Treatment of Heart Failure- Pharmacology of Drugs used in treatment of Heart Failure

1. Dr. Netravathi
Associate Professor
Dept of Pharmacology
J. N. M.C
BELAGAVI

2.  Describe:
 Pathophysiology of heart failure and sites of
drug intervention
 Drug groups used in heart failure and
discussion of individual groups based on
mechanism, common adverse effects.
 Therapeutics in acute and chronic heart failure
2

4. “Clinical syndrome that can result from any
structural or functional cardiac disorder that
impairs the ability of the ventricle to fill with
or eject blood.”
HEART FAILURE

5. 1. Ischemic heart disease,
2. Cardiomyopathy,
3. Hypertension.
4. Valvular heart disease,
5. Congenital heart disease,
6. Hyperdynamic circulation (anaemia, thyrotoxicosis),
7. Right heart failure (RV infarct, pulmonary hypertension,
pulmonary embolism, cor pulmonale (COPD))
CAUSES OF HEART FAILURE

7.  Impaired cardiac contractility as in myocardial
infarction and cardiomyopathy
 Ventricular outflow obstruction (pressure overload)
as in hypertension and aortic stenosis
 Impaired ventricular fillings as in mitral stenosis and
constrictive pericarditis
 Volume overload as in mitral regurgitation
MECHANISMS LEADING TO HEART FAILURE

8.  Infections
 Arrhythmias
 Physical, Dietary, Fluid, Environmental, and Emotional,
Excesses.
 Myocardial infarction
 Pulmonary embolism
 Anemia
 Thyrotoxicosis and pregnancy
 Aggravation of hypertension
 Rheumatic, Viral, and Other Forms of Myocarditis
 Infective endocarditis
PRECIPITATING FACTORS:

9. The heart depends on a number of adaptive
mechanisms for maintenance of its pumping
function:
1. The Frank Starling mechanism (cardiac dilatation)
2. Myocardial hypertrophy
3. Increased release of catecholamines, activation of
renin-angiotensin-aldosteron system and other
Neurohumoral adjustments
These effects are compensatory at first,
pathological later
ADAPTIVE MECHANISMS:

11. Heart failure
↓Cardiac output
Sympathetic nervous system activation
Vasoconstriction
Elevated cardiac
filling pressures
Na & water
retention
CARDIAC REMODELING
Renin
Angiotensin I
Angiotensin II
Aldosterone

12. N/H changes Changes Effect
 Sympathetic activity
 HR , contractility,
vasoconst.   V return,
 filling
Arteriolar constriction 
After load  workload
 O2 consumption
 Renin-Angiotensin –
Aldosterone
Salt & water retention VR Vasoconstriction 
 after load
 Vasopressin Increased B.P Increased B.P
 interleukins &TNF May have roles in myocyte
hypertrophy
Apoptosis
Endothelin
Vasoconstriction VR  After load

13. Case scenario
 A 65-year-old man has developed
shortness of breath with exertion
several weeks after experiencing a viral
illness. This is accompanied by swelling
of the feet and ankles and increasing
fatigue.

14.  O/E
 He is found to be mildly short of breath
lying down, but feels better sitting
upright.
 Pulse =105/min, regular
 B.P. = 90/60 mm Hg.
 JVP = increased
 His lungs show bibasilar crackles.
 The liver is enlarged
 Edema = 3+ of the ankles and feet.

15.  ECHOCARDIOGRAPHY:
 shows a dilated, poorly contracting heart
with a left ventricular ejection fraction of
about 20% (normal: 60%).
 The presumptive diagnosis is dilated
cardiomyopathy secondary to a viral
infection with stage C, class III heart
failure.
What treatment is indicated?

16. The treatment of HF may be divided into five
components:
(1) General measures.
(2) Correction of the underlying cause.
(3) Removal of the precipitating cause.
(4) Prevention of deterioration of cardiac function.
(5) Control of the congestive HF state.

