上海交通大学：《药理学 Pharmacology》课程教学资源（讲义课件）Drugs for Congestive Heart Failure

上游充通大 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 Drugs for Congestive Heart Failure ANMAN CHANCHAL HAO TONG UNIVEDSYNN

Drugs for Congestive Heart Failure Drugs for Congestive Heart Failure

上游充通大学 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 What Are The Symptoms of Heart Failure? Think FACES -Fatigue -Activities limited Chest congestion -Edema or ankle swelling -Shortness of breath

Think FACES... •Fatigue •Activities limited •Chest congestion •Edema or ankle swelling •Shortness of breath What Are The Symptoms What Are The Symptoms of Heart Failure? of Heart Failure?

上游充通大 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 Renal perfusion Activation of renin-angiotensin- adosterone system ↓Cardiac ↓Firing of arterial Activation of output baroreceptors Vasoconstriction sympathetic (Carotid sinus, Salt and water retention nervous system Aortic arch) Endothelial ↑Endothelin Short-term dysfunction ↓Nitric oxide Maintenance of bood pressure Longer-term Worsening of tissue perfusion Worsening of fluid retention Progressive cardiomyocyte death and fibrosis Death

上游充通大 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 Drugs used in CHF Cardiac glycosides:digoxin,cedilanide RAS inhibitors: Diuretics:hydrochlorothiazide,furosemide Beta-blockers Vasodilators O TONG UNI Others

Drugs used in CHF Drugs used in CHF Cardiac glycosides: digoxin, cedilanide RAS inhibitors: Diuretics: hydrochlorothiazide, furosemide Beta-blockers Vasodilators Others

上浒充通大学 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 Section 1:RAAS inhibitors ACE Inhibitors in Heart Failure angiotensinogen blood renin normal kidney hypertension pressure angiotensin I plasma myocardial volume angiotensin converting dysfunction, moderate enzyme(ACE) myocardial angiotensin ll dysfunction, aldosterone severe OUTFLOW RESISTANCE adrenal gland blood vasoconstriction pressure

Section 1: RAAS inhibitors Section 1: RAAS inhibitors ACE Inhibitors in Heart Failure ACE Inhibitors in Heart Failure

上游充通大淫 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 Mechanism of Action of ACEI Afterload reduction Preload reduction Reduction of facilitation of sympathetic nervous system o Reduction of cardiac hypertrophy Drugs of choice in heart failure(with diuretics) Current investigational use:Acute myocardial infarction

Mechanism of Action Mechanism of Action of ACEI of ACEI  Afterload reduction  Preload reduction  Reduction of facilitation of sympathetic nervous system  Reduction of cardiac hypertrophy  Drugs of choice in heart failure (with diuretics)  Current investigational use: Acute myocardial infarction

上游充通大淫 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 Aldosterone antagonist Spironolactone Aldosterone antagonist,K-sparing diuretic Prevention of aldosterone effects on: Kidney -Heart? ● Aldosterone inappropriately elevated in CHF Mobilizes edema fluid in heart failure ● Prevention of hypokalemia induced by loop diuretics(protection against digitalis toxicity?) Prolongs life in CHF patients

Aldosterone antagonist Aldosterone antagonist  Aldosterone antagonist, K-sparing diuretic  Prevention of aldosterone effects on: – Kidney – Heart?  Aldosterone inappropriately elevated in CHF  Mobilizes edema fluid in heart failure  Prevention of hypokalemia induced by loop diuretics (protection against digitalis toxicity?)  Prolongs life in CHF patients Spironolactone Spironolactone

上游充通大 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 Section 2:Diuretics Mechanism of Action in Heart Failure Preload reduction:reduction of excess plasma volume and edema fluid Afterload reduction:lowered blood pressure IAO TONG

Section 2: Diuretics Section 2: Diuretics  Preload reduction: reduction of excess plasma volume and edema fluid  Afterload reduction: lowered blood pressure Mechanism of Action in Heart Failure Mechanism of Action in Heart Failure hydrochlorothiazide

上游充通大 SHANGHAI JIAO TONG UNIVERSITY 1896 1920 1987 2006 Section 3 B-Adrenoceptor blockers Mechanism of action: 1.Antagonize the sympathetic nerve activity ①↓damage on cardiac muscle from CA ②↓renin,↓RAS,↓cardiac load ③↑B-R,come back the transmit ability ④↑sensitivity ofβ-R to catecholamines 2.Antioxidation blocking a-R carvedilol NC UN 3.Antiarrhythmia and improve myocardial ischemia

Section 3 Section 3 β-Adrenoceptor blockers Adrenoceptor blockers Mechanism of action: 1. Antagonize the sympathetic nerve activity ①↓damage on cardiac muscle from CA ②↓renin , ↓RAS，↓ cardiac load ③↑β-R，come back the transmit ability ④↑sensitivity of β-R to catecholamines 2. Antioxidation , blocking α1 -R — carvedilol 3. Antiarrhythmia and improve myocardial ischemia

arvedilol or Metoprolol uropou 2006 Trial (COMET) 1511 patients receive carvedilol (25 mg BID); 1518 receive metoprolol (50 mg BID) NYHA II-IV;EF<.35;ACE-I+ diuretic (if tolerated) Mean 58 months in trial Carvedilol reduced all- cause (HR.83)and CV(.80) mortality relative to meto Poole-Wilson.Lancet 2003:362:7-13

Carvedilol or Metoprolol European Carvedilol or Metoprolol European Trial (COMET) Trial (COMET)  1511 patients receive carvedilol (25 mg BID); 1518 receive metoprolol (50 mg BID)  NYHA II-IV; EF<.35; ACE-I + diuretic (if tolerated)  Mean 58 months in trial  Carvedilol reduced all￾cause (HR .83) and CV (.80) mortality relative to meto 0 10 20 30 40 All CV Car Met % Poole-Wilson. Lancet 2003;362:7-13 Deaths Deaths