THERAPY OF

CONGESTIVE HEART FAILURE

Ms.Farsana
16.5.2009M

Guide.
Dr.U.P.Rathnakar.
MD.DIH.PGDHM
 CONTENTS

 INTRODUTION
 DEFINITION
 NEUROHUMORAL MECHANISM
 TYPES OF HEART FAILURE
 DRUGS USED IN HEART FAILURE
 CLINICAL SUMMARY
 CONGESTIVE HEART FAILURE
 Major contributor to morbidity & mortality

 1.5-2% of population-some form of cardiac failure

 Prevalence↑ to 6-10% in patients > 65 yrs of age

 Coronary heart disease – predominant cause

 Hypertension – major risk factor

 Incidence - lower in women than men

 DEFINITION
 “Heterogeneous syndrome in which
abnormalities of cardiac function are
responsible for the inability of the heart to
pump blood at an output sufficient to meet
the requirements of tissues or the ability to
do so only at elevated diastolic pressure and
volume.”
 DEFINITION
“ The situation when the heart is
incapable of maintaining a cardiac
output adequate to accommodate
metabolic requirements and the venous
return.”

E.Braunwald
NEUROHUMORAL RESPONSE-
VICIOUS CYCLE
 TYPES OF HEART FAILURE
 SYSTOLIC DYSFUNCTION  DIASTOLIC DYSFUNCTION
large
 dilated  small/ normal size
impaired
systolic performance

 Clinical symptoms-
breathlessness
fatigue
↓exercise tolerance

 Unable to develop wall tension

 Ejection fraction at rest –
normal or near normal
 SYMPTOMS OF CHF

LEFT HEART
RIGHT FAILURE
HEART
FAILURE

CAUSES
• Hypertension
CAUSES • Valvular Disease
• Myocardial
• Secondary to left infarction
sided failure
• Pulmonary
emphysema
• Pulmonary valve
lesions
• Tricuspid valvular
stenosis
 Types of heart failure…..
 Low output heart failure:
 Low CO (Mitral stenosis, ischemic heart disease)

 High output heart failure:

 Increased CO , insufficient to meet demands of
body (Thyrotoxicosis, Beriberi, Anaemia)

 Acute heart failure

 Pulmonary edema
 NYHA CLASSIFICATION
 Class I:  Class II:
 No limitation of  Mild limitation of
exercise tolerance exercise tolerance
 No symptoms during  Symptoms provoked by
daily activities ordinary activities
 Class III:  Class IV:
 Moderate limitation of  Severe limitation of
excercise tolerance exercise tolerance
 Symptoms provoked by  Symptoms- present at
less than ordinary rest
activities
 STAGES OF HEART FAILURE
 Stage A:
 High risk for developing heart failure, no structural or
functional heart disorder

 Stage B:
 Structural disorder, no symptoms

 Stage C:
 Symptoms of heart failure in context of an underlying
structural heart problem

 Stage D:
 Require hospital based support, heart transplant or
palliative care
 Chronic Congestive Heart Failure

EVOLUTION OF CLINICAL STAGES

NORMAL STAGE A

No symptoms
Normal exerciseAsymptomatic
Normal LV fxn
LV Dysfunction STAGE B
No symptoms
Normal exercise Compensated
Abnormal LV fxn CHF
No symptoms
Exercise
Decompensated STAGE C
Abnormal LV fxn CHF
Symptoms
Exercise Refractory
Abnormal LV fxn CHF
Symptoms not controlled
with treatment
STAGE D
 HEART FAILURE
PATHOPHYSIOLO
Inotropic agents, Digoxin ⊗
↓ CARDIAC OUTPUT
Digoxin ⊗
↑ CARDIAC FILLING PR
RENIN ⊗ SYM. N.S ACTIVATED
β blockers
⊗ Vasodilators
ANG-I VASOCONSTRICTION

ACEI ⊗
⊗ Na+ & H2O RETENTION
ANG-II
⊗
AT1 blockers
⊗
CARDIAC REMODELLING
ALDOSTERONE ⊗
Spironolactone
⊗ ⊗
Diuretics
CLASSIFICATION OF DRUGS FOR
HEART FAILURE

