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Heart Failure
CONTRACTILITY
PRELOAD
AFTERLOAD
STROKE
VOLUME
- Synergistic LV contraction
- LV wall integrity
- Valvular competence
CARDIAC OUTPUT
HEART
RATE
Heart failure
is the pathophysiological state in which the heart is
unable to pump sufficient blood to satisfy the metabolic
demands of the body with enough preload.
Heart failure is a complex, progressive disorder, in which the
cardiac output is insufficient for the needs of the body. It is often
accompanied by abnormal increases in blood volume and
interstitial fluid
HEART FAILURE
causes
HEART FAILURE
pathogenesis
Heart Failure
Pathophysiology
Cardiac injury
Increased load
Reduced systemic perfusion
Activation of RAS, SNS, and cytokines
Altered gene
expression
Growth and
remodeling
Ischemia and
energy depletion
Apoptosis
Necrosis
Cell death
Direct
toxicity
Neurohumoral stimulation
RAS and sympathetic-adrenergic
Vasoconstriction
increased heart rate
Salt and water retention increased energy
(augments preload)
expenditure
Hypertrophy
HEART FAILURE
pathogenesis
Diminished
cardiac
performance leads to a
precardial congestion of
venous
blood.
Congestion in front of
the left ventricle causes
dyspnea and pulmonary
edema.
Ankle
edemas,
enlarged
liver,
and
ascites signal congestion
in front of the right
ventricle.
Effects of Neurohormonal
Stimulation in Heart Failure
Heart
Heart rate
Contractility
Stroke volume
Cardiac output
Conduction velocity
Myocardial oxygen
consumption
Peripheral Circulation
Arterial vasoconstriction
Venoconstriction
Systemic vascular
resistance
Redistribution of blood
flow
Renal vasoconstriction
HEART FAILURE
compensatory mechanisms
The major responses include the following:
tachycardia an early manifestation of increased
sympathetic tone;
increased peripheral vascular resistance;
retention of salt and water by the kidney an early
compensatory response, mediated by the rennin
angiotensin aldosterone system;
cardiomegaly (enlargement of the heart);
apoptosis results in a reduction in the number of
functioning myocytes and their replacement by
connective tissue.
HEART FAILURE
compensatory mechanisms
Thus,
compensatory
include activation of the
mechanisms
Increased
release
of
norepinephrine raises cardiac
rate and evokes peripheral
vasoconstriction.
Increased
production
of
angiotensin II promotes both
vasoconstriction and release of
aldosterone from the adrenals.
These compensations increase
cardiac afterload and plasma
volume is expanded because the
HEART FAILURE
compensatory mechanisms
Although
such
auxiliary
measures
afford
transient
counter
help
in
of
myocardial
insufficiency:
HEART FAILURE
compensatory mechanisms
Thus, these compensatory
responses increase the work
of the heart and, therefore,
can contribute to further
decline in cardiac function.
If the adaptive mechanisms
fail to maintain cardiac
output, heart failure is
decompensated.
Increased
cardiac
workload
Increased
venous
return
Increased force
and rate of
myocardial
contraction
Renal
retention of
sodium and water
Edema
Increased
Sympathetic
Activity
Diminished
renal
blood flow
Renin release
Vasoconstriction
Angiotensin II
Aldosterone
Digoxin
Cardiac Output
Peripheral vasoconstriction
Blood flow
Diuretics
Neurohormonal
Activation
ACE Inhibitors
Blockers
Clinical manifestation
Left heart failure: SOB (Shortness of breath or
Dyspnea), cough,rales,gallop
Right heart failure: gastrointestinal
congestion,anorexia,nausea,a sense of fullness after
meals,hepato-jugular reflux,swelling of feet or ankles
Low cardiac output: fatigue and weakness,oliguria
Biventricular heart failure:both clinical manifestation of left
and right heart failure,one of which maybe predominant.
