Tài liệu Heart failure

Pharmacologic Therapy

Glucoside (Digoxin).

- Increase myocardial contractility (Inhibition of Na, KATPase -> Altered balance of Na/Ca exchange -> Enhanced Ca storage/release). Enhanced vagal tone (reduce heart rate). Digoxin may attenuate the neuro-hormonal activation associated with HF.

- The serum haft-life of digoxin is 36 h; the usual daily dose is 0.125-0.375mg

- Therapeutic dose: 0,5-0,8-2,0 ng/ml serum. The toxic – therapeutic ration is narrow

- Drug interactions which decrease digoxin release: Quinidin, Verapamil, Spironolacton, Amiodarone.

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Biventricular heart failure • Constant dyspnea, the excess fluid accumulation in the whole body. • Jugular venous distension. • Increased venous pressure. • Hepatomegaly. • Pericardial effusion, pleural effusion, ascites. • Decreased systolic blood pressure, increased diastolic blood pressure. • Chest X-ray: cardiomegaly. • ECG: biventricular hypertrophy. X-Ray Image Right-sided heart failure Left-sided heart failure Electrocardiography RIGHT-SIDED HEART FAILURE ECG: Right heart axis, right atrial hypertrophy, right ventricular hypertrophy LEFT-SIDED HEART FAILURE ECG: Left heart axis, left atrial hypertrophy, left ventricular hypertrophy Echocardiography RIGHT-SIDED HEART FAILURE LEFT-SIDED HEART FAILURE Heart failure classification Có Nguy cơ cao ST song không có bệnh tim thực tổn hoặc không có biểu hiện suy tim A Có bệnh tim thực tổn nhưng không có biểu hiện suy tim B Bệnh tim thực tổn đã hoặc đang có biểu hiện suy tim C Suy tim trơ, đòi hỏi phải các biện pháp điều trị đặc biệt D Patients have no limitation of physical activity I Patients have slight limitation of physical activity Có triệu chứng khi gắng sức nhẹ II III Có triệu chứng ngay cả lúc nghỉ IV The ACC/AHA staging system NYHA classification for heart failure Patients are at high risk for heart failure but have no structural heart disease or symptoms of heart failure Patients have structural heart disease but have no symptoms of heart failure Patients have structural heart disease and have symptoms of heart failure Patients have refractory heart failure requiring specialized interventions Patients have no limitation of physical activity Patients have slight limitation of physical activity Patients have marked limitation of physical activity Patients have symptoms even at rest and are unable to carry on any physical activity without discomfort TREATMENT Schematic therapy of progressive chronic heart failure The role of drugs in the treatment of heart failure • Reduce Mortality: – ACE inhibitors or ARBs – Beta blockers – Spironolactone; Eplerenone • Improve symptoms: – Diuretics – Digoxin (low dose) – Nitrates • May be harmful: use cautiously after due consideration: – Inotropes and inotropic dilators – Antiarrhythmics, expect Beta blockers and amiodarone – Calcium channel blockers – Digoxin (high dose) Nonpharmacologic Therapy • Rest: reduce cardiac load. Severe heart failure: bed rest, down in Fowler's position, massage legs to prevent venous thrombosis. • Sodium restriction: • Salts cause increased osmotic pressure, increased circulatory volume and increase the burden on the heart • Normal: 6-18g NaCl/day=2,4-7,2g (100-300 mmol) Natri/day. • Sodium restriction : <3g NaCl/day  <1,2g (50  mmol) Natri/day. • Completed sodium restriction : <1,2g NaCl/day  0,48g (20 mmol) Natri/day. Nonpharmacologic Therapy – Fluid and free water restriction reduce circulatory volume and decrease the burden on the heart: 500-100ml/day – Administration of supplemental oxygen may relieve dyspnea, improve oxygen delivery, reduce the work of breathing and limit