DRUGS USED IN THE TREATMENT OF
HEART FAILURE
Hanna Winiarska MD, PhD
I. Positive inotropic drugs:
1.Cardiac Glycosides –
a. no effect on mortality
b. reduce hospitalization
c. increase quality of life
Mechanism of action: inhibition of Na+/K+-ATPase
in cardiac myocytes – increased Ca intracellular
level
Pharmacological effects:
Cardiac effects:
1. positive inotropic effect – increased
contractility
2. electrical effects:
a. decrease in action potential duration as a
result of increased K+ conductance
b. reduced resting membrane potential (less
negative) due to inhibition of the Na pump
and reduced intracellular K+ concentration
c. overloading of the intracellular Ca++ stores
and oscillation in the free intracellular Ca++
ion concentration - delayed
afterdepolarizations, (ectopic beat,
bigeminy) - positive batmotropic effect
d. cardioselective parasympathomimetic
effects (atrial and atrioventricular nodal
tissue) in low doses – negative chronotropic
and dromotropic effect
e. toxic doses - stimulation of sympathetic
activity
Effects on other organs:
a. decrease in vascular tone
b. GI tract – anorexia, nausea, vomiting,
diarrhea (direct effects and stimulation of
chemoreceptor trigger zone in cns)
c. CNS – vagal and chemoreceptor zone
stimulation; disorientation, hallucinations
(especially in the elderly), visual
disturbances (aberrations of color
perception), agitation and conmvulsions
d. Gynecomastia (peripheral estrogenic action
or hypothalamic stimulation)
Toxicity of cardiac glycosides:
Psychiatric - delirium, fatigue, malaise, confusion,
dizziness, abnormal dreams
Visual- blurred or yellow vision, halos
Gastrointestinal -anorexia, nausea, vomiting,
abdominal pain
Respiratory - enhanced ventilatory response to
hypoxia
Cardiac arrhythmias - atrial and ventricular ectopic
arrhythmias
Conduction disturbances - sinoatrial and
atrioventricular node conductions disturbances
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Interaction with potassium, calcium and
magnesium ions
K+- hypokalemia increases the toxicity of cardiac
glycosides
Ca2+ - hypercalcemia facilitates the toxic actions of
cardiac glycosides
Mg2+ - hypomagnesemia, a risk factor for
arrhythmias
Clinical uses of digitalis:
1. heart failure (STAGE B-D; NYHA class I-IV)
in patients with atrial fibrillation
2. symptomatic heart failure (Stage C-D; NYHA
class II-IV) in patients with sinus rhythm
3. atrial fibrillation in patients without HF
(second-line therapy)
Contraindication:
1. ventricular arrhythmias
2. arrhythmias associated with pr-excitation
syndrome
3. hypertrophic cardiomyopathy
4. recent myocardial infarction with sinus rhythm
5. sinus bradycardia, second- or third-degree AV
conduction delay
Preparations: digoxin
Other positive inotropic drugs used in heart
failure:
Clinical indications:
Acute or decompensated heart failure - patients
with peripheral hypoperfusion (hypotension,
decreased renal function) with or without congestion
or pulmonary edema refractory to diuretics and
vasodilators at optimal doses
Beneficial hemodynamic effect may be
counteracted by the risk of arrhythmias and
myocardial ischemia
1. drugs that inhibit phosphodiesterases (PDE-I)
a. selective- bipyridines (ENOXIMONE,
MILRINONE)
mechanism of action: selective inhibition of
isoform III of PDE;
pharmacodynamic effects: increased myocardial
contractility; some vasodilating effect
toxicity - nausea, vomiting, thrombocytopenia, liver
enzyme changes.
