Tratamiento farmacolgicode la insuficiencia cardaca

1

CHRONIC CONGESTIVE HEART FAILURE American Heart
Association in collaboration with Sociedad
Española de Cardiologia June,
1999
2

Committee on Post Graduate Education, Council on
Clinical Cardiology, American Heart
Association Developed in collaboration with the
Sociedad Española de Cardiologia Prepared
by Ann F. Bolger, MD José Lopez Sendón, MD The
content of these slides is current as of June,
1999. (Slide 62 updated 9/00) Future revisions
will be posted on the American Heart Association
website (www.americanheart.org).
3

DEFINITION
The situation when the heart is incapable of
maintaining a cardiac output adequate to
accommodate metabolic requirements and the
venous return."
E. Braunwald
4
Chronic Congestive Heart Failure
EVOLUTION OF CLINICAL STAGES

NORMAL
No symptoms Normal exercise Normal LV fxn
Asymptomatic LV Dysfunction
Compensated CHF
No symptoms Normal exercise Abnormal LV fxn
Decompensated CHF
No symptoms Exercise Abnormal LV fxn
Symptoms Exercise Abnormal LV fxn
Refractory CHF
Symptoms not controlled with treatment
5

DETERMINANTS OF VENTRICULAR FUNCTION
CONTRACTILITY
PRELOAD
AFTERLOAD
STROKE VOLUME
HEART RATE
CARDIAC OUTPUT
6

TREATMENT OBJECTIVES
Survival Morbidity Exercise capacity Quality
of life Neurohormonal changes Progression of
CHF Symptoms
7

TREATMENT Correction of aggravating factors
MEDICATIONS
8

TREATMENT PHARMACOLOGIC THERAPY
DIURETICS INOTROPES VASODILATORS NEUROHORMONAL
ANTAGONISTS OTHERS (Anticoagulants,
antiarrhythmics, etc)
9

DRUGS HEMODYNAMIC EFFECTS
Normal
A
I
Stroke Volume
A V
V
CHF
D
Ventricular Filling Pressure
10

PHARMACOLOGIC THERAPY
Neurohumoral Control
Improved symptoms
Decreasedmortality

Prevention of CHF
yes
?
DIURETICS
NO
?
yes

yes
DIGOXIN
minimal
yes
mort.
no
INOTROPES
?
yes
yes
no
Vasodil.(Nitrates)
?
yes
ACEI
YES
yes
YES
Other neurohormonal control drugs
/ -
yes
YES
?
11

TREATMENT
Normal
AsymptomaticLV dysfunction EF lt40
Symptomatic CHF NYHA II
ACEI
Symptomatic CHF NYHA - III
Diuretics mild Neurohormonal inhibitors
Digoxin?
Symptomatic CHF NYHA - IV
Loop Diuretics
Inotropes Specialized therapy Transplant
Secondary prevention Modification of physical
activity
12
DIURETICS
Thiazides Inhibit active exchange of Cl-Na in
the cortical diluting segment of the ascending
loop of Henle
Cortex
K-sparing Inhibit reabsorption of Na in
the distal convoluted and collecting tubule
Loop diuretics Inhibit exchange of Cl-Na-K in
the thick segment of the ascending loop of Henle
Medulla
Loop of Henle
Collecting tubule
13
THIAZIDESMECHANISM 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
14
LOOP DIURETICSMECHANISM OF ACTION
Excrete 15 - 20 of filtered Na Elimination of
K, Ca and Mg Resistance of afferent
arterioles - Cortical flow and GFR -
Release renal PGs - NSAIDs may antagonize
diuresis
15
K-SPARING DIURETICS MECHANISM OF ACTION
16
DIURETIC EFFECTS
Volume and preload Improve symptoms of
congestion No direct effect on CO, but excessive
preload reduction may Improves arterial
distensibility Neurohormonal activation Levels
of NA, Ang II and ARP Exception with
spironolactone
17
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
18
DIURETICSADVERSE REACTIONS Thiazide and Loop
Diuretics
Idiosyncratic effects Blood dyscrasia,
cholestatic jaundice and acute
pancreatitis Gastrointestinal effects Genitourinar
y effects Impotence and menstrual cramps
Deafness, nephrotoxicity (Loop diuretics)
19
DIURETICSADVERSE REACTIONS K-SPARING DIURETICS
Changes in electrolytes Na, K,
acidosis Musculoskeletal Cramps,
weakness Cutaneous allergic reactions Rash,
pruritis
20
DIGOXIN
Na-K ATPase
Na-Ca Exchange
Na
K
Na
Ca
Ca
Myofilaments
K
Na
CONTRACTILITY
21
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 Durat
ion 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
22

