Cardiac Glycosides and Therapy of Congestive Heart Failure Philip Marcus, MD MPH.

Cardiac Glycosides and Therapy of Cardiac Glycosides and Therapy of Congestive Heart FailureCongestive Heart Failure

Philip Marcus, MD MPHPhilip Marcus, MD MPH

Pathophysiology of Congestive Heart Pathophysiology of Congestive Heart FailureFailure

Inability of the heart to pump blood in amounts Inability of the heart to pump blood in amounts sufficient to meet metabolic needs of the tissuessufficient to meet metabolic needs of the tissuesWill result in:Will result in:– FatigueFatigue– Decreased exercise toleranceDecreased exercise tolerance– DyspneaDyspnea– OrthopneaOrthopnea– Venous distentionVenous distention– EdemaEdema– CardiomegalyCardiomegaly– HepatomegalyHepatomegaly– TachycardiaTachycardia

Progressive disease that begins long before Progressive disease that begins long before signs and symptoms are evidentsigns and symptoms are evident

Pathophysiology of Congestive Heart Pathophysiology of Congestive Heart FailureFailure

Etiology of Congestive Heart FailureEtiology of Congestive Heart Failure– HypertensionHypertension– Coronary artery diseaseCoronary artery disease– Acute myocardial infarctionAcute myocardial infarction– CardiomyopathyCardiomyopathy

Primary defect in CHF (systolic dysfunction)Primary defect in CHF (systolic dysfunction)– Reduction in contractile force of cardiac muscleReduction in contractile force of cardiac muscle– Decreased Cardiac Output (reduced ejection fraction)Decreased Cardiac Output (reduced ejection fraction)

Diastolic DysfunctionDiastolic Dysfunction– Elevated end-diastolic pressureElevated end-diastolic pressure– Normal-sized chamber (LV)Normal-sized chamber (LV)– Inability to fill and relax ventricleInability to fill and relax ventricle

Physiologic Adaptations to Reduced Physiologic Adaptations to Reduced Cardiac Output (Cardiac Output (to improve perfusionto improve perfusion))

Cardiac DilatationCardiac Dilatation

Increased sympathetic toneIncreased sympathetic tone– Increased heart rateIncreased heart rate– Increased contractilityIncreased contractility– Increase in venous toneIncrease in venous tone

Increase in Increase in preloadpreload– Increase in arteriolar toneIncrease in arteriolar tone

Increase in Increase in afterloadafterload

Physiologic Adaptations to Reduced Physiologic Adaptations to Reduced Cardiac Output (Cardiac Output (to improve perfusionto improve perfusion))

Water retention and increase in blood volumeWater retention and increase in blood volume– Reduction in CO leads to decrease in RBFReduction in CO leads to decrease in RBF– Reduced RBF leads to decrease in GFRReduced RBF leads to decrease in GFR– Decrease in GFR leads to decreased urine productionDecrease in GFR leads to decreased urine production

– Decrease in RBF leads to increase in renin activityDecrease in RBF leads to increase in renin activity– Increase in renin causes increase in Increase in renin causes increase in aldosteronealdosterone– Increased aldosterone leads to sodium and water Increased aldosterone leads to sodium and water

retentionretention

Determinants of Cardiac PerformanceDeterminants of Cardiac Performance

PreloadPreload– Measure of LV filling (stretch)Measure of LV filling (stretch)– Measure LVEDV, LVEDPMeasure LVEDV, LVEDP– In CHF, preload increases and cardiac performance In CHF, preload increases and cardiac performance

(SV, Stroke work) decrease(SV, Stroke work) decrease– Increased preload secondary to:Increased preload secondary to:

Increase in blood volumeIncrease in blood volumeIncrease in venous toneIncrease in venous tone

Reduction of high filling pressure is goal of therapyReduction of high filling pressure is goal of therapy


AfterloadAfterload– Resistance against which the heart must pump bloodResistance against which the heart must pump blood– Represented by aortic impedance and systemic vascular Represented by aortic impedance and systemic vascular

resistanceresistance– SVR increases in CHF secondary to:SVR increases in CHF secondary to:

Increased sympathetic outflowIncreased sympathetic outflow

Increase in circulating catecholaminesIncrease in circulating catecholamines

Activation of renin-angiotensin-aldosterone systemActivation of renin-angiotensin-aldosterone system

– Increase in SVR further reduces C.O.Increase in SVR further reduces C.O.

