Pharmacologic Therapy
Glucoside (Digoxin).
- Increase myocardial contractility (Inhibition of Na, KATPase -> Altered balance of Na/Ca exchange -> Enhanced Ca storage/release). Enhanced vagal tone (reduce heart rate). Digoxin may attenuate the neuro-hormonal activation associated with HF.
- The serum haft-life of digoxin is 36 h; the usual daily dose is 0.125-0.375mg
- Therapeutic dose: 0,5-0,8-2,0 ng/ml serum. The toxic – therapeutic ration is narrow
- Drug interactions which decrease digoxin release: Quinidin, Verapamil, Spironolacton, Amiodarone.
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Biventricular heart failure
• Constant dyspnea, the excess fluid accumulation
in the whole body.
• Jugular venous distension.
• Increased venous pressure.
• Hepatomegaly.
• Pericardial effusion, pleural effusion, ascites.
• Decreased systolic blood pressure, increased
diastolic blood pressure.
• Chest X-ray: cardiomegaly.
• ECG: biventricular hypertrophy.
X-Ray Image
Right-sided heart failure Left-sided heart failure
Electrocardiography
RIGHT-SIDED
HEART FAILURE
ECG:
Right heart axis, right atrial
hypertrophy, right ventricular
hypertrophy
LEFT-SIDED HEART
FAILURE
ECG:
Left heart axis, left atrial
hypertrophy, left ventricular
hypertrophy
Echocardiography
RIGHT-SIDED HEART FAILURE
LEFT-SIDED HEART FAILURE
Heart failure classification
Có Nguy cơ cao ST song không có bệnh
tim thực tổn hoặc không có biểu hiện suy
tim
A
Có bệnh tim thực tổn nhưng không có biểu
hiện suy tim
B
Bệnh tim thực tổn đã hoặc đang có biểu
hiện suy tim
C
Suy tim trơ, đòi hỏi phải các biện pháp điều
trị đặc biệt
D
Patients have no limitation of
physical activity
I
Patients have slight limitation of
physical activity
Có triệu chứng khi gắng sức nhẹ
II
III
Có triệu chứng ngay cả lúc nghỉ IV
The ACC/AHA staging system NYHA classification for heart failure
Patients are at high risk for heart
failure but have no structural heart
disease or symptoms of heart failure
Patients have structural heart disease
but have no symptoms of heart
failure
Patients have structural heart disease
and have symptoms of heart failure
Patients have refractory heart failure
requiring specialized interventions
Patients have no limitation of
physical activity
Patients have slight limitation of physical
activity
Patients have marked limitation of
physical activity
Patients have symptoms even at rest
and are unable to carry on any
physical activity without discomfort
TREATMENT
Schematic therapy of progressive
chronic heart failure
The role of drugs in the treatment
of heart failure
• Reduce Mortality:
– ACE inhibitors or ARBs
– Beta blockers
– Spironolactone; Eplerenone
• Improve symptoms:
– Diuretics
– Digoxin (low dose)
– Nitrates
• May be harmful: use cautiously after due
consideration:
– Inotropes and inotropic dilators
– Antiarrhythmics, expect Beta blockers and amiodarone
– Calcium channel blockers
– Digoxin (high dose)
Nonpharmacologic Therapy
• Rest: reduce cardiac load. Severe heart failure: bed rest, down in
Fowler's position, massage legs to prevent venous thrombosis.
• Sodium restriction:
• Salts cause increased osmotic pressure, increased circulatory
volume and increase the burden on the heart
• Normal: 6-18g NaCl/day=2,4-7,2g (100-300 mmol) Natri/day.
• Sodium restriction : <3g NaCl/day <1,2g (50 mmol)
Natri/day.
• Completed sodium restriction : <1,2g NaCl/day 0,48g (20
mmol) Natri/day.
Nonpharmacologic Therapy
– Fluid and free water restriction reduce circulatory volume and
decrease the burden on the heart: 500-100ml/day
– Administration of supplemental oxygen may relieve dyspnea,
improve oxygen delivery, reduce the work of breathing and limit
pulmonary vasoconstriction
– Lifestyle/Risk modification
• Reducing Alcohol intake, cessation of smoking, cafe...
