Diuretics（利尿药） Shi-Hong Zhang（张世红） shzhang713@zju.edu.cn Dept. Pharmacology, School of Medicine, Zhejiang University

Definition Diuretics are drugs that can promote the production of urine and sodium excretion (natriuresis). Sodium excretion is usually accompanied with the excretion of other cations, as well as anions.

Dilute urine urine concentration urine concentration Ca2+, K+, Mg2+ 10％Na+ 65-70％Na+ H2O 25％Na+ 2~5％Na+ 正常人每天产生原尿180L，含钠600g，但99%被重吸收。近曲小管、髓袢降支、集合管存在水通道，可重吸收大部分水分，尿液被浓缩。在髓袢升支和远曲小管缺乏水通道，电解质被重吸收，尿液被稀释。 urine concentration 尿液的浓缩与稀释 urine concentration

Proximal convoluted tubule近曲小管 HCO3- resorption: carbonic anhydrase (CA，碳酸酐酶) Organic acid secretory systems 有机酸分泌系统 are located in the middle third of the proximal tubule: uric acid, NSAIDs, diuretics, antibiotics. Organic base secretory systems 有机碱分泌系统: creatinine肌酐, choline胆碱, etc CA inhibitor Acetazolamide 乙酰唑胺 ㈠

Thick ascending limb of loop of Henle髓袢 25% of the filtered sodium Water is impermeable due to lack of AQP水通道蛋白 Loop diuretics （袢利尿药） ㈠ 袢利尿药影响各离子的重吸收。 Cation resorption阳离子重吸收

Distal convoluted tubule远曲小管 10% of the filtered NaCl Water impermeable ㈠ Thiazide diuretics （噻嗪类利尿药） 进入细胞的钾离子和氯离子可通过各自的离子通道进入细胞间隙和血液 ⊕ parathyroid hormone （PTH,甲状旁腺激素）

^ ㈠ Collecting tubule集合管 Potassium-retaining diuretics （保钾利尿药） 2-5% of NaCl reabsorbed Principal cells 主细胞are the major sites of Na+, K+, and H2O transportation（Na+、Cl-重吸收，K+分泌） Intercalated cells闰细胞 are the primary sites of proton secretion（H+分泌，少量K+重吸收） ^ Potassium-retaining diuretics （保钾利尿药） ㈠ 保钾利尿药：抗醛固酮或抑制钠通道

肾小管转运系统及利尿药、脱水药作用部位 拮抗抗利尿激素的作用可显著提高血浆钠的水平，对低钠血症患者有利，但同样可升高其他溶质的浓度 及钠通道阻断剂 肾小管转运系统及利尿药、脱水药作用部位

Classification of diuretics Loop diuretics: high-ceiling diuretics (high efficacy), act at thick ascending limb of Henle loop, inhibit Na+-K+-2Cl- symporter: furosemide (呋塞米) Thiazide diuretics: moderate efficacy, act at distal convoluted tubule, inhibit Na+-Cl- symporter: hydrochlorothiazide (氢氯噻嗪) K+-retaining (sparing) diuretics: low efficacy, act at late distal tubule and collecting duct, inhibit renal epithelial Na+ channels or aldosteron: spironolactone (螺内酯) Carbonic anhydrase inhibitors: acetazolamide (乙酰唑胺) 碳酸酐酶抑制剂 Osmotic diuretics渗透性利尿药: mannitol (甘露醇) 袢利尿药 噻嗪类利尿药 保钾利尿药

常用利尿药对电解质排泄及排钠力的比较 药物 尿电解质排泄 主要作用部位 机制 Na+ K+ Cl- HCO3- 高效 利尿药 +++ + ++++ ± 髓袢升支粗段髓质和皮质部 抑制Na+ -K+-2Cl-共同转运系统 中效 ++ 远曲小管近段 抑制Na+ -Cl-共同转运系统 低效 - 远曲小管远段和集合管 对抗醛固酮，阻滞Na+通道 乙酰 唑胺 近曲小管 抑制胞内H+形成，抑制H+ -Na+交换

