardiac output without direct
inotropic effects.
Uses
• For the intravenous treatment of patients with
acutely congestive heart failure who have dyspnea at
rest or with minimal activity

Bosentan
• Bosentan is an oral dual endothelin receptor antagonist.
• It is a sulfonamide-derived compound.
Mechanism of action
• Bosentan is a specific and competitive antagonist at endothelin
receptor types endothelin A (ETA) and endothelin B (ETB).
• It has slightly higher affinity for the ETA receptor than endothelin
ETB.
• Endothelin 1 is an extremely potent endogenous vasoconstrictor
and bronchoconstrictor.
• Bosentan blocks the action of endothelin 1 by binding to endothelin
A and endothelin B receptors in the endothelium and vascular
smooth muscle.
• Thus Bosentan decreases both pulmonary and systemic vascular
resistance.
Uses
• It is used in the treatment of pulmonary arterial hypertension
(PAH).
• It is used to reduce the number of active digital ulcers.

Tezosentan
• Tezosentan is an intravenous endothelin receptor A/B
antagonist.
• It has pyridinylpyrimidine skeleton.
Mechanism of action
• Tezosentan competitively antagonizes the specific
binding of endothelin-1 (ET-1) and endothelin-3 (ET-3)
on cells and tissues carrying ETA and ETB receptors.
• This results in vasodilatory responses leading to an
improvement in cardiac index.
Uses
• It acts as a vasodilator and was designed as a therapy
for patients with acute heart failure.
• It is used to treat pulmonary arterial hypertension.

 Cardiac cells: Contractile muscle cells (CMC) and
Special conducting tissue.
 Normal cardiac rhythm
Impulse generation: S.A node at a rate of 60-100per min.
Impulse propagation: SAN AVNHis-Purkinje  CMC
AV nodal delay = 0.15sec
 Arrhythmia: Any different from the Normal rhythm.
Abnormal: - Origination, rate/ regularity, conduction.
Arrhythmias can be: Brady-arrhythmia or tachy-
arrhythmia.
ANTIARRHYTHMIC DRUGS

Phases of cardiac AP
 Phase 0: fast inward Na+ current
 Phase 1: transient outward K+- current
 Phase 2: Plateau, due to balanced depolarizing Ca++-
current and repolarizing K+ current
 Phase 3: repolarization of cardiac cell
 Phase 4: Resting Membrane Potential

25
All of the antiarrhythmic drugs act by altering ion fluxes
within excitable tissues in the myocardium. The three
ions of primary importance are Na+, Ca2+, and K+.
Antiarrhythmic drugs can be classified by their ability to
directly or indirectly block flux of one or more of these
ions across the membranes of excitable cardiac muscle
cells
Therapeutic Classes
Four classes of drugs are used in the treatment of
arrhythmia:
Class-I: (sodium channels blockers).
Class-II (b-adrenergic blockers)
Class-III (potassium channels blockers)
Class-IV (cardioselective CCBs)

26
Class-I Antiarrhythmic Drugs:
They are called membrane stabilizing (depressant) drugs, act on sodium channels
and block the depolarizing inward Na+ current. They bind Na+ channels in the
open or inactivated state and dissociate from the channels in the resting state.
They affect arrhythmic hearts more than normal hearts (use dependent channels
blockade).
According to the rate of dissociation from the sodium channels, Class-I
drugs could be subdivided into:
Class-IA (intermediate rate of dissociation)
Class-IB (rapid rate of dissociation)
Class-IC (slow rate of dissociation)
N
H
N
O
H
O
H
Quinidine
Class-IA Drugs
N
O
N
N
H2
H
O
NH2
N
N
Ph
Procainamide, Pronestyl Disopyramide, Norpace

Quinidine
• As early as the 18th century, the bark of the
cinchona plant was used to treat "rebellious
palpitations"
• Studies in the early 20th century identified
quinidine , a diastereomer of the antimalarial
quinine, as the most potent of the
antiarrhythmic substances extracted from the
cinchona plant, and
• by the 1920s, quinidine was used as an
antiarrhythmic agent.
• Quinidine is used to maintain sinus rhythm in
patients with atrial flutter or atrial fibrillation
and to prevent recurrence of ventricular
tachycardia or ventricular fibrillation
N
H
N
O
H
O
H
27

28
N
N
H
O
Class-IB Drugs
N
NH2
H
O
O
NH2
Lidocaine, Xylocaine Tocainide, Tonocard Mexiletine, Mexitil
N
N
O
H
O
Encainide Enkaid
Class-IC Drugs
N
N
O
H
O N
N
O
H
O
H
N
N
O
H
O
H
O
N
N
O
H
O
H
Encanide ODE
MODE
NDE
Metabolism of Enkanid

29
Class-II Antiarrhythmic Drugs:
O N
OH H
O
O
Esmolol, Brevibloc
They decrease inward calcium current by blocking the b-
adrenergic receptors and inhibiting sympathetic activation of
cardiac automaticity and conduction.
Propranolol, Acebutolol, Metoprolol and Esmolol,
Class-III Antiarrhythmic Drugs:
Drugs from this class share the ability to block potassium channels; some members are able to
block other channels as well. Potassium channels are activated during the repolarization (Phase
3) of the action potential; thus, their blockade prolongs action potential duration resulting in an
increase in effective refractory period
N
O
O
I
I
O
Amiodarone, Cordarone
N
OH H
N
H
S
O
O
C
H3
Sotalol, Betapace
Class-IV Antiarrhythmic Drugs:
These are the cardioselective CCBs namely Verapamil, Biperidil and Diltiazem they decrease
the conduction velocity and increase the refractory period

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