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Internal Medicine Lecture 7. CONGESTIVE HEART FAILURE V. Babadzhan, D.M. Professor of Medicine, Kharkov State Medical University Department of Internal Medicine 2, Clinical Immunology and Allergology DEFINITION
Internal Medicine Lecture 7. CONGESTIVE HEART FAILURE V. Babadzhan, D.M. Professor of Medicine, Kharkov State Medical University Department of Internal Medicine 2, Clinical Immunology and Allergology DEFINITION The situation when the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return. E. Braunwald Incidence and prevalence Heart failure is an epidemic affecting 1-2 million Ukraineans and nearly 15 million people worldwide. Heart failure carries worse prognosis, as 50% of patients with heart failure will die within 5 year, and in patient with sever heart failure more than 50% will die within 2 year. DETERMINANTS OF VENTRICULAR FUNCTION CONTRACTILITY PRELOAD AFTERLOAD STROKE VOLUME - Synergistic LV contraction - LV wall integrity - Valvular competence HEART RATE CARDIAC OUTPUT Pathophysiology of heart failure HORMONAL PUMP DYSFUNCTION MYOCARDIAL REMODELING CYTOKINE CIRCULATORY INSUFFICIENCY NEUROREGULATORY HEART FAILURE DIAGNOSIS HISTORY. PHYSICAL EXAMINATION. APPROPRIAT INVESTIGATION. 1. SYMPTOMS OF HEART FAILURE (AT REST OR DURING EXERCISE). 2.Objective evidence of cardiac dysfunction. 3.Response to treatment directed towards heart failure. CRITERIA FOR CONGESTIVE HEART FAILURE MAJOR CRITERIA 1.Paroxysmal nocturnal dyspnea or orthopnea. 2.Rales. 3.Cardiomegaly. 4.Acute pulmonary edema. 5.S3 Gallop. 6.Increased venous pressure 16 cm of water. 7.Circulation time 25 sec. 8.Hepatojugular reflux. MINOR CRITERIA 1.Ankle edema. 2.Night cough. 3.Dyspnea on exertion. 4.Pleural effusion. 5.Vital capacity decreased 1/3 from maximum. 6.Tachycardia (rate 120/min). MAJOR OR MINOR Weight loss 4.5 Kg in 5 days in response to treatment. Symptomatic classification of exercise tolerance New York Heart Association (NYHA) NYHA Class I: No complaints under heavy physical load. NYHA Class II: Complaints under heavy physical load. NYHA Class III: Complaints under light physical load. NYHA Class IV : Complaints at rest. Descriptive terms in heart failure Acute vs Chronic heart failure. Systolic vs Diastolic. Right vs Left heart failure. Types of Heart Failure include left, right or both sides left ventricular heart failure most common systolic failure: unable to contract diastolic failure: unable to relax right ventricular heart failure usually occurs after left failure less blood received causes right damage less pumping by right side venous pooling of blood in legs Causes of Chronic Heart Failure Systolic dysfunction: Coronary artery disease. Hypertension. Dilated Cardiomyopathy. Myocarditis. Causes of Chronic Heart Failure cont. Diastolic Dysfunction: Coronary artery disease. Systemic Hypertension. Diabetis Mellitus. Aortic stenosis. Hypertrophic cardiomypathy. Infiltrative cardiomypathy Endocardial fibrosis. Normal aging process. Causes of worsening Heart Failure cont. Cardiac: Atrial fibrillation. Other supraventricular or ventricular arrhythmias. Bradycardia. Appearance or worsening mitral or ticusped regurgitation. Myocardial ischaemia. Excessive preload reduction(diuretics,ace inhibitors). Causes of worsening Heart Failure Non- cardiac: Non compliance