indication: short-term parenteral treatment of acute
HF; alternative for patients on beta-blocker
therapy
2. beta-adrenoreceptor stimulants (dobutamine,
dopamine)
Dopamine - inotropic, chronotropic and
vasoactive properties – dose dependent
0.5-2(3)ug/kg/min – dopaminergic receptors 
 renal blood flow
2(3) – 5 ug/kg/min – stimulation of beta-1
receptors  inotropic effect, chronotropic
effect   CO
5-10 ug/kg/min – stimulation of beta-1 and
alpha-1 receptors  vasoactive effect
unpredictable
> (10)15-20 ug/kg/min – activation of alpha-1
receptors   SVR
Onset of action – within minutes
Hemodynamic response – variable among
patients
Dobutamine - agent with predominant direct
beta-1 agonist effects and weak beta-2 and
alpha-1 effects
compared to dopamine
– equal or greater inotropic action
-  in PCWP and SVR with increasing doses
- less chronotropic at lower infusion rates
- preferred in patients with  CO, normal or
moderately  PCWP and moderate or severe
hypotension
Levosimendan
- calcium sensitizer, binds to troponin-C in
cardiomyocytes;
- mild PDE inhibitory action;
- significant vasodilating action via ATPsensitive action;
Indication: patients with decompensated
chronic HF; alternative for patients on betablocker therapy
II.Diuretics
Loop diuretics (furosemide, bumetanide,
torasemide)
Thiazides (hydrochlorothiazide)
Potassium sparing diuretics (aldosterone antagonists
– spironolactone, eplerenone; triamterene)
Clinical use of diuretics in patients with HF:
1. indications: patients with fluid retention
(edema, dyspnoe)
2. contraindications: orthostatic hypotonia,
side effects related to particular drug
3. the choice of therapy:
a. mild heart failure – thiazides
b. moderate heart failure – loop diuretic
(typically furosemide 40 mg 1-2/day)
c. severe heart failure – loop diuretic
(furosemide 120-250mg in one dose or
bumetanide 3-5mg/day; or combination
of loop diuretics and thiazidemetolazone)
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potassium sparing diuretics – additive
therapy in patients with hypokalemia
e. aldosterone antagonists
(spironolactone, eplerenone) – additive
therapy (to improve survival rate) in
patients with HF
4. adequate monitoring of daily weights, blood
pressure, and blood electrolyte levels
5. side effects: hypokalemia/hyperkalemia,
hyponatremia, hyperuricemia,
hypomagnesemia, acid-base equilibrium
disturbances
III. Vasodilators
1. ACE inhibitors (ACE-Is)
Mechanism of action : inhibition of the conversion
of the angiotensin I to angiotensin II; increase in
bradykinin levels; increase of rennin release and
angiotensin I formation.
Effects of ACE inhibition in heart failure
1. reduced afterload and systolic wall stress increased cardiac output, reduced heart rate,
increased exercise tolerance
2. decreased blood pressure
3. increased renal blood flow – increased
natriuresis
4. reduced venous return to heart
(venodilation) - diminished preload and
diastolic wall stress
5. improvement in ventricular geometry
(changes in preload and afterload,
prevention of the growth effects of
angiotensin II, decrease aldosteron induced
cardiac fibrosis)
Clinical use of ACE-I in patients with heart
failure:
chronic heart failure (STAGE A-D; NYHA class IIV) with left ventricle dysfunction (LVEF<40-45%)
– first-line therapy!
Contraindications:
1. pregnancy
2. hypotension
3. angineurotic edema - during previous
therapy with ACE-Is
4. bilateral renal stenosis or stenosis of the
artery to a single remaining kidney, others
severe kidney’s diseases
5. hyperkalemia K>5.5mmol/l
Adverse effects of ACE-I
1. related to decreased AT II plasma level:
a. hypotension
b. hyperkalemia
c. worsening of renal function
(patients with low renal perfusion
pressure)
d. fetopathic potential
2. related to increased bradykinin plasma level
a. dry cough (5-10% patients)
d.
b. angineurotic edema 0,1-0,2% of
patients
2. Angiotensin II receptor antagonists (ARBs)
Mechanism of action: ARBs bind to AT1 receptor
and inhibit biological effects of angiotensin II
Differences between ACE-I and ARBs
ARBs reduce activation of AT1 more
1.
