DA-1 AGONISTA Farmacología y Fisiología FENOLDOPAM (Corlopam) R. Sheinbaum, MD R. Reyna, RN O. Wenker, MD

Afinidades Receptor Dopamina GOLDBERG and RAJFER

Agonistas Receptor Dopamina Acciones de los Agonistas Dopaminérgicos Dopamina Fenoldopam DA1 (vasodilatación) +++ +++ DA2 (vasodilatación, emesis +++ - inhibición prolactina)  (vasoconstricción) ++ - 1 (inotrópico, cronotrópico) +++ -  2 (vasodilatación) + - SLIDE D3 Dopamine interacts with a variety of adrenergic receptors and both major subtypes of peripheral dopaminergic receptors. Its interaction with these different receptor types is somewhat dose dependent, although clearly there is overlap of receptor activation at many doses. In contrast, fenoldopam interacts only with DA1 receptors, and therefore is not associated with the adverse effects related to alpha1 and beta1 activation. Reference Frishman WH, Hotchkiss H. Selective and nonselective dopamine receptor agonists: an innovative approach to cardiovascular disease treatment. Am Heart J 1996;132:861-870. Frishman WH, Hotchkiss H. Am Heart J, 1996;132:861-867

Dopamina y Fenoldopam SLIDE D3 Dopamine interacts with a variety of adrenergic receptors and both major subtypes of peripheral dopaminergic receptors. Its interaction with these different receptor types is somewhat dose dependent, although clearly there is overlap of receptor activation at many doses. In contrast, fenoldopam interacts only with DA1 receptors, and therefore is not associated with the adverse effects related to alpha1 and beta1 activation. Reference Frishman WH, Hotchkiss H. Selective and nonselective dopamine receptor agonists: an innovative approach to cardiovascular disease treatment. Am Heart J 1996;132:861-870.

Efectos Fisiológicos Fenoldopam SLIDE D6 Fenoldopam’s activation of dopaminergic receptors on the proximal and distal renal tubules inhibits sodium reabsorption and results in diuresis and natriuresis, whereas activation of the renal vascular receptors in both afferent and efferent glomerular arterioles results in an increase in renal blood flow. In general, glomerular filtration rate increases in hypertensive patients and is maintained in normotensive patients. Animal studies indicate that fenoldopam also causes vasodilation in the splanchnic and coronary vascular beds. A study in dogs with experimental occlusion of the left anterior descending coronary artery demonstrated that fenoldopam improved the perfusion of normal and ischemic borderline myocardium. A study in pigs demonstrated a dose-dependent increase in gut mucosal oxygenation with fenoldopam. References Shi Y, Zalewski A, Bravette B, et al. Selective dopamine-1 receptor agonist augments regional myocardial blood flow: comparison of fenoldopam and dopamine. Am Heart J 1992;124:418-423. Shusterman NH, Elliott WJ, White WB. Fenoldopam, but not nitroprusside, improves renal function in severely hypertensive patients with impaired renal function. Am J Med 1993;95:161-168. Germann R, Hasibeder W, Haisjackl M, et al. Dopamine-1-receptor stimulation and mucosal tissue oxygenation in the porcine jejunum. Crit Care Med 1995;23:1560-1566.

Metabolismo del Fenoldopam Metabolismo vía conjugación Metabolitos farmacologicamente inactivos No interacciones citocromo P450 No interacciones metabólicas con drugas 88% unido a albúmina Eliminación: 90% orina, 10% heces No necesario ajustar la dosis en alteraciones hepáticas orenales SLIDE E6 Fenoldopam has a short half-life of 4 to 5 minutes. Steady state is reached at 20 minutes. Plasma drug levels are dose proportional at steady state. Plasma levels remain constant with prolonged (up to 48 hours) continuous constant-rate infusion. The plasma level decay at infusion termination is rapid and predictable even after prolonged infusion. There is no accumulation at higher doses or with prolonged infusion times up to 48 hours. Pharmacokinetics are linear and are best described by the one-compartment model.

Farmacocinética  t½ (aprox. 5 min)  Pequeño volumen de distribución  Rápido alcance de estado de estabilidad (aprox. 30 min)  Concentraciones Plasmáticas proporcionales a la to dosis  No alteraciones farmacocinéticas en infusión de 48 hr  Al suspenderse se elimina rápidamente SLIDE E6 Fenoldopam has a short half-life of 4 to 5 minutes. Steady state is reached at 20 minutes. Plasma drug levels are dose proportional at steady state. Plasma levels remain constant with prolonged (up to 48 hours) continuous constant-rate infusion. The plasma level decay at infusion termination is rapid and predictable even after prolonged infusion. There is no accumulation at higher doses or with prolonged infusion times up to 48 hours. Pharmacokinetics are linear and are best described by the one-compartment model.

Plasma Fenoldopam (ng/ml) Farmacocinética Time (hr) 1 2 3 4 5 6 10 20 30 40 Onset Plasma Fenoldopam (ng/ml) 40 Offset 0.00 g/kg/min 30 0.04  g/kg/min 0.1  g/kg/min 20 0.4  g/kg/min 0.8  g/kg/min SLIDE E6 Fenoldopam has a short half-life of 4 to 5 minutes. Steady state is reached at 20 minutes. Plasma drug levels are dose proportional at steady state. Plasma levels remain constant with prolonged (up to 48 hours) continuous constant-rate infusion. The plasma level decay at infusion termination is rapid and predictable even after prolonged infusion. There is no accumulation at higher doses or with prolonged infusion times up to 48 hours. Pharmacokinetics are linear and are best described by the one-compartment model. 10 48 49 50 51 52 53 54 Time (hr) Neurex: data on file

Resumen Agonista selectivo DA1 Efectos hemodinámicos predecibles Rápida iniciación del Efecto dosis respuesta predecible para presiones sanguíneas bajas Mejora del flujo sanguíneo en una variedad de lechos vasculares SLIDE E6 Fenoldopam has a short half-life of 4 to 5 minutes. Steady state is reached at 20 minutes. Plasma drug levels are dose proportional at steady state. Plasma levels remain constant with prolonged (up to 48 hours) continuous constant-rate infusion. The plasma level decay at infusion termination is rapid and predictable even after prolonged infusion. There is no accumulation at higher doses or with prolonged infusion times up to 48 hours. Pharmacokinetics are linear and are best described by the one-compartment model.