Carbonic anhydrase inhibitors Basic Pharmacology of Diuretics Carbonic anhydrase inhibitors 碳酸酐酶抑制剂 H+-Na+交换重吸收Na+，抑制HCO3重吸收，进入细胞的钾离子通过钾通道返回细胞间隙或血液。因水通道的存在，电解质的重吸收伴随水分的转移，导致氯离子的顺浓度梯度弥散入细胞间隙。 其他同类药物为：dichlorphenamide双氯非那胺，methazolamide醋甲唑胺、brinzolamide布林佐胺，dorzolamide多佐胺 ㈠ Acetazolamide 乙酰唑胺

Acetazolamide乙酰唑胺 Pharmacological effects: Inhibits bicarbonate (HCO3-) reabsorption (excretion rises to 35% of filtered load); HCO3- depletion leads to enhanced (compensatory) NaCl reabsorption by the remainder of the nephron肾单位. 近曲小管重吸收减弱可被髓袢部位补偿，导致利尿效果不明显。远曲小管的代偿作用有限。

Acetazolamide乙酰唑胺 Clinical use: open angle glaucoma, metabolic alkalosis代谢性碱中毒, prevention of acute mountain sickness (pulmonary, cerebral edema), urinary alkalinization碱化尿液 , short-term add-on therapy of edema. 高山病：因压力下降O2入血减少，而呼出CO2增多，造成呼吸性碱中毒和水肿。机体可代偿性增加尿中HCO3-的排泄，减少H+排泄，并增加Cl-的重吸收。乙酰唑胺可促进这些代偿过程，并引起代谢性酸中毒，增加肺通气量，提高肺泡氧分压。 乙酰唑胺很少用来治疗水肿，但有研究表明与其他利尿药的短期联用可增加利尿效果。因代酸的副作用不长期使用

Acetazolamide乙酰唑胺 Adverse effects: Sulfonamide toxicity: allergic reaction, marrow depression, skin toxicity, renal toxicity Significant bicarbonate loss and hyperchloremic metabolic acidosis高氯性代谢性酸中毒 Renal stones (Ca salts deposits) Renal potassium wasting (K+ excretion ↑ in collecting tubule) Drowsiness困倦 and paresthesias感觉异常 Rapid development of tolerance 集合管钠离子重吸收和钾离子分泌增加，导致低血钾。HCO3-重吸收减少，Cl-重吸收增加导致高氯性酸中毒

Loop diuretics袢利尿药 sulfonamide derivatives 磺胺类衍生物 phenoxyacetic acid derivatives 苯氧乙酸衍生物 依他尼酸 呋塞米 sulfonylurea derivatives 磺酰尿类衍生物 布美他尼 Torsemide 托拉塞米 The diuretic activity correlates with their secretion by the proximal tubule

Furosemide呋塞米 ㈠ Loop diuretics NKCC2仅存在于肾脏，NKCC1广泛分布于全身，包括CNS。有研究发现袢利尿药的结合于转运体的氯离子结合位点.钙离子在远曲小管可被重吸收，较少发生低钙血症。镁离子排出增加，导致低镁血症；Cl-排出大于Na+排出（远曲小管和集合管和代偿一部分Na的重吸收），长期使用导致HCO3-排出减少，H+排出增加，发生低氯性碱中毒

Furosemide Pharmacodynamics (1) Diuretic effects Inhibits the Na+-K+-2Cl- symporter of the luminal membrane in the thick portion of the ascending limb of the loop of Henle, and reduces the reabsorption of Na+, K+ and Cl-. Increases excretion of Ca2+, Mg2+ by abolition of transepithelial potential difference跨膜电位差.

Furosemide (1) Diuretic effects Blocks kidney’s ability to concentrate urine, impairs kidney’s ability to excrete a dilute urine by decreasing the hypertonic medullary interstitium髓质部高渗. Most efficacious among the diuretics, because the ascending limb accounts for the reabsorption of 25-30% of filtered NaCl and downstream sites are not able to compensate for this increased Na+ load.

