Pharmacodynamics of loop diuretic, furosemide, in hepatic and renal dysfunction

呋塞米（FM）是一种袢利尿剂，据报道，这种药物的利尿作用在肝肾功能不全的患者中经常下降。然而，这种现象所涉及的因素尚未阐明。因此，本研究以大鼠和人体肝肾功能障碍为研究对象，探讨FM的药代动力学和药效学关系，并以尿Na+K排泄率作为评价FM利尿作用的指标，建立一种新的评价FM利尿作用的方法。从FM的作用机制来看，该指标比尿钠排泄率更可靠，在药物排泄-反应曲线上，急性肝衰竭大鼠对FM的表观敏感性低于正常大鼠。而急性肾功能衰竭（ARF）大鼠血清中TNF-α水平明显高于正常大鼠。水重吸收和离子重吸收的改变提示肾单位远端功能的改变。在与内分泌系统无关的离体灌流肾中，ARF大鼠对FM的敏感性也增加。因此，肾内因素也影响肾脏疾病的反应。

Furosemide(FM), a loop diuretic, has been reported that the diuretic action of this drug is frequently decreased in patients with hepatic and renal dysfunction. However, the factors involved in this phenomenon have not been elucidated yet. Thus, in this study, we have investigated the pharmacokinetic-pharmacodynamic relationship of FM in rats and humans with hepatic or renal dysfunction.A new evaluation method for diuretic response to FM was develop using the urinary excretion rate of (Na+K) as an index of diuresis. In view of the action mechanism of FM, this index was more reliable than the urinary excretion rate of Na.In the drug excretion-response curve, apparent sensitivity to FM was lower in the rat with aute hepatic failure(AHF) than in normal rat. On the other hand, it was higher in the rat with aute renal failure(ARF) than normal rat. The altered function at distal parts of the nephron was suggested by the change of reabsorption of water and ions in these rats. This alteration of reabsorption may be related with the change of endocrine system, especially with the plasma concentration of aldosterone.In the isolated perfused kidney, which was indepandent from endocrine system, the increased sensitivity to FM was also observed in ARF rats. Therfore, interarenal factors also affected to the response in renal disease.