IVMS-CV Pharmacology- Management of Congestive Heart Failure

CV Pharmacology-Pharmacological Management of Congestive Heart Failure : CV Pharmacology-Pharmacological Management of Congestive Heart Failure Prepared and Presented by: Marc Imhotep Cray, M.D. Professor Pharmacology Recommended Reading: Management of Congestive Heart Failure Formative Assessment Practice question Clinical: E-Medicine Article Congestive Heart Failure and Pulmonary Edema

Lecture Learning Objectives: : 2 Lecture Learning Objectives: By the end of this lecture the learner should: Understand the underlying hemodynamic abnormalities in heart failure and the therapeutic approaches to its treatment Understand the properties of angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and vasodilators used to treat heart failure and the rationale behind their use Understand the properties of intravenous agents (dobutamine, dopamine and PDE inhibitors) used in the treatment of heart failure Understand the actions of beta blockers and the rationale for their use in the treatment of heart failure Know the pharmacologic action, toxicities and uses of cardiac glycosides

Definition of CHF (see notes page) : 3 Definition of CHF (see notes page) Congestive heart failure (CHF) is an imbalance in pump function in which the heart fails to adequately maintain the circulation of blood. The most severe manifestation of 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 Article Congestive Heart Failure and Pulmonary Edema

Drugs Used in Heart Failure : 4 Drugs Used in Heart Failure From: Medical Pharmacology at a Glance (At a Glance Series (Oxford, England). by M. J. Neal

Classification of CHF : 5 Classification of CHF There are many different ways to categorize heart failure, including: the side of the heart involved, (left heart failure versus right heart failure) whether the abnormality is due to contraction or relaxation of the heart (Systolic Dysfunction vs. Diastolic Dysfunction ) 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) whether the abnormality is due to low cardiac output with high systemic vascular resistance or high cardiac output with low vascular resistance (low-output heart failure vs. high-output heart failure) the degree of functional impairment conferred by the abnormality (as in the NYHA functional classification) From: http://en.wikipedia.org/wiki/Congestive_heart_failure#Classification

Congestive Heart Failure: Causes : 6 Congestive Heart Failure: Causes From: http://www.cvpharmacology.com/clinical topics/heart failure.htm

Congestive Heart Failure: Causes (cont.) : 7 Congestive Heart Failure: Causes (cont.) Arrhythmias: In patients with heart disease and with a history of congestive failure, an acute arrhythmia is a common precipitating cause of CHF. Tachyarrhythmias decrease filling time and as a result decrease cardiac output A-V dissociation results in loss of the atrial contribution to ventricular filling. Therefore end-diastolic volume is reduced with an attendant reduction in cardiac output Abnormal intraventricular conduction may cause a reduced synchronicity of contraction with a reduction in myocardial performance Severe bradycardia in 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 disease

Congestive Heart Failure: Causes (cont.) : 8 Congestive Heart Failure: Causes (cont.) Myocardial Infarction: A myocardial infarction, reducing left ventricular function, may precipitate CHF in a previously hemodynamically compensated patient 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 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. Other causes: Thyrotoxicosis Pregnancy Infection Anemia Rheumatic and other forms of Myocarditis Physical, dietary, fluid, environmental and emotional excesses Infective Endocarditis

Pathophysiology in CHF : 9 Pathophysiology in CHF CHF is summarized best as an imbalance in Starling forces or 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.htm

Pathophysiology in CHF(2) : 10 Pathophysiology 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.htm

New York Heart Association (NYHA) Functional Classification : 11 New York Heart Association (NYHA) Functional Classification The New York Heart Association (NYHA) Functional Classification provides a simple way of classifying the extent of heart failure. It places patients in one of four categories based on how much they are limited during physical activity limitations/symptoms are in regards to normal breathing and varying degrees in shortness of breath and or angina pain

Framingham Criteria for Congestive Heart Failure : 12 Framingham Criteria for Congestive Heart Failure Diagnosis of CHF requires 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 distention Rales Radiographic cardiomegaly (increasing heart size on chest radiography) Acute pulmonary edema S3 gallop Increased central venous pressure (>16 cm H2O at right atrium) Hepatojugular reflux Weight loss  >4.5 kg in 5 days in response to treatment Minor criteria: Bilateral ankle edema Nocturnal cough Dyspnea on ordinary exertion Hepatomegaly Pleural effusion Decrease in vital capacity by one third from maximum recorded Tachycardia (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.htm

New York Heart Association (NYHA) Functional Classification : 13 New York Heart Association (NYHA) Functional Classification Source: http://www.medicalcriteria.com/criteria/nyha.htm

PATHOPHYSIOLOGY AND PHARMACOLOGY OF HEART FAILURE : 14 PATHOPHYSIOLOGY AND PHARMACOLOGY OF HEART FAILURE Also see notes page

Rationale for Drug Therapy (Clickable) : 15 Rationale 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 Effect B E= Inotropic Effect

Overview of CHF Pharmacological Management : 16 Overview of CHF Pharmacological Management Treatment of CHF aims to relieve symptoms, to maintain a euvolemic state (normal fluid level in the circulatory system), and to improve prognosis by delaying progression of heart failure and reducing cardiovascular risk

Overview of CHF Pharmacological Management(2) Also see Notes Page : 17 Overview of CHF Pharmacological Management(2) Also see Notes Page Drugs used include: diuretic agents, vasodilator agents, positive inotropes, ACE inhibitors, beta blockers, aldosterone antagonists Related Terms: contractility (inotropy), heart rate (chronotropy) conduction velocity (dromotropy)

