Drugs Used In the Treatment of Congestive Heart Failure(Cont) Garrett J. Gross, Ph.D. Drugs Used In the Treatment of Congestive Heart Failure(Cont) Garrett J. Gross, Ph.D.

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DETERMINANTS OF VENTRICULAR FUNCTION DETERMINANTS OF VENTRICULAR FUNCTION STROKE VOLUME PRELOAD CONTRACTILITY CARDIAC OUTPUT HEART RATE - Synergistic LV contraction - LV wall integrity - Valvular competence AFTERLOAD

Frank-Starling Law

DETERMINANTS OF VENTRICULAR FUNCTION DETERMINANTS OF VENTRICULAR FUNCTION STROKE VOLUME PRELOAD CONTRACTILITY CARDIAC OUTPUT HEART RATE - Synergistic LV contraction - LV wall integrity - Valvular competence AFTERLOAD

DETERMINANTS OF VENTRICULAR FUNCTION DETERMINANTS OF VENTRICULAR FUNCTION STROKE VOLUME PRELOAD CONTRACTILITY CARDIAC OUTPUT HEART RATE - Synergistic LV contraction - LV wall integrity - Valvular competence AFTERLOAD

Venous Vasodilatation Venous Vasodilatation MIXED  -adrenergic Blockers ACEI Angiotensin II inhibitors K + channel activators Nitroprusside MIXED  -adrenergic Blockers ACEI Angiotensin II inhibitors K + channel activators Nitroprusside VENOUS Nitrates Molsidomine VENOUS Nitrates Molsidomine ARTERIAL Minoxidil Hydralazin ARTERIAL Minoxidil Hydralazin VASODILATORS CLASSIFICATION VASODILATORS CLASSIFICATION Arterial Vasodilatation Arterial Vasodilatation

1- VENOUS VASODILATATION Preload 2- Coronary vasodilatation Myocardial perfusion 3- Arterial vasodilatation Afterload 4- Others 1- VENOUS VASODILATATION Preload 2- Coronary vasodilatation Myocardial perfusion 3- Arterial vasodilatation Afterload 4- Others Pulmonary congestion Ventricular size Vent. Wall stress MVO 2 NITRATES HEMODYNAMIC EFFECTS Cardiac output Blood pressure

Placebo Enalapril PROBABILITY OF DEATH MONTHS p< p< CONSENSUS N Engl J Med 1987;316:1429 CONSENSUS N Engl J Med 1987;316:1429 ACEI SURVIVAL

VASOCONSTRICTION VASODILATATION Kininogen Kallikrein Inactive Fragments Angiotensinogen Angiotensin I RENIN Kininase II Inhibitor ALDOSTERONE SYMPATHETIC VASOPRESSIN PROSTAGLANDINS tPA ANGIOTENSIN II BRADYKININ ACEI MECHANISM OF ACTION ACEI MECHANISM OF ACTION A.C.E.

ACEI HEMODYNAMIC EFFECTS ACEI HEMODYNAMIC EFFECTS Arteriovenous Vasodilatation - 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 Arteriovenous Vasodilatation - 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

ACEI ADVANTAGES Inhibit LV remodeling post-MI Modify the progression of chronic CHF - Survival - Hospitalizations - Improve the quality of life In contrast to others vasodilators, do not produce neurohormonal activation or reflex tachycardia Tolerance to its effects does not develop Inhibit LV remodeling post-MI Modify the progression of chronic CHF - Survival - Hospitalizations - Improve the quality of life In contrast to others vasodilators, do not produce neurohormonal activation or reflex tachycardia Tolerance to its effects does not develop

ACEI UNDESIRABLE EFFECTS Inherent in their mechanism of action - Hypotension - Hyperkalemia - Angioneurotic edema Due to their chemical structure - Cutaneous eruptions - Neutropenia, thrombocytopenia - Digestive upset 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. - Dry cough - Renal Insuff. - Dysgeusia - Proteinuria - Dysgeusia - Proteinuria

ANGIOTENSIN II INHIBITORS MECHANISM OF ACTION ANGIOTENSIN II INHIBITORS MECHANISM OF ACTION RENIN Angiotensinogen Angiotensin I ANGIOTENSIN II Angiotensin I ANGIOTENSIN II ACE Other paths Vasoconstriction Proliferative Action Proliferative Action Vasodilatation Antiproliferative Action Antiproliferative Action AT1 AT2 AT1 RECEPTOR BLOCKERS AT1 RECEPTOR BLOCKERS RECEPTORS

AT1 RECEPTOR BLOCKERS DRUGS AT1 RECEPTOR BLOCKERS DRUGS Losartan Valsartan Irbersartan Candesartan Losartan Valsartan Irbersartan Candesartan Competitive and selective blocking of AT1 receptors Competitive and selective blocking of AT1 receptors

0.6 PROBABILITY OF DEATH 0 0 Placebo (273) Prazosin (183) Hz + ISDN (186) MONTHS VHefT-1 N Engl J Med 1986;314:1547 VHefT-1 N Engl J Med 1986;314:1547 NITRATES SURVIVAL

CARDIAC GLYCOSIDES SYMPATHOMIMETICS Catecholamines ß-adrenergic agonists PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone Others CARDIAC GLYCOSIDES SYMPATHOMIMETICS Catecholamines ß-adrenergic agonists PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone Others Milrinone Piroximone Milrinone Piroximone POSITIVE INOTROPES

Inamrine&Mirinone

3. Nesiritide:  natriuretic peptide a. New treatment for acute congestive heart failure and dyspnea at rest

ß-ADRENERGIC BLOCKERS INDICATIONS and UTILIZATION Not clearly established Begin with very low doses Slow augmentation of dose Slow withdrawal ? Not clearly established Begin with very low doses Slow augmentation of dose Slow withdrawal ?

ß-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS  Density of ß 1 receptors Inhibit cardiotoxicity of catecholamines  Neurohormonal  activation  HR Antihypertensive and antianginal Antiarrhythmic Antioxidant Antiproliferative  Density of ß 1 receptors Inhibit cardiotoxicity of catecholamines  Neurohormonal  activation  HR Antihypertensive and antianginal Antiarrhythmic Antioxidant Antiproliferative

ALDOSTERONE Retention Na + Retention H 2 O Excretion K + Excretion Mg 2+ Retention Na + Retention H 2 O Excretion K + Excretion Mg 2+ Collagen deposition Fibrosis - myocardium - vessels Spironolactone Edema Arrhythmias Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) ALDOSTERONE INHIBITORS

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