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Cardiac Glycosides and Therapy of Congestive Heart Failure

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Title: Cardiac Glycosides and Therapy of Congestive Heart Failure


1
Cardiac Glycosides and Therapy of Congestive
Heart Failure
0
  • Philip Marcus, MD MPH

2
Pathophysiology of Congestive Heart Failure
0
  • Inability of the heart to pump blood in amounts
    sufficient to meet metabolic needs of the tissues
  • Will result in
  • Fatigue
  • Decreased exercise tolerance
  • Dyspnea
  • Orthopnea
  • Venous distention
  • Edema
  • Cardiomegaly
  • Hepatomegaly
  • Tachycardia
  • Progressive disease that begins long before signs
    and symptoms are evident

3
Pathophysiology of Congestive Heart Failure
0
  • Etiology of Congestive Heart Failure
  • Hypertension
  • Coronary artery disease
  • Acute myocardial infarction
  • Cardiomyopathy
  • Primary defect in CHF (systolic dysfunction)
  • Reduction in contractile force of cardiac muscle
  • Decreased Cardiac Output (reduced ejection
    fraction)
  • Diastolic Dysfunction
  • Elevated end-diastolic pressure
  • Normal-sized chamber (LV)
  • Inability to fill and relax ventricle

4
Physiologic Adaptations to Reduced Cardiac Output
(to improve perfusion)
0
  • Cardiac Dilatation
  • Increased sympathetic tone
  • Increased heart rate
  • Increased contractility
  • Increase in venous tone
  • Increase in preload
  • Increase in arteriolar tone
  • Increase in afterload

5
Physiologic Adaptations to Reduced Cardiac Output
(to improve perfusion)
0
  • Water retention and increase in blood volume
  • Reduction in CO leads to decrease in RBF
  • Reduced RBF leads to decrease in GFR
  • Decrease in GFR leads to decreased urine
    production
  • Decrease in RBF leads to increase in renin
    activity
  • Increase in renin causes increase in aldosterone
  • Increased aldosterone leads to sodium and water
    retention

6
0
7
Determinants of Cardiac Performance
0
  • Preload
  • Measure of LV filling (stretch)
  • Measure LVEDV, LVEDP
  • In CHF, preload increases and cardiac performance
    (SV, Stroke work) decrease
  • Increased preload secondary to
  • Increase in blood volume
  • Increase in venous tone
  • Reduction of high filling pressure is goal of
    therapy

8
Determinants of Cardiac Performance
0
  • Afterload
  • Resistance against which the heart must pump
    blood
  • Represented by aortic impedance and systemic
    vascular resistance
  • SVR increases in CHF secondary to
  • Increased sympathetic outflow
  • Increase in circulating catecholamines
  • Activation of renin-angiotensin-aldosterone
    system
  • Increase in SVR further reduces C.O.
  • Reduction of SVR is one goal of treatment

9
Determinants of Cardiac Performance
0
  • Contractility
  • Vigor of contraction of heart muscle
  • As contractility decreases, velocity of muscle
    shortening and rate of intraventricular pressure
    development decrease (dP/dt)
  • Goal of inotropic therapy is to increase
    contractility
  • Heart Rate

10
0
Left Ventricular Dysfunction
Remodeling
Arrhythmia
Low Ejection Fraction
Death
Pump Failure
Congestive Heart Failure Pathophysiology
Chronic Heart Failure
11
Classification of Heart Failure
0
  • Stage A
  • High risk of developing heart failure
  • No structural disorder of the heart or signs of
    symptoms of heart failure
  • Stage B
  • Structural disorder of the heart
  • No signs or symptoms of heart failure
  • Stage C
  • Past or current symptoms of heart failure
    associated with underlying structural heart
    disease
  • Stage D
  • End-stage heart failure and need for specialized
    treatment strategies

12
CLASSIFICATION OF CHF
0
Congestion at Rest
Dry Them Out
NO
YES
Warm/Dry Warm/Wet PCWP normal
PCWP ? CI normal
CI normal Cold/Dry
Cold/Wet PCWP normal/? PCWP ? CI
? CI ?
NO
Low Perfusion at Rest
COMMON
YES
13
Agents used to treat CHF
0
  • Inotropic agents
  • Diuretics
  • Antialdosterone therapy
  • Vasodilators
  • b-blockers
  • Salt restriction

