DRUGS USED IN CONGESTIVE HEART FAILURE (CHF)
section 1 introduction
1. The conception of CHF
Congestive Heart Failure (CHF) is a condition in which the heart is unable to
pump sufficient blood (cardiac output (CO) decreased) to satisfy the oxygen and
nutritional needs of the body.
CHF is a complex clinical syndrome characterized by impaired ventricular
performance, exercise intolerance, a high incidence of ventricular arrhythmias, and
shortened life expectancy.
The signs and symptoms of heart failure include tachycardia, decreased exercise
tolerance and shortness of breath, peripheral and pulmonary edema, and
cardiomegaly.
Virtually all forms of cardiovascular disease can lead to heart failure, such as
coronary artery disease, hypertension, and infection of the heart. The number of
newly diagnosed patients with CHF is increased because more individuals now
survive acute myocardial infarction.
2. The physiological and pathological changes of CHF
1) changes of myocardial function and structure

There is an initial lesion which leads to decrease in myocardial
contractility and cardiac compliance, increase in heart rate, increase in cardiac
preload and afterload; in the end decreases CO and leads to excessive fluid
accumulation in the body.

excessive fluid retention + heart failure = congestive heart failure

Changes ("remodeling") of the heart and vasculature in CHF
2) changes of neuroendocrine system
As the result of decreased ventricular function, there is a decrease in cardiac
output that activates a variety of neuroendocrine adaptive mechanisms including:
Increased
sympathetic
nervous
system
activity (and
increased
plasma
catecholamines)
Increased activity of the renin-angiotensin-aldosterone system
Increased release of arginine-vasopressin endothelin, etc.
The vasopressor-sodium retentive mechanisms are offset somewhat by the release
of vasodilator-natriuretic substances: Atrial natriuretic factor (ANF), Dopamine,
Prostaglandins (PGE2 and PGI2).
3) changes of myocardiac β-adrenergic receptors
Down-regulatory changes in the β1-receptor-Gs protein-effector system.
(1) down regulation of β1-R in the cardiac myocyte
(2) Gs↓, β1-R and GS uncoupling
(3) the activity of GRKs↑
3. Classification of drugs used in CHF
(1) Angiotensin converting enzyme inhibitors ， Angiotensin Ⅱ type 1 (AT1)
receptor antagonist，Aldosterone antagonist
(2) Diuretics
(3) β-R blockers
(4) cardiac glucosides
(5) Other drugs used in CHF
a. Calcium channel blockers
b. phosphodiesterase (PDE) inhibitors
c. Other vasodilators
4. Rationale for pharmacologic intervention in CHF
The goals in treating heart failure are to improve the patient's quality of life and
to prolong it. Improving hemodynamics with inotropic drugs does not decrease
mortality; long-term treatment directed towards neurohormonal factors with ACE
inhibitors and beta-blockers can decrease mortality
5. Current recommendations for the treatment of chronic heart failure
The current consensus recommendation is that all patients with heart failure
should first be evaluated to assess LV ejection fraction. Patients with systolic
dysfunction (EF<40%) should then undergo the following treatment: Patients with
evidence of fluid retention should receive a diuretic. Treatment with an ACE inhibitor
and a beta-blocker (carvedilol, metoprolol, or bisoprolol) should be initiated and
maintained unless specifically contraindicated. Digoxin may be added if needed to
reduce symptoms or to slow the ventricular repsonse in patients with rapid atrial
fibrillation.
Patients with severe heart failure should probably not receive a beta-blocker
Angiotensin II (type 1) receptor antagonists may be used in patients who are
intolerant of ACE inhibitors
Spironolactone, an aldosterone antagonist, may reduce mortality in patients with
severe heart failure
section 2
Angiotensin converting enzyme inhibitors(ACEI)
1. Drugs: Catopril, Enalapril, Cilazapril, Benazapril.
2. the mechanism of action in treatment of CHF
1)Inhibit ACE
(1) decreased the formation of angiotensin II both in circulation and local tissue
(2) decreased aldosterone secretion
decreased salt & water retention
(3) decreased degradation of bradykinin
2)Effect on hemodynamics
3)
decreased
sympathetic
activity
by
decreased
angiotensin-mediated
norepinephrine release
4) Inhibit proliferation and hypertrophy of cardiac myocytes and vascular smooth
muscle cells, reverse myocardial and vascular remodeling
5) Protect vascular endothelial cell4. Clinical use and evaluation
ACEI are used as first-line agents for CHF therapy and decrease mortality,
prevent and reverse myocardial remodeling. no reflex tachycardia (unlike
vasodilators), therefore safe for use in persons with ischemic heart disease。
Angiotensin II type 1 receptor antagonist
1. Drugs: Losartan, Valsartan, Irbesartan
2. Clinical use and evaluaton
It is similar to ACEI, but has no cough. Clinical trials have not yet firmly
establish that angiotensin receptor antagonists (losartan, candesartan, valsartan) are as
effective as ACE inhibitors in treating heart failure, but it appears that therapeutic
efficacy may be comparable
Aldosterone antaganists
Spironolactone
eplerenone
Section 3 Diuretics
Mechanism:

decreased salt & water retention (blood volume) leads to decreased ventricular
preload