For progressive
duration
Congestive heart
failure is classified
into acute and
chronic heart
failure
For anatomical
type
Congestive heart
failure is
classified into left
side, right side
and biventricular
heart failure
Progression of Heart
Failure
Coronary artery disease Cardiomyopathic factors
Atrial Fibrillation
Hypertension
Valvular disease
Left ventricular
injury
Diabetes
Pathologic
Remodeling
Death
Low ejection
fraction
Asymptomatic
LV Dysfunction
Compensated
No symptoms
Exercise
Abnormal LV fxn
Decompensated
Symptoms
Exercise
Abnormal LV fxn
Refractory
Symptoms not
controlled
with treatment
HEART FAILURE
Therapeutic strategies
the removal retained salt and water with diuretics;
reduction of afterload and salt and water retention
by means of angiotensin-converting enzyme (ACE)
inhibitors;
reduction of excessive sympathetic stimulation by
means of blockers;
reduction of preload or afterload with vasodilators;
direct augmentation of depressed cardiac
contractility w i t h p o s i t i v e i n o t r o p i c d r u g s
such as digitalis glycosides.
HEART FAILURE
Therapeutic strategies
HEART FAILURE
Therapeutic strategies
HEART FAILURE
Inotropic drugs - cardiac glycosides
CARDIAC GLYCOSIDES
pharmacokinetics
CARDIAC GLYCOSIDES
Mechanism of action
CARDIAC GLYCOSIDES
Mechanism of action
Digitalis inhibit Na+/K+ - ATP- ase of the cell membrane in the
cardiac muscle. Inhibition of Na+/K+ ATP - ase results in an
increase in intracellular sodium. This leads to a rapid rise in
cytosolic Ca2+ levels, which causes contraction.
CARDIAC GLYCOSIDES
pharmacologic effects
The increase in contractility evoked by digitalis results
in increased cardiac output. This beneficial effect permit a
decrease in the compensatory sympathetic response. It is
especially beneficial - reduced heart rate, preload, and
afterload permit the heart to function more efficiently.
Cardiac glycosides evoke the decrease in
atrioventricular conduction velocity and slowing
ventricular rate (mediated by the vagus nerve - central
vagal stimulation).
CLINICAL USES
Congestive heart failure
CLINICAL USES
Congestive heart failure
Because the half-lives of cardiac
glycosides are long, the drugs
accumulate significantly in the body,
and dosing regimens must be carefully
designed and monitored.
At present, no effective oral
inotropic agent exist other than digoxin.
Patients with mild to moderate heart
failure will often respond to treatment
with ACE inhibitors and diuretics,
and they do not require digoxin.
CLINICAL USES
Congestive heart failure
However, careful clinical studies indicate that while digitalis
may improve functional status, it does not prolong life. Other
agents diuretics, ACE inhibitors, vasodilators may be equally
effective and less toxic, and some of these alternative therapies
do prolong life.
CLINICAL USES
Congestive heart failure
HEART FAILURE
Digitalis toxicity
The major signs of digitalis toxicity are
Cardiac arrhythmias - sinus bradycardia, AV-block, ventricular
extrasystoles, ventricular fibrillation (ECG),
anorexia, nausea, vomiting, and diarrhea
TREATMENT
Treatment of digitalis toxicity includes several steps:
Discontinuing cardiac glycoside therapy;
Correction of potassium or magnesium deficiency mild
toxicity may often be managed by omitting 1 or 2 doses
of digitalis and giving oral or parenteral K+ supplements.
Antiarrhythmic drugs lidocaine or phenytoin, or
propranolol.
Digoxin antibodies to digoxin (digoxin immune Fab)
are extremely effective. They are effective for poisoning
with many cardiac glycosides. They bind and inactivate
the drug.
blockers,
phosphodiesterase inhibitors (PDE - inhibitors), and
vasodilators.
