Transcript Thiazides

Diuretic Agents
Weiwei HU
[email protected]
Dept. Pharmacology, Medical School, Zhejiang University
10％Na+
65-70％Na+
酮
25％Na+
Proximal Tubule
HCO3- reabsorption: carbonic
anhydrase (CA)
Organic acid secretory systems
are located in the middle third of
the proximal tubule: uric acid,
NSAIDs, diuretics, antibiotics.
Organic base secretory systems:
H2R antagonists, choline,
morphine, etc.
Ө
acetazolamide
Proximal Tubule
Organic acid secretory systems
are located in the middle third of
the proximal tubule: uric acid,
NSAIDs, diuretics, antibiotics.
Organic base secretory systems:
H2R antagonists, choline,
morphine, etc.
Loop of Henle
25% of the filtered sodium
Water impermeable
Ө
Loop diuretics
Distal Convoluted Tubule
10% of the filtered NaCl
Water impermeable
Ө
K+
thiazide
diuretics
⊕
parathyroid hormone
Collecting Tubule
^
 2–5% of NaCl reabsorbed
 Principal cells are the major
sites of Na+, K+, and H2O
transportation
 Intercalated cells are the
primary sites of proton
secretion.
Classification of diuretics
Loop diuretics: high-ceiling diuretics (high efficacy), acting at
thick ascending limb of Henle loop, inhibiting
Na+-K+-2Cl- symport：furosemide (呋塞米)
Thiazide diuretics: moderate efficacy, acting at distal
convoluted tubule, inhibiting Na+-Cl- symport:
hydrochlorothiazide (氢氯噻嗪)
K+-sparing diuretics: low efficacy, late distal tubule and
collecting duct, inhibiting ADH and renal
epithelial Na+ channels: spironolactone (螺内酯)
Carbonic anhydrase inhibitors: acetazolamide (乙酰唑胺)
Osmotic diuretics: mannitol (甘露醇)
常用利尿药对电解质排泄及排钠力的比较
尿电解质排泄
药物
Na+
高效
利尿药
+++
K+
+
Cl++++
HCO30
滤过
Na+量
%
主要作用部位
机制
23
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
利尿药
++
+
++
+
8
远曲小管近段
抑制Na+ -Cl-共同
转运系统
低效
利尿药
+
-
+
0
2
远曲小管远段
和集合管
对抗醛固酮，阻
滞Na+通道
近曲小管
抑制胞内H+形成，
抑制H+ -Na+交换
乙酰
唑胺
+
++
0
+++
4
Basic Pharmacology of Diuretic Agents
Carbonic Anhydrase Inhibitors
acetazolamide (乙酰唑胺）
• Inhibit bicarbonate reabsorption;
• HCO3- depletion leads to enhanced
NaCl reabsorption by the remainder of the nephron;
• Causes significant bicarbonate losses and hyperchloremic
metabolic acidosis;
• Clinical use: glaucoma, metabolic alkalosis, acute mountain
sickness (cerebral edema), urinary alkalinization
Basic Pharmacology of Diuretic Agents
Carbonic Anhydrase Inhibitors
Toxicity:
• Hyperchloremic metabolic acidosis
• Renal stones
• Renal potassium wasting
• Drowsiness and paresthesias
• Allergy
Loop diuretics
sulfonamide derivative
呋塞米
布美他尼
phenoxyacetic acid derivative
依他尼酸
the diuretic activity correlates
with their secretion by the
proximal tubule
Foresemide
Pharmacodynamics
(1) Diuretic effects
 Inhibiting the Na+-K+-2Cl- symport of the luminal membrane in
the thick portion of the ascending limb of the loop of Henle, and
reducing the reabsorption of Na+, K+ and Cl-.
 Most efficacious among the diuretic drugs, 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.
Foresemide
 Impairing kidney’s ability to excrete a dilute urine.
 Blocking kidney’s ability to concentrate urine
during hydropenia, by decreasing the hypertonic
medullary interstitium.
