Diuretics（利尿药） Shi-Hong Zhang（张世红）email@example.com 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 Ca2+, K+, Mg2+ 10％Na+ 65-70％Na+ H2O 25％Na+ 2~5％Na+ urine concentration urine concentration 尿液的浓缩与稀释
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 ㈠ CA inhibitor Acetazolamide 乙酰唑胺
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 ㈠ Loop diuretics （袢利尿药） 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） ⊕ parathyroid hormone （PTH,甲状旁腺激素）
Collecting tubule集合管 • 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） ^ ㈠ Potassium-retaining diuretics （保钾利尿药）
袢利尿药 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) 噻嗪类利尿药 保钾利尿药
Basic Pharmacology of Diuretics Carbonic anhydrase inhibitors 碳酸酐酶抑制剂 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.
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.
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
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
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
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:leftheart 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-).
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.
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 thepatients 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.
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.
Thiazides噻嗪类 Indapamide 吲达帕胺 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 Chlortalidone氯噻酮 Metolazone美托拉宗
Thiazides • Come from the effortto 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 administeredorally, 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.
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 edemain 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)
Thiazides 4. Adverse effects (3) Hypersensitivity • 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 ^ ㈠ Potassiu-retaining diuretics （保钾利尿药）
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.
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
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 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
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.