to the prescribed regimen(salt,liquid,medication). Recently co-prescribed drugs (antiarrhythmic,beta-blockers,non steroidal anti-inflmatory drugs,verapamil,diltiazem). Renal dysfunction. Infection. Pulmonary embolism. Thyroid dysfunction. Anemia. Alcohol abuse. The Heart Failure Milieu Clinical Presentation Disease Proccess Ventricular Dysfunction Haemdynamic Abnormalities Compansatory Mechanism Metabolic Changes Symptomes And Physical finding Metabolic Changes Azotemia. Hyponatraemia. Hypokalemia. Hypomagnesemia. Hyperuricemia. Acidosis/Alkalosis. Hypoxia/O2 desaturation. Decreased MVO2. Symptomes Fatigue,weakness and decreased exercice tolerance. Dyspnea and fluied retention symptomes. Nocturia. Gastrointestinal symptomes. Diminished mentation. Physical Findings Peripheral edema. Ascites. Jugular venous distension. Rales. Tachycardia. Hypotention. Cachexia. Disease specific findings. Compensatory Mechanisms Systemic organ failure Renal failure. Hepatic failure. Respiratory failure. Multi-organ failure. Pulmonary embolism. Peripheral& cerebral embolism. Evaluation of heart failure patient Physical Examination History Laboratory tests Diagnostic studies Investigation Laboratory Complete Blood Count. Serum electrolytes, blood urea nitrogen,serum creatinine. Liver function test. Prothrombin time. Lipid profile. Thyroid function test. Anaemia evaluation. Arterial blood gases. Serum drug levels(digoxin,phenytoin). Atrial natriuretic peptides. Urin analysis. Chest X- ray Chest roentgenogram of patient with heart failure. This roentgenogram demonstrates cardiomegaly (cardiothoracic ratio 0.77), pulmonary congestion, and bilateral pleural effusions (note blunted costophrenic angles). 12-Leads ECG Other investigation Transthoracic Echocardiography. Stress Echo. Exercise stress testing. 24- hour Holter monitoring. Nuclear imaging,thallium perfusion scan,cardiac MRI. Coronary angiography Chronic Congestive Heart Failure No symptoms Normal exercise Normal LV fxn EVOLUTION OF CLINICAL STAGES NORMAL Asymptomatic LV Dysfunction No symptoms Normal exercise Abnormal LV fxn Compensated CHF Decompensated CHF No symptoms Exercise Abnormal LV fxn Symptoms Exercise Abnormal LV fxn Refractory CHF Symptoms not controlled with treatment Treatment Options Non-pharmacological. General advice and measures. Exercise and exercice training.reduce cardiac work. Rest. Weight loss. Low Na diet. Pharmacological therapy. Angiotensin-converting enzyme inhibitors(aci). Beta-adrenoreceptor antagonists. Cardiac glycosides. Diuretics. Vasodilators(nitrats,hydralazine). Antiarrhythmic agent. Anticoagulantion. Oxyggen. Divices and surgery. Revascularization. Pacemaker. Implantable cardioverter defibrillator(icd). Cadiac trnsplantation. Ultrafiltration,haemodialysis. TREATMENT Correction of aggravating factors Pregnancy Arrhythmias (AF) Infections Hyperthyroidism Thromboembolism Endocarditis Obesity Hypertension Physical activity Dietary excess MEDICATIONS TREATMENT PHARMACOLOGIC THERAPY DIURETICS INOTROPES VASODILATORS NEUROHORMONAL ANTAGONISTS OTHERS (Anticoagulants, antiarrhythmics, etc) TREATMENT Normal Asymptomatic LV dysfunction EF 40% Symptomatic CHF ACEI NYHA II Diuretics mild Neurohormonal inhibitors Digoxin? Secondary prevention Modification of physical activity Symptomatic CHF NYHA - III Loop Diuretics Symptomatic CHF NYHA - IV