Therapy of Congestive CHF

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 & mortalityMajor contributor to morbidity & mortality

1.5-2% of population-some form of cardiac failure1.5-2% of population-some form of cardiac failure

PrevalencePrevalence↑ ↑ to 6-10% in patients > 65 yrs of ageto 6-10% in patients > 65 yrs of age

Coronary heart disease – predominant causeCoronary heart disease – predominant cause

Hypertension – major risk factor Hypertension – major risk factor

Incidence - lower in women than menIncidence - lower in women than men

DEFINITION

““Heterogeneous syndrome in which Heterogeneous syndrome in which abnormalities of cardiac function are abnormalities of cardiac function are responsible for the inability of the heart to responsible for the inability of the heart to pump blood at an output sufficient to pump blood at an output sufficient to meet the requirements of tissues or the meet the requirements of tissues or the ability to do so only at elevated diastolic ability to do so only at elevated diastolic pressure and volume.”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 DYSFUNCTIONSYSTOLIC DYSFUNCTION largelarge dilateddilated impaired impaired systolic systolic

performanceperformance

Clinical symptoms-Clinical symptoms- breathlessnessbreathlessness fatiguefatigue ↓↓exercise toleranceexercise tolerance

Unable to develop wall Unable to develop wall tensiontension

DIASTOLIC DYSFUNCTIONDIASTOLIC DYSFUNCTION

small/ normal sizesmall/ normal size

Ejection fraction at rest –Ejection fraction at rest –normal or near normalnormal or near normal

SYMPTOMS OF CHF

LEFT HEART FAILURE

CAUSES• Hypertension• Valvular

Disease• Myocardial

infarction

CAUSES• Secondary to left

sided failure• Pulmonary

emphysema• Pulmonary valve

lesions • Tricuspid valvular

stenosis

RIGHT HEART

FAILURE

Low output heart failure:Low output heart failure: Low CO (Mitral stenosis, ischemic heart Low CO (Mitral stenosis, ischemic heart

disease)disease)

High output heart failure:High output heart failure: Increased CO , insufficient to meet demands of Increased CO , insufficient to meet demands of

body (Thyrotoxicosis, Beriberi, Anaemia)body (Thyrotoxicosis, Beriberi, Anaemia)

Acute heart failureAcute heart failure Pulmonary edemaPulmonary edema

Types of heart failure…..