– Reduction of SVR is one goal of treatmentReduction of SVR is one goal of treatment


ContractilityContractility– Vigor of contraction of heart muscleVigor of contraction of heart muscle

– As contractility decreases, velocity of muscle As contractility decreases, velocity of muscle shortening and rate of intraventricular shortening and rate of intraventricular pressure development decrease (dP/dt)pressure development decrease (dP/dt)

– Goal of inotropic therapy is to increase Goal of inotropic therapy is to increase contractilitycontractility

Heart RateHeart Rate

Left Ventricular Dysfunction

Remodeling

Low Ejection Fraction

Death

Arrhythmia

Pump Failure

Chronic Heart Failure

Congestive Heart Failure: Pathophysiology

Classification of Heart FailureClassification of Heart Failure

Stage AStage A– High risk of developing heart failureHigh risk of developing heart failure– No structural disorder of the heart or signs of No structural disorder of the heart or signs of

symptoms of heart failuresymptoms of heart failure

Stage BStage B– Structural disorder of the heartStructural disorder of the heart– No signs or symptoms of heart failureNo signs or symptoms of heart failure

Stage CStage C– Past or current symptoms of heart failure associated Past or current symptoms of heart failure associated

with underlying structural heart diseasewith underlying structural heart disease

Stage DStage D– End-stage heart failure and need for specialized End-stage heart failure and need for specialized

treatment strategiestreatment strategies

CLASSIFICATION OF CHFCLASSIFICATION OF CHFCongestion at Rest

Low

Perfusion at

Rest

NO YES

NO

YES

Warm/Dry Warm/Wet

PCWP normal PCWP ↑ CI normal CI normal

Cold/Dry Cold/Wet

PCWP normal/↑ PCWP ↑

CI ↓ CI ↓

COMMON

Dry Them Out

Agents used to treat CHF:Agents used to treat CHF:

Inotropic agentsInotropic agents

DiureticsDiuretics– Antialdosterone therapyAntialdosterone therapy

VasodilatorsVasodilators

-blockers-blockers

Salt restrictionSalt restriction

Recent shift from hemodynamic to neurohumoral alterations

Diuretics in CHFDiuretics in CHF

Diuretic therapy results in:Diuretic therapy results in:– Improvement in sodium excretionImprovement in sodium excretion– Improvement in symptoms of fluid overloadImprovement in symptoms of fluid overload– Improvement in exercise toleranceImprovement in exercise tolerance– Improvement of cardiac functionImprovement of cardiac function

Should not be prescribed as monotherapyShould not be prescribed as monotherapy– Start for symptom controlStart for symptom control

Titrate to avoid excess volume depletionTitrate to avoid excess volume depletionUnder-titration can diminish response to ACE Under-titration can diminish response to ACE inhibitors and increase frequency of adverse inhibitors and increase frequency of adverse effects of treatment with effects of treatment with blockersblockers

Possible means of increasing Possible means of increasing myocardial contractilitymyocardial contractility

Increased intracellular CaIncreased intracellular Ca++++

– Increased cAMPIncreased cAMPStimulation of Stimulation of -receptors-receptorsStimulation of adenylate cyclaseStimulation of adenylate cyclaseInhibition of phosphodiesterase IIIInhibition of phosphodiesterase III

– cAMP independent mechanismscAMP independent mechanismsMembrane channelsMembrane channels

– Activation of CaActivation of Ca++++ and Na and Na++ channels channels– Inhibition of KInhibition of K++ channels channels

Membrane pumpsMembrane pumps– Inhibition of NaInhibition of Na++/ K/ K++ ATPase ATPase– Inhibition of NaInhibition of Na++/ Ca/ Ca++++ exchange exchange– Other mechanisms (stimulation of Other mechanisms (stimulation of receptors) receptors)

Increased sensitivity of contractile proteins to CaIncreased sensitivity of contractile proteins to Ca++++

Inotropic agents:Inotropic agents:

Act on heart muscle to improve contractility and Act on heart muscle to improve contractility and increase C.O.increase C.O.