 Increasing excretion of Ca2+, Mg2+ by abolition of
transepithelial potential difference.
 Inhibit Carbonic Anhydrase at large dose, increase
excretion of HCO3-
urine dilute
loop diuretics
urine concentration
Foresemide
(2) Vasodilatation (induced renal
prostaglandin synthesis)
 Renal vasodilatation: renal blood flow 
 Dilating veins: cardiac preload ,
pulmonary edema 
Foresemide
Clinical Indications:
(1) Severe edema: not first choice for chronic
edema, used for those are ineffective by thiazides
(2) Acute pulmonary edema: heart failure
(3) Hypercalcemia
(4) Detoxication of toxins or drug overdose
Foresemide
Clinical Indications:
(5) Others:
In mild hyperkalemia;
Acute renal failure: increase the rate of urine flow and
renal blood flow, ameliorate cell edema and jam in the
kidney tubules. Normally combined with dopamine.
Anion overdose: bromide, fluoride, and iodide
Foresemide
Toxicity
(1) Hypokalemia, hypomagnesemia, hyponatremia,
hypochloremic metabolic alkalosis
(2) Ototoxicity: hearing damage, contraindicated to
combine with aminoglycoside antibiotics or the patients
who have diminished renal function.
(3) Hyperuricemia: decreased excretion and enhancement
of uric acid reabsorption in the proximal tubule, .
Foresemide
Toxicity
(4) Allergic reactions: Skin rash, interstitial nephritis.
(5) Other effects: nausea, vomit, GI bleeding.
Other loop diuretic drugs
Bumetanide 布美他尼：stronger than furosemide,
but less adverse effects
Torasemide 托拉塞米：stronger and longer
actions
Etacrynic acid 依他尼酸：weaker actions and
more severe adverse effects
Thiazides
• This kind of drugs are come from the effort to
synthesize more potent carbonic anhydrase
inhibitors.
• Some of the thiazides retain significant carbonic
anhydrase inhibitory activity.
Thiazides
长效 苄氟噻嗪
短效 氯噻嗪
短效 氢氯噻嗪
中效 氢氟噻嗪
长效 甲氯噻嗪
长效 泊利噻嗪
中效 三氯噻嗪
Thiazides
1. Pharmacokinetics
 All of the thiazides can be administered orally,
chlorothiazide is the only thiazide available for
parenteral administration.
 All of the thiazides are secreted by the organic
acid secretory system in the proximal tubule,
and compete with the secretion of uric acid.
Thiazides
2. Pharmacodynamics
(1) Diuretic effects
 Acting on distal convoluted tubule, inhibiting Na+-Clsymport, decreasing kidney’s ability to dilute urine
 Increasing the excretion of Na+, Cl-, K+, Mg2+, HCO3-, but
increasing the reabsorption of Ca2+ in distal convoluted
tubule
(2) The action of thiazides depends in part on renal
prostaglandin production like loop diuretics.
thiazides
urine dilute
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;
(3) Nephrolithiasis due to idiopathic hypercalciuria (先天性
高尿钙症)
 Increase Ca2+ reabsorption.
Thiazides
(4) Diabetes insipidus (尿崩症）
 Thiazides have the unique ability to produce a
hyperosmolar urine, and 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 the
drug.
Thiazides
4. Adverse effects
(1) Imbalance of electrolytes
hypokalemia
hypomagnesemia
hyponatremia
cautions: dose individualization, K+ supplement
(2) Dysfunction of metabolism
hyperglycemia
hyperlipidemia
hyperuricemia
contraindicated in diabetes and gout (痛风) patients
Thiazides
4. Adverse effects
(3) Hypersensitivity
 Bone marrow suppression, dermatitis, necrotizing vasculitis,
interstitial nephritis, etc.
