The effect of food on pharmacokinetics and pharmacodynamics of fenoldopam in class III heart failure.

Eighteen patients with New York Heart Association class III congestive heart failure were given single 100 mg oral doses of fenoldopam with food or fasting in a random-order single-blind crossover trial. Before and after each fenoldopam dose, thermodilution cardiac output, right atrial pressure, pulmonary artery pressure, and pulmonary capillary wedge pressure (PCWP) were measured with a balloon-tipped pulmonary artery catheter, and heart rates and blood pressures were recorded with an automated sphygmomanometer. Compared with fasting, bioavailability of fenoldopam was decreased significantly when administered with food: mean peak plasma fenoldopam level decreased from 26.5 (+/- 4.1 SEM) ng/ml to 10.9 (+/- 1.7 SEM) ng/ml (p = 0.0004) and mean area under the concentration-time curve was decreased from 44.7 (+/- 5.8 SEM) ng.hr/ml to 26.8 (+/- 4.1 SEM) ng.hr/ml (p = 0.0001). Fenoldopam administration to fasting patients resulted in decreases in mean arterial pressure, systemic vascular resistance, and PCWP and significant increases in cardiac index without change in heart rate. The maximum changes in mean cardiac index, systemic vascular resistance, and PCWP were greatest 1 hour after oral administration and did not persist beyond 3 hours after administration. In fasting patients, changes in cardiac index were correlated with plasma fenoldopam levels, whereas changes in PCWP and mean arterial pressure did not correlate significantly with the observed fenoldopam level.

Single-dose effects of ibopamine hydrochloride on renal function in patients with congestive heart failure.

To examine the renal effects of ibopamine HCl we evaluated 15 patients with New York Heart Association Class II-III congestive heart failure and mild renal insufficiency (creatinine clearance [CLcr] = 45-85 ml min-1). Diuretics and vasodilators were withheld and a sodium (Na+)-restricted diet was initiated. All patients exhibited positive Na+ balance at the time of evaluation. Hourly urine volumes, urine chemistries, serum chemistries, PAH and inulin/iothalamate clearances were determined 2 h pre and 4 h post a single 200 mg oral dose of ibopamine. Effective renal plasma flow, creatinine clearance, filtration fraction, and the fractional excretion of sodium and potassium were not significantly altered postdose. A significant increase in urine output and decrease in urine osmolality were seen at all time points postdose. A significant reduction in serum potassium (2 and 3 h) and blood urea nitrogen (1, 3 and 4 h) concentrations occurred. Measurements of glomerular filtration rate by inulin or [125I]-iothalamate produced differing results in the patient groups studied. We conclude that a single dose of ibopamine does not produce significant improvements in renal function in patients with congestive heart failure, mild renal insufficiency and positive sodium balance.

Assessment of hemodynamic tolerance from a 24-hour intravenous infusion of fenoldopam mesylate in congestive heart failure.

To determine the maintenance of pharmacodynamic effects of fenoldopam mesylate, a dopamine-1 agonist, the invasive hemodynamic profiles of 33 patients with New York Heart Association functional class III to IV congestive heart failure were examined. Fenoldopam mesylate was initiated at 0.1 micrograms/kg/min and titrated to a cardiac index greater than or equal to 25% above baseline. Upon achievement of optimal hemodynamics, maintenance infusion was begun (mean dose 0.6 micrograms/kg/min). Fenoldopam mesylate (baseline vs maximal effect) decreased systemic vascular resistance by 37% (p less than 0.001), left ventricular filling pressure by 16% (p less than 0.05) and mean arterial pressure by 11% (p less than 0.05), with an associated augmentation in cardiac index and stroke volume index by 27% (p less than 0.001). Attenuation of hemodynamic effect (maximal effect vs time) was noted in cardiac index (14% p less than 0.001), systemic vascular resistance (13% p less than 0.05) and stroke volume index (13% p less than 0.05). None of the parameters exhibited complete attenuation to baseline values. Fenoldopam mesylate improves cardiac output and lowers systemic vascular resistance with relative attenuation of pharmacodynamic effect during a 24-hour intravenous infusion.

Elucidation of the nifedipine-quinidine interaction.

Four case reports have been published that document a clinically significant drug interaction between nifedipine and quinidine in patients with left ventricular dysfunction. To define the population at risk and the mechanisms involved in manifestations of this interaction, 12 patients currently treated with quinidine for either ventricular or supraventricular arrhythmias were stratified into two groups based on left ventricular ejection fraction (EF) measurements (group A greater than 35%; group B less than 35%). The interaction was conducted through two phases: oral quinidine (Q) and oral quinidine plus nifedipine (N + Q). Pharmacokinetic modeling of total body clearance (CL) and AUC were assessed for each phase. One patient (group A, 70% EF) exhibited the interaction with a 41% decrease in steady-state serum quinidine concentrations. The patient's AUC and CL were 48.2 micrograms/ml.hr (Q) versus 28.6 micrograms/ml.hr (N + Q) and 94.4 ml/min (Q) versus 159.1 ml/min (N + Q), respectively. There was no difference in AUC or CL between the Q and N + Q phases or between groups A and B for the entire population. The N + Q interaction is not hemodynamically mediated. Clinical consideration of the possibility of this low-frequency interaction should be noted.

Continuous monitoring of mixed venous oxygen saturation as an indicator of pharmacologic intervention.

This prospective study evaluated the ability of continuous SvO2 measurements to predict the onset and duration of action of the oral vasodilator, fenoldopam. Eight patients with New York Heart Association functional class 3 CHF received 100 mg fenoldopam in the fasted state. Serial hemodynamic parameters and SvO2 measurements were obtained at baseline and up to eight hours postdose. Although wide interpatient variability was observed, the SvO2-time response curve produced a similar trend as the CI-time response curve. The SvO2 may be a useful drug monitoring parameter in patients with NYHA class 3 CHF. Seriously ill patients may not have a good CI/SvO2 correlation. This is most likely due to an unstable oxygen consumption rate at the tissue level. Therefore, we recommend establishing the relationship between CI and SvO2 prior to its use as a drug monitoring parameter.

Effects of food ingestion on hemodynamics in chronic congestive heart failure.

This study evaluates the effects of a standardized meal on cardiovascular hemodynamics in 12 patients with New York Heart Association Class III congestive heart failure. This was done as part of a larger study in which an orally active dopaminergic agonist was given on two mornings, once with a standardized breakfast and once fasting, and one morning a placebo was given with the breakfast. The order of days was randomized. Hemodynamic data were obtained over 8 h each day. There were significant changes in several hemodynamic variables after the placebo-food regimen lasting up to 1.5 h: cardiac index rose from 1.8 +/- 0.4 to 2.2 +/- 0.5 L/min.m2 at 30 min (p less than .001) and to 2.0 +/- 0.5 L/min.m2 at one hour (p less than .05); stroke volume index rose from 20 +/- 7 to 24 +/- 7 ml/min at 30 min (p less than .05) and to 23 +/- 7 ml/min at one hour (p less than .05); systemic vascular resistance fell from 1890 +/- 685 to 1534 +/- 497 dyne.sec/cm5 at 30 min (p less than .001) and to 1668 +/- 524 dyne.sec/cm5 at one hour (p less than .05). Mixed venous oxygen saturation was measured continuously in seven patients and rose significantly at one and 1.5 h. We conclude that food ingestion can have a significant effect on cardiovascular hemodynamics and that this effect should be considered when therapeutic effects are to be guided by invasive hemodynamic monitoring in this population.