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1. Dr Htet Htet
MBBS, MMedSc
Drug therapy of
congestive heart failure
All rights reserved

2. OBJECTIVES OF LECTURE
• To understand the basic pathophysiology & complications of congestive
heart failure (recall for pharmacology of drugs)
• To be able to discuss the pharmacological basis of different drugs used in the
treatment of heart failure and their important pharmacokinetic &
pharmacodynamic actions.

3. Lecture outline
• What is congestive heart failure? How does a heart fail?
• Types of treatment for heart failure
• Pathophysiological changes of heart failure (for pharmacological
basis of drugs)
• What are our pharmacological targets?
• Objectives of drug therapy
• Pharmacology of individual drugs

4. What is Heart Failure?
• A disorder in which the heart
loses its ability to pump blood
efficiently throughout the
body.
↓Cardiac Output
• Heart failure occurs when CO
is inadequate to provide the
oxygen needed by the body.

5. HOW DOES A HEART FAIL?
– Varies with the underlying etiology ,
–  workload to overcome pressure or volume overload
– Becomes Hypertrophy
– Leads to cardiac dilatation (left ventricle fails to eject its
normal end diastolic volume)
– CO

6. Types of treatment
• is a progressive disease
• Characterized by gradual reduction in cardiac performance
• With many episodes of acute decompensation, often requires
hospitalization.
• Treatment is directed at two conditions with somewhat different
goals:
–  symptoms and slowing progression as much as possible during
relatively stable periods
– Managing acute episodes of decompensated heart failure.

7. WHAT ARE THE
CONSEQUENCES OF
DECREASED CARDIAC
OUTPUT?
Pathophysiological changes
Mainly as compensatory to
maintain CO & tissue
perfusion

8. Pathophysiological changes
1. Venous return
2. Outflow resistance
3. Contractility of myocardium/Heart rate
4. Salt and water retention

9. Venous return (preload)
• Due to  CO   blood volume remains after systole  
stretch of myocardial fibers (which tries to increase stroke
volume in normal heart due to Frank Starling mechanism)
• But in failed heart  did not response
• As heart failure worsens   preload (increased venous
pressure) contributes to symptoms
– Dyspnoea (due to increased venous pressure in lungs)
– Hepatic enlargement (hepatomegaly)
– Ascites
– Dependent oedema

10. Afterload (outflow resistance)
• Afterload is the resistance against which the heart must pump
blood.
• Pulmonary resistance & systemic resistance
•  systemic resistance   CO
• Consequence:
– Due to  CO   blood pressure  activation of baroreceptors  leads
to sympathetic activation   catecholamine
– Due to  CO   RBF → activation of RAA system → which also
contributes to sympathetic activation
– Tries to increase CO
– But chronic sympathetic activation leads to deleterious effect further
causing increase burden on failed heart.

11. Myocardial contractility & Heart rate
– Due to  CO   BP  activation of baroreceptors  activation of
sympathetic system (activate β1 of heart)  which tries to increase FOC
& HR  to maintain CO
– But chronic sympathetic activation leads to deleterious effect further
causing increase burden on failed heart.

12. Salt and water retention
• Due to  CO & RBF  increase RAA activation (renin
angiotensin aldosterone activation)
– Angiotensin  sympathetic activation
– Aldosterone  causes salt and water retention via renal tubules
– Both tries to compensate the low CO & low BP
– But it can worsen the venous pressure (preload)
– more fluid accumulation in the interstitium
– Worsens the signs of heart failure.

13. Myocardial remodeling in heart failure
• LV remodeling is a process of progressive alteration of ventricular size,
shape and function owing to the influence of mechanical, neurohumoral and
possibly genetic factors in several clinical conditions including:
– Myocardial infarction
– Cardiomyopathy
– Hypertension
– Valvular heart disease
• Hall marks are : hypertrophy, loss of myocytes and interstitial fibrosis.
• Remodelling continues for months after initial insult: finally to significant
impairment of overall function of the heart as a pump.

15.  CARDIAC OUTPUT  RENAL BLOOD FLOW
 RAA
ANGIOTENSIN
ALDOSTERONE
SYMPATHETIC
ACTIVATION
Vasoconstriction
Salt and water retension
Oliguria
 Plasma volumeGeneralized edema
 VR in pul : vein
Pulmonary congestion
Pulmonary edema
Dyspnoea, cyanosis
RV hypertrophy
Right sided HF
Liver congestion
Splenomegaly
Ascities
Leg edema
 HR

16. What are our pharmacological targets?
• Preload
• Afterload
• Contractility
• Chronic sympathetic activation
• Remodelling process
Treatment is directed at two conditions with somewhat different
goals:
 symptoms and slowing progression as much as possible during relatively
stable periods (chronic stable heart failure)
Managing acute episodes of decompensated heart failure.