Furosemide (2) Vasodilatation (induced-synthesis of renal prostaglandin) Renal vasodilatation: renal blood flow  Dilates veins: cardiac preload , pulmonary edema  吲哚美辛可抑制呋塞米的排钠作用

Furosemide Clinical Indications: (1) Severe edema: not the first choice for chronic edema following cardiac, hepatic or renal diseases, used for those that are intractable by thiazides (噻嗪类利尿药). (2) Acute pulmonary edema: left heart failure (3) Prevention of acute renal failure: in the early stage, increases the rate of urine flow and enhance K+ excretion, but do not ameliorates renal failure. (4) Hypercalcemia高钙血症 (5) Detoxication解毒 of toxins or drug overdose: mild hyperkalemia高钾血症; anion overdose: bromide (Br-), fluoride (F-), and iodide (I-). 严重高钾血症可用葡酸钙拮抗钾对心脏的毒性作用，用碳酸氢钠碱化血液，促进钾入胞内，增加肾脏远曲小管的钠钾交换，促进排出钾

Furosemide Adverse effects and toxicity (1) Water-electrolyte imbalance: dehydration脱水、 hypokalemia低钾血症、hypomagnesemia低镁血症、 hyponatremia低钠血症、 hyperchloremic metabolic alkalosis低氯性代谢性碱中毒，can be reversed by K+ replacement (combined with Mg2+) and correction of hypovolemia血容量过低. 镁对胞内钾有稳定作用，所以补钾要先补镁；钙离子在髓袢重吸收减少，但在远曲小管的重吸收可代偿，所以较少发生低钙血症。速尿抑制髓袢升支粗段对Cl-的主动重吸收从而造成钠、Cl-排出增加，而远曲小管加强排H+、K+以重吸收更多的钠，造成氢离子丢失加上HCO3重吸收剧减，发生低氯性代碱

Furosemide Adverse effects and toxicity (2) Ototoxicity耳毒性: tinnitus, vertigo, hearing damage, contraindicated to combine with aminoglycoside antibiotics 氨基糖苷类抗生素or the patients who have diminished renal function. (3) Hyperuricemia高尿酸血症: caused by competitive excretion竞争性分泌 with uric acid and enhancement of uric acid reabsorption in the proximal tubule.

Furosemide Adverse effects and toxicity (5) Allergic reactions: Skin rash, eosinophilia嗜酸粒细胞增多症 and, less often, interstitial nephritis间质性肾炎 (6) Other effects: RAAS activity , postdiuretic Na+ retention, arrhythmias (hypokalemia), hyperglycemia, increase in LDL cholesterol, etc. Note: Consumption of NSAIDs is a major cause of apparent diuretic resistance. postdiuretic Na+ retention与药物半衰期短及药效降低后引起的代偿性重吸收增加造成。限钠及增加给药次数可减轻。

Other loop diuretic drugs Loop diuretics袢利尿药 Other loop diuretic drugs Bumetanide 布美他尼：40-50 times more potent than furosemide, more reliable absorption (80% vs 10-90%), less ototoxicity. Torasemide 托拉塞米：stronger and longer action, more reliable absorption (80%), less K+/Ca2+ waste. Etacrynic acid 依他尼酸：weaker action with more severe adverse effects, less allergic reaction. 布美他尼

Thiazides噻嗪类 苄氟噻嗪 氯噻嗪 氢氯噻嗪 氢氟噻嗪 甲氯噻嗪 泊利噻嗪 三氯噻嗪 Indapamide 吲达帕胺 Chlortalidone氯噻酮 Metolazone美托拉宗

Thiazides Come from the effort to synthesize more potent carbonic anhydrase inhibitors碳酸酐酶抑制剂. Some retain significant carbonic anhydrase inhibitory activity. The prototypical thiazide is hydrochlorothiazide氢氯噻嗪. All can be administered orally, chlorothiazide is the only thiazide available for parenteral胃肠外 administration. All are secreted by the organic acid secretory system in the proximal tubule, and compete with the secretion of uric acid. Are classified into short-, medium-, and long-acting thiazides according to action duration (<12h, 12-24h, >24h).

