Brater D C
Drugs. 1981 Dec;22(6):477-94. doi: 10.2165/00003495-198122060-00004.
Resistance to diuretics occurs frequently in clinical settings. Most attention to this phenomenon has been directed toward the pathophysiology of the disease state, with little focus on the pharmacology of the diuretics themselves. This review summarises the pathogenesis and emphasises the pharmacological determinants of response to diuretics, including absorption, delivery to the kidney, and response to amounts of diuretic reaching the site of action. In normal subjects, overall response to organic acid diuretics such as frusemide (furosemide) is determined by the total amount of drug delivered into the urine (reflecting amounts of drug reaching the intraluminal site of action), the time course of delivery, and the relationship between amounts of drug reaching the urine and response (the dynamics of response). The conditions of azotaemia, inhibition of synthesis of prostaglandins, and the oedematous disorders of congestive heart failure, cirrhotic liver disease and nephrotic syndrome are examined in the above context. In azotaemic subjects, delivery of organic acid diuretics to their intraluminal site of action is inhibited by accumulated endogenous organic acids which compete for transport into the nephron at the organic acid secretory site of the proximal tubule. Whether the dynamics of response are changed has not been investigated. During inhibition of synthesis of prostaglandins, and in the oedematous disorders, there appear to be no changes in handling of frusemide; i.e. bioavailability, total drug delivered into the urine and the time course of delivery are comparable with that in normal subjects unless concomitant renal dysfunction exists. Resistance in these conditions is therefore due to a change in the dynamics of response.
在临床环境中，利尿剂抵抗现象频繁出现。对这一现象的关注大多集中在疾病状态的病理生理学上，而对利尿剂本身的药理学关注较少。本综述总结了其发病机制，并强调了利尿剂反应的药理学决定因素，包括吸收、输送到肾脏以及对到达作用部位的利尿剂剂量的反应。在正常受试者中，对呋塞米（速尿）等有机酸利尿剂的总体反应取决于排入尿液的药物总量（反映到达管腔内作用部位的药物量）、输送的时间进程以及到达尿液的药物量与反应之间的关系（反应动力学）。在上述背景下，对氮质血症、前列腺素合成抑制以及充血性心力衰竭、肝硬化和肾病综合征的水肿性疾病的情况进行了研究。在氮质血症患者中，有机酸利尿剂向其管腔内作用部位的输送受到内源性有机酸积累的抑制，这些内源性有机酸在近端小管的有机酸分泌部位竞争转运进入肾单位。反应动力学是否发生变化尚未得到研究。在前列腺素合成抑制期间以及在水肿性疾病中，呋塞米的处理似乎没有变化；即生物利用度、排入尿液的总药物量和输送的时间进程与正常受试者相当，除非存在伴随的肾功能障碍。因此，在这些情况下的抵抗是由于反应动力学的改变。
