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IVMS-CV-Pharmacology- Management of Congestive Heart Failure



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IVMS-CV-Pharmacology- Management of Congestive Heart Failure

  1. 1. CV Pharmacology Pharmacological Management of Congestive Heart Failure Prepared and Presented by: Marc Imhotep Cray, M.D. BMS & CK Teacher Companion Reading (Notes): Pharmacological Treatment of Heart Failure (Klabunde) Drugs Acting on the Cardiovascular System (Cray) Formative Assessment Cardiovascular Pharmacology Review Test Clinical: e-Medicine article Congestive Heart Failure and Pulmonary Edema
  2. 2. 2 Learning Objectives: 1. Understand the underlying hemodynamic abnormalities in heart failure and the therapeutic approaches to its treatment 2. 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 3. Understand the properties of intravenous agents (dobutamine, dopamine and PDE inhibitors) used in the treatment of heart failure 4. Understand the actions of beta blockers and the rationale for their use in the treatment of heart failure 5. Know the pharmacologic action, toxicities and uses of cardiac glycosides By the end of this presentation the learner should:
  3. 3. 3 Definition of HF  Chronic heart failure (HF) is an imbalance in pump function in which heart fails to adequately maintain circulation of blood.  The most severe manifestation of HF, 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… See cloud e-Medicine Article Congestive Heart Failure and Pulmonary Edema
  4. 4. 4 Classification of HF 1. The side of the heart involved, (left heart failure versus right heart failure) 2. Whether the abnormality is due to contraction or relaxation of the heart (Systolic Dysfunction vs. 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 resistance or 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) There are many different ways to categorize heart failure, including:
  5. 5. 5 Congestive Heart Failure: Causes •Myocardial infarction •Coronary artery disease •Valve disease •Idiopathic cardiomyopathy •Viral or bacterial cardiomyopathy •Myocarditis •Pericarditis •Arrhythmias •Chronic hypertension •Thyroid disease •Pregnancy •Septic shock
  6. 6. 6 Congestive 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 HF  Tachyarrhythmias decrease filling time and as a result decrease cardiac output  A-V dissociation results in loss of the atrial contribution to ventricular filling.  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 HF  Increased stroke volume may not be possible if the patient has significant heart disease
  7. 7. 7 Congestive Heart Failure: Causes (cont.) 2. Myocardial Infarction: A myocardial infarction, reducing left ventricular function, may precipitate HF 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.
  8. 8. Congestive Heart Failure: Causes (cont.) 8 5. Other causes: • Thyrotoxicosis • Pregnancy • Infection • Anemia • Rheumatic and other forms of Myocarditis • Physical, dietary, fluid • Environmental and emotional excesses • Infective Endocarditis
  9. 9. 9 Pathophysiology in HF  HF 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. topics/heart failure-2.htm Cardiac and Vascular Changes Accompanying Heart Failure Cardiac Decreased SV and CO Increased end-diastolic pressure Vascular Increased SVR Decreased arterial pressure Decreased venous compliance Increased venous pressure Increased blood volume
  10. 10. Pathophysiology in HF(2) 10 Compensatory Mechanisms During Heart Failure Cardiac Frank-Starling mechanism Ventricular dilation or hypertrophy Tachycardia Autonomic Nerves Increased sympathetic adrenergic activity Reduced vagal activity to heart Hormones Renin-angiotensin-aldosterone system (RAAS) Vasopressin (antidiuretic hormone/ADH) Circulating catecholamines Natriuretic peptides
  11. 11. 11 Pathophysiology in HF (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:
  12. 12. The renin-angiotensin- aldosterone system (RAAS) 12 Source:
  13. 13. Physiologic Effects of AII 13 N.B.The RAAS is modulated by natriuretic peptides (ANP and BNP) released by the heart. These natriuretic peptides acts as an important counter-regulatory system Constricts resistance vessels (via AII [AT1] receptors) thereby increasing systemic vascular resistance and arterial pressure Stimulates sodium transport (reabsorption) at several renal tubular sites, thereby increasing sodium and water retention Acts on adrenal cortex to release aldosterone, which in turn acts on kidneys to increase sodium and fluid retention Stimulates release of vasopressin (antidiuretic hormone, ADH) from the posterior pituitary, which increases fluid retention by kidneys Stimulates thirst centers within the brain Facilitates norepinephrine release from sympathetic nerve endings and inhibits norepinephrine re-uptake by nerve endings, thereby enhancing sympathetic adrenergic function Stimulates cardiac hypertrophy and vascular hypertrophy
  14. 14. 14 Source: Pathophys. & Pharm. in HF Illustrated
  15. 15. Clinical Perspective and Considerations 15 Heart failure, inability of circulatory system to meet metabolic demands of body, is a multifaceted “disease state” (syndrome) involving several organ systems and neurohumoral factors including heart, kidney, vascular system and brain There are several forms of heart failure with multiple etiologies The treatment of heart failure is a particularly difficult therapeutic problem with no single drug or drug class adequate to provide complete relief from the signs and symptoms of the syndrome
  16. 16. Clinical Perspective and Considerations (2) 16 The drugs used and their specific therapeutic approaches depend on underlying pathophysiology and severity of the disease While drug therapy is capable of symptomatic relief, it does not correct the underlying pathology Regardless of treatment, 50 % of individuals die within 5 years of developing HF. In an era where morbidity and mortality from other cardiovascular diseases are decreasing, deaths from HF are increasing
  17. 17. Framingham Criteria for Congestive Heart Failure 17 Diagnosis of HF 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
  18. 18. Framingham Criteria for Congestive Heart Failure (2) 18 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.) N.B. 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 nephrotic syndrome)
  19. 19. 19 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
  20. 20. 20 New York Heart Association (NYHA) Functional Classification (2) NYHA Class Symptoms I No symptoms and no limitation in ordinary physical activity, e.g. shortness of breath when walking, climbing stairs etc. II mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity. III Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances (20-100 m). Comfortable only at rest. IV Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. Source:
  21. 21. 21 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
  22. 22. DRUGS AND DRUG CLASSES USED TO TREAT HEART FAILURE (See last slide for complete list) 22 1. Vasodilators - Drugs that decrease either preload or afterload  ACE inhibitors, AT1 blockers, and other vasodilators and diuretics a) Arterial selective vasodilators decrease PVR and afterload on the failing myocardium  reduction in afterload leads to an increased CO and improved tissue perfusion b) Venous selective vasodilators increase venous capacitance, thus decreasing preload  A small reduction in venous tone can result in a pooling of large amounts of blood  This would decrease left ventricular filling pressure and pulmonary congestion
  23. 23. DRUGS AND DRUG CLASSES USED TO TREAT HEART FAILURE (2) 23 c) The major vasodilators used are ACE inhibitors and angiotensin II receptor antagonists (ARBs) d) Other agents include organic nitrates, hydralazine and nitroprusside ( all 3 reduce both preload & afterload) e) In addition, diuretics promote the elimination of edematous fluid, improving tissue perfusion and pulmonary function N.B. Chronic thiazide diuretic Tx also results in relaxation of resistance vessels)
  24. 24. DRUGS AND DRUG CLASSES USED TO TREAT HEART FAILURE (3) 24 2. Positive Inotropic Agents Drugs that increase contractile force; beta1 receptor agonists, cAMP PDE inhibitors, cardiac glycosides 3. Beta blockers (not acute HF, but decrease mortality in chronic HF) 4. Diuretics Cornerstone drugs in the treatment of heart failure. Noteworthy are loop diuretics and aldosterone receptor antagonists. N.B. In addition to effects on circulatory system, some of these agents also block the cellular responses that lead to cardiac remodeling and hypertrophy
