慢性心力衰竭利尿剂抵抗的发病机制与治疗进展

利尿剂是减轻心力衰竭症状、改善血流动力学的核心治疗药物.但随着病情发展,利尿剂抵抗已经成为心力衰竭治疗过程中的障碍.对近年来慢性心力衰竭利尿剂抵抗的文献进行梳理,从中西医结合角度探讨慢性心力衰竭利尿剂抵抗的发病机制、治疗方法,为相关研究提供参考.     

Physiologic and rheologic effects of the antisickling agent ethacrynic acid and its N-butylated derivative on normal and sickle erythrocytes.

Ethacrynic acid, a loop diuretic, has been shown to inhibit hemoglobin S polymerization. Until now, however, most studies were performed using purified solutions of hemoglobin S. The experiments reported here were designed to examine the effects of ethacrynic acid and its n-butryic acid derivative on the rheological and physiological properties of intact red blood cells. Using net and unidirectional flux measurements, both agents were shown to cause ion and water loss from normal and sickle erythrocytes. Since cell shrinkage adversely influences red cell rheology, it is unlikely that this class of compounds, despite its ability to inhibit hemoglobin S polymerization, will prove useful in the treatment of sickle cell disease.     

Renal effects of FK453: A potent non-xanthine adenosine A1 receptor antagonist

The renal effects of FK453, a potent and selective non-xanthine adenosine A₁ receptor antagonist, were examined and compared with FR113452 (less active enantiomer of FK453), typical adenosine receptor antagonists, and diuretics. In rats FK453 possessed diuretic activity similar to 1, 3-dipropyl-8-cyclopentylxanthine (DPCPX, adenosine A₁ receptor antagonist), hydrochlorothiazide, and furosemide, but neither FR113452 nor CP66713 (an adenosine A₂ receptor antagonist) possessed diuretic activity. Urinary uric acid excretion in rats increased with FK453, but other drugs had no effect. These diuretic and uricosuric activities of FK453 were also observed in dogs. In anesthetized dogs, FK453 increased the renal blood flow (RBF), inulin clearance (Cin), and p-aminohippuric acid clearance (C_PAH). However, hydrochlorothiazide had no effect on RBF, Cin, and C_PAH. Furthermore, osmolar clearance experiments suggested that the renal site of action of FK453 was different from hydrochlorothiazide and furosemide. These results demonstrate that FK453 has diuretic activity and increases urinary uric acid excretion and suggest that the diuretic activity of FK453 is related to adenosine A₁ receptor antagonism; also, the diuretic mechanism of action and the renal site of action of FK453 are different from those of hydrochlorothiazide and furosemide. FK453 is a useful compound to clarify the physiological role of the adenosine A₁ receptor in the kidney. © 1995 Wiley-Liss, Inc.     

Comparative hypotensive activity of REV 6207 and enalapril in the conscious furosemide-treated monkey

The cardiovascular effects of ascending doses (0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg i.v.) of two angiotensin l-converting enzyme (ACE) inhibitors, REV 6207 and enalapril, were assessed in conscious furosemide-treated (3 mg/kg s.c.) monkeys. Both ACE inhibitors produced a dose-related inhibition of the pressor response to angiotensin l (0.66 μ/kg i.v.) with concomitant decreases in mean arterial pressure and no change in heart rate. The calculated ED₅₀ values for REV 6207 (0.316 mg/kg) and enalapril (0.275 mg/kg) were similar and both abolished the pressor response to angiotensin l at a dose of 3 mg/kg. The results of the study show that REV 6207 is a potent nonsulfhydryl-containing ACE-inhibitor with blood-pressure-lowering activity comparable to enalapril in the conscious monkey with high renin activity.     

Point-of-Care Saliva Osmolarity Testing for the Screening of Hydration in Older Adults With Hypertension

