Lecture Topics 利尿药. Diuretics. Diuretic Classes. Definition of diuretic:
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1 利尿药 Diuretics 四川大学药理教研室朱玲副教授 Lecture Topics You need to know these things: high efficacy furosemide moderate hydrochlorothiazide low spironolactonum triameterenum Mechanism of action Clinical indications Toxicity/adverse reactions Definition of diuretic: Diuretics are drugs which block renal ionic transport, causing diuresis in increasing urine volume Often associated with natriuresis------increase in sodium excretion Drugs that interfere with renal transport may be useful in management of clinical disorders Diuretics often act at different sites of the tubule transport system Diuretic Classes Carbonic Anhydrase Inhibitors Loop Diuretics Thiazides Potassium Sparing Diuretics Osmotic Agents Overview of Kidney Functions of the Urinary System 1. Excretion: removal of organic wastes from body fluids 2. Elimination: discharge of waste products 3. Homeostatic regulation: of blood plasma volume and solute concentration 1
2 The Structure of the Kidney Physiology Review Body fluid and electrolyte composition are regulated by the kidney Glomerular filtrate ---- blood L Proximal tubule Loop of henle Distal Convoluted Tubule Collecting tubule --- urine 1.8L Glomerulus The glomerular capillaries are very leaky about 400 times as high as other capillaries Produce a filtrate that is similar to blood plasma except proteins and cellular elements 2
3 Q: Increasing of filtrate can increasing urine volume? A: Reabsorb will be increased following the increasing of filtrate urine volume will not increase Proximal tubule Many solutes are reabsorbed 85% of filtered sodium bicarbonate 60% of sodium chloride 60% of water nearly all of filtered organic solutes, including glucose and amino acids Proximal tubule--properties 60~65% sodium reabsorbed actively Water and chloride are reabsorbed passively in direct proportion to salt -H + exchanger Carbonic Anhydrase Inhibitors -----Acetazolamide 乙酰唑胺 (Diamox) CA CA acetazolamide Causes significant bicarbonate loss Metabolic acidosis Limited effectiveness : increases sodium chloride reabsorption in the distal tubule Uses: Glaucoma, urinary alkalinization, metabolic alkalosis, acute mountain sickness. 3
4 Pilocarpine (parasympathomimetic) Physostigmine (indirect parasympathomimetic) Timolol (beta-adrenergic blocker) Epinephrine (sympathomimetic) Carbonic anhydrase inhibitors Glaucoma Loop of Henle Thin limb Water reabsorption driving force---osmotic pressure -- due to hypertonic medullary fluid Aquaporins AQPs No active salt reabsorption No drugs interfere with this site Osmotic Diuretics introduction Mannitol (Osmitrol) is an example of osmotic diuretic. Osmotic Diuretics introduction Pharmacokinetics? Usually administered by IV; Oral administration results in an osmotic diarrhea Mannitol properties/mechanism of action Not metabolized, freely filtered at the glomerulus Cause water to be retained within the proximal tubule and descending limb of loop of Henle Urine volume increases with mannitol excretion due to direct osmotic effects Osmotic Diuretics---- Clinical Uses To increase urine volume To decrease intracranial or intraocular pressure Cerebral edema, glaucoma, acute renal failure Toxicity Extracellular volume expansion Dehydration and hypernatremia 4
5 Loop of Henle thick ascending limb(tal) Active sodium reabsorption Reabsorption of sodium chloride is dependent upon the / /2Cl - cotransporter Impermeable to water Diluting segment Osmotic pressure of urine dilution hypertonic Carbamide Urea recycle ATP concentration hypertonic paracellular pathway Diagrammatic presentation of nephron showing the reabsorption / /2Cl - co-transporter / ATPase increase in intracellular increase in lumen-positive electrical potential increase in reabsorption of Mg ++ and Ca ++. Medullary portions of the thick ascending limb Reabsorption of electrolyte play an important role on concentration of urine Reabsorption of carbamide Contribute to medullary hypertonicity 5
