Nincs diac

1
CONGESTIVE HEART FAILURE DEFINITION 1920's -
"organ physiology" paradigm - interplay between
the abnormal heart and the circulation. The
focus on circulatory abnormalities 1960's -
"cell biochemistry" paradigm - depressed
contractility and impaired relaxation 1980's -
"gene expression" paradigm - molecular
alterations in the myocardial cells Heart
failure is a clinical syndrome in which impaired
cardiac pumping decreases ejection and impedes
venous return. These haemodynamic abnormalities
are generally complicated by depressed myocardial
contractility and relaxation, which reflect
biochemical and biophysical disorders in the
myocardial cells. This latter, in turn, are due
to partly to molecular abnormalities that not
only impair the heart's performance, but also
acceletrate the deterioration of the myocardium
and hastens myocardial cell death. PATHOPHYSIOLOGY
OF HEART FAILURE Heart failure can develop a.)
Acutely resulting from acute myocardial
infarction secondary to an infectious or
infiltrating process (virus, bacterial,
rotozoal) b.) Chronically (over months or years)
as the end-stage of different heart diseases.
This low output failure can result from a.)
decrease in myocardial contractile reserve, due
to myocardial infarction
cardiomyopathy increased afterload (eg.
hypertension) b.) valvular disease (eg. aortic
stenosis or mitral regurgitation) c.)
prolonged rhythm disturbances (eg. ventricular
tachycardia)
2
The primary signs and symptoms of all types of
CHF include tachycardia decreased
exercise tolerance shortness of breath
peripheral and pulmonary edema
cardiomegaly Cardinal feature cardiac output (CO
falls short of what is required for normal tissue
perfusion Reason decrease in cardiac
contractility Low output failure responds to
positive inotropic drugs High output failure the
demands of the body are so great that even
increased CO is insufficient (eg.
hyperthyreodism, beri-beri, anaemia,
arteriovenous shunt). Respond poorly to positive
inotropic drugs. Haemodynamics of heart
failure Forward or inotropic failure - reduced
ejection into the aorta and pulmonary artery
Backward or lusitropic failure - inadequate
emptying of the venous reservoirs
3
SITE OF FAILURE BACKWARD FAILURE FORWARD
FAILURE Right heart failure Increased
systemic Reduced ejection into venous
pressure pulmonary artery Left heart
failure Increased pulmonary Reduced ejection
into the a venous pressure aorta Because
blood flows in a circle, none of these occurs in
pure form. In "Forward failure" - when the
ventricle empties poorly, the filling is
reduced In "Backward failure" - when filling is
reduced, the stroke volume is reduced In right
ventricular failure the increase in systemic
venous pressure and decreased ejection of blood
into the pulmonary artery reduce the output of
the left ventricle In left ventricular
failure increased pulmonary venous pressure ?
impedes the blood out of the lungs ? increases
pulmonary capillary pressure. This is transmitted
across the pulmonary circulation and results in
increased pulmonary arterial pressure which can
impair right ventricular ejection.
4
Signs and symptoms of heart failure The clinical
picture in heart failure consists of signs
(the objective manifestations of depressed
cardiac performance), symptoms (abnormalities
perceived by the patient). Left heart failure is
a "forward failure" - reduced ejection,
"backward failure" - rise in pulmonary
capillary pressure. Systemic reflex activation
vasoconstriction ? increased blood pressure (to
maintain perfusion of vital organs
ie. heart, brain) Despite the increased
sympathetic tone perfusion decreases to the
skeletal muscle fatigue and skeletal muscle
myopathy to the kidneys oliguria, sodium
and water retention to the tissues cyanosis
Because of the backward failure ? pulmonary
congestion ? impaired respiration Dyspnea
(difficulty breathing) due to arterial hypoxia,
and decreased lung compliance (excess
fluid transudates from the pulmonary capillaries)
depth and rate of breathing increase).
Typical in supine position. Mild HF dyspnea
occurs only during heavy exercise Severe HF
dyspnea is present at rest (bubbling noises
during respiration) End-stage HF fluid fills
the bronchial system pulmonary edema Right
heart failure is a backward failure rather than
a forward failure. The central venous
pressure is over the maximum. Edema (liver,
kidneys, spleen, GIT, skin, genitalies)
Cyanosis
5
Cardiomegaly - one of the major signs of heart
failure. Initially due to the operation of the
Frank-Starling relationship Remodelling of the
ventricular wall is a complex process Pressure
overload (hypertension, aortic stenosis ?
inward' hypertrophy, reduced
ventricular cavity (concentric hypertropy) Volume
overload (aortic regurgitation) ? the ventricle
dilates (eccentric
hypertrophy) Grading of severity of heart failure
according to the New York Heart Association
(NYHA) NYHA I. Signs of heart failure appears
only heavy exertion and disappear after its
discontinuation NYHA II. On normal workload
signs of CHF appears in the evening but disappear
after night rest NYHA III. At rest minimal
signs of CHF causing no complains but marked
signs of CHF on walking, which are not fully
relieved by night rest. NYHA IV. Signs of CHF
even at bed rest.
6
Compensatory mechanisms in heart
failure Extrinsic reflex mechanisms for
compensation Sympathetic nervous system
(SNS) Renin-angiotensin-aldosterone hormonal
response. Increased sympathetic outflow
tachycardia, increased contractility,
increased vascular tone (venous
tone) increased ventricular filling
pressure dilatation of the heart
increased fiber stretch Increased aldosterone
secretion sodium and water retention
increased blood volume edema.
