Sjöström P
Department of Internal Medicine, University Hospital, Uppsala, Sweden.
Scand J Urol Nephrol Suppl. 1988;111:1-66.
Although most patients respond well to loop diuretics, poor response is sometimes a problem and some underlying mechanisms were addressed in this study. The renal response to continuous infusion of furosemide was investigated in eight healthy volunteers during controlled isotonic dehydration and after full restoration of volume losses. A rapidly reversible acute tolerance developed in parallel with dehydration and activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS). Dehydration also reduced the renal clearance of furosemide substantially, but only decreased the urinary delivery rate of the drug (the principal determinant of the diuretic effect) to a minimal extent. Delayed tolerance to an i.v. bolus dose of furosemide was found in 12 healthy volunteers after 1 week of oral furosemide treatment with and without angiotensin converting enzyme inhibition. No pharmacokinetic changes were seen. This type of tolerance was not related to dehydration or activation of RAAS. Thus, the induced decrease in renal sensitivity to furosemide was probably due to an intrarenal (structural?) adaptation. The pharmacokinetics and pharmacodynamics of piretanide were studied in six healthy volunteers and 22 patients with chronic renal failure (glomerular filtration rate 1-28 ml/min). Poor response to the diuretic action of the drug was found in the patients. This was entirely due to a decrease in the fraction of piretanide excreted unchanged in the urine, and the renal sensitivity to the drug was normal. Multiple daily doses of piretanide of maximally 24 mg are recommended for optimal efficiency in renal failure. Substantial changes in pharmacokinetics of furosemide were found after manipulation of plasma albumin in five patients with nephrosis, while the urinary delivery of the drug scarcely changed. Neither the induced alterations in proteinuria nor those in plasma volume influenced the renal sensitivity to furosemide significantly. Some methodological observations proved to be of significance. Creatinine was found to be an unreliable marker of GFR because of its substantial tubular secretion and reabsorption, both of which were related to the degree of hydration. Likewise, lithium was considered an unreliable marker of proximal tubular reabsorption, since there were reasons to suspect furosemide-sensitive distal lithium reabsorption.
尽管大多数患者对袢利尿剂反应良好，但反应不佳有时也是个问题，本研究探讨了一些潜在机制。在八名健康志愿者处于等渗性脱水控制状态及失液完全恢复后，研究了他们对持续输注呋塞米的肾脏反应。随着脱水以及交感神经系统和肾素 - 血管紧张素 - 醛固酮系统（RAAS）的激活，快速可逆的急性耐受性随之产生。脱水还显著降低了呋塞米的肾脏清除率，但仅将药物的尿排泄率（利尿作用的主要决定因素）降至最低程度。在12名健康志愿者接受1周口服呋塞米治疗（有或无血管紧张素转换酶抑制）后，发现他们对静脉推注呋塞米存在延迟耐受性。未观察到药代动力学变化。这种耐受性类型与脱水或RAAS激活无关。因此，诱导的肾脏对呋塞米敏感性降低可能是由于肾内（结构？）适应性改变。在六名健康志愿者和22名慢性肾衰竭患者（肾小球滤过率1 - 28 ml/min）中研究了吡咯他尼的药代动力学和药效学。发现患者对该药物的利尿作用反应不佳。这完全是由于尿液中以原形排泄的吡咯他尼分数降低，而肾脏对该药物的敏感性正常。对于肾衰竭患者，建议每日多次给予最大剂量为24 mg的吡咯他尼以达到最佳疗效。在五名肾病患者中，血浆白蛋白改变后发现呋塞米的药代动力学有显著变化，而药物的尿排泄几乎没有改变。诱导的蛋白尿改变和血浆容量改变均未显著影响肾脏对呋塞米的敏感性。一些方法学观察结果被证明具有重要意义。由于肌酐存在大量肾小管分泌和重吸收，且两者均与水化程度相关，因此发现肌酐是肾小球滤过率不可靠的标志物。同样，锂被认为是近端肾小管重吸收不可靠的标志物，因为有理由怀疑存在呋塞米敏感的远端锂重吸收。
