Download heart failure

CARDIAC GLYCOSIDES
& OTHER DRUGS USED
IN HEART FAILURE
Refresh Your Memory!
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Cardiac Output (CO): The volume of blood pumped by each
ventricle each minute
Cardiac Output= heart rate X stroke volume
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Stroke Volume (SV): The volume of blood pumped out of each
ventricle with each contraction or beat of the heart.
Stroke volume = end-diastolic volume – end-systolic volume
End-diastolic volume (EDV): the volume of blood in the
ventricle at the end of diastole when filling is complete
End-systolic volume (ESV): the volume of blood in the
ventricle at the end of systole when emptying is complete
Ejection Fraction (EF): Stroke Volume
End-diastolic volume
Definition of HF (HEART
FAILURE)
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HF occurs when CO is inadequate to provide the
oxygen needed by the body
5-year mortality rate ~50%
The most common cause of HF in the USA is
CAD
In systolic failure, the mechanical pumping action
(contractility) & the ejection fraction of the heart ↓
In diastolic failure, stiffening & loss of adequate
relaxation plays a major role in ↓ CO & ejection
fraction may be normal.
Therapies used in HF
Control of Normal Cardiac
Contractility
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The vigor of contraction of the heart muscle is
determined by several processes that lead to the
movement of actin and myosin filaments in the cardiac
sarcomere
The contrcation of the heart (during systole) results
from:
Ca+2
interacts with actin-tropnintropomyosin system
Actin-myosin
interaction
(Activator)
From the Sarcoplasmic
Reticulum (SR) + trigger
calcium that enters the cell
during the plateau of AP
Contraction
Control of Normal Cardiac
Contractility
Sites for drug action
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ß-agonists cause ↑ in “trigger” Ca influx through
an action on L-type Ca channels.
Conversely, CCBs ↓ this influx & ↓ contractility.
Na-Ca exchanger uses Na gradient to move Ca
against its concentration gradient from the
cytoplasm to the extracellular space.
Na+/K+ ATPase, by removing intracellular Na, is
the major determinant of Na concentration in the
cell.
The Na influx through voltage-gated channels,
which occurs as a normal part of almost all cardiac
APs, is another determinant.
Na+/K+ ATPase appears to be the primary target
of cardiac glycosides
Pathophysiology of Cardiac
Performance
1.
2.
3.
4.
Cardiac performance is a function of
four primary factors:
Preload
Afterload
Contractility of the heart
Heart Rate
Preload

Preload: determines the ventricular enddiastolic pressure and volume = “atrial
pressure”
In normal
hearts
Preload

Increase end-diastolic
fibre length
Increase Force of
contraction
In HF this response is reduced or even reversed
Preload

LV function curve (any measure of LV
performance (e.g. SV, SW) + LV filing pressure.
Preload
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In HF, preload increases because of:
- increased blood volume and
- increased venous tone
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if preload > 20-25 mmHg pulmonary congestion
Treatments that reduces preload:
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1. Salt restriction & diuretics >>> to reduce the high filling pressure
2. Vasodilators (e.g. nitroglycerine) >>> redistributing the blood away
from the chest into peripheral veins
Afterload
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The resistance against which the heart must pump
blood;
Represented by: aortic impedance and SVR
E.g: increased arterial pressure and obstruction to
outflow (e.g. aortic stenosis)
In HF, SVR will increase, because:
1. Circulating cathcolamines
2. + RAS (angiotensin II is a vasoconstrictor)
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Treatments: drugs that will reduce arteriolar tone
Contractility of the heart
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Determined largely by the intrinsic strength
and integrity of muscle cells
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Force of heart contraction is decreased by:
1. ischemic heart disease (MI, chronic severe ischemia)
2. specific disorders affecting the heart muscle such as
HTN and myocarditis
3. disorders of heart muscle of unknown cause (e.g.
idiopathic)
Heart Rate
is a major determinant of CO.
 in HF, compensatory sympathetic activation
of β-adrenoceptors comes into play to
maintain CO
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Pathophysiology of HF
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may involve the right ventricle, the left ventricle or both,
but the majority of patients with HF have symptoms
due to an impairment of left ventricular function.