Recent shift from hemodynamic to neurohumoral
alterations
14
Diuretics in CHF
0
  • Diuretic therapy results in
  • Improvement in sodium excretion
  • Improvement in symptoms of fluid overload
  • Improvement in exercise tolerance
  • Improvement of cardiac function
  • Should not be prescribed as monotherapy
  • Start for symptom control
  • Titrate to avoid excess volume depletion
  • Under-titration can diminish response to ACE
    inhibitors and increase frequency of adverse
    effects of treatment with b-blockers

15
Possible means of increasing myocardial
contractility
0
  • Increased intracellular Ca
  • Increased cAMP
  • Stimulation of b-receptors
  • Stimulation of adenylate cyclase
  • Inhibition of phosphodiesterase III
  • cAMP independent mechanisms
  • Membrane channels
  • Activation of Ca and Na channels
  • Inhibition of K channels
  • Membrane pumps
  • Inhibition of Na/ K ATPase
  • Inhibition of Na/ Ca exchange
  • Other mechanisms (stimulation of a receptors)
  • Increased sensitivity of contractile proteins to
    Ca

16
Inotropic agents
0
  • Act on heart muscle to improve contractility and
    increase C.O.
  • b1 adrenergic agonists
  • Dopamine
  • Dobutamine
  • Bipyridine compounds
  • Inamrinone
  • Milrinone
  • Cardiac (digitalis) glycosides
  • Digoxin
  • Digitoxin (discontinued Oct., 2000)

17
Common Foxglove PlantD. Purpurea
0
18
Cardiac Glycosides
0
  • All compounds exert similar pharmacological
    effects
  • Agents differ in pharmacokinetic characteristics
  • Derived from naturally occurring compounds
    obtained from leaves of
  • Digitalis purpurea (digitoxin)
  • Digitalis lanata (digoxin)
  • Known to ancient Egyptians
  • Withering (1785) described effects of extract of
    Foxglove plant in patients with dropsy
  • An Account of the Foxglove, and Some of Its
    Medical Uses With Practical Remarks on Dropsy
    and Other Diseases

19
0
20
0
21
Cardiac Glycosides (Chemistry)
0
  • Steroid nucleus combines with unsaturated
    5-member lactone ring at C17 position and series
    of sugars linked to C3 of the nucleus
  • Lactone ring and steroid nucleus essential for
    activity (aglycone)
  • Sugar moiety influences
  • Absorption
  • Half-life
  • Metabolism

22
Cardiac Glycosides Pharmacological effects
0
  • Pharmacodynamics
  • Mechanical effects
  • Electrical effects
  • Direct
  • Indirect (involve reflex actions)
  • Extracardiac effects
  • Digitalis toxicity
  • Pharmacokinetics
  • Clinical use

23
Mechanical Effects
0
  • Acts on cardiac muscle to increase contractile
    force
  • inotropic action
  • Mechanism of inotropic action
  • Inhibition of Na-K ATPase (sodium pump)
  • Promotes Ca accumulation
  • Increases force of contraction by facilitating
    interaction of myocardial contractile proteins
  • Increases intensity of interaction of actin and
    myosin filaments of cardiac sarcomere
  • Caused by increases in free Ca in vicinity of
    contractile proteins during systole

24
0
Ion Fluxes across the Cardiac Cell Membrane
25
Relationship of K to digitalis action
0
  • Potassium competes with digitalis for binding to
    Na-K ATPase
  • When Potassium levels low, digitalis binding
    increases
  • Increased binding produces excess inhibition of
    Na-K ATPase with resultant toxicity
  • K must be kept within normal range

26
Digitalis Effects
0
  • In patients with CHF
  • Enhances contractility (inotropic)
  • Reduces SVR (which occurred via compensatory
    processes)
  • Heart size decreases
  • C.O. increases
  • As efficiency improves, MVO2 decreases
  • In normal patients
  • Increases SVR
  • Increases peripheral vasoconstriction (direct)
  • Increases central sympathetic outflow
  • Increases contractility
  • No change in C.O.