• Weight loss in obesity patient
• Avoid stress
• Stop inotropic: Verapamil, Disopyramide, Flecainide.
• Identify precipitating and exacarbating factors and any
concomitant factors relevant to HF: sepsis, Arrhythmias
Pharmacologic Therapy
Glucoside (Digoxin).
• Increase myocardial contractility (Inhibition of Na, K
ATPase Altered balance of Na/Ca exchange Enhanced
Ca storage/release). Enhanced vagal tone (reduce heart rate).
Digoxin may attenuate the neuro-hormonal activation
associated with HF.
• The serum haft-life of digoxin is 36 h; the usual daily dose is
0.125-0.375mg
• Therapeutic dose: 0,5-0,8-2,0 ng/ml serum. The toxic –
therapeutic ration is narrow
• Drug interactions which decrease digoxin release: Quinidin,
Verapamil, Spironolacton, Amiodarone...
Pharmacologic Therapy
Glucoside (Digoxin)
• Indication:
– Low-output cardiac failure, especially rapid atrial fibrillation
– No indication in High output cardiac failure: anemia, thyrotoxicosis,
fistula arteriovenous, Chronic cor-pulmonale.
• Contraindication:
– Bradycardiac, Block A-V II, III, ventricular fibrillation, ventricular
tachycardiac, WPW symdrome
• Caution:
– Acute myocardial infarction: increase oxygen demand.
– Electrolyte abnormalities: K+ vµ / Mg++
Pharmacologic Therapy
Glucoside (Digoxin)
• Digoxin toxicity
– Risk factors
– Clinical signs and symptoms
• Loss of appetide, nausea/vomiting, diarrhea.
• Visual disturbances, confusion, dizziness, nightmares.
• Increased automaticity and depressed conduction
• Treatment:
– Stop the drug, control Electrolyte abnormalitie, kalemia.
– 20-50ml KCl 10%, oral or IV 13-15 mmol/h.
– Atropin 0,5-1 mg IV: sinus bradycardiac, bloc AV.
– Lidocain IV1-4mg/phót: ventricular arrhythmia.
– Antidotal therapy with antibody (Fab) fragments.
dig study
(Digitalis Investigators Group)
Placebo Digoxin
n 4303 3397
NYHA II (%) 55 53
NYHA III 31 31
NYHA IV 2 2
CAD 70(%) 71(%)
ACE (%) 95 94
Death after 3,5 years 30 (%) 30 (%)
Severe heart failure 34,7 26,8 **
N Eng J Med 1997, 336: 525-33.
drugs in treatment hf
Diuretics
• Mechanism: Removal of excess extracellular fluid with diuretics
to treat peripheral and/or pulmonary edema is one of the
mainstays of volume management. Diuretics reduce magnesium
absorption and hypomagnesaemia may occur with prolonged use
• Classification:
– Thiazides
• Indication with normal renal function.
• Inhibit sodium transport in the distal tubule.
• Hydrochlorothiazide (Thiazide): The potential adverse metabolic
effects of thiazide therapy include hypokalemia, hyponatremia,
hyperuricemia, elevations in the plasma glucose and cholesterol
concentrations, and magnesium depletion
• Indapamide little effect on lipid
drugs in treatment hf
• Loop diuretics: Furosemide, Bumetanide.
– Act in the thick ascending limb of the loop of Henle.
– Inhibit sodium and chloride reabsorption. Side effect: Electrolyte
imbalances (particularly hypokalemia and hypomagnesemia)
– Use in renal impairment. Direct intravenous vasodilators
• Potassium-sparing diuretics: Spironolacton, Triamterene,
Amiloride.
– Act in the principal cells in the cortical collecting tubule.
– Have relatively weak natriuretic activity
– ThËn träng khi dïng kÌm IEC, gi¶m viªm kh«ng steroide ( K+)
– Increase BUN, Nephrolithiasis (Triamterene); gynecomastia
(Spironolactone).
