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

呋塞米(FM)是一种环状利尿剂，据报道，在肝肾功能不全的患者中，该药物的利尿作用经常减弱。然而，这一现象所涉及的因素尚不清楚。因此，在本研究中，我们研究了FM在肝肾功能不全的大鼠和人类体内的药代动力学-药效学关系，建立了一种以尿钠排泄率作为利尿指标的利尿剂疗效评价方法。从FM的作用机制来看，这一指标比尿钠排泄率更可靠。在药物排泄-反应曲线上，急性肝功能衰竭大鼠对FM的表观敏感性低于正常大鼠。而急性肾功能衰竭(ARF)大鼠则明显高于正常大鼠。这些大鼠对水和离子的重吸收的改变提示了肾单位远端功能的改变。这种重吸收的改变可能与内分泌系统的改变有关，特别是与血浆醛固酮浓度有关。在不依赖内分泌系统的离体灌流肾中，ARF大鼠对FM的敏感性也增加。因此，肾内因素对肾脏疾病的反应也有影响。

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.