18. DRUG THERAPY
• To increase force of contraction
– Digoxin
– β agoists (dobutamine, dopamine)
– Bipyridines (milrinone)
• To reduce cardiac workload
– To decrease preload (venodilators) (diuretics, nitrates)
– To decrease afterload (arterial vasodilators)
– To decrease preload and afterload (ACEI, ARB) (nitrates, sodium
nitroprusside)
• To prolong the survival
– β adrenoreceptor blockers

19. CARDIAC GLYCOSIDES
“Digitalis”
is used in a generic sense when
referring to any of preparations
from various species of fox glove
Source
Digitalis purpurea
(Common Foxglove)
Was described as early as 1250 AD
“Digoxin”
is the only derivative of digitalis in
current use.

20. SR
RyR2
Na+-K+
ATPase
3Na+
2K+
L-type Ca+
channel
Ca2+
Ca2+
2Na+
Ca2+
Ca2+
Digoxin
 Na+
intracellularly
 Ca2+
intracellularly

21. Failed heart
 FOC

22. (a) Mechanism of action of digoxin
• cardiac glycosides increases intracellular Ca2+ concentration.
• It is the result of 2 step process.
• First, inhibit Na+/K+ pump by binding on K+- binding site Na+/K+- ATPase on the cell
membrane which causes a rise in intracellular sodium.
• Secondly, a rise in intracellular sodium can slow down the extrusion of calcium
• because extrusion of calcium is by a Na+/Ca2+ exchange mechanism.
• Increased cytoplasmic calcium is transported to sarcoplasmic reticulum,
• Finally, increases the amount of calcium released by the action potential.

23. (b) Pharmacological action of digoxin
• Can be generally divided into two portions
– Cardiac effect
– Effect on other organs
1. Cardiac effect
At therapeutic dose
• Direct - increased FOC of heart
• Indirect - decreased HR ( d/t vagal stimulation & decreased
sympathetic activity ) may lead to AV block,
sinus bradycardia, cardiac arrest.
At higher concentration,
• Direct - increase automaticity of heart
• Indirect - sympathetic activation
• Both may lead to ventricular arrhythmias

24. 2. Effects on other organs
• CNS - through vagal and CTZ stimulation:
- disorientation, hallucination, visual disturbances (aberration
of color perception)
• GIT - by direct and through CNS (chemoreceptor trigger zone)
effect.
- ANVD (anorexia, nausea, vomiting, diarrhoea)
- gastrointestinal tract is most common site of digitalis toxicity
outside the heart
• d/t steroid structure - gynaecomastia (rare)

25. (c) Therapeutic Uses of digoxin
1. Heart failure with atrial fibrillation (use only when diuretics and
ACEI have failed to control the symptoms)
– Mild symptoms – slow loading dose
– Acute heart failure – rapid digitalization
2. Treatment of atrial arrhythmia (atrial fibrillation & flutter)

26. (d) Adverse effects of digoxin
• CNS - disorientation, hallucination, visual disturbances (aberration
of color perception)
• GIT - ANVD (anorexia, nausea, vomiting, diarrhoea)
- gastrointestinal tract is most common site of digitalis toxicity
outside the heart
• d/t steroid structure - gynaecomastia (rare)
• CVS - ventricular arrhythmia.
• interaction with electrolytes: hypokalaemia, hypercalcaemia can worsen the
toxicity.
• Narrow therapeutic index drug.

27. (e) Treatment of digitalis toxicity
• Check serum potassium.
• Digitalis antibodies (digoxin immune Fab)

28. How digoxin corrects heart failure?
• Due to FOC   CO   RBF (relieve oliguria)
• Due to better tissue perfusion  relieve cyanosis
• Due to blockage of AV node, conducting tissues → slow ventricular rate 
relieve tachycardia [stronger, slower heartbeat (increased efficiency) without
increased demand]
• Due to  CO  better emptying of the ventricles  increased venous return 
better drainage from the tissues with relief of congestion in the lungs and liver
and reduction of oedema, relief of dyspnoea,
- Better results are obtained in patients with atrial fibrillation than with normal
rhythm
- narrow Therapeutic Index (safety margin) → side-effects common

29. Why digoxin is used in atrial fibrillation, flutter?
- in atrial flutter and fibrillation,
- d/t its cardioselective parasympathomimetic effects on
atrioventricular conduction
- it controls an excessively high ventricular rate,
- improvement is due to direct effect of digitalis as well as the effect of
vagus on the SA node and conducting tissue.
- In atrial fibrillation, reduction of ventricular rate is the best measure
of glycoside effect

31. DRUG THERAPY
• To increase force of contraction
– Digoxin
– β agoists (dobutamine, dopamine)
– Bipyridines (milrinone)
• To reduce cardiac workload
– To decrease preload (venodilators) (diuretics, nitrates)
– To decrease afterload (arterial vasodilators)
– To decrease preload and afterload (ACEI, ARB) (nitrates, sodium
nitroprusside)
• To prolong the survival
– β adrenoreceptor blockers

32. Dobutamine
Mechanism of action
• Selective agonist on cardiac β1 activity.
Pharmacological action
• Increase CO
– Most commonly used inotropic agent other than digitalis
– Mainly inotropic rather than chronotropic action.
Route of administration
- given by IV infusion.
Adverse effects: cardiac arrhythmia.
Therapeutic use (clinical use)
• Mainly used in “Acute decompensated heart failure”.

