drugs for hf

8/12/2019 Drugs for HF

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Drugs uses for

Heart Failure


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Main Symptom

Cardinal manifestatation :

Dyspnea

Fatique

Fluid retentionResult from cardiac low ejection fraction

pulmonary & systemic congestion


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Main causes

Coronary artery disease MCI

Hypertension

Valvular heart disease

Cardiomyopathy Cor pulmonale


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Pathogenesis and Sequelae of Heart Failure

Adapted from Cohn J. N Engl J Med.1996;335:490-498.

Coronary arterydisease

Hypertension

Cardiomyopathy

Valvulardisease

Left

ventricular

dysfunction

Non-cardiacfactors

Remodeling

Low

ejection

fraction

Arrhythmia

Death

Pump

failure

Symptoms:DyspneaFatigue

Edema

Chronicheart

failure

Neurohormonalstimulation

Endothelialdysfunction

Vasoconstriction

Renal sodiumretention


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Compensatory changes in heart failure

Activation of SNS

Activation of RAS

Increased heart rate

Release of ADH

Release of atrial natriuretic peptide

Chamber enlargement

Myocardial hypertrophy


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NYHA Classification of heart failure

Class I: No limitation of physical activity

Class II: Slight limitation of physical activity

Class III: Marked limitation of physical

activity

Class IV: Unable to carry out physical

activity without discomfort


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New classification of heart failure

Stage A: Asymptomatic with no heart

damage but have risk factors for heart failure

Stage B: Asymptomatic but have signs ofstructural heart damage

Stage C: Have symptoms and heart damage Stage D: Endstage disease

ACC/AHA guidelines, 2001


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Factors aggravating heart failure

Myocardial ischemia or infarct

Dietary sodium excess

Excess fluid intake

Medication noncompliance

Arrhythmias Intercurrent illness (eg infection)

Conditions associated with increased metabolicdemand (eg pregnancy, thyrotoxicosis, excessive

physical activity) Administration of drug with negative inotropic

properties or fluid retaining properties (e. NSAIDs,corticosteroids)


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Goals of treatment

To improve symptoms and quality of life

To decrease likelihood of disease

progression

To reduce the risk of death and need for

hospitalisation


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Approach to the Patient with Heart Failure

Assessment of LV function (echocardiogram,radionuclide ventriculogram)

EF < 40%

Assessment of

volume status

Signs and symptoms

of fluid retention

No signs and symptoms of

fluid retention

Diuretic

(titrate to euvolemic state)

ACE Inhibitor

-blockerDigoxin

M t f HF


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Management of HF


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The role of angiotensin II in the progression of heart failure

Coronary artery disease Cardiac overloadCardiomyopathy

Left ventricular dysfunction

Arterial blood pressure

Angiotensin II

Peripheral organ blood flow

Skeletal muscleblood flow

Exercise intolerance

Renalblood flow

Oedema

Card iac remodel l ing

Renin release

Aldosterone re lease

Vasoconstriction Na+ and water retention Inotropy and hypertrophy ofvascular and cardiac cells

Left ventricular

dilation & hypertrophy

Pump failure


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Actions of Angiotensin II

Site of Action Cellular Effect Consequence

Myocyte, IP3and Ca++increase Constriction

Cardiocyte Protein kinase C Expression of proto-Fibroblast stimulation oncogenes; cell growth

SympatheticNerve Endings Enhanced NE release Enhanced Vasoconstriction

Glomeruli Efferent arteriolar Promotes

constriction microalbuminuriaEnlarges glomerular pores Proteinuria

Juxtaglomerular Renin inhibition Relief of raisedApparatus intraglomerular pressure

Adrenal Cortex Synthesis of Aldosterone Increased sodium retention

and kaliuresis

Fibrinolytic Increase of plasminogen Impaired fibrinolysisSystem activator inhibitor-1


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ACE Inhibitors: physiologic benefits

