PubMed · 2896916
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1988-05-14. Enoximone.. https://pubmed.ncbi.nlm.nih.gov/2896916/
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Although digitalis preparations have been in use for greater than 200 years, it is only within the last 2 decades that the central hemodynamic and neurohumoral effects occurring over several hours following intravenous administration of digoxin have been investigated in patients with congestive heart failure (CHF). Although digoxin has been shown to stimulate myocardial contractility in tissue preparations, its positive inotropic activity does not consistently translate into improvements in hemodynamic measurements in humans. Digoxin given intravenously results in increased cardiac index and decreased heart rate, left ventricular filling pressure, and right atrial pressure, as well as in acute attenuation of neurohumoral abnormalities, in patients with chronic CHF who have abnormal baseline hemodynamic measurements. Unlike other drugs with positive inotropic activity, however, digoxin does not influence hemodynamics in normal volunteers or in CHF patients in whom hemodynamics have been normalized with other therapies. These differing effects may be related to the drug's diverse peripheral vascular effects in CHF patients in whom vasodilation may occur in comparison with those that occur in normal subjects in whom the peripheral vasoconstrictor effects may prevent the inotropic effects of the drug from being translated into an increase in cardiac output. The hemodynamic effects of digoxin in patients with chronic CHF due primarily to diastolic dysfunction have not been fully investigated. Intravenous digoxin produces hemodynamic effects in patients with CHF associated with acute myocardial infarction, but these changes are small compared with those resulting from the administration of dobutamine. Digoxin does not appear to influence hemodynamic measurements in patients with right ventricular dysfunction unless concomitant left ventricular failure is present. In patients with chronic left ventricular dysfunction, the hemodynamic effects of intravenous digoxin and vasodilators are enhanced when these agents are given in combination.
Considerable effort and resources have been directed at the development and study of positive inotropic drugs over the past 10-15 years. Much has been learned about the physiology and pharmacology of myocardial contraction, the application of agents to augment contractility, and, importantly, the general and specific limitations of positive inotropic therapy. Studies on acute inotropic intervention have now shown that a drug's ability to augment overall cardiac performance is heavily dependent on its effects on vasculature, vascular control, and ventricular-vascular coupling. The clinical research on new agents has served to remind us how difficult it is to formulate the "ideal" positive inotropic or cardiovascular support drug for the critical care setting. The vast effort to develop a chronically and orally administrable drug to replace or even supplement digitalis has generally been disappointing. The dopaminergic agents (e.g., ibopamine, levodopa) act primarily via vasodilation and their effectiveness and role in managing heart failure remain unresolved. The initial excitement about the phosphodiesterase III inhibitors (e.g., amrinone, milrinone, enoximone) has been tempered by the results of large well-designed trials indicating variable effectiveness and a prominent adverse effect profile. During long-term oral administration none of these agents has been shown to improve clinical status or exercise capacity beyond that achieved by digoxin, when administered either separately or in combination with digoxin. The Prospective Randomized Milrinone Survival Evaluation (PROMISE) trial, showing that repeated oral administration of milrinone can increase mortality in heart failure, is having a devastating effect on the further development of this class of drugs.(ABSTRACT TRUNCATED AT 250 WORDS)
Therapeutic approaches to the management of heart failure have traditionally focused on shortterm hemodynamic and symptomatic goals, but present evidence suggests that most therapeutic decisions have long-term consequences. Treatment may change the rate of disease progression, modify the need for additional therapy, influence the number of hospitalizations, and alter the risk of death. However, there may be little relation between a drug's short-term effect on cardiac function or cardiovascular symptoms and its long-term effect on survival. Some therapeutic interventions favorably influence the outcome of patients with heart failure, even though they exert negative inotropic effects; others adversely affect the outcome of patients, even though they markedly improve cardiac performance. This discordance might be explained if the most important predictor of response to a therapeutic intervention in heart failure were the effect of the pharmacologic agent on neurohormonal systems rather than on hemodynamic variables. In general, drugs that decrease the effects of the sympathetic nervous system (digitalis glycosides) and the renin-angiotensin system (angiotensin-converting enzyme [ACE] inhibitors) reduce the risk of worsening heart failure. Conversely, drugs that potentiate the effects, or increase the activity, of the sympathetic nervous system (phosphodiesterase inhibitors) or the renin-angiotensin system (calcium antagonists) increase cardiovascular morbidity and mortality. These observations suggest that physicians should no longer focus on short-term hemodynamic or symptomatic goals in the treatment of heart failure but, instead, should manage patients to improve both the quality and quantity of life.