HEART FAILURE

OVERVIEW
HEART FAILURE:
Complex, progressive disorder in which the
heart is unable to pump sufficient blood to
meet the needs of the body

manifestations:
Dyspnea
Fatigue
Fluid retention
Impaired ability of the heart to adequately
fill with and/or eject blood

Causes:
Arteriosclerotic heart disease
Myocardial infarction
Hypertensive heart disease
Valvular heart disease
Dilated cardiomyopathy
Congenital heart disease
Left systolic dysfunction secondary to CAD
Most common cause of HF
70% of cases

Accompanied by abnormal increase in

blood volume and interstitial fluid
Dyspnea pulmonary congestion (left
sided HF)
Peripheral edema (right sided HF)
Role of physiologic compensatory
mechanisms in the progression of HF
Chronic activation of SNS and Renin-
angiotensin-aldosteron axis
Cardiac remodeling
Loss of myocytes
Hypertrophy
fibrosis
Geometry of the heart less elliptical and
more spherical interfere with its ability to
efficiently function as pump neurohormonal
activation (vicious cycle)
 Goals of pharmacologic
intervention in HF
Alleviate symptoms
Slow disease progression
Improve survival

6 classes of drugs
Renin-angiotensin inhibitors
B-adrenoceptor blockers
Diuretics
Direct vasodilators
Inotropic agents
Aldosterone antagonists
Can use 1 or more of these drugs depending
on the severity of HF

Reduction of myocardial load

Decrease extracellular fluid volume
Improve cardiac contractility
Slow the rate of cardiac remodeling
 Compensatory physiological
responses in Heart Failure
Dec
HF Dec CO Dec BP
Renal BF

Inc
Inc venous Sympathetic Inc RA
pressure activity II

Inc
Aldosterone
Inc
capillary
filtration
Inc Na+ and
EDEMA H20 retention
1. Increase sympathetic activity
baroreceptors ( sense a decrease in BP)
Attempt to sustain tissue perfusion
- adrenergic receptors
Increase HR
Increase force of contraction
1 stimulation
Vasoconstriction
Enhance venous return
Increase cardiac preload

Increases the work of the heart in long

term, contribute to further decline in cardiac
function
2. Activation of renin-angiotensin system
Dec CO dec BF to kidneys release
reninangiotensin II aldosterone
Increase peripheral resistance
Na+ and water retention

Increase blood volume

Increase Venous return

Increase venous pressure

Peripheral edema
Pulmonary edema
3. Myocardial hypertrophy
Increase in size and chambers dilate and become
more globular
Initially stretches the muscle stronger
contraction
Excessive elongation weak contraction
diminishes the ability to eject blood systolic HF

Diastolic HF hypertrophy ( inability to relax and

accept blood) decrease ventricular volume
decrease filling decrease CO
Common in elderly women

Diastolic dysfunction s/s of HF with normal

function of left ventricle
Compensated HF adaptive mechanism
adequately restore CO
May increase workload of the heart contribute
to further decline in cardiac performance

Decompensated HF adaptive mechanism fail

to maintain CO
Therapeutic strategy
Chronic HF management
Reduction of physical activity
Low dietary intake of Na+ (<1,500mg/d)
Treat co-morbid conditions
Use of diuretics
Inhibitors of renin-angiotensin system
Inotropic agents
Identify those precipitating/ exacerbating
factors for the development of HF

NSAIDS
alcohol
CCB
High dose -blockers
Antiarrhythmic drugs
 DRUGS USED IN HEART
FAILURE

ANGIOTENSIN-
RECEPTOR
ACE INHIBITORS BLOCKERS

Candesartan
Captopril
Losartan
Enalapril
Fosinopril Telmisartan
Lisinopril Valsartan
Quinapril
Ramipril
DRUGS USED IN HEART
FAILURE

BETA
ADRENOCEPTOR DIURETICS
BLOCKERS
Bumetanide
Furosemide
Atenolol Hydrochlorothiazide
Carvedilol Metolazone
Metoprolol
DRUGS USED IN HEART
FAILURE

DIRECT
VASODILATORS INOTROPICS

Digoxin
Hydralazine Dobutamine
Isosorbide dinitrate
Inamrinone (amrinon)
Isosorbide mononitrate
Sodium nitroprusside Milrinone
DRUGS USED IN HEART
FAILURE

ALDOSTERONE ANTAGONISTS

Eplerenone
Spironolactone
INHIBITORS OF RENIN-ANGIOTENSIN
SYSTEM
HEART FAILURE activate RAS via 2
mechanisms
Increase renin release by JG cells in afferent
arterioles in response to diminished renal
perfusion pressure
Renin release is promoted by sympathetic
stimulation and activation of receptors

