1. Diuretics [,daijuə'retiks]利尿药

2. 1 Introduction Definition of diuretic:
Agents that increases both renal water and sodium excretion.

3. Renal anatomy

4. Nephron ['nefrɔn]肾单位

5. [ɡlɔ'merjuləs]
肾小球
Antidiuretic Hormone
[me‘dʌlə] 髓质

6. Major Segments of the Nephron and Their Functions

7. 3 1 4 2

8. Proximal convoluted tubule cell
['kɔnvə,lu:tid]旋绕的 CA
Carbonic anhydrase
[kɑ:'bɔnik]
[æn'haidreis] 碳的
脱水酶

9. Acetazolamide乙酰唑胺 Carbonic anhydrase inhibitors [,æsitə'zɔləmaid]
Therapeutic uses：
1 Edema (limited use)：
Monotherapy: low efficacy;
Combination use with natriuretic [,neitrijuə'retik] (促)尿钠排泄的 diuretics with enhanced natriuretic response;
2 Open-angle glaucoma (major use);
Adverse effects:
Metabolic acidosis, hypokalemia, renal stone, renal lesions

10. Thick ascending limb cell

11. Loop diuretics (high efficacy diuretics)
Furosemide
[fju:'rəusəmaid]呋塞米
Mechanism and Site of Action:
Inhibiting Na+-K+-2Cl- symporter同向转运 in the thick ascending limb.

12. Effects on urinary excretion
1 Increasing in the urinary excretion of Na+( up to 25% of the filtered load of Na+), Cl-, K+, Ca2+, Mg2+; 2 Blocking the kidney’s ability to concentrate urine during hydropenia [haidrə’pi:niə] (体内)缺水; and impairing the kidney’s ability to excrete a dilute urine during water diuresis [,daijuə'ri:sis]水利尿.

13. Therapeutic uses
1 Edema: in Nephrotic [ni'frɔtik]肾病的 syndrome, liver cirrhosis [si'rəusis]硬化, chronic congestive heart failure; 2 Acute pulmonary edema： A rapid increase in venous capacitance; a brisk natriuresis [,neitrijuə'ri:sis]尿钠排泄 reduces left ventricular filling pressures;

14. 3 Acute hyperkalemia [,haipəkei'li:miə]高血钾;
4 Acute hypercalcemia [,haipə,kæl'si:miə]高血钙；
5 Hypertensive crisis；
6 To facilitate more rapid renal elimination of the offending drug.

15. Adverse effects 1 Abnormalities of fluid and electrolyte balance:
hypotension [,haipəu'tenʃən]
hypokalemia [,haipəukə'li:mjə]低血钾: cardiac arrhythmias
hyponatremia [,haipəunə'tri:miə]低血钠
hypochloremia [,kaipəuklɔ:'ri:miə]低血氯
metabolic alkalosis [,ælkə'ləusis]代谢性碱中毒
hypomagnesemia ['haipə,mæɡnə'si:miə]低血镁: risk factor for cardiac arrhythmias
hypocalcemia [,haipəukæl‘si:miə]低血钙: leading to tetany [’tetəni]抽搐

16. 2 Metabolic adverse reactions:
Hyperuricemia: gout;
Hyperglycemia: diabetes mellitus;
3 Ototoxicity [,əutə‘tɔksiti]耳毒性
Tinnitus [ti'naitəs]耳鸣, hearing impairment, deafness, vertigo ['və:tiɡəu]眩晕, and a sense of fullness in the ears.
4 Others:
Skin rashes, photosensitivity, paresthesia [,pærəs'θiːʒə]感觉异常, bone marrow depression, and gastrointestinal disturbances.

17. Distal convoluted tubule cell

18. Thiazides diuretics
Mechanism and site of Action: Inhibiting NaCl transport in the distal convoluted tubule cell

19. Effects on urinary excretion
1 Increasing Na+ and Cl- excretion;
2 Increasing the excretion of K+;
3 Increasing uric acid excretion following acute administration; decreasing uric acid excretion following chronic administration;
4 Decreasing Ca2+ excretion, increasing Ca2+ reabsorption;

20. Adverse effects and precautions
1 Most serious adverse effects of thiazides are related to abnormalities of fluid and electrolyte balance, including:
extracellular volume depletion
hypotension [,haipəu'tenʃən]
hypokalemia [,haipəukə'li:mjə]低血钾: cardiac arrhythmias
hyponatremia [,haipəunə'tri:miə]低血钠
hypochloremia [,kaipəuklɔ:'ri:miə]低血氯
metabolic alkalosis [,ælkə'ləusis]代谢性碱中毒
hypomagnesemia ['haipə,mæɡnə'si:miə]低血镁: risk factor for cardiac arrhythmias
hypercalcemia [,haɪpəkæl‘simɪə] 高血钙
hyperuricemia [,haipəjuəri'si:miə]]高尿酸血症

21. 2 Decreasing glucose tolerance; 3 Increasing plasma levels of LDL cholesterol [kə'lestərɔl]胆固醇, total cholesterol, and total triglycerides [trai'ɡlisəraid, -rid]甘油三酯; 4 Diuretic-associated drug interactions .