1. ORAL DRUGS
• MANAGEMENT OF AMBULATORY HEART
FAILURE

3. PARENTERAL DRUGS
• HOSPITALISED HEART FAILURE PATIENTS
 ORAL DRUGS
1. DIURETICS

3. ALDOSTERONE ANTAGONISTS

5. VASODILATORS:
 ANGIOTENSIN CONVERTING ENZYME INHIBITORS
 ANGIOTENSIN RECEPTOR BLOCKERS
 NITROVASODILATORS

 BETA ADRENERGIC RECEPTOR ANTAGONISTS

 CARDIAC GLYCOSIDES

 ANTICOAGULANT & ANTIPLATELET DRUGS

 PARENTERAL DRUGS
1. DIURETICS

3. PARENTERAL VASODILATORS
 SODIUM NITROPRUSSIDE
 NITROGLYCERIN

 BETA ADRENERGIC & DOPAMINE

RECEPTOR AGONIST

 PHOSPHODIESTERASE INHIBITORS
 CLASSIFICATION
 Drugs which relieve congestive symptoms & restore
cardiac performance
 Inotropic drugs:
Digoxin, Dobutamine/Dopamine, Amrinone/Milrinone
 Diuretics:

Furosemide, Thiazides
 Vasodilators:

ACE inhibitors/ARBs, Hydralazine, nitrate, Nitroprusside.

β blockers: Carvedilol, Metoprolol, Bisoprolol

 Drugs reverses disease progression:

ACE inhibitors/ARBs, β blockers, aldosterone antagonists
DIURETICS
 SITES OF ACTION

Thiazide
diuretics

Spironolactone
Thiazide
diuretics
Loop diuretics
 LOOP DIURETICS
FUROSEMIDE ,BUMETANIDE, TORSAMIDE

Management of congestive symptoms of mild- severe

heart failure

Loop diuretics

↓ECF volume &↓venous return,↓preload

Reduces edema & cardiac size

 MECHANISM OF ACTION
Furosemide iv
↓ ↓
↑systemic venous capacitance ↓ LV filling
pressure

Rapid symptomatic
relief
 THIAZIDE DIURETICS
 CHLORTHALIDONE, METOLAZONE

 In mild-moderate HF - treatment of volume

retention

 Used in combination

 Exhibit true synergism with Loop diuretic

ADVERSE EFFECTS OF DIURETICS
 Loop diuretics:  Thiazide diuretic:
Hypokalaemia Hypokalaemia
Hyponatraemia Hypercalcaemia
Hypocalcaemia

 Skin rashes, nausea, vomiting, diarrhoea, magnesium

depletion
 DIURETIC RESISTANCE
 After chronic use in advanced CHF

Rx
 Combination therapy: Thiazide + Spironolactone
/Eplerenone
 CURRENT STATUS
 Monotherapy – Not preferred

 Deleterious effect on neurohumoral activation

 Loop diuretics are commonly used in heart failure

with edema.

 Used in combination with ACE inhibitors, ARBs, β

blockers
ALDOSTERONE ANTAGONISTS
ACTIONS OF ALDOSTERONE
 ALDOSTERONE ANTAGONISTS
 SPIRONOLACTONE & EPLERENONE

 Aldosterone antagonist block these actions

 Reverses pathologic remodeling
 Acts as K+ sparing diuretic

DOSES
Drug initial dose target dose
Spironolactone- 25mg 25-50mg
Eplerenone - 25mg 50mg
 ALDOSTERONE ANTAGONISTS-
ADVERSE EFFECT
 Hyperkalaemia

 Gynaecomastia

 Uremia

 Impotence

 Drowsiness, confusion

 Abdominal upset
 CURRENT STATUS
 RALES (Randomized Aldactone Evaluation Study )-
Spironolactone- increased survival, reduced
morbidity in severe heart failure

 EPHESUS (Eplerenone Post-Acute Myocardial

Infarction Heart Failure Efficacy and Survival )-
Eplerenone- increased survival & reduced morbidity
RAAS &DRUGS AFFECTING THE SYSTEM
RENIN ANGIOTENSIN SYSTEM & DRUGS

ACE INHIBITORS

ARBs
ANGIOTENSIN CONVERTING ENZYME
INHIBITORS
 Considered as the cornerstone of the therapy of HF

 First line treatment

 Indicated- heart failure of any severity

Long term effects of ACE inhibitors
Blockade of ANG-II mediated ventricular
hypertrophy, remodeling, accelerated myocyte
apoptosis & fibrosis.

Drug Initial dose Target dose

Enalapril - 2.5mg 10-20mg
Lisinopril - 10mg 20-35mg
Ramipril - 5mg 5mg
Trandolapril- 0.5mg 4mg
 ADVERSE EFFECTS
 Dry cough

 Angioedema

 Hypotension

 Renal failure

 Hyperkalaemia
 CURRENT STATUS
 CONSENSUS (Co-operative North Scandinavian
Enalapril Study) I,

 SOLVD (Studies On Left Ventricular Dysfunction)

-T – Enalapril-reduced mortality
 ANGIOTENSIN RECEPTOR BLOCKERS
 Haemodynamic effect similar to ACE inhibitors

 Symptomatic relief & survival benefit

 Alternative in patients intolerant to ACE inhibitor

 DOSES
 Drug initial dose target dose
 Losartan 25mg
 Candesartan 4-8mg 32mg
 Valsartan 40mg 160mg
 ARBs-ADVERSE EFFECT
 Hypotension