7
Intrinsic compensatory mechanism myocardial
hypertrophy Increased muscle mass (to maintain
cardiac performance) Hypoxic myocardium
Decreased oxygen supply to the myocardium
2
1
normal
Developed tension
Velocity of contraction
normal
failing
failing
PCWP (Hgmm)
LOAD
Depressed contractility in heart failure
reflected either as a reduced peak tension
development (1) or depressed force-velocity curve
(2)
8
Pathophysiology of cardiac performance Cardiac
performance depends on at least 4 primary
function A PRELOAD (LVEDP, LVEDV, reflected as
central venous pressure) Preload refers to the
diatolic loading conditions of the heart - Left
ventricle left atrial pressure (or pulmonary
capillary wedge pressure PCWP) - Right
ventricle right atrial pressure for the right
ventricle. These are the "filling
pressures" Left ventricular function curve (SV
or SW against the filling pressure) The
ascending limb (bellow 15 mmHg) represents the
classic Frank-Starling relation. Beyond
approximately 15 mmHg, there is a plateau of
performance. Preload greater than 20-25 mmHg
result in pulmonary congestion.
9
The Frank-Starling low of the heart describes the
property of cardiac muscle to increase its
contractility as the length of the myocardial
fiber (stretch) is increased. To accomplish this
increase in stretch, more blood must be returned
to the heart by a.) Increased sympathetic tone
causing ? vasoconstriction ? decreased venous
blood storage (pooling) ? increased
end-diastolic volume (or filling pressure) and
CO. b.) Redistribution of blood from viscera to
heart c.) Fluid or sodium retention due to
decreased renal perfusion, and renin-angiotensin-
aldosterone activation. This increases volume of
blood returned to the heart and also may cause
edema. REDUCTION OF PRELOAD DIURETICS B
AFTERLOAD is the resistance against which the
heart must pump blood. Systemic vascular
resistance is frequently increased in CHF
(increased sympathetic outflow and circulating
catecholamines). This may speed
failure. REDUCTION OF AFTERLOAD ARTERIAL
VASODILATORS C CONTRACTILITY is the vigor of
contraction of heart muscle. In CHF the
primarily defect reduction in the intrinsic
contractility (dP/dt) INCREASE IN CONTRACTILITY
POSITIVE INOTROPIC DRUGS. D HEART RATE is the
major determinant of cardiac output (CO) - When
CO decreases HR increases (beta-adrenoreceptor
activation) - Consequences - diastole shortens
- myocardial perfusion worsens - hypoxia
10
CARDIAC HYPERTROPHY The most important intrinsic
compensatory mechanisms. Complex biochemnical
biophysical mechanisms in the background. a.)
Energetics in the failing heart Imbalance betwen
energy production and energy utilization. Cause
is the overload itself Result "state of energy
starvation" (increased energy utilization and
decreased high energy phosphate
production). b.) Structural changes in the
chronically overloaded heart Failing heart is
not equal with a normal enlarged heart
(sportmens heart) Architectural
changes Pressure overload - the walls of the
heart thicken Volume overload - dilated
heart Chronic heart failure hyperthrophied
heart myocyte necrosis (fibroblast
poliferation) muscle is replaced by
connective tissue the heart begins to
dilate wall tension incerases
propensity for arrhythmias c.) Altered blood
supply Imbalance between the capillary density
and muscle mass (increased intercapillary
distance) Decreased coronary reserve
(underperfused subendocardium) Subendocardial
necrosis
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d.) Altered proportion of mitochondria and
myofibrils Imbalance between myofibrils and
mitochondria (more energy-consuming
myofibrils must be supplied with ATP by
relatively fewer mitochondria) Exacerbated
energy starvation NOTE a.) Many of these sings
and symptoms of CHF are a direct result of these
compensatory mechanisms. b.) Despite all
attempts to compensate, the cardiac function
deteriorate VITIOUS CYCLE occur, and CO
cannot be maintained without medical
intervention Arrhythmogenic mechanisms in the
hyperthropied heart Enlargement and fibrosis
of the atria and ventricles increased
susceptibility to arrhythmias (slow
conduction ? reentrant arrhyhtmias) Increased
calcium accumulation in the cells ? initiate
triggered activity. Lowered resting potential
(sodium pump inhibition) ? slow conduction.
Acidosis ? slowing of conduction SUDDEN CARDIAC
DEATH Altered gene expression in the chronically
overloaded, failing heart Gives the answer Why
the prognosis is so poor in this patients?
Appearance of abnormal proteins (accelerated
potein synthesis) Abnormalities in gene
expression (accelerate the deterioration) The
detrimental consequences of hypertrophy seems to
represent a price' that the overload heart must
pay in order to accelerate protein sysnthesis.
12
The heart's response to overload can be divided
in three phases that have different functional
and prognostic implications. a.) First
short-term stage of acute heart
failure Clinical left heart failure, pulmonary
congestion Pathological dilatation of the left
ventricle Histological swelling and separation
of myofibrils Biochemical glicogene and ATP
levels decreased, lactate slightly increased b.)
