水腫，利尿劑

水腫形成的機轉：

1. 血壓愈高， Na+ excretion rate 就愈高。而腎臟有問題時曲線會往右移。
2. 體內淨Na含量（Net Na+）＝intake－excretion（腎）－excretion（其他：sweating，fever會更多；feces；vomiting；……）
3. ECF Volume的變動會反映在不同的地方：
   1. 在peritoneal cavity的積水就是ascites
   2. 在肺部的就變 pulmonary edema
   3. 積在靜脈的就是 venus congestion。如右心衰竭
   4. 或跑到 interstitial space，就變成 peripheral edema。起因是 plasma protein 減少，像是 nephrotic syndrome，severe burns，肝臟製造 albumin變少等等。
   5. 或是其他地方
4. sensed ECFV 是指動脈周圍的ECFV，這裡的ECFV才會壓迫到血管而被 CV system，kidney 感應到

edema，venous congestion 的機轉有三：

1. pressure-natriuresis relationship 向右移。為 predisposing factor。因為身體會代償回來，不會edema，但會 hypertension。
2. dietary Na+ intake增加。同上，也是 predisposing factor。不會edema，但會 hypertension。
3. 會影響體內任一 compartment 中 ECFV 的因素。這會讓 sensed ECFV 減少，而回饋會讓 sensed ECFV回復正常，但流出的ECFV會被 trapped 在出問題的 compartment 中：
   1. liver cirrhosis：↑lymph in the space of Disse → spillover by the glissonian wall into the peritoneal cavity → 形成 ascites
   2. 左心衰竭：↑肺血管的 hydrostatic pressure → pulmonary edema
   3. chronic R't side heart failure：venous congestion, hepatic, splenic congestion, peripheral tissue edema。
   4. ↓plasma protein level, esp. Albumin（如 nephrotic syndrome, severe burns, 肝臟疾病）：全部的血管水都拉不住，會 generalized peripheral edema
   5. idiopathic peripheral edema

臨床上利尿劑的角色

對 edema 的處理方法：

1. 解決 underlying disease
2. 限塩
3. 給利尿劑

各種情形下給利尿劑的方法：

1. massive pulmonary edema：IV loop diuretics
2. chronic heart failure 的 mild pulmonary edema, venous congestion：PO thiazide, loop, (MR antagonists，要合併其他藥物) 可降低 morbidity, mortality
3. liver cirrhosis with ascites：主要要減少 paracentesis 的次
4. chronic renal failure：耐受性↑，dose要重
5. nephrotic syndrome：效果差
6. chronic renal failure + cirrhosis：↑QOL，預後不會比較好。但要保守，慢慢拉（避免 dehydration → renal failure 加重）。

基本上可以用下圖來 summary：

• 通常用利尿劑都不是在處理 underlying，有問題的edema 通常是局部的，而用了利尿劑會讓 sensed ECV ↓，可能會 hypotension, malaise, asthenia

Diuretic resistance

臨床上常見為併用 NSAIDs。COX-2 inhibitor 也會。在volume contraction, congestive heart failure, and cirrhosis 這些會讓 renal perfusion 下降的疾病中，RAAS和交感神經會活化，Prostaglandin, esp. PGE2 是個重要的 counterregulatory mechanism。 Prostaglandins 會在 distal nephron 減少 NaCl 再吸收，拮抗 ADH 的作用，使得血液從cortex跑到 juxtamedullary regions 。NSAID 則會抑制 prostaglandin 的這些效果，而讓鈉水滯留。因此給NSAIDs 可能會讓 congestive heart failure exacerbation，產生hypertension。

• In chronic renal failure, a reduction in RBF decreases delivery of diuretics to the kidney, and accumulation of endogenous organic acids competes with loop diuretics for transport at the proximal tubule. Consequently, diuretic concentration at the active site in the tubular lumen is diminished.
• In nephrotic syndrome, binding of diuretics to luminal albumin was postulated to limit response; however, the validity of this concept has been challenged (Agarwal et al., 2000).
• In hepatic cirrhosis, nephrotic syndrome, and heart failure, nephrons may have diminished diuretic responsiveness because of increased proximal tubular Na+ reabsorption, leading to diminished Na+ delivery to distal nephron segments (Knauf and Mutschler, 1997).

處理方法：

1. Bed rest may restore drug responsiveness by improving the renal circulation.
2. An increase in dose of loop diuretic may restore responsiveness; however, nothing is gained by increasing the dose above that which causes a near-maximal effect (the ceiling dose) of the diuretic.
3. Administration of smaller doses more frequently or a continuous intravenous infusion of a loop diuretic (Ferguson et al., 1997) will increase the length of time that an effective diuretic concentration is at the active site.
4. Use of combination therapy to sequentially block more than one site in the nephron may result in a synergistic interaction between two diuretics. For instance, a combination of a loop diuretic with a K+-sparing or a thiazide diuretic may improve therapeutic response; however, nothing is gained by the administration of two drugs of the same type.
   Thiazide diuretics with significant proximal tubular effects (e.g., metolazone) are particularly well suited for sequential blockade when co-administered with a loop diuretic. This combination should be used with caution and the patient followed closely in the first few weeks of therapy. Significant complications may ensue, including severe hyponatremia, hypokalemia, and volume depletion. The patient should be warned to stop both drugs and contact his or her physician if weight loss exceeds 5 pounds per week.
5. Reducing salt intake will diminish postdiuretic Na+ retention that can nullify previous increases in Na+ excretion.
6. Scheduling of diuretic administration shortly before food intake will provide effective diuretic concentration in the tubular lumen when salt load is highest.

對K+的影響

目前市售的所有的利尿劑都會影響 K+ homeostasis

各利尿劑的機轉：

Reference: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e > Section III. Modulation of Cardiovascular Function > Chapter 25. Regulation of Renal Function and Vascular Volume > Clinical Use of Diuretics