33. Dopamine
Mechanism of action
• Dose related action on D1, β1 & 1
Pharmacological action
• Low dose  activate D1  causes increase in RBF
• Intermediate dose  activate β1  causes increase FOC, HR, CO
Route of administration
- given by IV infusion.
Adverse effects: cardiac arrhythmia.
Therapeutic use (clinical use)
• Mainly used in “Acute decompensated heart failure”.

34. DRUG THERAPY
• To increase force of contraction
– Digoxin
– β agoists (dobutamine, dopamine)
– Bipyridines (milrinone)
• To reduce cardiac workload
– To decrease preload (venodilators) (diuretics, nitrates)
– To decrease afterload (arterial vasodilators)
– To decrease preload and afterload (ACEI, ARB) (nitrates, sodium
nitroprusside)
• To prolong the survival
– β adrenoreceptor blockers

35. Bipyridines (milrinone)
Mechanism of action
• Inhibits phosphodiesterase type 3 enzyme
• Decrease cAMP breakdown   cAMP  FOC of heart
Pharmacological action
• causes increase FOC
Route of administration
- parentral
Adverse effects: cardiac arrhythmia.
Therapeutic use (clinical use)
• Only for acute heart failure or severe exacerbation of chronic heart failure.

36. DRUG THERAPY
• To increase force of contraction
– Digoxin
– β agoists (dobutamine, dopamine)
– Bipyridines (milrinone)
• To reduce cardiac workload
– To decrease preload (venodilators) (diuretics, nitrates)
– To decrease afterload (arterial vasodilators)
– To decrease preload and afterload (ACEI, ARB) (nitrates, sodium
nitroprusside)
• To prolong the survival
– β adrenoreceptor blockers

37. Diuretics (Thiazide)
Mechanism of action
• Hydrochlorothiazide, Chlorthalidone (Milder diuretics) inhibits Na+-Cl-
symport in PCT (primary convulated tubule) of nephrons
Pharmacological action
• Mild diuresis action + venodilation action
• Can cause salt and water excretion & reduction of preload
Route of administration: Long duration of action. Given orally.
Adverse effects: electrolyte imbalance (esp hypokalaemia which can
worsen digitalis toxicity)
Therapeutic use (clinical use)
• chronic heart failure, usually in combination with others

38. Diuretics (Furosemide)
Mechanism of action
• Highly potent loop diuretics, inhibits Na+-K+-Cl- symport in Loop of Henle of
nephrons
Pharmacological action
• diuresis action + venodilation action + decrease in LV filling pressure
• Can cause salt and water excretion & reduction of preload
• benefits patients with pulmonary edema even before diuresis ensues
Route of administration: available as oral as well as IV.

39. ADVANTAGES IN HEART FAILURE
• Quick onset, short duration → repeated as necessary
THERAPEUTIC USE:- first choice in acute CHF, to relieve morbidity
- as necessary, in chronic heart failure
UNTOWARD EFFECTS
• hypotension (advantage in hypertensive HF)
• dehydration; hypokalaemia (offset by K-sparing diuretics)
• temporary deafness, with large doses (OTOTOXICITY)

40. DRUG THERAPY
• To increase force of contraction
– Digoxin
– β agoists (dobutamine, dopamine)
– Bipyridines (milrinone)
• To reduce cardiac workload
– To decrease preload (venodilators) (diuretics, nitrates)
– To decrease afterload (arterial vasodilators)
– To decrease preload and afterload (ACEI, ARB) (nitrates, sodium
nitroprusside)
• To prolong the survival
– β adrenoreceptor blockers

41. Nitrates
• MOA (refer to antianginal lecture)
• PA
– Reduction in preload (low dose – venodilation)
– Reduction in afterload (high dose – arterial dilation)
• Usefulness of nitrates in heart failure
– Choice of vasodilators depend on patient’s symptoms:
– Nitrates are useful for patients with pulmonary congestion, dyspnoea symptoms
– In patients with severe chronic heart failure – problem involves both elevated
venous filling pressures & decreased cardiac output – therefore, dilation of both
arteries and veins is required.

