HEART FAILURE

MED PHARM2/02/10

HEART FAILURE (HF)

AGE >65 INCIDENCE 1:100HOSPITALIZATIONS-500,000/yr

DEATHS 200,000/yrANNUAL MORTALITY-40-50%

HF

Clinically HF may be considered to be the condition in which an abnormality of cardiac structure or function is responsible for the inability of the heart to fill with or eject blood at a rate commensurate with tissue needs.

HF FORMS

Systolic ventricle unable to contract

normally LVEF is <50% Sx due to inadequate

out- put

HF FORMS

Diastolic ventricle unable to relax and

fill normally LVEF is preserved >50% Sx related to increased fill- ing pressures Estimated at 20-50% of HF More in elderly women

McMurray J. N Engl J Med 2010;362:228-238

Clinical Classifications of Heart Failure Severity

D and Kfoury A. N Engl J Med 2006;355:1922-1925

Pathophysiological Mechanisms of and Treatment Options for End-Stage Heart Failure

HEART FAILURE

UNDERLYING CAUSES Ischemic heart disease-75% Cardiomyopathy Treatable causes Congenital Valvular Hypertension

ACUTE HEART FAILURE PRECIPITATING CAUSES

Arrhyhthmias ThyrotoxicosisPregnancy MyocarditisMyocardial infarction PEInfective endocarditis InfectionHTN AnemiaPhysical,dietary,fluid,environmental or

emotional excesses

HEART FAILURE NEUROHUMORAL ACTIVATION

RENIN ANGIOTENSIN ALDOSTERONE ANGIOTENSIN II ALDOSTERONE SYMAPATHETIC NERVOUS SYSTEM NOREPINEPHRINE VASOPRESSIN(ADH) ENDOTHELIN CYTOKINES

Table 1. Homeostatic Responses to Impaired Cardiac Performance (Due in part to activation of the renin-angiotensin-aldosterone system (RAAS)

and of the sympathetic nervous system).

Response Short-Term Effects* Long Term Effects

Salt and water retention Augments preload to increase cardiac output

Pulmonary congestion and peripheral edema

Vasoconstriction Maintains blood pressure for perfusion of vital organs

Exacerbates pump dysfunction (increased cardiac afterload and energy expenditure)

Sympathetic stimulation Increases heart rate and ejection (increased output)

Increases energy expenditure and causes arrhythmias

Cardiac hypertrophy Adaptive: increased sarcomere number with increased cardiac output

Maladaptive: accelerated cell death, arrhythmias

*Short-term effects occur in acute heart failure and are adaptive. Long-term effects occur in chronic heart failure and are mainly maladaptive. Medical management of chronic heart failure includes the use of drugs with actions reversing or limiting the pathogenesis of the maladaptive changes of heart failure.

HF PATHOPHYSIOLOGY

Homeostatic responses to impaired cardiac performance

ACTIVATION of: Renin angiotensin aldosterone

system Sympathetic nervous system Early responses - BeneficialLater these responses: Detrimental

Consequences of Neurohormonal Activation in HF

PATHOGENESIS of HEART FAILURE

PATHOGENESIS of HEART FAILURE

Jessup, M. et al. N Engl J Med 2003;348:2007-2018

Ventricular Remodeling after Infarction (Panel A) and in Diastolic and Systolic Heart Failure (Panel B)

DIASTOLIC HEART FAILURE EJECTION FRACTION PRESERVED

POOR TOLERANCE TO: ATRIAL FIBRILLATION TACHYCARDIA HYPERTENSION ISCHEMIA

TREATMENT

HF

ACUTE Acute stress for a chronically burdened heartCHRONIC Adaptive changes evolve over time Patient adjusts and tolerates Acute decompensation occurs with precipitating causes

PHARMACOTHERAPY OF HEART FAILURE

DRUGS FOR ACUTE DECOMPENSATED HF

DIURETICS FUROSEMIDE /HCTZ

VASODILATORS NITROPRUSSIDE NITROGLYCERIN

 

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Schematized pharmacodynamics of loop and thiazide diuretics; namely, the relationship between diuretic at the intraluminal site of action and response expressed as fractional excretion of sodium (FENa).

DIURETICS for ADHF

Loop diuretics-furosemide

Thiazide diuretics-hydrochlorthiazide

DISEASE and SHIFT of DR CURVES

Decrease in renal blood flow= less drug @ site of action

Competition for secretion in PT

Increased ADH to increase Na-K-2Cl sym.