 Hyperkalemia

 Headache, dizziness
 CURRENT STATUS
 Val-HeFT(Valsartan Heart Failure Trial) -
Valsartan- reduced morbidity

 CHARM (Candesartan in Heart Failure Assessment

of Reduction in Morbidity and Mortality)
-Candesartan-well tolerated

 ELITE (Evaluation of Losartan in the Elderly) -

Losartan v/s Captopril
VASODILATORS
 VASODILATORS

1. NITROVASODILATORS
 SODIUM NITROPRUSSIDE
 ORGANIC NITRATES
 NESIRITIDE
 HYDRALAZINE

 Reserved for those – intolerant to ACEIs or ARBs

 Reduces preload & afterload ➙improves symptoms of
HF
 NITROVASODILATORS
 Dilates arteries & veins
 Stimulates nitric oxide pathway
 Reduces ventricular filling pressure

 Not used as single agent

 Tolerance
 Limited effect on systemic vascular resistance
 SODIUM NITROPRUSSIDE
 Prodrug, potent vasodilator (iv)

 ↓Ventricular filling pressure & systemic vascular

resistance

 Rapid onset & offset of action

 Titrable dose

 Management of decompensated heart failure in

intensive care units
 SODIUM NITROPRUSSIDE-
CURRENT STATUS
 Decompensated heart failure:
 Sodium nitroprusside+ Loop diuretic + iv inotropic drug

 Acute heart failure due to MI:

 1 of the choice of iv vasodilators
 ORGANIC NITRATES
 Selective vasodilator: on epicardial coronary vasculature

 Reduces preload due to increase in peripheral venous

capacitance

 Patients who do not tolerate ACE inhibitors

 Management of acute congestive heart failure after

MI: (NTG ointment can also be used)
 NESIRITIDE
 Recombinant human B type natriuretic peptide
(BNP)

 Circulating BNP: correlates with CHF

 Binds to surface receptors on vascular smooth

muscle

 Activates cGMP
1. NATRIURESIS
2. DIURESIS
3. VASODILATATION
 NESIRITIDE-ADVERSE EFFECT
 Dose dependent hypotension

 Nausea, vomiting

 Nervousness

 Nephrotoxicity
 CURRENT STATUS
 VAMC (Vasodilation in the Acute Management of
CHF) Trial-Acute decompensated heart failure

 Heart failure resistant to Nitroprusside

 HYDRALAZINE
 Direct acting arterial vasodilator

 Moderate inotropic activity

 CHF with renal dysfunction & who cannot tolerate

ACE inhibitors

 CURRENT STATUS
 (A-HeFT) African-American Heart Failure Trial-
reduction in all cause mortality
 BETA RECEPTOR BLOCKERS
 CARVEDILOL, METOPROLOL, BISOPROLOL

 Beneficial role-due to adrenergic overactivity in

CHF

 In mild- moderate heart failure

 MECHANISM OF ACTION

CARVEDILOL

• Improves left ventricular structure, ↓chamber size,

↑ejection fraction
• ↓ cardiac hypertrophy & myocyte apoptosis - antagonism of
damaging effects of cardiac β1 receptor
 DOSES
Drug Initial dose Target dose
Carvedilol 3.125mg 25-50mg (BD)
Bisoprolol 1.25mg 10mg (OD)
Metoprolol 12.5-25mg 200mg (OD)
Nebivolol 1.25mg 10mg (OD)
 ADVERSE EFFECTS
 Rebound hypertension & Anginal attack
 Bradycardia
 Hypoglycemia
 Fatigue
 Sleep disturbances
 Depression
 CURRENT STATUS
 CAPRICORN (Carvedilol Post Infarct Survival
Control in LV Dysfunction Trial)- Carvedilol-
reduction in combined end point of all cause
mortality & MI

 CIBIS II-Bisoprolol- increased survival, improved

ejection fraction, reduced morbidity & mortality

 MERIT-HF(Metoprolol Randomized Intervention

Trial in Congestive Heart Failure) -Metoprolol-
reduced mortality, disease progression
 CARDIAC GLYCOSIDES
 Cyclopentanoperhydrophenanthrene ring

 Cardiac inotropic property

 Source Glycosides
Digitalis purpurea Digitoxin, Gitoxin
Digitalis lanata Digitoxin, Digoxin,
Gitoxin
Strophanthus gratus Strophanthin G
 PHARMACOLOGICAL ACTIONS OF
DIGOXIN
 HEART
 FOC: dose dependent ↑ in FOC
 Tone: no effect
 Rate: decrease
 Electrophysiological properties:
 ↑Digoxin doses- ↓RMP
 ↓ Digoxin- ↑excitability
 ECG

