Congestive Heart Failure and Digitalis

New York Heart Association: Classifications of Heart FailureClass I - no limitation of physical activityClass II - slight limitation of activitydyspnea with moderate physical activityClass III - marked limitation of activitydyspnea with minimal physical activityClass IV - severe symptoms at rest

Classification SystemsNYHA based on exercise capacity (functional system)Class IClass IIClass IIIClass IVACC/AHA staging of heart failure (progression)Stage AStage BStage CStage D

New Approach to the Classification of Heart FailureModified from Hunt SA et al. J Am Coll Cardiol. 2001;38:21012113.

New Classification of Heart Failure ACC/AHA Staging v/s NYHA Functional Class

1Hunt SA et al. J Am Coll Cardiol. 2001;38:21012113. 2New York Heart Association/Little Brown and Company, 1964. Adapted from: Farrell MH et al.JAMA.2002;287:890897.ACC/AHA HF Stage1NYHA Functional Class2AAt high risk for heart failure but without structural heart disease or symptoms of heart failure (eg, patients with HTN or coronary artery disease)BStructural heart disease but without symptoms of heart failureCStructural heart disease with prior or current symptoms of heart failureDRefractory heart failure requiring specialized interventionsIAsymptomaticII Symptomatic with moderate exertionIV Symptomatic at restIII Symptomatic with minimal exertionNone

Cardiovascular responses to heart failure Inadequate cardiac outputSystemic vasoconstrictionAdrenergic nervous system(norepinephrine)Renin angiotensin system (aldosterone)Tachycardia

Pathophysiology of HFCardiac injury > depressed cardiac function poor tissue perfusionCardiac output must increaseActivation of neurohormonal axisNorepi, AVP, angiotensin II, endothelinChronic Neurohormonal release is dysfunctionalAlterations in HR, contractilityMyocardial hypertrophy and ischemia

Conditions that may precipitate CHFInfectionsArrhythmiasMyocardial infarctionPulmonary embolismUndue physical exertionExcessive Na intake

Hemorrhage, anemiaPregnancyIn- and trans-fusionsAnesthesia/surgeryHigh altitudeHypertensionD/C digitalis

Pharmacotherapeutic approaches in heart failureReduction of volume overload (reduce preload)Diuretics Ventricular unloading (reduce afterload)Acute: nitroglycerin, sodium nitroprussideChronic: inhibit renin-angiotensin-aldosterone system, diuretics, ACE inhibitors, angiotensin antagonists Beta-blockers (also reduce sympathetic activation)Inotropic interventions (improve Starling function)Acute: dobutamineChronic: phosphodiesterase inhibitors, digitalis

Effects of ouabain on cardiac function in a patient with CHF

Effects of ouabain on the CV system of a patient in CHF

Effects of ouabain on the CV system of a normal human volunteer

Digitalization can increase myocardial efficiency in CHF

Determinants of myocardial oxygen demandIntramyocardial tensionblood pressure, ventricular volumeMyocardial contractilityHeart rate

Fiber shortening (Fenn effect)Activation energyBasal (resting) metabolism

Ventricular function (Starling) curves:normal, CHF and with digitalis ventricular end-diastolic volumenormalCHF + digitalisCHFcongestive symptoms,edema, dyspneainadequate,fatigueCardiac Outputadequate

Mechanism of positive inotropic effect of digitalisROCdigitalisVOC = voltage-operated channelROC = receptor-operated channelPMCA = plasma membrane Ca2+ ATP-ase

Effect of ouabain on cardiac cellular functions

Digitalis: positive inotropic mechanismInhibition of Na, K ATPaseAltered balance of Na/Ca exchangeEnhanced Ca storage/releaseIncreased binding of Ca to troponinIncreased actin/myosin ATPaseIncreased contractility

Pharmacotherapeutic approaches in heart failureReduction of volume overload (reduce preload)diureticsVentricular unloading (reduce afterload)Acute: nitroglycerin, sodium nitroprussideChronic: inhibit renin-angiotensin-aldosterone system, diuretics, ACE inhibitors, angiotensin antagonistsBeta-blockers (also reduce sympathetic activation)Inotropic interventions (improve Starling function)Acute: dobutamineChronic: phosphodiesterase inhibitors, digitalis

dobutaminePositive inotropic effect via beta-1 receptorsReduces afterload via beta-2 receptorsMinor activation of alpha-1 receptors

May promote sinus tachycardia, PVCs, angina, headache, hypertensionHalf life about 2 minutes. IV infusion to titrate dobutamine effects.

milrinoneRelatively selective inhibitor of type III cyclic nucleotide phosphodiesterase (cGMP inhibited cAMP hydrolysis) (exerts positive inotropic effect and vasodilation and bronchodilation).Indicated for IV treatment of heart failure. Chronic oral dosage associated with increased mortality. Half life is about 2 hours. Excreted mainly in urine, adjust dosage in renal disease.Adverse reactions included PVCs, SVT, VT and VF

Cardiovascular responses to heart failure Inadequate cardiac outputSystemic vasoconstrictionAdrenergic nervous system(norepinephrine)Renin angiotensin system (aldosterone)TachycardiaBeta blockers

Beta adrenergic blockers:decrease renin release and afterload (and decrease sympathetic activation of heart)Propranolol MetoprololCarvedilol decreases afterload in part by alpha adrenoceptor antagonism

Use of beta-blockers in carefully monitored patients CHF may be beneficial. Until recently, beta blockers were considered to be contraindicated in CHF.