6 Available Loop Diuretics Furosemide (Lasix) Bumetanide (Bumex) Torsemide (Demadex) Ethycrinic acid Na-K-2Cl SYMPORT INHIBITORS Furosemide Also Called: Loop Diuretics High Ceiling Diuretics Bumetanide Torsemide Ethacrynic Acid MECHANISM OF ACTION Loop Diuretics Inhibition of NaCl reabsorption in the thick ascending limb of the loop of Henle Inhibit the / /2Cl - transport system in the luminal membrane ATP paracellular pathway Loop diuretics block / /2Cl - co-transporter This transporter and / ATPase Intracellular lumen-positive electrical potential reabsorption of Mg ++ and Ca ++ 6
7 Properties of loop diuretics Increase Cl - excretion Increase Mg ++ Ca ++ excretion hypomagnesemia occurs hypocalcemia not usually occurs Alter kidney ability of dilute and concentrate urine Properties of loop diuretics High efficacy Furosemide: Dilation of blood vessels increases renal blood flow esp. renal cortex Indomethacin? Pharmacokinetics Loop diuretics Rapidly absorbed following oral administration Acts rapidly Eliminated by a renal secretion and glomerular filtration (half-life -- depend on renal function) Clinical Uses 1. Acute pulmonary edema-decrease left ventricular pressure 2. Hyperkalemia Loop diuretics 3. Management of severe edema Clinical Uses 4. Acute renal failure---increase the rate of urine flow, flush intratubular casts 5. Acute hypercalcemia Loop diuretics 6. Accelerate toxin/drugs clearance Toxicity Loop diuretics Blood V Mg ++ Ca ++ CL - (Hypokalemia metabolic alkalosis; Hypomagnesemia) Ototoxicity: ---not be used with aminoglycoside antibiotics etc Hyperuricemia: ---gout GI, Allergic reactions: 7
8 Distal Convoluted Tubule Impermeable to water Sodium reabsorption by sodium and chloride co-transporter Further dilution of tubular fluids Calcium is actively reabsorbed -k + exchanger Less reabsorption of electrolytes in the distal convoluted tubule than loop A -Cl - cotransporter Ca 2+ is reabsorbed via calcium channel, regulated by parathyroid hormone Na-Cl SYMPORT INHIBITORS PTH Also Called: Thiazide Diuretics Thiazide-Like Diuretics Hydrochlorothiazide Chlorthalidone Chlorothiazide Metolazone 噻嗪类 Thiazides H 2ON 2S R 2 N N R 1 A. 氢氯噻嗪 Hydrochlorothiazide Cl H 2ON 2S H N S O 2 N H H 吲达帕胺 (indapamide) 氯噻酮 Chlortalidon O Cl HN H 2NO 2S OH B. 氯噻嗪 (Chlorothiazide) Cl N N H H 2ON 2S S O 2 Thiazides Oral administration Secreted by the organic acid secretory system compete with uric acid for secretion {uric acid secretory rates may decline} 8
9 PTH Thiazides Mechanism of action Diuretic action: Inhibition of NaCl reabsorption from the distal convoluted tubule (luminal side) -k + exchanger In the collecting tubule k+ Enhance calcium reabsorption in the distal convoluted tubule (unclear mechanism) Properties of thiazides Increase Cl - excretion Alter kidney ability of dilute urine Moderate efficacy Effect & Clinical Uses Hypertension diuretic, mild vasodilator action Edema--Congestive heart failure -- -reduce salt and water retention Thiazides Nephrolithiasis ----(due to idiopathic hypercalciuria) Nephrogenic diabetes insipidus Diabetes insipidus Impaired renal water conservation Inadequate vasopressin secretion (Central or cranial diabetes insipidus) Inadequate kidney response to vasopressin (nephrogenic diabetes insipidus) Thiazides 9