Arteriovenous Vasodilatation

pulmonary arterial diastolic pressurepulmonary capillary wedge pressureleft ventricular end-diastolic pressuresystemic vascular resistancesystemic blood pressuremaximal oxygen uptake (MVO2)


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ACE Inhibitors: physiologic benefits

LV function and cardiac output renal, coronary, cerebral blood flow No change in heart rate or myocardial

contractility no neurohormonal activation

resultant diuresis and natriuresis


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Indication and Uses

Recommended for all stage of HF

Low dose should be initiallydoubled as tolerated to the targeted doses Reassess Blood pressure, renal function (serum creatinin),

electrolyte (serum potassium) within 1-2 weeks treatment

Contraindication :

History of angioedema An-uric renal failure

Stenosis a. renalis bilateral

Spesial precaution :

SBP 3mg/dL

Serum K+ >5.5 mEq/L


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Alternatives

Hydralazine + ISDN, AT-II inhibitor (= Angiotensin receptorblocker = ARB)

ARB :

Indication & Use same as ACE inhibitors except no incidencof cough and less of angioedema

Clinical evidence less than ACEI, but for long-term th/ in HFhemodynamic, neurohormonal and clinical effectconsistent with ACEI


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Conclusions to ACE Inhibitor Therapy

All patients with symptomatic heart failure and those in

functional class I with significantly reduced leftventricular function should be treated with an ACE

inhibitor, unless contraindicated or not tolerated

ACE inhibitors should be continued indefinitely

It is important to titrate to the dosage regimen used in

the clinical trials in the absence of symptoms or

adverse effects on end-organ perfusion

In very severe heart failure, hydralazine and nitrates

added to ACE inhibitor therapy can further improve

cardiac output


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Effects of SNS Activation in Heart Failure

Dysfunction/death of cardiac myocytes

Provokes myocardial ischemia

Provokes arrhythmias

Impairs cardiac performance

These effects are mediated via stimulation

of band a1receptorsAm J Hypertens 1998; 11: 23S-37S


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Eichhorn EJ, JCF.2000;6(suppl 1):40-46.

LVEF

Time (months)

Biologic

Effect

Pharmacologic Effect

-Blocker

Initiated

-Blocker Discontinued

0 1 3 6 8

-Blocker EffectsOn Ejection Fraction in Heart Failure

C dil l i H t F il


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Carvedilol in Heart Failure

Effective receptor-blockade approach to heart

failure

Negative inotropic effect counteracted by

vasodilation

Provides anti-proliferative, anti-arrhythmic

activity and inhibition of apoptosis

Prevents renin secretionDrugs of Today 1998; 34 (Suppl B): 1-23.


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COPERNICUS: Effect on Mortality

11.4%

18.5%

0

2

4

6

8

10

12

14

16

18

20

Carvedilol (n=1156) Placebo (n=1133)

35%

Mortalit

y(%)

22nd Congress of European Society of Cardiology, August 2000


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CARDIAC INSUFFICIENCY BISOPROLOL STUDY-II (CIBIS II)

Tota l mor ta l i ty A l l caus e hospi tal i zat i on CV deaths Combi ned endpoint Sudden death Hospi tali zati on f

wor sening HF

-50%

-40%

-30%

-20%

-10%

0%

Riskreduction

34%

20%

29%

21%

44%

36%Moderate to severe HF, LVEF < 35%

N=2647, t = 1.3 years

Bisoprolol (10 mg od) vs placebo

Lancet 1999; 353 : 913


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Randomized Evaluation of Strategies for left ventricular


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Reduces total mortality by 54.3%

8.1

3.7

0

1

2

34

5

6

7

8

9

No.o

fdeaths(%)

ACE Inhibitor + diuretic + digitalis

ACE inhibitor + diuretic + digitalis + Metoprolol

extended release Circulation 2000; 101: 378-384

Dysfunction Pilot Study (RESOLVD)


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Management of Complications


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Management of Complications

Transient worsening of heart failure (e.g. increasing dyspnea,

decreasing exercise capacity)

Increase dose of diuretic and/or ACE inhibitor

If necessary, reduce carvedilol dose and/or prolong titration

interval

Search for other possible causes (e.g. thyroid malfunction,infection, non-compliant drug intake, excessive liquid intake, etc.)