DIGOXINDIGITALIZATION STRATEGIES
Maintenance Dose
Loading dose (mg)
(mg) 0.125-0.5 / d 0.25 / d
i.v 0.5 0.25 / 4 h ILD 0.75-1
oral 12-24 h 0.75 0.25 / 6 h 1.25-1.5
oral 2-5 d 0.25 / 6-12 h 1.5-1.75
ILD average INITIAL dose required for digoxin
loading
23

DIGOXINHEMODYNAMIC EFFECTS
Cardiac output LV ejection fraction LVEDP Exer
cise tolerance Natriuresis Neurohormonal
activation
24

DIGOXIN NEUROHORMONAL EFFECTS
Plasma Noradrenaline Peripheral nervous
system activity RAAS activity Vagal
tone Normalizes arterial baroreceptors
25

DIGOXIN EFFECT ON CHF PROGRESSION
30
Placebo n93 DIGOXIN Withdrawal
WORSENING OF CHF
20
p 0.001
DIGOXIN 0.125 - 0.5 mg /d (0.7 - 2.0 ng/ml) EF
lt 35 Class I-III (digoxindiureticACEI) Also
significantly decreased exercise time and LVEF.
10
DIGOXIN n85
0
60
100
80
20
0
40
RADIANCE N Engl J Med 19933291
Days
26

OVERALL MORTALITY
Placebo n3403

p 0.8
DIGOXIN n3397
0
48
12
24
36
DIG N Engl J Med 1997336525
Months
27

DIGOXIN LONG TERM EFFECTS
Survival similar to placebo Fewer hospital
admissions More serious arrhythmias More
myocardial infarctions
28

DIGOXIN CLINICAL USES
AF with rapid ventricular response CHF refractory
to other drugs Other indications? Can be
combined with other drugs
29

DIGOXINCONTRAINDICATIONS
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
30

DIGOXIN TOXICITYCARDIAC MANIFESTATIONS
ARRHYTHMIAS - Ventricular (PVCs, TV, VF) -
Supraventricular (PACs, SVT) BLOCKS - S-A and
A-V blocks CHF EXACERBATION
31

DIGOXIN TOXICITYEXTRACARDIAC MANIFESTATIONS
GASTROINTESTINAL - Nausea, vomiting, diarrhea
NERVOUS - Depression, disorientation,
paresthesias VISUAL - Blurred vision,
scotomas and yellow-green vision
HYPERESTROGENISM - Gynecomastia, galactorrhea
32
POSITIVE INOTROPES
CARDIAC GLYCOSIDES SYMPATHOMIMETICS Catecholamine
s ß-adrenergic agonists PHOSPHODIESTERASE
INHIBITORS Amrinone Enoximone Others
Milrinone Piroximone
33

ß-ADRENERGIC STIMULANTS CLASSIFICATION
B1 Stimulants Increase contractility Dobutamine D
oxaminol Xamoterol Butopamine Prenalterol Tazolol
Mixed
Dopamine
34

DOPAMINE AND DOBUTAMINEEFFECTS
DA (µg / Kg / min)
Dobutamine
lt 2
2 - 5
gt 5
Receptors
DA1 / DA2
ß1
ß1 a
ß1
Contractility




Heart Rate




Arterial Press.




Renal perfusion




Arrhythmia
-



35

POSITIVE INOTROPES CONCLUSIONS
May increase mortality Safer in lower doses Use
only in refractory CHF NOT for use as chronic
therapy
36

VASODILATOR DRUGSPRINCIPLES
Normal Contractility
Normal Contractility
CO
VV
AV
Diminished Contractility
Diminished Contractility
PRELOAD
AFTERLOAD
37

VASODILATORS CLASSIFICATION
Venous Vasodilatation
VENOUS Nitrates Molsidomine
MIXED Calcium antagonists a-adrenergic
Blockers ACEI Angiotensin II inhibitors K
channel activators Nitroprusside
ARTERIAL Minoxidil Hydralazine
Arterial Vasodilatation
38

NITRATESHEMODYNAMIC EFFECTS
1- VENOUS VASODILATATION
Preload2- Coronary vasodilatation Myocardial
perfusion 3- Arterial vasodilatation
Afterload 4- Others
Pulmonary congestionVentricular sizeVent. Wall
stressMVO2
39

