diuretics and dehydrant agents
DESCRIPTION
Diuretics and Dehydrant Agents. Jin Wang Institute of Pharmacology School of Medicine Shandong University [email protected]. Section1 Diuretics. Definition - PowerPoint PPT PresentationTRANSCRIPT
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Diuretics and Dehydrant Agents
Jin WangJin WangInstitute of PharmacologyInstitute of Pharmacology
School of MedicineSchool of MedicineShandong UniversityShandong [email protected]@sdu.edu.cn
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Section1 Diuretics
Definition
Diuretics are a family of drugs that act on kidney and promote the excretion of urine (including water and electrolyte).
(mainly used in edema)
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The physiological basis of diuretics
ⅠExcretion function of kidney
ⅡUrinary physiology of kidney and the sites of diuretics
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Excretion of inorganic ion
Excretion of organic ion
Excretion of water
ⅠExcretion function of kidney
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ⅠExcretion function of kidney
1. Excretion of inorganic ion Convection Via ion channels Simple diffusion Facilitated diffusion Active transport (primary) Active transport (secondary) Symporter Antiporter
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spacelumentubular cell
K+
2Cl-
Na+Na+
Cl-
K+K+
Ca2+
Mg2+
ATP
Na+-K+-2Cl- Symporter
Na+-K+
ATPase
Na+
K+
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spacelumen
Cl-
Na+Na+
Cl-K+
ATP
Ca2+Na+
Ca2+
K+
K+
tubular cell
Na+-Cl- Symporter
Na+-K+
ATPase
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HCO3-+H+
Na+
K+
Na+
ATP
H2O+CO
2
CO2+ H2O
H++ HCO3-
H2CO
3CA
CA
tubular celllumen space
Na+-H+ Antiporter
Na+-K+
ATPase
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Excretion of inorganic ions
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ⅠExcretion function of kidney
2. Excretion of organic ionSecondary active transport Anionic transport system Cationic transport system
Pay attention: competition
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Excretion of organic ions
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ⅠExcretion function of kidney
3. Excretion of waterWater channel – aquaporins (AQPs)
Noble prize in chemistry 2003
Peter Agre(1949-)
1988 protein1991 -cDNA2003 Nobel prize
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AQP
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Characteristics of AQPs
Water permeation: unique
Water follows passively
Driven by Na+-K+ ATPase
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Filtration
Reabsorption
Secretion
Excretion
ⅡUrinary physiology of kidney and the sites of diuretics
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原尿量
终尿量
Filtration of glomerular
blood
Tubule fluid
glomerular
tubulus
urine
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Reabsorption of renal tubule and collecting tube
Proximal tubulesHenle’s loopDistal convoluted tubulesCollecting tubules
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1. Proximal tubule
2. thick ascending limb of Henle’s loop
3. Distal tubule and collecting ducts
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Proximal Tubule
Na+/ K+ ATPase: maintains gradient Na+ flows down via channel Na+_ H+ exchange: carbonic anhydrase (CA) AQP1/7: Water follows passively
65%~70% of Na+ and water reabsorption Cl- 、 Ca2+ 、 K+ 、 Mg2+ reabsorption
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HCO3-+H+
Na+
K+
Na+
ATP
H2O+CO
2
CO2+ H2O
H++ HCO3-
H2CO
3CA
CA
tubular celllumen space
Proximal tubule
acetazolamide
Na+
Na+
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TAL: thick ascending limb