Inotropes Specialized therapy Transplant DIURETICS Cortex Thiazides Inhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of Henle K-sparing Inhibit reabsorption of Na in the distal convoluted and collecting tubule Medulla Loop of Henle Loop diuretics Inhibit exchange of Cl-Na-K in the thick segment of the ascending loop of Henle Collecting tubule CLINICAL AND PHARMACOLOGIC PROPERTIES OF DIURETICS Drugs Thiazide diuretics Relative potency Site of Action Onset of Action Advantages Adverse Effects Hydrochlorothiazide Oral: mg/day Moderate Excreted into proximal tubule, inhibition of Na and Cl, absorption in distal segment 1-2 h Mild, relatively nontoxic, oral administration, antihypertensive K loss. hyperglycemia, decreases platelets. ineffective when GFR 20 ml/min. hyperuricemia Loop diuretics Furosemide mg 1, 2. or 3 times/day; IV: 40 mg initially; may increase to mg, depending on response Torosimide 5-10 mg/d Ethacrynic acid IV: 50 mg initially; may increase, depending on response High Inhibition of Cl transport in ascending limb of loop of Henle Oral: 1 h IV: min Rapid onset, potency, independent of acid-base balance, effective even when GFR is reduced Excessive diuresis; hypovolemia; K loss and hypokalemia; hyperuricemia; transient or irreversible deafness with IV administration, especially when used with aminoglycoside antibiotic DIURETICS ADVERSE REACTIONS Thiazide and Loop Diuretics Changes in electrolytes: Volume Na +, K +, Ca ++, Mg ++ metabolic alkalosis Metabolic changes: glycemia, uremia, gout LDL-C and TG Cutaneous allergic reactions POSITIVE INOTROPES CARDIAC GLYCOSIDES SYMPATHOMIMETICS Catecholamines ß-adrenergic agonists PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone Others Milrinone Piroximone DOPAMINE AND DOBUTAMINE EFFECTS DA (µg / Kg / min) Dobutamine 5 Receptors DA 1 / DA 2 ß 1 ß 1 + α ß 1 Contractility ± Heart Rate ± + ++ ± Arterial Press. ± Renal perfusion ++ + ± + Arrhythmia - ± ++ ± POSITIVE INOTROPES Agent Dose and Route Comment ADRENERGIC AGONISTS Epinephrine Norepinephrine mug SC or IM ( ml of 1/1000 solution of hydrochloride salt); mug IV (slowly) every 5-15 min; titrate as needed 2-4 mug of NE base/min IV; titrate as needed Nonselective alpha and beta agonist; increases BP, heart rate Bronchodilation Alpha and beta 1 agonist Vasoconstriction predominates Extravasation causes tissue necrosis; infuse through IV cannula Dobutamine (mug/kg)/min IV Selective betai agonist with greater effect on contractility than heart rate; a congener of dopamine but not a dopaminergic agonist DOPAMINERGIC AG ONLSTS Dopamine 2-5 (mug/kg)/min IV (dopaminergic range) 5-10 (mug/kg)/min IV (dopaminergic and beta range) (mug/kgvmin IV (beta range) (mug/kg)/min IV (alpha range) Pharmacologic effects are dose dependent: renal and mesenteric vasodilation predominate at lower doses; cardiac stimulation and vasoconstriction develop as the dose is increased POSITIVE INOTROPES CONCLUSIONS May increase mortality Safer in lower doses Use only in refractory CHF NOT for use as chronic therapy VASODILATORS CLASSIFICATION Arterial Vasodilatation VENOUS Nitrates Molsidomine MIXED Calcium antagonists α-adrenergic Blockers ACEI Angiotensin II inhibitors K + channel activators Nitroprusside ARTERIAL Minoxidil Hydralazine Venous Vasodilatation NITRATES HEMODYNAMIC EFFECTS 1- VENOUS VASODILATATION Preload