Second long-term stage of compensatory
hyperfunction Clinical relief of
symptoms Pathological hypertrophy Histological
increased size of cardiac fibers, minimal
fibrosis Biochemical glycogen, ATP normal,
lactate increased. Miofibrillar mass increased
relative to that of the mitochondrial mass. 3.)
Third long-term stage of progressive exhaustion,
cell death and fibrosis Clinical reappearance
of heart failure Pathological fibrous
replacement of muscular tissue Histological
connective tissue, fatty dystrophy Biochemical
as in second stage, exept decline in protein
systhesis and marked decline in DNA levels.
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NEUROHUMORAL AND RENAL MECHANISMS IN HEART
FAILURE Neurohumoral systems may play both a
detrimental and protective role in the
pathogenesis of CHF. Compensatory mechanisms
activated in CHF vasoconstrictive and
antinatriuretic vasodilatory and
natriuretic The biologic activities of these
systems are antagonistic. Vasoconstrictive-antinat
riuretic Vasodilatory-natriuretic Renin-angioten
sin-aldosterone system Atrial natriuretic factor
(ANF) Sympathetic nervous system
(SNS) Prostaglandins Vasopressin Dopamine Th
romboxane Kallikrein, kinins Endothelin ED
RF 1. Vasoconstrictive-antinatriuretic
system a.) Sympathetic nervous system (SNS)
Increased activity of SNS occurs early in the
course of CHF and contributes to clinical
deterioration and mortality in HF (1)
Adrenergic receptor function Increased
sympathetic activity ? receptor down-regulation
ACE inhibitors (eg. Captopril) ?
resensitization (reduced NA release)
Evidence for decreased level of Gs and increased
level of Gi Future tool? (2) Baroreceptor
or baroreflex abnormalities in heart failure
Baroreflex control of the heart is impaired
(structural changes in baroreceptors or
arterial wall).
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(3) Sympathetic stimulation is involved in LV
remodelling loss of myocardial
cells gene expression Increased
sympathetic drive induces a.) myocardial
hypertrophy and fibroblast hyperplasia through
stimulation of ?1 and ? receptors b.)
accelerated myocardial cell lost - apoptosis c.)
NA may induce apoptosis through ? receptor
activation d.) changes in myocardial gene
expression which results in progressive
worsening in contractility (downregulation of
the adult type, high ATP-ase activity ?-myosin
heavy chain isoform and upregulation of the fetal
type, low ATP-ase activity ?-myosin heavy
chain isoform) b.) Renin-angiotensin
system Angiotensin II (AGII) is the key element
with multiple biologic activity AG II
influences cardiac metabolism, involved in the
development of ventricular hypertrophy through
its growth promoting effects. Interaction with
other neurohumoral systems (enhances NA
synthesis, reduces NA reuptake, facilitates NA
release from nerve endings). Antagonistic with
the ANF system
15
Plasma RAS maintains circulatory homeostasis
during acute and subacute alterations in cardiac
output Tissue RAS contributes to maintain
homeostasis during impairment of CO 1. Activation
of the RAS


Occurs in response to reduction in cardiac
output. Arterial constriction ? ?
SABP? and DABP? Catecholamine release
? Angiotensin II. ? aldosteron secretion ?
(adrenal cortex) sodium retention
water retention
potassium
excretion Increased blood
pressure water intake ?
vasopressin
secretion ? adrenocorticotropic hormon ?


AGII
binding to AT1 receptor leads to cardiac
remodelling which includes upregulation of
many early active cardiac myocyte genes
induction of late markers of cardiac hypertrophy
(a-actin) and growth factors such as
TGF? shift to fetal type myocardium AGII
binding to AT2 receptor may oppose the effect of
AGII on AT1 receptors
16
c.) Vasopressin Crutial role in hyponatremia
in CHF (V2 linked hydro-osmotic effect) In
small concentrations ? vasodilator (EDRF
release?) 2. Vasodilatory-natriuretic
systems a.) Atrial natriuretic factor
(ANF) Maintains renal haemodynamic function,
attenuates the RAS system ANF levels are
elevated in CHF (indicator of developing
dysfunction) In CHF relative ANF
deficiency Therapeutical value ANF
replacement ? b.) Prostaglandins Endogenous
vasodilator PGs (PGI2) opposing the effect of the
vasoconstrictive endogenous agents c.)
Dopamine Therapeutic agent in CHF d.)
Endothelium derived vasoactive agents Both
vasodilator (EDRF -- NO ?) and vasoconstrictor
(endothelin) Endothelin - renal and systemic
vasoconstrictor, activates RES
17
CELLULAR MECHANISMS IN HEART FAILURE 1. Role of
calcium levels Calcium regulates -
contraction/and relaxation. Intracellular
calcium is modulated by cAMP and IP3 "second
messenger" systems Extrusion of calcium
is regulated by calcium pump (CaATP-ase) and
calcium- sodium exchange In CHF abnormal
calcium handling is apparent 2. cAMP It is an
important "second messenger" modulates calcium
handling activates protein kinases (Ca2
entry) regulates calcium sequestration into
the SR regulates myofilament responsiveness
to calcium In CHF reduced cAMP levels are
apparent. 3. Sarcolemmal receptors and
mechanisms Homologous ? receptor
downregulation ? cAMP dependent protein kinase
phosphorilates the ? receptors ?
desensitization In CHF the SR cacium uptake
function is altered 4. Altered myocardial
responsiveness to calcium In CHF altered
responsiveness to Ca2 (reduced Ca2 affinity to
troponin C) Altered gene expression ?
abnormal protein synthesis ? fatal myosin isoforms
18
Factors stimulate cell growth Cell
deformation Stretch activated ion
channels Cytoskeletal rearrangements
(microtubules, desmin) Extracellular growth
factors FGF (fibroblast growth factor) TGF?
