Drugs Used In the Treatment ofDrugs Used In the Treatment ofCongestive Heart Failure(Cont)Congestive Heart Failure(Cont)

Garrett J. Gross, Ph.D.Garrett J. Gross, Ph.D.

Drugs Used In the Treatment ofDrugs Used In the Treatment ofCongestive Heart Failure(Cont)Congestive Heart Failure(Cont)

Garrett J. Gross, Ph.D.Garrett J. Gross, Ph.D.

BLOCKERSBLOCKERS

ATAT1 1 BLOCKERSBLOCKERS

DETERMINANTS OF

VENTRICULAR FUNCTION DETERMINANTS OF

VENTRICULAR FUNCTION

STROKE VOLUMESTROKE VOLUME

PRELOADPRELOAD

CONTRACTILITYCONTRACTILITY

CARDIAC OUTPUTCARDIAC OUTPUT

HEART RATE

HEART RATE

- Synergistic LV contraction - LV wall integrity - Valvular competence

- Synergistic LV contraction - LV wall integrity - Valvular competence

AFTERLOADAFTERLOAD

Frank-Starling Law

DETERMINANTS OF

VENTRICULAR FUNCTION DETERMINANTS OF

VENTRICULAR FUNCTION

STROKE VOLUMESTROKE VOLUME

PRELOADPRELOAD

CONTRACTILITYCONTRACTILITY

CARDIAC OUTPUTCARDIAC OUTPUT

HEART RATE

HEART RATE

- Synergistic LV contraction - LV wall integrity - Valvular competence

- Synergistic LV contraction - LV wall integrity - Valvular competence

AFTERLOADAFTERLOAD

DETERMINANTS OF

VENTRICULAR FUNCTION DETERMINANTS OF

VENTRICULAR FUNCTION

STROKE VOLUMESTROKE VOLUME

PRELOADPRELOAD

CONTRACTILITYCONTRACTILITY

CARDIAC OUTPUTCARDIAC OUTPUT

HEART RATE

HEART RATE

- Synergistic LV contraction - LV wall integrity - Valvular competence

- Synergistic LV contraction - LV wall integrity - Valvular competence

AFTERLOADAFTERLOAD

Venous Vasodilatation

Venous Vasodilatation

MIXED -adrenergic Blockers

ACEIAngiotensin II inhibitors

K+ channel activatorsNitroprusside

MIXED -adrenergic Blockers

ACEIAngiotensin II inhibitors

K+ channel activatorsNitroprusside

VENOUSNitrates

Molsidomine

VENOUSNitrates

Molsidomine

ARTERIALMinoxidil

Hydralazin

ARTERIALMinoxidil

Hydralazin

VASODILATORSCLASSIFICATIONVASODILATORSCLASSIFICATION

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 congestionVentricular sizeVent. Wall stressMVO2

Pulmonary congestionVentricular sizeVent. Wall stressMVO2

NITRATESHEMODYNAMIC EFFECTS

NITRATESHEMODYNAMIC EFFECTS

• Cardiac output

• Blood pressure

• Cardiac output

• Blood pressure

PlaceboPlacebo

EnalaprilEnalapril

1212111110109988776655

PROBABILITYOFDEATH

PROBABILITYOFDEATH

MONTHSMONTHS

0.10.1

0.80.8

00

0.20.2

0.30.3

0.70.7

0.40.4

0.50.5

0.60.6p< 0.001p< 0.001

p< 0.002p< 0.002

CONSENSUSN Engl J Med 1987;316:1429CONSENSUSN Engl J Med 1987;316:1429

ACEI SURVIVALACEI SURVIVAL

4433221100

VASOCONSTRICTIONVASOCONSTRICTION VASODILATATION VASODILATATION

KininogenKininogen

KallikreinKallikrein

Inactive FragmentsInactive Fragments

AngiotensinogenAngiotensinogen

Angiotensin IAngiotensin I

RENINRENIN

Kininase IIKininase IIInhibitorInhibitor

ALDOSTERONEALDOSTERONE

SYMPATHETICSYMPATHETICVASOPRESSINVASOPRESSIN

PROSTAGLANDINSPROSTAGLANDINS

tPAtPA

ANGIOTENSIN IIANGIOTENSIN II

BRADYKININBRADYKININ

ACEIMECHANISM OF ACTION

ACEIMECHANISM OF ACTION

A.C.E.A.C.E.

