Effects of long-term therapy with oral ibopamine on resting hemodynamics and exercise capacity in patients with heart failure: relationship to the generation of N-methyldopamine and to plasma norepinephrine levels.

Abstract

N-Methyldopamine (epinine), one of the few modifications of the dopamine (DA) molecule that retains agonist activity at the DA, receptor, was administered orally as the diisobutyric ester, ibopamine (100, 200, and 300 mg), to 15 patients with congestive heart failure. An increase in cardiac index and decline in systemic vascular resistance was observed with each dose, and these hemodynamic effects persisted for 3 to 6 hr. Small transient increments in right atrial and pulmonary capillary wedge pressures occurred 0.5 hr after ingestion of 200 and 300 mg of ibopamine, but these pressures returned to baseline or lower levels within 30 min. Heart rate and mean arterial pressure were unchanged. Plasma concentrations of epinine peaked 0.5 hr after administration of drug and then declined to minimal levels at 3 hr. Ten patients enrolled in a trial to evaluate the efficacy of long-term therapy with ibopamine; after 8 weeks of treatment, the initial hemodynamic responses to the drug were attenuated and no significant improvement in oxygen uptake at peak exercise was observed. A decline in plasma norepinephrine concentrations, which could be attributed to activation of a2-adrenoceptors and/or DA2 receptors on sympathetic nerves, was observed after initial administration of ibopamine and persisted after long-term drug ingestion; no long-term hemodynamic benefit could be ascribed to the reduction in sympathetic activity. Circulation 73, No. 4, 740-748, 1986. THE ADMINISTRATION of dopamine to patients with congestive heart failure may effect an improvement in the performance of the impaired myocardium, and thus an oral formulation of this drug would be desirable. 2 The beneficial actions of dopamine in patients with heart failure have been attributed not only to a positive inotropic effect that is mediated by activation of the 8,1-adrenoceptor, but also to its agonist activity at the dopamine vascular (DA1) receptor.3 Activation of the DA1 receptor in the renal vascular bed appears primarily responsible for the marked natriuresis produced by this drug. N-Methyldopamine (epinine) is one of the few modifications of the dopamine molecule that retains full agonist activity at the DA1 receptor.4 Ibopamine is the diisobutyric ester of epinine, and after ingestion, it is hydrolyzed by plasma esterases to yield epinine.5 Initial studies have demonstrated beneficial short-term hemodynamic responses to ibopamine in patients with heart failure.-9 This investigation was undertaken to evaluate the hemodynamic actions and bioavailability of ibopamine after short-and long-term administration to patients with chronic congestive heart failure, and to assess the role of the sympathetic nervous system in modulating the hemodynamic responses to the drug.

Renal Dopamine Receptor Function in Hypertension

“…While ibopamine was initially shown to be effective in patients with congestive heart failure during short-term administration lasting for a few days, 113 its effects were not persistent in patients when administered for 8 weeks. 114 However, a recent clinical trial 115 with ibopamine in patients with heart failure had to be terminated early because of the excess mortality seen in the ibopamine group (25%) compared with the placebo group (20%). Although the reasons for the excess mortality are not clear, a mechanism involving increased extracellular calcium resulting from ␤-adrenoceptor stimulation may play a role in the increased mortality in the ibopamine group.…”

Early cardiovascular changes with ibopamine: evidence for a biphasic haemodynamic action.

“…Epinine levels fell to a nadir at 3 h by which time the maximum inotropic effect has previously been observed (Rajfer et al, 1986;Col et al, 1983). There is thus a discrepancy between plasma epinine levels and inotropic effects.…”

Biospectra Analysis: Model Proteome Characterizations for Linking Molecular Structure and Biological Response

“…These three compounds are full agonists both at dopamine and at adrenergic receptors. 22,[41][42][43][44] Ranking next in the hierarchical clustering are compounds in cluster E (allyl norapomorphine 7 and norapomorphine 8 (CCS > 0.80)), which are dopamine agonists. 21,22 Extension of this investigation to the entire 1567 compound database is shown in Figure 4 and groups 1-4 in Figure 5) elicit similar pharmacological and biological responses that are unique for each group.…”