ObjectivesOlder adults have an elevated risk of dehydration, a state with proven detrimental cognitive and physical effects. Furthermore, the use of diuretics by hypertensive patients further compounds this risk. This prospective study investigated the diagnostic accuracy of point-of-care (POC) salivary osmolarity (SOSM) measurement for the detection of dehydration in hypertensive adults with and without diuretic pharmacotherapy.DesignProspective diagnostic accuracy study.SettingHome visits to patients recruited from 4 community health centers in West Sulawesi, Indonesia.ParticipantsA total of 148 hypertensive older adults (57 men, 91 women). The mean ages of male and female patients were 69.4 ± 11.4 and 68.1 ± 7.8 years, respectively.MethodsHypertensive adults were divided into 2 groups based on the presence of diuretics in their pharmacotherapeutic regimen. First-morning mid-stream urine samples were used to perform urine specific gravity (USG) testing. Same-day SOSM measurements were obtained using a POC saliva testing system.ResultsBoth USG (P = .0002) and SOSM (P < .0001) were significantly elevated in hypertensive patients with diuretic pharmacotherapy. At a USG threshold of ≥1.030, 86% of diuretic users were classified as dehydrated compared with 55% of non-using participants. A strong correlation was observed between USG and SOSM measurements (r = 0.78, P < .0001). Using a USG threshold of ≥1.030 as a hydration classifier, an SOSM threshold of ≥93 mOsm had a sensitivity of 78.6% and a specificity of 91.1% for detecting dehydration.Conclusions and ImplicationsHypertensive patients on diuretics have significantly higher first-morning USG and SOSM values, indicating a higher likelihood of dehydration relative to those on other classes of antihypertensive medication. POC SOSM assessment correlates strongly with first-morning USG assessment, and represents a rapid and noninvasive alternative to urinary hydration assessment that may be applicable for routine use in populations with elevated risk of dehydration.     

Sensitivity of residual nephrons to high dose furosemide described by diuretic efficiency

Ten haemodialysis (HD) patients with a median residual creatinine clearance (CL_CR) of 1.9 ml·min^–1·1.73 m^–2 (range 0.6–5.3) were treated with oral furosemide (F) 2.0 g. Overall-efficiency (O-E, daily sodium excretion/total urinary F) and total-efficiency (-E, increase in daily sodium excretion/total urinary F) were measured on the last 24 hours of each interdialysis interval. In addition, O-E was measured during the complete interdialysis interval in 10 HD patients with a median CL_CR of 5.6 ml·min^–1·1.73 m^–2 (range 0.7–6.8) treated for 1 year with a fixed oral dose of F between 250–1000 mg (median 625 mg).In the short study the median O-E was 10.6 mmol·mg^–1 (range 1.9–22.0) and -E 6.2 mmol·mg^–1 (range 1.3–11.2). The fractional excretion of sodium FE_Na was significantly increased from 9.6% (range 4.1–22.9) to 27% (range 14.6–56.2) during F treatment. A positive correlation was found between the basal FE_Na and -E. In the long-term study median O-E was 6.4 mmol·mg^–1. O-E and FE_Na showed no change over time although median RCC decreased from 5.6 to 1.9 ml·min^–1·1.73 m^–2 and median F excretion from 11.8 to 7.5 mg per day.It can be concluded that diuretic efficiency in haemodialysis patients is dependent on FE_Na and the state of hydration during the interdialysis interval.     

1例心力衰竭伴痛风发作患者的药物分析及文献回顾

摘 要 目的：探索心力衰竭伴利尿药诱发痛风性关节炎患者的合理用药原则。方法: 临床药师通过参与1例心力衰竭应用呋塞米诱发痛风性关节炎患者的诊疗和药物分析调整,充分考虑到患者疾病症状及可能诱导痛风发作的药物,建议停用相关药物,并调整治疗药物。结果: 临床药师考虑该患者自身特点,调整了合理治疗方案,医师采纳建议后,患者痛风症状缓解,心力衰竭得到控制,病情改善。结论:心力衰竭合并痛风史的患者应用利尿药,极易诱发痛风,建议小剂量使用对血尿酸水平影响相对较少的利尿药。临床药师通过参与临床治疗,发挥药师的专业优势,优化用药方案,可降低患者发生不良反应风险,促进患者安全合理用药。     

Captopril and the diuretic requirements in moderate and severe chronic heart failure

The effect of captopril on diuretic requirements was assessedin 16 patients with moderate (13 NY HA Class III, 1 NY HA ClassII) or severe (3NYHA Class IV) stable non-oedematous chronicheart failure. The dose of diuretics was halved before captoprilwas started and follow-up was continued for two months. In allthree patients in NYHA Class IV the diuretic dosage had to beincreased to a dose close to, or the same as, the original doseof diuretics in order to keep them from congestive heart failure.One patient improved on the new regime but gained 3·5kg in weight during follow-up. Of the 13 patients with moderateheart failure, seven showed an improvement in symptoms and exerciseduration on the combination of captopril and the lower doseof diuretics (mean 6·9 to 12·5 min, P0·001);two patients did not improve and gained 1·7 kg and 2·3kg in weight, respectively; three patients required the originaldose of diuretics to keep them from congestive heart failureand one patient lost weight on the reduced dose of diureticsbut showed no improvement clinically or on treadmill exercisetesting. Thus captopril does not have a diuretic sparing effectin patients with severe chronic heart failure. Those treatedneed the original dose of diuretics for maximal symptomaticbenefit. Captopril does have a diuretic sparing effect in somepatients with moderate chronic heart failure.     