Angiotensin II potent vasoconnstrictor

Aldosterone salt and water retension

Increase preload and afterload

Other effects of angiotensin II and aldosterone
Remodeling
Fibrosis
Inflammatory changes
ACE INHIBITORS
Agent of choice for HF
MOA
Blocks angiotensin I angiotensin II
Diminish the rate of bradykinin(vasodilator)
inactivation
Decrease aldosterone secretion

Actions on the heart:

Decrease vascular resistance, venous tone and
BP
Reduce preload and afterload increase CO
Angiotensinog Decrease output of
en
SNS

Increase
Decrease vasodilation of
Angiotensin angiotensin
I vascular smooth
II
muscle

Decrease
retention of
ACE
sodium and water
inhibitor
s

Inhibit degradation of Increase levels of

bradykinin bradykinins
ACE INHIBITORS
Blunt the usual angiotensin II-mediated increase
in epinephrine and aldosterone seen in HF
Improve clinical S/S in patient receiving thiazide or
loop diuretics and/or digoxin
Decrease morbidity and mortality
Placeb
o
Commulative
mortality
Enalapril

Time

Reduces arrhythmic death, MI and strokes

ACE INHIBITORS

Indications:
Maybe considered as single agent with mild
dyspnea on exertion and do not show S/S of
volume overload (edema)
Used in all stages of Left ventricular failure
Greatest benefits in those with lowest EF
Beneficial to post MI (long term use)
Recommended to be initiated immediately in
patients with MI
Maybe used in combination with diuretics,
blockers, digoxin and aldosterone antagonists
(dependent on the disease severity)
ACE INHIBITORS

KINETICS
Adequately but incompletely absorbed following
oral administration
Presence of food decreases its absorption
Pro-drugs that require activation by hydrolysis
via hepatic enzymes except CAPTOPRIL

Renal elimination of the active moiety is

important for most ACE inhibitors except
FOSINOPRIL
 Plasma half lives of active compounds are
variable (2-12 hours)

Once daily
Ramipril
Fosinopril

Adverse effects:
Postural hypotension
Real insufficiency
Hyperkalemia
Angioedema
Persistent dry cough
Not used in pregnant women toxic to fetus
ANGIOTENSIN RECEPTOR BLOCKERS
Nonpeptide, orally active compounds
Extremely potent competitive antagonists of
the angiotensin type I receptor

Losartan prototype drug

Do not affect bradykinin levels

Not therapeutically identical with ACE inhibitors
ANGIOTENSIN RECEPTOR BLOCKERS

Actions on the CVS

As a substitute for ACE inhibitors in those with
severe cough or angioedema
Indicated for treatment of hypertension

Pharmacokinetics:
All are orally active and require once a day
dosing
Losartan first approved member and it
undergoes extensive first-pass hepatic
metabolism including its conversion to active
metabolite
 Elimination of metabolites and parent
compound
Urine and feces

All are highly protein bound (>90%)

All have large volume of distribution except
Candesartan

Adverse effects:
Similar to ACE inhibitors
Contraindicated in pregnancy
 BLOCKERS
Negative inotropic effect
Improve systolic function and reverse cardiac
remodeling

Prevent changes that occurs in chronic

activation of SNS (decrease HR and release of
Renin)
Prevent the direct deleterious effects of NE on
the cardiac muscle fibers, decrease
remodeling, hypertrophy and cell death
 BLOCKERS
2 drugs approved for treatment of HF
(decrease morbidity and mortality)
Carvedilol nonselective adrenoceptor
antagonist and also blocks adrenoceptor
Metoprolol 1 selective

Recommended to all patients with heart

disease except those who are high risk but
have no symptoms and those who are in
acute HF
 Start at low doses and gradually titrated to
effective doses based on patient tolerance

Hypertensive patients have also benefits

DIURETICS
Relieve pulmonary congestion and peripheral
edema
Reduce symptoms of volume overload
(orthopnea, Paroxysmal nuctornal dyspnea)

Decrease plasma volume decrease venous

return decrease preload decrease cardiac
workload and O2 demand

Decrease afterload by reducing plasma

volumedecrease BP
DIURETICS

Thiazides relatively mild diuretics and loss

efficacy if ECC(estimated creatinine clearance)
is <50ml/min(normal 97-137)

Loop diuretics;
Used in patients who require extensive diuresis
and those with renal insufficiency
Most commonly used in HF
Overdose profound hypovolemia
DIRECT VASODILATORS
Dilation of venous vesselsdecrease cardiac
preload due to increase venous capacitance
Ex: nitrates

Arterial dilators decrease arteriolar resistance

and decrease afterload

If patient is intolerant of ACE inhibitors, or

blockers or if additional vasodilator response is
required, a combination of hydralazine and ISDN
may be used