pulmonary vasoconstriction – Lifestyle/Risk modification • Reducing Alcohol intake, cessation of smoking, cafe... • Weight loss in obesity patient • Avoid stress • Stop inotropic: Verapamil, Disopyramide, Flecainide. • Identify precipitating and exacarbating factors and any concomitant factors relevant to HF: sepsis, Arrhythmias Pharmacologic Therapy Glucoside (Digoxin). • Increase myocardial contractility (Inhibition of Na, K ATPase  Altered balance of Na/Ca exchange  Enhanced Ca storage/release). Enhanced vagal tone (reduce heart rate). Digoxin may attenuate the neuro-hormonal activation associated with HF. • The serum haft-life of digoxin is 36 h; the usual daily dose is 0.125-0.375mg • Therapeutic dose: 0,5-0,8-2,0 ng/ml serum. The toxic – therapeutic ration is narrow • Drug interactions which decrease digoxin release: Quinidin, Verapamil, Spironolacton, Amiodarone... Pharmacologic Therapy Glucoside (Digoxin) • Indication: – Low-output cardiac failure, especially rapid atrial fibrillation – No indication in High output cardiac failure: anemia, thyrotoxicosis, fistula arteriovenous, Chronic cor-pulmonale. • Contraindication: – Bradycardiac, Block A-V II, III, ventricular fibrillation, ventricular tachycardiac, WPW symdrome • Caution: – Acute myocardial infarction: increase oxygen demand. – Electrolyte abnormalities:  K+ vµ / Mg++ Pharmacologic Therapy Glucoside (Digoxin) • Digoxin toxicity – Risk factors – Clinical signs and symptoms • Loss of appetide, nausea/vomiting, diarrhea. • Visual disturbances, confusion, dizziness, nightmares. • Increased automaticity and depressed conduction • Treatment: – Stop the drug, control Electrolyte abnormalitie, kalemia. – 20-50ml KCl 10%, oral or IV 13-15 mmol/h. – Atropin 0,5-1 mg IV: sinus bradycardiac, bloc AV. – Lidocain IV1-4mg/phót: ventricular arrhythmia. – Antidotal therapy with antibody (Fab) fragments. dig study (Digitalis Investigators Group) Placebo Digoxin n 4303 3397 NYHA II (%) 55 53 NYHA III 31 31 NYHA IV 2 2 CAD 70(%) 71(%) ACE (%) 95 94 Death after 3,5 years 30 (%) 30 (%) Severe heart failure 34,7 26,8 ** N Eng J Med 1997, 336: 525-33. drugs in treatment hf Diuretics • Mechanism: Removal of excess extracellular fluid with diuretics to treat peripheral and/or pulmonary edema is one of the mainstays of volume management. Diuretics reduce magnesium absorption and hypomagnesaemia may occur with prolonged use • Classification: – Thiazides • Indication with normal renal function. • Inhibit sodium transport in the distal tubule. • Hydrochlorothiazide (Thiazide): The potential adverse metabolic effects of thiazide therapy include hypokalemia, hyponatremia, hyperuricemia, elevations in the plasma glucose and cholesterol concentrations, and magnesium depletion • Indapamide little effect on lipid drugs in treatment hf • Loop diuretics: Furosemide, Bumetanide. – Act in the thick ascending limb of the loop of Henle. – Inhibit sodium and chloride reabsorption. Side effect: Electrolyte imbalances (particularly hypokalemia and hypomagnesemia) – Use in renal impairment. Direct intravenous vasodilators • Potassium-sparing diuretics: Spironolacton, Triamterene, Amiloride. – Act in the principal cells in the cortical collecting tubule. – Have relatively weak natriuretic activity – ThËn träng khi dïng kÌm IEC, gi¶m viªm kh«ng steroide ( K+) – Increase BUN, Nephrolithiasis (Triamterene); gynecomastia (Spironolactone). Diuretics aldosterone antagonist has obvious benefits in the treatment of heart failure because it does not merely diuretic • Often used in combination with other diuretics (Loop, thiazides) – Increase the diuretic effect – Reduce drug effect – Reduce the side effects • Improve turns