17.  General measures:
Rest, salt restriction
 Removal of the cause:
This deserves top priority in all cases and includes
 surgical measures correcting valvular lesions
or congenital malformations and
 medical measures for treating hypertension or
infective endocarditis when present
 Removal of precipitating causes of heart failure

18. Heart failure
↓Cardiac output
Sympathetic nervous system activation
Vasoconstriction
Elevated cardiac
filling pressures
Na & water
retention
CARDIAC REMODELING
Renin
Angiotensin I
Angiotensin II
Aldosterone

19. Heart failure
↓Cardiac output
Sympathetic nervous system activation
Vasoconstriction
Elevated cardiac
filling pressures
Na & water
retention
CARDIAC REMODELING
Renin
Angiotensin I
Angiotensin II
Aldosterone
Digoxin, Inotropes
Digoxin
β
Blockers
Renin
Inhibitors
ACE-I
ARBs
Spironolactone
Diuretics

20. Goals of management of HF
I. Relief of congestive/low output symptoms and
restoration of cardiac performance
II. Arrest/reversal of disease progression and
prolongation of survival

21. I. Relief of congestive/low output
symptoms and restoration of cardiac
performance
 Inotropic drugs
 Digoxin, Dobutamine/Dopamine, Amrinone/
milrinone
 Diuretics
 Furosemide, Thiazides

22.  RAS inhibitors
 ACE inhibitors/ARBs/DRI
 Vasodiltors
 Hydralazine, Nitrate, Nitroprusside
 β blockers
 Metoprolol, Bisoprolol, Carvedilol, Nebivolol

23. II. Arrest/reversal of disease progression
and prolongation of survival
 ACEinhibitors / ARBs/DRI, β blockers
 Aldosterone antagonist – Spironolactone,
eplerenone

24.  Intravenous inotropes are frequently used to
support myocardial function in patients with
acute left ventricular failure and following
cardiac surgery.
 Dobutamine, and dopamine are intravenous
adrenergic agonists.

25.  Increase myocardial contractility and output in a
hypodynamic heart without a proportionate
increase in O2 consumption.
 Efficiency of failing heart is increased.
 ‘Cardiac stimulants’ (Adr,
theophylline) increase O2 consumption
rather disproportionately and tend to decrease
myocardial efficiency

26. Digoxin,
Renal clearance
Emergency use
Digitoxin
Hepatic clearance
For maintenance
use

27.  Systole is shortened and diastole is prolonged.
 More complete emptying of failing and dilated
ventricles cardiac output is increased.
 Heart rate is decreased by digitalis

28.  ECG : at high doses—may also produce
arrhythmias.
 The changes are:
• Decreased amplitude or inversion of T wave.
• Increased P-R interval (slowing of A-V
conduction), A-V block at toxic doses.
• Shortening of Q-T interval (reflecting shortening
of systole).
• Depression of ST segment

29. Action on Blood vessels:
 Mild direct vasoconstrictor.
 In CHF this effect is compensated by its
improved circulation sympathetic
overactivity is withdrawn.
 Venous tone  improved in normal and CHF.

30. GIT:
 Most common site of digitalis toxicity outside
heart.
 Anorexia, nausea, vomiting and diarrhoea.
Kidney: diuretic
CNS:
 Higher does  vagal and CTZ stimulation,
disorientation and hallucinations, visual
disturbances.

31. ca++
ATPase
ca++
Na+
In therapeutic dose leads to partial inhibition of Na+/K+
ATPase enzyme
Na+
Na+
Na+
Na+ Na+
Na+
 intracellular Na+ resulting in:
Na + /ca + +
exchange
ca++
Na+
K+
ca++
ca++
ca++
sarcoplasmic reticulum
ca++
ca++
ca++ ca++
ca++
ca++
ca++
ca++
 

troponin
Actin Myosin
 Force Of Contractility

32.  Two main indications of digitalis are
 CHF
 Control of ventricular rate in atrial
fibrillation/ flutter

33. Current status of digoxin in HF
Digoxin is used in only two conditions:
1. Acute decompensated state of HF for
symptomatic improvement.
2. When heart failure is associated with
atrial fibrillation.

34.  Atrial fibrillation (AF) Digitalis is the drug of
choice for controlling ventricular rate in AF.
 However, it is incapable of curing AF, i.e. does
not revert it to sinus rhythm.
 Other drugs: β blocker or verapamil
 Paroxysmal supraventricular tachycardia -
PSVT

36. Anorexia, nausea, vomiting (early toxicity)
abdominal discomfort or pain and diarrhea.
Headache, malaise, fatigue, drowsiness, confusion,
delirium, hallucination or rarely convulsions.
Blurred vision, chromatopsia mostly for yellow
and green vision, transient amblyopia or diplopia.

