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PHARMACOTHERAPEUTICS
OF HEART FAILURE
Anton Kohút
Cardiac failure is characterized by
inadequate cardiac output, which
leads secondarily to an increased
central venous pressure (increased
pre-load) and to peripheral
vasoconstriction (increased after-load)
Causes of HF
•
primary myocardial damage:
- diffuse in inflammation
- local in MI
•
•
•
blood pressure overload - hypertension
volume overload – valve damages
defects in heart filling:
- constrictive pericarditis
- heart tamponade
•
cardiac arrhythmias
- extreme bradycardia or tachycardia
HEART FAILURE (HF)
insuficient cardiac output

central venous pressure ( pre-load)

peripheral vasoconstriction
( after-load)
Compensatory mechanisms in
HF
•
activity of sympathetic nervous
system
•
fluid retention
•
myocardial hypertrophia
•  Increased sympatomimetic activity:
•  activation of -adrenergic receptors 
increase in heart rate and a greater force of
contraction
•  vasoconstriction enhances venous return and
increase cardiac output
•  these compensatory responses increase of
cardiac work and, therefore, can contribute to the
further decline in cardiac function
•  Fluid retention:
•  fall in cardiac output decrease blood flow to the
kidney  release of renin and synthesis of angiotensin II
and aldosterone  increase of peripheral resistance and
retention of sodium and water
•  blood volume increase, more blood is returned to the
heart
•  if heart is unable to pump this extra volume  venous
pressure increases and edema of the peripheral tissues
and lung occurs
•  these compensatory responses increase of cardiac work
and, therefore, can contribute to the further decline in
cardiac function
•  Myocardial hypertrophy:
•  the heart increases in size and the chambers
dilate
•  stretching of the heart muscle lead to a stronger
contraction of the heart
•  however, excessive elongation of the fibers
results in weaker contractions
Acute left HF
•
Paroxysmal night dyspnea
•
Asthma cardiale
•
Lung edema
Chronic left HF
•
Cardial dyspnea
•
Fatigue, muscle weakness, sweting,
oliguria
•
Tachycardia
Chronic right HF
•
•
•
•
•
•
•
jugular vein filling
Hepatomegalia
Cardial edema
Latent edema – fluid retention 2-5 l
Chronic edema
Hydrothorax, hydropericard, ascites
Cyanosis
Pathophysiology of congestive heart
failure
Pharmacotherapy
1. Cardiotonics
a. cardiac glycosides (digoxin, digitoxin, ouabain),
b. sympathomimetics (dobutamine),
c. PDE III inhibitors (amrinone, milrinone)
2. ACE inhibitors (captopril, enalapril, lisinopril, eilasapril),
3. Vasodilatators
a. -receptor blocators (prazosin, phentolamine, labetalol),
b. nitrates (sodium nitroprusside),
c. direct vasodilators (hydralazine, nicorandil),
d. Ca++ channels blocators (nifedipine, amlodipine),
4. Diuretics
Basic therapy of HF
•
cause elimination
•
diet
• pharmacotherapy
Pharmacotherapy
•
ACE-I
•
Diuretics
•
Cardioglycosides
•
-blockers
Cardiotonics
a. cardiac glycosides (digoxin, digitoxin,
ouabain),
b. sympathomimetics (dobutamine),
c. PDE III inhibitors (amrinone,
milrinone)
Cardioglycosides
Cardioglycosides
•
digitoxin – Digitalis
purpurea
•
digoxin – Digitalis
lanata
•
strophantin
(ouabain) –
Strophantus gratus
Mechanism of digitoxin action
Mechanism of action
Na+/K+-ATPase inhibition
intracellular Na+
Na+/Ca2+ exchanger activation
intracellular Ca2+
in cardiac contractility
1 .I n heart failure the cardiac glycosides increase
cardiac output
(better perfusion of peripheral tissue) and reduce
central venous pressure (decrease of tissue fluid
volume).
2 . After glycoside in patients with cardiac failure,
marked diuresis occurs:
- increased renal blood flow
- inhibtion of Na+/K+-ATPase of the tubules
(inhibition of renal-sodium transport)
3 .Glycosides cause cardiac slowing - increase
of vagal activity.
 At higher dosage - an increase in AV conduction
time is detectable (increase of P-R interval on ECG)
4. Larger doses of glycosides-AV conduction
can progress to an AV block.
 ectopic beats which can progress to a
