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Corlopam

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Corlopam

CLINICAL PHARMACOLOGY

Mechanism of Action

Fenoldopam is a rapid-acting vasodilator. It is an agonist for D1-like dopamine receptors and binds with moderate affinity to α2-adrenoceptors. It has no significant affinity for D2-like receptors, α1 and β adrenoceptors, 5HT1 and 5HT2 receptors, or muscarinic receptors. Fenoldopam is a racemic mixture with the R-isomer responsible for the biological activity. The R-isomer has approximately 250-fold higher affinity for D1-like receptors than does the S-isomer. In non-clinical studies, fenoldopam had no agonist effect on presynaptic D2-like dopamine receptors, or α- or β;-adrenoceptors, nor did it affect angiotensin-converting enzyme activity. Fenoldopam may increase norepinephrine plasma concentration.

In animals, fenoldopam has vasodilating effects in coronary, renal, mesenteric and peripheral arteries. All vascular beds, however, do not respond uniformly to fenoldopam. Vasodilating effects have been demonstrated in renal efferent and afferent arterioles.

Pharmacokinetics

Adult Patients: Fenoldopam, administered as a constant infusion at dosages of 0.01 to 1.6 mcg/kg/min, produced steady-state plasma concentrations that were proportional to infusion rates. The elimination half-life was about 5 minutes in mild to moderate hypertensives, with little difference between the R (active) and S isomers. Steady state concentrations are attained in about 20 minutes (4 half-lives). The steady state plasma concentrations of fenoldopam, at comparable infusion rates, were similar in normotensive patients and in patients with mild to moderate hypertension or hypertensive emergencies.

The pharmacokinetics of fenoldopam were not influenced by age, gender, or race in adult patients with a hypertensive emergency. There have been no formal drug-drug interaction studies using intravenous fenoldopam. Clearance of parent (active) fenoldopam is not altered in adult patients with end-stage renal disease on continuous ambulatory peritoneal dialysis (CAPD) and is not altered in adult patients with severe hepatic failure. The effects of hemodialysis on the pharmacokinetics of fenoldopam have not been evaluated.

Pediatric Patients: In children, aged 1 month to 12 years old, steady-state fenoldopam plasma concentrations were proportional to dose (0.05 mcg/kg/min to 3.2 mcg/kg/min). The elimination half-life and clearance were 3 to 5 minutes and 3 L/h/kg, respectively.

In radiolabeled studies in rats, no more than 0.005% of fenoldopam crossed the blood-brain barrier.

Excretion and Metabolism

Radiolabeled studies show that about 90% of infused fenoldopam is eliminated in urine, 10% in feces. Elimination is largely by conjugation, without participation of cytochrome P-450 enzymes. The principal routes of conjugation are methylation, glucuronidation, and sulfation. Only 4% of the administered dose is excreted unchanged. Animal data indicate that the metabolites are inactive.

Pharmacodynamics and Clinical Studies

Adult Patients: In a randomized double-blind, placebo-controlled, 5-group study in 32 patients with mild to moderate essential hypertension (diastolic blood pressure between 95 and 119 mm Hg), and a mean baseline pressure of about 154/98 mm Hg, and heart rate of about 75 bpm, fixed-rate IV infusions of fenoldopam produced dose-related reductions in systolic and diastolic blood pressures. Infusions were maintained at a fixed rate for 48 hours. Table 1 shows the results of the study. The onset of response was rapid at all infusion rates, with the 15-minute response representing 50 to 100% of the 1-hour response in all groups. There was some suggestion of partial tolerance at 48 hours in the 2 higher dose infusions, but a substantial effect persisted through 48 hours. When infusions were stopped, blood pressure gradually returned to pretreatment values with no evidence of rebound. This study suggests that there is no greater response to 0.8 mcg/kg/min than to 0.4 mcg/kg/min.