vicious circle in chronic congestive heart failure: • Reduce the harmful effects of aldosterone Aldosterone for heart failure treatment Aldosterone  Arterial compliance  Baroreceptor function  Norepinephrine uptake  Endothelial function  PAI-1  K+  Mg++  Fibrosis  Norepinephrine Uptake  Heart rate variability  LV mass & fibrosis  Na+  Edema  Remodeling  Arrhythmia  Ischemic Events Progression of HF Sudden cardiac death Pitt B, Zannad F, Remme WJ, et al. N Engl J Med. 1999;341:709-717. *Protocol used a starting dose of 25 mg/day whereas the mean daily dose was 25 mg. RALES: Study design Suy tim NYHA III, IV LVEF ≤ 35% ACEI + Loop diuretics ± digoxin Spironolactone 25 – 50 mg/day* (n = 822) Placebo (n = 841) Primary Endpoint • Total mortality Secondary Endpoints • Total mortality • Cardiac hospitalization • Cardiac mortality or cardiac hospitalization 3 n¨m RALES: All - cause mortality 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0.55 0.50 0.45 0 3 6 9 12 15 18 21 24 27 30 33 36 Reduce the risk of death 30% 95% Cl (18%-40%) P<0.001 Spironolactone + Standard therapy Standard therapy (ACE + Loop diuretic + digoxin) Probability of survival Months Pitt B, Zannad F, Remme WJ, et al. N Engl J Med, 1999;341:709-717. drugs in treatment hf Vasodilators. • Compensatory mechanism in heart failure  artery and veins spasm   preload and afterload. – Pulmonary vasoconstriction because of Hypoxic blood, increasing blood flow through the lungs for a long time (shunt left - right),  left atrial pressure (mitral stenosis, heart failure). – Side effects: lowering BP. Caution in aortic stenosis, Hypertrophic cardiomyopathy, Restrictive cardiomyopathy. drugs in treatment hf Vasodilators. • ACEs –  Angiotensine II (vasoconstriction),  Bradikinine (vasodilation) – Vasoconstriction   preload and afterload. – Contraindicationi: Renal artery stenosis (bilateral). – Side effect: hypotension, cough, hyperkalemia. – ACE inhibitors should be used with caution in hypotension patients treated with Potassium-sparing diuretics – Benazepril (Cibacene 10 mg), Enalapril (Renitec, Ednyt), Captopril (Capoten, Lopril). • Angiotensin II receptor antagonists ACEs the role of ACE in the treatment of heart failure CONSENSUS I (1) SOLVD (2) Placebo Enalapril Placebo Enalapril n 126 127 1284 1285 NYHA II (%) 0 0 57 57 NYHA III 0 0 31 30 NYHA IV 100 100 2 2 CAD(%) 74 72 72 79 Death (%) 44 26 39.7 35.2 (1) N Eng J Med 1987, 316:1429-35. (2) N Eng J Med 1991, 325:293-302. Charm trial candesartan or placebo in clinical HF patients Primary end-point: cardiovascular mortality and rehospitalization due to HF charm trial • intolerant : reduced CV mortality and rehospitalization 23% (p=0,0004) by candesartan. • Candesartan added standard treatment (ACEI and betablocker) reduced CV mortality and rehospitalization 15% (p=0,011). Nitrates • Nhóm Nitrates: – Vasodilator of the venous system and reduction of preload; while reducing myocardial ischemia, decreased cardiac filling pressure and directly vasodilator of coronary arteries. Nitrates are mainly used in patients with heart failure in CAD patients, or can not use ACE/ARB – Side effects: headache, hypotension, rash, etc. Do not use along with sinadefil. – Administration: oral, topical patch, transdermal, Translingual spray or IV. Isosorbide dinitrate (1) A-HeFT (African American Heart Failure Trial) • 1050 African-American patients with NYHA III-IV and EF <35%. • Random. isosorbide dinitrate 20 mg + hydralazine 37,5 mg hoÆc gi¶ dîc. • General Mortality :6,2 % so víi 10,2 % (p=0,02) • Rehospitalization due to HF: 16,4% so víi 24,4% (p= 0,001). Isosorbide dinitrate (2) Thö nghiÖm A-HeFT (African American Heart Failure Trial) Beta