Angiotensin II antagonists
Angiotensin II antagonists (ACE inhibitors
angiotensin converting enzyme) - By reducing
circulating angiotensin II levels (angiotensin II is the
potent vasoconstrictor) ACE inhibitors also decrease
the secretion of aldosterone resulting in decreased
sodium and water retention. They are now considered,
along with diuretics, to be first line drugs for chronic
heart failure.
The angiotensin receptor blockers losartan have the
same benefits as ACE-inhibitors (captopril, enalapril,
ramipril).
Beta adrenoceptor agonists - Dobutamine (1selective agonist) and dopamine are often useful in acute
failure. Dobutamine must be given by intravenous infusion
and is primarily used in the treatment of acute heart failure
in a hospital setting.
Beta adrenoceptor antagonists - Carvedilol,
labetalol, metoprolol are useful to reduce progression of
chronic heart failure.
blockers are not of value in acute failure and may
be detrimental if systolic dysfunction is marked.
Carvedilol and metoprolol reduce morbidity and mortality
associated with heart failure. Treatment should be started
at low doses and gradually titrated to effective doses based
on patient tolerance.
TREATMENT
Correction of aggravating factors
Pregnancy
Endocarditis
Arrhythmias (AF)
Obesity
Infections
Hypertension
Hyperthyroidism
Physical activity
Thromboembolism
Dietary excess
MEDICATIONS
PHARMACOLOGIC THERAPY
Improved
symptoms
Decreased
mortality
Prevention
of CHF
Neurohumoral
Control
DIURETICS
yes
NO
DIGOXIN
yes
minimal
yes
INOTROPES
yes
mort.
no
Vasodil.(Nitrates)
yes
yes
no
yes
YES
yes
YES
yes
+/-
YES
ACEI
Other neurohormonal
control drugs
TREATMENT
Normal
Asymptomatic
LV dysfunction
EF <40%
Symptomatic CHF
ACEI
NYHA II
Diuretics mild
Neurohormonal
inhibitors
Digoxin?
Symptomatic CHF
NYHA - III
Loop
Diuretics
Secondary prevention
Modification of physical activity
Symptomatic CHF
NYHA - IV
Inotropes
Specialized therapy
Transplant
DIURETICS
Thiazides
Cortex
K-sparing
Inhibit reabsorption of Na in the
distal convoluted and collecting tubule
Loop diuretics
Medulla
Loop of Henle
Collecting tubule
THIAZIDES
MECHANISM OF ACTION
Excrete 5 - 10% of filtered Na+
Elimination of K
Inhibit carbonic anhydrase:
increase elimination of HCO3
Excretion of uric acid, Ca and Mg
No dose - effect relationship
LOOP DIURETICS
MECHANISM OF ACTION
Excrete 15 - 20% of filtered Na+
Elimination of K+, Ca+ and Mg++
Resistance of afferent arterioles
- Cortical flow and GFR
-
K-SPARING DIURETICS
MECHANISM OF ACTION
Eliminate < 5% of filtered Na+
Inhibit exchange of Na+ for K+ or H+
Spironolactone = competitive
antagonist for the aldosterone receptor
Amiloride and triamterene block
Na+ channels controlled by aldosterone
DIURETIC EFFECTS
Volume and preload
Improve symptoms of congestion
No direct effect on CO, but excessive preload reduction may
Improves arterial distensibility
Neurohormonal activatio
Levels of NA, Ang II and ARP
Exception:
with spironolactone
DIURETICS
ADVERSE REACTIONS
Thiazide and Loop Diuretics
Changes in electrolytes:
Volume
Na+, K+, Ca++, Mg++
metabolic alkalosis
Metabolic changes:
glycemia, uremia, gout
LDL-C and TG
Cutaneous allergic reactions
DIURETICS
ADVERSE REACTIONS
K-SPARING DIURETICS
Changes in electrolytes
Na+,
K+, acidosis
Musculoskeletal:
Cramps, weakness
Cutaneous allergic reactions :
DIGOXIN
Na-K ATPase
Na
K+ Na+
Na-Ca Exchange
Na+
Myofilaments
CONTRACTILITY
Ca++
Ca++
DIGOXIN
PHARMACOKINETIC PROPERTIES
Oral absorption (%)
Protein binding (%)
Volume of distribution (l/Kg)
Half life
Elimination
Onset (min)
i.v.