  25. 25. 25 Overview of HF Pharmacological Management Treatment of HF 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
  26. 26. 26 Overview of HF Pharmacological Management(2) Drugs used include: 1. diuretic agents, 2. vasodilator agents, 3. positive inotropes, 4. ACE inhibitors, 5. beta blockers, 6. aldosterone antagonists Related Terms: 1. contractility (inotropy), 2. heart rate (chronotropy) 3. conduction velocity (dromotropy)
  27. 27. 27 Overview of HF 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/ARBs), particularly using candesartan, is an acceptable alternative if the patient is unable to tolerate ACEI therapy
  28. 28. 28 Overview of HF 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
  29. 29. Cardiorenal Effects of ACEIs 29 Vasodilation (arterial & venous) - reduce arterial & venous pressure - reduce ventricular afterload & preload Decrease blood volume - natriuretic - diuretic Depress sympathetic activity Inhibit cardiac and vascular hypertrophy
  30. 30. Overview of HF Pharmacological Management (5) 30 Many ACE inhibitors have been developed  Captopril was the first agent developed and hence is the prototype Enalapril is a prodrug that is de-esterified by plasma esterases to enalaprilat Most of the ACEIs are activated in this fashion Benazepril - Metabolized to benazeprilat Captopril Enalapril - Metabolized to enalaprilat Fosinopril - Metabolized to fosinoprilat Lisinopril Moexipril- Metabolized to moexiprilat Quinapril - Metabolized to quinaprilat Ramipril - Metabolized to ramiprilat Trandolapril-Metabolized to tandolaprilat Perindopril - metabolized to perindoprilat
  31. 31. 31 Overview of HF Pharmacological Management (6) Commonly used Angiotensin Converting Enzyme (ACE) Inhibitors
  32. 32. 32 Overview of HF Pharmacological Management(7) MOA of Angiotensin Converting Enzyme (ACE) Inhibitors
  33. 33. 33 Overview of HF Pharmacological Management (8) 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 HF, usually for moderate HF  Thiazide diuretics (e.g. hydrochlorothiazide, chlorthalidone, chlorthiazide) – may be useful for mild HF, but typically used in severe HF in combination with loop diuretics, resulting in a synergistic effect
  34. 34. 34 Overview of HF Pharmacological Management (9) 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 HF  Eplerenone (Inspra®) is specifically indicated for post-MI reduction of cardiovascular risk
  35. 35. 35 Overview of HF Pharmacological Management (10) Beta blockers  Until recently (within the last 20 years), β- blockers were contraindicated in HF, owing to their negative inotropic effect and ability to produce bradycardia – effects which worsen heart failure  However, current guidelines recommend β- 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
  36. 36. 36 Overview of HF Pharmacological Management (11) Beta blockers cont. As with ACEI therapy, the addition of a β-blocker can decrease mortality and improve left ventricular function  Several β-blockers are specifically indicated for HF including: 1. bisoprolol, 2. carvedilol, and 3. extended-release metoprolol antagonism of β1 inotropic and chronotropic effects decreases the amount of work the heart must perform
  37. 37. 37 Overview of HF Pharmacological Management (12) 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
  38. 38. Overview of HF Pharmacological Management (13) 38 CARDIAC GLYCOSIDES (Digitalis ) (Some history) Cardiac glycosides are one of the oldest groups of drugs used in cardiovascular therapeutics There is evidence of use in Egyptian and Roman times William Withering published medical accounts of use of the "foxglove" for the treatment of "dropsy." Originally, extracts of d. purpurea were used  Two active principals, digoxin and digitoxin, are now used in cardiovascular therapeutics The uses of these drugs are in heart failure and supraventricular tachyarrhythmias. These agents have a low therapeutic index Digitalis purpurea (Common Foxglove)
