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CARDIOVASCULAR SYSTEM

CONGESTIVE HEART FAILURE TREATMENT


 Le coeur est un muscle (myocarde),
contenu dans un sac (péricarde) et qui
comporte quatre valves.

 Il reçoit le sang veineux en


provenance des viscères et du cerveau
au niveau des cavités droites. Le
ventricule droit éjecte ce sang veineux,
par l'artère pulmonaire, dans les
poumons où se fait l'échange du gaz
carbonique (qui est soufflé à
l'expiration) contre de l'oxygène (qui
provient de l'air inspiré).

 Le sang ainsi oxygéné va dans les


cavités gauches ; il est éjecté par le
ventricule gauche dans l'aorte et les
artères périphériques, pour alimenter
les membres, les viscères, le cerveau
Insuffisance cardiaque
 Ancienne définition : Incapacité du coeur à assurer un débit
cardiaque suffisant aux besoins métaboliques des tissus

 Actuellement : Syndrome complexe initié par une dysfonction


cardiaque associant :
 Inadéquation des conditions de charge du coeur
 Phénomènes congestifs
 Déficits énergétiques des tissus
 Mise en jeu excessive des mécanismes de régulation neuro –
hormonaux ( S∑et SRAA) de la volémie

 Elle est associée à des cas de comorbidité cardiovasculaire :


maladie coronarienne, IM, mort soudaine
Introduction
5

Congestive heart failure

Congestion = volume overload Myocardial dysfunction = pump failure

Congestion, edema, Hemodynamics Pathologic Increased


ascites localized alteration cardiac arrhythmogenic
differently depending on remodeling instability
failed side of the heart

oedeme aigu des poumons est un etat pathologique où le coeur est incapable de
pomper le sang à une vitesse adequate pour repondre aux besoins des tissus
Insuffisance cardiaque : Physiopathologie

• diminution de la fonction pompe


• diminution du débit en aval (corrigé par les régulation)
• augmentation des pressions en amont :
- capillaires pulmonaires (œdème pulmonaire)
- secteur veineux périphérique (oedèmes périphériques)
• dilatation du ou des cavités ventriculaires
• hypertrophie du muscle cardiaque
• conséquences néfastes de ces modifications cardiaques :
- augmentation du travail du cœur
- augmentation de la consommation d’oxygène du cœur
- dilatation de la valve mitrale et fuite mitrale
- troubles du rythme auriculaire (FA)
- troubles du rythme ventriculaire (ESV, TV, FV)
Insuffisance
cardiaque
gauche
Symptomes

 Lorsque le muscle cardiaque


devient défaillant, le
retentissement se fait d'abord
en amont :
 quand le ventricule gauche
n'éjecte plus suffisamment de
sang→engorgement dans les
poumons, qui se traduit d'abord
par un essoufflement (dyspnée),
puis par un passage d'eau dans
les alvéoles (oedème pulmonaire)
Insuffisance
cardiaque
Symptoms droite
8

 Quand le ventricule droit ne


fonctionne plus correctement,
le sang veineux stagne dans
les tissus, d'où un gros foie
douloureux , dilatation des
veines du cou et des
oedèmes des jambes.

 L ’insuffisance cardiaque
droite peut être isolée ou
s ’ajouter à l ’insuffisance
cardiaque gauche
(insuffisance cardiaque
globale)

 Un coeur insuffisant ne
parvient plus à éliminer
Ankle edema
l'eau et le sel: la diurèse
baisse et il y a une
surcharge hydrosodée.
COMPENSATORY RESPONSES DURING
HEART FAILURE:
 CARDIAC OUTPUT

 CAROTID SINUS FIRING  RENAL BLOOD FLOW

 SYMPATHETIC Délétères à long  RENIN RELEASE


DISCHARGE cours

 FORCE REMODELING
 RATE  PRELOAD  AFTERLOAD CARDIOMEGALY
A compensatory
ALDOSTERONE structural
response
EDEMA
CARDIAC OUTPUT
EDEMA : Compensatory response
TACHYCARDIA: An early mediated by the renin angiotensin
compensatory response mediated by aldosterone system & by
increased sympathetic tone increased sympathetic outflow
Pathophysiology : compensatory responses
10