27
Electrical Effects
0
  • Therapeutic and Toxicological Importance
  • Digitalis glycosides useful for treatment of
    arrhythmias
  • Atrial fibrillation
  • Atrial flutter
  • May also cause arrhythmias
  • Complex effects
  • Direct effects
  • Indirect effects

28
Electrical Effects
0
  • Digitalis alters electrical activity of
    non-contractile tissue
  • S-A node
  • A-V node
  • Purkinje fibers
  • Alters electrical activity of atrial and
    ventricular muscle
  • Can alter
  • Automaticity
  • Refractoriness
  • Impulse conduction

29
Direct Electrical Effects
0
  • Result from inhibition of Na-K ATPase
  • Alters distribution of ions across cardiac cell
    membrane
  • Alters electrical responsiveness of cells
  • Direct effects heightened by hypokalemia

30
Direct Electrical Actions
0
  • Direct actions on membranes of cardiac cells
    follow well-defined progression
  • Early, brief prolongation of action potential
  • Protracted period of shortening of action
    potential, especially plateau
  • ? Result of inc. K conductance
  • Caused by inc. intracellular Ca
  • Contributes to shortening of atrial and
    ventricular refractoriness
  • Decreased conduction velocity through A-V node
    and in Purkinje system
  • Increased refractory period in A-V node

31
Direct Electrical Actions
0
  • Automaticity increases, particularly in
    ventricular tissue
  • Decreased activity of normal pacemaker tissue
  • Decreased ventricular refractory period
  • Increase A-V block
  • Ectopic foci can therefore be generated,
    particularly in Purkinje system
  • PVCs, bigeminy
  • Ventricular tachycardia
  • Ventricular fibrillation

32
EKG Effects of Digitalis Glycosides
0
  • P-R interval prolongation
  • Prolonged A-V nodal conduction
  • T-wave depression
  • Increase in repolarization of subendocardial
    tissue
  • ST depression
  • QT interval shortening
  • Decreased time for ventricular systole

33
Indirect Electrical Effects
0
  • Digitalis increases vagal influences
  • Increased rate of vagal firing
  • Slows spontaneous discharge of SA node
  • Suppresses conduction through AV node
  • Causes reflex reduction in sympathetic tone
  • Increase in vagal firing and decrease in
    sympathetic tone causes
  • Decrease in SA automaticity
  • Decrease in AV conduction (A-V block)
  • Actions are complimentary

34
Digital Glycosides Specific Effects
0
  • SA Node
  • Slows pacemaker activity
  • Increased vagal activity
  • Decreased sympathetic activity
  • AV Node
  • Decreased conduction through AV node
  • Increased refractoriness of AV node
  • A-V block
  • Purkinje Fibers
  • Increased automaticity
  • Ectopic foci
  • Ventricular arrhythmias

35
Cardiotoxicity of Digitalis
0
  • Arrhythmia production
  • Most serious adverse effect
  • Secondary to alteration of electrical properties
  • Assess all patients for alterations in rate and
    rhythm
  • All arrhythmias seen
  • Bradycardia
  • A-V block, A-V junctional rhythm
  • Ventricular tachycardia
  • Ventricular fibrillation

36
Cardiotoxicity of Digitalis
0
  • Mechanism of arrhythmia generation
  • Inc. automaticity of atrial and ventricular
    tissue
  • ectopy
  • Dec. conduction through A-V node
  • A-V block
  • Both factors due to Na-K ATPase inhibition
  • Augmented by hypokalemia

37
Cardiotoxicity of Digitalis
0
  • Predisposing factors
  • Hypokalemia
  • Digitalis toxicity
  • Myocarditis
  • Hypercalcemia
  • Hypomagnesemia
  • Hypothyroidism
  • Age
  • Renal disease
  • Hypoxemia

38
Digitalis Toxicity
0
  • Defined solely as elevation in serum digitalis
    level
  • Digoxin gt 2.5 ng/ml
  • Digitoxin gt35 ng/ml (of historical interest)
  • Digoxin levels may rise secondary to use of
  • Amiodarone
  • Verapamil
  • Diltiazem
  • Quinidine

39
Digitalis Toxicity Management
0
  • Discontinue drug
  • Correct hypokalemia
  • Antiarrhythmics
  • Lidocaine
  • Phenytoin
  • Pacemaker Insertion
  • Digibind administration
  • Digoxin-specific Fab fragments
  • Prevents tissue binding of digoxin
  • 30 minute onset of action
  • Clearance within 3-4 days
  • Digoxin Fab fragments in urine
  • Dialysis ineffective

40
Extracardiac Effects of Digitalis
0
  • Gastrointestinal
  • Anorexia
  • Nausea
  • Vomiting
  • Central Nervous System
  • Fatigue
  • Visual disturbances
  • Halos around lights
  • Alteration of color perception
  • Hallucinations
  • Disorientation

