Fenoldopam

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Abstract
Fenoldopam is a dopamine agonist that causes peripheral vasodilation via stimulation of dopamine1 (D1) receptors. The efficacy of an intravenous infusion of fenoldopam in decreasing blood pressure in patients with a hypertensive urgency, including patients who developed hypertension after coronary artery bypass graft surgery, and in a small number of patients with hypertensive emergency, is similar to that of sodium nitroprusside. However, unlike sodium nitroprusside, fenoldopam also increases renal blood flow and causes diuresis and natriuresis. There is no evidence of rebound hypertension after stopping the infusion. As the tolerability profile of fenoldopam is generally similar to that of sodium nitroprusside, fenoldopam appears to be an effective alternative to sodium nitroprusside in the immediate treatment of patients who develop severe hypertension and in whom oral treatment is not practical. Fenoldopam may be particularly useful in patients who develop hypertension after coronary artery bypass graft surgery, but further studies are required to confirm its role in hypertensive emergency. Fenoldopam binds selectively to dopamine1 (D1) receptors. In vitro and in vivo studies have shown that fenoldopam causes vasodilation via stimulation of these receptors. In dogs, intracoronary administration of fenoldopam 20 nmol/L increased coronary blood flow mainly because of vasodilation, but at high dosages (>500 nmol/L) the increase was mainly secondary to a positive inotropic effect. Mesenteric vascular resistance decreased and blood flow increased by a maximum of 69% after intravenous administration of fenoldopam 30 μg/kg to spontaneously hypertensive rats. Dosages of fenoldopam that significantly reduced blood pressure in dogs had little effect on renal blood flow, whereas dosages of sodium nitroprusside that similarly reduced blood pressure significantly decreased renal blood flow. Low dosages of fenoldopam that did not decrease blood pressure in dogs produced D1 receptor-mediated dose-related renal vasodilation, diuresis and natriuresis when administered directly into the renal artery. Intravenous infusion of fenoldopam 0.025 to 0.5 μg/kg/min caused small decreases in diastolic blood pressure (DBP) in healthy volunteers and a dose-related increase in heart rate without altering systolic blood pressure (SBP). In patients with severe hypertension, however, fenoldopam ≤0.8 μg/kg/min dose-dependently decreased blood pressure. In such patients, intravenous infusion of fenoldopam 0.1 to 0.9 μg/kg/min in incremental dosages decreased SBP (baseline values >180mm Hg) and DBP (baseline values >120mm Hg) by 18.5 to 28% and 22 to 31.5%, respectively. In a further study, decreases in blood pressure of about 30% were accompanied by a 35.6% decrease in total peripheral resistance, a 33% reduction in pulmonary capillary wedge pressure and a 6% increase in cardiac index. In patients with severe hypertension, dosages that decreased DBP by 40mm Hg improved left ventricular function. In both healthy volunteers and patients with hypertension, intravenous infusion of therapeutic dosages of fenoldopam significantly increased renal blood flow and decreased renal vascular resistance without altering glomerular filtration rate. During reduction of severely elevated blood pressure, fenoldopam significantly increased creatinine clearance, urinary flow and excretion of sodium and potassium. In contrast, sodium nitroprusside decreased creatinine clearance and had little effect on other parameters of renal function. Fenoldopam infusion dose-dependently increased plasma renin activity and angiotensin II levels in healthy volunteers, but did not increase plasma renin activity, aldosterone or prolactin levels in patients with severe hypertension. As concomitant administration of enalapril elicited an additive, but not a synergistic antihypertensive effect, it appears that activation of the renin-angiotensin system does not significantly antagonise the antihypertensive effect of fenoldopam. Steady-state fenoldopam plasma concentrations (Css) were reached between 30 and 120 minutes after starting infusion. In healthy volunteers Css values were 1.06, 2.8 and 12.76 μg/L during intravenous infusion of 0.025, 0.1 and 0.5 μg/kg/min, respectively. In patients with hypertension, Css values were 8.53 and 14.25 μg/L during intravenous infusion of fenoldopam 0.25 and 0.375 μg/kg/min, respectively. Two hours after stopping infusion, plasma concentration declined to 150mm Hg. Once goal blood pressure was reached, maintenance infusion was usually continued for 24 hours, and subsequently, oral antihypertensive therapy was substituted. Treatment with fenoldopam or sodium nitroprusside reduced mean DBP to a similar extent and to goal levels in most patients. The time to achieve goal blood pressure with fenoldopam was similar to that with sodium nitroprusside. There was no evidence of rebound hypertension on cessation of either drug. Fenoldopam was superior to placebo in patients with hypertension after non-cardiac surgery and decreased blood pressure to a similar extent to sodium nitroprusside after coronary artery bypass graft (CABG) surgery. Intravenous infusion of fenoldopam 0.1 to 1.6 μg/kg/min was significantly more effective than intravenous nifedipine 0.63 to 1.25 mg/h in decreasing mean arterial blood pressure in patients with hypertension after CABG surgery. Adverse events attributed to fenoldopam in the treatment of hypertensive emergencies and urgencies were usually mild and related to the vasodilatory action of the drug and occurred during the first 24 hours of infusion. Headache was reported in 11 to 36% of patients, flushing in 7 to 11%, nausea in about 20%, dizziness in about 10% and asymptomatic ST-segment abnormalities in 6 to 33%. During fixed-dose continuous infusions, the...