Increased
preload

Edemas

↓ Cardiac output
Ventricular remodeling
Water and sodium retention

↑ sympathetic activity

Activation of RAAS* Tachycardia


&
Increased
* Renin Angiotensin Aldosterone System ↓ Renal flow afterload
Goals of CHF therapy
11

 Direct goal  Increase cardiac output

 How  ?
 Improving pumping action
 Reduce cardiac workload

 Treatment in this case will


 Improve symptoms
 Slow or reverse deterioration in myocardial function
 Prolong survival

 Drugs can also be used to


 treat underlying conditions,
 control arrhythmias,
 prevent thrombosis, https://www.youtube.com/watch?v=zeSDuiTbM9o
 treat anemia. https://www.youtube.com/watch?v=51S3tTirR_g
CHF therapy
12

Non- • Identify and correct precipitating symptoms : smoking,


pharmacological diet, medication compliance
treatment • Surgeries …

Relieve symptoms • Dyspnea, congestion, fatigue, …

• Increase cardiac contractility


• Decrease preload ( left ventricular pressure)
Enhance cardiac • Decrease afterload (systemic vascular resistance)
performance • Normalize heart rate and rhythm
• Reduce the neurohormonal components of heart failure
• Control fluid retention
Pathophysiology  Pharmacotherapy
13

Increased Positive inotropes


preload  Digitalis glycosides
 Others
Edemas

Diuretics
Ventricular remodeling ↓ Cardiac output

Water and sodium retention

↑ sympathetic activity
Activation of RAAS

ACE inhibitors β Blockers


ARBs Vasodilators
↓ Renal flow
CONGESTIVE HEART FAILURE
TREATMENT
DIURETICS
Diuretics
 Used to reduce plasma volume and edema  relieve the symptoms of volume
overload
 Characteristics :
 Should be associated to ACE inhibitors at the minimal effective doses
 Majority of CHF patients require chronic administration of diuretics to maintain
euvolemia
 Diuretic resistance :
 Daily dose  compensatory increase in renal tubular Na+ reabsorption 
prevention of effective diuresis
 Reduction of diuretic dosing intervals may be warranted

 Loop diuretics : furosemide, bumetanide and torsemide


 Loop diuretics are the most efficient : Greatest natriuretic activity  preferred
for reducing plasma volume in heart failure.
 Are effective in renal insufficiency
 Enhance K+ secretion particularly in the presence of elevated aldosterone levels,
as is typical in CHF
Diuretics

 Thiazide diuretics :
 Monotherapy with thiazide diuretics has a limited role in CHF.
 Combination therapy with loop diuretics is often effective in those refractory to loop diuretics alone

 K+ sparing diuretics:
 Weak diuretics, but achieve volume reduction with limited K+ and Mg2+ wasting
 Aldosterone antagonists:
 LV systolic decreases renal flow→overactivation of RAA axis and → aldosterone
levels in CHF
 Spironolactone induces 30% reduction in mortality ( progressive heart failure,
sudden cardiac death)
 Gynecomastia: 10% men
 Severe hyperkalemia 2% all patient
The pathophysiologic effects of hyperaldosteronemia
are diverse and extend beyond Na+ and fluid retention

MECHANISM PATHOPHYSIOLOGIC EFFECT


Increased Na+ and water retention Edema, elevated cardiac filling pressures

K+ and Mg2+ loss Arrhythmogenesis and risk of sudden cardiac


death
Reduced myocardial NE uptake Potentiation of NE affects: myocardial
remodeling and arrhythmogenesis
Reduced baroreceptor sensitivity Reduced parasympathetic activity and risk of
sudden cardiac death
Myocardial fibrosis, fibroblast proliferation Remodeling and ventricular dysfunction

Alterations in Na+ channel expression Increased excitability and contractility of


cardiac myocytes
VASODILATORS
Vasodilators
20

 Objective
 :Reduction in preload through venodilatation or
 reduction in afterload through arteriolar dilation or both

 Remember that :
 Vasodilation = increase in peripheral perfusion ??
 Reflex tachycardia !