oral
Maximal effect (h)
i.v.
oral
Duration
Therapeutic level (ng/ml)
60 - 75
25
6 (3-9)
36 (26-46) h
Renal
5 - 30
30 - 90
2-4
3-6
2 - 6 days
0.5 - 2
DIGOXIN
DIGITALIZATION STRATEGIES
oral 12-24 h
oral 2-5 d
1.5-1.75
Maintenance
Dose
(mg)
0.125-0.5 / d
0.25 / d
DIGOXIN
HEMODYNAMIC EFFECTS
Cardiac output
LVejection fraction
LVEDP
Exercisetolerance
Natriuresis
Neurohormonalactivation
DIGOXIN
NEUROHORMONAL EFFECTS
Plasma Noradrenaline
Peripheral nervous system activity
RAAS activity
Vagal tone
DIGOXIN
EFFECT ON CHF PROGRESSION
30
WORSENING OF CHF %
Placebo n=93
DIGOXIN
Withdrawal
20
p = 0.001
10
DIGOXIN n=85
RADIANCE
N Engl J Med 1993;329:1
20
40
60
Days
80 100
OVERALL MORTALITY
50
40
30
Placebo
20
p = 0.8
n=3403
10
DIGOXIN
n=3397
DIG
0
0
12
24
36
48 Months
DIGOXIN
LONG TERM EFFECTS
Survival similar to placebo
Fewer hospital admissions
More serious arrhythmias
More myocardial infarctions
DIGOXIN
CLINICAL USES
AF with rapid ventricular response
CHF refractory to other drugs
Other indications?
Can be combined with other drugs
DIGOXIN
CONTRAINDICATIONS
ABSOLUTE:
- Digoxin toxicity
RELATIVE
- Advanced A-V block without pacemaker
- Bradycardia or sick sinus without PM
- PVCs and TV
- Marked hypokalemia
- W-P-W with atrial fibrillation
DIGOXIN TOXICITY
CARDIAC MANIFESTATIONS
ARRHYTHMIAS :
- Ventricular (PVCs, TV, VF)
- Supraventricular (PACs, SVT)
BLOCKS:
- S-A and A-V blocks
CHF EXACERBATION
DIGOXIN TOXICITY
EXTRACARDIAC MANIFESTATIONS
GASTROINTESTINAL:
- Nausea, vomiting, diarrhea
NERVOUS:
- Depression, disorientation, paresthesias
VISUAL:
- Blurred vision, scotomas and yellow-green vision
POSITIVE INOTROPES
CARDIAC GLYCOSIDES
SYMPATHOMIMETICS
Catecholamines
-adrenergic agonists
PHOSPHODIESTERASE INHIBITORS
Amrinone
Milrinone
Enoximone
Piroximone
Others
-ADRENERGIC STIMULANTS
CLASSIFICATION
B1 Stimulants
Increase contractility
Dobutamine
Doxaminol Xamoterol
ButopaminePrenalterol Tazolol
B2 Stimulants
Pirbuterol
Carbuterol
Tretoquinol
Salbutamol
Mixed
Dopamine
Terbutaline
Salmefamol
Soterenol
Quinterenol
Dobutamine
<2
DA1 / DA2
2-5
1
>5
1 +
Contractility
++
++
++
Heart Rate
++
Arterial Press.