(type ? transforming factor) Extracellular
neurohormonal pharmacological modulators ?-adreno
ceptor stimulants ?-adrenoceptor
stimulants angiotensin II and endothelin thyroxi
n, insulin growth hormone (GS/TGF-I
ratio) glucocorticoids cytokines TNF
? Intracellular energy deficit decreased high
energy phosphates (ATP, CP) increased products
of excessive energy utilisation (ADP, AMP,
ceratine) Intracellular second messengers cAMP,
cAMP-dependent kinases calcium and IP3/DG/PKC
pathway Cellular protooncogens c-fos, c-myc,
c-jun Cellular signalling factors citochrome-c
and apoptotic protein activting
factor-1 caspases protoapoptotic proteins
(bax) Death receptors Fas TNF receptors
19
Genetic factors in the development of heart
failure 1. Non-familial hypertrophic
cardiomyopathy (NF-HCM) LV mass is partially
determined by familial influence and 60 of the
variability can be explained by heritable
factors. Local RAS gene polimorphism ?
predisposition to hypertrophy. Genetic
polimorphism in intron 16 of ACE gene,
characterised by an insertion (I) or a deletion
(D) of a 287-bp sequence. This ACE I/D
polimorphism is strongly related to ACE plasma
level and myocardial concentration. 2. Familial
hypertrophic cardiomyopathy (FHC) Genetically
heterogenous - 7 genes have been identified as
responsible for the disease 14q11-12 - b
myosin heavy chain 1q3 - cardiac troponine
T 15q2 - a-tropomyosin 11p11.2 - cardiac
myosin binding protein c 12q - regulatory
light chain of myosin 3p - essential light
chain of myosin 19p13-q13 - cardiac troponine
I
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Catabolic/anabolic imbalance The general feature
of neuroendocrine abnormalities A
catabolic/anabolic imbalance exists in HF. TNF?
is a key factor regulating energy metabolism,
immune status, neuroendocrine and hormonal
function. Catabolic/anabolic status in CHF can
be estimated by the cortisol/DHEA
(dehydroepiandosterone) ratio. This ratio is
highest in cachectic patients and correlates
strongly with the degree of immune activation,
represented by circulating TNF? and soluble TNF
receptor 1 and 2. Cytokines induce programmed
cell death (apoptosis) which is present in the
skeletal musculature especially in cachectic
patients. Growth hormone (GH) - insulin like
growth factor-I (IGF-I) axis is abnormal in
severe CHF. In cachectic CHF patients GH is
elevated and IGF-I is normal or low. Insulin
resistance is frequently observed in CHF.
(Insulin is the strongest endogenous anabolic
hormone which regulates the metabolic status of
peripheral musculature. (Fasting insulin levels
are only increased in non-cachectic patients.
This might be due to a compensatory metabolic
mechanism to overcome the insulin resistance).
Use of insulin sensitizers might be useful!
Immune activation is present in CHF. TNF? could
be casual for the metabolic disturbances
elevated metabolic rate impaired tissue
flow altered fat and protein metabolism TNF?
is mainly elevated in cachectic CHF patients and
it is the strongest predictor of the degree of
weight loss.
21
Apoptosis in heart failure Apoptosis is an
important mode of cell death (progressive loss of
cardiac myocytes) in heart failure. AGII promotes
apoptosis Apoptotic pathways 1. Cytochrome c- is
released in response to an apoptotic stimulus
from the mitochondria. Cytochrome c, in the
presence of dATP, forms an activation complex
with apoptotic protein- activating factor-1 and
caspase-9. This complex activates downstream
caspases which leads to the final morphological
and biochemical changes. This pathway is tightly
regulated by a group of antiapoptotic proteins,
such as Bcl-2 and proapoptotic proteins, such as
Bax. Further regulation occurs downstream by
various inhibitors of caspases. Bcl-2 is
upregulated soon after coronary artery
occlusion, espcially in the salvagable myocardium
but is decreased in chronic HF induced by
pressure overload. Apoptosis occurs in a high
rate during reperfusion . The overexpression of
BCL-2 effectively reduces reperfusion injury by
reducing myocyte apoptosis. Bcl-2/Bax balance is
important in the increased rate of apoptosis in
cardiac myocytes.. 2. Death receptors (e.g.
Fas, and TNF receptors) and caspase 8 also
activate downstream caspases. Expression of Fas
is upregulated in cardiac myocytes during
ischaemia and heart failure. Antiapoptotic
therapy includes Beta adrenoceptor blockers
e.g. Carvedilol ACE inhibitors Caspase
inhibitors Some hypertrophic signalling factors,
such as cardiotrophin-1 via gp 130, insulin-like
growth factor-1 via phosphoinositide-3-kinase,
and calcineurin via the nuclear factor of
activated T-cells seem to be protective.