(4) Others
 Weakness, fatigability, and paresthesias
 Chlortalidone (氯噻酮)
 Indapamide (吲达帕胺)
 Metolazone (美托拉宗)
 Quinethazone (喹乙宗)
 Xipamide (希帕胺)
Potassium-sparing diuretics
(1) Antagonize aldosterone at the late distal tubule
and cortical collecting tubule
Spironolactone 螺内酯
Eplerenone 依普利酮
(2) Inhibit Na+ influx in the luminal membrane
Triamterene
Amiloride
氨苯喋啶
阿米洛利
Potassium-sparing diuretics
Spironolactone (antisterone)




A synthetic steroid
Blocking aldosterone receptor
Decreasing Na+ reabsorption and K+ excretion
Weaker, slow acting, and lasting duration
Eplerenone, a new spironolactone analog with
greater selectivity for the aldosterone receptor.
Action of
spironolactone:
Blocking the effects of
aldosterone
AIP: aldosterone induced
protein
1. Activation of Na+
membrane-bound
channels
2. Redistribute (3)
3. De novo synthesis of (3)
4. Activation of membranebound Na+/K+ ATPase
5. Redistribution of (4)
6. De novo synthesis of (4)
7. Changes in permeability
of tight junctions
8. 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
renal excretion, has a shorter half-life and must
be given more frequently than amiloride.
 Blocking renal epithelial Na+ channels:
decreasing Na+-K+ exchange
spironolactone
Potassium-sparing diuretics
Clinical Indications:
 In states of mineralocorticoid excess:
Primary hypersecretion (Conn's syndrome,
ectopic ACTH production)
Secondary aldosteronism (from heart failure,
hepatic cirrhosis, nephrotic syndrome, and
other conditions associated with diminished
effective intravascular volume)
 Combined with other diuretic drugs
Potassium-sparing diuretics
Toxicity
(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
(5) Kidney Stones: triamterene (poorly soluble)
(6) GI reactions
(7) CNS reactions: headache, fatigue
Dehydrant Agents (Osmotic Diuretics)
• Increase plasma osmotic pressure, induce
tissue dehydration.
• Excreted usually by glomerular filtration and
not reabsorbed, to induce osmotic diuretic
effects.
• To reduce increased intracranial pressure
and to promote prompt removal of renal
toxins.
Mannitol
OH
OH
甘露醇
OH OH
OH
OH
Pharmacodynamics
(1) Dehydrant effects
(2) Diuretic effects (osmotic diuretic effects)
Mannitol
Clinical Indications
(1) Increase in urine volume
(2) Reduction of intracranial and intraocular
pressure: used in brain edema and glaucoma
(3) Acute renal failure: prevention and early treatment
Mannitol
Toxicity
(1) Extracellular volume expansion: pulmonary
edema, etc.
(2) Hypernatremia and dehydration: headache,
nausea, vomiting, etc.
 Contraindicated in anuric due to severe renal
diseases, active cranial bleeding, heart failure
Other dehydrant drugs
Sorbitol 山梨醇
Hypertonic glucose (50%) 高渗葡萄糖
Diuretic Combinations
1. 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.
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 potassiumsparing diuretic can significantly lower potassium
excretion.
it should be avoided in patients with renal insufficiency
CASE
A 65-year-old man comes to the emergency department with
severe shortness of breath. His wife reports that he has long
known that he is hypertensive but never had symptoms, so he
refused to take antihypertensive medications. During the last
month, he has noted increasing ankle edema, reduced exercise
tolerance, and difficulty sleeping lying down, but he reports no
episodes of chest pain or discomfort. He now has pitting edema
to the knees and is acutely uncomfortable lying down. Vital
signs include blood pressure of 190/140 mm Hg, pulse 120/ min,
and respirations 20/min. Chest auscultation reveals loud
rhonchi, but an electrocardiogram is negative except for
evidence of left ventricular hypertrophy. He is given a diuretic
intravenously and admitted to intensive care. What diuretic
would be most appropriate for this man’s case of acute
pulmonary edema associated with heart failure? What are the
possible toxicities of this therapy?