CV Pharmacology-Pharmacological Management of Congestive Heart FailurePrepared and Presented by: Marc Imhotep Cray, M.D.Professor PharmacologyRecommended Reading:Management of Congestive Heart FailureFormative AssessmentPractice questionClinical:E-Medicine ArticleCongestive Heart Failure and Pulmonary Edema2Lecture Learning Objectives:By the end of this lecture the learner should:1.Understand the underlying hemodynamic abnormalities in heart failure and the therapeutic approaches to its treatment2.Understand the properties of angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and vasodilators used to treat heart failure and the rationale behind their use3.Understand the properties of intravenous agents (dobutamine, dopamine and PDE inhibitors) used in the treatment of heart failure4.Understand the actions of beta blockers and the rationale for their use in the treatment of heart failure5.Know the pharmacologic action, toxicities and uses of cardiac glycosides 3Definition of CHF(see notes page)Congestive heart failure(CHF)is an imbalance in pump functionin which the heart fails to adequately maintain the circulation of blood. The most severe manifestationof CHF, pulmonary edema, develops when this imbalance causes an increase in lung fluid secondary to leakage from pulmonary capillaries into the interstitium and alveoli of the lung…Modified from: E-Medicine ArticleCongestive Heart Failure and Pulmonary Edema4Drugs Used in Heart FailureFrom: Medical Pharmacology at a Glance (At a Glance Series (Oxford, England).by M. J. Neal 5Classification of CHFThere are many different ways to categorize heart failure, including:1.the side of the heart involved, (left heart failure versus right heart failure) 2.whether the abnormality is due to contractionor relaxation of the heart (Systolic Dysfunctionvs. Diastolic Dysfunction) 3.whether the problem is primarily increased venous back pressure (behind) the heart, or failure to supply adequate arterial perfusion (in front of) the heart (backward vs. forward failure) 4.whether the abnormality is due to low cardiac output with high systemic vascular resistanceor high cardiac output with low vascular resistance (low-output heart failure vs. high-output heart failure)5.the degree of functional impairment conferred by the abnormality (as in the NYHA functional classification) From: http://en.wikipedia.org/wiki/Congestive_heart_failure#Classification6Congestive Heart Failure: CausesFrom: http://www.cvpharmacology.com/clinical topics/heart failure.htm7Congestive Heart Failure: Causes (cont.)1.Arrhythmias:In patients with heart disease and with a history of congestive failure, an acute arrhythmia is a common precipitating cause of CHF. Tachyarrhythmiasdecrease filling time and as a result decrease cardiac outputA-V dissociationresults in loss of the atrial contribution to ventricular filling. Therefore end-diastolic volume is reduced with an attendant reduction in cardiac output Abnormal intraventricular conductionmay cause a reduced synchronicity of contraction with a reduction in myocardial performanceSevere bradycardiain the absence of increased stroke volume can seriously reduce cardiac output and thus precipitate CHF. Increased stroke volume may not be possible if the patient has significant heart disease8Congestive Heart Failure: Causes (cont.)2.Myocardial Infarction:A myocardial infarction, reducing left ventricular function, may precipitate CHF in a previously hemodynamically compensated patient 3.Pulmonary Embolism:Physically inactive patients with low cardiac output may develop deep venous thrombi which may produce pulmonary emboli and elevation of pulmonary arterial pressure. Increased pulmonary artery pressure may worsen or cause left ventricular failure 4.Systemic Hypertension: Rapid increases in arterial blood pressure with associated increases in peripheral resistance can increase afterload to an extent sufficient to produce heart failure. 