泽泻炮制前后化学成分及其利尿作用研究

目的分析比较泽泻饮片麸炒、盐炙、土炒、酒炙炮制前后14种三萜类成分的含量,探讨泽泻及其不同炮制品的利尿作用。方法采用超高液相色谱-质谱联用(UPLC-MS),色谱柱为Waters CORTECS UPLC C18(2.1 mm×100 mm,1.6μm),以乙腈-水为流动相进行梯度洗脱,单四级杆质谱采用正离子SIR模式,测定泽泻生品和炮制品饮片中16-羰基-23-乙酰泽泻醇A、16-羰基-24-乙酰泽泻醇A、泽泻醇C、泽泻醇F、23-乙酰泽泻醇C、泽泻醇L、24-乙酰泽泻醇F、泽泻醇A、23-乙酰泽泻醇A、24-乙酰泽泻醇A、泽泻醇G、泽泻醇B、23-乙酰泽泻醇B、11-去氧泽泻醇B共14种三萜类成分的含量,探讨泽泻炮制过程中化学成分含量变化;采用水负荷大鼠代谢笼法,比较泽泻炮制前后的利尿作用。结果经方法学验证,所建立UPLC-MS同时测定泽泻饮片中14种三萜类成分的方法符合分析要求。与生品比较,泽泻炮制品化学成分最主要的变化是泽泻三萜类24、25位环氧环发生开环转化,23-乙酰泽泻醇B、泽泻醇B、11-去氧泽泻醇B和23-乙酰泽泻醇C含量下降,而泽泻醇A类化合物含量升高,且盐炙泽泻的化学成分转化最为明显。动物实验结果显示:生品组和各炮制品组1 h尿量较空白对照组显著增加,且利尿效应酒炙品>土炒品>麸炒品>盐炙品>生品;生品组和盐炙品组2 h尿量与空白对照组比较差异无统计学意义,而酒炙品组、土炒品组、麸炒品组尿量较空白对照组显著增加,且利尿效应酒炙品>土炒品>麸炒品。结论本研究建立的UPLC-MS测定泽泻生品及不同炮制品中化学成分含量方法准确、快速。泽泻炮制后化学成分发生明显变化,泽泻经酒炙、土炒和麸炒后较生品利尿作用显著增强。     

Urine neutrophil gelatinase-associated lipocalin levels predict acute kidney injury in acute decompensated heart failure patients

Abstract

Background: Acute heart failure (HF) syndromes are frequently complicated with cardiorenal syndromes. The aim of this study was to evaluate the performance of admission neutrophil gelatinase associated lipocalin (NGAL) levels to predict diuretic dose requirement and to predict the occurrence of acute kidney injury (AKI) in patients presenting with acute decompensated HF. Methods: Patients admitted with HF symptoms between December 2010 and October 2011 were prospectively enrolled. Samples were obtained for NGAL and brain natriuretic peptide. Patients were followed up until discharge or for three days, whichever happened first. They were grouped either to have AKI according to “Acute Kidney Injury Network” criteria or not (“no-AKI”). Results: One hundred patients were enrolled. Urine NGAL levels were higher in AKI group (median 31.3 vs. 16.2 ng/mL) (p?<?0.001). Oral furosemide using rates on admission was 60.5% in AKI group, 31.6% in no-AKI group. More AKI developed in patients using less furosemide orally on admission (p?=?0.023). Although the mean furosemide doses were similar on the first day (80?mg), diuretic dose increment was less on the following days in AKI group. Urine NGAL levels with 12?ng/mL cut-off value had sensitivity of 79% and specificity of 67% for predicting AKI. Multiple logistic regression analysis yielded an odds ratio of 10.9 for NGAL levels to predict AKI. Conclusion: Urine NGAL level in decompensated HF patients was not a significant predictor of diuretic dose requirement, but was a good marker for predicting AKI at 12?ng/mL cut-off value.