Thiazides 1. Pharmacodynamics (1) Diuretic effects Act on distal convoluted tubule, inhibit Na+-Cl- symporter, decrease kidney’s ability to dilute urine Increase the excretion of Na+, Cl-, K+, Mg2+, HCO3-, but increase the reabsorption of Ca2+ in distal convoluted tubule The diuretic action of thiazides depends in part on renal prostaglandin production like loop diuretics. 噻嗪类利尿药增加镁离子排出的机制未明。

Thiazides ㈠ Thiazide diuretics （噻嗪类利尿药） ⊕ parathyroid hormone ⊕ （甲状旁腺激素）

Thiazides 3. Clinical indications: (1) Antihypertensive effects Blood volume , spasm responsiveness of arterial smooth muscles  (2) Edema: Used in treatment of mild and moderate edema in cardiac and renal diseases, and hepatic diseases with cautions (risk of hypokalemia); Restriction of Na+ intake should be attempted at the same time. (3) Nephrolithiasis 肾结石due to idiopathic hypercalciuria (特发性高尿钙症): Increase Ca2+ reabsorption.

Thiazides (4) Nephrogenic diabetes insipidus (尿崩症） Mechanisms remain unknown, may relate to the ability to produce a hyperosmolar urine. Can substitute for the antidiuretic hormone (ADH) in the treatment of nephrogenic diabetes insipidus. The urine volume of such individuals may drop from 11 L/day to 3 L/day when treated with thiazides.

Thiazides 4. Adverse effects (1) Imbalance of electrolytes hypokalemia hypomagnesemia hyponatremia hypochloremia cautions: dose individualization, K+ supplementation (2) Dysfunction of metabolism hyperglycemia hyperlipidemia hyperuricemia contraindicated in patients with diabetes and gout (痛风) 高血糖可能与低血钾造成胰岛素分泌减少有关

Thiazides 4. Adverse effects (3) Hypersensitivity (4) Others Bone marrow suppression, necrotizing vasculitis坏死性血管炎, interstitial nephritis间质性肾炎, etc. Photosensitivity or generalized dermatitis皮炎 (4) Others Weakness, fatigability易疲劳, and paresthesias感觉异常

Potassium-sparing diuretics (1) Antagonize aldosterone 拮抗醛固酮 at the late distal tubule and cortical collecting tubule Spironolactone 螺内酯，安体舒通 Eplerenone 依普利酮 (2) Inhibit Na+ influx in the luminal membrane Triamterene 氨苯喋啶 Amiloride 阿米洛利

Potassium-sparing diuretics ^ Potassiu-retaining diuretics （保钾利尿药） ㈠

Potassium-sparing diuretics Spironolactone (antisterone) A synthetic steroid Blocks aldosterone receptors Decreases Na+ reabsorption and K+ excretion Weak, slow-acting, and lasting duration Eplerenone, a new spironolactone analog with greater selectivity for aldosterone receptors.

AIP: aldosterone induced protein Action of spironolactone: Blocks the effects of aldosterone AIP: aldosterone induced protein Activation of Na+ membrane-bound channels Redistribute (3) De novo synthesis of (3) Activation of membrane-bound Na+/K+ ATPase Redistribution of (4) De novo synthesis of (4) Changes in permeability of tight junctions Increased mitochondrial production of ATP

Potassium-sparing diuretics Triamterene 氨苯喋啶 Amiloride 阿米洛利 Amiloride is excreted unchanged in the urine. Triamterene is metabolized in the liver and excreted from kidney, has a shorter half-life and must be given more frequently than amiloride. Both induce blue fluorescent urine. Block renal epithelial Na+ channels: decreases Na+-K+ exchange

Potassium-sparing diuretics Clinical Indications: Mineralocorticoid盐皮质激素 excess: Primary hypersecretion (Conn's syndrome, ectopic ACTH production) Secondary aldosteronism (醛固酮增多症, from heart failure, hepatic cirrhosis硬化, nephrotic syndrome肾病综合征, and other conditions associated with diminished effective intravascular volume) Combined with other diuretic drugs

Potassium-sparing diuretics Adverse effects (1) Hyperkalemia (2) Hyperchloremic metabolic acidosis: by inhibiting H+ secretion in parallel with K+ secretion (3) Sex hormone-like effects: gynecomastia(男性乳腺发育) (4) Acute renal failure: only found in the combination of triamterene with indomethacin (氨苯蝶啶+吲哚美辛) (5) Kidney stones: triamterene (poorly soluble) (6) Megaloblastosis巨幼红细胞性贫血: Triamterene (folic acid antagonist) (7) GI reactions: nausea, vomiting (8) CNS reactions: headache, fatigue, diziness

