Congestive heart failure positive inotropics

The most salient pathophysiological features of congestive heart failure (CHF) are diminution of ventricular contractility and profound, sympathetically mediated vasoconstriction. Agents with both peripheral vasodilating [24] and positive inotropic [25] activities ameliorate the symptoms of CHF. 

Flosequinan has a positive inotropic effect and shows a tendency to increase the heart rate, atrioventricular conduction in patients with atrial fibrillation and neurohormonal activation. Although the precise mechanisms involved have remained unclear up to now [29], this drug has been used to treat congestive heart failure (CHF). The FDA approved flosequinan (Manoplax) in 1993. However, the drug was withdrawn a year later because the PROFILE (prospective randomized flosequinan longevity evaluation) study indicated that flosequinan had adverse effects on survival, and that beneficial effects on the symptoms of heart failure did not last beyond the first 3 months of therapy, after which patients on the dmg had a higher rate of hospitalization than patients taking a placebo [14]. 

The discovery of the positive inotropic and systemic vasodilator activities of bipyridine-derived compounds, like amrinone (7) and milrinone (8), has markedly stimulated research aimed at the development of structurally related non-steroidal, non-catecholamine cardiotonics. In this context, a wide variety of pyridazinone derivatives have been prepared and investigated in search for novel agents useful for the chronic management of congestive heart failure. 

Myocardial cell membrane ATPase, the enzyme present in heart muscle, is the site of action of the cardiac steroid glycosides, which have a specific action on the heart muscle. These drugs increase the force of contraction of the muscle (positive inotropic effect) as well as its conductivity and automaticity. They are also valuable in treating congestive heart failure, in which the circulatory needs of organs are no longer satisfied, and heart arrhythmias, in which the rhythm of the cardiac contractions is upset. The effect of the drug is that the force of contraction increases and the heart rate is slowed (chronotropic effect). Consequently, the cardiac output is elevated while the size of the heart decreases. 

Dopamine itself has long been used as an inotropic agent in acute treatment of congestive heart failure. Both that compound and a number of its analogues have a positive action on contractility as a consequence of their adrenergic agonist activity. 

Dopamine and dobutamine are sometimes used to stimulate the heart in cases of acute or severe heart failure (see Chapter 20). Dopamine and dobutamine exert a fairly specific positive inotropic effect, presumably through their ability to stimulate beta-1 receptors on the myocardium.60 Other beta-1 agonists (epinephrine, prenalterol, etc.) will also increase myocardial contractility, but most of these other beta-1 agonists will also increase heart rate or have other side effects that prevent their use in congestive heart failure. Dopamine and dobutamine are usually reserved for patients with advanced cases of congestive heart failure who do not respond to other positive inotropic drugs (e.g., digitalis).6,72... 

Jaski BE, Filer MA, Wright RF, Braunwald E, Colucci WS. Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose-response relationships and comparison to nitroprusside. J Clin Invest 1985 75(2) 643-9. 

Coined WS, Wright RF, Braunwald E. New positive inotropic agents in the treatment of congestive heart failure. Mechanisms of action and recent clinical developments. N Engl J Med 1986 314(5) 290-9 1986 314(6) 349-58. 

Quinidine may be associated with a syndrome called cinchonism, which is characterized by headache, vertigo, and tinnitus. Procainamide may result in hypotension or a reversible syndrome similar to lupus erythematosus. Patients may develop positive antinuclear antibody (ANA) titers and complain of rash, arthralgia, and arthritis. Disopyramide is poorly tolerated due to its anticholinergic effects (urinary retention, dry mouth, blurred vision), and its use should be avoided in patients with congestive heart failure (CHF) due to negative inotropic effects. 

In vivo, racemic dobutamine increases the inotropic activity of the heart to a much greater extent than it increa.ses chronotropic activity. This pharmacological profile has led to its use in treating congestive heart failure. Since /3 receptors are involved positively in both inotropic and chronotropic effects of the heart, the selective inotropic effect. seen with dobutamine cannot simply be due to its activity at P% receptors. Rather, this effect is the result of a combination of the inotropic effect of (-t- )-dohutamine on Px receptors and that of (-)-dobutamine mediated through 0 receptors. Thus, this is a case where a racemic mixture provides a more desirable pharmacological and therapeutic cITect than would cither enantiomer alone. 

Digitalis glycosides are positive inotropic agents used in the management of patients with congestive heart failure. They control ventricular rate in supraventricular arrhythmias including atrial fibrillation and atrial flutter. 

Amidon TM, Parmley WW. Is there a role for positive inotropic agents in congestive heart failure focus on mortality. Clin Cardiol 1994 17 641-647. 

Some PHOSPHODIESTERASE INHIBITORS (e.g. cnoximone and milrinone) are valuable, and some exert most of their effect on the myocardium (those acting at a heart-specific subtype of this enzyme (type III phosphodiesterase) to raise the intracellular concentration of cAMP) and may be used as positive INOTROPIC AGENTS in the short-term treatment of severe congestive heart failure. 

Digoxin Na+,K+-ATPase in myocardial cell membrane Congestive heart failure slowing of heart rate, decrease in AV condition, positive inotropic effect... 

Describe the beneficial effects of diuretics, vasodilators. ACE inhibitors, and other drugs that lack positive inotropic effects in congestive heart failure. 

Although they are extremely useful in congestive heart failure, captopril and the other ACE inhibitors have no positive inotropic effect on the heart. The answer is (B). 

Amrinone is a positive inotropic agent useful in the management of severe congestive heart failure. It is effective even in unresponsive, fully digitalized patients. 

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