11 adrenergic agonists adrenergic agonists– DopamineDopamine– DobutamineDobutamine

Bipyridine compoundsBipyridine compounds– Inamrinone Inamrinone – MilrinoneMilrinone

Cardiac (digitalis) glycosidesCardiac (digitalis) glycosides– DigoxinDigoxin– Digitoxin (discontinued Oct., 2000)Digitoxin (discontinued Oct., 2000)

Common Foxglove PlantCommon Foxglove PlantD. PurpureaD. Purpurea

Cardiac Glycosides:Cardiac Glycosides:

All compounds exert similar pharmacological All compounds exert similar pharmacological effectseffectsAgents differ in pharmacokinetic Agents differ in pharmacokinetic characteristicscharacteristicsDerived from naturally occurring compounds Derived from naturally occurring compounds obtained from leaves of:obtained from leaves of:– Digitalis purpurea (digitoxin)Digitalis purpurea (digitoxin)– Digitalis lanata (digoxin)Digitalis lanata (digoxin)

Known to ancient EgyptiansKnown to ancient EgyptiansWithering (1785) described effects of extract Withering (1785) described effects of extract of Foxglove plant in patients with of Foxglove plant in patients with dropsydropsy– An Account of the Foxglove, and Some of Its Medical Uses: With An Account of the Foxglove, and Some of Its Medical Uses: With

Practical Remarks on Dropsy and Other DiseasesPractical Remarks on Dropsy and Other Diseases

Cardiac Glycosides (Chemistry):Cardiac Glycosides (Chemistry):

Steroid nucleus combines with unsaturated 5-Steroid nucleus combines with unsaturated 5-member lactone ring at C17 position and series member lactone ring at C17 position and series of sugars linked to C3 of the nucleusof sugars linked to C3 of the nucleusLactone ring and steroid nucleus essential for Lactone ring and steroid nucleus essential for activity (=aglycone)activity (=aglycone)Sugar moiety influencesSugar moiety influences– AbsorptionAbsorption– Half-lifeHalf-life– MetabolismMetabolism

Cardiac Glycosides: Cardiac Glycosides: Pharmacological effectsPharmacological effects

PharmacodynamicsPharmacodynamics– Mechanical effectsMechanical effects– Electrical effectsElectrical effects

DirectDirectIndirect (involve reflex actions)Indirect (involve reflex actions)

Extracardiac effectsExtracardiac effectsDigitalis toxicityDigitalis toxicityPharmacokineticsPharmacokineticsClinical useClinical use

Mechanical Effects:Mechanical Effects:

Acts on cardiac muscle to increase contractile forceActs on cardiac muscle to increase contractile force= = + inotropic action+ inotropic actionMechanism of inotropic actionMechanism of inotropic action– Inhibition of NaInhibition of Na++-K-K++ ATPase ATPase (sodium pump)(sodium pump)

Promotes CaPromotes Ca++++ accumulation accumulation

– Increases force of contraction by facilitating Increases force of contraction by facilitating interaction of myocardial contractile proteinsinteraction of myocardial contractile proteins

Increases intensity of interaction of actin and myosin Increases intensity of interaction of actin and myosin filaments of cardiac sarcomerefilaments of cardiac sarcomereCaused by increases in free [CaCaused by increases in free [Ca++++] in vicinity of contractile ] in vicinity of contractile proteins during systole proteins during systole

Ion Fluxes across the Cardiac Cell Membrane

Relationship of [KRelationship of [K++] to digitalis action] to digitalis action

Potassium competes with digitalis for Potassium competes with digitalis for binding to Nabinding to Na++-K-K++ ATPase ATPase

When Potassium levels low, digitalis When Potassium levels low, digitalis binding increasesbinding increases– Increased binding produces excess inhibition Increased binding produces excess inhibition

of Naof Na++-K-K++ ATPase with resultant toxicity ATPase with resultant toxicity– [K[K++] must be kept within ] must be kept within normal normal rangerange

Digitalis Effects:Digitalis Effects:

In patients with CHFIn patients with CHF– Enhances contractility (inotropic)Enhances contractility (inotropic)– Reduces SVR (which occurred via compensatory processes)Reduces SVR (which occurred via compensatory processes)– Heart size decreasesHeart size decreases– C.O. increasesC.O. increases– As efficiency improves, MVOAs efficiency improves, MVO22 decreases decreases

In normal patientsIn normal patients– Increases SVRIncreases SVR

Increases peripheral vasoconstriction (direct)Increases peripheral vasoconstriction (direct)Increases central sympathetic outflowIncreases central sympathetic outflow

– Increases contractilityIncreases contractility– No change in C.O.No change in C.O.

