MUDr. Jiřina Petrželková
Definition
 Heart failure is a condition when the heart
cannot satisfy the circulatory needs of the
body despite a sufficient blood supply to the
heart
 Vital organs chronically suffer from inadequate
blood perfusion
 dysfunction of the myocard of ventricles due to
various diseases
 It is a leading cause of mortality and morbidity
Epidemiology
 Prevalence
 1 -2% overal; 6-10 % in elderly population
 Morbidity
– One of the most common cardiac
causes of hospitalizations and outpatient
visits
 Mortality
– 50% in 5 years in general
– 50% in 1 year in severe cases
A growing epidemy
 4.7 million symptomatic patients, estimated
10 million in 2037
 Incidence: About 550,000 new cases/year
 More deaths from heart failure than from all
forms of cancer
 Prevalence is 1% between the the ages of 50
– 59, progressively increasing to >10% over
age 80
 $30 billion/year (5% to 7% of total health
care cost)
Main manifestation of CHD
 Symptoms: dyspnea + fatigue → limit
exercise tolerance,
 Signs: Fluid retention → pulmonary
congestion and peripheral oedema,
Causes of CHF
 Coronary Artery Disease (CAD) – 2/3
 Hypertension (HTN)
 Cardiomyopathy (Idiopathic dilated
cardiomyopathy - IDC)
 Valve disease (mitral, aortal)
Classification of CHF
 Which side of heart is affected
– Left (more common, pulmonary
congestion)
– Right (hemostasis in peripheral vessels -
oedema)
 Which heart function is affected
– Systolic (↓ contraction and EF, dilated LV)
– Diastolic (↓ relaxation, preserved EF)
Forms of Heart Failure
Systolic dysfunction
– Pumping problem
– More common
– Common cause: CAD
– Reduced ejection fraction
(REF) < 40%
Diastolic dysfunction
– Filling problem
– Less common
– Common cause: HTN
– Preserved ejection
fraction (PEF)
Homeostatic responses to impaired
cardiac output
ACTIVATION of:
 Renin-angiotensin-aldosterone system
(angiotensin II, aldosteron) due to
reduced renal blood flow
 Sympathetic nervous system (noradrenalin)
– increased output
 Vassopresin (ADH), Endothelin, Cytokines
Early responses - Beneficial
Later these responses: Detrimental
Pathofysiology of heart failure
Drugs for CCF
1. ACE Inhibitors/ARB/ renin inhibitors
2. Beta blockers
3. Diuretics
4. Digoxin
5. Other Cardiac Inotropes –
6. Dobutamine, Milrinone
7. Other vasodilatators
1A. Angiotensin-converting
enzyme inhibitors
ACE inhibitors improve
 mortality
 morbidity
 exercise tolerance
 left ventricular ejection fraction.
1A. ACE inhibitors
 First-line treatment in CHF
 Beneficial across all functional classes of HF
 Reduce risk of developing HF in high-risk patients
(previous MI, > 55 y.o. with vascular disease or
DM)
 Start low, titrate to target (doses shown effective
in clinical trials)
RAAS – target of ACEI action
Practical issues with ACEI - 2
Initial and target doses:
– Captopril: 6.25 mg tid target: 50 mg tid
– Enalapril: 2.5 mg bid target: 10-20 mg bid
– Lisinopril: 2.5-5 mg qd target: 20-40 mg qd
– Ramipril: 1.25-2.5 mg qd target: 10 mg qd
– Fosinopril: 5-10 mg qd target: 40 mg qd
– Quinapril: 10 mg bid target: 40 mg bid
ACEI – adverse events
 Dry irritating persistent cough ( 10-15 %)
 Hyperkalemia (aldosteron reduced)
 Angioedema 0,1 – 0,2 %)
 Fetal toxicity
1B. Angiotensin Receptor AT-1
Blockers (ARB)
 Competitive antagonists of
Angiotensin II (AT-1 receptors).
 No inhibition of ACE, bradykinin
(no cough)
1B. ARB – „sartans“
ARBs are recommended for routine
administration to symptomatic and
asymptomatic patients with an LVEF ≤
40% who are intolerant to ACEI
for reasons other than
hyperkalemia or renal insufficiency.