effectively than do ACE-I; ACE-I do not
inhibit the alternative angiotensin II
generating pathway
2. ARBs indirectly activate AT2 receptors
increasing angiotensin II level
3. ARBs do not increase ACE substrates
(bradykinin)
Indications:
1. alternative therapy for patients who cannot
tolerate ACE-Is (caught, angioedema)
2. in combination with ACE-Is in symptomatic
patients despite the use of standard therapy who
cannot tolerate aldosteron antagonists
3. Combination nitrates/hydralazine
Nitrates (isosorbide
dinitrate)
 relatively selective for
veins – decreases
ventricular filling
pressure (low doses)
 in higher doses
decreases the systemic
and pulmonary
arterial resistance
 adverse effects:
- hypotension
- tachycardia
- dizziness, headache
- fluid retention
Hydralazine
 direct action in
vascular smooth
muscle
 reduces right and left
ventricular afterload
 has direct moderate
positive inotropic
activity
 has minimal effect on
venous capacitance
(should be combined
with agents with
venodilating activity –
organic nitrate)
 reduces renal vascular
resistance and
increases renal blood
flow – may be useful
in heart-failure patients
with renal dysfunction
who cannot tolerate an
ACE-I
 adverse effects:
- hypotension
- headache, dizziness
- lupus erythematosuslike syndrome
Clinical indications:
- an alternative to an ACE-I/ARB when are not
tolerated
- as add-on therapy to an ACE-I/ARB
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4.Nesiritide
recombinant human brain natriuretic peptide
(BNP)
pharmacological action: venous, arterial,
coronary vasodilator
indications: management of acute heart failure;
patients with AHF with fluid overload, with PCWP
>18-20 mmHg despite of high doses of diuretics and
NTG iv; should be avoided in patients with
SBP<90-100mmHg
5.Ca2+channel antagonists
The use of amlodipine or felodipine may be
considered in patients requiring:
 additional control of blood pressure or
 afterload reduction
 or if other vasodilators are contraindicated
or poorly tolerated
verapamil and diltiazem may be useful in the
treatment of diastolic heart failure (by slowing
heart rate may facilitate diastolic relaxation and
lower diastolic filling pressures); are contraindicated
in patients with systolic heart failure
IV. beta-adrenergic receptor antagonists :
First-line drugs in HF
Effects of beta-blockers in patients with HF:
1. improve in left ventricular structure and
function
2. decrease in chamber size
3. increase in ejection fraction
4. decrease in malignant ventricular
arrhythmias
5. reduce of oxidative stress in the
mycoradium
Clinical use of beta-adrenergic receptor antagonists
in HF (metoprolol, carvedilol, bisoprolol,
nebivolol):
1.indications:
beta-blockers should be prescribed to:
 all patients with stable HF due to left ventricular
systolic dysfunction
 patients with normal LVEF or with diastolic
dysfunction to reduce HR and increase diastolic
period
IN GENERAL, BETA-BLOCKERS ARE USED
TOGETHER WITH AN ACE INHIBITORS
Procedure for starting a beta-blocker:
*patient should be on a background therapy with
ACE-I
*patient should be stable
*therapy should be started with a very low doses
and titrate up to maintenance dose
*the dose may be doubled every 1-2 weeks if the
preceding dose was well tolerated
*patient should be monitor for the symptoms of
worsening of HF and side effects of beta-blockers (
initiation of therapy can cause fluid retention)
Contraindication: hypotension, decompensated
HF, asthma, symptomatic atrioventricular blocks
and bradycardia
V. IVABRADINE
Mechanism of action: inhibition of the If channel in
the sinus node
Its only known pharmacological effect is TO SLOW
THE HEART RATE in patients in sinus rhythm (it
does not slow the ventricular rate in AF)
Should be considered
1. to reduce the risk of HF hospitalization in
patients in sinus rhythm with an EF ≤35%, a
heart rate ≥70 b.p.m., and persisting
symptoms (NYHA class II–IV) despite
treatment with an evidence-based dose of
beta-blocker (or maximum tolerated dose
below that), ACE inhibitor (or ARB), and
an aldosteron antagonist (or ARB)
2. to reduce the risk of HF hospitalization in
patients in sinus rhythm with an EF ≤35%
and a heart rate ≥70 b.p.m. who are unable
to tolerate a beta-blocker.Patients should
also receive an ACE inhibitor (or ARB) and
an MRA (or ARB)
VI. Anticoagulation and antiplatelet drugs in HF
Anticoagulation therapy with warfarin is
recommended for patients:
 with atrial fibrillation or a history of previous
embolic event,
 if there is evidence of a left venticular thrombus,
 if the left ventricular dysfunction is severe and
the ventricles are markedly dilated
Aspirin therapy:
 patients with coronary artery disease related HF
VII. Antiarrhytmic drugs in HF
ALL antyarrhythmic drugs have negative inotropic
and proarrhythmic properties.
It is not recommended to use antyarrhythmic drugs
in patients with HF. Possible exception is
amiodarone (agent with additional beta-adrenergic
suppressing properties). Patients with HF and
ventricular arrhythmias should be managed with
implanted cardiac defibrillator (ICD).
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