37. May be due to steroidal structure.

38. Any type of arrhythmia may be
produced including:
 Bradycardia,
 Heart block,
 Ventricular extrasystole
 Ventricular fibrillation.

39. 1. Stop Digoxin
2. KCl syrup or slow release or I.V. with ECG monitoring if
plasma potassium is low or normal.
3. In acute toxicity give specific digitalis antibodies (Fab
fragment).

40.  Ventricular arrhythmia without A-V block is
treated by lidocaine I.V. or beta blockers.
Partial heart block is treated by atropine.
is treated by Diphenylhydantoin (phenytoin)

41.  MOA in HF is to reduce venous pressure and ventricular
preload.
reduces edema and symptoms and pulmonary congestion
reduction in cardiac size
 leads to increase pump efficacy
Aldosterone antagonists: spironolactone, Eplerenone
 Additional benefits - these agents reduce the myocardial and
vascular fibrosis and barorecceptor dysfunction caused by
aldosterone.

42. -Almost all cases of symptomatic heart failure are treated
with a diuretic
-High ceiling diuretics (furosemide, bumetanide) are the
diuretics of choice for mobilizing edema fluid
-IV Furosemide- increases systemic venous capacitance
and produces rapid symptomatic relief in acute LVF
“Diuretics may be added intermittently for
symptom relief”

43.  CHF pts respond favorably to β blockers in mild to
moderate cases.
 Bisoprolol , Carvedilol, metoprolol &Nebivolol
showed a reduction in mortality in pts with stable
severe HF.
 MOA  attenuation of the adverse effects of high conc.
Of catecholamines.
 reduced remodelling through inhibition of
mitogenic activity of catecholamines.
 decreased HR.

44. - Afterload decreased by reducing peripheral
resistance.
- Preload decreased by reducing salt and water
retention.
-Also retard/prevent ventricular hypertrophy,
myocardial cell apoptosis, fibrosis, intercellular
matrix changes and remodeling
**Intolerant to ACEI ARB’s

45. -ACE inhibitors and ARBs are the sheet anchor of
drug therapy in CHF
-ACE inhibitors/ARBs have been established in
mild to severe (NYHA class I to IV) CHF with
reduced EF,
-As well as in subjects with asymptomatic systolic
dysfunction.
-An overall 20% reduction in mortality has been
obtained by the use of ACE inhibitors in heart
failure

46.  Goal: To reduce TPR
 Reduce preload
 Reduce afterload
 Relieve symptoms
 Increase exercise tolerance
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Hydralazine,
Nitrates
Nitroprusside

47.  Venodilators
 Reduce preload
 Cause peripheral pooling of blood and reduce ventricular
end-diastolic pressure and volume
 Afford relief in acute LVF or severe CHF
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48. Nitroglycerin
 Quick onset (sub-lingual) t 1/2 10-30 min.
 For acute ischemia or acute heart failure
 Orally active (5-15 mg), t 1/2 4-8 hr.
 Also administered I.V. (2-10mg/hr) for peripheral vasodilation
Isosorbide dinitrate
 Administered I.V t1/2 40.min (Produces symptomatic relief)
 Oral:20 - 40 mg t1/2 duration of action 6-10 hr.
(For chronic administration)
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49.  New York Heart Association (NYHA) classification
Class I → Normal physical exercises do not cause
fatigue, dyspnoea or palpitations
Class II → Comfortable at rest but normal physical
activities cause fatigue, dyspnoea and palpitations
Class III → Comfortable at rest but gentle physical
activities produce marked symptoms of CHF
Class IV → Symptoms of CHF occur at rest and are
exacerbated by any physical activity
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50. 52

53. 1. A 65-year-old woman has been admitted to
the coronary care unit with a left ventricular
myocardial infarction. If this patient develops
acute severe congestive failure with pulmonary
edema, which one of the following would be
most useful?
(A) Furosemide
(B) Captopril
(C Propranolol
(D) Spironolactone

54. 2. All of the following drugs are
used for the treatment of
congestive heart failure EXCEPT:
A. Nitroglycerine
B. Spironolactone
C. Ramipril
D. Trimetazidine

55. Thank You