NITRATES FUNCTIONAL CAPACITY
392
n24
384


EXERCISE TIME,
267
seconds
4 weeks
Control
1ST dose
ISOSORBIDE 5 - MONONITRATE
Jansen W et alMed Welt 1982331756
20 mg / 8h
40

NITRATESSURVIVAL
0.7
Placebo (273)Prazosin (183)Hz ISDN (186)
0.6
0.5
PROBABILITYOFDEATH
0.4
0.3
0.2
0.1
0
0
6
12
18
24
30
36
42
VHefT-1 N Engl J Med 19863141547
MONTHS
41

NITRATESTOLERANCE
" Decrease in the effect of a drug when
administered in a long-acting form"
42

NITRATES TOLERANCE
Can be avoided or minimized - Intermittent
administration - Use the lowest possible dose -
Intersperse a nitrate-free interval Allow peaks
and valleys in plasma levels - Vascular smooth
muscle recovers its nitrate sensitivity
during the nadirs - Patches remove after 8-10 h
43

NITRATESTOLERANCE
T O L E R A N C E
H A L F L I F E
s.l. NTG ISDN I 5-MN Percutaneous NTG
44

NITRATES CONTRAINDICATIONS
Previous hypersensitivity Hypotension ( lt 80
mmHg) AMI with low ventricular filling pressure
1st trimester of pregnancy
WITH CAUTION

• Constrictive pericarditis
• Intracranial hypertension
• Hypertrophic cardiomyopathy

45

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.
46

ACEI MECHANISM OF ACTION
VASOCONSTRICTION
VASODILATATION
ALDOSTERONE
PROSTAGLANDINS
VASOPRESSIN
tPA
Kininogen
SYMPATHETIC
Kallikrein
Angiotensinogen
RENIN
BRADYKININ
Angiotensin I
Kininase II
A.C.E.
Inhibitor
ANGIOTENSIN II
Inactive Fragments
47

ACEI HEMODYNAMIC EFFECTS
Arteriovenous Vasodilatation - PAD, PCWP and
LVEDP - SVR and BP - CO and exercise
tolerance No change in HR / contractility MVO2 R
enal, coronary and cerebral flow Diuresis and
natriuresis
48

ACEIFUNCTIONAL CAPACITY
100
No Additional Treatment Necessary ()
95
Quinapril continued n114
90
plt0.001
85
Quinapril stopped Placebo n110
80
Class II-III
75
16
Quinapril Heart Failure Trial JACC 1993221557
Weeks
49

ACEIADVANTAGES
Inhibit LV remodeling post-MI Modify the
progression of chronic CHF - Survival -
Hospitalizations - Improve the quality of
life In contrast to others vasodilators,
do not produce neurohormonal
activationor reflex tachycardia Tolerance to its
effects does not develop
50

ACEI SURVIVAL
0.8
0.7
Placebo
0.6
PROBABILITYOFDEATH
plt 0.001
0.5
0.4
plt 0.002
0.3
Enalapril
0.2
0.1
0
CONSENSUS N Engl J Med 19873161429
0
12
11
10
9
8
7
6
5
4
3
2
1
MONTHS
51

ACEI SURVIVAL
50
p 0.30
Placebo n2117
40
MORTALITY
30
20
Enalapril n2111
10
n 4228 No CHF symptoms EF lt 35
0
0
6
12
24
18
30
36
42
48
SOLVD (Prevention)N Engl J Med 1992327685
Months
52

ACEI SURVIVAL
p 0.0036
Placebo n1284
MORTALITY
Enalapril n1285
n 2589 CHF - NYHA II-III - EF lt 35
0
6
12
24
18
30
36
42
48
SOLVD (Treatment)N Engl J M 1991325293
Months
53

ACEI SURVIVAL
30
Asymptomatic ventricular dysfunction post MI
Placebo
n1116
20
Mortality,
Captopril
n1115
10
n 2231 3 - 16 days post AMI EF lt 40 12.5 ---
150 mg / day
² -19
p0.019
SAVE N Engl J Med 1992327669
0
4
3
0
1
2
Years
54

ACEI SURVIVAL POST MI
ACEI
Benefit

Pt Selection
Captopril
0.5 / 5 wk
ISIS-4
All with AMI
Lisinopril
0.8 / 6 wk
GISSI-3
All with AMI
EF lt 40 asymptomatic
Captopril
SAVE
4.2 / 3.5 yr
Zofenopril
SMILE
4.1 / 1 yr
Ant. AMI, No TRL
Vent Dysfx / Clinical CHF EF lt 35
Trandolapril
7.6 / 3 yr
TRACE
Ramipril
AIRE
6 / 1 yr
Clinical CHF
55
ACEIINDICATIONS
Clinical cardiac insufficiency - All patients
Asymptomatic ventricular dysfunction - LVEF
lt 35
56