Impact of atrial tachycardia on circulation

Effect of digitalis on a supra-ventricular tachycardia

Effects of lanatoside C on paroxysmal atrial flutter

Circus movement atrial flutter model: effect of digitalis

Vagal (ACh) actions on supraventricular parts of the heartDecreases SA node automaticity (and slows heart rate)Decreases duration of atrial muscle action potential (and decreases refractory period)Slows AV nodal conduction velocity and increases AV nodal refractory period

All of the above effects are caused by a single mechanism of action: increased potassium permeability

Effects of transient release of acetylcholine on atrial action potential and contractile force

Vagal (ACh) actions on supraventricular parts of the heartDecreases SA node automaticity (and slows heart rate)

Decreases duration of atrial muscle action potential (and decreases refractory period)

Slows AV nodal conduction velocity and increases AV nodal refractory period

Effect of digoxin on AV nodal conduction in normally innervated human heart

Lack of effect of digoxin on AV nodal conduction in transplanted (denervated) human heart

Pharmacokinetics of digoxinWell, but variously absorbed from GI tract, bioavailability = 70 13%Vd = (3.12 CLcr + 3.83) 30% and proportional to thyroid statusMost excreted in urine unchanged, elimination depends on kidney functionHalf life = 39 13 hours (1.6 days)

Accumulation of digoxin during chronic dosing

Pharmacokinetics of digitoxinWell absorbed from GI tract, bioavailability > 90%Vd = 0.54 0.14 liters/kg Non-polar compound, elimination depends on liver functionHalf life = 6.7 1.7 days

Non-uniform bioavailability of several generic and trade name digoxin preparations

Some adverse reactions to digitalisCNSheadache, malaise, confusion, dizziness, changes in color vision

GIanorexia, nausea, vomiting, diarrhea

CVbradycardia, heart block (various degrees), arrhythmias, ventricular tachycardia, fibrillation, hyperkalemia

digoxin in hospitalized patients22.4% of patients (est. failure 8%)CHF (78%), arrhythmias (21%), other (1%)RoutePO (79%), IV (15%), IM (6%)Adverse reactionsArrhythmias 8.5%GI disturbances 3.1%CNS toxicity 0.1%Gynecomastia 0.1%

Digitalis toxicityIn various studiesThe minimal inotropic dose of = about 1/5 of the lethal dose

The minimal toxic dose = about 2/3 of the lethal dose

Thus, the therapeutic window is narrow

Diagnosis of digoxin toxicityAre there predisposing factors?large dose, decreased eliminationAre there extracardiac symptoms?anorexia, nausea/vomiting, visual signsArrhythmias present?Arrhythmias change when digoxin withheld?What is serum digoxin concentration?

Serum digoxin levels in 179 patientsSerum concentrations at which the probability of digoxin induced arrhythmias is 10% = 1.7, 50% = 2.5, 90% = 3.3

Treatment of acute digoxin intoxication by digoxin immune Fab (Digibind)

Simplified diagram of apparent digitalis-induced changes in ANS activityCNS output of autonomic toneDose of digitalissympatheticparasympatheticslowingVTVF - deathpartial AV blockPVCs

Digoxin overviewAbout 50% of patients with CHF have elevated endogenous ouabain (EO)EO level is inversely correlated with the cardiac index. Digoxin reduces hospitalization for worsening heart failureDigoxin increases the risk of death from any cause in women, but not in men.Digoxin only benefits some patients - perhaps patients with low levels of EO (untested at this time)Improves the quality but not the length of life

2006 HF Treatment Algorithm by StageStage A treat HTN smoking cessation treat lipid disorders exercise treat diabetesStage BStage CStage D stage A ACE-inhibitors beta-blockers ICD ? stage A, B ACE-inhibitors beta-blockers diuretics spironolactone digitalis bivent pacing +/- ICD ARBs ?Angina nitrate amlodipine PCI CABGAF warfarin rate control cardioversion stages A, B, and C IV inotropes ? MCS (bridge to Tx) heart transplantation IV inotropes MCS (permanent) hospice careAntiendothelin agents, anticytokines, oral inotropes, cardiac support devices, cell and gene Rx

Mortality Reductions with ACE - I051015202530Relative Risk Reduction (%)CONSENSUSSOLVDSAVEAIREHOPEn = 253n = 4228n = 2231n = 1986n = 3577CONSENSUS: NEJM 1987;316:1429-435, SOLVD: NEJM 1991;325:293-302, SAVE: NEJM 1992;327:669-677AIRE: Lancet 1993;342:821-828, HOPE: Lancet 2000;355:253-259

Tidak ada jalan menuju pengetahuan selain keingintahuan yang ditempuh dengan BELAJAR

*NYHA:I cardiac dz, but asymptomaticII dyspnea with heavy exertionIII dyspnea with light exertionIV dyspnea at rest

ACC/AHAA: risk for HFB: asymptomatic HFC: symptomatic HFD: refractory/end stage HF*Correlates with new definitions of hypertensionThink of ACC/AHA class A as pre-CHFAllows earlier identification of at-risk population*Norepi increases cardiac contractility and rate, systemic vasoconstriction and sodium retentionAVP (arginine-vasopressin) causes water retention to expand plasma volumeAngiotensin II promotes systemic vasoconstriction, induces sodium retention, promotes pathologic remodeling of the myocardiumEndothelin potent vasoconstrictor, with positive inotropic effects; stimulates further secretion of AVP and aldosterone*Progressive algorithmEach stage involves all modalities of previous stage, plus some additional tx options Right now, I want you to focus on treatments in stage A remember, this is pre-CHF; it involves primarily preventive measures, the most important of which is HTN control*Have you ever noticed the cool names in cardiology trials?

Wow your cardiology colleagues by stating, well, obviously the COPERNICUS trial proved the effectiveness of carvedilol in patients with severe HF but I thought it was interesting that the CAPRICORN study was able to extrapolate that effect to those patients who only had post-MI LVD.