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					Pharmacotherapy of Heart Failure

“A pathophysiological condition where the heart
is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return."

E. Braunwald

Heart failure is a complex of symptoms - fatigue, shortness of breath, and congestion that are related to the inadequate perfusion of tissue during exertion and often to the retention of fluid. Its primary cause is an impairment of the heart's ability to fill or empty the left ventricle properly (Cohn, 1996).

Congestive heart failure is the pathophysiologic state in which the heart is unable to pump blood at a rate commensurate with the requirements of metabolizing tissues, or can do so only from an elevated filling pressure (Braunwald and Bristow, 2000).

The principal goals of Treatment are; 1. To improve or maintain quality of life & to delay death. 2. Improve or prevent symptoms from worsening 3. Avoid side effects of treatment & decrease occurrence of major morbid events

Types of Heart Failure
Acute & Chronic heart failure Left & Right heart failure Systolic & Diastolic heart failure Low & High output failure

Chronic Heart Failure Evolution of Clinical Stages
No symptoms Normal exercise Normal LV fxn

Asymptomatic LV Dysfunction No symptoms Compensated Normal exercise CHF Abnormal LV fxn No symptoms Decompensated Exercise CHF Abnormal LV fxn Symptoms Refractory Exercise CHF Abnormal LV fxn
Symptoms not controlled with treatment

Right Heart Failure –
The inability of the right side of the heart to adequately pump venous blood into the pulmonary circulation, causing a back-up of fluid in the body, resulting in edema.

Left Heart Failure –

The inability of the left side of the heart to pump into the systemic circulation. Back-up behind the leftventricle causes accumulation of fluid in the lungs.

Diastolic Dysfunction
Causes - HTN, Ventricular hypertrophy –IHD, Stenotic valvular disease. Characterized by a hypertrophic myocardium & normal contractility Diastolic dysfunction may induce dyspnea on exertion

Systolic dysfunction
Causes- MI, Cardiomyopathies Characterized by LV dilatation, wall thinning & reduced contractility ACE inhibitors, Diuretics, Digitalis, and B-blockers

New York Heart Association Functional Classification of Congestive Heart Failure
Class-I No limitations of activity; ordinary activity does not cause undue fatigue, palpitations, dyspnea or anginal pain Class-II Slight limitations of activity; asymptomatic at rest; ordinary activity results in fatigue, palpitations, dyspnea or anginal pain Class-III Marked limitations of activity; usually asymptomatic at rest; less than ordinary activity causes fatigue, palpitations, dyspnea or anginal pain
Class-IV Inability to carry on any physical activity without discomfort; symptoms at rest; increased discomfort with any physical activity

Ventricular Remodeling in CHF

Spectrum of Heart Failure
PND and orthopnea Dyspnea at rest

Dyspnea on exertion

Pulmonary Edema

Cardiogenic Shock

Asymptomatic CHF

Symptoms of HF
Fatigue Activity decrease Cough (especially supine) Edema Shortness of breath

Symptoms & Signs of HF:

• Fatigue (low cardiac out-put) • Shortness of breath •  JVP • Rales • Edema • Radiologic congestion • Cardiomegaly

DIET Approach to the Patient With Heart Failure
– Etiology – Severity (LV dysfunction)

– – – – Diet Exercise Lifestyle CV Risk

– Diuretic/ACE inhibitor – -blocker – Spirololactone – Digoxin

– Optimize ACE inhibitor – Optimize diuretics

Compensatory Mechanisms in Heart Failure

Pathophysiology of cardiac performance
Cardiac performance is a function of 4 factors; 1. 2. 3. 4. Preload Afterload Contractility Heart Rate

Treatment Objectives
Survival Morbidity Exercise capacity Quality of life Neurohormonal changes Progression of CHF symptoms

Assess LV Function (echo, gated RNA)
•EF < 40%-systolic dysfunction •EF 40-55%-systolic/diastolic dysfunction

•EF >55%-diastolic dysfunction

Assess Volume Status

Signs and Symptoms of Fluid Retention Loop Diuretic
+/- Thiazide
(titrate to euvolemic state)

No Signs and Symptoms of Fluid Retention

ACE inhibitor/ARB if ACE intolerant
Combination Rx if  HF, hospitalization or -blocker intolerant

-blocker (NYHA II-IV)
(NYHA Class III-IV CHF/EF<35%/Cr<200/K<5)

Add Digoxin for symptom control

Drugs used for Tt of Heart Failure
Positive inotropic drugs – – Cardiac Gylcosides –Digoxin, Digitoxin -Phosphodiesterase inhibitors: -Milrinone, Inamrinone. ACE Inhibitors – Enalapril, Lisinopril Angiotensin II Receptor Blockers (ARBs)- Losartan, Diuretics – Frusemide, Spironolactone Vasodilators--Hydralazine, Sodium Nitropruside

Primary Targets of Treatments CHF

Cardiac glycosides
Foxglove - Digitalis purpurea Extract called digitalis Long history as a folk remedy for congestive heart failure William Withering investigated this remedy from 1775-1785 - first scientific study of a medicinal plant

Currently available cardiac glycosides
– Digoxin, digitoxin & ouabain

Digoxin is the most preferred

Digitalis purpurea

Mechanism of Action
Na-K ATPase


Na-Ca Exchange







Na-K ATPase

Na-Ca Exchange
Na+ Ca2+


Na+ Na+




Mechanism of Action…

Inhibit Na-K ATPase, intracellular Na Ca through Na-Ca exchange which causes contraction of the myocardium.