Table 1: PHARMACODYNAMIC EFFECTS OF FENOLDOPAM IN MILD TO MODERATE ADULT HYPERTENSIVE PATIENTS

Time Point and Mean Change From Time Zero SE Drug Dosage (mcg/kg/min)
Placebo
n = 7
0.04
n = 7
0.1
n = 7
0.4
n = 5
0.8
n = 6
15 Minutes of Infusion*
  Systolic BP 0 6 -15 6 -19 8 -14 4 -24 6
  Diastolic BP 0 2 -5 3 -12 4 -15 3 -20 4
  Heart rate +2 2 +3 2 +5 1 +16 3 +19 3
30 Minutes of Infusion*
  Systolic BP -6 5 -17 6 -18 6 -14 8 -26 6
  Diastolic BP -6 3 -7 3 -16 4 -14 3 -20 2
  Heart rate +2 2 +3 2 +10 2 +18 3 +23 3
1 Hour of Infusion*
  Systolic BP -15 4 -22 7 -22 7 -26 9 -22 9
  Diastolic BP -5 3 -9 2 -18 4 -19 4 -21 1
  Heart rate +1 3 +5 2 +12 3 +19 4 +25 4
4 Hours of Infusion*
  Systolic BP -14 5 -16 9 -31 15 -22 11 -25 7
  Diastolic BP -14 8 -8 4 -19 9 -25 3 -20 1
  Heart rate +5 3 +6 3 +10 4 +21 2 +27 7
24 Hours of Infusion*
  Systolic BP -20 6 -23 8 -35 7 -22 6 -23 11
  Diastolic BP -11 6 -11 5 -23 10 -22 5 -13 3
  Heart rate +6 3 +5 3 +13 2 +17 4 +15 3
48 Hours of Infusion*
  Systolic BP -12 8 -31 6 -22 8 -9 6 -14 10
  Diastolic BP -9 5 -10 6 -9 7 -9 2 -9 3
  Heart rate +1 2 0 4 +1 4 +12 3 +8 3
*Mean change from time zero S.E.

In a multicenter, randomized, double-blind comparison of four infusion rates, fenoldopam was administered as constant rate infusions of 0.01, 0.03, 0.1 and 0.3 mcg/kg/min for up to 24 hours to 94 adult patients experiencing hypertensive emergencies (defined as diastolic blood pressure ≥ 120 mm Hg with evidence of compromise of end-organ function involving the cardiovascular, renal, cerebral or retinal systems). Infusion rates could be doubled after one hour if clinically indicated. There were dose-related, rapid-onset, decreases in systolic and diastolic blood pressures and increases in heart rate (Table 2).

Table 2: PHARMACODYNAMIC EFFECTS OF FENOLDOPAM IN ADULT HYPERTENSIVE EMERGENCY PATIENTS

Time Point and Pharmacodynamic Parameters Drug Dosage mcg/kg/min
0.01
n = 25
0.03
n = 24
0.1
n = 22
0.3
n = 23
Pre-Infusion Baseline
  Systolic BP - mean SE 210 21 208 26 205 24 211 17
  Diastolic BP - mean SE 136 16 135 11 133 14 136 15
Heart rate – mean SE 87 20 84 14 81 19 80 14
15 minutes of Infusion*
  Systolic BP -5 4 -7 4 -16 4 -19 4
  Diastolic BP -5 3 -8 3 -12 2 -21 2
  Heart rate -2 3 +1 1 +2 1 +11 2
30 Minutes of Infusion*
  Systolic BP -6 4 -11 4 -21 3 -16 4
  Diastolic BP -10 3 -12 3 -17 3 -20 2
  Heart rate -2 3 -1 1 +3 2 +12 3
1 Hour of Infusion*
  Systolic BP -5 3 -9 4 -19 4 -22 4
  Diastolic BP -8 3 -13 3 -18 2 -23 2
  Heart rate -1 3 0 2 +3 2 +11 3
4 Hours of Infusion*
  Systolic BP -14 4 -20 5 -23 4 -37 4
  Diastolic BP -12 3 -18 3 -21 3 -29 3
  Heart rate -2 4 0 2 +4 2 +11 2
* Mean change from baseline S.E.

Two hundred thirty-six (236) severely hypertensive adult patients (DBP ≥ 120 mm Hg), with or without end-organ compromise, were randomized to receive in 2 open-label studies either fenoldopam or nitroprusside. The response rate was 79% (92/117) in the fenoldopam group and 77% (90/119) in the nitroprusside group. Response required a decline in supine diastolic blood pressure to less than 110 mm Hg if the baseline were between 120 and 150 mm Hg, inclusive, or by ≥ 40 mm Hg if the baseline were ≥ 150 mm Hg. Patients were titrated to the desired effect. For fenoldopam, the dose ranged from 0.1 to 1.5 mcg/kg/min; for nitroprusside, the dose ranged from 1 to 8 mcg/kg/min. As in the study in mild to moderate hypertensives, most of the effect seen at 1 hour is present at 15 minutes. The additional effect seen after 1 hour occurs in all groups and may not be drug-related (there was no placebo group for evaluation).

