The document provides a comprehensive overview of heart failure, including its definition, types, pathophysiology, symptoms, and pharmacotherapy options. It discusses various medications used in treatment, such as ACE inhibitors, beta blockers, and diuretics, along with their mechanisms of action, adverse effects, and treatment principles. Additionally, it highlights the importance of managing heart failure through neurohumoral modulation, preload and afterload reduction, and increasing cardiac contractility.

1. HEART FAILURE
PROF. SANJAY KHATTRI
PROFESSOR
DEPARTMENT OF PHARMACOLOGY & THERAPEUTICS
KING GEORGE’S MEDICAL UNIVERSITY
LUCKNOW, UP

2. DEFINITION
• American Heart Association
complex clinical syndrome that results from any structural or
functional impairment of ventricular filling or ejection of blood leading
to cardinal manifestations of dyspnea, fatigue, and fluid retention

3. TYPES
• Acute heart failure
• Chronic heart failure
• Heart Failure with Reduced Ejection Fraction(HFrEF)
• Heart Failure with Preserved Ejection Fraction(HFpEF)
• High-Output Heart Failure
• Systolic Heart Failure
• Diastolic Heart Failure
• Left Heart Failure
• Right Heart Failure

8. PATHOPHYSIOLOGY
PROGRESSIVE DISEASE
• Ventricular Remodeling
MECHANISMS OF DISEASE PROGRESSION
• Neurohormonal Activation
• Vasodilatory Hormones
• Endothelin, Inflammatory Cytokines, and Oxidative Stress
• Novel Biologic Targets
• Dyssynchrony and Electrical Instability
• Secondary Mitral Regurgitation

9. • CARDIORENAL AND ABDOMINAL INTERACTIONS
• GUT CONGESTION, THE MICROBIOME, AND INFLAMMATION
• HIGH-OUTPUT STATES

12. SYMPTOMS
• Symptoms of Congestion: Pulmonary Versus Systemic
• Symptoms of Reduced Perfusion
• Other Symptoms

13. New York Heart Association Functional Classification

14. Assessment of patients presenting with heart failure

16. PHARMACOTHERAPY
Symptoms
• INOTROPIC DRUGS
• DIURETICS
• RAAS INHIBITORS
• VASODILATORS
• SYNTHETIC BNP
• BETA BLOCKERS
Disease progression
• ACE INHIBITORS
• ARB’S
• ALDOSTERONE ANTAGONIST
• NEPRILYSIN INHIBITOR

17. TREATMENT PRINCIPLES
1. Neurohumoral Modulation
2. Preload Reduction
3. Afterload Reduction
4. Increasing Cardiac Contractility
5. Heart Rate Reduction

18. Neurohumoral Modulation
• ACEIs
• ARBs
• β blockers
• MRAs

19. ANGIOTENSIN CONVERTING ENZYME INHIBITORS
Mechanism of Action:
 Angiotensin II interacts with AT1 and AT2
 4 major cardiovascular actions mediated by the AT1 receptor:
1. vasoconstriction
2. stimulation of aldosterone release from the adrenal glands
3. direct hypertrophic and proliferative effects on cardiomyocytes and
fibroblasts, respectively
4. stimulation of NE release from sympathetic nerve endings and the
adrenal medulla

21. • Other Actions:
• ACE inactivates bradykinin and substance P
• ACEIs increase bradykinin and substance P levels
• 2 prominent consequences:
cough, the most frequent ADR (~5%); and
angioedema, a rare (~0.7%), but life-threatening condition presenting
with swelling of the skin and mucous membranes of the throat and
asphyxia

22. Examples of ACE Inhibitors:
• Captopril
• Enalapril
• Lisinopril
• Ramipril
• Trandolapril

23. Adverse effects of ACE Inhibitors
• Dry cough
• Creatinine plasma concentration increase
• Hypotension
• Hyperkalemia
• Angioedema
• Allergic skin reactions
Contraindication: Bilateral renal artery stenosis

24. ANGIOTENSIN RECEPTOR ANTAGONISTS
• highly selective
• competitive antagonists at the AT1 receptors
• AT1 receptor mediates major effects of Angiotensin II
• therapeutic alternatives to ACEIs and second choice in all stages of
heart failure in patients who do not tolerate ACEIs
• same pharmacological profile as ACEIs with the exception of not
inducing cough

25. Examples of ARB’s:
• Candesartan
• Losartan
• Valsartan
Adverse effects: Similar to ACE but no cough
Contraindications: As ACEI

26. ΒETA ADRENERGIC RECEPTOR ANTAGONISTS
Major Effects of catecholamines on heart(beta 1):
• Increase heart rate (chronotropy)
• Increase force of contraction (inotropy)
• Quicken the rate of force development (clinotropy)
• Accelerate cardiac muscle relaxation (lusitropy)
• Acceleration of the atrial-ventricular conduction rate (dromotropy)
• Enhance cardiac myocyte automaticity
• Lower the threshold for arrhythmias (bathmotropy)

27. β blockers competitively:
• reduce heart rate and force
• slow relaxation
• slow AV conduction
• suppress arrhythmia
• lower renin levels

28. • therapy must be initiated in a clinically stable condition and at very
low doses (1/8 of target)
• dose escalation requires time (e.g., doubling every 4 weeks in
ambulatory settings)
• “start low, go slow”