抑制碳酸酐酶及胞内H+形成，抑制H+ -Na+交换 常用利尿药对电解质排泄及排钠力的比较 药物 尿电解质排泄 主要作用部位 机制 Na+ K+ Cl- HCO3- 高效 利尿药 +++ + ++++ ± 髓袢升支粗段髓质和皮质部 抑制Na+ -K+-2Cl-共同转运系统 中效 ++ 远曲小管近段 抑制Na+ -Cl-共同转运系统 低效 - 远曲小管远段和集合管 对抗醛固酮，阻滞Na+通道 乙酰 唑胺 近曲小管 抑制碳酸酐酶及胞内H+形成，抑制H+ -Na+交换

Dehydrant Agents (Osmotic Diuretics) An osmotic agent is inert pharmacologically, freely filtered at glomerulus and undergo limited reabsorption. Dehydrant effect Diuretic effect (osmotic diuretic effect)

Mannitol甘露醇 Clinical Indications OH OH OH OH OH OH Clinical Indications (1) Given by iv infusion, results in increase in urine volume (2) Reduction of intracranial and intraocular pressure: used in brain edema following brain injury and glaucoma (3) Acute renal failure: prevention and early treatment (4) Dialysis disequillibrium syndrome 甘露醇对急性肾功能衰竭的预防作用可能与清理肾小管堵塞，稀释肾毒性物质以及减少肾小管的水肿有关。但治疗作用不确定. 透析造成胞外低渗，水分进入细胞，导致细胞水肿，低血压及中枢神经系统症状如头痛恶心肌肉痉挛惊厥等。

Mannitol Adverse effects (1) Extracellular volume expansion: pulmonary edema, etc. (2) Hyponatremia and dehydration: headache, nausea, vomiting, etc. Contraindicated in anuric无尿症 due to severe renal diseases, active cranial bleeding, heart failure

Dehydrant Agents (Osmotic Diuretics) Other dehydrant drugs Urea 尿素 Isosorbide 异山梨醇 Sorbitol 山梨醇 Glycerin 甘油 Hypertonic glucose (50%) 高渗葡萄糖 Hypertonic saline (7.5-10%) 高渗盐水

Clinical pharmacology of diuretic Natriuresis induced by diuretics is finite (diuretic braking). Mechanisms include activation of the sympathetic nervous system, activation of renion-angiotensin-aldosterone axis, decreased aterial blood pressure, hypertrophy of renal epithelial cells, increased expression of renal epithelial cells, increased expression of renal epithelial transporters, and perhaps alterations in nariuretic hormones such as atrial natriuretic peptide (ANP). Diuretic resistance may be induced by NSAIDs and decrease in RBF, which diminish the concentration of diuretics at the active site in the tubular lumen.

Clinical pharmacology of diuretic Options to deal with diuretic resistance: 1) Bed rest 2) Increase the dose 3) Smaller dose more frequently or iv infusion 4) Combination therapy 5) Reduce salt intake 6) Administration shortly before food intake

Diuretic combinations Loop Agents & Thiazides Salt and water reabsorption in either the thick ascending limb or the distal convoluted tubule can increase when the other is blocked. Thiazide diuretics may produce a mild natriuresis in the proximal tubule that is usually masked by increased reabsorption in the thick ascending limb. Mobilize large amounts of fluid and K+-wasting is extremely common. High risk to induce hyponatremia, hypotension, and worsening renal function.  Reserve for the occasional patient with high resistance to loop diuretics Metolazone and hydrochlorothiazide are the two thiazides most commonly used in combination with a loop diuretic.

Diuretic combinations 2. Potassium-Sparing Diuretics & Loop Agents or Thiazides When hypokalemia cannot be managed with dietary NaCl restriction or KCl supplements in patients using loop diuretics or thiazides, the addition of a potassium-sparing diuretic can significantly lower potassium excretion. it should be avoided in patients with renal insufficiency.