 Only ACEI, ARBs & (hydralazine + isosorbide dinitrate) demonstrably improve survival
 Nitrovasodilators
 Advantages   LV filling pressure ;  pulmonary and systemic vascular resistance & 
coronary blood flow (improve systolic and diastolic ventricular function )
 Disadvantages  no effect on systemic vascular resistance & tolerance

 Hydralazine – nitrovasodilators combination 


 Improvement in hemodynamics
 Hydralazine may decrease nitrate tolerance by an antioxidant effect that attenuates
superoxide formation, thereby increasing the bioavailable NO levels
Pharmacological effects
Effects on Myocardial O2 Requirements

Venodilation Arteriolar dilation


Increase in venous capacitance Decrease peripheral arteriolar
resistance

Decrease in venous return to


the heart Reduces ventricular pressure at
the end of systole ESP =
Decrease in ventricular end- afterload
diastolic volume = preload

Reduction of myocardial work


Reduction of O2 demand & consumption
Vasodilator Drugs Used to Treat Heart Failure
DRUG CLASS EXAMPLES MECHANISM OF PRELOAD REDUCTION AFTERLOAD REDUCTION
Vasodilators VASODILATING ACTION

Organic nitrates Nitroglycerin, isosorbide NO-mediated vasodilation +++ +


dinitrate

NO donors Nitroprusside NO-mediated vasodilation +++ +++

ACE inhibitors Captopril, enalapril, lisinopril Inhibition of AngII generation, ++ ++


BK degradation

Ang II receptor blockers Losartan, candesartan AT1 receptors blockade ++ ++

PDE inhibitors Milrinone, inamrinone Inhibition of cyclic AMP ++ ++


degradation

K+ channel agonist Hydralazine Unknown + +++


Minoxidil Hyperpolarization of vascular + +++
smooth muscle cells

1 antagonists Doxazosin, prazosin Selective  1 adrenergic +++ ++


receptor blockade

Non selective antagonists Phentolamine Non selective  adrenergic +++ +++


receptor blockade

/1 antagonists Carvedilol, labetalol Selective 1 adrenergic ++ ++


receptor blockade

Ca2+ channel blockers Amlodipine, nifedipine, Inhibition of L-type Ca2+ + +++


felodipine channels
RAAS
Drugs targeting RAAS
 ACEI
 Improve survival in patients with CHF due to systolic dysfunction independent of etiology
 Actions : suppress AngII (and aldosterone) production, decrease sympathetic nervous
system activity, and potentiate the effects of diuretics in CHF
 Chronic therapy
 AngII "escape“ = AngII levels frequently return to baseline due in part to AngII production
via ACE-independent enzymes
 Clinical data = sustained clinical effectiveness !!  alternate mechanisms contribute to the
clinical benefits of ACE inhibitors in CHF
 Explanation : Bradykinin and other kinins oppose AngII-induced vascular smooth muscle cell
and cardiac fibroblasts proliferation and inhibit unfavorable extracellular matrix
deposition.
 Preferential arterial vasodilators   systemic arterial pressure,  CO & NO change in
heart rate

 ARBs
 Advantages over ACEI : no AngII "escape“ &  bradykinin-mediated side effects
 Excellent alternative in CHF patients intolerant of ACE inhibitors
 ARB + aldosterone antagonist :  in LV ejection fraction and quality of life scores in
patients with CHF due to systolic dysfunction
Beta receptor antagonists
 CHF is fundamentally a disorder of impaired stroke volume and cardiac output
 CHF symptom relief from short-term sympathomimetics e.g. dobutamine
 Studies :
 Long-term sympathomimetic use is associated with increased CHF mortality rates
 -Blockers in CHF  mortality
 Mainly metoprolol & carvedilol

 Explanation : -Blockers
 Prevent myocardial ischemia without significantly influencing serum electrolytes
 Decrease the frequency of unstable tachyarrhythmias to which CHF patients are
particularly prone
 Prevent or delay progression of myocardial contractile dysfunction by inhibiting
maladaptive proliferative cell signaling in the myocardium, reducing catecholamine-
induced cardiomyocyte toxicity, and decreasing myocyte apoptosis
 May induce positive LV remodeling by decreasing oxidative stress in the myocardium

 Therapy is initiated at very low doses, generally less than one-tenth of the final
target dose, and titrated cautiously upward
Positive inotropic drugs
Cardiac glycosides
27