blockers • Indication in patients with HF due to systolic dysfunction of left ventricle, event with Diabetes Type 2 or Peripheral vascular disease. – LVEF≤ 40% (IA). – Heart Failure with Preserved Systolic Function due to old MI (IA), Hypertension (IB), atrial fibrillation need to control of ventricular rate (IB). – Old patients with HF due to systolic dysfunction of left ventricle (IB). • Contraindication: asthma. Caution: (1) Recurrent Hypoglycemia in Diabetes; (2) Asthma; (3) Limbs ischemic rest pain , (4) Bradycardiac (<55 b/m) or (5) Hypotension (Systolic BP < 80 mmHg). Activation of the Sympathetic Nervous System in Heart Failure Increased central sympathetic tone Increased cardiac sympathetic activation Increased renal and blood vessels sympathetic activation 1 receptors 2 receptors 1 receptors Hypertrophy and dead myocardial cell Dilated cardiomyopathy, cardiac ischemia, arrhythmias Vasoconstriction Increased reabsorption of water Beta blockers • indicated in the treatment of severe chronic heart failure when other routine full of drugs. The beta-blocker used to treat heart failure include: carvedilol (Dilatrend); Metoprolol (Betaloc) and Bisoprolol (Concor). • Mechanism is to prevent the effects of excessive stimulation of the sympathetic nervous system in chronic congestive heart failure, improve prognosis, but the actual benefits only appear slow and long-termi. • Start with a low dose (prior to discharge), monitored, increasing the dose very slowly (no earlier than two weeks / time) to achieve therapeutic doses within 8-12 weeks, and then maintained the highest dose which can be tolerated. • If it is difficult to increase the dose, we will increased the dose slowly, reduce the target dose.If side effects develop or worsening heart failure, add / adjust the dose of diuretics or inotropic US-Carvedilol Study CIBIS-II Study Drugs increasing cardiac contractility • Inotropes agents: indicated in acute/severve/decompensated heart failure. • Side effects: Increased cardiac ischemic, heart rate, peripheral vasocontriction. • Dopamine: advocated in heart failure with hypotension but increasing heart rate. – 1-3μg/kg/min: mesenteric and renal vasodilation, increased blood flow to the kidneys and urine output. – 2-5μg/kg/min: increase the contractility of the heart muscle (beta-receptor stimulation) – >5-10 μg/mg/min: peripheral vasoconstriction, increased vascular resistance adversely affecting cardiac output (alpha receptor stimulation). • Dobutamine: – Selective β1 stimulation (weakly on β2 and α): improve haemodynamic, directly myocardiac contracity, dilate arteries for reflectance -> reduce afterload and increase cardiac output, create little change in heart rate and BP. – The initial dose: 1-2 g / kg / min IV, adjust to be effective. – Using 2-4 day course by course to reduce the symptoms of heart failure. – Not recommended for the treatment in diastolic dysfunctional heart failure patients (eg: hypertrophic cardiomyopathy) or heart failure with increased cardiac out. Drugs increasing cardiac contractility – The phosphodiesterase inhibitors: increase the contractility of the heart muscle and vasodilation by increasing AMPc. – Two drugs used in clinical are Amrinone and Milrinone, indicated for acute or short-term treatment in severe heart failure patients. • Amrinone has effects as Dobutamin but makes stronger vasodilation, hypotension if used with other vasodilators. • Dose: • Amrinone IV 750 μg/kg/2-3 minutes then 2.5 to 10.0 micrograms/kg/min. • Milrinone: Initial dose 50 μg/kg/10 mins IV then 0.375 - 0.75 microg/kg /min – Side effects: May cause atrial fibrillati

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