Relaxed VSMC leads to decreased ventricular afterload
Clinical Effect:

decreased symptoms of heart failure (ie. edema)
Administration:
start
with a thazide diuretic and switch to a more powerful agent as required
check
serum electrolytes to prevent K+ loss
section 4
β-adrenoreceptor antagonis
β-Blockers and Heart Failure
A number of studies beginning in the 1970s have shown that β-blockers can
improve symptoms and ventricular function in patients with moderate to severe heart
failure, and may slow the progression of heart failure in some patients (reviewed in
Bristow, Circulation 101:558 (2000)).
•
Though β-blockers were widely considered to be contraindicated for patients
with heart failure only a decade ago, they are now considered first-line therapy for
patients with mild to moderate heart failure。
1. The mechanism of action in treatment of CHF

(1)Effects on hemodynamics

(2) Anti-sympathetic activity and Up-regulate β 1-R in failing
heart.

(3) inhibit RAAS →↓cardiac load

(4) Anti-arrhythmia and anti-myocardial ischemia
2. clinical uses and evaluation
β-adrenoreceptor antagonis are now considered first-line therapy for patients
with mild to moderate heart failure
•
The adverse effects of beta-blockers in patients with heart failure include
worsening of symptoms, hypotension, and bradycardia
a. These symptoms can be minimized by initiating therapy with low doses and
gradually increasing dosage until tolerable therapeutic doses are reached
b. β-blockers are contraindicated in patients with asthma or severe bradycardia
•
Agents that are currently used to treat CHF ( The Medical Letter 42:54
(2000) ) include:
a. Carvedilol, a nonselective beta-blocker with alpha1-adrenergic antagonist
(vasodilator) activity, but longer acting than labetolol; this agent also possesses
significant antioxidant properties which may be beneficial (FDA-approved)
b. Metoprolol,
a
relatively
selective
beta1-adrenergic
antagonist
(not
FDA-approved for CHF)
c. Bisoporol, a beta1-selective adrenergic antagonist (not FDA-approved for
CHF)
•
Other beta-blockers agents that have been investigated for use in treating
CHF include:
a. Labetolol, a nonselective beta-blocker with alpha1-adrenergic antagonist
(vasodilator) activity
b. Bucindolol,
a
non-selective
beta-blocker
with
vasodilator
activity
(mechanism unknown)
Aldosterone Antagonists
•
Recent clinical trials indicate that adding spironolactone to standard
treatment can significantly decrease mortality in patients with severe heart failure
section 5
cardiac glucosides
1. Digitalis coming from foxglove plant (Digitalis purpurea) has been used
clinically for over 200 years to treat heart failure and edema (dropsy). Drugs: digoxin,
digitoxin, strophanthin K
2. Pharmacological action:
1）positive inotropic action
The mechanism: The cardiac glycosides inhibit the Na+-K+ -ATPase pump,
which causes an increase in intracellular Na+, increasing the rate of the Na+,
Ca++-exchanger, and thereby causing an increase in intracellular Ca++, leads to
increased cardiac muscle contractility. inhibit Na+-K+ ATPase→intracellular Na+
concentration ↑ → Na+-Ca2+ exchange ↑ → intracellular Ca2+ concentration ↑ →
increased cardiac muscle contractility
2) Negative chronotropic action
a. ↑vagal stimulation
b. Resume sensitivity of carotid sinus baroreceptor.
c.↑sensitivity of cardiac muscle to Ach.
3) Electrophysiological effect
↓AV conduction shorten ERP of atria， ↑ P-f autorhythmicity, shorten
ERP
4) Effect on nerve-incretion:
1. Inhibit sympathetic activity directly, ↑ sympathetic activity (intoxication
dose)
2. ↑ vagal activity
3. ↓ renin secretion, ↓RAAS
4. ↑ ANP secretion
5) Diuresis
effect
1.↑CO，renal blood flow↑
2.↓Na+-K+-ATPase，↓Na+ reabasorption in the tubules，↓ H2O and Na+
retention.
3. Pharmacokinetics
drug
F
T1/2
PPB%
excretion
Last time
digitoxin
90~100%
5d
97%
hepatic
2~3w
digoxin
60~80%
36h
25%
renal
3~6d
strophanthin K
2~5%
19h
0
renal
1~3d
4. Clinical use
(1) Digoxin therapy is indicated in CHF patients with severe left ventricular
systolic dysfunction. At present no good oral inotropic agents exist other than digoxin.
The recent Digitalis Investigation Group (DIG) clinical trial indicated digoxin
did not reduce overall mortality in patients with heart failure (who were receiving
diuretics and ACE inhibitors), but did reduce the rate of hospitalization.
(2) Certain types of arrhythmia:
Electrical effects: parasympathomimetic effect; prolonged refractoriness of AV
node
They are also of great value in the control of atrial fibrillation and atrial flutter
because of the ability to reduce the ventricular rate by prolonging the refractory
period of conduction tissue. Digitalis may convert atrial flutter to atrial fibrillation.
Digitalis are also of great value in the control of paroxysmal atrial tachycardia as
a result of reflex vagal stimulation.
5. Toxicity, prevention and management
Therapeutic plasma concentration: 0.5-1.5 ng/ml
Toxic plasma concentration: >2 ng/ml
The digitalis show only a small difference between a therapeutic dose and doses
that are toxic or even fatal.
To avoid exceeding therapeutic range during digitalization, the dose should be
adjusted according to the health of the patient; plasma digoxin levels should be
monitored in the development of CHF.
Symptoms of Toxicity: narrow therapeutic index \ even minor variations in
bioavailability leads to serious digitalis toxicity
Cardiac
toxicity:
cardiac
arrhythmia:
ventricular
premature
beat,
atrioventricular conduction block, ventricular tachycardia, ventricular fibrillation and
etc.
gastrointestial (GI) toxicity:

anorexia, nausea, vomiting and diarrhea
CNS toxicity: headache, fatigue, confusion, blurred vision, alteration of color
perception.
8. Treatment of digitalis toxicity
1) Stop using cardiac glycosides and K+-depleting diuretics.
2) KCL is administered orally or by slow, careful intravenous infusion if
hypokalemia is present;
3) Phenytoin can be given for ventricular and atrial arrhythmia.
4) Lidocaine can be used to treat ventricular tachyarrhymias.
5) Atropine can be used to treat A-V block.
9. Drugs interacting with digoxin--Interactions:
Serious cardiac arrhythmias may develop if: hypokalemia develops (due to
diuretic therapy or diarrhea); given quinidine therapy (prevents digoxin clearance)
Section 6
the other drugs used in CHF
Calcium channel blockers
Though most clinical trials have indicated that calcium channel blockers are
detrimental in patients with heart failure, specific calcium channel blockers may be
beneficial (reviewed by Elkayam, Cardiology 89 Suppl 1:38-46 (1998)):
•
Amlodipine, a long-acting dihydropyridine, has been shown to reduce
mortality in patients with CHF due to nonischemic cardiomyopathy. Amlodipine also
prevent and reverse myocardial hypertrophy,
Other inotropic drugs
•
Beta-Adrenergic Agonists
Beta1-adrenergic agonists (dopamine, dobutamine, prenalterol, xamoterol) have been
used to treat acute, but have limited usefulness in chronic CHF because of their
arrhythmogenic effects, short duration of action, the development of tolerance, and
necessity of parenteral administration.
Dopamine (i.v.) is used in acute heart failure (cardiogenic shock) to increase blood
pressure and increase cardiac output.
Dobutamine is a somewhat selective beta1-adrenergic agonist that lacks
vasoconstrictor activity and causes minimal changes in heart rate.
Phosphodisterase (PDE) inhibitors: Amrinone, Milrinone, Vesnarinone etc. The
agents increase myocardial and vascular smooth muscle cAMP concentrations
through inhibition of PDE activity.↑ mortality, only used in acute CHF
Other Vasodilators
Concurrent therapy with vasodilators, such as hydralazine and isosorbide
dinitrate, can improve symptoms, but most can not reduce mortality. This
combination may be useful in patients who cannot tolerate ACE inhibitors.
1. The mechanism of action
dilate vessel→decrease the load of heart→myocardial oxygen consumption↓
→↑cardiac output
2.drugs
(1)organic nitrates: nitroglycerin, et al. (2)Hydralazine (3)Sodium nitroprusside
(4)prazosin