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.

Pharmacokinetics of intravenous bepridil in patients with coronary disease.

The pharmacokinetics of intravenous bepridil (1-[2-(N-benzylanilino)-1-(isobutoxymethyl)ethyl]pyrrolidine ) were studied in 16 patients undergoing cardiac catheterization for evaluation of coronary disease, all with normal base-line hemodynamic and renal functions. Ten patients received 3 mg/kg and six patients received 4 mg/kg of bepridil infused over a period of 30 min. Plasma bepridil concentrations were measured by HPLC and analyzed by model-dependent and model-independent methods. The mean (+/- SD) maximum plasma bepridil concentrations at the end of the infusion were 2047 +/- 820 ng/mL (3 mg/kg) and 2478 +/- 1426 ng/mL (4 mg/kg). Postinfusion bepridil concentrations were best described by a two-compartment open model. The model-dependent harmonic mean distribution and elimination half-lives were 1.7 h (range: 1.1-2.2 h) and 19.7 h (range: 8.0-61.9 h), respectively. The harmonic mean elimination half-life from model-independent analysis was 14.9 h (range: 7.4-64.0 h). The arithmetic means of other model-independent kinetic parameters were systemic clearance, 0.524 +/- 0.215 L X kg-1 X h-1; Vd, 15.3 +/- 10.9 L/kg; and Vdss, 10.1 +/- 6.0 L/kg. Model-dependent and model-independent estimates of half-life and clearance agreed reasonably well. Bepridil was well tolerated, effecting little or no change in central hemodynamics or EKG intervals. The extensive distribution and relatively slow clearance of bepridil account for its long elimination half-life. Intravenous bepridil appears to be a safe calcium (II) antagonist that is suitable for once-a-day dosing.

Pharmacokinetics and pharmacodynamics of milrinone in chronic congestive heart failure.

The acute hemodynamic effects and pharmacokinetics of bolus intravenous milrinone administration were assessed in 13 patients with severe congestive heart failure. Serial hemodynamics were measured and blood samples were obtained to determine plasma milrinone concentration and calculation of pharmacokinetic variables after administration of milrinone at 12.5, 25, 50 and 75 micrograms/kg, allowing at least 6 hours to elapse between consecutive milrinone doses. At each dose milrinone effected prompt but very short-lived increases in cardiac output and left ventricular stroke work and decreases in pulmonary artery pressure, right atrial pressure and systemic and pulmonary vascular resistance in a non-dose-dependent fashion. Pulmonary artery wedge pressure decreased in a dose-related manner. Heart rate increased significantly after the 75-micrograms/kg dose and mean arterial pressure decreased significantly only after the 50- and 75-micrograms/kg milrinone dose. The time-dependent decline in plasma milrinone concentration was biexponential and log linear, conforming to an open 2-compartment model of drug distribution and elimination. Mean plasma milrinone clearance (+/- standard error) was 0.15 +/- 0.03 liters/min/kg, volume of distribution was 0.35 +/- 0.02 liters/kg and mean elimination half-life was 1.7 hours.

Comparative vasoactive therapy for heart failure.

Dopamine and dobutamine increase myocardial contractility by beta-adrenergic stimulation. Both agents provide significant support for decompensating congestive heart failure (CHF) patients. At the same time, both agents can have significant adverse effects. In 1981, it was reported that amrinone, a bipyridine derivative, produced hemodynamic changes similar to those of dobutamine. To confirm these results, the hemodynamic and clinical effects of amrinone were compared with those of dopamine and dobutamine in 15 consecutive patients with CHF. Although each drug improved maximal cardiac index to a similar extent, dopamine did not decrease pulmonary artery wedge pressure and caused a greater increase in heart rate. Dobutamine and amrinone conferred similar hemodynamic benefits: cardiac index improved from 2.4 +/- 0.2 to 3.4 +/- 0.2 liters/min/m2 with dobutamine and from 2.1 +/- 0.2 to 3.2 +/- 0.2 liters/min/m2 with amrinone. Pulmonary artery wedge pressure decreased similarly: from 19 +/- 2 to 13 +/- 1 mm Hg with dobutamine and from 18 +/- 2 to 12 +/- 1 mm Hg with amrinone. Dobutamine and amrinone produced similar modest decreases in mean arterial pressure and increments in heart rate. Dopamine was poorly tolerated; 5 patients developed such severe adverse reactions that this drug was discontinued prematurely. Dobutamine and amrinone were much better tolerated. Although amrinone caused asymptomatic tachycardia (heart rate increase greater than 20% over baseline) in 4 patients, no patient developed an adverse reaction warranting its premature termination.

Hemodynamic effects of intravenous bepridil in patients with normal left ventricular function.

Calcium-channel blockers are known to have depressant effects on atrioventricular (AV) nodal conduction and myocardial contractility. Because of these known depressant effects, bepridil hydrochloride, a new, long-acting, antianginal and antiarrhythmic calcium-channel blocker, was administered intravenously to patients without heart failure to determine acute hemodynamic effects. The patients studied had normal ventricular function, were without electrocardiographic conduction disturbances and were taking no drug except sublingual nitroglycerin for at least 24 hours before bepridil infusion. The study protocol included right- and left-sided cardiac catheterization with infusion of bepridil at 2 mg/kg for 15 minutes followed by 1 mg/kg for 15 minutes in 10 patients, and infusion of bepridil at 3 mg/kg for 15 minutes followed by 1 mg/kg for 15 minutes in 8 patients. Pressures, Fick cardiac output, resistances, left ventricular (LV) dP/dt, LV stroke work index and rate-pressure product of the left ventricle were monitored. There were no significant changes during bepridil infusion at either dose for cardiac output, systemic vascular and pulmonary vascular resistances, LV stroke work index, heart rate, arterial blood pressure and rate-pressure product. There was mild depression of LV dP/dt during bepridil infusion. Further, LV end-diastolic pressure, pulmonary capillary wedge pressure and pulmonary arterial pressures were significantly increased during bepridil infusion. There were no apparent changes in AV nodal or intraventricular conduction during bepridil infusion. We conclude that bepridil appears to be a safe drug for intravenous administration despite mild depression of myocardial function in patients with normal baseline hemodynamic function who are not receiving concomitant beta-blocker therapy.

Acute pharmacodynamics and pharmacokinetics of oral amrinone.

Amrinone was administered orally as a single 100-mg dose to six male patients with moderate-severe congestive heart failure to determine the acute pharmacodynamic effects and pharmacokinetics of the drug. Following right heart catherization and amrinone administration, measurements of hemodynamic parameters including cardiac index (Cl), right atrial pressure (RA), pulmonary capillary wedge pressure (PCW), and serum amrinone concentrations (SAC) were made at hourly intervals for up to 8 hours. Cl increased (29.0 per cent) significantly (P less than 0.05) at 3 hours after dose. PCW declined quickly after dose and was significantly (P less than 0.05) lower (-31.3 per cent) than control at 3 hours. RA declined gradually, and a significant (P less than 0.05) reduction (-25.2 per cent) was achieved 5 hours after the dose. Amrinone was absorbed quickly (tmax = 1.4 hour), and the disappearance of amrinone from serum was log-linear (t1/2 = 5.1 hours). The time courses of per cent change in Cl and SAC were similar, and the correlation between the average per cent change in Cl and average SAC was linear and significant (r = 0.80; P less than 0.05).