Pediatric Patients: In a randomized, multi-center, double-blind, placebo-controlled, dose-ranging study, pediatric patients were randomized in equal proportions to 1 of 5 treatment groups: 0.05, 0.2, 0.8, or 3.2 mcg/kg/min fenoldopam or placebo. Fenoldopam or placebo was administered as a blinded continuous IV infusion for 30 minutes. Following this, open-label titration of fenoldopam was given to induce hypotension or normotension (defined as mean arterial pressure, MAP, between 50 and 80 mmHg for patients > 1 month of age and MAP between 40 and 70 mmHg for patients < /= 1 month). Seventy-seven pediatric patients (up to 12 years of age – Tanner Stages 1 and 2) were treated for at least two hours. Of these, 2 were < 1 month of age, 25 were between 1 month of age and 1 year of age, 7 were between 1 and 2 years of age, and 43 were between 2 and 12 years of age. Of the 77 patients enrolled in the trial, 58 were enrolled in association with surgery, and 19 were treated in an ICU setting.

The lowest dosage at which decreases in MAP were seen during blinded administration was 0.2 mcg/kg/min. The dose at which the maximum effect was seen was 0.8 mcg/kg/min. Doses higher than 0.8 mcg/kg/min generally produced no further decreases in MAP but did worsen tachycardia (Table 3). Changes in blood pressure and heart rate occurred as early as 5 minutes after starting infusion. Doses as high as 4 mcg/kg/min were administered during the open-label period. The effects increased with time for 15 to 25 minutes, and an effect could still be detected after an average of 4 hours of infusion. When the infusion was discontinued, blood pressure and heart rates approached baseline values during the following 30 minutes

Table 3: PHARMACODYNAMIC EFFECTS OF FENOLDOPAM IN PEDIATRIC PATIENTS Baseline Mean and Mean Change SE

  Drug Dosage (mcg/kg/min)
  Placebo
n = 16
0.05
n = 15*
0.2
n = 16
0.8
n = 15
3.2
n = 15
Pre-Infusion Baseline
  Mean Arterial Pressure 81 4 77 5 76 4 88 6 74 4
  Systolic BP 108 5 103 6 104 6 117 7 98 4
  Diastolic BP 62 4 61 4 57 3 69 6 56 3
  Heart rate 106 8 110 7 119 7 125 6 122 6
Change at 5 Minutes of Infusion
  Mean Arterial Pressure 4 2 3 3 -2 2 -3 3 -6 3
  Systolic BP 5 3 3 3 -2 3 -5 3 -8 3
  Diastolic BP 4 2 6 2 -1 2 -2 2 -4 2
  Heart rate 2 3 -2 3 -1 3 4 3 -2 3
Change at 30 Minutes of Infusion(LOCF)
  Mean Arterial Pressure 0 3 -1 3 -2 3 -10 3 -10 3
  Systolic BP -3 4 0 4 -3 4 -12 4 -10 4
  Diastolic BP 0 3 1 3 -2 3 -8 3 -6 3
  Heart rate -6 4 -4 4 5 4 7 4 14 4
* For Mean Arterial Pressure, n=14; otherwise, n=15.
Dropouts were accounted for using the Last Observation Carried Forward (LOCF) method of analysis.

Animal Toxicology

Unusual toxicologic findings (arterial lesions in the rat) with fenoldopam are summarized below. These findings have not been observed in mice or dogs. No evidence of a similar lesion in humans has been observed.

Arterial lesions characterized by medial necrosis and hemorrhage have been seen in renal and splanchnic arteries of rats given fenoldopam mesylate by continuous intravenous infusion at doses of 1 to 100 mcg/kg/min for 24 hours. The incidence of these lesions is dose related. Arterial lesions morphologically identical to those observed with fenoldopam have been reported in rats infused with dopamine. Data suggest that the mechanism for this injury involves activation of D1-like dopaminergic

receptors. Such lesions have not been seen in dogs given doses up to 100 mcg/kg/min by continuous intravenous infusion for 24 hours, nor were they seen in dogs infused at the same dose for 6 hours daily for 24 days. The clinical significance of this finding is not known.

Oral administration of fenoldopam doses of 10 to 15 mg/kg/day or 20 to 25 mg/kg/day to rats for 24 months induced a higher incidence of polyarteritis nodosa compared to controls. Such lesions were not seen in rats given 5 mg/kg/day of fenoldopam or in mice given the drug at doses up to 50 mg/kg/day for 24 months.

Last reviewed on RxList: 10/24/2008
This monograph has been modified to include the generic and brand name in many instances.

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