Therapy of Congestive CHF
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THERAPY OF CONGESTIVE HEART FAILURE
Ms.Farsana 16.5.2009M
Guide.Dr.U.P.Rathnakar.
MD.DIH.PGDHM
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CONTENTS
INTRODUTION DEFINITION NEUROHUMORAL MECHANISM TYPES OF HEART FAILURE DRUGS USED IN HEART FAILURE CLINICAL SUMMARY
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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
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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.”
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DEFINITION
“ The situation when the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return.”
E.Braunwald
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NEUROHUMORAL RESPONSE- VICIOUS CYCLE
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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
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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
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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…..
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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
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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
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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
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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
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CLASSIFICATION OF DRUGS FOR HEART FAILURE
1. ORAL DRUGS • MANAGEMENT OF AMBULATORY HEART
FAILURE
2. PARENTERAL DRUGS• HOSPITALISED HEART FAILURE PATIENTS
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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
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PARENTERAL DRUGS
1. DIURETICS
2. PARENTERAL VASODILATORS1. SODIUM NITROPRUSSIDE 2. NITROGLYCERIN
3. BETA ADRENERGIC & DOPAMINE RECEPTOR AGONIST
4. PHOSPHODIESTERASE INHIBITORS
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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
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DIURETICS
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SITES OF ACTION
Loop diuretics
Thiazide diuretics
Thiazide diuretics
Spironolactone
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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
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MECHANISM OF ACTION
Furosemide ivFurosemide iv ↓ ↓ ↓ ↓
↑↑ssystemic venous capacitance ystemic venous capacitance ↓ ↓ LV filling LV filling pressurepressure
Rapid symptomatic relief
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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
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ADVERSE EFFECTS OF DIURETICS Loop diuretics:
HypokalaemiaHyponatraemia Hypocalcaemia
Thiazide diuretic:HypokalaemiaHypercalcaemia
Skin rashes, nausea, vomiting, diarrhoea, magnesium depletion
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DIURETIC RESISTANCE After chronic use in advanced CHF
Rx
Combination therapy: Thiazide + Spironolactone /Eplerenone
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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
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ALDOSTERONE ANTAGONISTS
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ACTIONS OF ALDOSTERONE
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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
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HyperkalaemiaHyperkalaemia
GynaecomastiaGynaecomastia
UremiaUremia ImpotenceImpotence
Drowsiness, confusionDrowsiness, confusion
Abdominal upset Abdominal upset
ALDOSTERONE ANTAGONISTS-ADVERSE EFFECT
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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
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RAAS &DRUGS AFFECTING THE SYSTEM
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RENIN ANGIOTENSIN SYSTEM & DRUGS
ACE INHIBITORS
ARBs
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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
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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
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ADVERSE EFFECTS Dry coughDry cough
Angioedema Angioedema
HypotensionHypotension
Renal failure Renal failure
HyperkalaemiaHyperkalaemia
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CURRENT STATUS CONSENSUS (Co-operative North Scandinavian
Enalapril Study) I,
SOLVD (Studies On Left Ventricular Dysfunction) -T – Enalapril-reduced mortality
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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
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ARBs-ADVERSE EFFECT Hypotension Hyperkalemia
Headache, dizziness
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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
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VASODILATORS
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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
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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
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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
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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
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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)
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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
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NESIRITIDE-ADVERSE EFFECT Dose dependent hypotension
Nausea, vomiting
Nervousness Nephrotoxicity
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CURRENT STATUS VAMC (Vasodilation in the Acute Management of
CHF) Trial-Acute decompensated heart failure
Heart failure resistant to Nitroprusside
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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
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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
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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
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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)
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ADVERSE EFFECTS Rebound hypertension & Anginal attack Bradycardia Hypoglycemia Fatigue Sleep disturbances Depression
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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
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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
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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
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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)
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MECHANISM OF ACTION
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DIGOXIN-BENEFITS Reduces heart rate Relieves symptoms Enhances diuresis
DOSE DIGOXIN- 0.0625mg,0.125mg,0.25mg
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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
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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 )
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CONTRAINDICATIONS
1. In partial AV block
2. Diastolic dysfunction
3. Wolff -Parkinson -White syndrome
4. Suspected digitalis toxicity
5. Hypertropic obstructive cardiomyopathy
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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
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ANTICOAGULANT DRUGS Warfarin recommended - atrial fibrillationWarfarin recommended - atrial fibrillation
Higher incidence of stroke & thromboembolismHigher incidence of stroke & thromboembolism
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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
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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
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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
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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
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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
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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)
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CLINICAL SUMMARYCLINICAL SUMMARY
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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.
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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.
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