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may range from the predominantly diastolic
dysfunction of a normal-sized chamber with
normal emptying but impaired filling to the
predominantly systolic dysfunction (EF<45%) of
a markedly dilated chamber with reduced wall
motion but preserved filling.
Pathophysiology of HF
Ventricular
Dysfunction
Diastolic
“inadequate relaxation to
permit normal filling”
CO
Systolic
“ inadequate
force generation
to eject blood
normally”
CO
EF normal
Often due to
hypertrophy or stiffening
of the myocardium
EF (< 45%)
Typical for
Acute failure,
e.g. MI
Doesn’t respond
optimally to +ve
inotropic agents
Rarely, “high output”
HF occurs
Pathophysiology of HF
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1.
2.
3.
4.
biventricular dysfunction LV failure
usually occurs first
Isolated right-sided failure is usually
associated with stenosis or spasm of the
pulmonary artery, for example:
Idiopathic or secondary pulmonary arterial HTN
Collagen vascular disorders, sarcoidosis, fibrosis
Drug-induced pulomonary HTN (heroin, methylphenidate,
fenfluramine, dexfenfluramine)
COPD
Signs & symptoms (S&Ss)
Weakness, Fatigue, Confusion
 decreased exercise tolerance (DOE)
 shortness of breath (SOB)
 Paroxysmal Nocturnal Dyspnea (PND)
 Cough
 Orthopnea (2-3 pillows)
 Reflex tachycardia
 peripheral and pulmonary edema
 cardiomegaly
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Compensatory Mechanisms
(1) Sympathetic outflow , parasympathetic outflow
This will cause: tachycardia, contractility, vasoconstriction
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Initially beneficial: force, preload and HR  CO
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Later: Arteriolar tone will afterload, CO, EF,
and renal perfusion
Compensatory Mechanisms
(2) Angiotensin II production
Vasoconstriction
May cause direct damage to
cardiac myocytes ( fibrosis
and vascular and
myocardial hypertrophy
+ Aldosterone
Myocardial
fibrosis
K+, Mg+
loss
Cardiac
Arrhythmia
Na+ and water
retention
1. afterload
2. (remodelling (of
heart and vessels)
Compensatory Mechanisms
(3) Myocardial Hypertrophy
<<The most important intrinsic compensatory mechanism>>
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The increase in muscle mass helps to maintain cardiac
performance in the face of adverse effects such as pressure
or volume overload, loss of functional tissue (e.g. MI) or
decrease in the contractility.
However, after initial beneficial effect:
- ischemic changes
- impairment of diastolic filling
- alteration of ventricular geometry
Compensatory Mechanisms
Basic Pharmacology of
Drugs Used in Heart
Failure
Cardiac Glycosides
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Digitalis purpurea = “foxglove plant”
Digitalis Lanata “white foxglove”
Digoxin is the prototype
influence
Pharmacokinetics
essential for
activity
Cardiac Glycosides
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Solubility is not pH dependent (WHY?)
Because they lack an easily ionisable group
Pharmacokinetics:
 Digoxin: well absorped P.O.