41
Therapeutic Uses of Digitalis
0
  • Congestive Heart Failure
  • Indicated in patients with severe LV dysfunction
  • Primarily used after diuretics and vasodilators
  • Not useful in diastolic dysfunction or
    right-sided heart failure
  • Most efficacious when S3 noted on examination
  • Atrial arrhythmias
  • Indicated in atrial fibrillation and atrial
    flutter
  • Used to slow ventricular response
  • Therapeutic serum levels
  • Digoxin 0.5-2.2 ng/ml
  • Digitoxin 9-25 ng/ml

42
0
43
Digoxin Pharmacokinetics
0
  • Variable oral absorption
  • Liquid more complete and less variable than
    tablets
  • VD 6-7 L/kg
  • Binds strongly to proteins in extravascular space
  • Renal excretion
  • Clearance slowed in renal dysfunction
  • 37 excreted per day
  • Minimal hepatic metabolism (lt20)
  • Half-life 1.6 days (30-40 hours)
  • 5xhalf-life to attain plateau (7 days)
  • Digitalization
  • Oral and IV administration

44
Digitoxin Pharmacokinetics
0
  • Absorption almost complete (gt90)
  • Less polar and more lipid soluble than Digoxin
  • Cholestyramine can alter enterohepatic cycling
  • Elimination primarily via hepatic metabolism
    (gt80)
  • Large capacity of the liver to metabolize
  • Inducible
  • gt95 bound to albumin
  • VD 0.6 L/kg
  • Half-life 7 days
  • 4 weeks to reach plateau
  • Oral administration
  • Of Historical Interest No longer available

45
Bipyridines
0
  • Inamrinone, formerly amrinone
  • Milrinone (Primacor)
  • More potent, higher selectivity for PDE
  • Phosphodiesterase III inhibitors
  • Results in increase in cAMP
  • Increases Ca during action potential
  • Similar effects to b-receptor stimulation
  • Vasodilator effects occur
  • Decreases preload and afterload
  • Partially responsible for improved C.O.
  • Little change in BP
  • Used via IV route by continuous infusion

46
Bipyridines
0
47
Bipyridines Inamrinone and Milrinone
0
  • Indicated for short-term management of severe CHF
    not responding to digitalis, diuretics,
    vasodilators
  • Inamrinone has not been shown to prolong survival
    or reduce incidence of sudden death
  • Milrinone has been shown to increase mortality
    without definite benefit

48
Bipyridines
0
  • Inamrinone metabolized by conjugative pathways
  • t1/2 2-3 hours (Milrinone 30-60 minutes)
  • Excreted in urine as inamrinone and metabolites
  • Potentiate arrhythmias in high-risk patients
    treated
  • Adverse effects
  • Thrombocytopenia (3 with inamrinone)
  • Hepatic toxicity

49
Vasodilators in CHF
0
  • Useful in reducing preload and/or afterload
  • Arterial dilators primarily reduce afterload
  • Decrease SVR
  • Decrease impedance
  • Venous dilators primarily reduce preload
  • Cause increase in venous capacitance
  • Pooling of blood in veins
  • Decrease in venous return
  • Relief of congestion

50
Vasodilators in CHF
0
  • Organic nitrates
  • Direct vasodilators
  • Angiotensin-converting enzyme inhibitors
  • Beneficial effects in the treatment and
    prevention of heart failure
  • Decrease morbidity and mortality

51
0
52
0
Assessment of LV Function (Echocardiogram,
Radionuclide Ventriculogram)
EF lt 40
Assessment of Volume Status
Signs and Symptoms of Fluid Retention
No Signs and Symptoms of Fluid Retention
ACE Inhibitor
Diuretic (Titrate to Euvolemic State)
Digoxin
B-Blocker
Recommended Approach to the Patient with Heart
Failure
53
New Vasodilators
0
  • Nesiritide (Natrecor)
  • Natriuretic peptide
  • Bosentan (Tracleer)
  • Endothelin receptor antagonist
  • Epoprostenol (Flolan)
  • Prostacyclin (PGI2)

54
Nesiritide (Natrecor)
0
  • Human B-type natriuretic peptide (hBNP)
  • Endogenous 32-amino acid peptide hormone
  • Structurally similar to atrial natriuretic
    peptide (ANP)
  • Manufactured from E. coli using recombinant DNA
    technology
  • Binds to particulate guanylate cyclase receptor
  • Vascular smooth muscle
  • Endothelial cells
  • Increases intracellular cGMP smooth muscle
    relaxation
  • Relaxes arterial and venous tissue pre-contracted
    with endothelin-1 or phenylephrine