 Digitalis glycosides are mainly derived from Digitalis


purpurea , digitalis lanata
 300 cardioactive agents of plant origin are identified
 Can be found in
 Other plants : oleander & others
 Skin of some toads
Purple Foxglove plant
 Digoxin is the only one of pharmacological importance:

Nerium oleander Adonis vernalis Bufo vulgaris


Cardiac glycosides : Cardiovascular
28
effects
 Positive inotropic effect
 Increased cardiac output
 Control of cardiac arrhythmias (mainly a vagal
dependent action)
 Slowing of atrial sinus rate
 Slowing of atrioventricular impulse conduction

 Diuresis and reduction of edema (circulatory


improvement)
 Reductions in: blood volume and heart rate
MECHANISM OF POSITIVE INOTROPIC EFFECT:

• Myocte depolarisationshift of Na
and Ca in the cell
• Ca2+ enter via Ltype channel,and
by Na +Ca2+ exchanger and
facilitate Ca2+ release from SR via
Ryanodine Receptors (RyR)Ca2+
intracellularmyocardial
contraction
• During repolarisation , Ca2+ is re-
sequestered in SR by Ca2+ -ATPase
SERCA2, removed from the cell by
Na +Ca2+ exchanger and to a lesser
extent by Ca2+ -ATPase
• The electrochemical potential of Na
+ is maintained by active transport
out of Na by Na+,K+,ATPase
Cardiac action potential
30

Non nodal
tissues
Rapid
Repolarization Plateau

Rapid
Depolarization

Delayed

Diastolic Repolarization
Potential
Cardiac excitation-contraction coupling
1 2

4
3
6

6 5
Depolarisation cardiomyocytaire : Repolarisation cardiomyocytaire :
 le calcium intracellulaire est sequestré à
nouveau dans le réticulum sarcoplasmique par
 La dépolarisation est initiée par une Ca2+‐ ATPase (SERCA2) et par un
l’ouverture des canaux Na voltage antiporteur Na+/Ca2+.
dependants et l’entrée des ions Na  La capacité d’échange Na+/Ca2+ de cet
 La dépolarisation rapide inactive les cx antiporteur dépend étroitement de la
sodiques et ouvre les cx K et les canaux concentration intracellulaire de sodium:
calciques voltage dépendants de type L
favorisant l’entrée des ions Ca2+  d’une part l’antiporteur utilise le gradient
extracellulaire sodique pour déplacer du calcium vers
 L’augmentation modérée de la l’espace extracellulaire contre son propre
concentration calcique intracellulaire gradient de concentration.
induit la libération du Ca2+ stocké dans  D’autre part, les concentrations
le réticulum cytoplasmique (via le extracellulaires de Na+ et Ca2+ sont
récepteur à la ryanodine RYR), c’est « la
libération de calcium induite par le bien moins variables que les concentrations
calcium » intracellulaires dans des conditions
physiologiques.
 L’augmentation massive de la
concentration calcique intracellulaire est  Le sodium entré dans la cellule est ensuite
disponible pour interagir avec les externalisé par la Na+/K+ ATPase.
protéines contractiles, augmentant la
force de contraction.
Ca2+ is Ca 2+ entry via L
removed by channel triggers the
re-capture release of Ca2+
in SR by from SR (2)
Ca2+ - 2
ATPase 1 Ca2+
SERCA2
intracellular
4
myocardial
contraction

4 3

Ca2
removed
Na balance is from the
5 instored by cell by
NA+K+ Na+Ca2+
ATPase exchanger
Mecanism of action
 Glycosides bind & inhibit the phosphorylates  subunit Na
+/K + ATPase pump ↓Na+ extrusion .

 Increased intracellular [Na + ]slows extrusion of Ca 2+ via the


Na + /Ca 2+ exchange transporter.
 Increased [Ca 2+ ] is stored in the sarcoplasmic reticulum, and
thus increases the amount of Ca 2+ released by each action
potentialpostive inotropic effect
 Extracellular K+ promotes dephosphorylation of the enzyme
and also thereby decreases the affinity of the enzyme for
cardiac glycosides:
 Increased extracellular K+ reverses some of the toxic effects of
the cardiac glycosides.
Increase of the
amount of Ca 2+
released by each
action
Increased [Ca 2+ ] is
potentialpostive
stored in the
inotropic effect
sarcoplasmic
reticulum
4

Increased
intracellular (Na+)
slows extrusion of Ca
2+ via the Na + /Ca
2
2+ exchange

transporter.