Pulmonary congestion Ventricular size Vent. Wall stress MVO 2 2- Coronary vasodilatation Myocardial perfusion 3- Arterial vasodilatation Afterload Cardiac output Blood pressure 4- Others CLINICAL AND PHARMACOLOGIC PROPERTIES OF VASODILATORS Classification Drugs Site of Action Onset of Action Advantages Adverse Effects Nitrates Nitrogtycerin Sublingual: 0.4 mg pm Spray: 0.4 mg pm IV: μg/min Isosorbide dinitrate Sublingual:2.5-10mg q 2-4 h Oral: mg q 4-6 h Nitrate receptor Immediate Immediate Immediate min min 2-5 min min Rapid onset; various routes of admnistration; good for emergencies Headache; hypotension; methemoglobinemia; tolerance if not given intermittently Arterial vasodilators Hydralazine Oral: mg q 6 h Minoxidil Oral: mg twice daily Diazoxid IV: 1-3 mg/kg up to 150 mg rapidly Nitroprusside (μg/min) Smooth muscle min Immediately Specific arteriolar vasodilator Dilates arteries and veins Tachycardia; lupus phenomenon; long-term benefit requires nitrates Hypotension; thiocyanate accumulation Tachycardia; aggravates angine; marked fluid retensiot; hair growth on face and body, coarsening of facial features Hyperglycemia, hyperuricemia, sodium retension Cianide toxicity PROBABILITY OF DEATH NITRATES SURVIVAL Placebo (273) Prazosin (183) Hz + ISDN (186) VHefT-1 0 N Engl J Med 1986;314: MONTHS NITRATES TOLERANCE Decrease in the effect of a drug when administered in a long-acting form Develops with all nitrates Is dose-dependent Disappears in 24 h. after stopping the drug Tolerance can be avoided - Using the least effective dose - Creating discontinuous plasma levels NITRATES CONTRAINDICATIONS Previous hypersensitivity Hypotension ( 80 mmhg) AMI with low ventricular filling pressure 1 st trimester of pregnancy WITH CAUTION: Constrictive pericarditis Intracranial hypertension Hypertrophic cardiomyopathy ACE-Inhibitors MECHANISM OF ACTION VASOCONSTRICTION ALDOSTERONE VASOPRESSIN SYMPATHETIC Angiotensinogen RENIN Angiotensin I VASODILATATION PROSTAGLANDINS Kininogen Kallikrein tpa BRADYKININ A.C.E. Inhibitor Kininase II ANGIOTENSIN II Inactive Fragments ACEI HEMODYNAMIC EFFECTS Arteriovenous Vasodilatation - PAD, PCWP and LVEDP - SVR and BP - CO and exercise tolerance No change in HR / contractility MVO 2 Renal, coronary and cerebral flow Diuresis and natriuresis No Additional Treatment Necessary (%) ACEI FUNCTIONAL CAPACITY Class II-III Quinapril continued n=114 p 0.001 Quinapril stopped Placebo n= Quinapril Heart Failure Trial JACC 1993;22:1557 Weeks ACEI INDICATIONS Clinical cardiac insufficiency - All patients Asymptomatic ventricular dysfunction - LVEF 35 % ACEI UNDESIRABLE EFFECTS Inherent in their mechanism of action - Hypotension - Hyperkalemia - Angioneurotic edema Due to their chemical structure - Cutaneous eruptions - Neutropenia, thrombocytopenia - Digestive upset - Dry cough - Renal Insuff. - Dysgeusia - Proteinuria ACEI CONTRAINDICATIONS Renal artery stenosis Renal insufficiency Hyperkalemia Arterial hypotension Intolerance (due to side effects) ANGIOTENSIN II INHIBITORS MECHANISM OF ACTION RENIN Angiotensinogen Other paths AT1 RECEPTOR BLOCKERS AT1 Angiotensin I ACE ANGIOTENSIN II RECEPTORS AT2 Vasoconstriction Proliferative Action Vasodilatation Antiproliferative Action AT1 RECEPTOR BLOCKERS DRUGS Losartan Valsartan Irbersartan Candersartan Competitive and selective blocking of AT1 