Distal tubular hypertrophy- increased Na-K ATP-ase

Diuretic(D) Vasodilator(V) Inotrope(I)

Diuretic(D) Vasodilator(V) Inotrope(I)

Relationship Between Ventricular Outflow Resistance and Stroke Volume in Patients With Systolic Ventricular Dysfunction: The Action of Vasodilators:

Griffiths, M. J.D. et al. N Engl J Med 2005;353:2683-2695

Regulation of the Relaxation of Vascular Smooth Muscle by Nitric Oxide

IV SODIUM NITROPRUSSIDEACTION

Direct relaxation of all vascular smooth muscleBalanced arteriolar and venous dilation

Decrease in afterload & preload Increase in cardiac output Decrease in myocardial oxygen consumption Duration of use is limited by production of

cyanide & thiocyanate

Relationship Between Ventricular Outflow Resistance and Stroke Volume in Patients With Systolic Ventricular Dysfunction: The Action of Vasodilators:

Drug Therapy for Chronic HF Due to Systolic Dysfunction

DIURETICS ACE-INHIBITORS* ARBs* HYDRALAZINE + ISOSORBIDE* BETA BLOCKERS* SPIRONOLACTONE* DIGOXIN* = SURVIVAL BENEFIT

ACE-IARB

ANGIOTENSIN II ACTIONS TISSUE ACTIONS ARTERY STIMULATES CONTRACTION & GROWTH ADRENAL SECRETION OF ALDOSTERONE KIDNEY INHIBITS RENIN RELEASE

INCREASES TUBULAR REABSORPTION OF NaVASOCONSTRICTION-EFFERENT ARTERIOLERELEASES PROSTAGLANDINSAFFECTS EMBRYOGENESIS

SYMAPTHETIC NERVOUS SYSTEM INCREASE CENTRAL OUTFLOWFACILITATES PERIPHERAL TRANSMISSIONINCREASES ADRENAL RELEASE OF EPINEPHRINE

HEART INCREASES VENTRICULAR CONTRACTILITYPROMOTES GROWTH (REMODELING)

BRAIN STIMULATES THIRST & RELEASE of ADH

A II ACTIONS

HEART FAILURE THERAPYAngiotensin Converting Enzyme Inhibitors

ReduceIschemic events Hospital AdmissionsMortality

BenefitsGreatest in those with more severe failure

In asymptomatic left ventricular dysfunction:Delay onset symptomatic heart failureReduce cardiovascular events

MECHANISM(s) UNKNOWN

HEART FAILURE THERAPY

Angiotensin Receptor Blockkers (ARB’s)

Equivalent to ACE-inhibitors

Bloc

ANGIOTENSIN CONVERTING ENZYME INHIBITORS/ARBs

Adverse Effects:Teratogenic effectsAngioedemaCough (not with ARB)Renal insufficiencyHyperkalemia

Vasodilators for Chronic Stable Systolic HF

When other drugs are not tolerated or are not effective:

Oral useIsosorbide dinitrate - preload reductionHydralazine - afterload reduction

HYDRALAZINE

A direct acting vasodilator May prevent oxidation of NO

Hemodynamics- Decrease in systemic vascular resistance for afterload reduction

HYDRALAZINE

Adverse Effects:Fluid retentionLupus-like syndrome in

slow acetylators Reflex tachycardia

Relationship Between Ventricular Outflow Resistance and Stroke Volume in Patients With Systolic Ventricular Dysfunction: The Action of Vasodilators:

ISOSORBIDE DINITRATE

ACTION:Preload reduction due to venous relaxation

Long acting

USES: Oral with Hydralazine Heart failure-when ACE inhibitors/ARBs

contraindicated or there is not adequate response standard therapy ADR: Headache, Nitrate tolerance Interaction wiih sildenafil(et al)

ALDOSTERONEANTAGONISTS

Weber K. N Engl J Med 2001;345:1689-1697

The Renin-Angiotensin-Aldosterone System

Dluhy R and Williams G. N Engl J Med 2004;351:8-10

Physiologic and Pathophysiologic Effects of Aldosterone on the Kidney and Heart in Relation to Dietary Salt Levels

Weber K. N Engl J Med 2001;345:1689-1697

Extraadrenal Production of Aldosterone by Endothelial and Vascular Smooth-Muscle Cells in an Intramyocardial Coronary Artery

DELETERIOUS ACTIONS of ALDOSTERONE Sodium retention SNS activation Potassium loss PNS inhibition Cardiac and vascular fibrosis Direct vascular damage

ALDOSTERONE ANTAGONIST

Spironolactone

(Aldactone)