 Because of narrow therapeutic index, even minor
variations in bioavaliability can cause toxicity or
loss of effect
 T1/2= 36-40 hrs
 Enterohepatic cycling contributes for long t1/2 of
digitoxin
Cardiac Glycosides
Pharmacodynamics:
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Mechanical Effects
Electrical Effects
At molecular level, all cardiac glycosides inhibit
Na+/K+ ATPase; “sodium pump”
Different isoforms in different tissues;  & 
subunits
Different affinities of cardiac glycosides
↑free Ca+2 in vicinity of contractile proteins
during systole
intensity of interaction
intensity of contraction
Mainly by: 1. Intracellular Na + & 2. Expulsion of Ca +2 by Na + -Ca +2 exchanger
Proposed: 3. Facilitation of Ca +2 entry through Na + and Ca +2 voltage gated
channels & 4. Ca+2 release from SR
Cardiac Glycosides
Mechanical Effects
Cardiac Glycosides
Direct
Electrical Effects
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Autonomic
Direct Effects (in absence of toxicity):
- early brief prolongation of action potential followed by
shortening of plateau phase ( K+ conductance because of  Ca+2 in
cells) → atrial and ventricular refractoriness
if toxic dose:
1. ↓resting membrane potential (becomes less negative)
(because of inhibition of Na pump, less –ve inside cell)
2. Oscillatory depolarising afterpotential will evoke (because of
overloading intracellular Ca+2 and oscillating ion conc.)
If < threshold
If  threshold
Cardiac Glycosides- Toxicity
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If  threshold
A new action potential
will be produced
premature beat “ectopic
beat”, if in ventricle
bigeminy in ECG (ST
depression and inverted T wave)
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If < threshold
Afterpotentials will
interfere with the
normal conduction
because of further
reduction of resting
potential
Cardiac Glycosides- Toxicity
If toxicity
deteriorates
Self-sustaining
arrhythmia
“tachycardia”
If allowed to
progress
Fibrillation
(if in ventricle)
Fatal
Digitalis-induced bigeminy
Cardiac Glycosides
Electrical Effects: (Continued)
2. Autonomic Effects
Parasympathetic
•At therapeutic levels;
parasympathetic effects
predominates
• Atropine-blockable
effects: slow HR
• cholinomimetic effects
useful in treatment of
certain arrhythmias
Sympathetic
If toxic levels:
sympathetic
outflow will
These effects not
essential for typical
toxicity
Cardiac Glycosides
Effects on other organs
-
Less affinity, because of different isoforms
GIT: most common site of toxicty outside heart: N & V,
anorexia, diarrhea
 direct effects on GIT & affects CNS + CTZ
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CNS: - vagal + CTZ
- - less often, disorientation, hallucination (elderly)
- - visual disturbances (aberrations of color perceptions)
- - agitation, convulsion
- Gynecomastia: rare
Digitalis interactions with
electrolytes
Careful evaluation of serum electrolytes in
patients on digitalis:
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K+: (1) competes with digoxin on binding to Na+/K+
ATPase (2) abnormal cardiac automaticity is inhibited by
hyperkalemia
Ca+2: facilitates toxic actions of digoxin by accelerating
overloading of intracellular Ca +2 stores
Mg+2: Opposite effects of Ca +2
Summary: K+, Mg+2 and Ca+2 will increase risk of digoxin
toxicity
Treatment of digitalis toxicity
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If mild: manifested only by GIT and visual disturbances etc
lower dose only
If moderate/arrhythmia:
- serum ~, K+ and ECG monitored
- correct electrolyte status (K+, Mg+2, Ca+2) if abnormal
- If PVB or brief runs of bigeminy
Withdrawal of digoxin
Oral K+ supplements
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If severe (suicidal OD):
1. Insertion of temporary cardiac pacemaker catheter
2. Digitalis AB (digoxin immune fab)
Treatment of digitalis toxicity
In case of severe digitalis toxicity:
antiarrhythmic drugs can lead to cardiac
arrest because automaticity is already
depressed
 No need for K+ supplements in this case, as it
will be already elevated because of loss from
skeletal muscle cells and tissues
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OTHER +VE INOTROPIC
DRUGS
Phosphodiesterase inhibitors
e.g. Bipyridines (Inamrinone, milrinone),
Bipyridines:
1. selective inhibition of isozyme-3 (cardiac & smooth
muscles)→↑cAMP & cGMP
↑contractiliy
vasodilation
2.↑ Influx of Ca+2
3. Influence SR: ↑ intracellular Ca+2 movement
↑CO
↓LVFP
↓ PVR
Phosphodiesterase inhibitors
milrinone (continued)
 Available only parenterally (can be given P.O.)
 t1/2= 3-6 hours, (10-40% excreted in urine)
 Given only for short term use
 Used only in acute HF or for an exacerbation of
chronic HF
 Not used for long term because of TOXICITY
-adrenoceptor stimulants
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Dobutamine : selective 1- receptor agonist in
cardiac cells.