1. No AQPs: impermeable to water
2. Transports Na+ by Na+ - K+ - 2Cl- symporter
25-35% of Na+ reabsorbed
Reabsorption of Ca2+ , Mg2+ and Cl-
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spacelumen
tubular cell
K+
2Cl-
Na+Na+
Cl-
K+K+
Ca2+
Mg2+
ATP
Symporter
Thick ascending limb of Henle’s loop
Furosemide
K+
Cl-
Na+
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NaHCO3NaClNaCl
K+
K+
Mg2+
H2O
2Cl-
Ca2+
Ca2+
(+PTH)
Na+NaCl醛固酮K+
H2O(+ADH)
H+K+
2Cl-
Na+皮质部
髓质部
近曲小管
髓袢
远曲小管 集合管
稀释
浓缩高
渗高
渗
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Distal Convoluted Tubule
5~10% of Na+ reabsorbed (1) Na+-Cl- symporter
(2) Ca2+-channel (3) Na+-Ca2+ exchange : parathyroid hormone (PTH) (4) No AQPs: impermeable to water
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spacelumen
Cl-
Na+Na+
Cl-K+
Thiazides
ATP
Ca2+Na+
Ca2+
K+
K+
Distal convoluted tubule
tubular cell
PTH
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Collecting Duct
Water permeability: main site
Controlled by ADH
Via AQPs(2,3,4)
Driven by medulla osmotic gradient 2-5% of Na+ reabsorbed :
Via Na+ channels
Regulated by ADS
K+ secretion : major site
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lumen space
ATP
R
ADHR
Na+
K+
H2O
Cl-
ADSADS-R
K+ -Na+exchange
principal cell
Na+
K+
Na+
K+
spironolactone
Triamterene
Amiloride
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NaHCO3NaCl Na+
K+
K+
Mg2+
H2O
2Cl-
Ca2+
Ca2+
(+PTH)
Na+NaCl醛固酮K+
H2O(+ADH)
H+K+
2Cl-
Na+皮质部
髓质部
近曲小管
髓袢
远曲小管 集合管
稀释
浓缩高
渗高
渗
Cl-
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Diuretics
Classification
Common used Diuretics
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Classification of Diuretics
Ⅰ. Loop (high efficacy diuretics) diuretics
Ⅱ. Thiazide (moderate efficacy ) diuretics
Ⅲ. Potassium-sparing (low efficacy) diuretics
Ⅳ. Carbonic anhydrase inhibitors
Ⅴ. Osmotic diuretics (dehydrants)
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Common used Diuretics
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Ⅰ.loop diuretics (High efficacy diuretics)
Furosemide (呋塞米 ,
呋喃苯氨酸 ,速尿 )
Etacrynic acid (依他尼酸 ,利尿酸 )
Bumetanide (布美他尼 )
Torsemide ( 托拉塞米 )
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Pharmacokinetics
1.Absorption 2.Distribution:PPBR>95% 3.Elimination:Anionic transport system
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Pharmacological actions
1. Diuresis: fast and strong
Site of action: Thick ascending limb of henle’s loop
Mechanism: ↓ Na+- K+-2Cl- cotransporter
Result: Na+, K+, 2Cl-, Mg2+, Ca2+ excretion↑
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spacelumen
tubular cell
K+
2Cl-
Na+Na+
Cl-
K+K+
Ca2+
Mg2+
ATP
Symporter
Thick ascending limb of Henle’s loop
Furosemide
K+
Cl-
Na+
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NaHCO3NaClNaCl
K+
K+
Mg2+
H2O
2Cl-
Ca2+
Ca2+
(+PTH)
Na+NaClADSK+
H2O(ADH)
H+K+
2Cl-
Na+皮质部
髓质部
近曲小管
髓袢
远曲小管 集合管
稀释
浓缩
高
渗高
渗Loop diuretics
肾的稀释功能肾的浓缩功能
高
渗
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2. Vasodilation
Renal vessel dilation→renal blood flow↑
Vessel dilation → heart load ↓
Possible mechanism: ↑ PGE2 synthesis
Pharmacological actions
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1. Acute pulmonary and cerebral edema2. Severe edema
Cautions3. Renal failure4. Hypercalcemia5. Overdose of some toxicants
Clinical uses
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Adverse reactions
1. Electrolyte disorders hyponatremia, hypomagnesemia,
hypochloremia alkalosis, hypokalemia ※
CHF: ↑ digitalis intoxication Hepatic cirrhosis: hepatic coma
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2. Ototoxicity: dose-related
Ethacrynic acid > Furosemide > Bumetanide
Pay attention!