NYHA CLASSIFICATION

Class I: No limitation of

exercise tolerance No symptoms during

daily activities

Class II: Mild limitation of

exercise tolerance Symptoms provoked

by ordinary activities

Class III: Moderate limitation of

excercise tolerance Symptoms provoked by

less than ordinary activities

Class IV: Severe limitation of

exercise tolerance Symptoms- present

at rest

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

EVOLUTION OF CLINICAL STAGESEVOLUTION OF CLINICAL STAGES

NORMALNORMAL

Asymptomatic LV DysfunctionAsymptomatic LV Dysfunction

CompensatedCHF

CompensatedCHF

DecompensatedCHF

DecompensatedCHF

No symptomsNormal exerciseNormal LV fxn

No symptomsNormal exerciseAbnormal LV fxn

No symptoms ExerciseAbnormal LV fxn

Symptoms ExerciseAbnormal LV fxn

RefractoryCHF

RefractoryCHF

Symptoms not controlled with treatment

Chronic Congestive Heart FailureChronic Congestive Heart Failure

STAGE A

STAGE B

STAGE C

STAGE D

HEART FAILURE

↓ CARDIAC OUTPUT

SYM. N.S ACTIVATEDRENIN↑ CARDIAC FILLING PR

VASOCONSTRICTION

CARDIAC REMODELLING

ANG-I

ANG-II

ALDOSTERONE

Na+ & H2O RETENTION

⊗Inotropic agents, Inotropic agents, DigoxinDigoxin

DigoxinDigoxin ⊗

ACEIACEI⊗

VasodilatorsVasodilators⊗

⊗DiureticsDiuretics

⊗ββ blockers blockers

⊗

⊗

⊗ATAT11 blockers blockers

⊗

⊗SpironolactonSpironolacton

ee

PATHOPHYSIOLOGY

CLASSIFICATION OF DRUGS FOR HEART FAILURE

1. ORAL DRUGS • MANAGEMENT OF AMBULATORY HEART

FAILURE

2. PARENTERAL DRUGS• HOSPITALISED HEART FAILURE PATIENTS

ORAL DRUGS

1.1. DIURETICSDIURETICS

2.2. ALDOSTERONE ANTAGONISTSALDOSTERONE ANTAGONISTS

3.3. VASODILATORS:VASODILATORS:1.1. ANGIOTENSIN CONVERTING ENZYME INHIBITORSANGIOTENSIN CONVERTING ENZYME INHIBITORS2.2. ANGIOTENSIN RECEPTOR BLOCKERSANGIOTENSIN RECEPTOR BLOCKERS3.3. NITROVASODILATORSNITROVASODILATORS

4.4. BETA ADRENERGIC RECEPTOR ANTAGONISTSBETA ADRENERGIC RECEPTOR ANTAGONISTS

5.5. CARDIAC GLYCOSIDESCARDIAC GLYCOSIDES

6.6. ANTICOAGULANT & ANTIPLATELET DRUGSANTICOAGULANT & ANTIPLATELET DRUGS

PARENTERAL DRUGS

1. DIURETICS

2. PARENTERAL VASODILATORS1. SODIUM NITROPRUSSIDE 2. NITROGLYCERIN

3. BETA ADRENERGIC & DOPAMINE RECEPTOR AGONIST

4. 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

Loop diuretics

Thiazide diuretics

Thiazide diuretics

Spironolactone

LOOP DIURETICS

Loop diuretics

↓ECF volume &↓venous return,↓preload

Reduces edema & cardiac size

FUROSEMIDE ,BUMETANIDE, TORSAMIDE

Management of congestive symptoms of mild- severe heart failure

MECHANISM OF ACTION

Furosemide ivFurosemide iv ↓ ↓ ↓ ↓

↑↑ssystemic venous capacitance ystemic venous capacitance ↓ ↓ LV filling LV filling pressurepressure

Rapid symptomatic relief

THIAZIDE DIURETICSTHIAZIDE DIURETICS CHLORTHALIDONE, METOLAZONECHLORTHALIDONE, METOLAZONE

In mild-moderate HF - treatment of volume In mild-moderate HF - treatment of volume retentionretention

Used in combinationUsed in combination

Exhibit true synergism with Loop diureticExhibit true synergism with Loop diuretic

ADVERSE EFFECTS OF DIURETICS Loop diuretics:

HypokalaemiaHyponatraemia Hypocalcaemia

Thiazide diuretic:HypokalaemiaHypercalcaemia

Skin rashes, nausea, vomiting, diarrhoea, magnesium depletion

DIURETIC RESISTANCE After chronic use in advanced CHF

Rx

Combination therapy: Thiazide + Spironolactone /Eplerenone

Monotherapy – Not preferredMonotherapy – Not preferred

Deleterious effect on neurohumoral activationDeleterious effect on neurohumoral activation

Loop diuretics are commonly used in heart Loop diuretics are commonly used in heart failure with edema.failure with edema.

Used in combination with ACE inhibitors, ARBs, Used in combination with ACE inhibitors, ARBs, ββ blockersblockers

CURRENT STATUS

ALDOSTERONE ANTAGONISTS

ACTIONS OF ALDOSTERONE

ALDOSTERONE ANTAGONISTSALDOSTERONE ANTAGONISTS

SPIRONOLACTONE & EPLERENONESPIRONOLACTONE & EPLERENONE

Aldosterone antagonist block these actions Reverses pathologic remodeling Acts as K+ sparing diuretic

DOSESDOSES

Drug initial dose target doseDrug initial dose target dose

Spironolactone- 25mg 25-50mgSpironolactone- 25mg 25-50mg

Eplerenone - 25mg 50mgEplerenone - 25mg 50mg

HyperkalaemiaHyperkalaemia

GynaecomastiaGynaecomastia

UremiaUremia ImpotenceImpotence

Drowsiness, confusionDrowsiness, confusion

Abdominal upset Abdominal upset

ALDOSTERONE ANTAGONISTS-ADVERSE EFFECT

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 Considered as the cornerstone of the therapy of HFHF

