Download 3. Treatment of CHF

TREATMENT OF
CONGESTIVE HEART
FAILURE (CHF)
DIGITALIS GLYCOSIDES AND
OTHER POSITIVE INOTROPIC
AGENTS
Common Diseases
Contributing to CHF
 Cardiomyopathy
-
 Hypertension
 Myocardial ischemia & infarction
 Cardiac valve disease
 Coronary artery disease
Clinical Features of CHF
 Reduced force of cardiac




contraction
Reduced cardiac output
Reduced tissue perfusion
Edema (congestion)
Increased peripheral
vascular resistance
 Important definitions :
 Afterload: pressure exerted on the left ventricle
during systole which is dependent on the
peripheral vascular resistance.
 Preload : end-diastolic pressure when the
ventricle has become filled.(depend on venous
return, venous pressure, and blood volume)
Congestive Heart Failure
heart 
Events Dilated
ischemia of
As compensation
mechanism the heart
will increase the
incoming volume of
blood so the heart can
eject more blood
The heart can’t
eject blood , so it
remains inside
the heart after
systole
cardiomyocytes
 ↓contraction
↑ afterload
↑ preload
Which type of drugs do we choose to treat this disease
β blockers to
decrease
sympathetic
activity.
Especially
HR to
increase
diastolic time
To refill left
ventricle
Positive inotropic
drugs to increase
contractility
Diuretics to
relieve the edema
ACEI or ARB to
inhibit the action
of anigiotensin
Drugs
used in HF
Noninotropic
Inotropic
(cardiotonic)
dobutamine
digoxin
ACEI
spironoloactone
ARB
Phosphodiesterase III
inhibitors
βblockers
diuretics
Used in acute or decompensated HF
CARDIOTONIC DRUGS
Cardiac Glycosides
Cardiac glycosides: drugs used in treatment of
CHF and cardiac arrhythmia
 Mechanism of the beneficial positive inotropic
pharmacodynamic effect
 The principal beneficial effect of digitalis in CHF is the
increase in cardiac contractility (+ve inotropism)
leading to the following:
o increased cardiac output
o decreased cardiac size (via ↓EDV & ↓ ESV)
o decreased venous pressure and blood
volume
o diuresis and relief of edema (due to ↑ CO &
↓capillary permeability)
o Decrease O2 consumption.
Physiology of contraction
As you know 1st the cell depolarizes
then contraction occurs
In depolarization
Ca++ will enter the cell
Ca++ will trigger the release of Ca++ from the
sarcoplasmic reticulum
In repolarization
Ca++ will return to the sarcoplasmic reticulum
Intracellular Ca++ leaves by
means of Na/Ca exchanger
Intracellular Na
leavs by means of
Na/ K ATPase
continued
Na/Ca exchanger depends on Na electricgradient
Inside the cell
outside
Less
Na
More
Na
Na
Na/K ATPase
K
Na
Na/Ca exchanger
Ca
This exchanger operates bidirectionally
In repolarization
In depolarization
Ca++
in
Na+ out
Ca++ out
Na+ in
Mechanism of action of cardiac
glycosides
Cardiac
glycosides
Inhibit
Na/K
ATPase
↑ intracellular
Na
Inhibition of
Na/Ca
exchanger
↑intracellular
Ca
↑contractility
Pharmacological Actions of
Digitalis Glycosides
pharmacokienetics
Moderate binding
to plasma protein
Good oral absorption
Excreted through
kidney (slow the
elimination )
Not stable in blood
because in heart failure
there is relative renal
impairment*
 Inotropism. Digitalis exerts positive inotropic effect