Diuretics aldosterone antagonist has
obvious benefits in the treatment of heart
failure because it does not merely diuretic
• Often used in combination with other diuretics
(Loop, thiazides)
– Increase the diuretic effect
– Reduce drug effect
– Reduce the side effects
• Improve turns vicious circle in chronic
congestive heart failure:
• Reduce the harmful effects of aldosterone
Aldosterone for heart failure treatment
Aldosterone
Arterial compliance
Baroreceptor function
Norepinephrine uptake
Endothelial function
PAI-1
K+ Mg++
Fibrosis
Norepinephrine
Uptake
Heart rate
variability
LV
mass
&
fibrosis
Na+
Edema Remodeling Arrhythmia
Ischemic
Events
Progression of HF Sudden cardiac death
Pitt B, Zannad F, Remme WJ, et al. N Engl J Med. 1999;341:709-717.
*Protocol used a starting dose of 25 mg/day whereas the mean daily dose was 25 mg.
RALES: Study design
Suy tim NYHA III, IV
LVEF ≤ 35%
ACEI + Loop diuretics ± digoxin
Spironolactone
25 – 50 mg/day*
(n = 822)
Placebo
(n = 841)
Primary Endpoint
• Total mortality
Secondary Endpoints
• Total mortality
• Cardiac hospitalization
• Cardiac mortality or cardiac
hospitalization
3 n¨m
RALES: All - cause mortality
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0 3 6 9 12 15 18 21 24 27 30 33 36
Reduce the risk of death 30%
95% Cl (18%-40%)
P<0.001
Spironolactone
+ Standard therapy
Standard therapy (ACE +
Loop diuretic + digoxin)
Probability
of survival
Months
Pitt B, Zannad F, Remme WJ, et al. N Engl J Med, 1999;341:709-717.
drugs in treatment hf
Vasodilators.
• Compensatory mechanism in heart failure artery
and veins spasm preload and afterload.
– Pulmonary vasoconstriction because of Hypoxic blood,
increasing blood flow through the lungs for a long time
(shunt left - right), left atrial pressure (mitral stenosis,
heart failure).
– Side effects: lowering BP. Caution in aortic stenosis,
Hypertrophic cardiomyopathy, Restrictive
cardiomyopathy.
drugs in treatment hf
Vasodilators.
• ACEs
– Angiotensine II (vasoconstriction), Bradikinine
(vasodilation)
– Vasoconstriction preload and afterload.
– Contraindicationi: Renal artery stenosis (bilateral).
– Side effect: hypotension, cough, hyperkalemia.
– ACE inhibitors should be used with caution in hypotension patients treated
with Potassium-sparing diuretics
– Benazepril (Cibacene 10 mg), Enalapril (Renitec, Ednyt), Captopril
(Capoten, Lopril).
• Angiotensin II receptor antagonists
ACEs
the role of ACE in the
treatment of heart failure
CONSENSUS I (1) SOLVD (2)
Placebo Enalapril Placebo Enalapril
n 126 127 1284 1285
NYHA II (%) 0 0 57 57
NYHA III 0 0 31 30
NYHA IV 100 100 2 2
CAD(%) 74 72 72 79
Death (%) 44 26 39.7 35.2
(1) N Eng J Med 1987, 316:1429-35. (2) N Eng J Med 1991, 325:293-302.
Charm trial
candesartan or placebo in clinical HF patients
Primary end-point: cardiovascular
mortality and rehospitalization due to
HF
charm trial
• intolerant : reduced CV mortality and
rehospitalization 23% (p=0,0004) by
candesartan.
• Candesartan added standard treatment
(ACEI and betablocker) reduced CV mortality
and rehospitalization 15% (p=0,011).
Nitrates
• Nhóm Nitrates:
– Vasodilator of the venous system and reduction of preload; while
reducing myocardial ischemia, decreased cardiac filling pressure
and directly vasodilator of coronary arteries. Nitrates are mainly used
in patients with heart failure in CAD patients, or can not use
ACE/ARB
– Side effects: headache, hypotension, rash, etc. Do not use along
with sinadefil.
– Administration: oral, topical patch, transdermal, Translingual spray or
IV.
Isosorbide dinitrate (1)
A-HeFT (African American Heart Failure Trial)
• 1050 African-American patients with NYHA III-IV and
EF <35%.
• Random. isosorbide dinitrate 20 mg + hydralazine
37,5 mg hoÆc gi¶ dîc.