First line treatmentFirst line treatment

Indicated- heart failure of any severityIndicated- 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 coughDry cough

Angioedema Angioedema

HypotensionHypotension

Renal failure Renal failure

HyperkalaemiaHyperkalaemia

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 inhibitorsHaemodynamic effect similar to ACE inhibitors

Symptomatic relief & survival benefitSymptomatic relief & survival benefit Alternative in patients intolerant to ACE inhibitorAlternative in patients intolerant to ACE inhibitor

DOSESDOSES Drug initial dose target doseDrug initial dose target dose

Losartan 25mgLosartan 25mg Candesartan 4-8mg 32mgCandesartan 4-8mg 32mg Valsartan 40mg 160mgValsartan 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

1.1. NITROVASODILATORSNITROVASODILATORS1.1. SODIUM NITROPRUSSIDESODIUM NITROPRUSSIDE

2.2. ORGANIC NITRATESORGANIC NITRATES

2.2. NESIRITIDENESIRITIDE

3.3. HYDRALAZINE HYDRALAZINE

Reserved for those – intolerant to ACEIs or ARBs Reserved for those – intolerant to ACEIs or ARBs Reduces preload & afterload Reduces preload & afterload ➙improves symptoms ➙improves symptoms

of HF of HF

NITROVASODILATORS

Dilates arteries & veins Dilates arteries & veins Stimulates nitric oxide pathwayStimulates nitric oxide pathway Reduces ventricular filling pressureReduces ventricular filling pressure

Not used as single agentNot used as single agent Tolerance Tolerance Limited effect on systemic vascular resistanceLimited effect on systemic vascular resistance

SODIUM NITROPRUSSIDE Prodrug, potent vasodilator (iv)Prodrug, potent vasodilator (iv)

↓↓VVentricular filling pressure & systemic vascular entricular filling pressure & systemic vascular resistanceresistance

Rapid onset & offset of actionRapid onset & offset of action

Titrable dose Titrable dose

Management of decompensated heart failure in Management of decompensated heart failure in intensive care unitsintensive 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)Recombinant human B type natriuretic peptide (BNP)

Circulating BNP: correlates with CHFCirculating BNP: correlates with CHF

Binds to surface receptors on vascular smooth muscle

Activates cGMP1.1. NATRIURESISNATRIURESIS

2.2. DIURESISDIURESIS

3.3. VASODILATATIONVASODILATATION

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 vasodilatorDirect acting arterial vasodilator

Moderate inotropic activityModerate inotropic activity

CHF with renal dysfunction & who cannot CHF with renal dysfunction & who cannot tolerate ACE inhibitorstolerate ACE inhibitors

CURRENT STATUSCURRENT STATUS (A-HeFT) African-American Heart Failure

Trial-reduction in all cause mortality

BETA RECEPTOR BLOCKERS CARVEDILOL, METOPROLOL, BISOPROLOL CARVEDILOL, METOPROLOL, BISOPROLOL

Beneficial role-due to adrenergic overactivity in Beneficial role-due to adrenergic overactivity in CHFCHF

In mild- moderate heart failureIn mild- moderate heart failure

MECHANISM OF ACTION

1.1. Improves left ventricular structure, ↓chamber size, Improves left ventricular structure, ↓chamber size, ↑ejection fraction↑ejection fraction

2.2. ↓↓ cardiac hypertrophy & myocyte apoptosis - antagonism cardiac hypertrophy & myocyte apoptosis - antagonism of damaging effects of cardiac of damaging effects of cardiac ββ11 receptor receptor

CARVEDILOL

DOSES DOSES Drug Initial dose Target doseDrug Initial dose Target dose

Carvedilol 3.125mg 25-50mg (BD)Carvedilol 3.125mg 25-50mg (BD)

Bisoprolol 1.25mg 10mg (OD)Bisoprolol 1.25mg 10mg (OD)

Metoprolol 12.5-25mg 200mg (OD)Metoprolol 12.5-25mg 200mg (OD)

Nebivolol 1.25mg 10mg (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 ringCyclopentanoperhydrophenanthrene ring

Cardiac inotropic propertyCardiac inotropic property

Source Source GlycosidesGlycosides

DigitalisDigitalis purpureapurpurea Digitoxin, Gitoxin Digitoxin, Gitoxin

DigitalisDigitalis lanata lanata Digitoxin, Digoxin, Digitoxin, Digoxin, Gitoxin Gitoxin

