Diuretics
Shi Lihong
•
Diuretics are a family of drugs that promote the excretion of urine. They are used to reduce water accumulation or edema associated with heart failure, cirrhosis therapy, as well as to treat high blood pressure.
Introduction
• each diuretic agent acts upon a single
anatomic segment of the nephron. Because these segments have distinctive transport functions, the actions of each diuretic agent can be best understood in relation to its site of action in the nephron and the normal physiology of that segment.
Review the pathways of Na+ and water reabsorption along the human nephron
Nephron Structure
Nephron Structure
Renal Epithelial Cell Polarity Drives Na+ and Water Transport interstitial Tubular Fluid Blood
Proximal Tubule
• Na+ flows down concentration gradient • Na/K ATPase maintains gradient • Water follows passively • 67% of Na and water reabsorption
Proximal tubule:
carbonic acid
Reabsorption of Na+ : 60%-65% + pump (1) Na +--Na+ (2)H exchange
Carbon dioxide
Loop of Henle
• TDL permeable to water but not Na+ • TAL impermeable to water and transports
Na+ by Na+ - K+ - 2Cl -- contransporter • Differences in permeabilities creates the countercurrent multiplier which creates interstitial osmolar gradient • 35% of filtered load of Na + absorbed by the TAL, tubular fluid is diluted. • Reabsorption of Ca 2 + , Mg 2 + and Cl -• •
TDL:thick decending limb TAL:thick ascending limb
(1)Na+-K+-2Cl－ Co-transporter (2)impermeable to water (3)reabsorption of Ca 2+ 、Mg2+
Distal Convoluted Tubule
• 5% of filtered load of Na+ reabsorbed • Segment mostly impermeable to water
• (1) Na+-Cl－cotransporter
• (2)Ca2+ -channel (3) Na+-K+ exchange : aldsterone
(4) Na+-Ca2+exchange : parathyroid hormone(PTH) (5)impermeable to water
Reabsorption of Na+:5%- 10 % (1) Na+- Cl－ symporter (2) Na+-K+exchange aldosterone (3)Ca2+ -channel (4) Na+-Ca2+exchange parathyroid hormone(PTH) (5)impermeable to water
Cortical Collecting Duct
• Water permeability controlled by antidiuretic
hormone (ADH)
• Driving force for water reabsorption is
created by the countercurrent multiplier
• 2-3% of filtered Na+ reabsorbed here via Na+
channels that are regulated by aldosterone
• Major site of K+ secretion
Reabsorption of Na+: 2%- 5 %
(1)Na+ - channel
(2) K+ channel
(3) H+-- Na+ exchange
(4) Na+-K+ exchange: aldosterone
Classes of Diuretics
Ⅰ. High efficacy diuretics (loop diuretics) Ⅱ. Moderate efficacy diuretics Ⅲ. Low efficacy diuretics (Potassium-sparing diuretics)
Ⅰ. High efficacy diuretics (loop diuretics)
Available Loop Diuretics
• Furosemide • Bumetanide • Ethacrynic acid
Molecular Mechanism of Action
• 1. Site of action:
Inhibition of the apical Na-K-2Cl co-transporter of the TAL • 2. Mechanism: Competition with Cl- ion for Cl－ joint-part of Na+ K+ -2Cl－ cotransporter
Pharmacological Effects of Loop Diuretics
1. Diuresis: • ↑ Na +, Cl - and K + excretion • ↑ excretion of Ca2+, Mg2+ • (Loss of TAL electrostatic driving force) • ↑ K+ and H+ excretion ( Increased electrostatic driving force) 2. ↑ renal blood flow: ↓renal vascular resistance
Pharmacokinetics
• p.o. & intravenous administration • Rapid oral absorption, bioavailability
ranges from 65-100% • Rapid onset of action and high efficacy • extensively bound to plasma proteins • secreted by proximal tubule organic acid transporters uric acid (尿酸) ↑ gout probenecid (丙磺舒)
Therapeutic Uses
1. Acute and Severe edema
• Edema of cardiac, hepatic or renal
origin • Acute pulmonary edema • 1) dilating arteriole → afterload↓ 2)↓blood volume→preload↓ 3) dilating pulmonary vessels
Therapeutic Uses
• 2. acute renal failure: early stage • 3. Hypercalcemia : administrate
saline simultaneously • 4. Overdose of some toxicants: bromide , fluoride , iodide
Adverse reactions
1.
