Drugs for Heart Failure 1

Two Major Forms of Heart Failure Heart failure with left ventricular (LV) systolic dysfunction Diastolic heart failure, also known as heart failure with preserved LV ejection fraction Note: In this chapter, we will focus primarily on the treatment of form #1 2

Heart Failure Progressive, often fatal disorder Characterized by left ventricular dysfunction, reduced cardiac output, insufficient tissue perfusion, and signs of fluid retention Affects nearly 5 million Americans 3

Pathophysiology of Heart Failure Inadequate tissue perfusion Volume overload Chronic hypertension Myocardial infarction Valvular heart disease Coronary artery disease Congenital heart disease Dysrhythmias Aging of the myocardium 4

Pathophysiology of Heart Failure Cardiac remodeling Physiologic adaptations to reduced cardiac output (CO) Cardiac dilation Increased sympathetic tone Water retention and increased blood volume Natriuretic peptides 5

Drugs for Heart Failure Diuretics RAAS inhibitors ACE inhibitors Angiotensin II receptor blockers Aldosterone antagonists Direct renin inhibitors Beta blockers Digoxin Other inotropic agents Other vasodilators 6

Fig. 48–2. The vicious cycle of maladaptive compensatory responses to a failing heart. 7

and New York Heart Association (NYHA) Classification of Heart Failure. Fig. 48–3. American College of Cardiology/American Heart Association (ACC/AHA) Stage and New York Heart Association (NYHA) Classification of Heart Failure. 8

Drugs Used to Treat Heart Failure Diuretics Drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) Beta blockers Digoxin and other cardiac glycosides Inotropic agents (other than cardiac glycosides) Vasodilators: other than ACE inhibitors and angiotensin-receptor blockers (ARBs) 9

Diuretics Thiazide diuretics High-ceiling (loop) diuretics Potassium-sparing diuretics 10

Drugs That Inhibit the RAAS ACE inhibitors Hemodynamic benefits Arteriolar dilation Venous dilation Suppression of aldosterone release Impact on cardiac remodeling ACE inhibitors have favorable impact 11

Drugs That Inhibit the RAAS ACE inhibitors (cont’d) Adverse effects Hypotension Hyperkalemia Intractable cough Angioedema Renal failure if patient has bilateral renal artery stenosis Can cause fetal injury 12

Drugs That Inhibit the RAAS Angiotensin II receptor blockers Clinical trials have shown that ARBs improve LV ejection fraction, reduce HF symptoms, increase exercise tolerance, decrease hospitalization, enhance quality of life, and reduce mortality 13

Drugs That Inhibit the RAAS Aldosterone antagonists Spironolactone (Aldactone) and eplerenone (Inspra) Current studies recommend adding an aldosterone antagonist to standard HF therapy in patients with moderately severe or severe symptoms 14

Drugs That Inhibit the RAAS Direct renin inhibitors Benefits in HF should be equal to those of ACE inhibitors or ARBs Aliskiren (Tekturna) is being tested in HF Not yet approved for HF treatment 15

Beta Blockers Action Adverse effects With careful control of dosage, can improve patient status Protect from excessive sympathetic stimulation Protect against dysrhythmias Adverse effects Fluid retention or worsening of HF Fatigue Hypotension Bradycardia or heart block 16

Digoxin and Cardiac Glycosides Positive inotropic actions Increase myocardial contractile force Alter electrical activity of the heart Favorably affect neurohormonal systems Second-line agents 17

Inotropic Agents Sympathomimetics Dopamine (Intropin) Catecholamine Activates beta1-adrenergic receptors in the heart, kidney, and blood vessels Increases heart rate Dilates renal blood vessels Activates alpha1 receptors 18

Inotropic Agents Sympathomimetics (cont’d) Dobutamine Synthetic catecholamine Selective activation of beta1-adrenergic receptors Phosphodiesterase inhibitors Inamrinone—inodilator Milrinone (Primacor) 19

Vasodilators Isosorbide dinitrate plus hydralazine Intravenous vasodilators for acute care Nitroglycerin Principal adverse effects Hypotension Resultant reflex tachycardia Sodium nitroprusside (Nitropress) Principal adverse effect Profound hypotension Nesiritide (Natrecor) Symptomatic hypotension 20

Cardiac (Digitalis) Glycosides Digoxin (Lanoxin, Lanoxicaps, Digitek) Naturally occurring compound Profound effects on the mechanical and electrical properties of the heart Increases myocardial contractility Increased cardiac output Adverse effect Can cause severe dysrhythmias 21

Digoxin (Lanoxin) Effects Positive inotropic action on the heart Increases the force of ventricular contraction Increases myocardial contractility Relationship of potassium to inotropic action Potassium levels must be kept in normal physiologic range Hemodynamic benefits Increased cardiac output Decreased sympathetic tone Increased urine production Decreased renin release 22

Fig. 48–4. Ion fluxes across the cardiac cell membrane. 23

Digoxin (Lanoxin) Neurohormonal benefits Electrical effects Modulates the activity of the neurohormonal system Suppresses renin release in the kidney Decreases sympathetic outflow from the CNS Increases the sensitivity of cardiac baroreceptors Electrical effects Alters the electrical properties of the heart Increases the firing rate of vagal fibers Increases the responsiveness of the SA node to acetylcholine 24

Digoxin (Lanoxin) Adverse effects Cardiac dysrhythmias Predisposing factors Hypokalemia Elevated digoxin level Narrow therapeutic range Heart disease Diagnosing digoxin-induced dysrhythmias Managing digoxin-induced dysrhythmias 25

Digoxin (Lanoxin) Adverse effects (cont’d) Noncardiac adverse effects Anorexia, nausea, vomiting, fatigue Measures to reduce adverse effects Education 26

Digoxin (Lanoxin) Drug interactions Pharmacokinetics Diuretics ACE inhibitors and ARBs Sympathomimetics Quinidine Verapamil Pharmacokinetics Absorption Distributed widely and crosses the placenta Eliminated primarily by renal excretion Half-life about 1.5 days 27

Management of Heart Failure Stage A No symptoms of HF No structural or functional cardiac abnormalities Hypertension, CAD, diabetes, family history of cardiomyopathy, personal history of alcohol abuse, rheumatic fever, or treatment with a cardiotoxic drug (eg, doxorubicin, trastuzumab) Management directed at reducing risk 28

Management of Heart Failure Stage B No signs and symptoms of HF Goal of management is to prevent development of symptomatic HF Treatment is the same as for stage A with the addition of ACE inhibitors or ARBs 29

Management of Heart Failure Stage C Symptoms of HF Structural heart disease Four major goals Relieve pulmonary and peripheral congestive symptoms Improve functional capacity and quality of life Slow cardiac remodeling and progression of LV dysfunction Prolong life 30

Management of Heart Failure Stage C (cont’d) Drug therapy Diuretics ACE inhibitors and ARBs Aldosterone antagonists Beta blockers Digoxin Isosorbide dinitrate/hydralazine Drugs to avoid Antidysrhythmic agents Calcium channel blockers NSAIDs 31

Management of Heart Failure Stage C (cont’d) Device therapy Implanted cardioverter-defibrillators Cardiac resynchronization Exercise training Evaluating treatment Based on symptoms and physical findings 32

Management of Heart Failure Stage D Marked symptoms of HF Advanced structural heart disease Repeated hospitalizations Best solution is a heart transplant LV mechanical assist device used until heart is available Management Control of fluid retention Loop diuretic, thiazide diuretic Dopamine, dobutamine Beta blockers pose high risk for worsening HF 33