5.Other causes:Thyrotoxicosis Pregnancy Infection Anemia Rheumatic and other forms of Myocarditis Physical, dietary, fluid, environmental and emotional excesses Infective Endocarditis 9Pathophysiology in CHFCHF is summarized best as an imbalance in Starling forcesor an imbalance in the degree of end-diastolic fiber stretch proportional to the systolic mechanical work expended in an ensuing contraction. See: http://www.cvpharmacology.com/clinical topics/heart failure-2.htm10Pathophysiology in CHF(2)The fundamental abnormality in heart failure is embodied in: depression of the myocardial force-velocity relationship and length-active tension curves that result in impairment of myocardial contractility. (see Figure, right) When a normal heart transitions from the resting state (1) to exercise (2) a significant increase in ventricular performance occurs. By contrast in the failing heart, the exercise-induced increases in ventricular performance are minimal (3' to 3). From: http://www.pharmacology2000.com/Cardio/CHF/chfobj1.htm11New York Heart Association (NYHA) Functional ClassificationThe New York Heart Association (NYHA) Functional Classificationprovides a simple way of classifying the extent of heart failure. It places patients in one of four categoriesbased on how much they are limited during physical activitylimitations/symptoms are in regards to normal breathing and varying degrees in shortness of breath and or angina pain12Framingham Criteria for Congestive Heart FailureDiagnosis of CHFrequires the simultaneous presence of at least 2 major criteria or 1 major criterion in conjunction with 2 minor criteria.Major criteria:Paroxysmal nocturnal dyspnea Neck vein distentionRalesRadiographic cardiomegaly (increasing heart size on chest radiography)Acute pulmonary edemaS3 gallopIncreased central venous pressure (>16 cm H2O at right atrium)Hepatojugular refluxWeight loss>4.5 kg in 5 days in response to treatmentMinor criteria: Bilateral ankle edemaNocturnal coughDyspnea on ordinary exertionHepatomegalyPleural effusionDecrease in vital capacity by one third from maximum recordedTachycardia (heart rate>120 beats/min.)Minor criteria are acceptable only if they can not be attributed to another medical condition (such as pulmonary hypertension, chronic lung disease, cirrhosis, ascites, or the nephrotic syndrome).The Framingham Heart Study criteria are 100% sensitive and 78% specific for identifying persons with definite congestive heart failure.From: http://www.medicalcriteria.com/criteria/framingham.htm13New York Heart Association (NYHA) Functional ClassificationNYHA ClassSymptomsINo symptoms and no limitationin ordinary physical activity, e.g. shortness of breath when walking, climbing stairs etc.IImild symptoms(mild shortness of breath and/or angina) and slight limitationduring ordinary activity.IIIMarked limitation in activitydue to symptoms, even during less-than-ordinary activity, e.g. walking short distances (20-100 m).Comfortable only at rest.IVSevere limitations.Experiences symptoms even while at rest. Mostly bedbound patients.Source: http://www.medicalcriteria.com/criteria/nyha.htm14PATHOPHYSIOLOGY AND PHARMACOLOGY OF HEART FAILUREAlso see notes page15Rationale for Drug Therapy(Clickable)The primary goal of drug therapy in heart failure is to improve cardiac function and reduce the clinical symptoms associated with heart failure (e.g., edema, shortness of breath, exercise intolerance). B D= Vasodilator EffectB E= Inotropic Effect16Overview of CHF Pharmacological ManagementTreatment of CHF aimsto relieve symptoms, to maintain a euvolemicstate (normal fluid level in the circulatory system), and to improve prognosis by delaying progression of heart failure and reducing cardiovascular risk 17Overview of CHF Pharmacological Management(2) Also see Notes PageDrugs used include:1.diuretic agents, 2.vasodilator agents, 3.positive inotropes, 4.ACE inhibitors, 5.beta blockers, 6.aldosterone antagonistsRelated Terms:1.contractility (inotropy),2.heart rate (chronotropy)3.conduction velocity (dromotropy)18Overview of CHF Pharmacological Management(3)Angiotensin-modulating agentsACE inhibitor (ACE) therapyis recommended for all patients with systolic heart failure, irrespective of symptomatic severity or blood pressureACE inhibitorsimprove symptoms, decrease mortality and reduce ventricular hypertrophy Angiotensin II receptor antagonist therapy(also referred to as