Digitalis inhibit Na+k+


ATPase ↓Na+
1
extrusion
Cardiac glycosides
 Cardiac effects:
 Therapeutic concentrations :
 Positive inotropic action: increase myocardiac contractility
 in cardiac output,↓ preload, improves blood flow to
periphery & kidneys,↓ edema, & . fluid excretion 
fluid retention in lung & extremities is decreased
 Negative chronotropic action (increase in vagal tone)
 Negative dromotropic action (decrease conduction )

 At higher concentrations:
 increase in sympathetic nervous system activity that influences
cardiac tissue automaticity, the genesis of atrial and ventricular
arrhythmias.
Cardiac glycosides : PK

 Oral bioavailability is 70-80%. in patient with normal renal function.


 10% of the population have Enterobacterium Lentum which inactivates
digoxin in an inactive metabolite drug resistance

 Digoxin t½= 36-48h

 Cross BFP , Excreted unchanged by the kidney

 The principal reservoir is skeletal muscle

 Individual dosage regimen according to plasma concentrations and


patient response
Cardiac glycosides : Toxicity
 GI : anorexia, nausea & vomiting (central & GI irritation) : earlier signs of toxicity
 Cardiac : arrhythmias : bradycardia , AV block & tachyarrhythmias
 Neurologic :
 Eyes : blurred vision and yellow, green, or blue chromatopsia (a condition in which
objects appear unnaturally colored).
 CNS: delirium, restlessness, confusion, dizziness, seizures

 Intoxication with digitalis can be precipitated by


 hypokalemia, hypoxemia, hypomagnesemia, hypercalcemia, and disturbances in acid-
base balance
 Renal impairment
 Drug interactions : verapamil, amiodarone, propafenone, and spironolactone.

 Treatment of intoxication
 Oral KCl or SLOW KCl infusion (with frequent monitoring of ECG and kalemia)
 Anti-arrhythmic agents : lidocaine, propranolol, and phenytoin
 Atropine if severe sinus bradycardia
 Glycosides antibodies : Purified Fab fragments from anti-digoxin antisera (DIGIBIND)
Cardiac glycosides : Indications
 Systolic heart failure : clinical experience
 Digoxin reduces symptoms and the need for hospitalization
and improves quality of life of patients with heart failure
 Digoxin does not prolong survival !!
 Patients who have been withdrawn from digoxin have
experienced a worsening of heart failure

 Digoxin is used now in


 CHF patients with LV systolic dysfunction + atrial fibrillation
 Patients in sinus rhythm who remain symptomatic despite
maximal therapy with ACE inhibitors and adrenergic
receptor antagonists
Other inotropic positive medication
 Adrenergic Agonists  cAMP & are consistently associated with
increased risks of hospitalization and death

 Dopamine
 Low doses  2 g/kg : renal blood flow  maintain an adequate GFR
in hospitalized CHF patients with impaired renal function refractory to
diuretics
 Intermediate doses 2-5 g/kg :  myocardial contractility
 Tachycardia may actually provoke ischemia (and ischemia-induced malignant
arrhythmias) in patients with coronary artery disease

 Dobutamine
 -agonist of choice for the management of CHF patients with systolic
dysfunction
 Pharmacologic tolerance may limit infusion efficacy beyond 4 days 
addition or substitution with a class III PDE inhibitor may be necessary to
maintain adequate circulatory support.
Other inotropic positive medication
 Phosphodiesterase inhibitors : Inamrinone &
milrinone : PDE3 I
 Pharmacological effects (inodilators)
 Stimulate myocardial contractility
 Cause balanced arterial and venous
dilation
 Consequent fall in systemic and pulmonary
vascular resistances and left and right-heart
filling pressure

 Approved for short-term circulation support


in advanced CHF : Milrinone = agent of
choice because
 Enhanced selectivity for PDE3,
 Short t1/2
 Favorable side-effect profile