22
Apoptotic stimulus citochrom c release from
the mitochondrium activation complex caspase-c
ascade activation morphological and
biochemical alterations
Pprotein-activating factor caspase 9
Antiapoptotic protein Bcl-2
Proapoptotic protein Bax
death receptors Fas és TNF
23

GOALS OF DRUG THERAPY FOR CHF The major goal of
therapy is to increase cardiac contractility
(positive inotropic action) improve
cardiac output to stop progression 1.)
Improving the ability of the heart to meet the
demands placed upon it (eg. by increasing
contractility), or 2.) By reducing the demands
being placed on the heart (eg. by reducing
afterload with vasodilators) A Drugs
which enhance contractility of the failing
myocardium a.) Cardiac glycosides b.) dopamine
and dobutamine c.) PDE III inhibitors (amrinone,
milrinone) B Vasodilators To reduce preload and
afterload a.) Venodilators (nitrites and
nitrates) b.) Direct acting arterial dilators
(hydralazine and minoxidil) c.)
Alpha-adrenoreceptor blocking agents
(prazosin) d.) Calcium antagonists
(nifedipine) C ACE inhibitors To reduce
afterload and inhibit the progression of
hypertrophy (gene expression ?) Captopril,
Enalapril, Ramipril D Antiarrhythmic agents To
reduce irregular ventricular arrhythmias and
prevent sudden death E Diuretics Use to
decrease edema, reduce blood volume. However,
vigorous diuresis can be harmful (excessive
reduction in preload which leads to a further
decrease in CO).
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Role of positive inotropic drugs in the treatment
of CHF Positive inotropic agents are able to 1.
Increase the extent and the speed of myocardial
shortening (when preload, afterload, heart rate
are kept constant). Act in normal myocardium,
some play a physiologic role NE, E. 2. Improve
contractility of the failing heart during
polonged administration Goals for use of positive
inotropic drugs 1. Immediate lie-saving
situations (after cardiac surgery, intensive
care) i.v. DOPAMINE, DOBUTAMINE, DOPEXAMINE,
ENOXIMONE, LEVOSIMENDAN, are useful if
depression of myocardial function is thought to
be reversible and is primarily related to
abnormal excitation-contraction coupling 2.
Chronic heart failre from NYHA II to NYHA IV they
remain the part of the therapy despite full
therapy with diuretics, vasodilators and ACE
inhibitors. Aim to improve the symptoms and
quality of life if possible to improve survival.
CARDIAC GLYCOSIDES, PDE INHIBITORS.
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CARDIAC GLYCOSIDES Egyptans 3000 years ago. In
the 18th century William Withering described the
clinical effects of an extract of the foxglove
plant (Digitalis purpurea). Chemistry All of the
used cardiac steroids, or cardenolides combine a
steroid nucleus with an unsaturated lactone ring
at the 17 position and a series of sugars linked
to carbon 3 of the nucleus. The lactone
ring and the steroid nucleus are essential for
activity. The pharmacological active principle is
the genin or aglicone. Three aspects of this
general structure are required for optimal
activity a.) the hydroxyl at position of
14 b.) the unsaturated (5 or 6 numbered) lactone
ring at position of 17 c.) the cis relationship
between rings C and D (all other natural steroids
are trans) The sugars are not necessary for
activity but greatly affect water solubility, the
speed of onset, potency and duration of action of
the drug. Sources of these drugs white and
purple foxglove (D lanata and D purpurea),
Mediterranean sea onion (squill), Strophantus
gratus, Oleander, lilly of the valley
etc. Certain toads skin glands bufadielonides (6
membered lactone ring)
26
PHARMACOLOGICAL ACTIONS 1.) POSITIVE INOTROPIC
ACTION (force of myocardial contractility) They
increase the force and velocity of cardiac
contractions (dP/dt). Mechanism of action
Inhibition of K-NaATP-ase (membrane bound
enzyme, associated with the "sodium pump") The
therapeutic direct action increase the intensity
of the "activate state" of the contractile
apparatus by increasing free Ca2 concentration
in the vicinity of the contractile proteins
during systole) The facilitation of
excitation-contraction coupling may be as a
result of 1.) Inhibition of Na-KATP-ase ?
reduced Na transport out ? increased Nai (1)
? reduced normal transport of Ca2
out (via Na/Ca2 exchange) ? increased Ca2i
(1/a) 2.) Facilitation of Ca2 entry, through
the voltage-gated Ca-channels, during the plateau
phase of action potential (2). 3.)
Increased release of stored Ca2 from the SR
(3). NOTE Toxic effects are well correlated to
inhibition of ATP-ase and to calcium overload.
Loss of intracellular K (increase in Na, and
increase in Cai) favours the induction of
arrhythmias.
27
Haemodynamic effects of cardiac glycosides a.)
Effects in patients with heart failure Cardiac
glycosides increases CO. All of the other
observed changes are secondary to this one
effect. b.) Relationship of ventricular
function N to A reduction in
myocardial contractility A to B compensation
(ie. increase in preload to increase output of
failing heart) B to C digitalis action (ie.
increased myocardial contractility) C to D
reduction in heart size (ie. decreased preload)
secondary to improved performance
(CO) during digitalis treatment D to E
reduction in filling pressure with no positive
inotropic intervention (eg. diuretics) c.)