Hydralazine decrease afterload

Organic Nitrates- decrease preload
 INOTROPIC DRUGS
Enhances cardiac muscle contractility
increase CO

Inotropic action due to increased

cytoplasmic calcium concentration enhance
contractility
 Digitalis glycosides
Cardiac glycosides
Most of the drugs came from digitalis
(foxglove) plants
Increase the contractility of heart muscle
widely used in HF

Influence the Na+ and Ca++ ion flows in the

cardiac muscle increase contraction of atrial
and ventricular myocardium (+ inotropic
action)
Show small difference between a
therapeutically effective dose and doses that
are toxic or even fatal

Low therapeutic index

Digoxin widely used agent

MOA:
Decrease Na+ concentration gradient
decrease ability of Na+/Ca++ exchanger to
move Ca++ out of the cell

Ca++ Na+ Na+

K+

Ca++ Na+ Na+

K+

free Ca++
 Increase contractility of the cardiac muscle CO
closely resemble that of the normal heart

Increase myocardial contractility decrease end

diastolic volume increase efficiency of
contraction increase EF improve
circulation reduce sympathetic activity reduce
Peripheral resistance reduce HR (due to vagal
tone enhancement) decrease O2 demand

Digoxin slows down conduction velocity

through the AV node (accounts for its use in AF)

Note: in the normal heart, (+) inotropic effect of

digitalis is counteracted by compensatory
autonomic reflexes
Therapeutic uses:
Indicated in severe left ventricular systolic
dysfunction after initiation of ACE inhibitors and
diuretics
Not indicated in patient with diastolic or right
sided heart failure

Major indication: HF with AF

Dobutamine (+) inotropic effect

No oral preparation

Mild to moderate HF respond to ACE (-) and

diuretics
Do not require digoxin
KINETICS
All digitalis glycosides possess the same
pharmacologic actions but varies in potency
and kinetics

Protein binding (%)

onset of action(mins) digitoxin

digoxin

half-life(days)

0 50 100
Digoxin
Very potent
Narrow margin of safety
Long half life (36 hours)
Mainly eliminated in the kidneys
Large Vd (accumulates in muscles)
Dose depends on lean body weight
Digitalization if needed

Digitoxin
Much longer half life
Extensively metabolized by liver before
excreted in feces
Adverse effects

Toxicity most common

Discontinue
Serum K+ determination
Monitor levels in renal insufficiency and
dose adjustment

Severe toxicity VTAC

give digoxin Immune fab bind and
deactivate the drug
Cardiac effects:
Arrythmia slowing of AV conduction
associated with atrial arrythmia
Predisposing factor: decrease intracellular K+

GI effects:
Anorexia, nausea/vomiting

CNS effects:
Headache, fatigue, confusion, blurred vision,
alteration of color perception, halos on dark
objects
Factors that predispose to digoxin toxicity
Electrolyte disturbances
hypokalemia ( loop or thiazide diuretics)
Hypercalcemia
Hypomagnesemia

drugs
Displace digoxin from
quininide
tissue-protein binding site
Verapamil
Compete with digoxin for
amiodarone
renal excretion

Increase plasma levels of

digoxin by 70-100%
Increase digoxin
concentration
may occur during Amiodarone
concurrent Erythromycin
Quinidine
therapy
Tetracyclines
Verapamil

Enhance
potential
cardiotoxicity

Corticosteroid
Thiazide
Decrease diuretics
K+ levels Loop diuretics
Other that predispose digoxin
toxicity

Hypothyroidism
Hypoxia
Renal failure
myocarditis
 Beta adrenergic agonists
(+) inotropic effect and vasodilation
 Dobutamine primarily used as inotropic agent in
hospital settings

Phosphodiesterase inhibitors
Inamrinone( formerly amrinone) and Milrinone
Increase intracellullar Ca++
Long term therapy increase risk of mortality
Short term not associated and sometimes
beneficial in refractory HF
ALDOSTERONE ANTAGONISTS
Advance heart disease elevated levels of
aldosterone due to angiotensin II stimulation
and reduce hepatic clearance

1. Spironolactone
Direct antagonist of aldosterone (salt retension,
hypertrophy and hypokalemia)
Reserve for most advance cases of HF
Adverse effects:
Gastric gastritis and peptic ulcer
CNS lethargy and confusion
Endocrine gynecomastia, dec libido, menstrual
irregularities
2. Eplerenone
competitive antagonists of aldosterone at
mineralocortcoid receptors
Lower incidence of endocrine related side
effects
Low affinity for glucocorticoids, androgen and
progesterone receptors

Reduce mortality in patient with LV systolic

dysfunction and HF after MI
Multiple
drugs in
treatment
of HF