DRUGS USED FOR RX OF

HEART FAILURE

MD2 LECTURE SERIES – PHARMACOLOGY

MBEYA, TANZANIA

Dr. Ng’weina Francis Magitta, MD, PhD

University of Dar es Salaam
Heart Failure

 Final common pathway for many CVDs whose

natural history results in symptomatic or
asymptomatic left ventricular dysfunction
 Cardinal manifestations of heart failure include
dyspnoea, fatigue and fluid retention
 Risk of death is 5-10% annually in patients
with mild symptoms and increases to as high
as 30-40% annually in patients with advanced
disease
HF – symptoms & signs
Clinical features of HF
Compensatory mechanisms in HF
Compensatory mechanisms in HF
Functional Classification - NYHA
Functional Classification – ACC/AHA
HF classes & severity
Drug Targets for Rx of HT
Strategy of treatment of CHF

The therapeutic goal for CHF is to increase cardiac

output.
1) Inotropic agents that increase the strength of
contraction of cardiac muscle
2) PDEI (phosphodiesterase inhibitors) agents that
increase cAMP to induce systoles and vasodilatation
3) Calcium sensitizers extracellular fluid volume
4)  adrenergic agonist
5)  adrenergic antagonist
6) Vasodilators: Calcium channel blocker
7) Decreasing RAS activity: ACEI and AT1 antagonist
8) Diuretic agents
Pharmacological mx of HF
Approach to Rx of HF
Classification1 Positive inotropic drugs
Cardiac glycosides
structure-activity relationship
A cardiac glycoside molecule consists of
an aglycone or genin, which possesses
the same pharmacologic activity as the
whole molecule combined chemically
with one or more sugars.
Cardiac Glycosides
Sources of Cardiac Glycosides
Cardiac Glycosides
 Cardiac glycosides
Aglycones Digitoxin = H at 12 C
Digoxin = OH at 12 C
CH3
12 17 O Unsaturated lactone
C D
CH3
OH Convey cardiotonic
O activity
A B
3
O steroid nucleus
H
C18 H31O9
Convey the
pharmacological
Sugars- 3 mols. of digitoxose activity
Modulate potency and
pharmacokinetic distribution
 1. The relationship between structure and
effects
CH3
12 C
17 O
C D
CH3 C14
OH O
C3 A B
O H
C18 H31O9 The Indispensable
parts of activity

The number of -OH and glycose

will decide water-solubility and lipid-solubility

 ctivity ： C17 Unsaturated lactone 、 C14 OH 、 C3 digitoxose

 lipid-solubility ： C3 water-solubility ： C12
Structural – Activity Relationship
 Process of drug through body
Drug Absorption Protein- Heptoent Biotransf Kidney T1/2
rate (%) binding eral- ormation excretion
(%) circulatio (%) (%)
n (%)

digitoxin 90~100 97 27 30~70 10 5~7 day

digoxin 60~85 <30 6.8 5~10 60~90 33~36 h

Cedilanide 20~40 5 Few Quite 90~100 33 h

few
Strophanthin 2~5 5 Few 0 90~100 12~19 h
K
 Pharmacologic action
I. Action of cardiac glycosides on the heart
1. Positive inotropic action ： Increasing
contractility of cardiac muscle in heart failure.
(1) characteristic:
A. myocardiac quick contraction, Q-T period↓

①rate of force ↑
②time to peak tension ↓
B. no increase oxygen consumption ： The
increase in output is not accompanied by an
equivalent increase in oxygen consumption

Factors of oxygen consumption

1 ） Myocardia contractility
2 ） Heart rate
3 ） Myocadiac fiber length and tone
Factors affect consumption of
oxygen
I. The force of cardiac contraction
II. Heart rate
III. Volume of ventricular
C. Effect of positive inotropic act

① cardiac output is increased

② compensatory sympathetic tone is reduced
③ cardiac preload and afterload is decreased
④ heart rate is reduced
⑤ myocardiac fiber tone and oxygen
consumption is decreased
⑥ increasing stroke volume causes a decrease
in end-systolic volume
(2) Machanism of cardiac glycoside on positive
inotropic action