ACEI

HEMODYNAMIC EFFECTSACEI

HEMODYNAMIC EFFECTS

Arteriovenous Vasodilatation- PCWP and LVEDP- SVR and BP- CO and exercise tolerance

No change in HR / contractilityMVO2

Renal, coronary and cerebral flowDiuresis and natriuresis

Arteriovenous Vasodilatation- PCWP and LVEDP- SVR and BP- CO and exercise tolerance

No change in HR / contractilityMVO2

Renal, coronary and cerebral flowDiuresis and natriuresis

ACEI

ADVANTAGESACEI

ADVANTAGESInhibit 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 activationor 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 activationor reflex tachycardia

Tolerance to its effects does not develop

ACEI

UNDESIRABLE EFFECTSACEI

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 ACTIONANGIOTENSIN II INHIBITORS

MECHANISM OF ACTION

RENINRENIN

AngiotensinogenAngiotensinogen Angiotensin I

ANGIOTENSIN II

Angiotensin I

ANGIOTENSIN II

ACEACEOther pathsOther paths

VasoconstrictionVasoconstriction Proliferative Action

Proliferative Action

VasodilatationVasodilatation Antiproliferative Action

Antiproliferative Action

AT1 AT1 AT2AT2

AT1 RECEPTOR BLOCKERS

AT1 RECEPTOR BLOCKERS

RECEPTORSRECEPTORS

AT1 RECEPTOR BLOCKERSDRUGS

AT1 RECEPTOR BLOCKERSDRUGS

Losartan

Valsartan

Irbersartan

Candesartan

Losartan

Valsartan

Irbersartan

Candesartan

Competitive and selective

blocking of AT1 receptors

Competitive and selective

blocking of AT1 receptors

0.60.6

PROBABILITYOFDEATH

PROBABILITYOFDEATH

00

Placebo (273)Prazosin (183)Hz + ISDN (186)

Placebo (273)Prazosin (183)Hz + ISDN (186)

MONTHSMONTHS

0.70.7

0.50.5

0.30.3

0.40.4

0.20.2

0.10.1

VHefT-1N Engl J Med 1986;314:1547VHefT-1N Engl J Med 1986;314:1547

NITRATESSURVIVALNITRATESSURVIVAL

00 66 1212 1818 2424 3030 3636 4242

CARDIAC GLYCOSIDES

SYMPATHOMIMETICSCatecholaminesß-adrenergic agonists

PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone

Others

CARDIAC GLYCOSIDES

SYMPATHOMIMETICSCatecholaminesß-adrenergic agonists

PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone

Others

MilrinonePiroximoneMilrinonePiroximone

POSITIVE INOTROPESPOSITIVE INOTROPES

Inamrine&Mirinone

3. Nesiritide: natriuretic peptide

a. New treatment for acute congestive heart failure and dyspnea at rest

ß-ADRENERGIC BLOCKERS INDICATIONS and UTILIZATIONß-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

ß-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS

Density of ß1 receptors

Inhibit cardiotoxicity of catecholamines

Neurohormonalactivation

HR

Antihypertensive and antianginal

Antiarrhythmic

Antioxidant

Antiproliferative

Density of ß1 receptors

Inhibit cardiotoxicity of catecholamines

Neurohormonalactivation

HR

Antihypertensive and antianginal

Antiarrhythmic

Antioxidant

Antiproliferative

ALDOSTERONEALDOSTERONE

Retention Na+

Retention H2O

Excretion K+

Excretion Mg2+

Retention Na+

Retention H2O

Excretion K+

Excretion Mg2+

Collagen

deposition

Fibrosis - myocardium

- vessels

SpironolactoneSpironolactone

Edema Edema

Arrhythmias Arrhythmias

Competitive antagonist of thealdosterone receptor(myocardium, arterial walls, kidney)

Competitive antagonist of thealdosterone receptor(myocardium, arterial walls, kidney)

ALDOSTERONE INHIBITORSALDOSTERONE INHIBITORS

BLOCKERSBLOCKERS

ATAT1 1 BLOCKERSBLOCKERS