29. Available Agents:
1. Metoprolol - β1 -selective agents
2. Bisoprolol - β1 -selective agents
3. Nebivolol - β1 selective additional vasodilatory actions
4. Carvedilol - nonselective β blocker and α1 receptor antagonist

30. Clinical Use:
• All patients with symptomatic heart failure and all patients with left
ventricular dysfunction after myocardial infarction should be treated
with a β blocker
• Should not be administered in new-onset or acutely decompensated
heart failure
Precautions:
• Heart rate lowering( 60-70 desirable)
• AV block (consider pacemaker)
• Bronchoconstriction (C/I in allergic bronchial asthma)
• Peripheral vasoconstriction (cold extremities)

31. MINERALOCORTICOID RECEPTOR ANTAGONISTS
Mechanism of Action:
• MRAs act as antagonists of nuclear receptors of aldosterone
• are K+-sparing diuretics
• additional efficacy in suppressing the consequences of neurohumoral
activation
Examples:
• spironolactone
• Eplerenone( FDA approved)
Adverse effect:
• Hyperkalemia

32. Guidelines for the use of MRAs in patients with heart failure are:
• Administer no more than 50 mg/day
• Do not use if the GFR is less than 30 mL/min (creatinine ~ 2 mg/dL)
• Be careful with elderly patients
• Be careful with diabetics, who carry a higher risk of hyperkalemia
• Do not combine with other K+-sparing diuretics

33. ANGIOTENSIN RECEPTOR AND NEPRILYSIN
INHIBITOR( ARNI)
• Sacubitril/Valsartan
• made by cocrystallizing valsartan with sacubritril
• prodrug that inhibits neprilysin
• peptidase - mediates enzymatic degradation and inactivation of
natriuretic peptides, bradykinin, and substance P
• inhibition of the RAAS
• natriuresis, diuresis and vasodilation
• inhibit thrombosis, fibrosis, cardiac myocyte hypertrophy, and renin
release

35. PRELOAD REDUCTION
Loop Diuretics
MOA:
inhibit the Na+-K+-2Cl symporter in the ascending limb of the loop of
Henle
Examples:
furosemide
torasemide
Bumetanide
Adverse effects: hypokalemia, hyponatremia, hypomagnesemia,
hyperuricemia, hypocalcemia , glucose intolerance

36. Thiazide Diuretics
MOA:
Blocks Na+-Cl cotransporter in the distal convoluted tubule
Examples:
hydrochlorothiazide, chlorthalidone
Adverse effects:
Hypokalemia, hyponatremia, hypomagnesemia, hyperuricemia,
hypercalcemia, glucose intolerance

37. K+-Sparing Diuretics
MOA:
• inhibit apical Na+ channels in distal segments of the tubule directly
(ENaC; e.g., amiloride, triamterene)
• or reduce its gene expression (MRAs spironolactone and eplerenone)
• weak diuretics
Adverse effects:
Hyperkalemia, gynecomastia, erectile dysfunction and menstrual
bleeding disorders (spironolactone)

38. AFTERLOAD REDUCTION
• Failing heart is exquisitely sensitive to increased arterial resistance
• Vasodilators are beneficial in heart failure by reducing afterload and
allowing the heart to expel blood against lower resistance

39. Hydralazine–Isosorbide Dinitrate
fixed-combination formulation in use contains 37.5 mg hydralazine and
20 mg ISDN and is uptitrated
Adverse effects:
• Hypotension
• Dizziness
• Headache
• Hydralazine doses greater than 200 mg have been associated with
lupus erythematosus

40. INCREASING CARDIAC CONTRACTILITY
• Failing heart is unable to generate force sufficient to meet the needs of
the body for perfusion of oxygenated blood
• Unfortunately, when used chronically, these agents do not improve life
expectancy or cardiac performance
• Chronic use is associated with excess mortality
• Only cardiac glycosides are used in the treatment of chronic heart failure

41. Cardiac Glycosides
Digoxin
• Digitalis lanata
• Only glycoside currently in use
• Increases force of contraction
• Decreases heart rate
• Other use- control of ventricular rate in atrial fibrillation/flutter

42. Mechanism of action of Digoxin

43. Adverse Effects:
• Therapeutic index extremely narrow
• 0.5 and 0.8 ng/ml - beneficial effects
• 1.2 ng/ml and greater- increased mortality
• Arrythmias- most frequent and dangerous
• GI symptoms- anorexia, nausea and vomiting
• Visual effects-altered color perception and coronas (halos)
Antidote:
• Antidigoxin immunotherapy
• Purified fab fragments from ovine antidigoxin antisera (digibind)

44. HEART RATE REDUCTION
Ivabradine
• selective inhibitor of cardiac pacemaker channels / funny currents
• given to patients with sinus rhythm with hr> 70 bpm with with systolic
dysfunction (EF<35%)

45. Drug Treatment of Acutely Decompensated
Heart Failure
• Diuretics
• Vasodilators- Nitroglycerin, Nitroprusside and Neseritide
• Positive Inotropic Agents- Dobutamine, Epinephrine, Nor-epinephrine,
Dopamine
• Phosphodiesterase Inhibitors- Milrinone and Enoximone
• Myofilament Calcium Sensitizers- Levosimendan and Pimobendan
• Other Drugs- Tolvaptan, Heparin and other anticoagulants