both in the normal and failing heart via inhibition of
Na+-K+ATPase at the cardiac sarcolemma.
Cardiac output (CO)
 Digitalis increases the stroke volume and hence the CO
 No increase in oxygen Consumption
 Decreased EDV & hence the dilated cardiac muscle
I.
II. Heart Rate
Digoxin can decrease heart rate by :
1- slowing SA nodal firing rate
2- slowing AV conduction.
3- increase refractory period.
Mechanism of
action
Indirect –vagaleffect through
Direct -extravagal-effect
on the heart
(parasympathomimetic)
-slowing SA node firing
rate
-slowing AV conduction
and prolongation of
refractory period of AV
node
↑ sensitivity of SA node to vagal stimulation thus
decrease in firing rate
Stimulation of vagal
central nuceli
III. Venous Pressure
IV. Diuresis
digitalis
↑cardiac
output
↑renal
blood flow
and so GFR
↓renin
angiotensin
system
edema
relieved
V. Myocardial
Automaticity/Conductivity
Therapeutic Uses of
Digitalis Glycosides
 Treatment of congestive heart failure
which does not respond optimally to
diuretics or ACEI.
 Treatment of atrial fibrillation and flutter
by slowing SA nodal firing rate as well as
AV conduction preventing the occurrence
of the life-threatening ventricular
arrhythmias.
 So we use digitals to treat atrial fibrillation and
flutter because they slow automaticity.
Adverse Effects of Digitalis
Glycosides
i.
Ventricular Arrhythmias
Digitalis  ↑ intracellular Ca
↑ Ca in sarcoplasmic
reticulum (become saturated)
Result in oscillating in Ca levels
inside the cell  oscillatory after
potential
 Arrhythmias resulting from oscillatory after potentials
include single and multiple ventricular premature beats
and ventricular tachy-arrhythmias
Adverse Effects of Digitalis
Glycosides
CNS side-effects
iii. Gynecomastia
 Stimulation of the vagal
 Gynecomastia may
center and chemoreceptor
occur in men either due
trigger zone (CTZ) results
to peripheral esterogenic
in nausea, vomiting,
actions of cardiac
diarrhea & anorexia
glycosides or
hypothalamic stimulation
 Other CNS effects include
blurred vision, headache,
dizziness, fatigue, and
hallucinations
ii.
iv. ↓conduction velocity
(AV block)
Treatment of Digitalis
Toxicity
Immediate withdrawal of digitalis
I.V. K+ supplementaion to
compensate for ↓intracellular K.
This may lead to
Hyperkalemia  ↓slope of
phase 4  ↓ automaticity
Complete AV
block
(contraindicated in
digitalis induced
heart block)
continued
If that doesn’t work
Lidocaine or phenytoin is effective against K+ digitalis-induced dysryhthmias
If that doesn’t work (severe case or resistance to drugs)
Use digoxin’s specific Fab fragments
•They are antibodies against digoxin.
•Produced from sheep(we give the sheep digoxin and then get
the antibodies produced against it).
•We separate the Fab portion from Fc portion by papain
•Fab portion is not antigenic thus, it doesn’t cause allergy (not
produced anaphylactic shock).
•Antibody will bind to digoxin forming a complex which can be
excreted through the kidneys increasing renal blood flow
Digoxin-specific Fab
fragments
 Digoxin-specific Fab fragments are used safely for