A. Inhibiting Na+-K+-ATPase in therapeutic dose

B. Increasing of calcium inward and induce the

releasing of calcium from sarcoplasmic reticulum
Mechanism of pharmacological act
Na+-K+-ATPase is a recetor of glycoside
↓ ↓
glycoside → α β
↓
Structure changes
↓
Enzyme activity ↓
↓
Na+↑, K+↓ in cell
↓
Ca2+Na+exchange↓ in cell)
 → Na+  i

Na+-K+-ATPase is the receptor of cardiac

glycosides , so cardiac glycosides act by inhibiting
the membrane Na+-K+-ATPase pump →  Na+  i
 →by Na ＋ /Ca 2+exchanger
→ Ca2+ i↑

Bidirectional exchange
① Na+ enter ↓ → Ca2+ ↓ outer
② Na+ outer ↑→Ca2+ ↑ enter
 → Ca 2+ i↑

Sarcoplasmic reticulum

Ca2+ -induced Ca2+ release

Sarcoplasmic reticulum release Ca 2+
Enhance the increased cytosolic calcium concentration
 2.Negative chronotropic action
A. Continuous effect of positive inotropic action
 Decreasing sinus rate
 Heart rate is decreased

B. Increasing sensitivity of myocardium to vagal

stimulation (increasing potassium outward and
resting potential, reduction of automaticity).
 Heart rate is decreased
 Atropine can antagonize (block)
3. Affects of glycosides to conductive tissues

A. Increasing conduction of the atrial muscle

fibers, because increasing excitation of
vagus nerve (increasing of potassium
outward).
Increasing resting potential.
Elevating rate of phase-0 depolarization.
Acceleration rate of depolarization phase-0
and atrial fibers conduction.
B. Slowing (depress) conduction at A-V node
(inhibiting Na-K- ATPase, reducing resting
potential),
potential and increase effective refractory
period
Rx: atrial fibrillation, atrial flutter, paroxymal
(and) or supraventricular tachycardia

C. Increasing automaticity of Purkinjie fibres ：

toxicity
Mechanism of toxicity

A. Inhibition of Na+-K+-ATPase by more than

30%, cardiac glycosides can induce toxicity
by the overload of intracellular free calcium
concentration in myocardium (decreasing
inotropic action)
B. Very low level of intracellular potassium
concentration, cardiac glycosides can easily
induce toxicity in myocardium (arrhythmia)
4. Affects of cardiac glycosides to ECG

A. Therapeutic dose
T-wave can become low, flat, isoelectric or
inverted
S-T segment falls below the isoelectric line
P-R interval is lengthened, which is associated
with slower or delayed A-V conduction
Q-T interval is shortened, ERP and APD is
shortened in Purkinje fibers
B. Higher dose: arrhythmias
The affects on ECG

T wave
It is characterized by an
descend ST segment on
the ECG
P-R
Q-T
P-P
II. Action of cardiac glycosides on neural and hormone

Directly inhibit or reflected decrease sympathetic activity

• Exciting increase the vagal activity
• Inhibit RAAS system, promote the excrete of ANP
• cause arrhythmias (toxic doses)
II. Action of cardiac glycosides on vascular and
kidney
• Vasoconstriction, increase in peripheral vascular
resistance
• Diuretic ， increase the blood flow through kidney and
inhibit Na+-K+-ATPase → Na ＋ decreased re-absorb
Clinical uses

1. Cardiac glycosides are given for CHF

Effects ： Best go with atrial fibrillation
Better hypertension congenital heart disease
not good anaemia lack of vitamin B1
not useful pericarditis

2. Some kinds of arrhythmias

Atrial fibrillation
Atrial flutter
Supraventricular Tachycardia
Toxic effects
1. Responses of stomach-intestines :
Anorexia, nausea ， vomiting ,
Abdominal pain and diarrhoea
2. CNS: visual disturbaces

