Pharmacotherapy of heart failure

台大藥理所 蘇銘嘉老師

IntroductionHeart failure

Etiology

1. Hypertension2. Valvular disease3. Congenital abnormalities4. Ischemic cardiomyopathy

Pathophysiological changes

1. Activation of RAASA. Exercise intoleranceB. Hypertrophy & Cardiac remodeling

2. Congestion of blood in venous systemA. Pulmonary edemaB. Reduced tissue perfusionC. Increase in end diastolic pressure

IntroductionHeart failure

Goals

1. Reduce symptom of dyspnea & fatigue2. Arrest ventricular hypertrophy & remodeling3. Increase survival

Strategy

1. Reduce weight & Na+ restriction2. Drugs for reducing preload3. Drugs for reducing afterload4. Drugs preventing cellular hypertrophy

A. Neurohormonal antagonistsB. β-blockers

5. Inotropic agents

(Nitroprusside 、 Diuretics)(Vasodilator 、 Diuretics)

(ACEI & ARB)(Carvedilol 、 Bisoprolol 、 Metoprolol)

Inotropic agentsInotropic agents

Classification

1. Cardiac glycosides2. Sympathomimetics

A. DopamineB. DobutamineC. Other β-agonists

3. Phosphodiesterase inhibitorA. Amrinone (Type III PDE inhibitor)

4. Drugs increasing myofibrillar calcium sensitivityA. SulmazoleB. Pimobendan

Inotropic agentsInotropic agents

Cardiac glycosides

1. Mechanism of actionA. Inhibition of Na+-K+-ATPase

2. Pharmacological actionA. Increase cardiac outputB. Reduce Na+ reabsorptionC. Sensitize baroreceptor reflex

3. Hemodynamic effectsA. Cause immediate decrease of cardiac filling pressureB. Increase of cardiac output & LVEFC. Reduce plasma renin & noradrenaline

Inotropic agentsInotropic agents

Cardiac glycosides

1. Clinical implicationsA. Low LVEF (Systolic dysfunction)B. PSVT 、 AF 、 Af

2. Adverse effectsA. GI discomfort

1) Nausea & VomitingB. Neurologic complaints

1) Visual disturbance (Green or Yellow vision)2) Confusion 、 Disorientation

C. Others1) VT 、 Vf2) Gynecomastia

Inotropic agentsInotropic agents

Cardiac glycosides

1. Enhance toxicity of cardiac glycosidesA. Hemodialysis (Increase K+ & Mg2+ loss)B. Increasing extracellular Ca2+ C. HypomagnesemiaD. Thiazide & Furosemide

2. Reduce toxicity of cardiac glycosidesA. Spironolactone

Inotropic agentsInotropic agents

Cardiac glycosides (Antidote)

1. K+ salt2. Cholestyramine3. Lidocaine 、 Dilantin4. Electric shock5. Fab fragment of digoxin antibody

Inotropic agentsInotropic agents

Cardiac glycosides (Effects of digitalis on cardiac electrical functions)

1. Atrial muscleA. ↓ ERPB. ↑ Conduction velocity & automaticity

2. AV nodeA. ↑ ERPB. ↓ Conduction velocityC. ↑ Automaticity & PR interval

3. Purkinje fiber & VentriclesA. ↓ ERP (Less effect on conduction)B. ↑ AutomaticityC. ↓ QT intervalD. T wave inversionE. ST segment depression

Chronic heart failure

• Rational steps– Reduce workload & Sodium restriction

• Control body weight• Control hypertension• Reduce activity

– Pharmacotherapy• Give diuretic• Give ACEI or β-blocker• Give β-blockers or ACEI + Digitalis• Give vasodilators

– Hydralazine (Arteriole dilator)– Nitrates (Vein & Venules dilator)– ACEI & ARB (Arteriole & Vein dilator)

Acute heart failure

• Therapeutic strategy – Hypovolemia

• Give fluid to increase LV filling pressure up to 15 mmHg– Pulmonary congestion

• LV filling pressure > 20 mmHg• Cardiac index > 2.5 L/min/m2

• Diuretics– Peripheral vasodilation

• Vasoactive drugs if BP is very low

Acute heart failure

• Therapeutic strategy – Power failure

• SBP < 100 mmHg• Cardiac index < 2.5 L/min/m2

• LV filling pressure > 20 mmHg• Vasodilator• Inotropic agents

– Severe shock• SBP < 90 mmHg• Cardiac index < 2 L/min/m2

• LV filling pressure > 20 mmHg• Dopamine followed by Na nitroprusside• Circulatory assist

Acute heart failure

• Therapeutic strategy – RV infarct

• Volume infusion• Inotropic agent• Avoid diuretics

– Mitral regurgitation & Ventricular septal defect• Vasodilator• Inotropic drugs• Circulatory assist• Surgery