Vasodilatory Symptoms (dizziness, light headedness,

symptomatic hypotension)

Decrease diuretic dose and, if necessary, ACE inhibitor dose

If the cessation of both is not successful, reduce carvedilol dose

and/or prolong titration interval

Management of Complications (Contd )


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Management of Complications (Contd.)

Bradycardia (Pulse rate below 55 beats/min)

Check and eventually reduce digitalis dose

If necessary, reduce carvedilol dose and/or prolong

titration interval

Withdraw carvedilol only in the event that hemodynamics

are affected

Symptoms of Bronchial obstruction

Search for other possible causes (e.g., concurrent

infection, subacute pulmonary edema)

Reduce dose of, or withdraw, carvedilol only after

possible causes for symptoms have been ruled out

Role of Aldosterone


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Role of Aldosterone

Sodium & water retention, Potassium & Magnesium loss

Renal fibrosis

Vascular inflammation & fibrosis

Vasoconstrictor


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Deleterious Effects of

Aldosterone

Cardiovascular Disease

Vascular inflammationand injury

Prothrombotic

effectsPotassium and

magnesium loss

Central

hypertensive

effects

Endothelial

dysfunciton

Ventricular

arrhythtmiasSodium

Retention

Catecholaminepotentiation

Myocardial

Fibrosis

McMahon EG: Current Opinion Pharmacol, 1:190-196, 200

Aldosterone Antagonist


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Aldosterone Antagonist

Spironolactoneis the most widely used aldosterone antagonist.

Starting at 12.5 mg daily were added to ACEI therapy for patients with NYHAclass IV HF symptoms or class III symptoms and recent hospitalization.

The risk of death was reduced from 46% to 35% (30% relative risk reduction)

over 2 years, with a 35% reduction in HF hospitalization and an improvement in

functional class.

Serum Creatinine levels were below 2.0 mg/dL

Potassium replacements were stopped, serum potassium and renal function

were followed very closely.

Eplerenonein patients LVEF 40% clinical evidence of HF or diabetes mellitus

within 14 days of MI. Mortality was decreased from 13.6% to 11.8% at 1 year.

Hyperkalemia occurred in 5.5% of patients treated with eplerenone compared

with 3.9% of those given placebo overall and in up to 10.1% versus 4.6% ofpatients with estimated creatinine clearance less than 50 mL per min (98).

Special Attention


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Special Attention

Requires patient education avoid foods/drinks

high in potassium Not using NSAID

Discontinued using aldosterone antagonist when

loop diuretic th/ is interrupted or during an episode of

diarrhea

Requires close monitoring serum potassium and

renal function !!!!

Drugs dose used in HF


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Drugs dose used in HF

Diuretics


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Diuretics

Indicated in patients with symptoms of heart failure

who have evidence of fluid retention Enhance response to other drugs in heart failure such

as beta-blockers and ACE inhibitors

Therapy initiated with low doses followed by

increments in dosage until urine output increases and

weight decreases by 0.5-1kg daily

Close monitoring: serum electrolyte, creatinine & BP

Concomitant th/ may be consider in patient withpersistent fluid retention thiazide, spironolactone

Diuretic doses


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Diuretic doses


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Symptomatic Patients


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Symptomatic Patients

Other Drugs :

Vasodilator Hydralazine + Isosorbide dinitrate

VHeFT-I

mortality, improved functional class

as compared with use of digoxin and diureticsVHeFT-II

proved less effective than enalapril

Nesiritide

Venous & arterial vasodilator and increase Na+excretion

Inotropes (Dopamin, Dobutamin, PDE3I (Milrinone)

Not use routinely, should be reserved for ADHF with hypoperfusion


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Thanks' for your attention


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Thanks for your attention


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