LVEF – left ventricular ejection fraction
1B. Angiotensin receptor blockers
0 6 12 18 24
Telmisartan
Irbesartan
Olmesartan
Candesartan
Valsartan
Losartan
Eprosartan
Plasma half-life)
1C. Renin Inhibitors
Aliskiren
MoA: orally active, direct action
reduce plasma renin activity by 50-70 %
D: once daily, 150 – 300 mg orally
I: monotherapy or combination with ACEI
2. Beta blockers
 Acts primarily by inhibiting the
sympathetic nervous system.
 Competitive inhibition on β
adrenoceptors
 Anti-arrhythmic properties.
 Anti-oxidant properties.
2. Beta – Blockers
Cardiac effects
 Decrease contractility ( neg. inotropy)
 Decrease of heart rate ( neg. chronotropy)
 Decrease conduction velocity ( negative
dromotropy)
CARDIOPROTECTIVE EFECT (Saving myocardial effort=
decrease of O2 consumption )
Organ functions of B-B
 cardiovascular system : negative
chronotropic and inotropic effect => ↓ of BP
 renal system: ↓ renin secretion
 bronchus: bronchokonstriction
 eye: ↓ of intraocular pressure
 Metabolic effects: reduction of
glykogenolysis and lipolysis
Classification of B-B
 Non-selective (b1 + b2) propranolol, metipranol
 (Cardio)selective (b1) metoprolol, bisoprolol,
betaxolol, atenolol
 Non-selective with ISA (b1 + b2) pindolol
 (Cardio)selective (b1) with ISA acebutolol,
celiprolol
 Combining α + β blocade = carvedilol, labetalol
β -blockers of II. generation
2. Beta – blockers practical issues
 Start at low dose and monitor for bradycardia
 Carvedilol, bisoprolol and metoprolol are the
most commonly used for CHF amongst beta
blockers
Carvedilol: 3.125 mg bid target: 25-50 mg bid
Metoprolol: 6.25 mg bid target: 75 mg bid
Bisoprolol: 1.25 mg qd target: 10mg qd
ADRs of BBs
 Fluid retention (→ worsening CHF)
 Hypotension (→ fatigue)
 Bradycardia (→ fatigue)
 slow AV conduction (AV block)
 Bronchoconstriction (non- selective)
3. Diuretics
 decreasing the extra cellular volume
 useful in reducing the symptoms of volume
overload (dyspnea, oedema)
 recommended in pts with congestion
 decreasing the venous return
 have not proved effect on mortality
3. Diuretics
Loop diuretics furosemide
o the most effective – more intense and shorte diuresis
o commonly used in severe forms CHF
o combination with ACEI, spironolakton
Thiazides
o effective in mild cases only
o more gentle and prolonged diuresis
o combination with loop diuretics
o Less effective with a reduced kindey function
Hydrochlorothiazid, indapamid
ADRs of diuretics
Loop diuretics and thiazides cause
hypokalemia.
Potassium sparing diuretics help in
reducing the hypokalemia induced by loop
d. and thiazides
Risk of dehydration → hypovolemia → renal
dysfunction
Potassium sparing diuretics
Spironolactone - Aldosterone antagonist
 Aldosterone inhibition minimize potassium loss,
prevent sodium and water retention, endothelial
dysfunction and myocardial fibrosis.
 Spironolactone can be added to loop diuretics to
modestly enhance the diuresis; more
importantly, improve survival.
4. Cardiac glycosides
 Come from foxgloves and related plants containing
several cardiac glycosides (digoxin
is the most important therapeutically)…
Digitalis purpurea Digitalis lanata
4. Cardiac glycosides - digoxin
Inhibition of Na+/K + ATPase pump increase
intracellular sodium concentration increase
level of intracellular calcium ions
4. Digoxin
 Increase the refractoriness of AV node
thus decrease ventricular response to
atrial rate ….
