Diuretic Agents

Diuretic Agents

Weiwei [email protected]. Pharmacology, Medical School, Zhejiang University

2525 ％％ NaNa++

65-7065-70 ％％ NaNa++

1010 ％％ NaNa++

酮

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.

acetazolamideӨ

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

Loop diuretics

Ө

Distal Convoluted Tubule

10% of the filtered NaCl

Water impermeable

thiazide diuretics

parathyroid hormone

K+

Ө

⊕

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 diureticsLoop 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药物

尿电解质排泄滤过Na+ 量

%主要作用部位机制

Na+ K+ Cl- HCO3-

高效利尿药 +++ + ++++ 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

乙酰唑胺 + ++ 0 +++ 4 近曲小管抑制胞内 H+ 形成，抑制 H+ -Na+ 交换

Carbonic Anhydrase Inhibitorsacetazolamide (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 AgentsBasic Pharmacology of Diuretic Agents

Carbonic Anhydrase Inhibitors

Toxicity:

• Hyperchloremic metabolic acidosis

• Renal stones

• Renal potassium wasting

• Drowsiness and paresthesias

• Allergy

Basic Pharmacology of Diuretic AgentsBasic Pharmacology of Diuretic Agents

sulfonamide derivative phenoxyacetic acid derivative

the diuretic activity correlates with their secretion by the proximal tubule

Loop diureticsLoop diuretics

呋塞米呋塞米

布美他尼布美他尼

依他尼酸依他尼酸

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

-

Foresemide

loop diuretics loop diuretics urine concentrationurine concentration

urine diluteurine dilute

(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.

Foresemide

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.

苄氟噻嗪苄氟噻嗪氯噻嗪氯噻嗪氢氯噻嗪氢氯噻嗪氢氟噻嗪氢氟噻嗪甲氯噻嗪甲氯噻嗪泊利噻嗪泊利噻嗪三氯噻嗪三氯噻嗪

Thiazides

短效短效

中效

中效

长效

长效长效

1. PharmacokineticsAll 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+-Cl-

symport, 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

thiazides thiazides

urine diluteurine dilute

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

Thiazides

Chlortalidone ( 氯噻酮 )

Indapamide ( 吲达帕胺 )

Metolazone ( 美托拉宗 )

Quinethazone ( 喹乙宗 )

Xipamide ( 希帕胺 )

(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 氨苯喋啶 Amiloride 阿米洛利

Potassium-sparing diuretics

Spironolactone (antisterone)Spironolactone (antisterone)A synthetic steroidBlocking aldosterone receptorDecreasing Na+ reabsorption and K+ excretion Weaker, slow acting, and lasting duration

EplerenoneEplerenone, 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 membrane-

bound Na+/K+ ATPase5. Redistribution of (4)6. De novo synthesis of (4)7. Changes in permeability

of tight junctions8. Increased mitochondrial

production of ATP

TriamtereneTriamterene 氨苯喋啶氨苯喋啶AmilorideAmiloride 阿米洛利阿米洛利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 NaBlocking renal epithelial Na++ channels: channels: decreasing Nadecreasing Na++-K-K++ exchange exchange


spironolactone

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


ToxicityToxicity(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.

Pharmacodynamics(1) Dehydrant effects(2) Diuretic effects (osmotic diuretic effects)

MannitolMannitol 甘露醇甘露醇 OH OH OH OHOH OH OH OH

OH OHOH OH

Clinical IndicationsClinical 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

Mannitol

Other dehydrant drugs

Sorbitol 山梨醇Hypertonic glucose (50%) 高渗葡萄糖

Diuretic Combinations

1.1. Loop Agents & ThiazidesLoop 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.

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

Diuretic Combinations

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?

CASE

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Diuretic Agents