• General Mortality :6,2 % so víi 10,2 % (p=0,02)
• Rehospitalization due to HF: 16,4% so víi 24,4%
(p= 0,001).
Isosorbide dinitrate (2)
Thö nghiÖm A-HeFT (African American Heart Failure Trial)
Beta blockers
• Indication in patients with HF due to systolic dysfunction of left
ventricle, event with Diabetes Type 2 or Peripheral vascular
disease.
– LVEF≤ 40% (IA).
– Heart Failure with Preserved Systolic Function due to old MI (IA),
Hypertension (IB), atrial fibrillation need to control of ventricular rate
(IB).
– Old patients with HF due to systolic dysfunction of left ventricle (IB).
• Contraindication: asthma. Caution: (1) Recurrent
Hypoglycemia in Diabetes; (2) Asthma; (3) Limbs ischemic rest
pain , (4) Bradycardiac (<55 b/m) or (5) Hypotension (Systolic
BP < 80 mmHg).
Activation of the Sympathetic
Nervous System in Heart Failure
Increased central sympathetic tone
Increased cardiac
sympathetic activation
Increased renal and blood
vessels sympathetic activation
1 receptors 2 receptors 1 receptors
Hypertrophy and dead
myocardial cell
Dilated cardiomyopathy,
cardiac ischemia, arrhythmias
Vasoconstriction
Increased reabsorption
of water
Beta blockers
• indicated in the treatment of severe chronic heart failure when
other routine full of drugs. The beta-blocker used to treat heart
failure include: carvedilol (Dilatrend); Metoprolol (Betaloc) and
Bisoprolol (Concor).
• Mechanism is to prevent the effects of excessive stimulation of
the sympathetic nervous system in chronic congestive heart
failure, improve prognosis, but the actual benefits only appear
slow and long-termi.
• Start with a low dose (prior to discharge), monitored,
increasing the dose very slowly (no earlier than two weeks /
time) to achieve therapeutic doses within 8-12 weeks, and
then maintained the highest dose which can be tolerated.
• If it is difficult to increase the dose, we will increased the dose
slowly, reduce the target dose.If side effects develop or
worsening heart failure, add / adjust the dose of diuretics or
inotropic
US-Carvedilol Study
CIBIS-II Study
Drugs increasing cardiac contractility
• Inotropes agents: indicated in acute/severve/decompensated heart failure.
• Side effects: Increased cardiac ischemic, heart rate, peripheral vasocontriction.
• Dopamine: advocated in heart failure with hypotension but increasing heart rate.
– 1-3μg/kg/min: mesenteric and renal vasodilation, increased blood flow to the kidneys and
urine output.
– 2-5μg/kg/min: increase the contractility of the heart muscle (beta-receptor stimulation)
– >5-10 μg/mg/min: peripheral vasoconstriction, increased vascular resistance adversely
affecting cardiac output (alpha receptor stimulation).
• Dobutamine:
– Selective β1 stimulation (weakly on β2 and α): improve haemodynamic, directly
myocardiac contracity, dilate arteries for reflectance -> reduce afterload and increase
cardiac output, create little change in heart rate and BP.
– The initial dose: 1-2 g / kg / min IV, adjust to be effective.
– Using 2-4 day course by course to reduce the symptoms of heart failure.
– Not recommended for the treatment in diastolic dysfunctional heart failure patients (eg:
hypertrophic cardiomyopathy) or heart failure with increased cardiac out.
Drugs increasing cardiac contractility
– The phosphodiesterase inhibitors: increase the contractility of the heart
muscle and vasodilation by increasing AMPc.
– Two drugs used in clinical are Amrinone and Milrinone, indicated for acute
or short-term treatment in severe heart failure patients.
• Amrinone has effects as Dobutamin but makes stronger vasodilation,
hypotension if used with other vasodilators.
• Dose:
• Amrinone IV 750 μg/kg/2-3 minutes then 2.5 to 10.0
micrograms/kg/min.
• Milrinone: Initial dose 50 μg/kg/10 mins IV then 0.375 - 0.75 microg/kg
/min
– Side effects: May cause atrial fibrillati
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