 CO and  ventricular filling pressure with some
effect on HR
not active P.O
used for acute HF.
Intermittent infusion for chronic HF Tachyphylaxis
Careful in patients with CAD: tachycardia,
↑myocardial O2 consumption.
Dopamine has also been used in acute heart failure and may be
particularly helpful if there is a need to raise blood pressure
Doses are Important!
Dopamine
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Low dose (Renal Dose): 1-3 mcg/kg/minute:
increase renal blood flow and urine output
Intermediate dose (Cardiac Dose) 3-10
mcg/kg/minute: increase renal blood flow, heart
rate, cardiac contractility and cardiac output
(activates B1)
High dose > 10 mcg/kg/min: alpha-adrenergic
effects begin to predominate, vasoconstriction,
increased BP
DRUGS WITHOUT +VE
INOTROPIC EFFECTS USED
IN HF
Diuretics
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If mild HF: Thiazide ~
moderate/severe: Loop ~
MOA: ↓salt & water retention→ ↓preload
→↓edema & cardiac size
Spirolonactone: ~aldosterone antagonist decreases the morbidity and mortality associated
with HF (aldosterone may also cause myocardial
and vascular fibrosis and baroreceptor dysfunction
in addition to its renal effects).
•If there is no oedema, 1st line
treatment in HF.
•Reduce morbidity and mortality
and improve symptoms
ACE-I
SVR
Long term remodeling of
heart and vessels
Salt and water
retention
Venous and
arteriolar
dilation
Sympathetic
stimulation
Preload
Bradykinin
Afterload
AngiotensinII- receptor
antagonists
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Produce beneficial hemodynamic effects similar to
those of ACE-I..
BUT:
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Large clinical trials suggest that they should only
be used in patients who are intolerant of of ACE-I
(e.g. because of cough, angioedema)
Aliskiren, a renin inhibitor recently approved for hypertension,
is in clinical trials for heart failure.
Vasodilators
1.
2.
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Effective in Acute HF because they ↓preload or
afterload or both.
Some evidence that long term use of
Hydralazine and isosorbide dinitrate can
↓damaging remodeling of the heart
Recently, a synthetic form of the endogenous
brain natriuretic peptide (BNP) has been
approved for use in acute HF
Vasodilators
NEW
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A synthetic form of the endogenous peptide brain natriuretic
peptide (BNP) is approved for use in acute cardiac failure
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Nesiritide (Natrecor )
®
MOA: 1. ↑cGMP in smooth muscles (stimulates Guanelyl cyclase)
→↓venous and arteriolar tone
2. Causes diuresis
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V. short t1/2 = 18 minutes (why?)
Because it it metabolised extensively by the NEP in the liver, kidney and lungs
Vasodilators
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Bosentan (Tracleer®)
competitive inhibitor of endothelin
orally active
Showed benefits in experimental animal models,
but results in human trials have been disappointing
This drug is approved for use in pulmonary
hypertension
Has significant teratogenic and hepatotoxic effects
-blockers
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Used in chronic NOT acute HF (why?)