Effect of digitalis in normal patients (1)
Myocardial contractility increases (2) Vascular
tone increases (3) CO does not change or may
even decrease
28
2. Indirect (vagal) electrophysiolcical
effects a.) BRADYCARDIA both direct and vagal
effects Vagus effect is due to stimulation
of the vagal nucleus greater sensitivity
of the heart to Ach This can be abolished by
atropine or by vagotomy In lower doses,
cardioselective parasympathomimetic effects
predominate Cholinergic innervation in the
atria and AV node Less indirect effect on
Purkinje or ventricular function. In hear
failure tachycardia can abolish automatically
when CO is increased b.) SHORTENING OF THE
REFRACTORY PERIOD (RP) OF ATRIAL MUSCLE
Speeding of atrial rate ? atrial flutter
transfers to fibrillation c.) SLOWING CONDUCTION
THROUGH THE AV NODE Prolonged P-R interval
(1o heart block) Dropped beats (2o heart
block) Complete AV dissociation (3o heart
block) Slowing of ventricular rate during
atrial flutter or fibrillation Since ventricular
rate depens primarily on the activity of the AV
node, prolongation of the RP of the AV node ?
protects the ventricle from the rapid atrial
impulses ? ventricular rate will be slowed
29
3. Direct electrophysiological effects (1)
Atrial muscle Early, brief prolongation of
AP (increased membrane resistance), followed by
shortening of the AP (decreased membrane
resistance due to increased Ca2i ?
increased Kout). This results in AP shortening
of atrial and ventricular
refractoriness. (2) AV node Slowed
conduction, prolongation of RP (direct effect is
synergistic with vagal effects). (3)
Automaticity Digitalis increases the
automaticity in the latent pacemakers It
generates afterdepolarizations, afterpotentials"
? arrhythmias. Slowing of intracardiac
conduction (toxic doses) and increased
automaticity leads to - ES formation -
AV junctional rhythm - bigeminy - VT,
VF - asystole (cardiac standstill) Digitalis
can cause virtually every variety of
arrhythmia. Conduction disturbance (AV block)
due to Na pump inhibition Arrhythmias due to
oscillatory afterdepolarizations (caused by
overload of intracellular Ca2).
30
Electrocardiographic effects ECG changes
ST-segment depression, inversion of T wave, PR
prolongation, QT shortening. Induction or
increase of U waves. These precede signs of
toxicity such as bigeminal rhythm, ES, AV
dissociation and ventricular arrhythmias. Ventr
icular arrhythmias (1) Cardiac glycosides are
utilized as antiarrhythmic drugs
supraventricular tachyarrhythmias (increase the
RP of the AV node flutter 2 1
fibrillation 3 1) ? slower ventricular rate ?
increase in CO (diastolic filling time
increases) (2) Cardiac glycosides may cause
virtually any type of arrhythmias (ventricular or
supraventricular). Inhibition of
Na-KATP-ase ? Nai increases ? resting MP
reduces Increased rate of diatolic
depolarization of the Purkinje cells
Decreased AV conduction (direct and indirect
effects) Abnormal automaticity (delayed
afterdepolarizations) ? arrhythmias Vascular
system Direct constriction on arterial and
venous smooth muscle ? increased TPR and BP
(best seen after iv injection in normals)
Venoconstriction seen in CHF patients decreases
after cardiac glycosides (cardiac function?,
compensatory sympathetic tone?)
31
Gastrointestinal effects GIT is the main
extracardiac site of digitalis effect (unwanted
side effects) anorexia, nausea, vomiting,
diarrhea These effects are partially due to
the direct effects on the GIT or indirect ie.
stimulation of CNS, including chemoreceptor
trigger zone CNS effects Stimulates the vagal
nucleus in the medulla? slowing HR and increase
in GIT motility. Stimulates chemoreceptor
emetic zone in the area postrema ? nausea and
vomiting Visual changes - changes in color
vision Neurological symptoms- headache,
fatigue, disorientation, digitalis delirium seen
particularly in elderly, rare convulsions,
facial pain, similar to trigeminal
neuralgia Other effects Diuresis due to
increased cardiac function and circulation (renal
blood flow?) inhibition of KNaATP-ase
in the kidneys Interactions with K, Ca2 and
Mg2 K and Ca2 are antagonistic K and
digitalis (i) inhibit each-other's binding to
Na-KATP-ase, therefore, hyperkalemia
reduces, hypokalemia faciltates the effects of
cardiac glycosides Ca2
facilitates the toxic actions of digitalis
Mg2 opposes the effect of Ca2
32
Indications a.) Heart failure with atrial or
supraventricular tachyarrhythmias (flutter or
fibrillation) b.) Atrial flutter or fibrillation
with rapid ventricular rate c.) Acute
supraventricular tachycardia and decompensated
heart d.) Prevention of atrial fibrillation and
junctional tachycardia Contraindications a.)
Hypertrophic cardiomyopathy (hypertrophic
subaortic stenosis) cardiac glycosides
increase the obrtruction against ejection, and
inhibit relaxation b.) WPW syndrome (they
enhance the redtrograde pulse conduction, provoke
VT) c.) AV block Relative contraindications a.)
If the decompensation is caused by pericarditis,
valvular stenosis, cor pulmonale b.)