receptors ALDOSTERONE INHIBITORS Spironolactone ALDOSTERONE Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) Retention Na + Retention H 2 O Excretion K + Excretion Mg 2+ Edema Arrhythmias Collagen deposition Fibrosis - myocardium - vessels CLINICAL AND PHARMACOLOGIC PROPERTIES OF VASODILATORS Classification Drugs Site of Action Onset of Action Advantag es Adverse Effects Inhibitors of Angiotensin converting enzyme (ACE) Captopril 6.25 mg bid. up to 200 mg/d Enalapril mg/d Lisinopril 5-40 mg/d Quinapril mg/d Ramipril mg/d Quinapril mg bid; Angiotensin converting enzyme (ACE) [inhibition of] min 60 min 60 min min min Proven symptomat ic relief and improved survival Impaired renal function; proteinuria; dysgeusia; glomerulonephritis; leukopenia; cough Contraindications: pregnancy, bilateral renal artery stenosis Fosinopril 5-30 mg qd; Angiotensin e receptor antagonists Losartan mg once or twice daily Irbesartan 5-10 mg once or twice daily 2-4 h min Proven symptomat ic relief and improved survival Hypotension, ocute renal failure in bilateral renal artery stenosis, hyperkalemia Contraindications: pregnancy, bilateral renal artery stenosis ALDOSTERONE INHIBITORS INDICATIONS FOR DIURETIC EFFECT Pulmonary congestion (dyspnea) Systemic congestion (edema) FOR ELECTROLYTE EFFECTS Hypo K +, Hypo Mg + Arrhythmias Better than K + supplements FOR NEUROHORMONAL EFFECTS? Pending the RALES results CLINICAL AND PHARMACOLOGIC PROPERTIES OF DIURETICS Drugs Relative Potency Site of Action Onset of Action Advantages Adverse Effects Potassium-sparing diuretics Spironolactone Oral: mg bid to qid Moderate to low Aldosterone homolog, competitive inhibition for receptor site in distal tubule. Secondary: inhibition of aldosterone biosynthesis 2-3 days for maximum effect Useful in combination with more proximalacting diuretic to spare K Hyperkalemia when K salts are given concomitantly or renal function is reduced markedly ALDOSTERONE INHIBITORS CONTRAINDICATIONS Hyperkalemia Severe renal insufficiency Metabolic acidosis ß-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS Density of ß 1 receptors Inhibit cardiotoxicity of catecholamines Neurohormonal activation HR Antihypertensive and antianginal Antiarrhythmic Antioxidant Antiproliferative BETA-ADRENERGIC RECEPTOR BLOCKERS Drugs Site of Action Precautions and special considerations Carvedilol mg bid; titrate to target dose 25 mg bid. Bisoprolol 1.25 mg bid; titrate to target dose 10 mg bid. Metoprolol tartrate 6.25 mg bid; titrate to target dose 50 mg bid. Metoprolol succinate (extended release) mg bid; titrate to target dose 200 mg bid. Noncardioselectiv e β- and α1- adrenergic receptor block, without ISA Noncardioselectiv e, without ISA Cardioselective, without ISA Cardioselective, without ISA Should not be used in patients with asthma, chronic obstructive pulmonary disease (COPD) with bronchospasm, congestive heart.failufe, heart block (greater than first degree), sick sinus syndrome. Use with caution in insulindependent diabetics and patients with peripheral vascular disease. Should not be discontinued abruptly in patients with ischemic heart disease. Side effects Bronchospasm, peripheral arterial insufficiency, fatigue, insomnia, sexual dysfunction, exacerbation of congestive heart failure, may mask symptoms of hypoglycemia; hyperglycemia; hypertriglyceridemi