Electrical Effects:Electrical Effects:

Therapeutic and Therapeutic and ToxicologicalToxicological Importance ImportanceDigitalis glycosides useful for treatment of Digitalis glycosides useful for treatment of arrhythmiasarrhythmias– Atrial fibrillationAtrial fibrillation– Atrial flutterAtrial flutter

May also cause arrhythmiasMay also cause arrhythmiasComplex effectsComplex effects– Direct effectsDirect effects– Indirect effectsIndirect effects

Electrical Effects:Electrical Effects:

Digitalis alters electrical activity of non-contractile Digitalis alters electrical activity of non-contractile tissuetissue– S-A nodeS-A node– A-V nodeA-V node– Purkinje fibersPurkinje fibers

Alters electrical activity of atrial and ventricular Alters electrical activity of atrial and ventricular musclemuscleCan alter:Can alter:– AutomaticityAutomaticity– RefractorinessRefractoriness– Impulse conductionImpulse conduction

Direct Electrical Effects:Direct Electrical Effects:

Result from inhibition of NaResult from inhibition of Na++-K-K++ ATPase ATPase

Alters distribution of ions across cardiac Alters distribution of ions across cardiac cell membranecell membrane

Alters electrical responsiveness of cellsAlters electrical responsiveness of cells

Direct effects heightened by Direct effects heightened by hypokalemiahypokalemia

Direct Electrical Actions:Direct Electrical Actions:

Direct actions on membranes of cardiac cells follow Direct actions on membranes of cardiac cells follow well-defined progression:well-defined progression:– Early, brief prolongation of Early, brief prolongation of action potentialaction potential– Protracted period of shortening of Protracted period of shortening of action potentialaction potential, especially , especially

plateauplateau? Result of inc. K? Result of inc. K++ conductance conductance

Caused by inc. intracellular CaCaused by inc. intracellular Ca++++

Contributes to shortening of atrial and ventricular refractorinessContributes to shortening of atrial and ventricular refractoriness

– Decreased conduction velocity through A-V node and in Purkinje Decreased conduction velocity through A-V node and in Purkinje systemsystem

– Increased refractory period in A-V nodeIncreased refractory period in A-V node

Direct Electrical Actions:Direct Electrical Actions:

Automaticity increases, particularly in ventricular Automaticity increases, particularly in ventricular tissue:tissue:– Decreased activity of normal pacemaker tissueDecreased activity of normal pacemaker tissue– Decreased ventricular refractory periodDecreased ventricular refractory period– Increase A-V blockIncrease A-V block

Ectopic foci can therefore be generated, particularly Ectopic foci can therefore be generated, particularly in Purkinje systemin Purkinje system– PVCs, bigeminyPVCs, bigeminy– Ventricular tachycardiaVentricular tachycardia– Ventricular fibrillationVentricular fibrillation

EKG Effects of Digitalis Glycosides:EKG Effects of Digitalis Glycosides:

P-R interval prolongationP-R interval prolongation– Prolonged A-V nodal conductionProlonged A-V nodal conduction

T-wave depressionT-wave depression– Increase in repolarization of subendocardial Increase in repolarization of subendocardial

tissuetissue

ST depressionST depressionQT interval shorteningQT interval shortening– Decreased time for ventricular systoleDecreased time for ventricular systole

Indirect Electrical Effects:Indirect Electrical Effects:

Digitalis increases Digitalis increases vagal vagal influencesinfluences– Increased rate of vagal firingIncreased rate of vagal firing

Slows spontaneous discharge of SA nodeSlows spontaneous discharge of SA node

Suppresses conduction through AV nodeSuppresses conduction through AV node

Causes reflex reduction in sympathetic toneCauses reflex reduction in sympathetic tone

Increase in vagal firing and decrease in sympathetic Increase in vagal firing and decrease in sympathetic tone causes:tone causes:– Decrease in SA automaticityDecrease in SA automaticity– Decrease in AV conduction (A-V block)Decrease in AV conduction (A-V block)

Actions are complimentaryActions are complimentary

Digital Glycosides: Digital Glycosides: Specific EffectsSpecific Effects

SA NodeSA Node– Slows pacemaker activitySlows pacemaker activity

Increased vagal activityIncreased vagal activityDecreased sympathetic activityDecreased sympathetic activity

AV NodeAV Node– Decreased conduction through AV nodeDecreased conduction through AV node– Increased refractoriness of AV nodeIncreased refractoriness of AV node