Hyperthyreosis (high CO syndrome) c.) Acute
myocarditis d.) Acute myocardial infarction,
ischaemia e.) Hypokalemia, renal
insufficiency f.) Together with calcium
antagonists, beta blockers, quinidine (reduce
clearence of digitalis)
33
Toxic effects of digitalis Reason calcium
overload, NKATP-ase inhibition. Toxicity is
exacerbated by sympathomimetics increase in
calcium decrease in magnesium hypoxia
increased heart rate potassium
depletion Symptoms extreme bradycardia,
arrhythmias, anorexia, fatigue, headache, nausea,
neuralgic pain and altered color vision
(yellow hues) Treatment of toxicity Discontinue
cardiac glycosides Correct precipitating
factors (eg. electrolite disturbance) Treat
serious arrhythmias K salts with normal
renal function and constant monitoring
Antiarrhythmic drugs (Phenytoin, Lidocain)
Asystole may result in presence of complete heart
block and abolition of ventricular
arrhythmia Steroid binding resins (primarily
for digitoxin) and digoxin specific
antibodies may be useful to aid drug removal

34
OTHER POSITIVE INOTROPIC DRUGS A BETA ADRENERGIC
RECEPTOR AGONISTS DOPAMINE, DOBUTAMINE,
DOPEXAMINE The positive inotropic action is
accompanied only with little chronotropic
activity or incerase in TPR Use in acute
heart failure (iv) due to AMI ISOPROTERENOL is
NOT used in CHF (HR??) ARAMINE (METARAMINOL),
XAMOTEROL and METOPROLOL Partial ? agonists,
stimulate ? receptors ? positive inotropic action
during long- term administration ?
receptor antagonists when sympathetic drive
incerases (stress, exercise) Improves LV
diastolic function They could be detrimental
in NYHA IV Indication mild or moderate HF B
PDE INHIBITORS AMRINONE (INOCOR), MILRINONE
(PRIMACOR), ENOXIMONE Mechanism of action PDE
inhibition ? cAMP ? ? Ca2 influx through calcium
channels ? Increased release of Ca2 from SR
Result positive inotropic action, balanced veno
and arterial dilation Efficacy Negative
during prolonged therapy in mild and severe HF
Proarrhythmic No functional benefit,
incerased mortality compared to digoxin Since in
end-stage failure cAMP production is reduced
(downregulation of ? receptors) PDE inhibitors
and ? agonists are not adequately effective.
35
Preparations Narrow therapeutic range, small
therapeutic index. LANOXICAPS (LANOXIN) -
DIGOXIN LANATOZID C - duration is similar to
digoxin, but poor oral absorpt OUABAIN
(Strophantin) - short acting, only used
experimentally ACETYLSTROPHANTIDIN - ultra short
acting, only used experimentally ACIGOXIN
(ACETYLDIGITOXIN) - lanatoside A glycoside inj.
tabl. CARDITOXIN (DIGITOXIN) - tabl. DIGOXIN -
inj, solutio, tabl. ISOLANID (DESLANATOSID) -
Lanatoside C glycoside, inj, tabl. TALUSIN
(PROSCILLARIDIN) - tabl. DIGITALIS LEAF (whole
leaf preparation) - duration is similar to
digitalis but less potential Administra
tion Individual dosing ("titration) to achieve
adequate therapeutic effects and minimize
undesirable side effects or toxicity.
Digitalizing dose and maintenance dose
Tradicional large starting doses to achieve
high plasma levels and tissue concentration,
followed by smaller doses to maintain plasma
levels. Modern slower dosage is recommended
(large starting doses only in emergency
situation)
36
C CALCIUM SENSITIZERS SULMAZOL, PIMOBENDAN,
SIMENDAN, LEVOSIMENDAN Mechanism of action
Sensitisation of contractile proteins (troponin
C) for calcium ? positive inotropic action
Inhibits PDEIII enzyme ? cAMP? ?
vasodilatation ? unwanted tachycardia
? arrhythmia generation D
VASODILATORS NITRATES (NITROGLYCERIN,
NITROPRUSSID) CALCIUM ANTAGONISTS (NIFEDIPINE
CORINFAR ADALAT) DIRECTLY ACTING VASODILATORS
(HYDRELAYINE DEPRESSAN,
MINOXIDIL) ALFA-ADRENOCEPTOR BLOCKERS (PRASOZIN
MINIPRESS) Vasodilators therapy is
advocated systemic resistance is increased
in CHF vasodilators (e.g. Nitrates) reduce LV
filling pressure and increase CO However, most
vasodilators are not selective ? the initial
enthusiasm has waned The immediate
haemodynamic effects are not sustained in the
long-term They do not relate to long-term
clinical improvement They do not increase
excersise capacity There is no evidence that
they alter mortality Nitrates could be used
to delay progression of myocardial damage
37
E ACE INHIBITORS CAPTOPRIL (TENSIOMIN),
ENALAPRIL (RENITEC) Plasma RAS maintains
circulatory homeostasis during acute and subacute
alterations in cardiac output Tissue RAS
contributes to maintain homeostasis during
impairment of CO 1. Activation of the RAS


Occurs in
response to reduction in cardiac output.
Arterial constriction ? ? SABP? and DABP?
Catecholamine release ? Angiotensin II.
? aldosteron secretion ? (adrenal cortex)
sodium retention water retention

potassium excretion
Increased blood pressure water intake
?
vasopressin secretion ?
adrenocorticotropic hormon ?