AT1-antagonistsor angiotensin receptor blockers), particularly using candesartan, is an acceptable alternative if the patient is unable to tolerate ACEI therapy19Overview of CHF Pharmacological Management(4)Angiotensin-modulating agents cont.ACEIs and ARBsdecrease afterloadby antagonizing the vasopressor effect of angiotensin, thereby decreasing the amount of work the heart must perform It is also believed that angiotensin directly affects cardiac remodeling, and blocking its activitycan thereby slow deterioration of cardiac function20Overview of CHF Pharmacological Management(5)Also see Notes PageSome commonly used Angiotensin Converting Enzyme (ACE) Inhibitors-21Overview of CHF Pharmacological Management(6)Also see Notes PageMechanism of Angiotensin Converting Enzyme (ACE) InhibitorsFrom:http://yale128036029120.med.yale.edu/hypertension.htmFrom: http://www.mc.uky.edu/pharmacology/instruction/pha824hf/PHA824hf.html22Overview of CHF Pharmacological Management (7)DiureticsDiuretic therapy is indicated for relief of congestive symptoms. Several classes are used, with combinations reserved for severe heart failureLoop diuretics(e.g. furosemide, bumetanide) –most commonly usedclass in CHF, usually for moderate CHFThiazide diuretics(e.g. hydrochlorothiazide, chlorthalidone, chlorthiazide) –may be useful for mild CHF, but typically used in severe CHF in combination with loop diuretics, resulting in a synergistic effect.23Overview of CHF Pharmacological Management (8)Diuretics cont.Potassium-sparing diuretics(e.g. amiloride) –used first-line use to correct hypokalaemia. Spironolactoneis used as add-on therapy to ACEI plus loop diuretic in severe CHF Eplerenone(Inspra®) is specifically indicated for post-MI reduction of cardiovascular risk 24Overview of CHF Pharmacological Management (9)Beta blockersUntil recently (within the last 20 years), β-blockers were contraindicated in CHF, owing to their negative inotropiceffect and ability to produce bradycardia –effects which worsen heart failureHowever, current guidelinesrecommend β-blocker therapyfor patients with systolic heart failure due to left ventricular systolic dysfunctionafter stabilization with diuretic and ACEI therapy, irrespective of symptomatic severity or blood pressure25Overview of CHF Pharmacological Management (10)Beta blockers cont.As with ACEI therapy, the addition of a β-blocker can decrease mortality and improve left ventricular functionSeveral β-blockers are specifically indicated for CHF including: 1.bisoprolol, 2.carvedilol, and 3.extended-release metoprololantagonism of β1 inotropic and chronotropic effects decreases the amount of work the heart must perform26Overview of CHF Pharmacological Management (11)Beta blockers cont.It is also thought that catecholamines and other sympathomimetics have an effect on cardiac remodeling, and blocking their activity can slow the deterioration of cardiac functionSee: The Importance of Beta Blockers in the Treatment of Heart FailureAmerican Academy of Family Physicians27Overview of CHF Pharmacological Management(12)Positive inotropesDigoxin/Cardiac glycosides(a mildly positive inotrope and negative chronotrope), once used as first-line therapy, is now reserved for control of ventricular rhythm in patients with atrial fibrillation; or where adequate control is not achieved with an ACEI, a beta blocker and a loop diureticThere is no evidence that digoxin reduces mortality in CHF, although some studies suggest a decreased rate in hospital admissionsIt is contraindicated in cardiac tamponade and restrictive cardiomyopathy28Overview of CHF Pharmacological Management(13)Cardiac glycosidesMechanism of Positive Inotropic ActionCardiac glycosides inhibit the myocardial cell Na+, K+, ATPase.This enzyme is responsible for maintaining the ionic gradient of the myocardial cell.The inhibition of the Na+, K+, ATPase results in an increase in intracellular Na+. The decrease in the Na+ gradient diminishes the exchange of Na+ for Ca2+The increase in intracellular Ca2+ is responsible for the positive inotropic action.Click for full view and annotationsAlso see Notes Page29Antiarrhythmic Actions Cardiac glycosides also work in the carotid arch