– = A-V block= A-V block Purkinje FibersPurkinje Fibers– Increased automaticityIncreased automaticity– Ectopic fociEctopic foci– Ventricular arrhythmiasVentricular arrhythmias

Cardiotoxicity of Digitalis:Cardiotoxicity of Digitalis:Arrhythmia productionArrhythmia production– Most serious adverse effectMost serious adverse effect– Secondary to alteration of electrical propertiesSecondary to alteration of electrical properties– Assess all patients for alterations in Assess all patients for alterations in raterate and and rhythmrhythm

All arrhythmias seenAll arrhythmias seen– BradycardiaBradycardia– A-V block, A-V junctional rhythmA-V block, A-V junctional rhythm– Ventricular tachycardiaVentricular tachycardia– Ventricular fibrillationVentricular fibrillation

Cardiotoxicity of Digitalis:Cardiotoxicity of Digitalis:

Mechanism of arrhythmia generation:Mechanism of arrhythmia generation:– Inc. automaticity of atrial and ventricular tissueInc. automaticity of atrial and ventricular tissue

ectopyectopy

– Dec. conduction through A-V nodeDec. conduction through A-V nodeA-V blockA-V block

– Both factors due to Both factors due to NaNa++-K-K++ ATPase ATPase inhibitioninhibition

Augmented by hypokalemiaAugmented by hypokalemia

Cardiotoxicity of Digitalis:Cardiotoxicity of Digitalis:

Predisposing factors:Predisposing factors:– HypokalemiaHypokalemia– Digitalis toxicityDigitalis toxicity– MyocarditisMyocarditis– HypercalcemiaHypercalcemia– HypomagnesemiaHypomagnesemia– HypothyroidismHypothyroidism– AgeAge– Renal diseaseRenal disease– HypoxemiaHypoxemia

Digitalis Toxicity:Digitalis Toxicity:

Defined solely as elevation in serum Defined solely as elevation in serum digitalis digitalis levellevel– Digoxin > 2.5 ng/mlDigoxin > 2.5 ng/ml– Digitoxin >35 ng/ml (of historical interest)Digitoxin >35 ng/ml (of historical interest)

Digoxin levels may rise secondary to use of:Digoxin levels may rise secondary to use of:– AmiodaroneAmiodarone– VerapamilVerapamil– DiltiazemDiltiazem– Quinidine Quinidine

Digitalis Toxicity: ManagementDigitalis Toxicity: Management

Discontinue drugDiscontinue drugCorrect Correct hypokalemiahypokalemiaAntiarrhythmicsAntiarrhythmics– LidocaineLidocaine– PhenytoinPhenytoin

Pacemaker InsertionPacemaker Insertion

Digibind®Digibind® administration administration– Digoxin-specific Fab fragmentsDigoxin-specific Fab fragments

Prevents tissue binding of digoxinPrevents tissue binding of digoxin30 minute onset of action30 minute onset of actionClearance within 3-4 daysClearance within 3-4 days

– Digoxin + Fab fragments in urineDigoxin + Fab fragments in urine

Dialysis Dialysis ineffectiveineffective

Extracardiac Effects of Digitalis:Extracardiac Effects of Digitalis:

GastrointestinalGastrointestinal– AnorexiaAnorexia– NauseaNausea– Vomiting Vomiting

Central Nervous SystemCentral Nervous System– FatigueFatigue– Visual disturbancesVisual disturbances

Halos around lightsHalos around lightsAlteration of color perceptionAlteration of color perception

– HallucinationsHallucinations– DisorientationDisorientation

Therapeutic Uses of Digitalis:Therapeutic Uses of Digitalis:

Congestive Heart FailureCongestive Heart Failure– Indicated in patients with severe LV dysfunctionIndicated in patients with severe LV dysfunction

Primarily used Primarily used afterafter diuretics and vasodilators diuretics and vasodilatorsNot useful in diastolic dysfunction or right-sided heart failureNot useful in diastolic dysfunction or right-sided heart failureMost efficacious when S3 noted on examinationMost efficacious when S3 noted on examination

Atrial arrhythmiasAtrial arrhythmias– Indicated in atrial fibrillation and atrial flutterIndicated in atrial fibrillation and atrial flutter– Used to slow ventricular responseUsed to slow ventricular response

Therapeutic serum levelsTherapeutic serum levels– Digoxin 0.5-2.2 ng/mlDigoxin 0.5-2.2 ng/ml– Digitoxin 9-25 ng/ml