AGII binding to AT1
receptor leads to cardiac remodelling which
includes upregulation of many early active
cardiac myocyte genes induction of late
markers of cardiac hypertrophy (a-actin) and
growth factors such as TGF? shift to fetal
type myocardium AGII binding to AT2 receptor may
oppose the effect of AGII on AT1 receptors
38
2. Hyperaldosteronemia


AGII activates aldosterone secretion (
decreases hepatic aldosterone clearance) Incerase
d aldosterone levels are indicators of HF (like
the increased level of ANP) Elevated aldosterone
leads to myocardial fibrosis
sympathetic activation BRS
activation magnesium loss
arrhythmias Angiotensin receptor blockade ACE
inhibition fails to produce complete blockade of
the RAS ie. in response to the decrease in
plasma AGII levels following ACE inhibition, the
compensatory renin secretion rapidly restores
AGII levels and this attenuates the effects of
ACE inhibition. Similarly, cardiac ACE and
chymase are specific AGII forming enzymes which
are not abolished after chronic ACE inhibition.
AT1 receptor antagonists LOSARTAN, IBESARTAN,
VALSARTAN, LISINOPRIL, CANDESARTAN Combined ACE
inhibitor and AT1 receptor therapy AT1 receptors
are inhibited the ACE inhibition leads to
reduced sympathetic tone and generation of
vasodilator kinins. In addition in this case,
AGII acts on AT2 receptors which effect,
together with the increase in kinin production,
might be beneficial.
39
Efficacy reduction in symptoms of HF
increased exercise capacity delay in
progression of damage reduction in
mortality act in all patients with mild to
severe HF reduction in preload
(venodilatation) reduction in afterload
(arterial dilatation) improvement in
regional blood flow (renal vasodilatation)
improvement in coronary blood flow (due to
reduced NE release) reduction in
sympathetic tone and arrhythmias
prevention of cardiac hypertrophy and
dilatation prevention of cardiac
remodelling F BETA RECEPTOR ANTAGONISTS Sympathe
tic stimulation is involved in LV remodelling
loss of myocardial cells
gene expression Increased sympathetic drive
induces 1. myocardial hypertrophy and fibroblast
hyperplasia through stimulation of ?1 and
? receptors 2. accelerated myocardial cell lost
- apoptosis 3. NA may induce apoptosis through ?
receptor activation (this can be blocked by
CARVEDILOL) 4. changes in myocardial gene
expression which results in progressive
worsening in contractility (downregulation of
the adult type, high ATP-ase activity ?-myosin
heavy chain isoform and upregulation of the
fetal type, low ATP-ase activity ?-myosin heavy
chain isoform)
40
Beta-adrenoceptor blockers PROPRANOLOL,
METOPROLOL, BUCINDOLOL, CARVEDILOL First
generation PROPRANOLOL (non selective) blocks
all myocardial ? receptors and increases
systemic vascular resistance Second generation
METOPROLOL and BISOPROLOL (?1selective) produce
lower reduction in cardiac index because they do
not block cardiac ?2 receptors and they have no
effect on the ?2-mediated vasodilatation.
Metoprolol selectively upregulate ?1 receptors
and slightly improve maximal functional
capacity Third generation CARVEDILOL and
BUCINDOLOL are non-selective or mildly selective
agents. Their vasodilator (?1 adrenoceptor
blockade) activity may counteract their
negative inotropic and ?2 adrenoceptor blocking
effects thus they do not worsen haemodynamics.
They might yield a greater protection against
the increased sympathetic drive. (i) They do
not upregulate ?1 receptors, a mechanism that may
further reduce the sensitivity of the
heart to sympathetic drive. (ii) They also
block ?2 receptors which because of ?1
downregulation represents 40 of the total
adrenergic receptors in patients with heart
failure (dilated cardiomyopathy) and may
mediate the cAMP-dependent effects of
sympathetic stimulation even a greater extent
than ?1 receptors. (iii) Presynaptic ?2
receptors facilitate NA release. Thus, only
non-selective agents may decrease
cardiac NA release. (iv) Cardiac ?2 receptors
may favour malignant tachyarrhythmias through
cAMP.
41
CRITICAL EVALUATION OF DRUGS USED IN THE
TREATMENT OF CHF Positive inotropic drugs 1.
CARDIAC GLYCOSIDES (particularly digoxin)
Improvement in exercise tolerance (controlled
trials captopril-digoxin, milrinone- digoxin,
xamoterol-digoxin) In patients with sinus
rhythm its efficacy is questionable No
improvement in NYHA IV. Effect on cardiac
mortality is controversial USEFUL BUT WEAK
POSITIVE INOTROPIC DRUGS WITH LOW THERAPEUTIC
INDEX 2. PDEIII INHIBITORS (AMRINONE,
MILRINONE) Efficacy during prolonged therapy
in mild to severe HF is negative Danger in
arrhythmogenesis Lack in functional benefit
Increased mortality (cp. to digoxin) In
end-stage failure (cAMP production is reduced)
they are not effective 3. BETA-ADRENOCEPTOR
PARTIAL AGONISTS (XAMOTEROL) In normal
subjects positive inotropic action If
sympahetic drive is increased (exercise or severe
HF) acts as ?-blocker Improves LV diastolic
function Improves symptoms and quality of life
in mild and moderate HF 4. VASODILATORS Most
vasodilators are not selective The immediate
beneficial haemodynamic effects are not sustained
in the long-term Exercise capacity is not
improved There is no evidence that they alter
mortality Nitrates could be used to delay
progression of myocardial damage
42
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