 positive inotropic effect (↑contractility)
 negative chronotropic (↓heart rate)
 negative dromothropic (↓conduction)
 positive bathmotropic (decreased depolarisation
treshold)
Pharmacokinetic of digoxin
 Absorbtion from GI 60-75%
 Albumin binding 20-40 %
 T 1/2 = 36 hours
 Liver metabolization app. 20 %
 Renal elimination app. 75 %
 TDM (0,5-0,9 ng/ml = 0,6-1,1 nmol/l)
Practical issues with digoxin
 How to give
– General: 0.25 mg daily
– if > 70 yrs / renal insuff. / low lean body mass:
0.125 mg
 Monitoring
– Therapeutic range
– Toxicity common when > 2.0 ng/mL,
may occur at lower levels when↓K and ↓Mg
ADRs of digoxin
 Arrhythmias
–AV bloc
– Ectopic and re-entrant cardiac rhythms
 GI side effects
– Anorexia, nausea, vomiting
 Neurological complications
– Visual disturbance, disorientation, confusion
5. Other cardiac inotropes
Phosphodiesterase III Inhibitors
(Responsible for degradation of cAMP)
increase myocardial contractility
milrinone nad amrinone
5. Other cardiac inotropes
Sensitisation of cardiac muscle to calcium
(also in vascular smooth muscle)
Levosimendan – Ca sensitizator
I: severe hearth failure
cardiogenic shock
6. Other cardiac inotropes
Dobutamine is a beta-1 agonist which
increase contractility and cardiac output.
Targets of CHF treatment
 Mortality reduction (evidence based)
 – ACEI
 – AT1 blokatory
 – aldosteronu antagonists – spironolakton
 – beta-blockers
 Quality of life (mortality reduction not proved)
 – diuretics
 – digoxin
Sites of drug action in CHF therapy
DRUGS FOR CHF
Conclusion :
 ACE inhibitors are cornerstone in the
treatment of CCF.
 Beta blockers are used in selected
patients (mild/moderate failure, low
dose)
 Diuretics and digoxin are other drugs
useful in CCF in select patients.
Mechanisms of Arrhythmogenesis
 disorders of impulse generation
(abnormal automaticity, triggered activity
 disorders of impulse conduction
(conduction block, reentry)
 combination of both
Antiarrhythmic agents
Vaughan-Williams classification
Active
agents
Clinical use MoA
Class I a Prajmalin Limited use Interfere with Na+
channel / effects on
cardiac potentials
Class I b Lidocain Ventricular tachycardia
Class I c Propafenon Atrial fibrilation, reccurent
tachyarrhythmias
Class II B –blockers
(metoprolol,
atenolol
Tachyarrhythmias decrease conduction
through the AV node
Class III Amiodaron,
Sotalol
Dronedaron
Ibutilid
Vetnricular tachycardia
Atrial fibrilation - the most effective
AA
K+ channel blocker,
prolong repolarisation (
QT int.)
Class IV Ca channel
blockers
Atrial fibrilation - rate reduction
Paroxysmal supraventricular
tachycardia prevention
Ca++ channel blocker
„Class V“ Digoxin
Adenosin Supraventricular ventricular tachy Slow AV conduction
Most common arrhythmias in CHF
 Sinus bracykardia
 Sinus tachycardia
 Atrial tachycardia/ flutter/ fibrilation
 Ventricular arrhythmias
 Atrioventricular block
Atrial fibrillation
 Most common arrhythmia in HF
 Risk of trombo-embolic complication (stroke)
 Therapy in REF (systolic HF)
1. B – blocker
2. Digoxin ( alternative or addition to BB)
3. Amiodaron ( alternative monotherapy or addition to
BB or digoxin)
4. AV node ablation and pacing
 Therapy in PEF ( diastolic HF)
1. Verapamil/ Diltiazem
 Trombembolism profylaxis
REF – reduced Ejection fraction, PEF – preserved ejection fraction
Amiodaron
 Reduction of mortality by 30 %
 Long T ½ (40 – 50 days)
 Common ADRs: depend on the dose/duration of its
use
 Lung fibrosis
 Thyreopathy
 Optic neuritis
 Hepatotoxicity
 Arrhythmogenic effect
 Alveolitis
 Corneal deposits
 Skin changes
 Phototoxicity
Verapamil, diltiazem
 Non-dihydropyridine Ca++ channel
blockers
 Reduction of heart rate
 Reduction of AV conduction
 Contraindication – concurrent use with
B blockers, digoxin, atrioventricular
blocks
 Common interactions - inhibition of
CYP450
General principles for useof
antiarrhythmic agents
 May predispose to ventricular arrhythmias
 Currently their role is declining
 Rising importance of surgical treatment ( ICD –
implantable cardioverter defibrilator, RFA –
radiofrequency ablation)
 Many interractions with non- cardiac drugs –
enhancing arrythmogenic potential ( makrolides,
quinolone antibiotics, diuretics
 K+ channel blockers prolong QT interval ( amiodaron,
sotalol)