Digoxin Pharmacokinetics:Digoxin Pharmacokinetics:

Variable oral absorptionVariable oral absorption– Liquid more complete and less variable than tabletsLiquid more complete and less variable than tablets

VVDD = = 6-7 L/kg6-7 L/kg

Binds strongly to proteins in extravascular spaceBinds strongly to proteins in extravascular spaceRenal excretionRenal excretion– Clearance slowed in renal dysfunctionClearance slowed in renal dysfunction– 37% excreted per day37% excreted per day

Minimal hepatic metabolism (<20%)Minimal hepatic metabolism (<20%)Half-life = 1.6 days (30-40 hours)Half-life = 1.6 days (30-40 hours)5xhalf-life to attain plateau (7 days)5xhalf-life to attain plateau (7 days)– DigitalizationDigitalization

Oral and IV administrationOral and IV administration

Digitoxin Pharmacokinetics:Digitoxin Pharmacokinetics:

Absorption almost complete (>90%)Absorption almost complete (>90%)– Less polar and more lipid soluble than DLess polar and more lipid soluble than Digoxinigoxin– Cholestyramine can alter enterohepatic cyclingCholestyramine can alter enterohepatic cycling

Elimination primarily via hepatic metabolism (>80%)Elimination primarily via hepatic metabolism (>80%)– Large capacity of the liver to metabolizeLarge capacity of the liver to metabolize– InducibleInducible

>95% bound to albumin>95% bound to albumin

VVDD = = 0.6 L/kg0.6 L/kg

Half-life = 7 daysHalf-life = 7 days– 4 weeks to reach plateau4 weeks to reach plateau

Oral administrationOral administrationOf Historical Interest: No longer availableOf Historical Interest: No longer available

Bipyridines:Bipyridines:

Inamrinone, formerly amrinoneInamrinone, formerly amrinoneMilrinone (Primacor®) Milrinone (Primacor®) – More potent, higher selectivity for PDEMore potent, higher selectivity for PDE

Phosphodiesterase III inhibitorsPhosphodiesterase III inhibitors– Results in increase in cAMPResults in increase in cAMP– Increases Increases CaCa++++ during action potential during action potential

Similar effects toSimilar effects to receptor stimulationreceptor stimulationVasodilator effects occurVasodilator effects occur

– Decreases preload and afterloadDecreases preload and afterload– Partially responsible for improved C.O.Partially responsible for improved C.O.– Little change in BPLittle change in BP

Used via IV route by continuous infusionUsed via IV route by continuous infusion

BipyridinesBipyridines

Bipyridines: Bipyridines: Inamrinone and MilrinoneInamrinone and Milrinone

Indicated for Indicated for short-termshort-term management of management of severe CHF severe CHF not not responding to digitalis, responding to digitalis, diuretics, vasodilatorsdiuretics, vasodilatorsInamrinone has not been shown to prolong Inamrinone has not been shown to prolong survival or reduce incidence of sudden survival or reduce incidence of sudden deathdeathMilrinone has been shown to Milrinone has been shown to increaseincrease mortality mortality withoutwithout definite benefit definite benefit

Bipyridines: Bipyridines:

Inamrinone metabolized by conjugative pathwaysInamrinone metabolized by conjugative pathways– tt1/21/2 2-3 hours (Milrinone = 30-60 minutes) 2-3 hours (Milrinone = 30-60 minutes)

Excreted in urine as inamrinone and metabolitesExcreted in urine as inamrinone and metabolites

Potentiate arrhythmias in high-risk patients treatedPotentiate arrhythmias in high-risk patients treated

Adverse effects:Adverse effects:– Thrombocytopenia (3% with inamrinone)Thrombocytopenia (3% with inamrinone)– Hepatic toxicityHepatic toxicity

Vasodilators in CHF:Vasodilators in CHF:

Useful in reducing preload and/or afterloadUseful in reducing preload and/or afterloadArterial dilators primarily reduce afterloadArterial dilators primarily reduce afterload– Decrease SVRDecrease SVR– Decrease impedance Decrease impedance

Venous dilators primarily reduce preloadVenous dilators primarily reduce preload– Cause increase in venous capacitanceCause increase in venous capacitance– Pooling of blood in veinsPooling of blood in veins– Decrease in venous returnDecrease in venous return– Relief of congestionRelief of congestion

Vasodilators in CHF:Vasodilators in CHF:

Organic nitratesOrganic nitrates

Direct vasodilatorsDirect vasodilators

Angiotensin-converting enzyme inhibitorsAngiotensin-converting enzyme inhibitors– Beneficial effects in the treatment and Beneficial effects in the treatment and

prevention of heart failureprevention of heart failure– Decrease morbidity and mortalityDecrease morbidity and mortality

Assessment of LV Function

(Echocardiogram, Radionuclide Ventriculogram)

EF < 40%

Assessment of Volume Status

Signs and Symptoms of

Fluid Retention

Diuretic (Titrate to Euvolemic

State)

No Signs and Symptoms of Fluid

Retention

ACE Inhibitor

-Blocker

Digoxin

Recommended Approach to the Patient with Heart Failure

New VasodilatorsNew Vasodilators

Nesiritide (Natrecor®)Nesiritide (Natrecor®)– Natriuretic peptideNatriuretic peptide

Bosentan (Tracleer®)Bosentan (Tracleer®)– Endothelin receptor antagonistEndothelin receptor antagonist

Epoprostenol (Flolan®)Epoprostenol (Flolan®)– Prostacyclin (PGIProstacyclin (PGI22))

Nesiritide (Natrecor®)Nesiritide (Natrecor®)

Human B-type natriuretic peptide (hBNP)Human B-type natriuretic peptide (hBNP)– Endogenous 32-amino acid peptide hormoneEndogenous 32-amino acid peptide hormone

Structurally similar to atrial natriuretic peptide (ANP)Structurally similar to atrial natriuretic peptide (ANP)

– Manufactured from Manufactured from E. coliE. coli using recombinant DNA using recombinant DNA technologytechnology

– Binds to particulate Binds to particulate guanylate cyclaseguanylate cyclase receptor receptorVascular smooth muscleVascular smooth muscleEndothelial cellsEndothelial cells

– Increases intracellular cGMP » smooth muscle Increases intracellular cGMP » smooth muscle relaxationrelaxation

Relaxes arterial and venous tissue pre-contracted with Relaxes arterial and venous tissue pre-contracted with endothelin-1 or phenylephrineendothelin-1 or phenylephrine


Pharmacological ActionsPharmacological Actions– HemodynamicsHemodynamics

VenodilatationVenodilatationArterial DilatationArterial DilatationCoronary Artery DilatationCoronary Artery Dilatation

– NeurohumoralNeurohumoral aldosteronealdosterone norepinephrinenorepinephrine↓ ↓ endothelinendothelin

– RenalRenalDiuresisDiuresis↑↑ GFRGFRNatriuresisNatriuresis

Lusitropic

Anti-fibrotic

Anti-remodeling


Pharmacological ActionsPharmacological ActionsProduces dose dependent reductions in PCWP Produces dose dependent reductions in PCWP and systemic arterial pressure in patients with and systemic arterial pressure in patients with heart failureheart failure

Improves dyspneaImproves dyspnea

No effect on cardiac contractilityNo effect on cardiac contractility

No effect of conduction or refractory timesNo effect of conduction or refractory times

Indicated in acutely decompensated CHFIndicated in acutely decompensated CHF


PharmacokineticsPharmacokinetics– IV Bolus and InfusionIV Bolus and Infusion– Biphasic disposition from plasmaBiphasic disposition from plasma

Mean terminal elimination half-life = 18 min.Mean terminal elimination half-life = 18 min.Mean initial elimination half-life = 2 min.Mean initial elimination half-life = 2 min.

– Cleared from circulation via 3 independent Cleared from circulation via 3 independent mechanismsmechanisms

Binding to cell surface clearance receptors with cellular Binding to cell surface clearance receptors with cellular internalization and lysosomal proteolysisinternalization and lysosomal proteolysisProteolytic cleavage of peptide by endopeptidaseProteolytic cleavage of peptide by endopeptidaseRenal filtrationRenal filtration

Heart Failure Management Heart Failure Management Recommendations Recommendations

Stage A (High Risk of Developing Heart Stage A (High Risk of Developing Heart Failure)Failure)– Risk-factor managementRisk-factor management

Control of hypertension, diabetes, lipid disordersControl of hypertension, diabetes, lipid disorders

– Use of ACE Inhibitor in patients with Use of ACE Inhibitor in patients with atherosclerotic heart disease, hypertension, atherosclerotic heart disease, hypertension, diabetes, or other risk factorsdiabetes, or other risk factors