  39. 39. 39 Overview of HF Pharmacological Management (14) 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 HF, although some studies suggest a decreased rate in hospital admissions  It is contraindicated in cardiac tamponade and restrictive cardiomyopathy N.B. Cardiac glycosides not first line Tx for HF due to risk of toxicities
  40. 40. 40 Overview of HF Pharmacological Management(15) Cardiac glycosides Mechanism of Positive Inotropic Action  Cardiac glycosides inhibit the myocardial cell Na+, K+, ATPase  This enzyme is responsible for maintaining ionic gradient of myocardial cell.  Inhibition of the Na+, K+, ATPase results in an increase in intracellular Na+. Decrease in Na+ gradient diminishes exchange of Na+ for Ca2+  Increase in intracellular Ca2+ is responsible for the positive inotropic action
  41. 41. 41 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: 1. Increases SA nodal refractory period 2. Slows SA nodal conduction velocity  At the AV node (major site of antiarrhythmic action) the increase in vagal tone: 1. Increases AV nodal refractory period 2. Slows AV nodal conduction velocity Overview of HF Pharmacological Management(15) Cardiac glycosides
  42. 42. 42 Pharmacokinetics of Cardiac Glycosides AGENT GASTRO INTESTINAL ABSORPTION ONSET OF ACTION (MIN) PEAK EFFECT (HR) AVERAG E HALF LIFE PRINCIPAL METABOLIC ROUTE (EXCRETORY PATHWAY) AVERAGE DIGITALIZING DOSES USUAL DAILY ORAL MAINTENAN CE DOSESoral IV Digoxin 30 to 100% 15 to 30 1 1/2 to 5 36 to 48 hours Renal; some gastrointestinal excretion 1.25 to 1.5 mg 0.75 to 1.00 mg 0.25 to 0.5 mg Digitoxin 90 to 100% 25 to 120 4 to 12 4 to 6 days Hepatic; renal excretion of metabolites 0.7 to 1.2 mg 1.00 mg 0.1 mg Special Considerations / Next Slide Overview of HF Pharmacological Management(16) Cardiac glycosides
  43. 43. Special Considerations 43 Factors that can alter the therapeutic response to cardiac glycosides:  Renal disease decreased renal clearance of digoxin  Drug Interactions that: a) Decrease bioavailability Cholestyramine b) Decrease renal clearance Amiodarone ,Verapamil , Quinidine   Hypokalemia and Electrolytes Hypokalemia increases the likelihood of toxicity Alterations in potassium levels could be exacerbated by co-administration of diuretics  Age elderly are more sensitive to cardiac glycosides  Hypoxia increases the likelihood of toxicity
  44. 44. 44 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 antagonism of adenosine receptors, resulting in inotropic effects and modest diuretic effects Overview of HF Pharmacological Management(17)
  45. 45. 45 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 HF patients with an African American background, who respond less effectively to ACEI therapy See next slide Overview of HF Pharmacological Management (18)
  46. 46. Overview of HF Pharmacological Management (19) 46 Exner DV, Dries DL, Domanski MJ, Cohn JN (2001). "Lesser response to angiotensin-converting-enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction". N Engl J Med. 344 (18): 1351–7. doi:10.1056/NEJM200105033441802. Taylor AL, etal; (2004). African-American Heart Failure Trial Investigators. "Combination of isosorbide dinitrate and hydralazine in blacks with heart failure". N Engl J Med 351 (20): 2049–57. doi:10.1056/NEJMoa042934.
  47. 47. 47From: Medical Pharmacology at a Glance, 7th Ed. Michael J. Neal. 2012 John Wiley & Sons, Ltd: Pg. 49 Drugs Used in Heart Failure: Schematic Summary
  49. 49. Recommended links and resource for further study: Cardiovascular Physiology Concepts, 2nd edition, LLW (2011) Diuretics - thiazide diuretics - loop diuretics - natriuretic peptides Vasodilators (dilate arteries and veins) - angiotensin converting enzyme (ACE) inhibitors - angiotensin receptor blockers (ARBs) - direct acting arterial dilators - nitrodilators - natriuretic peptides - phosphodiesterase inhibitors Cardiostimulatory or inotropic drugs (stimulate contractility) - digitalis - beta-agonists (sympathomimetic drugs) - phosphodiesterase inhibitors Cardioinhibitory - beta-blockers - calcium-channel blockers (for diastolic dysfunction) Classes of drugs used in the treatment of heart failure by Richard E. Klabunde, PhD are given below. Clicking on the drug class will link you to the page describing the pharmacology of that drug class.