a, decreased highdensity lipoprotein (HDL) cholesterol (except for drugs with ISA and labetalol) ISA = intrinsic sympathomimetic activity. ß-ADRENERGIC BLOCKERS IDEAL CANDIDATE? Suspected adrenergic activation Arrhythmias Hypertension Angina ß-ADRENERGIC BLOCKERS CONTRAINDICATIONS Hypotension: BP 100 mmhg Bradycardia: HR 50 bpm Clinical instability Chronic bronchitis, ASTHMA Severe chronic renal insufficiency CALCIUM ANTAGONISTS POTENTIAL EFFECTS Antiischemic Peripheral Vasodilatation Inotropy CALCIUM ANTAGONISTS POSSIBLE UTILITY Diltiazem contraindicated Verapamil and Nifedipine not recommended Vasoselective (amlodipine, nisoldipine), may be useful in ischemia + CHF Amlodipine may be useful in nonischemic CHF DIGOXIN Na-K ATPase Na + K + Na-Ca Exchange Na + Ca ++ K + Na + Myofilaments Ca ++ CONTRACTILITY DIGOXIN PHARMACOKINETIC PROPERTIES Oral absorption (%) Protein binding (%) Volume of distribution (l/kg) Half life Elimination Onset (min) i.v. oral Maximal effect (h) i.v. oral Duration Therapeutic level (ng/ml) (3-9) 36 (26-46) h Renal days 0.5-2 DIGOXIN DIGITALIZATION STRATEGIES Loading dose (mg) Maintenance Dose i.v oral h oral 2-5 d (mg) / 4 h / 6 h 0.25 / 6-12 h / d ILD: / d ILD = average INITIAL dose required for digoxin loading DIGITALIZATION SCHEDULE + Oral. 24 h Digoxin Digitoxin Ouabain 0 h: 0.5 mg 8 h: 0.25 mg 16 h: 0.25 mg 24 h: 0.25 mg Thereafter, daily maintenance dose ++ Oral. 48 h 0.25 mg q 8 h x 6 Oral, gradual IV. 24 h Daily maintenance dose, oral Thereafter, daily maintenance dose mg/day (digitalization achieved in 5-7 days) ++ 0 h: 0.5 mg 6 h: 0.25 mg 12 h: mg 18 h: mg Thereafter, daily maintenance dose ++ 0 h: 0.6 mg 8 h: 0.3 mg 16 h: 0.2 mg 24 h: 0.1 mg Thereafter, daily maintenance dose 0.2 mg q 8 h x 6 Thereafter, daily maintenance dose 0.1 mg/day (digitalization achieved in days) 0 h: 0.6 mg 8 h: 0.3 mg 16 h: 0.2 mg 24 h: 0.1 mg Thereafter, daily maintenance dose mg/day 0.1 mg 5 times/wk to 1.5 mg/day 0 h: 0.3 mg 4 h: 0.2 mg 8 h: 0.1 mg 12 h: 0.1 mg ++ + Doses are designed to produce effective but prudent plasma and tissue concentrations (see text for details). ++ Abnormal renal function prolongs plasma half-life, necessitating reduction in suggested dosage.digoxindigitoxinouabainpreferred route*oral. IV DIGOXIN HEMODYNAMIC EFFECTS Cardiac output LV ejection fraction LVEDP Exercise tolerance Natriuresis Neurohormonal activation OVERALL MORTALITY % Placebo n=3403 p = DIGOXIN n= Months DIG N Engl J Med 1997;336:525 48 DIGOXIN LONG TERM EFFECTS Survival similar to placebo Fewer hospital admissions More serious arrhythmias More myocardial infarctions DIGOXIN CLINICAL USES AF with rapid ventricular response CHF refractory to other drugs Other indications? Can be combined with other drugs DIGOXIN CONTRAINDICATIONS ABSOLUTE: - Digoxin toxicity RELATIVE - Advanced A-V block without pacemaker - Bradycardia or sick sinus without PM - PVC s and TV - Marked hypokalemia - W-P-W with atrial fibrillation DIGOXIN TOXICITY CARDIAC MANIFESTATIONS ARRHYTHMIAS : - Ventricular (PVCs, TV, VF) - Supraventricular (PACs, SVT) BLOCKS: - S-A and A-V blocks CHF EXACERBATION TREATMENT OF DIGITALIS INTOXICATION Discontinue the drug ECG monitoring If serum K is low, 80 meq of potassium chloride IV should be given in 1 L 5% D/W at a rate of 6 ml/min (0.5
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