 Inamrinone : thrombocytopenia in 10% of


patients
New treatments for congestive heart
42
failure
 Negative chronotropic agent : ivabradine

 Neprilysin – RAS inhibitor :


Ivabradine PROCORALAN
43

 Novel heart rate–lowering drug  First agent that


blocks the If current (the so-called “funny current”)
in the SA node

 If = mixed Na+-K+ inward current that is


 Activated by hyperpolarization
 Modulated by the autonomic nervous system
 Responsible for diastolic depolarization and cardiac
impulse initiation

 Cardiac effects are specific to the sinus node with


no effect on intra-atrial, atrioventricular or
intraventricular conduction times, nor on myocardial
contractility or ventricular repolarisation

 Main phamacological effect : specific dose


dependent reduction in heart rate without affecting
 Contractility
 Conductivity
 Blood pressure
Ivabradine PROCORALAN
44

 Indications :
 Coronary artery diseases
 Chronic heart failure

 Ivabradine is not effective in the treatment or


prevention of cardiac arrhythmias and likely loses its
efficacy when a tachyarrhythmia occurs

 Metabolized by CYP3A4

 Main adverse effect : bradycardia & visual


disturbances (transient enhanced brightness in a limited
area of the visual field)
Neurohormonal system : NPs
45

 Natriuretic peptides (NP): hormones that help maintain sodium and fluid balance.

NPs levels are a reliable diagnostic


marker of dyspnea due to cardiac
causes and of the severity of HF

Elimination by:
• Receptor mediated degradation
• Breakdown by extracellular
proteases i.e. neprilysin
Neurohormonal system : neprilysin
46

 Neprilysin
 Other names : metalloendopeptidase, enkephalinase, neutral
endopeptidase 24.11 (NEP), vasopeptidase, an atriopeptidase.
 Expressed in several tissues but most commonly in the kidney.
 Catalyzes the degradation of numerous endogenous peptides,
such as
 ANP, BNP, CNP
 Bradykinin
 Substance P
 Adrenomedullin
 Glucagon  Nesiritide
 Vasoactive intestinal peptide  Neprilysin inhibitors
 Calcitonin gene-related peptide  :Candoxatri
 Omapatrilat :
 Enkephalins
 Angiotensin II
Neurohormonal system: modulators
47
Neurohormonal system: modulators
48

Nesiritide :
IV administration
Associated with significant hypotension
No proof of  morbidity & mortality
Neurohormonal system: modulators
49

Candoxatril :
• Oral drug
• Dose-dependent  ANP and
natriuresis & Angiotensin II
• Failed to show reduction in systemic
vascular or pulmonary resistance in
patients with HF
Neurohormonal system: modulators
50

Omapatrilat :
• First dual neprilysin / ACE I /
aminopeptidase P
• Promising results :  BP &
hemodynamic improvement in HF
patients
• Failed to show substantial benefit in
comparison with enalapril
• High occurrence and severity of
angioedema !!
Angiotensin receptor neprilysin inhibitor
51
ARNI
Angiotensin receptor neprilysin inhibitor
52
ARNI
 LCZ696 = complex of sacubitril + valsartan ENTRESTO
 Dual-acting crystalline complex composed of sacubitril and valsartan in their
anionic forms, sodium cations, and water molecules

 Oral ingestion (BID)

 Sacubitril prodrug  metabolized by esterases into sacubitrilate LBQ657


(t1/2 = 12h)

 Valsartan (t1/2 = 10h)

 Minimal metabolism of sacubitrilate & valsartan

 Excretion
 Sacubitril: 52-68% (primarily as LBQ657) in urine; 37-48% (primarily as
LBQ657) in feces
 Valsartan: 13% in urine; 86% in feces
Angiotensin receptor neprilysin inhibitor
53
ARNI
 Indications : patients with CHF (NYHA class II-IV) and
reduced ejection fraction

 Adverse effects:
 Most frequent (>10%) : hypotension, hyperkalemia
 1-10%: cough, dizziness, orthostatic hypotension
 <1% : angioedema

 Should NOT be administered concomitantly with ACEI


(or within 36 hours of the last dose of ACE inhibitor)