the treatment of the life-threatening cardiac glycosidesinduced arrhythmias and heart block
Digoxin-specific Fab fragments are produced by
purification of antibodies raised in sheep by
immunization against digoxin
The crude antiserum from sheep is fractionated to
separate the IgG fraction, which is cleaved into Fab
and Fc fragments by papain digestion
The Fab fragments are not antigenic and with no
complement binding
They are excreted fairly rapidly excreted by the kidney
as a digoxin-bound complex
Selective ß1- Adrenergic
Agonists
 Dobutamine (and dopamine), at doses equal to or less

o
o
o
o
than 5 µg/kg/min, have selective ß1- adrenergic agonistic
activity.
Beneficial effects in emergency treatment of acute CHF
(decompensated ) include the following:
1- Increased cardiac output as a result of enhanced
contractility without appreciably altering the heart rate.
2- Reduction of mean arterial blood pressure.
3- Lowering of the total peripheral vascular resistance and
consequently decreasing the afterload?? Read slide #3
4- Reduction of ventricular filling pressure
dobutamine
G- protein
receptor
Adenlyl
cyclase
cAMP
PKA
Phosphodiesterase III (PD-III)
Inhibitors (amrinone & milrinone)
cAMP
They increase Ca
indirectly
Phosphodiesterase III
PD-III inhibitors
 PD-III inhibitors are suitable only for acute CHF because
they can induce life-threatening arrhythmias on chronic
use same ß1- Adrenergic Agonists
Dobutamine and PD-III inhibitors are taken
parenteral and act in a short period
OTHER DRUGS OF USE IN CHF
WITHOUT INOTROPIC EFFECT
Diuretics
 Diuretics ↓cardiac preload by inhibiting sodium and water



o
retention
Cardiac pumping improves with the consequent reduction in
venous pressure relieving edema
Thiazide (e.g., hydrochlothiazide) and loop diuretics (e.g.,
frusemide) are routinely used in combination with digitalis
Potassium-sparing diuretics can be concurrently used to
correct hypokalemia
Spironolactone+Digitalis+ACEI  ↓mortality because
spironolactone antagonize aldosterone which cause
myocardial and vascular fibrosis
Angiotensin Converting
Enzyme Inhibitors (ACEIs)
ACEIs
 Action of AT1 receptor:
1- vasoconstriction of veins and arteries.
2- release of aldosteron in renal cortex.
3- sympathetic activity by NE in nerve terminal.
4- hypertrophy of the heart.
Action of AT 2 receptor:
1- release of NO so vasodilatation.
2- prevent hypertrophy.
Effect of ACEIs on
Bradykinin
Angiotension II activate sympathetic
nervous system in the brain and synapses
Angiotensin Converting
Enzyme Inhibitors (ACEIs)
ACEI
↓angiotension
II
↑bradykinin
↓sympathetic*
vasodilation
↓aldosterone
Decreased sodium
and water retention
 Ultimately both preload and afterload are reduced
 Clinical trials showed that the use of ACEIs in CHF has
significantly reduced morbidity and mortality
Adverse Effects of ACEIs
 1. Postural hypotension
 2. Hyperkalemia
 3. Renal insufficiency (don’t forget that in heart failure there is renal
insufficiency caused by decrease renal blood flow but still we use
ACEI)
 4. Persistent dry cough
 5. ACEIs are contraindicated in pregnancy
 ACEIs include agents like: captopril, enalapril,
lisinopril and many others
Angiotensin II Type-1 Receptor Antagonists (ARBs)
Physiologic functions of AT1 receptors according to their location
LOCATION
FUNCTION
Kidney
Glomerulus
Mesangial cell contraction  ↓GFR
Proximal tubule
Increased reabsorption of sodium
Juxtaglomerular apparatus
Decreased renin secretion
Heart
Inotropic effect and release of growth factors with
ensuing stimulation of cardiac myocyte
hypertrophy and increased extracellular matrix
production
Blood vessels
Vasconstriction with an increase in afterload as
well as local release of growth factors
Adrenal gland
Aldosterone and catecholamine release
Brain
Vasopressin release, stimulation of thirst;
autonomic activity and cardiovascular reflexes
Sympathetic nervous system
Increased sympathetic outflow
AT-1 Receptor Blockers
(ARBs)
 Agents include: Losartan and Valsartan
 They are recently approved for treatment of CHF
 They have the same beneficial effect of ACEIs except they don't
increase bradykinin.
 They don’t cause cough
 They enhance AT-2 function .
AT-1 Receptor Blockers
(ARBs)
 ARBs have the same side-effects of ACEIs, except
they don’t cause cough.
Nitrovasodilators
 Sodium nitroprusside I.V. infusion is used at a
dose of 0.1- 0.2 µg/kg/min only in acute CHF
to lower preload and afterload.
 Nitrates can be used also to decrease
preload (nitrates and hydralazine were used
to decrease preload and afterload).