SPIRONOLACTONE

Uses: Diuretic & severe heart failure

Toxicity: HyperkalemiaGynecomastia

Contraindications: AnuriaCautions: Hyperkalemia

Ace-inhibitors ARBs KCl supplements

SPIRONOLACTONE for SEVERE HEART FAILURE

REDUCED RISK of: Death-all causes -30% Death-cardiac causes -31% Hospitalization-cardiac causes -30% Aggravation of heart failure -35% IMPROVEMENT IN SYMPTOMS Change in NYHA functional class -

36%

Palmer B. N Engl J Med 2004;351:585-592

Risk Factors for Hyperkalemia with the Use of Drugs That Interfere with the Renin-Angiotensin-Aldosterone System

Palmer, B. F. N Engl J Med 2004;351:585-592

The Renin-Angiotensin-Aldosterone System and Regulation of Potassium Excretion in the Kidney

BETABLOCKERS

BETA-BLOCKERS for HF LV performance improved at 3 months EF improvement of 5-10% LV mass decrease at 18 months Improveed symptoms Reduced rate of hospitalizations Reduced mortality – 34%When used with ACE-I, diuretic & digoxin in NYHA class II –IV symptoms

HMMETOPemodynamic Responses to Pharmacological Interventions in Heart Failure

Dose-Dependent Effect of Carvedilol on Left Ventricular Ejection Fraction

Stevenson, L. W. N Engl J Med 2002;346:1346-1347

A Funnel Diagram Showing Use of Beta-Blocker Therapy in Patients with a History of Myocardial Infarction, Asymptomatic Left Ventricular Dysfunction, or Stable Heart Failure

HEART FAILURE THERAPY

Beta Blockers

Added to ACE-inhibitors there is:Decreased mortality and hospitalization

BETA BOCKERS – ADVERSE EFFECTS

CNS CardiovascularBad dreams Aggravation of severe CHFDepression Aggravation of occlusive

arterial disease Slow A-V conduction

PulmonaryBronchospasm in Asthmatics

Drug interactionsDrugs that impair A-V conduction (digoxin and some calcium channel blockers)

Sarcolemmal Exchange of Na+ and Ca2+ During Cell Depolarization and Repolarization

DIGOXIN IN HF

INCREASE IN CARDIAC WORK & CO

decrease in cardiac size diuresis decrease in blood volume relief of edema

HEART FAILURE THERAPY

DIGOXIN

With Diuretics and ACE-inhibitors NO mortality benefit Discontinuation-worsening HF Perhaps increase in mortality for women

Digitalis Intoxication

Signs/Symptoms:

Fatigue/weakness

Gastrointestinal

Visual

CNS

Digitalis Intoxication

Treatment:

Stop digitalis

Monitor ECG

Determine serum K+ - Give K+

Antiarrhythmic Drugs

Digitalis antibody

SUMMARYDiureticACEI*ARB*Vasodilators*Beta blockers*Aldosterone antagonist*Inotrope

*Mortality benefit

PHARMACOTHERAPY OF HEART FAILURE

Jessup, M. et al. N Engl J Med 2003;348:2007-2018

Stages of Heart Failure and Treatment Options for Systolic Heart Failure

DRUG LIST for CHF THERAPY

Diuretic-furosemide / hydrochlorthiazideInotrope-digoxinACE-I-captoprilARB-losartanIsosorbide- hydralazine when ACE-I or ARB

contraindicated or not fully effectiveAldosterone receptor blocker-

spironolactoneBeta-blocker-metoprololSodium nitroprusside

INOTROPES

DOPAMINE DOBUTAMINE

McMurray J. N Engl J Med 2010;362:228-238

Possible Findings in Patients with Left Ventricular Systolic Dysfunction and Recommendations for Treatment

McMurray J. N Engl J Med 2010;362:228-238

Algorithm for Systolic Heart Failure

McMurray J. N Engl J Med 2010;362:228-238

Evidence-Based Pharmacologic Treatment of Heart Failure

Copyright ©2005 American Heart Association

Hunt, S. A. et al. Circulation 2005;112:1825-1852

Stages in the development of HF/recommended therapy by stage

Relationship Between Ventricular Outflow Resistance and Stroke Volume in Patients With Systolic Ventricular Dysfunction

Relationship Between Ventricular Outflow Resistance and Stroke Volume in Patients With Systolic Ventricular Dysfunction

Weber K. N Engl J Med 2001;345:1689-1697

Reduction in the Risk of Death, Death from Cardiac Causes, and Cardiac-Related Illness among Patients Treated with Spironolactone, as Compared with Placebo, in the Randomized Aldactone

Evaluation Study