Heart-failure-ppt-prelim.pdf

HEART FAILURE Chapter 19  HEART FAILURE occurs when cardiac output is inadequate to provide the oxygen needed by the body a progressive disease that is characterized by a gradual reduction in cardiac performance, punctuated in many cases by episodes of acute decompen...

HEART FAILURE Chapter 19  HEART FAILURE occurs when cardiac output is inadequate to provide the oxygen needed by the body a progressive disease that is characterized by a gradual reduction in cardiac performance, punctuated in many cases by episodes of acute decompensation, often requiring hospitalization  most common causes are coronary artery disease and hypertension  Two Types of Heart Failure Systolic Failure Diastolic Failure  Systolic Failure reduced mechanical pumping action (contractility) and reduced ejection fraction  Diastolic Failure with stiffening and loss of adequate relaxation playing a major role in reducing filling and cardiac output ejection fraction may be normal even though stroke volume is significantly reduced PATHOPHYSIOLOGY OF HEART FAILURE  Symptoms of Heart Failure tachycardia decreased exercise tolerance shortness of breath peripheral and pulmonary edema cardiomegaly  "High-Output" Failure a rare form of heart failure the demands of the body are so great that even increased cardiac output is insufficient can result from hyperthyroidism, beriberi, anemia, and arteriovenous shunts  Compensatory Physiological Responses Increased sympathetic activity Activation of RAAS Myocardial hypertrophy  Myocardial Hypertrophy the most important intrinsic compensatory mechanism increase in muscle mass helps maintain cardiac performance however hypertrophy can lead to ischemic changes, impairment of diastolic filling, and alterations in ventricular geometry  REMODELING the term applied to dilation (other than due to passive stretch) and other slow structural changes that occur in the stressed myocardium  Pathophysiology of Cardiac Performance Cardiac performance is a function of four primary factors:  PRELOAD usually increased in heart failure because of increased blood volume and venous tone can be defined as the initial stretching of the cardiac myocytes prior to contraction  AFTERLOAD the resistance against which the heart must pump blood and is represented by aortic impedence and systemic vascular resistance  CONTRACTILITY reduction in intrinsic contractility in heart failure patients the heart is usually still capable of some increase in all of these measures of contractility in response to inotropic drugs  HEART RATE a major determinant of cardiac output first compensatory mechanism to maintain cardiac output -- INCREASE IN HEART RATE THROUGH SYMPATHETIC ACTIVATION OF β- ADRENORECEPTORS Basic Pharmacology of Drugs Used in Heart Failure  DIGITALIS the genus name for the family of plants that provide most of the medically useful cardiac glycosides (e.g. digoxin) Purple Foxglove - Digitalis purpurea White Foxglove - Digitalis lanata  DIGOXIN Lanoxin® a cardiac glycoside or cardenolides obtained from Digitalis lanata can also be found in oleander, lily of the valley and milkweed  Mechanism of Action Na+/K+ ATPase inhibition resulting in reduced Ca 2+ expulsion and increased Ca 2+ stored in sarcoplasmic reticulum  Effects Increase cardiac contractility (inotropic effect) cardiac parasympathomimetic effect (slowed sinus heart rate, slowed atrioventricular conduction)  Cardiac Effects increase cardiac contraction by increasing free calcium concentration through: - increase in intracellular Na concentration because of Na+/K+ inhibition - relative reduction of calcium expulsion from the cell by the sodium-calcium exchanger caused by the increase in intracellular sodium  Clinical Application Chronic symptomatic heart failure Rapid ventricular rate in atrial fibrillation  Toxicity N&V Diarrhea Cardiac Arrythmia Disorientation & Hallucination Visual Disturbances (blurred or yellow vision) Gynecomastia  Interaction with K, Ca & Mg Potassium & Digoxin - inhibit each other's binding to Na+/K+ ATPase Hyperkalemia - reduces the effect of Digoxin Hypokalemia - facilitate its actions and may lead to toxicity  Calcium - facilitates the toxic action of cardiac glycosides by accelerating the overloading of intracellular calcium stores Magnesium - opposite to the effect of calcium Other Positive Inotropic Drugs Used in Heart Failure  ISTAROXIME an investigational steroid derivative that increases contractility by inhibiting Na+/K+ ATPase but in addition, facilitates sequestration of Ca2+ by the sarcoplasmic reticulum (may render less arrhythmogenic) in Phase II clinical trials  Levosimendan sensitizes the troponin system to calcium, also appears to inhibit phosphodiesterase and to cause some vasodilation in addition to its inotropic effect  BIPYRIDINES Inamrinone (old name Amrinone) Milrinone (Primacor®)  Mechanism of Action phosphodiesterase type 3 inhibitor decrease cAMP breakdown  Effects Vasodilators lower peripheral vascular resistance Increase cardiac contractility  Clinical Application Acute decompensated heart failure  Toxicity Arrhythmia N&V Thrombocytopenia Bone marrow and liver toxicity  BETA-ADRENOCEPTOR STIMULANTS Dobutamine Dopamine  DOBUTAMINE most widely used produces an increase cardiac contractility, increase in cardiac output together with a decrease in ventricular filling pressure  Mechanism of Action Beta-1 selective agonist increases cAMP synthesis  Clinical Applications Acute decompensated heart failure Intermittent therapy in chronic failure reduces symptoms  Toxicity Arrhythmia  Drug Interaction Additive with other sympathomimetics  DOPAMINE used in acute heart failure and may be particularly helpful if there is a need to raise blood pressure  Mechanism of Action Dopamine receptor agonist Higher doses activate α and β adrenoceptors  Effects Increases renal blood flow Higher doses increase cardiac force and blood pressure  Clinical Applications Acute decompensated heart failure Shock  Toxicity Arrhythmia  Drug Interactions Additive with sympathomimetics  Drugs without Positive Inotropic Effects Used in Heart Failure  the first-line therapies for chronic heart failure  Diuretics ACE inhibitors ARBs Aldosterone Antagonists Beta-Blockers  Diuretics Vasodilators -important for acute heart failure  DIURETICS mainstay of heart failure management no direct effect on cardiac contractility used to reduce venous pressure and ventricular preload  Spironolactone/Eplerenone (aldosterone antagonist diuretics) + ACE inhibitors = additional benefit of decreasing morbidity and mortality Aldosterone - may cause myocardial and vascular fibrosis & baroreceptor dysfunction  LOOP DIURETICS Furosemide (Lasix®) Bumetanide Torsemide Ethacrynic Acid  Mechanism of Action decreases NaCl & KCl reabsorption in thick ascending limb of the loop of Henle in the Nephron  Effects Increased excretion of salt and water Reduces cardiac preload and afterload Reduces pulmonary and peripheral edema  Clinical Applications Acute & Chronic Heart Failure Severe Hypertension Edematous Conditions  Toxicity Hypovolemia Hypokalemia Orthostatic Hypotension Ototoxicity Sulfonamide Allergy  THIAZIDE DIURETICS Hydrochlorothiazide (Hytaz®)  Mechanism of Action decreases NaCl reabsorption in the distal convoluted tubule  Effects Same as Furosemide, but less efficacious  Clinical Applications Mild chronic failure Mild-Moderate Hypertension Hypercalciuria  Toxicity Hyponatremia Hypokalemia Hyperglycemia Hyperlipidemia Hyperuricemia Sulfonamide Allergy **hyperGLU**  ALDOSTERONE ANTAGONISTS Spironolactone (Aldactone®) Eplerenone  Mechanism of Action Block cytoplasmic aldosterone receptors in collecting tubules of nephron  Effects Increased salt and water excretion Reduces remodelling Reduces mortality  Clinical Applications Chronic Heart Failure Aldosteronism (Cirrhosis, Adrenal tumor) Hypertension  Toxicity Hyperkalemia Antiadrogen actions  ACE INHIBITORS reduce peripheral resistance and thereby reduce afterload reduce salt & water retention (by reducing aldosterone secretion) thereby reduce preload reduction in tissue angiotensin levels also reduces sympathetic activity through diminution of angiotensin's presynaptic effects on NE release  Mechanism of Action Inhibits ACE reduces AII formation by inhibiting formation of AI to AII  Effects Arteriolar and Venous dilation Reduces aldosterone secretion Increases cardiac output Reduces cardiac remodelling  Clinical Applications Chronic Heart Failure Hypertension Diabetic Renal Disease  Toxicity Dry Cough Hyperkalemia Angioneurotic Edema  Angiotensin II Receptor Blockers appear to have similar but more limited beneficial effects should be considered in patients intolerant of ACE inhibitor's incessant cough (Candesartan)  Mechanism of Action antagonizes AII effects at AT1 receptors  Effects & Clinical Applications Like ACEi Used in patients intolerant to ACEi  Toxicity Hyperkalemia Angioneurotic Edema  NATRIURETIC PEPTIDE approved for use in ACUTE heart failure NESIRITIDE (Natrecor®)  Mechanism of Action Activates BNP (Brain Natriuretic Peptide) receptors, increases cGMP (reduces venous and arteriolar tone)  Effects Vasodilation Diuresis  Clinical Application Acute Decompensated Heart Failure  Toxicity Renal damage Hypotension  Atrial Natriuretic Peptide (ANP) - Peritide Urodilatin - Ularitide  Bosentan (Tracleer) Tezosentan - orally active competitive inhibitor of endothelin  VASODILATORS effective in acute heart failure because they provide a reduction in preload (through venodilation), or reduction in afterload (through arteriolar dilation), or both  ISOSORBIDE DINITRATE Venodilator MOA: Releases Nitric Oxide (NO); activates guanylyl cyclase  Effects Venodilation Reduces preload and ventricular stretch  Clinical Applications Acute and Chronic Heart Failure Angina  Toxicity Postural hypotension Tachycardia Headache  HYDRALAZINE Arteriolar Dilator MOA: probably increase NO synthesis in endothelium  Effects Reduces blood pressure and afterload Results in increased cardiac output  Toxicity Tachycardia Fluid retention SLE-like symptoms  NITROPRUSSIDE Combined ateriolar and venodilator  Mechanism of Action Releases NO spontaneously activates guanylyl cyclase  Effects marked vasodilation Reduces preload and afterload  Clinical Applications Acute cardiac decompensation Hypertensive emergencies (Malignant Hypertension)  Toxicity Excessive hypotension Thiocyanate and Cyanide toxicity  BETA-ADRENOCEPTOR BLOCKERS Bisoprolol Carvedilol Metropolol  Mechanism of Action Competitively blocks Beta1 receptors  Effects Slows heart rate Reduces blood pressure Poorly understood effects Reduces heart failure mortality  Toxicity Bronchospasm Bradycardia Atrioventricular Block Acute Cardiac Decompensation FOUR STAGES OF HEART FAILURE DEVELOPMENT  STAGE A patients are at high risk because of other disease but have no signs or symptoms of heart failure  STAGE B patients have evidence of structural heart disease but no symptoms of heart failure  STAGE C patients have structural heart disease and symptoms of failure, and symptoms are responsive to ordinary therapy  STAGE D patients have heart failure refractory to ordinary therapy, and special interventions (resynchronization therapy, transplant) are required  CLASS I FAILURE stage C is reached associated with no limitations on ordinary activities and symptoms that occur only with greater than ordinary exercise  CLASS II characterized by slight limitation of ordinary activities, which result in fatigue and palpitations with ordinary physical activity  CLASS III failure results in no symptoms at rest, but fatigue, shortness of breath, and tachycardia occur with less than ordinary exercise  CLASS IV is associated with symptoms even when the patient is at rest