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CONGESTIVE HEART FAILURE: PATHOPHYSIOLOGY AND DRUG MECHANISMS

Pathophysiology
* Decreased cardiac contractility (depressed ventricular function
curve): this defect is fundamental in congestive failure; it appears in
a variety of conditions such as acute myocardial infarction, chronic
uncontrolled hypertension, and valvular disease. In chronic failure,
there is an underlying biochemical defect that is not understood.
* Decreased cardiac output and decreased ejection fraction: this con-
sequence of decreased contractility results in diminished tissue per-
fusion and increased pulmonary venous pressure (in "left heart fail-
ure") and/or increased peripheral venous pressure (in "right heart
failure").
* Autonomic compensatory mechanisms: increased sympathetic discharge
results from inadequate tissue perfusion and hypotension and causes
tachycardia, increased renin release, and increased peripheral
arteriolar and venous constriction. These effects increase the cardiac
work load and eventually lead to further decompensation.



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* Hormonal compensatory mechanisms: decreased renal blood flow and in-
creased renin release (which causes a rise in angiotensin II and
aldosterone levels) result in salt and water retention and an increase
in vascular pressures. These factors may lead to peripheral or pul-
monary edema. Atrial natriuretic factor (ANF, atriopeptin) is proba-
bly released in increased amounts early in failure and may aid cardiac
compensation through its vasodilating and diuretic effects, but its
beneficial action is apparently overcome by detrimental factors as
cardiac decompensation proceeds.
* Cardiac hypertrophy occurs as a further compensatory response to
failure.











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Therapeutic Rationale
* Reduce salt and water retention: Diuretics are the first line drugs
for use in most uncomplicated cases of congestive heart failure.
(Restriction of sodium intake is desirable but sometimes difficult to
achieve.) Reduction of blood volume decreases the size of the heart,
allowing it to function on a more favorable portion of the ventricular
function curve, and reduces the intracapillary pressure that leads to
edema. The diuretics are described in more detail in Chapter 13.

* Increase the force of cardiac contraction: Positive inotropic drugs
such as digitalis glycosides are effective in many cases of chronic
failure and move the heart to a higher ventricular function curve.
They are generally more toxic than the diuretics. Several positive in-
otropic substitutes for digitalis are available for use in special
circumstances.

* Reduce vascular tone: Vasodilators reduce the work of
the heart and improve cardiac ejection and tissue perfusion. They are
especially useful in acute failure, eg, that associated with myocar-
dial infarction and severe hypertension. Vasodilators are described
in greater detail in Chapters 2 and 5.

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Mechanisms
* Diuretics: The mechanisms by which these drugs act are discussed in
Chapter 6. Their efficacy in congestive heart failure reflects the
magnitude of the salt retention that occurs in failure.
* Positive inotropic drugs:
- Digitalis glycosides: Digitalis drugs act by inhibiting membraneNa,K-
ATPase, thereby causing an increase in intracellular sodium. In-
creased intracellular sodium results in an increase in in tracellular
calcium. The latter ion directly modulates the contractile process.
- Sympathomimetics: Beta-1 adrenoceptor stimulants such as dobutamine
and dopamine are valuable in some cases of acute failure since they
increase cardiac contractility and cause some vasodilation. In favor-
able cases, increased contractility is not accompanied by significant
tachycardia.
- Amrinone, milrinone, methylxanthines, and other PDE inhibitors:
These drugs cause an increase in cylic AMP by inhibiting cardiac
phosphodiesterase. The increase in cAMP results in an increase in
transmembrane calcium flux and a secondary increase in cardiac con
tractility. The same biochemical action increases cAMP in vascular
smooth muscle and results in vasodilation.


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* Vasodilators: Direct-acting agents (eg, nitrates, nitroprusside),
sympathoplegics (eg, prazosin), and angiotensin converting enzyme in-
hibitors (eg, captopril) reduce cardiac workload and increase cardiac
output in failure associated with high vascular pressures. Captopril
also decreases aldosterone levels, thereby reducing salt and water
retention.
















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