++
++
++
++
Receptors
Renal perfusion
Arrhythmia
POSITIVE INOTROPES
CONCLUSIONS
May increase mortality
Safer in lower doses
Use only in refractory CHF
NOT for use as chronic therapy
VASODILATORS
CLASSIFICATION
VENOUS
Nitrates
Molsidomine
MIXED
Arterial
Vasodilatation
Calcium antagonists
-adrenergic Blockers
ACEI
Angiotensin II inhibitors
K+ channel activators
Nitroprusside
ARTERIAL
Minoxidil
Hydralazine
Venous
Vasodilatation
NITRATES
HEMODYNAMIC EFFECTS
1- VENOUS VASODILATATION
Pulmonary congestion
Preload
Ventricular size
Vent. Wall stress
MVO2
2- Coronary vasodilatation
Myocardial perfusion
3- Arterial vasodilatation
Cardiac output
Afterload
Blood pressure
4- Others
NITRATES
TOLERANCE
Can be avoided or minimized
- Intermittent administration
NITRATES
CONTRAINDICATIONS
Previous hypersensitivity
Hypotension ( < 80 mmHg)
AMI with low ventricular filling pressure
1st trimester of pregnancy
WITH CAUTION:
Constrictive pericarditis
Intracranial hypertension
Hypertrophic cardiomyopathy
NITRATES
CLINICAL USES
Pulmonary congestion
Orthopnea and paroxysmal nocturnal dyspnea
CHF with myocardial ischemia
In acute CHF and pulmonary edema: NTG s.l. or i.v.
VASODILATATION
ALDOSTERONE
PROSTAGLANDINS
Kininogen
VASOPRESSIN
SYMPATHETIC
Kallikrein
Angiotensinogen
RENIN
Angiotensin I
A.C.E.
ANGIOTENSIN II
tPA
Inhibitor
BRADYKININ
Kininase II
Inactive Fragments
ACEI
HEMODYNAMIC EFFECTS
Arteriovenous Vasodilatation
-
SVR and BP
No change in HR / contractility
ACEI
FUNCTIONAL CAPACITY
100
No
Additional
Treatment
Necessary
(%)
95
Quinapril
continued
n=114
90
p<0.001
85
Quinapril
stopped
Placebo
n=110
80
Class II-III
75
Quinapril Heart Failure Trial
JACC 1993;22:1557
10
Weeks
12
14
16
18
20
ACEI
ADVANTAGES
Inhibit LV remodeling post-MI
Modify the progression of chronic CHF
-
Survival
Hospitalizations
ACEI
SURVIVAL POST MI
ACEI
Benefit
Pt Selection
ISIS-4
Captopril
0.5 / 5 wk
GISSI-3
Lisinopril
0.8 / 6 wk
SAVE
Captopril
4.2 / 3.5 yr
EF < 40
asymptomatic
SMILE
Zofenopril
4.1 / 1 yr
TRACE
Trandolapril
7.6 / 3 yr
EF < 35
AIRE
Ramipril
6 / 1 yr
Clinical CHF
ACEI
INDICATIONS
Clinical cardiac insufficiency
- All patients
Asymptomatic ventricular
dysfunction
- LVEF < 35 %
ACEI
UNDESIRABLE EFFECTS
Inherent in their mechanism of action
- Hypotension
- Dry cough
- Hyperkalemia
- Renal Insuff.