continous ventricular tachykardia and
eventually to ventricular fibrilation
5. Have a beneficial effect in certain type of
dysrhytmia - atrial tachycardia or fibrilat
Cardioglycoside side effects
(approx. 20%)
Cardiac
• arrhythmias (ventricular extrasystolia, atrial
tachycardia, SA  AV block, ventricular
tachycardia)
GIT
• anorhexia, nausea, vomitus, diarrhea
CNS
• headache, drowsiness, fatigue,
disorientation
• visual disturbances (yellow-green vision)
Cardioglycosides - CI
Absolute
• ventricular tachykardia in recent IM
• AV-block II. a III. degree
• i.v. calcium application
Relative
• HF with mechanical obstacle without
atrial fibrilation
• gravidity, breast feeding
Cardioglycosides - intoxication
Symptoms
a) mild intoxication
•
anorhexia, nausea, vomitus
•
bradycardia
•
headache
b) severe intoxication
•
visual disturbancies, disorientation
•
diarrhea
•
ventricular tachycardia, fibrilation
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SA  AV block
Intoxication therapy
•
discontinue drug application
•
stomach lavage + activated charcoal
•
kalium chloratum
•
in case of arrhythmias – fenytoin, lidocain
•
antiobodies
•
serum electrolyte control
Factors increasing risk of
intoxication
1. Disturbancies in electrolyte homeostasis
- hypokaliemia
- hypercalciemia
- hypomagneziemia
2. Drugs
- quinidine - clearance of digoxin - accumulation
- diuretics
- corticosteroids
3. Diseases
- hypoxia, renal failure, myocarditis
-blockers
-blockers – immediate effects
heart rate
BP
heart ejection fraction
vasoconstriction
Beta antagonists and cardiac rhytm
-blockers – chronic application
•
myocardial O2 consumption
•
heart rate  better myocardial blood supply by the
increased blood flow duration in diastole
•
metabolism amelioration –
anaerobic glycolysis
oxidative phosphorylation
energy reserve =
systolic function
sensitivity of -receptors
•
•
myocardial protection against toxic effects of
catechoamines
•
renin release
Angiotensin converting
enzyme inhibitors (ACE-I)
Angiotensin converting enzyme
inhibitors (ACE-I)
•
RAS – BP, water and mineral ion
regulation
•
angiotensin II – main role
in patophysiology of CVS diseases:
- hypertension
- chronic HF
SUBSTANCE
DESCRIPTION-EFFECTS
angiotensinogen
-2 globuline from liver
renin
protease - juxtaglomerular cells
angiotensin I
decapeptide – no biological effect
ACE (kinase II)
conversion of AT I to AT II
angiotensin II
octapeptide – potent
vasoconstrictor, aldosterone
release, secretion of growth
factors
aldosterone
mineralocorticoid
Effect of ACE-I
Effect of ACE-I dependes on renine levels:
•
high level - 
•
low level -  (old people, afroamericans)
ACE inhibition
•
inhibition of AT II production
•
inhibition of bradykinine degradation
•
in stimulation of aldosterone
secretion
•
•
of NA release from nerve terminals
in production of vasoconstricting
endotheline by damaged endothelium
ACE-I side effects
•
cough (10-15% of patients) AII
blockers
•
hypotension, headache, vertigo
•
fatigue, GI disturbances, allergies
ACEI





Captopril (CAPOTEN)
Enalapril (VASOTEC)
Enalaprilat (VASOTEC INJECTION)
Enalaprilat is not absorbed orally, but is
available for intravenous administration when
oral therapy is not appropriate.
Lisinopril (PRINIVIL, ZESTRIL)
Chronic HF therapy 1
•
•
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•
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ACE-I - “gold standard"
-blockers regularly after MI
AII A – in case of cough after ACE-I
in fluid retention - diuretics (thiazide, later
loop)
in atrial fibrilation - digoxin
digoxin in NYHA II-III in case of side
effects during ACE-I, diuretics, -blockers
therapy
Chronic HF therapy 2
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in ventricular arrhythmia - amiodaron
in hypertension  angina pectoris add
amlodipine
don`t use -blockers with ISA, prefer
blockers with vasodilating effects
(carvedilol)
control of other diseases (DM,
hyperlipoproteinemia)
life style
Diuretics
Actions of diuretics
•
Actions of loop diuretics
•
Potasium sparing diuretics