ACEIUNDESIRABLE EFFECTS
Inherent in their mechanism of action -
Hypotension - Hyperkalemia - Angioneurotic
edema Due to their chemical structure -
Cutaneous eruptions - Neutropenia,
thrombocytopenia - Digestive upset
- Dry cough - Renal Insuff.
- Dysgeusia - Proteinuria
57

ACEICONTRAINDICATIONS
Renal artery stenosis Renal insufficiency Hyperkal
emia Arterial hypotension Intolerance (due to
side effects)

58

ANGIOTENSIN II INHIBITORS MECHANISM OF ACTION
RENIN
Angiotensin IANGIOTENSIN II

Angiotensinogen
ACE
Other paths
AT1 RECEPTOR BLOCKERS
RECEPTORS
AT1
AT2
Vasoconstriction
Proliferative Action
Vasodilatation
Antiproliferative Action
59
AT1 RECEPTOR BLOCKERS DRUGS
Losartan Valsartan Irbersartan Candersartan
Competitive and selective blocking of AT1
receptors
60

ALDOSTERONE INHIBITORS
ALDOSTERONE
Spironolactone
Competitive antagonist of the aldosterone
receptor (myocardium, arterial walls, kidney)
Retention Na Retention H2O Excretion
K Excretion Mg2
Collagen deposition Fibrosis -
myocardium - vessels
Edema
Arrhythmias
61

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 1999341709-717
62

ALDOSTERONE INHIBITORS CONTRAINDICATIONS
Hyperkalemia Severe renal insufficiency
Metabolic acidosis
63
ß-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS
Density of ß1 receptors Inhibit cardiotoxicity
of catecholamines Neurohormonal activation
HR Antihypertensive and antianginal Antiarrhythmic
Antioxidant Antiproliferative
64

ß BLOCKERS SURVIVAL
50
ß Blocker
40
Placebo
30

20
10
0
lt 30
30-40
gt 40
BHAT JACC 1990161327
LV EJECTION FRACTION
65

ß BLOCKERS Mortality
ß BLOCKER
n2231
YES
No
Yes
13.3
24.3
ACEI
No
19.5
27.7
SAVE Circulation 1995923132
66

ß 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
Carvedilol 2.9 Initial low doses, progressive
p lt 0.0001
67
ß-ADRENERGIC BLOCKERS INDICATIONS and UTILIZATION
Not clearly established Begin with very low
doses Slow augmentation of dose Slow withdrawal ?
68
ß-ADRENERGIC BLOCKERS IDEAL CANDIDATE?
Suspected adrenergic activation Arrhythmias Hypert
ension Angina
69

ß-ADRENERGIC BLOCKERS CONTRAINDICATIONS
Hypotension BP lt 100 mmHg Bradycardia HR lt 50
bpm Clinical instability Chronic bronchitis,
ASTHMA Severe chronic renal insufficiency
70

CALCIUM ANTAGONISTS POTENTIAL EFFECTS
Antiischemic Peripheral Vasodilatation
Inotropy
71

CALCIUM ANTAGONISTS POSSIBLE UTILITY
Diltiazem contraindicated Verapamil and
Nifedipine not recommended Vasoselective
(amlodipine, nisoldipine), may be useful in
ischemia CHF Amlodipine may be useful in
nonischemic CHF
72

ANTICOAGULANTS
PREVIOUS EMBOLIC EPISODE ATRIAL
FIBRILLATION Identified thrombus LV Aneurysm (3-6
mo post MI) Class III-IV in the presence of -
EF lt 30 - Aneurysm or very dilated
LV Phlebitis Prolonged bed rest
73

ANTIARRHYTHMICS
Sustained VT, with/without symptoms - ß
Blockers - Amiodarone Sudden death from VF -
Consider implantable defibrillator
74

ANTIARRHYTHMICS MORTALITY
13.7
13.6
ns
MORTALITY AT 2 YEARS
n1486 5-21d post MI Amiodarone 200 mg/d Follow
up 1 - 4 years
102 / 743
101 / 743
EMIAT Am Coll Cardiol 1996
75

American Heart Association in collaboration
with Sociedad Española de Cardiologia CHRONIC
CONGESTIVE HEART FAILURE The content of these
slides is current as of June, 1999. Future
revisions will be posted on the American Heart
Association website (www.americanheart.org)