Overview of CHF Pharmacological Management(3) : 18 Overview of CHF Pharmacological Management(3) Angiotensin-modulating agents ACE inhibitor (ACE) therapy is recommended for all patients with systolic heart failure, irrespective of symptomatic severity or blood pressure ACE inhibitors improve symptoms, decrease mortality and reduce ventricular hypertrophy Angiotensin II receptor antagonist therapy (also referred to as AT1-antagonists or angiotensin receptor blockers), particularly using candesartan, is an acceptable alternative if the patient is unable to tolerate ACEI therapy

Overview of CHF Pharmacological Management(4) : 19 Overview of CHF Pharmacological Management(4) Angiotensin-modulating agents cont. ACEIs and ARBs decrease afterload by 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 activity can thereby slow deterioration of cardiac function

Overview of CHF Pharmacological Management(5) Also see Notes Page : 20 Overview of CHF Pharmacological Management(5) Also see Notes Page Some commonly used Angiotensin Converting Enzyme (ACE) Inhibitors-

Overview of CHF Pharmacological Management(6) Also see Notes Page : 21 Overview of CHF Pharmacological Management(6) Also see Notes Page Mechanism of Angiotensin Converting Enzyme (ACE) Inhibitors From: http://yale128036029120.med.yale.edu/hypertension.htm From: http://www.mc.uky.edu/pharmacology/instruction/pha824hf/PHA824hf.html

Overview of CHF Pharmacological Management (7) : 22 Overview of CHF Pharmacological Management (7) Diuretics Diuretic therapy is indicated for relief of congestive symptoms. Several classes are used, with combinations reserved for severe heart failure Loop diuretics (e.g. furosemide, bumetanide) – most commonly used class in CHF, usually for moderate CHF Thiazide 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.

Overview of CHF Pharmacological Management (8) : 23 Overview of CHF Pharmacological Management (8) Diuretics cont. Potassium-sparing diuretics (e.g. amiloride) – used first-line use to correct hypokalaemia. Spironolactone is 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

Overview of CHF Pharmacological Management (9) : 24 Overview of CHF Pharmacological Management (9) Beta blockers Until recently (within the last 20 years), ß-blockers were contraindicated in CHF, owing to their negative inotropic effect and ability to produce bradycardia – effects which worsen heart failure However, current guidelines recommend ß-blocker therapy for patients with systolic heart failure due to left ventricular systolic dysfunction after stabilization with diuretic and ACEI therapy, irrespective of symptomatic severity or blood pressure

Overview of CHF Pharmacological Management (10) : 25 Overview of CHF Pharmacological Management (10) Beta blockers cont. As with ACEI therapy, the addition of a ß-blocker can decrease mortality and improve left ventricular function Several ß-blockers are specifically indicated for CHF including: bisoprolol, carvedilol, and extended-release metoprolol antagonism of ß1 inotropic and chronotropic effects decreases the amount of work the heart must perform

Overview of CHF Pharmacological Management (11) : 26 Overview 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 function See: The Importance of Beta Blockers in the Treatment of Heart Failure American Academy of Family Physicians

Overview of CHF Pharmacological Management(12) : 27 Overview of CHF Pharmacological Management(12) Positive inotropes Digoxin / 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 diuretic There is no evidence that digoxin reduces mortality in CHF, although some studies suggest a decreased rate in hospital admissions It is contraindicated in cardiac tamponade and restrictive cardiomyopathy

Overview of CHF Pharmacological Management(13) Cardiac glycosides : 28 Overview of CHF Pharmacological Management(13) Cardiac glycosides Mechanism of Positive Inotropic Action Cardiac 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 annotations Also see Notes Page

Overview of CHF Pharmacological Management(14) Cardiac glycosides : 29 Antiarrhythmic 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 myocardium At the SA node this increase in vagal tone: Increases SA nodal refractory period Slows SA nodal conduction velocity At the AV node (major site of antiarrhythmic Action) the increase in vagal tone: Increases AV nodal refractory period Slows AV nodal conduction velocity Overview of CHF Pharmacological Management(14) Cardiac glycosides

Overview of CHF Pharmacological Management(15) Cardiac glycosides : 30 Pharmacokinetics of Cardiac Glycosides See notes for Special Considerations Overview of CHF Pharmacological Management(15) Cardiac glycosides

Overview of CHF Pharmacological Management(16) Cardiac glycosides : 31 Positive inotropes cont. The inotropic agent dobutamine is advised only in the short-term use of acutely decompensated heart failure, and has no other uses (Bata1 receptor Agonist) Phosphodiesterase inhibitors such as milrinone are sometimes utilized in severe cardiomyopathy (increase cAMP/See phosphodiesterase inhibitors ) The mechanism of action is through the antagonism of adenosine receptors, resulting in inotropic effects and modest diuretic effects Overview of CHF Pharmacological Management(16) Cardiac glycosides

Overview of CHF Pharmacological Management(17) : 32 Alternative vasodilators The combination of isosorbide dinitrate/hydralazine is the only vasodilator regimen, other than ACE inhibitors or angiotensin II receptor antagonists, with proven survival benefits This combination appears to be particularly beneficial in CHF patients with an African American background, who respond less effectively to ACEI therapy See notes page for references Overview of CHF Pharmacological Management(17)

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