In acute HF: RAS and sympathetic systems provide support for
the circulation…while in chronic HF: they will cause vasoconstriction,
volume expansion and progressive LV dysfunction
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Most patients with chronic HF respond favourably
to - blockers in spite of the fact that these drugs
can cause acute decompensation of cardiac
function
Decompensation: Failure of physiological compensation to
some stimulus
-blockers
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(MBC) Metoprolol, Bisoprolol and Carvedilol (and
nebivolol) decrease mortality in patients with stable
HF (stable severe HF)
Not with bucindolol
Full understanding of the beneficial effects in HF is
lacking but suggested mechanisms:
1. attenuation of the adverse effects of the high concentration
catechoamines (including apoptosis); 2. ↓Remodeling by
inhibition of mitogenic activity of catecholamines; 3. upregulation of  receptors; 4.  HR  diminish tachycardia
Clinical Pharmacology of
Drugs Used in Heart
Failure
Table 13-3. Steps in the treatment of chronic heart failure.
1. Reduce workload of the heart
a. Limit activity, put on bed rest
b. Reduce weight
c. Control hypertension
2. Restrict sodium intake
3. Restrict water (rarely required)
4. Give diuretics
5. Give ACE inhibitor or angiotensin receptor blocker
6. Give digitalis if systolic dysfunction with 3rd heart sound or
atrial fibrillation is present
7. Give b blockers to patients with stable class II-IV heart
failure
8. Give vasodilators
9. Cardiac resynchronization if wide QRS interval is present in
normal sinus rhythm
Vasodilators
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Can be divided into 1,2,3
ACE-Is  nonselective arteriolar & venous
dilators.
In patients with high filling pressures in whom the
principal symptom is dyspnea, venous dilators such
as long-acting nitrates will be most helpful in↓
filling pressures & the symptoms of pulmonary
congestion.
In patients in whom fatigue due to low LV output is
a primary symptom, an arteriolar dilator such as
hydralazine may be helpful in ↑ forward cardiac
output.
In severe chronic failure (both ↑ filling pressures &
↓ CO) dilation of both arterioles & veins is required
Beta Blockers (BRBs) & Calcium
Channel Blockers (CCBs)
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The rationale for BBs use is based on the
hypothesis …..
However, such therapy must be initiated very
cautiously at low doses, because…….
After several months: slight ↑EF, ↓HR, ↓
symptoms.
MBC: have been shown to reduce mortality.
CCBs appear to have no role in the treatment of
patients with HF.
Their depressant effects on the heart may worsen
HF.
Digitalis
Digoxin is indicated in patients with HF &
atrial fibrillation (AFib).
 It is also most helpful in patients with a
dilated heart & third heart sound.
 It is usually given after ACE inhibitors.
 When symptoms are mild, slow loading
(digitalization) is safer and just as effective
as the rapid method.
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Digitalis Interactions
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risk for serious digitalis-induced cardiac
arrhythmias if hypokalemia develops, as in
diuretic therapy or diarrhea
quinidine displaces digoxin from tissue binding
sites (a minor effect) & depresses renal digoxin
clearance (a major effect)→ ↑digoxin toxic effects
antibiotics that alter GI flora may ↑ digoxin
bioavailability in ~ 10% of patients.
agents that release catecholamines may sensitize
myocardium to digitalis-induced arrhythmias.
Management of Acute Heart
Failure
Acute HF occurs frequently in patients with
chronic HF;
 Those episodes are associated with:
- exertion, emotion;
- salt in diet;
- non-compliance with medication;
- metabolic demand (anaemia, fever etc).

Management of Acute Heart
Failure
Many of the signs and symptoms of acute
and chronic HF are identical
 However, their therapies diverge (why?)

Because of the: 1. The need for rapid response, 2. frequency and
severity of pulmonary vascular congestion & 3. The need for
more rapid recognition and evaluation of changing
hemodynamic status in case of acute HF
Management of Acute Heart
Failure
A particularly common and important cause
of HF-with or without chronic HF- is
myocardial infarction (MI)
 Patients with acute MI are best treated with
emergency revascularization with either
coronary angioplasty and a stent or a
thrombolytic agent.
 Even with revascularization, acute HF may
occur.
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Revascularization
A stent