42. DRUG THERAPY
• To increase force of contraction
– Digoxin
– β agoists (dobutamine, dopamine)
– Bipyridines (milrinone)
• To reduce cardiac workload
– To decrease preload (venodilators) (diuretics, nitrates)
– To decrease afterload (arterial vasodilators)
– To decrease preload and afterload (ACEI, ARB) (nitrates, sodium
nitroprusside)
• To prolong the survival
– β adrenoreceptor blockers

43. (HYDRALAZINE)
ARTERIAL VASODILATORS
Hydralazine
Why it is useful in heart failure (Pharmacological basis)
• Dilation of arteries  decreases afterload
• More helpful in patients with low LV cardiac output are primary symptoms
(fatigue).

44. DRUG THERAPY
• To increase force of contraction
– Digoxin
– β agoists (dobutamine, dopamine)
– Bipyridines (milrinone)
• To reduce cardiac workload
– To decrease preload (venodilators) (diuretics, nitrates)
– To decrease afterload (arterial vasodilators)
– To decrease preload and afterload (ACEI, ARB) (nitrates, sodium
nitroprusside)
• To prolong the survival
– β adrenoreceptor blockers

45. ACE INHIBITORS
Captopril, Enalapril, Lisinopril
Angiotensin converting enzyme inhibitor
Mechanism of action
• Inhibits angiotensin converting enzyme (which converts Angiotensin I to
angiotensin II)
• Reduce formation of antiogensin II (angiotensin II is a potent vasoconstrictor
in body & it causes production to aldosterone, which causes salt and water
retention from kidney).

47. Pharmacological action
ACEI decrease the formation of Ang II and aldosterone
• arterial dilatation → ↓ afterload
• venous dilatation → ↓ preload
• ↓aldosterone action → ↓ salt & water retention → ↓ vascular volume
• improve remodelling, slow ventricular dilatation
•  sympathetic activation

48. THERAPEUTIC USE
• First line therapy in chronic heart failure along with diuretics (especially patients
with LV dysfunction)
UNTOWARD EFFECTS
• first dose phenomenon (severe first dose hypotension)
• dry irritative cough ( breakdown of bradykinin)

50. Angiotensin II Receptor Blockers (ARB)
Losartan, Valsartan
As alternative, in patients who cannot tolerate ACEIs
do not produce local kinin effects → no cough as side-effect.
Otherwise, similar to ACEIs

52. • ACEI can also inhibit or delay cardiac
remodelling process.
• This is also an advantage of ACEI for usage in
heart failure.

53. Initial infarct
Expansion of infarct
(hours to days)
Global remodeling
(days to months)
Normal heart Hypertrophied heart
(diastolic heart failure)
Dilated heart
(systolic heart failure)

54. DRUG THERAPY
• To increase force of contraction
– Digoxin
– β agoists (dobutamine, dopamine)
– Bipyridines (milrinone)
• To reduce cardiac workload
– To decrease preload (venodilators) (diuretics, nitrates)
– To decrease afterload (arterial vasodilators)
– To decrease preload and afterload (ACEI, ARB) (nitrates, sodium
nitroprusside)
• To prolong the survival
– β adrenoreceptor blockers

55. BETA-BLOCKERS
Carvedilol, Bisoprolol, Metoprolol
- Paradox: cardio-depressant in heart failure

56. - Use of β blockers in heart failure are based on hypothesis that excessive tachycardia
and adverse effects of high catecholamine levels on the heart contribute to the
downward course of heart failure.
- Initiated cautiously at low dose
• Not all β blockers – (bisoprolol, metoprolol, carvedilol and nebivolol)

57. - Beneficial effects may be due to:
- preventing changes caused by chronic activation of sympathetic nervous
system.
- ↓ HR →
- ↓ renin release
- preventing direct effect of noradrenaline and angiotensin on cardiac muscle
fibres (remodelling)
- antihypertensive action (where applicable)
- Improvements:
- Rise in ejection fraction
- Slower heart rate
- Reduction of symptoms

58. Drawbacks:
- initial exacerbation of symptoms (worsening of HF).
- Therefore, very low starting dose, titrated gradually to
effective doses. In chronic stable HF.
• Only by experienced cardiologists.
• beneficial effects seen after months (delayed)
• NOT recommended: in acute HF

60. CARDIAC RESYNCHRONIZATION THERAPY (disease condition)
CARDIAC RESYNCHRONIZATION THERAPY (after CRT)

61. References

62. 1. Tripathi, KD. 2008. Essentials of Medical
Pharmacology. 6th Edition. India: Jaypee Brothers
Medical Publishers (P) Ltd.
2. http://www.ncbi.nlm.nih.gov/pubmed/14727944
3. https://www.youtube.com/watch?v=GnpLm9fzYxU
4. https://www.youtube.com/watch?v=3YddwXPWVSc
5. https://www.youtube.com/watch?v=zy_fK1P2odM
References