and baroreceptors to increase the sensitivity of these sites results enhanced neural traffic to CNS cardiovascular centers resulting in enhanced vagal outflow to the myocardiumAt the SA node this increase in vagal tone:1.Increases SA nodal refractory period2.Slows SA nodal conduction velocityAt the AV node (major site of antiarrhythmic Action) the increase in vagal tone:1.Increases AV nodal refractory period2.Slows AV nodal conduction velocity Overview of CHF Pharmacological Management(14)Cardiac glycosides30Pharmacokinetics of Cardiac GlycosidesAGENTGASTRO INTESTINAL ABSORPTIONONSET OF ACTION (MIN)PEAK EFFECT (HR) AVERAGE HALF LIFEPRINCIPAL METABOLIC ROUTE (EXCRETORY PATHWAY) AVERAGE DIGITALIZING DOSES USUAL DAILY ORAL MAINTENANCE DOSES oralintravenousDigoxin30 to 100% 15 to 30 1 1/2 to 536 to 48 hoursRenal; some gastrointestinal excretion1.25 to 1.5 mg0.75 to 1.00 mg 0.25 to 0.5 mg Digitoxin90 to 100%25 to 120 4 to 124 to 6 daysHepatic; renal excretion of metabolites0.7 to 1.2 mg1.00 mg 0.1 mg See notes for Special ConsiderationsOverview of CHF Pharmacological Management(15)Cardiac glycosides31Positive inotropes cont.The inotropic agent dobutamineis advised only in the short-term use of acutely decompensated heart failure, and has no other uses (Bata1 receptor Agonist)Phosphodiesterase inhibitorssuch as milrinoneare sometimes utilized in severe cardiomyopathy (increase cAMP/See phosphodiesterase inhibitors)The mechanism of actionis through the antagonism of adenosine receptors, resulting in inotropic effects and modest diuretic effectsOverview of CHF Pharmacological Management(16)Cardiac glycosides32Alternative vasodilatorsThe combination of isosorbide dinitrate/hydralazineis the only vasodilator regimen, other than ACE inhibitors or angiotensin II receptor antagonists, with proven survival benefitsThis combinationappears to be particularly beneficialin CHF patients with an African Americanbackground, who respond less effectively to ACEI therapySee notes page for referencesOverview of CHF Pharmacological Management(17)33Cardiovascular Animations and Interactive TutorialsCardiovascular System Topicsby ADAM Basic Heart CirculationBristol-Myers Squibb Heart Structureby Nucleus Communications Heart functions and ProblemsCardiology Associates Electrocardiogram -ECG TechnicianNobel eMuseum Hyper heartby Knowlege Weavers The Arrhythma CenterHeartCenterOnline Cardiac Cell DeathSan Diego State University Prenatal HeartHeartCenterOnline Congenital Heart DiseaseHeartCenterOnline 34Cardiovascular Animations and Interactive Tutorials(2)Valvular Functions and DiseasesHeartCenterOnline Electro Cardio Gramby Knowlege Weavers Mammal Fetal Circulation by HHMI Cardiology -Visible Heartby HHMI The Electrocardiogram BasicsMcGill University Heart AnimationsScience Museum of Minnesota Operation Heart Transplantfrom PBS Interpeting an EKGEKG TutorialRnCeus Interactive Blaufuss Medical Multimedia Heart Valves Movieby Marcy Thomas at Wellesley Aninations of Common Heart Defects and RepairMiami Children's Hospital Cadaver Dissection of the Human HeartVirtual AutopsyHBO 35Free Useful PluginsAdobe Acrobat Reader-Document DistributionAdobe Flash Player-Web Animation -The leading rich client for Internet content and applications across the broadest range of platforms.Adobe Shockwave Player-With Adobe Shockwave Player, you can enjoy multimedia games and learning applications, using exciting new 3D technology.Adobe Authorware Player-With Adobe Authorware Web Player, you can experience online learning applications on the Web.QuickTime Player-Streaming/Multimedia36Free Useful PluginsRealOne Player-Streaming/MultimediaMicrosoft Windows Media Player-Streaming/MultimediaMicrosoft Word Viewer-Viewing Word documents online (required if Word is not installed on resident computer; PC only)Microsoft PowerPoint Viewer-Viewing PowerPoint presentations online (required if PowerPoint is not installed on computer) Animated PowerPoint Add-in-needed if you do not have Office XPMicrosoft Excel Viewer-Viewing Excel documents online (required if Excel is not installed on resident computer; PC only)MDL Chimeinteractively displays 2D and 3D molecules directly in Web pages.