Adverse reactions
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3. Hyperuricemia
(1) reabsorption of uric acid ↑
(2) secretion of uric acid ↓
4. GI reactions
5. Allergic reactions
Adverse reactions
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Ⅱ. Thiazides(噻嗪类 ): (Moderate efficacy diuretics)
Hydrochlorothiazide
(氢氯噻嗪 ,双氢克尿噻 ,双克 )
Chlorothiazide (氯噻嗪 )
Chlortalidon (氯酞酮 )
Indapamide (吲哒帕胺,寿比山 )
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中效利尿药
噻嗪类
短效类< 12h
氢氯噻嗪( hydrochlorothiazide)氯噻嗪( chlorothiazide)
中效类12~24h
苄噻嗪( benzthiazide)氢氟噻嗪( hydroflumethiazide)环噻嗪( cyclothiazide)三氯噻嗪( trichlorothiazide)
长效类> 24h
苄氟噻嗪( bendrofluazide)甲氯噻嗪( methychlorothiazide) 环戊噻嗪( cyclopenthiazide)泊利噻嗪( polythiazide)
非噻嗪类 氯噻酮( Chlortralidone )吲达帕胺( Indapamide )美托拉宗( Metolazone )喹乙宗( Quinethazone )
Classifications
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1. Diuresis: moderate Site of action: early distal tubules
Mechanism: Na+-Cl- symporter inhibition CAI ( in large dose)
Results: Na+, K+, Cl- , Mg2+, HCO-3 excretion ↑
Ca2+ in urine ↓ (↑ Ca2+reabsorption in distal tubules)
Pharmacological actions
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spacelumen
Cl-
Na+Na+
Cl-K+
Thiazides
ATP
Ca2+Na+
Ca2+
K+
K+
Distal convoluted tubule
tubular cell
-+
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NaHCO3NaClNaCl
K+
K+
Mg2+
H2O
2Cl-
Ca2+
Ca2+
(PTH)
Na+NaClADSK+
H2O(ADH)
H+K+
2Cl-
Na+皮质部
髓质部
近曲小管
髓袢
远曲小管 集合管
稀释
浓缩
高
渗高
渗 高
渗
Thiazides
-+
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2. Anti-insipidus effect Possible mechanisms
1) ↓ PDE (磷酸二酯酶)→ intracellular cAMP↑→ water permeability ↑ → water reabsorption ↑
2) excretion of NaCl↑ → plasma Osm ↓ → thirst ↓ → drinking↓ → urine↓
Pharmacological actions
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Insipidus (尿崩症 )
尿崩症多是由于抗利尿激素缺乏、肾小管重吸收水的功能障碍,从而引起以多尿、烦渴、多饮与低比重尿为主要表现的一种疾病。本病是由于下丘脑—神经垂体部位的病变所致,但部分病例无明显病因,尿崩症可发生于任何年龄,但以青年为多见。
主要临床表现为多尿、烦渴与多饮,起病常较急。 24h 尿量可多达 5-10L ,但最多不超过 18L 。尿比重常在 1.005
以下,尿渗透压常为 50-200mOsm/kg H O ,尿色淡如清水。
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3. Anti-hypertension effect Mechanisms
Early stage: diuretic effect→↓blood volume
Late stage: excretion of Na+↑→Na+-Ca2+
exchange→↓Ca2+ in smooth cell→ artery
tension↓
Pharmacological actions
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1. Edema: major indication Mild and moderate cardiac edema:
first choice Renal edema
related to renal function Ascites due to cirrhosis:
combined with spironolactone
Clinical Uses
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2. Insipidus
3. Hypertension: first-line drugs Hydrochlorothiazide, Indapamide
4. Idiopathic hypercalciuria
Clinical Uses
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1. Electrolyte disorders Hypokalemia Hypomagnesemia Hyponatremia
2. Metabolic disorders Hyperglycemia Hyperlipidemia Hyperuricemia
3. Allergic reaction
Adverse reactions
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Ⅲ. Potassium-sparing diuretics
Spironolactone (螺内酯 , 安体舒通 )
Triamterene (氨苯蝶啶 ) Amiloride (阿米洛利 )
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distal tubules and collecting ducts
↑ Na+ excretion , K+ excretion↓
Site of action
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lumen space
ATP
R
ADHR
Na+
K+
H2O
Cl-
ADSADS-R
K+ -Na+交换
Tubular cell
Na+
K+
Na+
K+
ADH-R
spironolactone
Triamterene
Amiloride
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Antisterone : Spironolactone
Spironolactone aldosterone
O
O
CH3
CH3
SCOCH3O
CH
CH3
O
HO
OC
CH2OH
O
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Aldosterone antagonist
Mechanism : competing with ADS
Na+-K+ exchange ↓
Characteristics:
1. Effects dependent on ADS
2. Potassium-sparing diuretics
3. weak, slow and long
Pharmacological effects
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1. Edema with high activity of aldosternone:
eg. liver cirrhosis and nephritis syndrome
2. In combination with other diuretics: to
↑diuretic effect ; prevent K loss
3. congestive heart failure
diuretic effect ;( - ) myocardial
fibrosis
Clinical uses
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1. Hyperkalemia
2. Endocrine abnormality (impotence, gynecomastia, hirsutism)
3. GI reactions
4. CNS syndrome
Adverse reactions
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Triamterene (氨苯喋啶 ) Amiloride (阿米洛利 )
Non-steroid in structure,
not aldosterone antagonists
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Mechanism :
Block Na+ channel → ↓ Na+ reabsorb
→K+ secretion ↓
Clinical uses : intractable edema
Adverse reactions : Hyperkalemia , GI, megaloblastic anemia: Triamterene
Triamterene (氨苯喋啶 ) Amiloride (阿米洛利 )
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Ⅳ Carbonic anhydrase inhibitor (CAI)
Acetazolamide ( 乙酰唑胺 )Effects: CAI → H+ and H+-Na+ exchange↓→ Na+, water
and HCO3- excretion↑→diuresis
CAI in ciliary epithelial cells/neurons
→aqueous humor/CSF formation ↓
→intraocular / Intracranial pressure ↓
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HCO3-+H+
Na+
K+
Na+
ATP
H2O+CO
2
CO2+ H2O
H++ HCO3-
H2CO
3CA
CA
tubular celllumen space
Proximal tubule
acetazolamide
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Clinical uses
1. Glaucoma
2. Acute mountain sickness
3. Alkalization urine
4. Treatment of metabolic alkalosis
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Section2 Dehydrants
Common characteristics Poor penetration to capillaries membrane (i.v.) Filtrated by glomerulus easily Not be reabsorped by renal tubules Not be metabolized No toxicity and antigenicity
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Mannitol (甘露醇 ) Sorbitol (山梨醇) Isosorbide (异山梨醇) Hypertonic glucose (高渗葡萄糖) Glycerin (甘油)
Common used dehydrants
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Pharmacological actions 1. Dehydrant effect i.v.→plasma osmotic pressure↑→
pressure in extra fluid compartments↓ 2. Diuretic effect 1) glomerular infiltration ↑
2) tubular osmotic pressure ↑
Mannitol (甘露醇 , 20%)
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1. Brain edema 2. Glaucoma 3. Prevent acute renal failure
Clinical Uses
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Adverse reactions
Extracellular volume expansion
Cautions!
