CONGESTIVE HEART FAILURE: PATHOPHYSIOLOGY AND DRUG MECHANISMS Pathophysiology Decreased ca

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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. (PgDn key for more text) * 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. (PgDn key for more text) 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. (PgDn key for more text) 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. (PgDn key for more text) * 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. (Home to return to top of file)

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