 BLOOD VESSELS: Mild direct vasoconstrictor

action
 KIDNEY : Diuresis in CHF
 CENTRAL NERVOUS SYSTEM: High doses- CTZ
activation
 DIGOXIN
 Positive inotropic effect on failing myocardium

 Controls ventricular rate

 Narrow therapeutic window (0.8-2ng/ml)

MECHANISM OF ACTION
 DIGOXIN-BENEFITS
 Reduces heart rate
 Relieves symptoms
 Enhances diuresis

 DOSE
DIGOXIN- 0.0625mg,0.125mg,0.25mg
 ADVERSE EFFECT
CARDIAC TOXICITY NEUROLOLGICAL TOXOCITY
Cardiac Arrhythmia Delirium
Slows AV& SA Fatigue
conduction Confusion
Sinus bradycardia Dizziness
GI TOXICITY VISUAL TOXICITY
Anorexia Blurred vision
Nausea, vomiting White halos
Abdominal pain Diplopia
 TREATMENT OF DIGITALIS
TOXICITY
Stop Digoxin & Diuretics

Estimate serum potassium

Atropine if bradycardia

Mild toxicity- oral potassium in divided doses

SVT- oral/iv propranolol

Ventricular tachycardia- Lidocaine or phenytoin (iv)

Severe toxicity- Digibind (Antidigoxin specific Ab )

 CONTRAINDICATIONS

1. In partial AV block

3. Diastolic dysfunction

5. Wolff -Parkinson -White syndrome

7. Suspected digitalis toxicity

9. Hypertropic obstructive cardiomyopathy

 CURRENT STATUS
 Best course in CHF patients with Atrial fibrillation

 Heart failure intolerant to ACE inhibitors, ARBs,

β blockers & diuretics

 In patients with low ejection fraction & dilated

heart
 ANTICOAGULANT DRUGS
 Warfarin recommended - atrial fibrillation

 Higher incidence of stroke & thromboembolism

 SYMPATHOMIMETIC INOTROPIC
DRUGS
 Dopamine & Dobutamine

 Dopamine
 Endogenous catecholamine
 Positive inotropic agent
 Short term support of circulation in advanced HF

Mechanism of action:
 Renal vasodilation & improves g.f.r.
 Restore diuretic response
 3 dose effect of Dopamine
1) 2-5µg/kg/min Vasodilation-action on DA
receptors in splanchnic
&renal arterial bed

Vasodilation,↑myocardial
2) 5-10µg/kg/min
contractility,↑HR & CO (action
on DA & β1 receptor)

Vasoconstriction, ↓renal blood

3) > 20µg/kg/min flow& urine output. (action on ɑ1
receptor action)
 DOBUTAMINE
 Indicated: Acute heart failure due to MI

 Positive inotropic action:

 Increase renal blood flow
 Increase stroke volume
 Increase cardiac output
 PHOSPHODIESTERASE INHIBITORS
 PDE III inhibitors- reduce preload & after load

 INAMRINONE & MILRINONE

 Short term support of circulation
 Balanced arterial & venous dilation
 Stimulation of myocardial contractility,↑ CO
 MECHANISM OF ACTION
 Inodilator
 Selective PDE III inhibitors
 Reduce cellular cAMP degradation
 Decrease systemic & peripheral vascular resistance
 Increases LVEF

ADVERSE EFFECTS
Thrombocytopenia
Nausea
Diarrhoea
Lever damage
Fever
 DRUGS TO USE WITH CAUTION IN
CHF PATIENTS
 Anti-arrhythmic drugs- (aggravates heart failure)

 CCBs – Verapamil & Diltiazem

 Corticosteroids, NSAIDs

 Thiazolidinediones (fluid retention),

 Metformin- (lactic acidosis)
CLINICAL SUMMARY
References
 Goodman & Gillman's The pharmacological basis of
therapeutics- Lorenze.L.Brunton, John.S.Lazo, Keith.L.Parker-
11th edition.
 Essentials of medical pharmacology- K.D Tripathi-6th edition.
 Basic & clinical pharmacology-Betram.G.Katzung-10th edition
 Pharmacology & pharmacotherapeutics- R.S Satoskar, S.D
Bandarkar, Nirmala S. Rege.- 20th edition.
 Goodman & Gillman's The pharmacological basis of
therapeutics- Lorenze.L.Brunton, John.S.Lazo, Keith.L.Parker-
11th edition.
 Essentials of medical pharmacology- K.D Tripathi-6th edition.
 Basic & clinical pharmacology-Betram.G.Katzung-10th edition
 Pharmacology & pharmacotherapeutics- R.S Satoskar, S.D
Bandarkar, Nirmala S. Rege.- 20th edition.