Pharmacologic Actions
1. Increases Cardiac Output 2. Indirectly decreases sympathetic nervous system activity
Arteriolar dilation Venous dilation

3. Causes Vagal stimulation

Cardiac glycosides…
As a positive inotropic drug, digitalis improves myocardial contractility Useful in systolic heart failure Still the drug of choice for patients with CHF and rapid atrial fibrillation

Electrophysiological Effects
Decreased conduction velocity Decreases action potential duration: decreased refractory period in ventricles Enhanced automaticity due to
– Steeper phase 4 – Afterdepolarizations

Parasympathomimetic Effects
Decreased conduction velocity in the AV node increased effective refractory period in the AV Heart block (toxic concentrations)

Uses 1. Chronic Heart Failure 2. Atrial fibrillation
Overall Benefit of Digitalis to Myocardial Function   cardiac output –  cardiac efficiency –  heart rate –  cardiac size

Digitalis…… Adverse Effects Know this for exam
Cardiac – AV block – Bradycardia – Ventricular extrasystole – Arrhythmias Extra-Cardiac – GI – Nausea, Vomiting, Anorexia CNS – Disorientation, Hallucinations Misc - Gynecomastia

Serum Electrolytes & Digoxin
– Digitalis competes for K binding at Na/K ATPase – Hypokalemia: increase toxicity – Hyperkalemia: decrease toxicity

– Hypomagnesemia: increases toxicity

– Hypercalcemia: increases toxicity

Treatment of Digitalis Toxicity

Know this imp question for exam Reduce dose: Atropine- Corrects heart block KClAntiarrythmics- ventricular arrhythmias Fab antibodies- digipan

Phosphodiesterase Inhibitors
Inamrinone, milrinone

Mechanism of Action Inhibition of type III phosphodiesterase
– Increases intracellular cAMP
– cardiac output – peripheral vascular resistance

Phosphodiesterase Inhibitors:
Therapeutic Use Adverse Effects

Short term support in advanced cardiac failure Long term use not beneficial

Cardiac arrhythmias GI: Nausea and vomiting Sudden death

Diuretics: Mechanism of Action in Heart Failure
Loop Diuretics:
– Preload reduction: reduction of excess plasma volume and edema fluid – Afterload reduction: lowered blood pressure

– Aldosterone inappropriately elevated in CHF – Mobilizes edema fluid in heart failure

Prevention of aldosterone effects :
– Like vascular & myocardial fibrosis

Prolongs life in CHF patients

Angiotensin-converting enzyme (ACE) inhibitors

First-line therapy in the treatment of CHF The ACE inhibitors in the treatment of all stages of heart failure have been well proved Useful in both systolic and diastolic failure. Have profound effects on vasoconstriction & intravascular

Beneficial effects of ACE-I
Afterload reduction Preload reduction Reduction of facilitation of sympathetic nervous system Reduce the long term re modeling of heart

Mechanism of action: reduce preload and afterload Drugs used
– Sodium nitroprusside – Hydralazine

-Blockers in Heart Failure:

Mechanism of Action

-blockers: Bisoprolol, Metoprolol, Carvedilol
– Reduction in damaging sympathetic influences in the heart (tachycardia, arrhythmias, remodeling) – inhibition of renin release

– Beta blockade effects + peripheral vasodilatation via a1-adrenoceptor blockade – Attenuates oxygen free radical initiated lipid peroxidation – Inhibits vascular smooth muscle mitogenesis

Patient Selection for Successful  - Blocker Initiation Stable symptoms Stable background heart failure medications No recent CV hospitalization Stable CV status (no hypotension or bradycardia) Euvolemic status Start low and titrate slowly

Patients With Heart Failure Who Should Not Be Started on -blockers
General Contraindications
– Bronchospastic pulmonary disease – Severe bradycardia, high degree AV block, sick sinus syndrome

Heart Failure Considerations
– Congestive symptoms at rest (NYHA Class IV) – Patients who require intravenous therapy for HF – Unstable symptoms or recent changes in background medications – Hospitalized patients (especially for worsening HF)

Heart Failure Therapeutic Goal
Mild-Moderate Heart Failure –Primary goal = Reduce mortality –ACE inhibitors ± Diuretics –Prevent progression to symptoms –Prevent progressive LV dysfunction

Heart Failure Therapeutic Goal
Moderate-Severe Heart Failure –Primary goal = Reduce symptoms –Improve quality of life (QOL) –Reduce hospitalizations –Prevent sudden death

Steps in the treatment CHF
Reduce workload of the heart
Restrict Salt intake

Diuretics Angiotensin Converting Enzyme Inhibitors Digoxin if systolic dysfunction ± Atrial Fibrillation
β-blockers –stable case of II-IV HF patients


Severity of Heart Failure
Modes of Death
12% 24% 64%

CHF 26%

Sudden Death

Other Sudden Death
n = 103

59% 15%

n = 103



Other 56%


Sudden Death
n = 27

MERIT-HF Study Group. LANCET 1999;353:2001-07.

Goals & Outcomes
Improve symptoms Improve quality of life Prevent progression of LV dysfunction Reduce hospitalization and morbidity Reduce mortality
– Progression of HF – Sudden death

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