Electrolyte disorders:
hypokalemia※ CHF: ↑intoxication with digitalis Hepatic cirrhosis: coma
• hyperchloremia, hypomagnesemia,
2. Ototoxicity: dose-related hearing impairment: tinnitus, hearing loss, etc.
Adverse reactions
3. hyperuricemia
• (1) hypovolemia: ↑ reabsorption of uric acid • (2) competing with diuretic for organic acid
secretion route →secretion of uric acid↓
4. Others: GI reactions, allergic reactions
Ⅱ.Moderate efficacy diuretics
Thiazides: Hydrochlorothiazide chlorothiazide
Thiazide-like diuretics
Indapamide (吲哒帕 胺) •chlortalidone(氯酞酮)
Mechanism of Action
• Site: In cortex portion of TAL of Henle’s loop and
distal tubule • Bind to the electro neutral Na + -Cl - co transporter
• Impair Na+ and Cl- reabsorption
Increased K+ Excretion Due To:
• Increased urine flow • Increased Na+-K+ exchange • Increased aldosterone release
Pharmacological actions
• 1. Increased urinary excretion of:
• • • • • Na+ ClK+ Water HCO3- (dependent on structure)
↑Ca2+ reabsorption tubules
in
distal
Pharmacological actions
2. antidiuretic effect in patient with nephrogenic diabetes insipidus
1) ↓ PDE → intracellular cAMP↑→ water permeating the tubule↑ → reabsorption of water↑ • 2) excretion of NaCl↑ → plasma osmotic pressure↓ → thirst feeling↓ → amount of drinking↓ → urine↓
•
Pharmacological actions
• 3. anti-hypertension effect
early stage: diuretic effect → ↓ blood
flow late stage : excretion of Na+↑→ Na+Ca2+ exchange↓ → ↓Ca2+ in cell → tension of arteries↓
Clinical uses
1.
Chronic edema
mild to moderate cardiac edema: first choice ascites due to cirrhosis
2. nephrogenic diabetes insipidus
1) ↓ PDE → intracellular cAMP↑→ water permeating the tubule↑ → reabsorption of water↑ 2) excretion of NaCl↑→plasma osmotic pressure↓ → thirst feeling↓ → amount of drinking↓ → urine↓
• 3. hypertension
• •
early stage: ↓ blood flow
late stage : excretion of Na+↑→ Na+Ca2+ exchange↓ → ↓Ca2+ in cell tension of arterial↓ →
4. Primary hypercalciuria
5.Thiazide Use in Hypercalciuria Recurrent Ca2+ Calculi
• Thiazides promote
distal tubular Ca2+ reabsorption • Prevent “excess” excretion which could form stones in the ducts of the kidney
Adverse reactions
• 1. electrolyte disorders: Hypokalemia • 2. retention of uric acid and calcium • 3. hyperglycemia and hyperlipidemia • 4.
allergic reaction:
Ⅲ. Potassium-sparing diuretics
Spironolactone Triamterene Amiloride
Spironolactone
• 【 mechanism 】
• aldosterone antagonist • competing with ald. for ald-R in distal tubule and collecting duct → Na+-K+
exchange↓
【 characteristics 】 ※ low efficacy diuretics ※ slow onset ＆ long duration
Therapeutic Uses
• 1. Prevent K loss caused by other diuretics in:
• Hypertension • Refractory edema • Heart failure
• 2. Primary aldosteronism • 3.liver cirrhosis and syndrome (1)inactivation of ald.↓
nephritis
(2)circulation blood volume↓
Toxicity
• 1. Hyperkalemia - avoid excessive K
supplementation when patient is on spironolactone • 2. endocrine abnormality: gynecomastia , impotence
Triamterene and Amiloride
• Non-steroid in structure, not
aldosterone antagonists
Mechanism of Action
• Blockade of apical Na+
channel in the principal cells of the Collecting Duct.
• causes a drop in apical
membrane potential (less negative), which
is the driving force for
K+ secretion
Therapeutic uses
• Eliminate K wasting effects of
other diuretics in:
• Edema • Hypertension
§2 dehydrants
• Difficultly penetrate membrane • filtrated by glomerulus easily • Not be reabsorpted by renal tubules
• Not be metabolized
Osmotic Diuretics in Current Use
• Mannitol • Urea
• Glycerin
• Isosorbide
mannitol（甘露醇）
• Pharmacological actions • 1. dehydrant effect • 2. diuretic effect
1) glomerular infiltration↑ 2) inhibit Na+ - K+ - 2Cl－ symporter 3) ↑blood flow in medulla
Clinical uses
• 1. Brain edema
• 2. Glaucoma
• 3. Prevent acute renal failure
Adverse reaction
• extracellular volume expansion
• contraindication: chronic heart failure
Mechanism of Action:
Inhibition of Water Diffusion
• Free filtration in osmotically active
concentration • Osmotic pressure of nonreabsorbable solute prevents water reabsorption and increase urine volume
• Proximal tubule • Thin limb of the loop of Henle
Therapeutic Uses
Prophylaxis of renal failure
Mechanism:
• Urine volume increases • Urine low rate increases,reduce Na reabsorption
Therapeutic Uses
2. Reduction of pressure in extravascular fluid compartments • Reduction of CSF pressure and volume • Reduction of intraocular pressure
Toxicity of Osmotic Diuretics
• 1. Increased extracellular fluid
volume
• 2. Dehydration and hyponatrimia