Congestive Heart Failure and Digitalis

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Congestive Heart Failure and Digitalis

• October 11, 2007
• Frank F. Vincenzi

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New York Heart Association Classifications of
Heart Failure

• Class I - no limitation of physical activity
• Class II - slight limitation of activity
• dyspnea with moderate physical activity
• Class III - marked limitation of activity
• dyspnea with minimal physical activity
• Class IV - severe symptoms at rest

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Cardiovascular responses to heart failure












Inadequate cardiac output
Adrenergicnervoussystem (norepinephrine)
Reninangiotensinsystem(aldosterone)
Tachycardia
Systemic vasoconstriction
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Conditions that may precipitate CHF

• Infections
• Arrhythmias
• Myocardial infarction
• Pulmonary embolism
• Undue physical exertion
• Excessive Na intake

• Hemorrhage, anemia
• Pregnancy
• In- and trans-fusions
• Anesthesia/surgery
• High altitude
• Hypertension
• D/C digitalis

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Pharmacotherapeutic approaches in heart failure

• Reduction of volume overload (reduce preload)
• Diuretics (more about these later when we
  consider diuretics)
• Ventricular unloading (reduce afterload)
• Acute nitroglycerin, sodium nitroprusside
• Chronic inhibit renin-angiotensin-aldosterone
  system, diuretics, ACE inhibitors, angiotensin
  antagonists(More about these later - when we
  consider hypertension)
• Beta-blockers (also reduce sympathetic
  activation)
• Inotropic interventions (improve Starling
  function)
• Acute dobutamine
• Chronic phosphodiesterase inhibitors, digitalis

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Effects of ouabain on cardiac function in a
patient with CHF
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Effects of ouabain on the CV system of a patient
in CHF
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Effects of ouabain on the CV system of a normal
human volunteer
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Digitalization can increase myocardial efficiency
in CHF
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Digitalization can increase myocardial efficiency
in CHF
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Determinants of myocardial oxygen demand

• Intramyocardial tension
• blood pressure, ventricular volume
• Myocardial contractility
• Heart rate
• Fiber shortening (Fenn effect)
• Activation energy
• Basal (resting) metabolism

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Ventricular function (Starling) curvesnormal,
CHF and with digitalis









Cardiac Output
normal
CHF digitalis
adequate
CHF
inadequate, fatigue
congestive symptoms,
edema, dyspne
a
ventricular end-diastolic volume
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Mechanism of positive inotropic effect of
digitalis
ROC
digitalis
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Effect of ouabain on cardiac cellular functions
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Digitalis standard swindle of the positive
inotropic mechanism

• Inhibition of Na, K ATPase
• Altered balance of Na/Ca exchange
• Enhanced Ca storage/release
• Increased binding of Ca to troponin
• Increased actin/myosin ATPase
• Increased contractility

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Pharmacotherapeutic approaches in heart failure

• Reduction of volume overload (reduce preload)
• diuretics
• Ventricular unloading (reduce afterload)
• Acute nitroglycerin, sodium nitroprusside
• Chronic inhibit renin-angiotensin-aldosterone
  system, diuretics, ACE inhibitors, angiotensin
  antagonists
• Beta-blockers (also reduce sympathetic
  activation)
• Inotropic interventions (improve Starling
  function)
• Acute dobutamine
• Chronic phosphodiesterase inhibitors, digitalis

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dobutamine (Dobutrex)

• Positive inotropic effect via beta-1 receptors
• Reduces afterload via beta-2 receptors
• Minor activation of alpha-1 receptors
• May promote sinus tachycardia, PVCs, angina,
  headache, hypertension
• Half life about 2 minutes. IV infusion to
  titrate dobutamine effects.

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milrinone (Primacor)

• Relatively 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

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Cardiovascular responses to heart failure












Inadequate cardiac output
Beta blockers
Adrenergicnervoussystem (norepinephrine)
Reninangiotensinsystem(aldosterone)
Tachycardia
Systemic vasoconstriction
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Beta adrenergic blockersdecrease renin release
and afterload (and decrease sympathetic
activation of heart)

• Propranolol (Inderal)
• Metoprolol (Lopressor)
• Carvedilol (Coreg)
• 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.

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Impact of atrial tachycardia on circulation
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Effect of digitalis on a supra-ventricular
tachycardia
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Effects of lanatoside C on paroxysmal atrial
flutter
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Circus movement atrial flutter model effect of
digitalis
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Vagal (ACh) actions on supraventricular parts of
the heart

• Decreases 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
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Effects of transient release of acetylcholine on
atrial action potential and contractile force
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Vagal (ACh) actions on supraventricular parts of
the heart

• Decreases 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

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Effect of digoxin on AV nodal conduction in
normally innervated human heart
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Lack of effect of digoxin on AV nodal conduction
in transplanted (denervated) human heart
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Pharmacokinetics of digoxin

• Well, but variously absorbed from GI tract,
  bioavailability 70 13
• Vd (3.12 CLcr 3.83) 30 and proportional to
  thyroid status
• Most excreted in urine unchanged, elimination
  depends on kidney function
• Half life 39 13 hours (1.6 days)

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Accumulation of digoxin during chronic dosing
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Pharmacokinetics of digitoxin

• Well absorbed from GI tract, bioavailability gt
  90
• Vd 0.54 0.14 liters/kg
• Non-polar compound, elimination depends on liver
  function
• Half life 6.7 1.7 days

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Non-uniform bioavailability of several generic
and trade name digoxin preparations
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Some adverse reactions to digitalis

• CNS
• headache, malaise, confusion, dizziness, changes
  in color vision
• GI
• anorexia, nausea, vomiting, diarrhea
• CV
• bradycardia, heart block (various degrees),
  arrhythmias, ventricular tachycardia,
  fibrillation, hyperkalemia

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digoxin in hospitalized patients

• 22.4 of patients (est. failure 8)
• CHF (78), arrhythmias (21), other (1)
• Route
• PO (79), IV (15), IM (6)
• Adverse reactions
• Arrhythmias 8.5
• GI disturbances 3.1
• CNS toxicity 0.1
• Gynecomastia 0.1

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Digitalis toxicity

• In various studies
• The 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

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Diagnosis of digoxin toxicity

• Are there predisposing factors?
• large dose, decreased elimination
• Are there extracardiac symptoms?
• anorexia, nausea/vomiting, visual signs
• Arrhythmias present?
• Arrhythmias change when digoxin withheld?
• What is serum digoxin concentration?

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Serum digoxin levels in 179 patients
Serum concentrations at which the probability of
digoxin induced arrhythmias is 10 1.7, 50
2.5, 90 3.3
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Treatment of acute digoxin intoxication by
digoxin immune Fab (Digibind)
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Simplified diagram of apparent digitalis-induced
changes in ANS activity
VF - death
VT
sympathetic
CNS output of autonomic tone
PVCs
partial AV block
slowing
parasympathetic
Dose of digitalis
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Digoxin overview

• About 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 failure
• Digoxin 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