10 Probable mechanism on diabetes insipidus Cl - excretion plasma osmotic Less thirsty, drinking urine Inhibit phosphodiesteras permeability and reabsorption for water Thiazides Toxicity Hypokalemic metabolic alkalosis and Hyponatremia Hyperglycemia Hyperlipidemia Hyperuricemia, Ca ++ BUN Allergic reactions Thiazides Late distal and Collecting Tubule 2% to 5% of sodium chloride reabsorption Final site for sodium chloride reabsorption -- This site and late distal tubule -- where mineralocorticoids exert their effect -k + exchanger Potassium-Sparing Diuretic Agents In the collecting tubule and duct, sodium reabsorption and potassium excretion is regulated by aldosterone. Two mechanism of action of Potassium-Sparing Diuretic Agents Pharmacologic antagonism at mineralocorticoid receptors: Spironolactone (Aldactone) 螺内酯 Inhibition of sodium transport through the luminal membrane : o triameterenum 氨苯蝶啶 o amiloride Spironolactone (Aldactone) Synthetic steroid: competitive aldosterone antagonist Weak, slow, long-term Binds to cytoplasmic mineralocorticoid receptors -- preventing receptor complex translocation to the nucleus --- aldosterone induced protein --- retained and excreted 10
11 Effects of aldosterone on late distal tubule and collecting duct and diuretics mechanism of aldosterone antagonists Potassium-sparing diuretics ( 低效 ) Lumen urine AIP Alosterone -induced proteins R Nucleus mrna AIP Mitochondria ATP Aldosterone Aldosterone antagonists Interstitiial space 螺内酯 (Spironolactone, antisterone) Decreased urinary secretion Therapeutic uses: Edema with elevated aldosterone CHF Adverse effects: Headaches, mental disorders. Hyponatremia, hyperkalemia (renal insufficiency disabled), sex hormone-like effects: Gynecomastia O Increased urinary secretion Potassium-sparing diuretics Ca ++ Volume of urine CH 3 CH 3 SCOCH 3 O O Na CHANNEL INHIBITORS Also Called: K-Sparing Diuretics Triamterene Amiloride Triamterene (Dyrenium) Directly blocks entry through sodium-specific channels secretion reduced secretion increased Weak effect Lumen urine channel inhibitors Late distal tubule and Collecting duct ROMK H 2 O Principal cell (depolarization) Water channel molecules ATP R ADH Interstitial space Potassium-Sparing Diuretic Agents Toxicity Hyperkalemia Nausia vomiting diarrhea headache Folate deficiency Acute renal failure (combination with indomethacin) Kidney stone (poorly soluble) 11
12 Summary acetazolamide thiazide Summary of relative changes in urinary composition induced by diuretic drugs Decrease Increased Decreased Increase CA edecrin furosemide Spironolactone amiloride triamterene Acetazolamide Ca ++ HCO 3 - Volume of urine Loop diuretics Ca ++ Volume of urine Thiazide diuretics Ca ++ Volume of urine Potassium-sparing diuretics Ca ++ Volume of urine What else should doctor notice? Allergies to other medicines. Pregnant, or breast feeding baby. Diabetes. dehydrated easily. Pancreatitis [ 医 ] 胰腺炎. Kidney problems. Lupus 狼疮. Gout 痛风 or high risk for developing gout. Menstrual period 月经期 problems:potassiumsparing diuretics can make these problems worse. Interactions Interacting Drugs ACE Inhibitors / - Sparing Diuretics Aminoglycosides / Loop Diuretics Digoxin / Thiazide & Loop D. ß- Blockers / Thiazide Diuretics Steroids / Thiazide & Loop D. Carbamazepine or Chlorpropamide / Thiazide Potential Interactions Increased hyperkalemia Cardiac problems (monitor serum closely) Ototoxicity and nephrotoxicity. (monitor hearing and serum creatinine closely) Hypokalemia Increased digoxin binding & toxicity. (Monitor and cardiac function) Hyperglycemia, hyperlipidemia, hyperuricemia. Increased risk of hypokalemia (monitor K+ closely ) Increased risk of hyponatremia (monitor ) Question/important content: Loop diuretics thiazides Potassium sparing diuretics 1. What are the mechanisms of action for the above three classes of diuretics? 2. Describe the clinical uses and adverse reaction of three classes of diuretics. 12
13 Homework Q&A Why do we choose these combination to treat high BP? Losartan Potassium and hydrochlorothiazide tablets Many Thanks! 13
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