– Control of ventricular rate in patients with Control of ventricular rate in patients with supraventricular tachyarrhythmiasupraventricular tachyarrhythmia

– Treatment of thyroid disordersTreatment of thyroid disorders

Heart Failure Management Heart Failure Management RecommendationsRecommendations

Stage B (Left ventricular dysfunction Stage B (Left ventricular dysfunction without symptoms)without symptoms)– Use of ACE inhibitor in patients with history of Use of ACE inhibitor in patients with history of

MI, or reduced ejection fraction regardless of MI, or reduced ejection fraction regardless of history of MIhistory of MI

– Use of Use of ββ-blocker in patients with history of MI, -blocker in patients with history of MI, or reduced ejection fraction regardless of or reduced ejection fraction regardless of history of MIhistory of MI

– Valve replacement or repair in patients with Valve replacement or repair in patients with hemodynamically important valvular diseasehemodynamically important valvular disease

– Long-term use of systemic vasodilator in Long-term use of systemic vasodilator in patients with severe aortic regurgitationpatients with severe aortic regurgitation


Stage C (Symptomatic left ventricular Stage C (Symptomatic left ventricular dysfunction)dysfunction)– Use of diuretic in patients with fluid retentionUse of diuretic in patients with fluid retention– Use of ACE inhibitor (unless contraindicated)Use of ACE inhibitor (unless contraindicated)– Use of Use of ββ-blocker (unless contraindicated)-blocker (unless contraindicated)– Use of digoxin (unless contraindicated)Use of digoxin (unless contraindicated)– Discontinuation of drugs known to affect Discontinuation of drugs known to affect

patient status adverselypatient status adverselyNSAIDNSAIDAntiarrhythmicsAntiarrhythmicsCalcium channels blockersCalcium channels blockers


Stage C (Symptomatic left ventricular Stage C (Symptomatic left ventricular dysfunction)dysfunction)– Use of spironolactone in patients with Class IV Use of spironolactone in patients with Class IV

symptoms, preserved renal function, normal potassium symptoms, preserved renal function, normal potassium levelslevels

– Exercise (rehabilitation)Exercise (rehabilitation)– Use of angiotensin II receptor blocker in patients Use of angiotensin II receptor blocker in patients

treated with digoxin, diuretic, or treated with digoxin, diuretic, or ββ-blockers who cannot -blockers who cannot tolerate ACE inhibitors (cough/angioedema)tolerate ACE inhibitors (cough/angioedema)

– Use of hydralazine-nitrate combinationsUse of hydralazine-nitrate combinations– Addition of angiotensin II receptor blocker to ACE Addition of angiotensin II receptor blocker to ACE

inhibitorinhibitor

BosentanBosentan

Indicated for pulmonary hypertensionIndicated for pulmonary hypertension

Approved Nov. 20, 2001Approved Nov. 20, 2001

Endothelin-1 receptor antagonistEndothelin-1 receptor antagonist– Binds to ETBinds to ETAA and ET and ETBB receptors receptors

– Specific and competitive antagonistSpecific and competitive antagonist– Located in endothelium and vascular smooth muscleLocated in endothelium and vascular smooth muscle– ET-1 levels increased in PAH suggesting pathogenic ET-1 levels increased in PAH suggesting pathogenic

role for ET-1role for ET-1

BosentanBosentan

PharmacokineticsPharmacokinetics– Oral administrationOral administration

50% bioavailable50% bioavailable

Unaffected by foodUnaffected by food

– Highly protein bound (albumin)Highly protein bound (albumin)– 3 metabolites, 1 active contributing to 10-20% of 3 metabolites, 1 active contributing to 10-20% of

effecteffect– Inducer of CYP2C9 and CYP3A4Inducer of CYP2C9 and CYP3A4– Eliminated by biliary excretion and hepatic Eliminated by biliary excretion and hepatic

metabolismmetabolism

BosentanBosentan

Pregnancy category XPregnancy category X– Teratogenic in ratsTeratogenic in rats– Pregnancy should be excluded before start of Pregnancy should be excluded before start of

treatmenttreatment

May impair fertilityMay impair fertility

HepatotoxicHepatotoxic

Carcinogenic in miceCarcinogenic in mice

Cardiac Glycosides and Therapy of Congestive Heart Failure Philip Marcus, MD MPH.

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Transcript of Cardiac Glycosides and Therapy of Congestive Heart Failure Philip Marcus, MD MPH.