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表 常用利尿药药代动力学比较 药 物
利尿作用
开始时间( h) 峰值时间( h) 维持时间( h)
袢利尿药
呋塞米 口服 60 分静注 5 ~ 10分
1 ~ 2 15 ~ 20分
6 ~ 8 1 ~ 3
依他尼酸 口服 30 分静注 5 ~ 10分
1 ~ 2 15 ~ 20分
6 ~ 8 1 ~ 3
布美他尼 口服 30 分 静注 5 ~ 10分
1 ~ 2 15 ~ 20分
6 ~ 8 1 ~ 3
噻嗪类利尿药
氯噻嗪 2 4 6 ~ 12
氢氯噻嗪 2 4 6 ~ 12
氢氟噻嗪 1 ~ 2 3 ~ 4 18 ~ 24
苄氟噻嗪 1 ~ 2 6 ~ 12 18 ~ 24
环戊噻嗪 6 7 ~ 12 18 ~ 24
氯酞酮 2 6 48 ~ 72
留钾利尿药
螺内酯 24 48 ~ 72 72 ~ 96
氨苯蝶啶 2 ~ 4 6 7 ~ 9
阿米洛利 2 6 12 ~ 24
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常用利尿药对电解质排泄及排钠力比较
尿电解质的排泄
药物 Na+ K+
Cl- HCO3 排钠力(%)
主要作 用部位
机 制
袢利尿剂 +++ + +++ 0 ~ 23 髓袢升支粗段髓质和皮质部
抑制 Na+ 、 K+ 、 2Cl-共同转运系统
噻嗪类 ++ + ++ + ~ 8 髓袢升支粗段皮质部(远曲小管开始部 )
抑制 NaCl再吸收
保钾利尿药 + - - 0 ~ 2 远曲小管、集合管 竞争 ADS-R(螺内酯 )
阻滞 Na+通道(氨苯蝶啶 /阿米洛利 )
乙酰唑胺 + + - +++ ~ 4 近曲小管 抑制碳酸酐酶
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水肿时利尿药的选用及注意事项
在应用利尿药前要注意下列几点: ①对基本疾病作病因治疗; ②动员组织间水肿液或体腔中积液进入血液循环,便于利尿消肿。这就要求患者卧床休息并进行支持疗法等;
③用低盐饮食以减少体内Na+量; ④注意治疗失败的可能,如观察肾小球滤过率是否下降,醛固酮分泌是否继发性增多等。
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水肿时利尿药的选用及注意事项
( 1 )心源性水肿:一般选用噻嗪类利尿药,宜加用钾盐;对中度水肿可用氢氯噻嗪加留钾利尿药;对一般利尿药无效的严重水肿,可合用高效利尿药和留钾利尿药,要定期检查血钾含量。
( 2 )肾性水肿:急性肾炎时,一般不用利尿药,必要时用氢氯噻嗪;肾病综合征时,对高度水肿者可用噻嗪类药物加留钾利尿药。效果不明显时可用高效利尿药加留钾利尿药。
( 3 )肝性水肿:肝性水肿多伴有继发性醛固酮增多症,一般宜先用留钾利尿药,或留钾利尿药加噻嗪类利尿药,如疗效不显著,可合用留钾及高效利尿药。
( 4 )急性肺水肿及脑水肿:静脉注射高效利尿药
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Thank you