55
Nesiritide (Natrecor)
0
  • Pharmacological Actions
  • Hemodynamics
  • Venodilatation
  • Arterial Dilatation
  • Coronary Artery Dilatation
  • Neurohumoral
  • ? aldosterone
  • ? norepinephrine
  • ? endothelin
  • Renal
  • Diuresis
  • ? GFR
  • Natriuresis

Lusitropic Anti-fibrotic Anti-remodeling
56
Nesiritide (Natrecor)
0
  • Pharmacological Actions
  • Produces dose dependent reductions in PCWP and
    systemic arterial pressure in patients with heart
    failure
  • Improves dyspnea
  • No effect on cardiac contractility
  • No effect of conduction or refractory times
  • Indicated in acutely decompensated CHF

57
Nesiritide (Natrecor)
0
  • Pharmacokinetics
  • IV Bolus and Infusion
  • Biphasic disposition from plasma
  • Mean terminal elimination half-life 18 min.
  • Mean initial elimination half-life 2 min.
  • Cleared from circulation via 3 independent
    mechanisms
  • Binding to cell surface clearance receptors with
    cellular internalization and lysosomal
    proteolysis
  • Proteolytic cleavage of peptide by endopeptidase
  • Renal filtration

58
Heart Failure Management Recommendations
0
  • Stage A (High Risk of Developing Heart Failure)
  • Risk-factor management
  • Control of hypertension, diabetes, lipid
    disorders
  • Use of ACE Inhibitor in patients with
    atherosclerotic heart disease, hypertension,
    diabetes, or other risk factors
  • Control of ventricular rate in patients with
    supraventricular tachyarrhythmia
  • Treatment of thyroid disorders

59
Heart Failure Management Recommendations
0
  • Stage B (Left ventricular dysfunction without
    symptoms)
  • Use of ACE inhibitor in patients with history of
    MI, or reduced ejection fraction regardless of
    history of MI
  • Use of ß-blocker in patients with history of MI,
    or reduced ejection fraction regardless of
    history of MI
  • Valve replacement or repair in patients with
    hemodynamically important valvular disease
  • Long-term use of systemic vasodilator in patients
    with severe aortic regurgitation

60
Heart Failure Management Recommendations
0
  • Stage C (Symptomatic left ventricular
    dysfunction)
  • Use of diuretic in patients with fluid retention
  • Use of ACE inhibitor (unless contraindicated)
  • Use of ß-blocker (unless contraindicated)
  • Use of digoxin (unless contraindicated)
  • Discontinuation of drugs known to affect patient
    status adversely
  • NSAID
  • Antiarrhythmics
  • Calcium channels blockers

61
Heart Failure Management Recommendations
0
  • Stage C (Symptomatic left ventricular
    dysfunction)
  • Use of spironolactone in patients with Class IV
    symptoms, preserved renal function, normal
    potassium levels
  • Exercise (rehabilitation)
  • Use of angiotensin II receptor blocker in
    patients treated with digoxin, diuretic, or
    ß-blockers who cannot tolerate ACE inhibitors
    (cough/angioedema)
  • Use of hydralazine-nitrate combinations
  • Addition of angiotensin II receptor blocker to
    ACE inhibitor

62
Bosentan
0
  • Indicated for pulmonary hypertension
  • Approved Nov. 20, 2001
  • Endothelin-1 receptor antagonist
  • Binds to ETA and ETB receptors
  • Specific and competitive antagonist
  • Located in endothelium and vascular smooth muscle
  • ET-1 levels increased in PAH suggesting
    pathogenic role for ET-1

63
Bosentan
0
  • Pharmacokinetics
  • Oral administration
  • 50 bioavailable
  • Unaffected by food
  • Highly protein bound (albumin)
  • 3 metabolites, 1 active contributing to 10-20 of
    effect
  • Inducer of CYP2C9 and CYP3A4
  • Eliminated by biliary excretion and hepatic
    metabolism

64
Bosentan
0
  • Pregnancy category X
  • Teratogenic in rats
  • Pregnancy should be excluded before start of
    treatment
  • May impair fertility
  • Hepatotoxic
  • Carcinogenic in mice
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