- Angioneurotic edema
ACEI
CONTRAINDICATIONS
Renal artery stenosis
Renal insufficiency
Hyperkalemia
Arterial hypotension
Intolerance (due to side effects)
Angiotensinogen
Other paths
AT1
RECEPTOR
BLOCKERS
Vasoconstriction
AT1
Angiotensin I
ACE
ANGIOTENSIN II
RECEPTORS
Proliferative
Action
AT2
Vasodilatation
Antiproliferative
Action
Losartan
Valsartan
Irbersartan
Candersartan
Competitive and selective
blocking of AT1 receptors
ALDOSTERONE INHIBITORS
Spironolactone
ALDOSTERONE
Retention Na+
Retention H2O
Excretion K+
Excretion Mg2+
Edema
Collagen
deposition
Fibrosis
Arrhythmias
- myocardium
- vessels
ALDOSTERONE INHIBITORS
INDICATIONS
FOR DIURETIC EFFECT
Pulmonary congestion (dyspnea)
Systemic congestion (edema)
FOR ELECTROLYTE EFFECTS
Hypo K+, Hypo Mg+
Arrhythmias
Better than K+ supplements
FOR NEUROHORMONAL EFFECTS
Please see RALES results, N Engl J
Med 1999:341:709-717
ALDOSTERONE INHIBITORS
CONTRAINDICATIONS
Hyperkalemia
Severe renal insufficiency
Metabolic acidosis
-ADRENERGIC BLOCKERS
POSSIBLE BENEFICIAL EFFECTS
Density of 1 receptors
Inhibit cardiotoxicity of catecholamines
Neurohormonalactivation
HR
Antihypertensive and antianginal
Antiarrhythmic
Antioxidant
Antiproliferative
BLOCKERS
CARVEDILOL
4 studies in U.S.;
1 in Australia/New Zealand
U.S. studies with control group
Mortality with Placebo 8.2%
Mortality with Carvedilol2.9%
Initial low doses, progressive
p < 0.0001
-ADRENERGIC BLOCKERS
INDICATIONS
and UTILIZATION
-ADRENERGIC BLOCKERS
IDEAL CANDIDATE?
-ADRENERGIC BLOCKERS
CONTRAINDICATIONS
Hypotension: BP < 100 mmHg
Bradycardia: HR < 50 bpm
Clinical instability
Chronic bronchitis, ASTHMA
Severe chronic renal insufficiency
CALCIUM ANTAGONISTS
POTENTIAL EFFECTS
Antiischemic
Peripheral Vasodilatation
Inotropy
CALCIUM ANTAGONISTS
POSSIBLE UTILITY
Diltiazem contraindicated
Verapamil and Nifedipine
not recommended
Vasoselective (amlodipine, nisoldipine),
may be useful in ischemia + CHF
ANTICOAGULANTS
PREVIOUS EMBOLIC EPISODE
ATRIAL FIBRILLATION
Identified thrombus
LV Aneurysm (3-6 mo post MI)
Class III-IV in the presence of:
- EF < 30
- Aneurysm or very dilated LV
ANTIARRHYTHMICS
Sustained VT, with/without symptoms
- Blockers
- Amiodarone
Sudden death from VF
- Consider
implantable
defibrillator
ACE Inhibitors
The most appropriate vasodilators used in HF,
because they decr both arterial and venous
resistance.
Preventing the incr in (vasoconstrictor) angiotensin
II that is often present in HF.
Result: Incr cardiac output and because of the decr
in renovascular resistance, there is an incr in RBF
This, plus the decr in aldosterone, incr Na + and H2O
excretion decr blood vol and venous return to the
heart.
Also decr direct growth action that angiotensin has
on the heart.
[Angiotensin antagonists (e.g., losartan)may not
have the same benefits as ACE inhibitors].
Inotropic Drugs
Digoxin a cardiac glycoside extracted from foxglove
leaves (Digitalis sp) is the most important inotrope.
Increase the contractile force.
Particularly indicated in patients with atrial fibrillation.
Inhibits the Na+/K+-ATPase, which is responsible for
Na+/K+ exchange across the muscle cell membrane
incr [Na+]in incr [Ca2+]in incr force of myocardial
contraction.
Digoxin and K+ ions compete for a receptor (Na+/K+ATPase) on the ext membrane.
So, the effects of digoxin may be dengerously incr by
hypokalemia, produced, for example, by diuretics.
Sympathomimetic Agents
Activate cardiac -receptors AC cAMP
phosphorylation of L-type Ca2+ channels
(opens) incr [Ca2+]influx and the force of
myocardial contraction.
Dobutamine used in acute severe HF.
Dopamine incr renal perfusion by stimulates
dopamine receptors in the renal vasculature.