Strophanthus gratusStrophanthus gratus Strophanthin G Strophanthin G

PHARMACOLOGICAL ACTIONS OF DIGOXIN

HEART HEART FOC: dose dependent FOC: dose dependent ↑↑ in FOCin FOC Tone: no effect Tone: no effect Rate: decreaseRate: decrease Electrophysiological properties: Electrophysiological properties: ↑↑Digoxin doses- Digoxin doses- ↓↓RMPRMP ↓↓ Digoxin- Digoxin- ↑↑excitabilityexcitability ECGECG

BLOOD VESSELSBLOOD VESSELS:: Mild direct vasoconstrictor Mild direct vasoconstrictor actionaction

KIDNEY :KIDNEY : Diuresis in CHFDiuresis in CHF CENTRAL NERVOUS SYSTEMCENTRAL NERVOUS SYSTEM: : High doses- CTZ High doses- CTZ

activationactivation

DIGOXIN DIGOXIN Positive inotropic effect on failing myocardiumPositive inotropic effect on failing myocardium

Controls ventricular rateControls ventricular rate

Narrow therapeutic window (0.8-2ng/ml)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 EFFECTCARDIAC TOXICITY

Cardiac Arrhythmia Slows AV& SA

conduction Sinus bradycardia

NEUROLOLGICAL TOXOCITY Delirium Fatigue Confusion Dizziness

GI TOXICITYAnorexia Nausea, vomitingAbdominal pain

VISUAL TOXICITYBlurred visionWhite halosDiplopia

TREATMENT OF DIGITALIS TOXICITYStop 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

2. Diastolic dysfunction

3. Wolff -Parkinson -White syndrome

4. Suspected digitalis toxicity

5. 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 fibrillationWarfarin recommended - atrial fibrillation

Higher incidence of stroke & thromboembolismHigher incidence of stroke & thromboembolism

SYMPATHOMIMETIC INOTROPIC DRUGS

Dopamine & DobutamineDopamine & Dobutamine

DopamineDopamine Endogenous catecholamineEndogenous catecholamine Positive inotropic agentPositive inotropic agent Short term support of circulation in advanced HFShort term support of circulation in advanced HF

Mechanism of action:Mechanism of action: Renal vasodilation & improves g.f.r.Renal vasodilation & improves g.f.r. Restore diuretic response Restore diuretic response

3 dose effect of Dopamine1) 2-5µg/kg/min

2) 5-10µg/kg/min

3) > 20µg/kg/min

Vasodilation,↑myocardial contractility,↑HR & CO (action

on DA & β1 receptor)

Vasoconstriction, ↓renal blood flow& urine output. (action on ɑ1

receptor action)

Vasodilation-action on DA receptors in splanchnic

&renal arterial bed

DOBUTAMINE Indicated: Acute heart failure due to MIIndicated: Acute heart failure due to MI

Positive inotropic action:Positive inotropic action: Increase renal blood flowIncrease renal blood flow Increase stroke volumeIncrease stroke volume Increase cardiac outputIncrease cardiac output

PHOSPHODIESTERASE INHIBITORSPHOSPHODIESTERASE INHIBITORS PDE III inhibitors- reduce preload & after loadPDE III inhibitors- reduce preload & after load

INAMRINONE & MILRINONEINAMRINONE & MILRINONE1.1. Short term support of circulationShort term support of circulation

2.2. Balanced arterial & venous dilationBalanced arterial & venous dilation

3.3. Stimulation of myocardial contractility,Stimulation of myocardial contractility,↑ ↑ COCO

MECHANISM OF ACTION Inodilator Inodilator Selective PDE III inhibitors Selective PDE III inhibitors Reduce cellular cAMP degradationReduce cellular cAMP degradation Decrease systemic & peripheral vascular resistanceDecrease systemic & peripheral vascular resistance Increases LVEFIncreases LVEF

ADVERSE EFFECTSADVERSE EFFECTS ThrombocytopeniaThrombocytopenia

Nausea Nausea Diarrhoea Diarrhoea

Lever damageLever damageFever 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 SUMMARYCLINICAL 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.