22. Therapeutic Uses
1 Edema: associated with heart, liver, and renal disease
(ineffective when the GFR is less than 30 to 40 ml/min)
2 Hypertension;
3 Calcium nephrolithiasis [,nefrəuli‘θaiəsis]肾结石 and osteoporosis /,ɔstiəupə'rəusis/骨质疏松症: reducing urinary excretion of Ca2+;
4 Nephrogenic肾原性的 diabetes insipidus [in‘sipidəs] 尿崩症: mechanism remains unknown

23. Collecting tubule and collecting duct cells

24. Inhibitors of renal epithelial Na+ channels Triamterene and amiloride
Potassium-sparing diuretics 1:
Inhibitors of renal epithelial Na+ channels
Triamterene and amiloride
氨苯蝶啶及阿米洛利
Mechanism and site of action
Blocking epithelial Na+ channels in the luminal membrane of principal cells in the late distal tubule and collecting duct;

25. Effects on Urinary Excretion 1 Mildly increasing the excretion rates of Na+ and Cl-; 2 Decreasing the excretion rates of K+, H+, Ca2+, and Mg2+; 3 Decreasing uric acid excretion;

26. Adverse effects 1 Hyperkalemia;
2 Causing CNS, gastrointestinal, musculoskeletal [,mʌskjʊləʊ‘skelɪt(ə)l] 肌肉与骨骼的, dermatological [ˌdɜmətə’lɒdʒɪkl] 皮肤病学的, and hematological [,hi:məte‘lɔdʒikəl]血液学的 adverse effects.

27. Therapeutic Uses In combination with other diuretics: to treat edema or hypertension with increased efficacy and decreased potassium disorder.

28. Aldosterone antagonists Spironolactone /,spaiərənəu'læktəun/螺内酯
Mechanism and Site of Action
Competitively inhibit the binding of aldosterone to the mineralocorticoid [,minərələu'kɔ:tikɔid]盐皮质激素 receptor, finally increase sodium pump activity of the basolateral membrane and Na+ conductance of the luminal membrane.

29. Effects on urinary excretion 1 Mildly increases the excretion rates of Na+ and Cl-; 2 Decreasing the excretion rates of K+, H+, Ca2+, and Mg2+; 3 Decreasing uric acid excretion.

30. 1 Life-threatening hyperkalemia; 2 Others Therapeutic uses
Adverse effects
1 Life-threatening hyperkalemia;
2 Others
Therapeutic uses
Co-administration with thiazide or loop diuretics in the treatment of edema and hypertension with increased efficacy and decreased perturbations of K+ homeostasis.

31. Decrease Increased Decreased Increase
Relative changes in urinary composition induced by diuretic drugs
Decrease
Increased
Decreased
Increase
Ca+ excretion
Na+ excretion
K+ excretion
Volume of urine
Acetazolamide
Thiazide diuretics
Loop diuretics
Potassium sparing diuretics

32. Supplementary reading
Whether a patient should receive diuretics and, if so, what therapeutic regimen should be used (i.e., type of diuretic, dose, route of administration, and speed of mobilization of edema fluid) depend on the clinical situation. Massive pulmonary edema in patients with acute left-sided heart failure is a medical emergency requiring rapid, aggressive therapy including intravenous administration of a loop diuretic. In this setting, use of oral diuretics or diuretics with lesser efficacy is inappropriate. On the other hand, mild pulmonary and venous congestion associated with chronic heart failure is best treated with an oral loop or thiazide diuretic, the dosage of which should be titrated carefully to maximize the benefit-to-risk ratio. As mentioned previously, meta-analysis indicates that loop and thiazide diuretics decrease morbidity and mortality in heart failure patients, and two randomized clinical trials with mineralocorticoid receptor antagonists also demonstrate reduced morbidity and mortality in heart failure patients receiving optimal therapy with other drugs. Periodic ,piəri'ɔdik/定期的 administration of diuretics to cirrhotic [si’rɔtik] 肝硬化 patients with ascites [ə‘saɪtiːz] 腹水 may eliminate the necessity for or reduce the interval between paracenteses /,pærəsen'ti:sis/穿刺术, adding to patient comfort and sparing protein reserves that are lost during the paracenteses. Although diuretics can reduce edema associated with chronic renal failure, increased doses of the more powerful loop diuretics usually are required. In the nephrotic [ni‘frɔtik]肾病的 syndrome, the response to diuretics often is disappointing. In chronic renal failure and cirrhosis [sɪ’rəʊsɪs]硬化, edema will not pose an immediate health risk. Even so, uncomfortable, oppressive, and/or disfiguring损毁…的外形 edema can greatly reduce quality of life, and the decision to treat will be based in part on quality-of-life issues. In such cases, only partial removal of edema fluid should be attempted, and the fluid should be mobilized slowly using a diuretic regimen that accomplishes the task with minimal perturbation of normal physiology.

33. 大纲要求 Objective and requirements
Be familiar with the classification of diuretics;
Master the effects, mechanism, indications, and the major adverse reactions of frusemide, hydrochlorothiazid, spironolactone, and triamterene;
Be familiar with the effects and indications of mannitol.
Teaching contents
1. Diuretics
（1）Kidney function and production of urine; the classification and mechanism of diuretics.
（2）Ordinary used diuretics: ① Strong potent diuretics ：the effects, mechanism, indications, and the major adverse reactions of frusemide. ② Moderate potent diuretics: the effects, mechanism, indications, and major adverse reactions of hydrochlorothiazide. ③ Mild potent diuretics: the mechanism, indications, and major adverse reactions of spironolactone and triamterene.
2. Dehydrates
Effects and indications of mannitol.

34. Essential vocabulary
Diuretics Loop diuretics/Thiazides diuretics/Potassium sparing diuretics Natriuretic Hypokalemia/hyperkalemia Edema Ototoxicity