3. Arrhythmia:
1) Tachycardia
2)AV block
3)Bradycardia <60 beat/min
Prophylaxis and treatment of the toxicity

• Clear the signal of toxic and the indication of withdraw

• Inspect the concentration of digoxin (3ng/ml),
digitoxin(45ng/ml)

• If necessary ,potassium supplements and antiarrhythmic

drugs (phenytoin ,lidocaine,atropine )administered
• For severe intoxication ,antibodies specific to cardiac
glycosides are available
Method of administration

• Classical ： whole effect dose

quick or slow (have use digoxin within two
weeks)
The suitable dose to the patients
• Maintain ： 4 ～ 5 t ½
Digoxin 0.25mg/day , 6 ～ 7 day ( t ½ 33 ～
36 hours)
 Classification1 Positive inotropic drugs
 -Adrenoceptor agonists

They are used intravenously in CHF

emergencies
Example of  -Adrenoceptor agonists :
Dobutamine
• Exciting β1 Adrenoceptor → positive inotropic action
→the volume of output↑
• Exciting β2 Adrenoceptor→dilate the vascular →
afterload↓

have benefits within short time

Classification1 Positive inotropic drugs
Phosphodiesterase-Ⅲ inhibitors
Inodilator / inodilating drugs
Inhibiting the activity of PDE Ⅲ → cAMP↑→ causes
an increase in myocardial contractility and
vasodilatation →total peripheral resistance →cardiac
output ↑
Examples:
Armirinone: Inhibits the excess product of NO, TNF and
affects the neurohormone, anti-the forming of thrombus
milrinone: stronger 20 time
vesnarinone: myocardial contract element’s the
sensitivity to calcium
 Classification1 Positive inotropic drugs
Calcium
Pimobendan:
sensitizers
Inhibit PDE Ⅲ ; increase TnC’s sensitivity to calcium
 Classification 2 Diuretics

Diuretics inhibit sodium and water retention, →reduce the

volume of blood, →venous pressure and the thus cardiac
preload are reduced↓, increasing the efficiency of the heart as
a pump→ cardiac output ↑, so reduce oedema due to heart
failure
Heart failure
• Low-grade : Thiazides hydrochlorothiazide
• Higher-grade : Acute left heart failure
loop diuretics --- furosemide
Spironolacton
（ anti-aldosterone ,keep
Classification 3 Vasodilators
 Antiotensin converting enzyme inhibitor
(ACEI) and AT1 antagonist
 Calcium channel blocker
 Nitryl-vasodilators
 Hydralazine
ACE inhibitors & AT1 blockers
 Classification 3 Vasodilators
Angiotensin-converting-enzyme inhibitor (ACEI )
Captopril Enalapril
Methanism of anti-CHF:
1) Humour: Inhibit ACE→angiotensin Ⅱ and aldosterone
levels↓, reduce sodium retention, increase bradykinin
levels , ANP 、 NO 、 PGI2↑, reduce the release of NA
ET and renew the expression of βreceptor
2) This therefore causes vasodilatation (include coronary
artery) →reduction in peripheral resistance→ increase the
cardiac output, Increase the blood flow of kidney so
Improve the function of kidney
3) Prevent the remodel of the heart
AT1 antiagonists

Losartan
The function just like ACEⅠ
It dosen’t influence bradykinin levels

Clinical utilize:
• CHF
• Protection of kidney
 Calcium-channel blockers
Amlodipine
Vessel

Dilate artery
Dilate the coronary
Alleviate the LV Wall Tension
 Others --- Vasodilators
mechanism
Dilatation of the veins→ decreases preload
Dilatation of the artery→ decreases afterload

Decrease the oxygen demand of the heart

Nitrate esters: nitroglycerin , nitroprusside sodium

Hydralazine direct dilate the vascular
Prazosin ɑ- receptor blocker
 Classification 4  receptor blocker

Carvedilol
Labetalol
Metoprolol
Bisoprolol
Carvedilol
mechanism
• Anti RAAS system
• Anti-arrthymias
• Anti-myocardial ischemia

Cardiomyopathy
Beta- Blockers in HF
END!