Diuretics

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