Download Pharmacotherapeutic approaches in heart failure

Congestive Heart Failure and Digitalis
October 11, 2007
Frank F. Vincenzi
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
Cardiovascular responses to heart
failure
Inadequate cardiac output
Adrenergic
nervous
system
(norepinephrine)
Tachycardia
Renin
angiotensin
system
(aldosterone)
Systemic vasoconstriction
Conditions that may precipitate CHF
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•
•
•
•
Infections
Arrhythmias
Myocardial infarction
Pulmonary embolism
Undue physical
exertion
• Excessive Na intake
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•
•
•
•
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Hemorrhage, anemia
Pregnancy
In- and trans-fusions
Anesthesia/surgery
High altitude
Hypertension
D/C digitalis
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
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
20
control
digitalis
10
0
CO
LV work
LV O2
Efficiency (%)
Digitalization can increase
myocardial efficiency in CHF
Determinants of myocardial
oxygen demand
• Intramyocardial tension
– blood pressure, ventricular volume
• Myocardial contractility
• Heart rate
• Fiber shortening (Fenn effect)
• Activation energy
• Basal (resting) metabolism
Ventricular function (Starling) curves:
normal, CHF and with digitalis
Cardiac Output
normal
CHF + digitalis
adequate
CHF
inadequate,
fatigue
congestive symptoms,
edema, dyspne a
ventricular end-diastolic volume
Mechanism of positive inotropic effect of digitalis
VOC
ROC
PMCA
SR
Na/Ca
exchange
Ca2+
Na +
actin
myosin
mitochondria
Na/K
pump
K
+
digitalis
Effect of ouabain on cardiac cellular functions
control
digitalis 25 min
digitalis 47 min
membrane
potential
intracellular
calcium
contractile
tension
100 msec
adapted from Wei r & Hess, 1984
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
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
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.
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
Cardiovascular responses to heart
failure
Inadequate cardiac output
Beta blockers
Adrenergic
nervous
system
(norepinephrine)
Tachycardia
Renin
angiotensin
system
(aldosterone)
Systemic vasoconstriction
Beta adrenergic blockers:
decrease 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.
Impact of atrial tachycardia on circulation
Effect of
digitalis on a
supraventricular
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 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
Effects of transient release of acetylcholine on atrial
action potential and contractile force
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
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 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)
Accumulation of digoxin during chronic dosing
Pharmacokinetics of digitoxin
• Well absorbed from GI tract, bioavailability
> 90%
• Vd = 0.54 ± 0.14 liters/kg
• Non-polar compound, elimination depends on
liver function
• Half life = 6.7 ± 1.7 days
Non-uniform bioavailability of several generic
and trade name digoxin preparations
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
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%
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
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?
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
Treatment of acute digoxin intoxication by
digoxin immune Fab (Digibind®)
Simplified diagram of apparent digitalis-induced
changes in ANS activity
VF - death
CNS
output of
autonomic
tone
VT
sympathetic
PVCs
slowing
partial AV block
parasympathetic
Dose of digitalis
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